Ph.D THESIS by Venugopal Rao Veeramaneni

35

This thesis (chapters II, III, IV and V) deals with the synthesis and formation of

fused dihydro oxazolo derivatives from suitable precursors by reductive cyclization with

lithium aluminum hydride. Hence, the Introduction (Chapter I) to this thesis has been

described into two parts: the first part deals with reactions of LAH and the second part

deals with synthesis and formation of fused oxazolo derivatives by ring closure methods.

36

1.1 REDUCTION:

1.1.1 GENERAL

Reduction, one of the most widely used fundamental organic reactions, can be

accomplished by several brand methods including addition of hydrogen and/or electrons,

or hydride ions to a molecule or removal of oxygen or the other electronegative

substituents. The most important reducing agents from a synthetic point of view are of

two types, viz non-hydride reducing agents and hydride reducing reagents.1

1.1.2 Types of Reducing Agents

1.1.2 (a) Non-Hydride Reducing Agents

Catalytic hydrogenation: This reaction involves addition of the elemental H2

across a double bond as shown in Equation – 1.1.

H2C CH2 H H H3C CH3

(I) (II)

+

Equation – 1.1

Dissolving metal reductions: In general, this method is useful for the reduction

conjugated systems, enones, or aromatics. For saturated carbonyl compounds, hydride

reductions are better. The commonly used metals are Li, Na, K, Zn, Mg, Sn and Fe and

the commonly used solvents are NH3, HMPA, THF, DME and Crown ethers.

Electrochemical reductions: This reaction involves electrolysis at a mercury, lead

or cadmium cathode and tetramethylammonium chloride as catalyst.

Various non-hydridic procedures were developed for the reduction of organic

functional groups prior to the discovery of hydride reagents.1 Reduction of aldehydes to

the corresponding alcohols was achieved by zinc dust - acetic acid, sodium amalgam -

acetic acid, sodium in toluene - acetic acid or iron - acetic acid,2 as shown in Equation –

1.2.

CHO CH2OH

Fe / AcOH, Water

6.0 h, 100 oC, 75 - 80 %

2(H)

(III)(IV)

37

Equation – 1.2

Simple ketones were reduced to the corresponding alcohol using sodium in

ethanol,3 as shown in Equation – 1.3

Na/EtOH

65 %

O OH

(V) (VI)

Equation – 1.3

Equation 1.4 describes that the diaryl ketones were reduced to the alcohols by

using zinc and sodium hydroxide mixture in ethanol.4

Ph

PhO

Ph

PhOH

Zn/2NaOH/EtOH

70oC, 3.0 h, 96 %

2 (H)

(VII) (VIII)

Equation – 1.4

Aldehydes were reduced to corresponding carbinols using aluminum ethoxide in

ethanol5 or aluminum ethoxide in isopropyl alcohol.

6 This method has been applied to a

variety of aldehydes and ketones popularly known as “Meerwein- Ponndorf-Verley

reduction”. (Equation – 1.5)

Ph

PhO

Ph

PhOH

CHO CH2OH

(IX) (X)

(VII)(VIII)

Reflux/1.0 h 99 %

Al/iPrOH

8 - 9 hrs, 110 oC

60 %

Al (iPrO)3

Equation – 1.5

Carboxylic acid esters were reduced to the corresponding alcohols by sodium in

ethanol which is known as Bouveault and Blanck reduction.7 (Equation -1.6)

Na/EtOH

Steam bath, 65 - 75 %

nC11H23CO2Et nC11H23CH2OH

(XI) (XII)

38

Equation – 1.6

The non-hydridic reductive procedures often require elevated temperature, long

reaction time and are associated with low yields. However, the discovery of metal

hydrides and complex metal hydrides has dramatically changed the situation, not only for

the reduction of carbonyl groups, but also for the reduction of a wide variety of many

other functional groups.

1.1.2 (b) Hydride Reducing Agents

The first hydride-reducing agent is diborane, which was discovered in 1930s, the

structure of which was subject to considerable study and speculation.8 Professor H. I.

Schlesinger at University of Chicago was studied the reactions of diborane. The methods

available for the preparation of diborane were not satisfactory for large scale

preparations.

Hence, sodium borohydride was started to be used as a reducing agent,9 and

improved methods were available for preparing sodium borohydride.10

The alkaline

metal hydride route was successfully extended for the synthesis of the corresponding

aluminum derivatives.

1.2 Lithium aluminum hydride:

1.2.1 Synthesis & Physical Properties

Lithium aluminum hydride was synthesized in 1945 by the reaction of lithium

hydride and aluminum chloride in ether solution.11

4LiH + AlCl3 LiAlH4 + LiCl

3LiAlH4 + AlCl3 4AlH3 + 3LiCl

4AlH3 + 4LiH 4LiAlH4

The discovery of sodium borohydride in 1942 and of lithium aluminum hydride in

1945 brought a revolutionary change in procedures for the reduction of functional groups

in organic synthesis.12

As first described by W. G. Brown et al. 12

Lithium aluminum

hydride is an exceedingly powerful reducing agent and capable of reducing practically all

functional groups.

39

Consequently, it was quite difficult to apply this reagent for the selective

reduction of multifunctional molecule. Lithium aluminum hydride is capable of reducing

almost all of the organic functional groups rapidly to the lowest reduced state.13

It can

hydroaluminate double and triple bonds14

and can function as a base15

It is soluble in

variety of ethereal solvents such as ethyl ether (15.0 gm in 100 mL), tetrahydrofuran

(13.0 gm in 100 mL), monoglyme, diglyme , triglyme and reacts violently with water and

other protic solvents.

1.2.2 Reactivity & Synthetic Applications

Exploratory study of the reactivity of this reagent towards representative organic

functional groups is summarized below.16

Table – 1.1: Reactivity of various functional groups with LAH.

S.No. Reactant Product

1. Aldehyde Alcohol

2. Ketone Alcohol

3. Acid Chloride Alcohol / Aldehyde

4. Lactone Alcohol (diol)

5. Epoxide Alcohol

6. Ester Alcohol

7. Carboxylic acid Alcohol

8. Carboxylic acid salt Alcohol

9. tert.Amide Amine / Aldehyde

10. Nitrile Amine

11. Nitro Amino / Azo

12. Olefin No reaction.

The general mechanisms for reduction of some important class of carbonyl

compounds are shown as below:-

For Ketones:-

40

H

H H

HAl

O

R R

OLi

RR

HO

R

R

O

R

R

O

R

R 2O

R

R 4

OH

R R

LiOH, Al(OMe) +

H3Al

Li

H3Al

Li

H2Al

Li

LiAl4H2O

Scheme – 1.1

For Carboxylic esters:-

H

H H

HAl

O

R OR

OLi

ROR

H

H3Al

Li

H3Al O

OR

R

Li

-ROAlCH3

R H

O

R H

O

ROAlH2

H R OAlH2OR

H+

R OH

Scheme – 1.2

For Carboxamides:-

H

H H

HAl

O

R NH2

OLi

RNH2

HO

NH2

R

R H

NH2

R H

NH2H R N

H2

AlH2O- R NH2

H

H3Al

Li

H3Al

Li

-OAlH2

H+

Scheme – 1.3

The powerful hydride transfer properties of this reagent is the reason for the high

reactivity with aldehydes, ketones, esters, lactones, carboxylic acids, anhydrides, and

41

epoxides to give alcohols, and with amides, iminum ions, nitriles, and aliphatic nitro

compounds to give amines. Several methods are available for the workup procedure of

these reductions. A strongly recommended option16

involves a careful and successive

drop wise addition of n mL of 15 % NaOH solution, and 3n mL of water to the mixture

containing n grams of LiAlH4. These conditions provide a dry granular inorganic

precipitate that is easy to rinse and filter. Alternatively, solid Glauber’s salt

(Na2SO4.10H2O) can be added portion wise until the salts become white.17

In certain

instances, an acidic workup (10 % H2SO4) may prove advantageous because the

inorganic salts become solubilized in the aqueous phase.18

LAH can be used in dimerization of acetals and ketals along with titanium tetra

chloride (Equation 1.7).19

Allylic or benzylic alcohols can be symmetrically coupled by

treatment with LAH & TiCl4 (Equation 1.8). 20

Dehalogenation has been accomplished

with LAH (Equation 1.9).21

Oximes and imines have been converted to the corresponding

aldehyde or ketone by treatment with LAH-HMPA (Equation 1.10),22

episulfides can be

converted into olefins (Equation 1.11).23

Five membered cyclic sulfones can be

converted to cyclobutenes by treatment with BuLi followed by LAH (Equation 1.12),24

ethers are stable with LAH but THF when treated with LAH-AlCl3 gives 1- butanol.

LAH opens an epoxide (Equation 1.13),25

alcohols can also be reduced indirectly i.e. by

converting it to a sulfonate followed by the reduction of that compound, the two reactions

can be carried out without isolation of the sulfonate (Equation 1.14). 26

Fluorine

containing amide when treated with LAH alone results in amine, but when the reagent

was used in combination with AlCl3, fluorine is also displaced by hydrogen. (Equation

1.15)27

1.2.1Table – I

Eq. No. SCHEME Ref:

1.7 OEt

OEt

LAH/TiCl4

85 % OEt

EtO

(XIII) (XIV)

19

42

1.8 LAH/TiCl4HO

Ph OH

Ph

Ph Ph

Cis & Trans

(XV) (XVI)

20

1.9 x

x

LAH

(XVII) (XVIII)

21

1.10

NW

O+ W-NH2

LAH

HMPA

(XIX) (XX)

22

1.11

S

LAH

(XXI) (XVIII)

23

1.12

S

O

O

LAH

BuLi

(XXII) (XXIII)

24

47

1.13

O

LAH / AlCl3 OH

(XXIV) (XXV)

25

1.14

OOH

N

O

N

1)TsCl

2) LAH

(XXVI) (XXVII)

26

1.15 O

O

N

FF

O

HO

O

NH O

O

N

FF

HLAH/AlCl3

LAH

(XXVIII)(XXIX) (XXX)

27

The reduction of N,N-disubstituted amides with LAH leads to aldehydes where

amines are also formed as other products (Equation 1.16),28

Synthesis of Aziridines from

43

β-iodo azides by reductive cyclization with LAH (Equation 1.17),29

were reported in the

literature. 1 Molar equiv of LAH with 0.25 molar equiv of TiCl4 in THF is extremely

effective in reducing bromohydrins to olefins in high yields (Equation 1.18).30

Several

carboxylic esters and lactones were reduced to ether derivatives employing a reagent

prepared from LAH & BF3-Et2O (Equation 1.19).31

Aromatic aldehydes, ketones, acids

and esters were converted to corresponding halides in one pot operation with LAH

followed by treatment with HBr (Equation 1.20).32

Cyclohexene epoxides are

preferentially reduced by an axial approach of the nucleophile.33

Aromatic bromides are

reduced quite rapidly and quantitatively to the corresponding hydrocarbons by LAH in

THF (Equation 1.21).34

LAH was used for the stereospecific reduction of acetylenes

(Equation 1.22).35

1.2.1Table – I

Eq. No. SCHEME Ref:

1.16 LAH

N

O

Me

Et2O,

58 % (Aldehyde)

CHO NHMe

(XXXI)(XXXII) (XXXIII)

28

1.17 LAH

Et2O,

N3

I

N

(XXXIV) (XXXV)

29

1.18 LAH

THF, 93 %

Br

OH

(XXXVI) (XXXVII)

30

44

1.19 O OO

LAH

(XXXVIII)(XXXIX)

BF3.Et2O

31

1.20 COR CH2Br1) LAH / Et2O

2) HBr, 99 %

R = H, OH, OCH3

(XL) (XLI)

32

1.21 BrLAH

THF, 90 %

(XLII) (XLIII)

34

1.22 LAH

diglyme96 %

(XLIV) (XLV)

35

1.3. Cyclization methods:

In a cyclization process the ring is made by the formation of one new bond in an

intramoleculor fashion. Typical “Building Blocks” for cyclization reactions are as

follows.

Me

Me

O

O

. H

Me

H

O

Cl

. . .Me

O

..

eg.

Me2N N NMe2

. .. .

NO

NMe2N

NMe2

+

Ref. 95X-

NH2OH

(XLVI)(XLVII)

(XLVIII)

(XLIX)(L)

Bis-electrophiles

45

.

.

. . . . NH2

NH2

.

.

OH.

.MeNH2 MeNHNHMe PhNHOH

(LI) (LII) (LIII) (LIV) (LV)

Bis-nucleophiles .

CHO

NH2

.

.NC CN O

O O

.

.

.

(LVI) (LVII)(LVIII)

Nucleophile + electrophile combinations

There is a vast range of simple building blocks, of which only a few are

illustrated. Carbonyl groups are the most common electrophilic components, and

carbanions, nitrogen, oxygen and sulfur act as the most common nucleophilic

components.

Saturated heterocycles can be synthesized by intramoleculor cyclization by using

sodiumhydride, to give three membered ring or four membered ring.36

(Equation 1.23)

Ar1 Ar2

NH

Cl Cl

OMs 60 - 78 %N

Ar1

Ar2

Cl

Cl

.

.

. .

K2CO3

(LIX) (LX)

Equation 1.23

Or five membered ring. (Equation 1.24)

MsOOMs

NHBOC.

.

.

.

n = 1 2 3 60 62 53 %

HNn

. ..

.

NHBOC

NHOH

(LXI) (LXII)

n

Equation 1.24

Pyrrole derivatives can be prepared by a cyclization method (Paal-Knorr

Synthesis), in which carbonyl components act as electrophiles.37

(Equation 1.25)

46

O

O

Ph CONHPh

Ar

CHMe275.0 % N

R

Ph

Ar

CONHPh

CHMe2

RCH2NH2

(LXIII) (LXIV)

Equation 1.25

The formation of indole derivative by intramolecular cyclization of an N-

acyl-o-toluidine with strong bases at high temperatures38

is known as Madelung indole

synthesis. (Equation 1.26)

NH

R

O-

NH

R

O

NH

R

360 oC

NaOEt H+

H2O

(LXV) (LXVI)(LXVII)

Equation 1.26

Recently some ring systems were created by the addition of bis (nucleophile) +

bis (electrophile) combination.39

(Equation 1.27)

CO2But

O NHBOC

NO

CO2But

NHBOC

EtOH, Reflux 62 %

NH2OH.HCl

(LXVIII) (LXIX)

Equation 1.27

Iodocyclization can be used to prepare heterocycles40

(Equation 1.28).

Intramoleculor aza Wittig reaction is also another useful method for the preparation

variety of heterocycles.41

(Equation 1.29).

NH

Ts

R

MeO2C N

Ts

MeO2C

I

R

I2, K2CO3

45 - 82 %

(LXX)(LXXI)

Equation 1.28

47

O

ON3

Ph Me

N

OPh Me

P(OEt)3, 90 oC

87.0 %

(LXXII) (LXXIII)

Equation 1.29

Cyclization on to arenes is useful for making some benzo fused

heterocycles.42

(Equation 1.30).

BrNH2

R OH

NH

R

KNH2, NH3

(LXXIV) (LXXV)

Equation 1.30

Example for preparation of heterocycle derivative by radical cyclization, 43

(Equation 1.31) cyclization of radicals on to imines.44

(Equation 1.32)

N

CO2Et

Br

N

CO2Et

H

AIBN, 86 %

Bu3SnH

(LXXVI)(LXXVII)

Equation 1.31

N NH

R R(LXXVIII) (LXXIX)

Equation 1.32

Another cyclization method for preparation of heterocycles is via ring closing

metathesis (RCM).45

(Equation 1.33)

48

O O

R4

R2

R3

R4

R3

R2

(LXXX)

(LXXXI)

Equation 1.33

1.4 Introduction of Oxazoles:

Oxazole (LXXXII) is a five membered heterocycle that contains one oxygen and

one nitrogen as heteroatoms in 1 and 3 positions. The oxazolo moiety is frequently found

to be an integral part of many biologically active molecules and natural products.46 - 64

3 N O 1

(LXXXII)

2

4 5

Oxazole moiety is also found in fusion with other heterocycles such as pyridines,

piperidines, indoles, quinolines, benzoxazines, pyrimidines, naphthyridines, quinazolines

etc. A number of such structures and their use in different therapeutic areas have been

listed below.

N

O

OH

Atisine Alkaloid 46

(LXXXIII)

N O

Ph

CN

Natural Product 47

(LXXXIV)

N

OPh

O

HIV-1 inhibitor 48

(LXXXV)

49

O

O

N O

Antitumor agent 49

(LXXXVI)

N

O

O

N NBn

Antihypertensive agent 50

(LXXXVII)

NH

N

OPh

O

Anti viral Agent 51

(LXXXVIII)

N N

F

N

O

CO2H

O

N

Antibacterial agent 52

(LXXXIX)

N

N

O

O

S

Gastric Antisecretory agents 53

N

N

O

S

O(XC)

(XC1)

O

N

O

O

O

O

Used in the Treatment

of Congenital Disorders 54

(XCI)

N

OPh

CO2Et

EtO2C

Antihypertensive Drug 55

(XCII)

N

N O

O

Synthetic biproduct 56

(XCIII)

N

O

Synthetic important

product 57

(XCIV)

Synthetic important

product 58

N

O

Ph

O

OH(XCV)

Synthetic important

product 59

N

N

O

O

(XCVI)

Synthetic important

product 60

N

O(XCVII)

Synthetic important

product 61

N O

Ph(XCVIII)

Synthetic important

product 62

N

O

R1 R2

(XCIX)

Synthetic important

product 63

N

O

O2N Ar

NHR

(C)

N

O

Ph

O

O

(R)-(+) Salsolidine

Starting material 64

(CI)

50

N

N

O

O

S

Gastric Antisecretory agents

O

N

O

O

O

O

Used in the Treatment of Congenital Disorders Synthetic importent

product

N O

Ph

N

O

Ph

O

O

(R)-(+) SalsolidineStarting material


N

N

O

S

O

N

OPh

CO2Et

EtO2C

Antihypertensive Drug

N

N O

O

Synthetic biproduct

Synthetic importent product

N

O

O2N Ph

NH2Synthetic importent product

N

O


N

N

O

S

O

N

OPh

CO2Et

EtO2C

Antihypertensive Drug

N

O

Ph

O

O

(R)-(+) SalsolidineStarting material


N

O

O2N Ph

NH2

N

N O

O

Synthetic biproduct


N

O


N O

Ph

O

N

O

O

O

O

Used in the Treatment of Congenital Disorders

N

N

O

O

S


51

Synthesis of some known Oxazoles:

3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile (LXXXIV)47

was

prepared by condensation of phenylglycinol (CII) with glutaraldehyde (CII) in the

presence of potassium cyanide to give compound LXXXIV via piperidine intermediate

(CIII). (Equation – 1.34)

NH2

PhOH CHO CHO

N O

Ph

NC

KCN

(LXXXIV)

N O

Ph

NC(CII) (CIII)

(CIV)

Equation 1.34

Substituted 2,3-dihydrooxazolo [2,3-a] isoindol-5 (9bH) –one (LXXXV) was

synthesized, starting from substituted 2-aminobenzophenone (CV). Compound CV was

converted to the carboxylic acid (CVI) via diazotization, cyanation and hydrolysis. CVI

was then reacted with 2-aminoethanol followed by cyclization to give the target

compound LXXXV48

in the presence of catalytic amount of toluene-4-sulfonic acid in

toluene. (Equation – 1.35)

Ph

O

NH2

1. NaNO2 / NaCN

2. Conc. H2SO4 and H2O

Ph

O

COOHPTSA, Toluene

N

OPh

O

(LXXXV)

NH2CH2CH2OH

(CV) (CVI)

Equation 1.35

Oxazolo[3,2-a][1,8]naphthyridine derivatives (LXXXIX), were synthesized

starting from ethyl 3-(2,6-dichloro-5-fluoro-3-pyridyl)-3-oxopropionate (CVII) which

was treated with carbon disulfide in the presence of sodium hydride in DMA to give

CVIII. The latter on treatment with substituted 2-aminoethanol in the presence of

triethylamine in toluene gives CIX. Compound CIX on cyclization in the presence of

potassium tert-butoxide in dioxane gives the oxazolo derivative CX, which on treatment

with N-methylpiperzine in ethanol gives CXI. Hydrolysis of CXI yields the target

compound LXXXIX52

(Equation – 1.36)

52

N

CO2Et

O

F

Cl Cl

N

O

F

Cl ClCO2EtN

O

F

Cl ClCO2Et

SMe

SMeO

HN

R

N N O

F

Cl

R

O

CO2Et

N N O

F

N

R

O

CO2Et

N

N N O

F

N

R

O

CO2H

N

CS2/ MeI/ NaH NH2CH(R)CH2OH

(LXXXIX)

tBuO-K+

(CVII) (CVIII)(CIX)

(CX)

(CXI)

Equation 1.36

Synthesis of compound XCI was achieved starting from Sesamol (i.e. 5-hydroxy

2,3-benzodioxole, (CXII). Reacting it with carbon dioxide in the presence of sodium

hydride in diglyme gave 3,4-methylenedioxysalisylic acid (CXIII), which was then

treated with 2-aminoethanol in the presence of carbonyldiimidazole in dichloromethane

yielding the amino ethanol derivative CXIV. Compound CXIV was treated with

trimethyl orthoformate and formic acid in chloroform to give the final compound XCI54

(Equation – 1.37)

O

O

OH O

O

OH

COOH

O

O

OH

O

NH

OH

CO2 / NaH

Diglyme/ 68 %

CDI / NH2CH2CH2OH

HCO2H, CHCl351 %

O

N

O

O

O

O

CHCL3 / 79 %

(CX11)

(CXIV)(XCI)

CH(OMe)3

(CXIII)

Equation 1.37

Substituted oxazolo [3,2-a] pyridine carboxylate (CXII)55

was synthesized

starting from (2R) or (2S)-1-amino-2-propanol and ethyl acetoacetate to give the chiral

53

enamines CXVIII-R or CXVIII-S, which on reaction with acetyl phenylpropanoate

(CXVII), give oxazolopyridines (CXII-R) or (CXII-S). (Equation – 1.38)

O

MeO2C

O

HN

RO

OH

O

HN

RO

OH

N

O

CO2R

EtO2CN

O

CO2R

EtO2C

H2N Me

HO

H2N Me

HOO O

OEt

O O

OEt+

+

(CXVIII - R)

(XCV - R)(CXV - S)(XCVI)

(CXVI)

(CXVIII- S)

(CXVII)

(CXII - R) (CXII - S)

Equation – 1.38

1.5 References:

01. Herbert C. Brown and Krishnamurthy, S., Tetrahedron,; 1979, 35, 567-607.

02. (a) Bouis, J and Carlet, H., Libegs Ann. Chem, 1976, 124, 23; (b) Schorlemmer,

C., Ibid. 1975, 177, 303; (c) Hill, A. J and E. H. Nason, J. Am. Chem. Soc. 1924,

46, 2236; (d) Clarke, H. T and Dreeger, E. E., Org. Synth. Coll. 1941, 1, 304.

03. Thoms, H and Mannich, C., Ber. Dtsch. Chem. Ges, 1903, 36, 2544.

04. Wiseloge, F. Y and H. Sonneborn, Org. Synth. Coll, 1941, 1, 90.

05. (a) Verly, Bull. Soc. Chim. Fr. 1925, 37, 537. (b) Meerwin, H and Schmidt, R.,

Liebigs Ann. Chem. 1925, 444, 221.

06. Pondorf, W. Z. Angew. Chem, 1926, 39, 138.

07. Buveault, L and Blanck, Bull. Soc. Chim. Fr. 1974, 31, 674.

54

08. Stock, A., Hydrides of Boron and silicon, Cornell University press, Ithaca, New

Yark.

09. Schlesinger, H. I., Brown, H. C., Hoekstra, H. R and Rapp, L. R., J. Am. Chem.

Soc. 1953, 75, 199.

10. Schlesinger, H. I., Brown, H. C. and. Finholt, A. E., J. Am. Chem. Soc. 1953, 75,

205.

11. Finholt, A. E., Bond, Jr, A. C and Schlesinger, H. I., J. Am. Chem. Soc.1947, 69,

1199.

12. (a) Gaylord, N. G. Reduction with complex metal hydrides. Interscience, New

York (1956); (b) Wakar, E. R. H., Chem. Soc. Rev. 1976, 5, 23; (c) Brown, W.

G. Org.React. 1951 6, 469, (1951).

13. W. G. Brown, Org. React. 1951, 6, 469.

14. Ziegler. K., Bond. A. C., Schesinger, H. I. ; J. Am. Chem. Soc. 1947, 69, 1199.

15. Bates. R. B., Buchi. G., Matsuura, T., Shaffer, R. R.; J. Am. Chem. Soc. 1960, 82,

2327.

16. (a) Brown, H. C and Wiseman, P. M.; J. Am. Chem. Soc. 1966, 88, 1458. (b)

Fieser, L. F; Fieser, M.; F F, 1957, 1, 584.

17. Paquette, L. A., Gardlik, J. M., McCullough, K. J., Samodral, R., J. Am. Chem.

Soc. 1983, 105, 7649.

18. Sroog, C. E., Woodburn, H. M., Org. Synth. Coll. 4, 1963, 271.

19. Ishikawa; Mukaima; Bull. Chem. Soc. Jpn. 1978, 51, 2059.

20. Mc Murry, Silvestri, Fleming, J. Org. Chem. 1978, 43, 3249.

21. Larak, Text book functional group transformations: 1989, 151-152.

22. Wang, Sukenik, J. Org. Chem. 1985, 50, 5448.

23. Latif, Mishriky,Zeid J. Prakt. Chem. 1970, 312, 421.

24. Photis, Paquette, J. Am. Chem. Soc. 1974, 96, 4715.

25. Bailey, Marktscheffel, J. Org. Chem. 1960, 25, 1797.

26. (a) Bonner; J. Am. Chem. Soc. 1951, 73, 2872. (b) Corey, E. J and Achiwa;

J. Org. Chem. 1969, 34, 3667.

55

27. Pinder, Synthesis, 1980, 425-452.

28. Brown, Tsukamols, J. Am. Chem. Soc. 1964, 86, 1089.

29. Hassner, Mathews, J. Am. Chem. Soc., 1969, 91, 5046.

30. Mc Murry, Hoj, J. Org. Chem. 1975, 40, 3797.

31. (a) Pettit, Ghatak, Green, J. Org. Chem.,1961, 26, 1685. (b) Pettit; J. Org. Chem.

1960, 25, 875.

32. Bilger; Royer; Synthesis, 1988, 902.

33. Rickborn, B and Quartucci, J., Pettit, J. Org. Chem. 1964, 29, 3185.

34. Brown, H. C and Krishnamurthy, S., J. Org. Chem. 1969, 34, 3918.

35. Mangoon, E. F and Slaugh, L. H., Tetrahedron, 1967, 23, 4509.

36. Norbert De Kimpe, Altermann, W., J. Org. Chem., 1998, 63 ,6-11.

37. Kelvin L. B, Donald E. Butler., Tetrahedron Lett., 1992, 33,(17), 2283.

38. M.Madelung, Ber., 1912, 45, 1128.

39. Adlington, Baldwin., J. Chem. Soc. (P1), 2000, 303.

40. Knight., Synthetic letters, 1988, 731.

41. Hisato Takeuchi, Shun-ichi Yanagida.; J. Org. Chem., 1989, 54 ,431.

42. Peter Stanetty and Barbara Krumpak; J. Org. Chem., 1996, 61, 5130.

43. Eun Lee, Tae Seop Kang, Beom Jun Joo; Tetrahedron Lett., 1995, 36, 417-420.

44. Aldabbagh and Bowman; Org. Synth., 1997, 4, 267.

45. Sukbok Chang, Robert H. Grubbs J. Org. Chem., 1998, 63 ,864.

46. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496.

(b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761.

(c) Pellettier, S. W., Parthasarathy, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777.

(d) Naresh V. Mody, Pellettier, S. W., Tetrahedron; 1978, 34, 2421. (e) Pellettier,

S. W., Naresh V. Mody, Haridutt K. Desai, Janet Finer-Moore, Jacek Nowacki,

and Balawant S. Joshi. J. Org. Chem., 1983, 48 (11), 1787.

47. (a) Lue Guerrier, Jacques Royer, David S. Grierson and Henri-Philippe Husson.

J. Amer. Chem. Soc. 1983, 105, 7754. (b) Bonin M. Royer J. Grierson D.S and

Husson H. P., Tetrahedron Lett., 1986, 27 (14), 1569. (c) Jean-Charles Quirion,

56

David S. Grierson, Jacques Royer and Henri-Philippe Husson. Tetrahedron

Letters; 1988, 29 (27), 3311. (d) Naoki YYamazaki, Toshimasa Ito and Chihiro

Kibayashi, Syn. Lett., 1999, 1, 37. (e) Teran, J. L. Gnecco, D. Galindo, A. Juarez,

J. Bernes, S. and Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357. (f) Luis

F. Roa, Dino Gnecco, Alberto Galindo, Jorge Juarez and Sylvan Bernes,

Analytical Sciences, 2003, 19, 1223. (g) Mercedes Amat, Nuria Llor, Carmen

Escolano, Marta Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron

Asymmetry; 2003, 14, 293.

48. Alfred, M.; Harard, Z.; Bernhard, K.; Wolfang, S.; Thomas, P.; Wolfang, K.;

Hans, S.; Ulrike, L.; Herbert, L. J. Med. Chem. 1993, 36 (17), 2526.

49. JP 03, 109, 388.

50. Chia-Yang Shiau, Ji-Wang Chern, Kang-Chien Liu, Chao-Han Chan and

Mou-Hsiung Yen, J. Het. Chem., 1990, 27, 1467.

51. Mertens A, Zilch H, Leseru Konig B; EP 0640087, WO 9424405.

52. Hirosato, K.; Masshiro, T.; Yosimasa, I.; Fumio, S.; Goro, T. J. Med. Chem.

1990, 33 (7), 2012.

53. Fukumi, H. et al. Chem Pharama Bull., 1989, 47 (5), 1197. Fukumi, H.,

Sakamoto, T., Sugimoto, M., Tabata, K.; JP 1989242587.

54. Rogers, G. A. Santa Barbara, Christopher Marrs, Foothill Ranch, US 5985871,

JP 200152705, EP 1054674, WO 9944469.

55. (a) Esther caballero, Pilar Puebla, Manual Medarde and Arturo San Feliciano,

Tetrahedron; 1993, 49 (44), 10079. (b) Esther caballero, Pilar Puebla, Mar

Sanchez, Miguel A. Salvado, Santiago Garcia-Granda and Arturo San Feliciano,

J. Org.Chem., 1996, 61 (9), 1890. (c) Esther caballero, Pilar Puebla, Mar Sanchez,

Manuel Medarde, Lourdes Moran del Prado and Arturo San Feliciano,

Tetrahedron Asymmetry; 1996, 7 (7), 1985. (d) Martin, E.; Asuncion Moran,

Lusia, M. Martin.; Luis San Roman, Pilar Puebla, Manual, M.; Esther, C. and

Arturo San Feliciano. Bioorg Med Chem. Lett. 2000, 10 (4), 319.

57

56. Noberto Farfan, Rosa Santillan, Julian Guzaman, Belinda Castillo and Aurelio

Ortiz. Tetrahedron; 1994, 50 (33), 9951.

57. Crist N. Filer, Felix E. Granchelli, Albert H. Soloway and John L. Neumeyer.

J. Org. Chem., 1978, 43 (4), 672.

58. Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe

Husson. Tetrahedron Letters; 1988, 29 (27), 3311.

59. (a) Norton, P. Peet and Peter, B. Anzeveno, J. Het. Chem. 1979, 16, 877. (b) Hana

Divisova; Helena Havlisova; Peter Broke and Pavel Pazdera. Molecules,

2000, 5, 1166. (http://www.mdpi.org, One pot synthesis of some fused

quinqzolines; Hana Divisova and Pavel Pszdera. Online publication from

[email protected]) (c) Johannes F., Shaifullah Chowdhury, Christian Hametner,

Arkivoc, 2001, i, 163.

60. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov,

A. I. Arkivoc, 2003, xiii, 166.

61. Trevor, A. Crabb and Asmita V. Patel. Heterocycles. 1994, 37 (1), 431. (b) Marie-

Christine Lallemand; Mathieu Gaillard; Nicole Kunesch and Henri-Philippe

Husson. Heterocycles. 1998, 47 (2), 747.

62. Takayasu, Y. Jumpei, S and Kimio Higashiyama; Heterocycles, 2002, 58, 431.

63. Alexander, A. B and Eugene, V. B. Molecules, 2003, 8, 460.

(http://www.mdpi.org).

64. (a) Spath, E.; Dengel, F. Chem. Ber., 1938, 71B, 113. (b) Masatoshi, Y.; Kuniko,

H.; Shigetaka, I. and Nazmul, Q. Tetrahedron Letters; 1988, 29 (52), 6949.

58

59

2.1 INTRODUCTION:

The oxazolo moiety is found in many biologically active compounds and

synthetically important intermediates some of which were mentioned earlier in the first

chapter.

2.2 Present Work:

A survey of literature revealed that different oxazole derivatives showed various

types of pharmacological activities. However, not much work has been done on the

synthesis of fused oxazolo compounds. It was considered desirable to study the synthesis

of oxazolothiazines. It is conceivable that these oxazolothiazines can be synthesized from

2-aminothiophenol by ring closure with chloroacetic acid to obtain benzothiazines in the

first step. These benzothiazines can be used as building blocks for the synthesis of fused

oxazolo ring units.

2.3 Results and Discussion

Commercially available 2-aminothiophenol (1) was treated with chloroacetic

acid in the presence of sodium hydroxide to obtain 1,4-benzothiazine-3(4H)-one (2a, i.e.

24, R = R1 = H) in 76 % yield (equation – 2.1). 2a is a compound known

1 in literature.

However, it was further characterized in the present work by spectral and analytical data.

Thus, its IR (KBr) spectrum (Fig. 2.1) showed a peak at 3440 cm-1

, which may be

assigned to –NH- stretching vibration, and a strong peak at 1663 cm –1

in the carbonyl

region which may be assigned to the amide carbonyl grouping. Its 1H NMR (in CDCl3)

showed (Fig. 2.2) signals at δ 8.87 (bs, 1H, D2O exchangeable, amide proton), three

aromatic signals at 7.33 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.0 Hz,

2H), 6.88 (d, J = 7.8 Hz, 1H) and S – CH2 at 3.43 (s, 2H). Its mass spectrum (Fig. 2. 3)

showed the molecular ion peak at 166 (M+

+1, 100 %), as base peak.

NH

S

ONH2

SH ClCH2CO2H, NaOH, Water

100 °C, 6.0 h, 76.0 %

(1) (2a)

Equation – 2.1

60

In addition to the method given above, several other methods have also been

reported in the literature for the preparation of benzothiazinones. Thus, for example,

condensation2 of 2-aminothiophenol and ethyl 2-halo-2-alkylacetate at 150

°C, or the

addition of 2-bromo-2-alkylacetic acid esters in the presence of sodium ethoxide to

ethanol (multistep), or in the presence of glacial acetic acid and hydrochloric acid, 3

from

2-(2-nitro-phenylsulfanyl)-propionic acid4

at 240 °C for 2.0 hrs, from 2-aminobenzothiol

and 2-haloethyl acetate in DMF 5

at 90 – 95 °

C, from 2-bromomethyl – 4H-

benzo[1,4]thiazine-3-one in the presence of tributyltin hydride and AIBN in benzene,6 by

reaction7 of 2-aminobenzothiol and 2-bromoalkylacetic acid at 125

°C, 2-

aminobenzothiol and 2-chloroalkylacetic acid amide in the presence8 of potassium

carbonate in acetone for 16.0 hrs, from 2-(1-chloroethyl)-benzothiazole in presence of

potassium tert butoxide in isopropanol,9

from bis-(2-nitro phenyl)-disulfane in the

presence10

of samarium (II) iodide in THF (two steps), from 2,2-dimethyl-2,3-dihydro-

benzothiazole in presence of potassium carbonate,11

from 2-chloro-N-(2-

methylsulfanylphenyl)-2-aryl/alkyl acetamide at 195 °C under pressure,

12 from 2,2,2-

trichloro-1-aryl-ethanol & 2-amino benzothiol in presence of KOH, methanol,13

from 2-

acetoxy-4H-benzo[1,4]thiazine-3-one in presence of trifluroacetic acid,14

from 2,2I-

disulfonediyl-bis-aniline in presence of sodium hydride in DMF15

from 2-chloro-4H-

benzo[1,4]thiazin-3-one with arenes in presence of aluminum chloride.16

All these

reported methods involve more than one step, which are environmentally harmful with

fairly long reaction times. Therefore, there is always need for the development of an

improved or alternative procedure for the synthesis of substituted benzothiazines.

Table – 2.1: Some known methods to prepare compounds 2a - h

S.No. Reactant Product Conditions Ref:

1.

NH2

SH

NH

S

O

CH3CH(Br)COOH,

Zuletzt, 150 oC

2

61

2.

NH2

SH

NH

S

O

1. CH3CH(Br)COOEt, in

AcOH

2. Con. HCl

3

3.

NH2

S

HO2C R

NH

S

O

240 oC, 2.0 hrs

ii) NaBH4, Pd-C, Dioxane,

Water, 72 hrs

4

4.

NH2

SH

NH

S

O

R

RCH(X)COOEt

DMF, 90 – 95 oC

R = CH3, Ph

5

5.

NH

S

O

Br

NH

S

O

(Bu)3SnH, AIBN,

Benzene, Reflux

6

6.

NH2

SH

NH

S

O

CH3CH(Br)COOH

120 – 125 oC

7

7.

NH2

SH

NH

S

O

CH3CH(Cl)CONH2

K2CO3, Acetone, Refluxed for

16.0 hrs

8

8.

S

N

Cl NH

S

O

tBuO K

tBuOH, 64 %

9

9.

NO2

SS

O2N

NH

S

O

R

1) SmI, THF

2) RCH(Br)COOH

R = CH3, Ph

10

10. HN

S NH

S

O

R

K2CO3, Ether 11

62

11.

NH

O Cl

SMe

NH

S

O

Ph

195 °o

C,

Pressure

12

12.

NH2

SH

NH

S

O

Ph

KOH, Methanol, 2,2,2 –

trichloro-1-phenyl

13

13.

NH

S

O

OAc

NH

S

O

Ph

Benzene, TFA, Refluxed 14

14.

NH2

SS

H2N

NH

S

O

Ph

PhCH2CO2Et, NaH, DMF, 100

°oC, 86.0 %

15

15.

NH

S

O

OAc

NH

S

O

Ar

ArH, AlCl3, 10 min,

50 o

C

16

16.

NH2

SH

NH

S

O

CH3CH(Cl)CO2H

NaOH, Water

Refluxed for 4.0 hrs

17

17.

NH2

SH

NH

S

O

Ph

PhCH(Br)COOH,

Zuletzt, 150 oC

18

18.

NH2

SH

NH

S

O

Ph

1) PhCH(Br)COOMe, KI

2) NaOMe, C6H6, 80 ° o

C

19

19.

NH2

SH

NH

S

O

Ph

1) PhCH(Cl)COOH,

NaOH.

20

63

20.

NO2

S CO2R

NH

S

O

NaBH4, Pd-C, Dioxane,

Water, 72 hrs

21

21.

NH2

SH

NH

S

O

(CH3)2C(Br)COOH

KOH, EtOH

22

22.

NH2

SH

NH

S

O

(CH3)2C(X)COOEt

1) K2CO3

2) Con. HCl

23

23.

NH

S

O N

H

S

O

CH3I

LDA

24

Keeping this in view, two simple but new methods were developed for the

synthesis of benzothiazinones. In the first method, 2-aminothiophenol was reacted with

ethyl bromoacetate in aqueous sodium hydroxide at 80 °C for 1.0 hr, which resulted in the

formation of 2a in 94 % yield. In the other method, 2-aminothiophenol was treated with

ethyl 2-bromoacetate in the presence of microwaves using microwave oven for 5.0 min,

to yield 2a in 80 % yield. (Equation 2.2)

64

NH

S

ONH2

SH

BrCH2CO2Et, NaOH,

Water, MW, 4 - 5 min, 80 %

BrCH2CO2Et, NaOH,

Water, 80 oC, 1.0 hr, 94 %

(1) (2a)

Equation – 2.2

Substituted 1,4-benzothiazine-3(4H)-ones (2) were prepared in the above two

methods and also all derivatives 2a-h were prepared simultaneously in one lot by using

parallel synthesizer. The structures for these products were assigned on the basis of

analogy and on the basis of analytical and spectral data. (Table –2.2)

NH

S

O

R1

R

NH2

SHBrRR1CCO2Et, NaOH, Water, MW, 4 - 5 min, Parallel

(7 Reactions at a time) 65 - 89 %

(1) (2a-h)

Equation – 2.3

Table –2.2: Synthesis of 2 (a-h) from 1 and its data

1H NMR (200 MHz, CDCl3); IR (KBr) / cm

-1.

IR: 3196(-NH- Band), 1665(- CO - Stretching);

1H NMR: (CDCl3) δ 9.25 (bs, 1H, D2O

Exchangeable, NH), 7.29 (d, J = 7.52 Hz, 1H),

65

7.15 (d, J = 7.52 Hz, 1H), 7.03 (t, J = 7.52 Hz,

1H), 6.93 (t, J = 7.52 Hz, 1H), 3.60 – 3.50 (q, J =

6.98 Hz, 1H, SCH), 1.49 (d, J = 6.99 Hz, 3H,

SCHCH3); Mass: 180 (M++1, 100 %).

IR: 3422(-NH- Band), 1667 (- CO - Stretching);

1H NMR: (CDCl3) δ 10.57 (bs, 1H, D2O

Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, ),

7.18 (d, J = 7.81 Hz, 1H, ), 7.00 (d, J = 7.82 Hz,

2H, ), 1.34 (s, 6H, C(CH3)2; Mass: 194 (M+

+1,

100 %).

IR: 3195 (-NH- Band), 1662 (- CO - Stretching);

1H NMR: (CDCl3) δ 10.56 (bs, 1H, D2O

Exchangeable, NH), 7.31 (d, J = 7.81 Hz, 1H, ),

7.16 (d, J = 7.81 Hz, 1H, ), 7.00 – 6.94 (m, 2H, ),

3.45 – 3.38 (dd, J = 5.86 & 8.31 Hz, 1H, SCH),

1.81 – 1.70 (m, 1H, SCHCH2CH3), 1.54 – 1.39

(m, 1H, SCHCH2CH3), 0.96 (t, J = 7.33 Hz, 3H,

SCHCH2CH3); Mass: 194 (M++1, 100 %).

IR: 1670 (- CO - Stretching); 1H NMR: (CDCl3)

δ 10.56 (bs, 1H, D2O Exchangeable, NH), 7.31

(d, J = 7.81 Hz, 1H), 7.16 (m, 1H, ), 7.00 – 6.94

(m, 2H), 3.52 – 3.45 (d, J = 7.81 Hz, 1H, SCH),

1.77 – 1.67 (m, 1H, SCHCH2CH2), 1.52 – 1.33

(m, 3H, SCHCH2CH2 & SCHCH2CH2), 0.89 –

0.83 (t, J = 7.33 Hz, 3H, SCHCH2CH3); Mass:

208 (M++1, 100 %).


1H NMR: δ 9.17 (bs, 1H, D2O Exchangeable,

NH), 7.30 (d, J = 7.82 Hz, 1H), 7.16 (t, J = 7.81

66

Hz, 1H), 6.99 (t, J = 7.33 Hz, 1H), 6.88 (d, J =

7.81 Hz, 1H), 3.11 (d, J = 8.79 Hz, 1H, SCH),

1.97 – 1.90 (m, 1H, SCHCH(CH3)2), 1.05 (d, J =

6.83 Hz, 6H, SCHCH(CH3)2); Mass: 208 (M++1,

100 %).

IR: 1663 (- CO - Stretching); 1H NMR: (CDCl3)

δ 9.10 (bs, 1H, D2O Exchangeable, NH), 7.30 (d,

J = 7.33 Hz, 1H), 7.17 (t, J = 7.33 Hz, 1H), 7.00

(t, J = 7.81 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H),

3.39 (t, J = 7.08 Hz, 1H, SCH), 1.93 – 1.84 (m,

1H, SCHCH2), 1.66 – 1.50 (m, 1H, SCHCH2),

1.25 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.82

(m, 3H, SCHCH2 (CH2)4CH3; Mass: 250 (M+

+1, 100 %).


1H NMR (DMSOd6, 200 MHz): δ 10.43 (bs, 1H,

D2O Exchangeable, NH), 7.33 – 7.26 (m, 6H),

7.17 – 7.09 (m, 1H), 7.02 – 6.91 (m, 2H), 4.62 (s,

1H, Ph CH); Mass: 242 (M+

+1, 100 %), 241

(M++1, 20 %).

40

1,4-benzothiazine-3(4H)-one (2a) was treated with ethyl 2-bromoacetate in the

presence of potassium hydroxide in acetone at 60 °C for 30 min. Processing of the

reaction mixture gave a product which was found to be 3a (Equation 2.8) by comparison

of its physical constants with those reported in literature.25

Compound 3a has been further

characterized by spectral methods. Its IR spectrum showed no absorption above 3000 cm-

1 indicating absence of –NH- grouping. However, the IR spectrum showed (Fig. 2.4) two

strong sharp bands, one at 1744 cm-1

and the other at1680 cm-1

. The former has been

assigned to ester carbonyl grouping and the other assigned to amide carbonyl grouping.

Thus, its 1H NMR spectrum (Fig. 2.5) displayed signals at δ 7.38 (d, J = 6.84 Hz, 1H, Ar

- H), 7.21 (t, J = 7.33 Hz, 1H, Ar - H), 7.05 (d, J = 7.33 Hz, 1H, Ar - H), 6.87 (d, J = 8.30

Hz, 1H, Ar - H), 4.65 (s, 2H, N-CH2), 4.27 (q, J = 7.33 Hz, 2H, O – CH2), 3.46 (s, 2H, S

– CH2), 1.28 (t, J = 7.33 Hz, 3H, O – CH3) while the mass spectrum showed (Fig. 2.6)

m/z 252 (M++1, 100 %) and other peak at 206 (10 %) etc.

NH

S

ON

S

O

O

OEt

KOH / BrCH2CO2Et

acetone, 60 oC, 30 min

(2a)(3a)

Equation – 2.4

Subsequently, it has been found that 3a could also be prepared from 2a by

reaction in DMF using K2CO3 as base at 80°°C for 12 hrs. (Equation 2.9)

NH

S

ON

S

O

O

OEt

K2CO3, BrCH2CO2Et

DMF 80 oC, 12 hrs

(2a)(3a)

Equation – 2.5

41

2-Substituted-3,4-dihydro-3-oxo-2H-1,4-benzothiazine–4-acetic acid ethyl esters could

also be prepared using the above method. Structures of all products (3a – h) have been

assigned on the basis of analogy and on the basis of spectral & analytical data (Table –

2.3).

NH

S

ON

S

O

O

OEt

K2CO3, BrR1CHCO2Et

DMF 80 0C, 12.0 hrs

(2a - h) (3a - j)

RR

R1

Equation – 2.6

Table – 2.3: Synthesis of 3 (a-h) from 2 (a-j) and Data:

Structure 1H NMR (200 MHz, CDCl3); IR (KBr / Neat) / cm

-1.

IR1732 (ester- CO – Stretching), 1678 (amide- CO – Stretching); 1H

NMR: δ 7.37 (d, J = 7.32 Hz, 1H), 7.21 (t, J = 7.81 Hz, 1H ), 6.86

(d, J = 8.31 Hz, 1H), 4.75 – 4.54 (dd, J = 17.58 & 22.96 Hz, 2H,

NCH2), 4.30 – 4.19 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.58 – 3.50 (q,

J = 7.32 Hz, 1H SCHCH3), 1.47 (d, J = 6.84 Hz, 3H, SCHCH3), 1.28

(t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 266 (M+

+1, 100 %).

IR: 1750 (ester- CO – Stretching), 1672 (amide- CO – Stretching);

1H NMR: δ 7.36 (d, J = 7.82 Hz, 1H), 7.24 (t, J = 7.32 Hz, 1H),

7.05 (t, J = 7.33 Hz, 1H ), 6.83 (d, J = 8.30 Hz, 1H), 4.66 (s, 2H,

NCH2), 4.31 – 4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 1.47 (s, 6H),

1.29 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: 280 (M+

+1, 100 %).

IR: 1749(ester- CO – Stretching), 1674 (amide- CO – Stretching).


7.04 (t, J = 7.32 Hz, 1H), 6.83 (d, J = 8.31 Hz, 1H), 4.90 (d, J =

17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.25 (q, J

42

= 7.30 Hz, 2H, OCH2CH3), 3.39 (t, J = 7.57 Hz, 1H, SCHCH2CH3),

2.00 – 1.86 (m, 1H, SCHCH2CH3), 1.68 - 1.54 (m, 1H,

SCHCH2CH3), 1.29 (t, J = 7.33 Hz, 3H, OCH2CH3), 1.05 (t, J = 7.32

Hz, 3H, SCHCH2CH3); Mass: 280 (M+

+1, 100 %).



7.04 (t, J = 7.81 Hz, 1H), 6.83 (d, J = 7.82 Hz, 1H), 4.88 (d, J =

17.09 Hz, 1H, NCH2), 4.45 (d, J = 17.58 Hz, 1H, NCH2), 4.31 –

4.20 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.47 (t, J = 7.33 Hz, 1H,

SCH), 1.89 – 1.83 (m, 1H, SCHCH2), 1.65 – 1.42 (m, 3H, SCHCH2

& SCHCH2CH2), 1.29 (t, J = 7.32 Hz, 3H, OCH2CH3), 0.91 (t, J =

6.83 Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+

+1, 100 %).



7.02 (t, J = 7.81 Hz, 1H), 6.80 (d, J = 7.82 Hz, 1H), 5.09 (d, J =

17.58 Hz, 1H, NCH2), 4.30 – 4.17 (q, J = 7.33 Hz, 2H, OCH2CH3),

3.10 (d, J = 9.77 Hz, 1H), 2.90 (d, J = 14.65 Hz, 1H), 1.87 – 1.75

(m, 1H, SCH), 1.28 (t, J = 7.33 Hz, 1H, OCH2CH3), 1.03 (t, J = 6.83

Hz, 3H, SCHCH2CH2CH3); Mass: 294 (M+

+1, 100 %).

IR: 1749 (ester- CO – Stretching), 1673 (- CO - Stretching); 1H

NMR: (CDCl3) δ 7.36 (d, J = 7.33 Hz, 1H), 7.25 (t, J = 7.33 Hz,

1H), 7.02 (t, J = 7.81 Hz, 1H), 6.82 (d, J = 7.81 Hz, 1H), 4.44 (d, J =

17.58 Hz, 1H, NCH2), 4.44 (d, J = 17.58 Hz, 1H, NCH2), 4.29 –

4.18 (q, J = 7.33 Hz, 2H, OCH2CH3), 3.43 (t, J = 7.08 Hz, 1H,

SCH), 1.91 – 1.81(m, 1H, SCHCH2), 1.70 – 1.30 (m, 1H, SCHCH2),

1.27 (m, 8H, SCHCH2 (CH2)4CH3), 0.86 – 0.84 (m, 3H, SCHCH2

(CH2)4CH3); Mass: 236 (M+

+1, 100 %).


1H NMR: δ 7.43 – 7.35 (m, 2H, ), 7.31 – 7.17 (m, 5H), 6.98 (t, J =

43

7.32 Hz, 1H), 6.89 (d, J = 7.81 Hz, 1H), 4.97 (d, J = 17.58 Hz, 1H,

NCH2CO), 4.77 (s, 1H, SCHPh), 4.50 (d, J = 17.58 Hz, 1H,

NCH2CO), 4.34 – 4.23 (q, J = 7.33 Hz, OCH2CH3), 1.31 (t, J = 7.33

Hz, 3H, OCH2CH3); Mass: 328 (M+

+1, 100 %).

IR: 1739 (ester- CO – Stretching), 1676 (amide- CO – Stretching).

1H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23 (d, J = 7.79 Hz, 1H, ),

7.17 – 6.97 (m, 2H), 5.15 – 5.08 (dd, J = 5.37 & 9.94 Hz, 1H, NCH

CO), 4.28 – 4.14 (m, 2H, OCH2CH3), 3.41 (s, 2H, SCH2 ), 2.27 –

2.17 (m, 1H, NCHCH2CH3), 2.11 – 1.90 (m, 1H, NCHCH2CH3),

1.23 (t, J = 7.25 Hz, 3H, OCH2CH3), 0.82 (t, J = 7.25 Hz, 3H,

NCHCH2CH3); Mass: 281 (M+

+2, 15 %), 280 (M+

+1, 100 %), 234

(10 %).


1H NMR: δ 7.41 (d, J = 7.52 Hz, 1H), 7.23(d, J = 8.06 Hz, 1H), 7.17

– 6.97 (m, 2H), 5.25 – 5.18 (dd, J = 5.38 & 9.14 Hz, 1H, NCHCO),

4.28 – 4.16 (m, 2H, OCH2CH3), 3.40 (s, 2H, SCH2), 2.16 – 2.00 (m,

2H, NCHCH2), 1.27 – 1.16 (m, 5H, OCH2CH3 & NCHCH2CH2),

0.82 (t, J = 7.25 Hz, 3H, OCH2CH3); Mass: 295 (M+

+1, 30 %), 294

(100 %) and 248 (10 %).

54

It was considered desirable to study the effect of substituents in the cyclization

reaction yielding oxazolothiazines. All the compounds reported in Table 2.4 contain

hydrogen/alkyl groups at R1. It would be interesting to study the course of cyclisation if

R1 is substituted with aryl moiety having electron releasing / withdrawing groups.

Therefore, 3k and 3l, needed to build oxazolothiazines were prepared as follows:-

Commercially available phenylacetic acid (4) was refluxed in absolute ethanol in the

presence of conc. H2SO4 to give 5, which with N-bromosuccinimide in the presence of

catalytic amount of benzoyl peroxide gave 6.26

The latter was then reacted with 1,4-

benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate to give 3k (Scheme

2.1).

CO2H CO2Et CO2EtBr

N

S

O

CO2MePh(3k)

Ethanol, Con.H2SO4 (cat.),

8 0 °C, 4.0 hrs

NBS(1.05 eq), Benzoylperoxide (Cat) CCl4, 3.0 hrs

CO2MeBr

+

K2CO3, DMF

80 °C, 12.0 hrs

(4) (5) (6)

(6)

NH

S

O

(2a)

Scheme – 2.1

The structure of the compound 3k is supported by its spectral and analytical

data. Thus, its IR (KBr) showed peaks at 1748 (ester- CO – Stretching), 1676 (amide-

CO – Stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.41 – 7.28 (m, 7H,

ArH), 7.10 – 6.95 (m, 2H, ArH), 6.23 (s, 1H, PhCH), 3.83 (s, 3H, COOCH3), 3.53 (s,

2H, SCH2). Its mass spectrum showed peaks at m/z 313 (M+

+1, 25 %), 281 (100 %),

55

226 (60 %), 211 (75 %), 121 (60 %). Elemental Analysis: Mol. F: C17H15NO3S, Cal. C:

65.160, H: 4.829, N: 4.473; Experimental, C: 64.685, H: 5.032, N: 4.236.

S S

O

S

HO2C

S

EtO2C

S

EtO2C

O

OS

EtO2C

O

O

Br

N

S

O

O

OS

O O (3l)

AcCl, AlCl3, CH2Cl2,

0 - r.t, 3.0 hrs

(i) Morpholine, Sulfur, 100 °C, 12.0 hrs

(ii) Aq. HCl, 100 °C, 12.0 hrs

SOCl2, Ethanol

0 - 80 °C, 6.0hrs

Oxone, Acetone

water, r.t., 6.0 hrs

NBS(1.05 eq) Benzoylperoxide (Cat),

CCl4, 3.0 hrs

S

EtO2C

O

O

Br

+

K2CO3, DMF,

80 °C, 12.0 hrs

(7)

(8)(9)

(10)(11) (12)

(10)

NH

S

O

(2a)

Scheme – 2. 2

In order to prepare the intermediate 3l, thioanisole (7) was treated with acetyl

chloride in the presence of aluminum chloride to obtain 8,27

which on Willgerodt reaction

using morpholine and sulfur gave 4-methylthiophenylacetic acid (9).28

Compound 9 was

converted to ethyl ester 10 in the presence of thionyl chloride in ethanol.29

The

methylthio group of 10 was oxidized with oxone to obtain 4-methylsulfonylphenylacetic

56

acid (11). 11 was treated with N-bromosuccinimide in the presence of benzoyl peroxide

as a catalyst to give Bromo-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (12)30

which was reacted with 1,4-benzothiazine-3(4H)-one (2a) in the presence of potassium

carbonate to yield 3l. (Scheme 2.2)

The structure of the compound 3l is supported by its spectral and analytical data.

Thus, its IR (KBr) showed peaks at 1742 cm-1

(ester carbonyl stretching) and at 1664 cm-

1 (amide carbonyl stretching). Its

1H NMR (in CDCl3) showed signals at δ 7.92 (d, J =

8.31 Hz, 2H, ArH), 7.57 (d, J = 8.31 Hz, 2H, ArH), 7.44 – 7.40 (m, 1H, ArH), 7.33 – 7.14

(m, 2H, ArH), 7.11 – 6.97 (m, 2H, ArH), 6.89 – 6.82 (m, 1H, ArH), 6.16 (s, 1H, ArCH),

4.28 – 4.21 (m, 2H, CO2CH2CH3), 3.43 (s, 2H, SCH2), 3.04 (s, 3H, SO2CH3), 1.19 (t, J =

7.33 Hz, 3H, CO2CH2CH3). Its mass spectrum showed peaks at m/z 405 (M+

+1, 30 %),

359 (100 %), 304 (95 %), 165 (70 %) and 136 (80 %).

COOH CO2Et CO2EtBr

N

S

O

O

O

3m

OMe OMe OMe

MeO

CO2EtBr

OMe

+

Thionyl chloride

Ethanol

0 - 80 oC, 6.0 hrs

NBS(1.05 eq) Benzoylperoxide (Cat)

CCl4, 3.0 hrs

K2CO3, DMF

80 oC, 12.0 hrs

(13) (14) (15)

(15)

NH

S

O

(2a)

Scheme – 2. 3

57

To prepare 3m, commercially available 4-methoxyphenylacetic acid (13), was

esterified with thionyl chloride in ethanol

followed by bromination with N-

bromosuccinimide in the presence of benzoyl peroxide as catalyst to obtain ethyl 2-

bromo-2-(4-methoxyphenyl)acetate (15).31

compound 15 was reacted with 1,4-

benzothiazine-3(4H)-one (2a) in the presence of potassium carbonate as base in dry

dimethylformamide resulting in ethyl 2-(4-methoxyphenyl)-2-(3-oxo-3,4-dihydro-2H-

benzo[b][1,4]thiazin-4-yl) acetate (3m). (Scheme – 2.3) The structure of the compound

3m is supported by its spectral and analytical data. Thus, its IR (KBr) showed peaks at

1742 cm-1

(ester carbonyl stretching) and at 1674 cm-1

(amide carbonyl stretching). Its 1H

NMR (in CDCl3) showed signals at δ 7.38 – 7.30 (m, 1H, ), 7.23 (d, J = 9.13 Hz, 2H, ),

7.05 – 6.90 (m, 2H, ), 6.83 (d, J = 8.86 Hz, 2H, ), 6.17 (s, 1H, Benzylic H), 4.31 – 4.18

(m, 2H), 3.77 (s, 3H), 3.50 (s, 2H), 1.20 (t, J = 7.3 Hz, 3H). Its mass spectrum showed

peaks at m/z 358 (M+1

, 10 %), 357 (M+, 10 %), 193 (100 %).

Reductions with Lithium Aluminum Hydride (LAH):

Treatment of 3a with 1.1 eq. of LAH in THF45

followed by simple processing

gave a product, which was obtained as a syrupy liquid. The compound was found to be

homogenous on TLC. Its IR spectrum (Fig. 2.7) (Neat) did not show any diagnostic peaks

due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed signals (Fig. 2.8) at δ 7.14

(t, J = 7.81 Hz, 1H, Ar - H), 7.03 (d, J = 7.81 Hz, 1H, Ar - H), 6.66 (t, J = 7.32 Hz, 1H,

Ar - H), 6.52 (d, J = 8.30 Hz, 1H, Ar - H), 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H, O

CH CH2), 4.3 – 4.21(m, 1H, O CH2), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H, O CH2),

3.5 (m, 2H, N CH2), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H, S CH2), 2.70 – 2.60 (dd,

J = 9.28 and 11.72 Hz, 1H, S CH2). Its mass spectrum showed peaks (Fig. 2.9) at m/z194

(M+

+1, 100 %)and other peaks at 162 (30 %), 136 40%). Elemental Composition

(EIHRMS) Cal Mass: 193.05613, Exp. Mass: 193.056520, DBE: 6, C: 10, H: 11, N: 1,

O:1, S:1. Based on this data, the product was assigned as 1,2,3a,4-

tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine (16a). (Equation – 2.7)

58

N

S

O N

S

O

OEtO

LAH

THF, 0 °C - r.t 1 hr

(3a)(16a)

Equation – 2.7

It may be mentioned here that the product of LAH reduction in the above

reaction was expected to be 17, which was, however, not found to be formed. (Equation

– 2.8)

N

S

O N

S

O

OEtOH

LAH

THF, 0 - r.t1 hr

(3a)(17)

X

Equation – 2.8

The above reaction of 3a yielding 16a seems to be general one. It has been

extended to other N-substituted benzothiazinones (3) yielding (17). (Equation – 2.9)

N

S

ON

S

R1

O

OEtO

LAH

R1

RR

THF, 0 °C - r.t

1.0 hr

(3a -m) (16a- m)

Equation – 2.9

Structure confirmation: To further confirm the structure of the product 16 its

single crystal X-ray diffraction study was undertaken. For single crystal X-ray diffraction

study to be carried out, it is essential that the compound should be solid crystalline

substance as a first pre-requisite. Since the product 16a obtained in the present study was

59

a syrupy liquid and others being low melting solids, nitration of 16a was prepared hoping

that the nitro derivative of 16a would be a solid amenable to X-ray studies. Thus,

nitration of 16a with nitric acid in acetic anhydride yielded a product, which was

assigned 7-nitro-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]thiazine (18)

structure on the basis of its spectral data and analytical data.

N

S

O N

S

O

O2N

16a) (18)

HNO3

Ac2O

Equation –2.10

N

S

O

O2N

Ha

Ha

Hb

Ha

Hb

H

18

7

64

2

13

5

10

9

Hb

11

12

3

(18)

Thus, its IR (KBr) spectrum (Fig 2.10) showed peaks indicating absence of any

specific functional groups; Its 1H NMR (400 MHz, in CDCl3) showed signals (Fig 2.11)

at δ 5.07 (dd, J = 8.40 & 4.40 Hz, 2H, protons from carbon 2), Ha is 3.62 (dd, J = 10.0 &

8.40 Hz), 3 Hb is 3.19 (dd, J = 10.0 & 8.40 Hz), 8.04 (d, 2.4 Hz, 1H, from 7 position),

7.94 (dd, J = 8.80 & 2.40 Hz, 1H, from 8 position), 6.43 (d, J = 8.80 Hz, 1H), 3.60 (dt, J

= 7.60 & 8.80 Hz, 11Ha), 3.52 (ddd, J = 7.60, 6.40 & 2.80 Hz, 11Hb) and 4.36 (dt, J =

6.4 & 8.80 Hz, 12 Ha), 4.09 (ddd, J = 7.60, 6.40 & 2.80 Hz, 12Hb). In table 2.5 are

explained the Carbon 13, COSY and gHSQC.

In the steady state 1D nOe experiment on irradiation, the C-8 proton at 6.57

ppm showed the enhancement of signals at 3.7 and 3.5 ppm corresponding to C-11 Ha

and Hb protons respectively. From these results, aromatic C-8 proton was fixed at 6.57

60

ppm. The splitting of C-8 proton as doublet is due to coupling with C-7 proton. Hence,

the position of nitro group is assigned at C-6.

Table –2.4 Carbon 13, COSY and gHSQC of compound 18

Position COSY

(Fig: 2.15)

13C

(Fig: 2.12)

DEPT

(Fig: 2.13)

gHSQC

(Fig: 2.14)

2 (3Ha, 3.36)

(3Hb, 4.61)

85.82 CH (1H, 4.88)

3 (2H, 4.88) 26.82 CH2 (2Ha, 3.36)

(2H, 4.88) (2Hb, 4.61)

5 123.39 CH (5H, 7.78)

6 145.62

7 (8H, 6.57) 123.39 CH (7H, 7.87)

8 (7H, 7.87) 110.27 CH (8H, 6.57)

9 115.09

10 137.61

11 (12Ha, 4.12)

(12Hb, 4.32)

(11Hb, 3.72)

46.32 CH2 (11Ha, 3.49)

(12Ha, 4.12)

(12Hb, 4.32)

(11Hb, 3.49)

(11Hb, 3.72)

12 (11Ha, 3.49)

(11Hb, 3.72)

(12Hb, 4.32)

65.26 CH2 (12Ha, 4.12)

(11Ha, 3.49)

(11Hb, 3.72)

(12Hb, 4.12)

(12Ha, 4.32)

61

The possible major fragmentation pattern for 18 is deduced from Chemical

ionization mass spectrum (C I M S) is shown below (Fig. 2.16) Scheme – 2.4. And from

thermal analysis melting point is 160.04 °C (Fig. 2.17).

N

S

O

O2N

m/z = 239 M+1, 100 %

N O

O2N

m/z = 207, M+, 10 %

++

N O

m/z = 161, 2.0 %

+

NH

OH

m/z = 136, 8.0 %

+

OH

m/z = 122, 2.0 %

+

- NO2

- 46- 32

- S

- 25

- CH2CH2

- 14

- N

(18)(19)

(20)

(21)(22)

Scheme – 2.4

Point of attack: Having confirmed the structure of 18, it was considered

desirable to study the mechanism of formation of 16a (or 18) from its precursor 3a. For

that it is essential to know which of the two oxygens present in 3a would end up in 16a.

This was decided on the basis of the following sets of experiments: 3a was treated with

Lawsson’s reagent in dioxane to obtain thioamide derivative 3n (analytical data, Fig.

2.18, 1.19 & 2.20), which was reduced with LAH (1.1 equiv.) to obtain the tricyclic

oxazolo compound 16a instead of thiazolo compound (23). This result clearly indicates

that oxygen from amide was not involved in the cyclization, but that of ester carbonyl was

involved in the cyclization to produce tricyclic oxazolo compound 16a. Scheme – 2.5

62

N

S

O

CO2Et(3a)

N

S

S

CO2Et(3n)

Lawsson's Reagent,

dioxane, 100 °C, 6.0 h

N

S

O

N

S

S

(16a)

(23)

LAH (1.2 eq)

LAH (1.2 eq)

X

Scheme – 2.5

Table –2.5: Synthesis of 16 (a-m) from 3 (a-m) by reduction with LAH:

Structure Analytical Data: (IR cm-1

), 1H NMR (δδδδppm) (CDCl3, 200

MHz)

N

S

O

3a

IR: Did not show any diagnostic peaks due to –NH- and -CO-

groups; 1H NMR: (CDCl3, 200 MHz): δ 7.14 (t, J = 7.81 Hz, 1H),

7.03 (d, J = 7.81 Hz, 1H), 6.66 (t, J = 7.32 Hz, 1H), 6.52 (d, J =

8.30 Hz, 1H, 5.00 – 5.06 (dd, J= 3.41 and 9.27 Hz, 1H), 4.3 –

4.21(m, 1H), 4.12 – 4.01 (dd, J = 8.30 & 15.63 Hz, 1H), 3.5 (m,

2H), 3.15 – 3.08 (dd, J = 3.42 and 11.72 Hz, 1H), 2.70 – 2.60 (dd,

J = 9.28 and 11.72 Hz, 1H). Mass: m/z: 194 (M+

+1, 100 %)and

other peaks at 162 (30 %), 136 40%). EIHRMS: Cal Mass:

193.05613, Exp. Mass: 193.056520,

N

S

O

3b


groups; 1H NMR: (CDCl3, 200 MHz): δ 7.11 (d, J = 7.81Hz, 1H),

7.00 (t, J = 7.81 Hz, 1H), 6.65 (t, J = 7.57 Hz, 1H), 6.51 – 6.45

(dd, J = 3.41 and 8.01 Hz, 1H), 4.62 (d, J = 8.06 Hz, 1H), 4.31 –

4.13 (m, 1H), 4.10 – 3.98 (q, J = 8.30 Hz, 1H), 3.50 – 3.42 (m,

2H), 2.81 – 2.74 (dd, J = 7.81 Hz, 1H), 1.43 (d, J = 6.59 Hz, 3H);

Mass: m/z 208 (M+

+1, 100 %). 56 % YIELD

63

N

S

O

3c


groups; 1H NMR: (CDCl3, 200 MHz): δ 7.09 – 7.00 (m, 2H), 6.64

(t, J = 7.32 Hz, 1H), 6.49 – 6.45 (dd, J = 7.81 Hz, 1H), 4.88 (s,

1H), 4.29 – 4.22 (m, 1H), 4.12 – 4.00 (m, 1H), 3.53 - 3.47 (m,

2H), 1.41 – 1.40 (m, 1H), 1.44 – 1.41 (s, 6H); Mass: m/z 222 (M+

+1, 100 %).



(t, J = 7.1 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.68 (d, J= 8.06 Hz,

1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.00 Hz, 1H), 3.45 (t,

J = 7.3 Hz, 2H), 2.74 – 2.63 (m, 1H), 2.21 – 2.08 (m, 1H), 1.62 –

1.30 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H); Mass: 222 (M+1

, 100 %).

3e

16e

Pr

H

54



(t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 4.70 – 4.66 (d, J= 6.3

Hz, 1H), 4.26 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 8.3 Hz, 1H), 3.46

(t, J = 6.9 Hz, 2H), 2.75 – 2.71 (m, 1H), 2.05 (m, 1H), 1.66 – 1.54

(m, 1H), 1.51 – 1.43 (m, 2H), 1.00 – 0.85 (m, 3H); Mass: 236 (M+

+1, 100 %).

3f

16f

iPr

H

49


groups; 1H NMR: (CDCl3, 200 MHz): δ 7.16 (d, J = 7.6 Hz, 1H),

7.04 (t, J = 7.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 8.0

Hz, 1H), 4.83 (d, J= 8.5 Hz, 1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97

(q, J = 7.8 Hz, 1H), 3.48 – 3.42 (dd, J = 5.6 and 7.4 Hz, 2H), 2.80

– 2.74 (dd, J = 3.2 and 8.6 Hz, 1H), 2.50 – 2.35 (m, 1H), 1.14 (d, J

= 7.1 Hz, 3H), 1.05 (d, J = 7.1 Hz, 3H); Mass: 236 (M+

+1, 100

%).

3g IR: Did not show any diagnostic peaks due to –NH- and -CO-

64

16g

Hex

H

52


(t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 4.67 (d, J= 8.1 Hz,

1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.97 (q, J = 7.3 Hz, 1H), 3.49 –

3.42 (m 2H), 2.78 – 2.70 (m, 1H), 2.07 – 2.04 (m, 1H), 1.69 – 1.30

(m, 9H), 0.88 – 0.85 (m, 3H); Mass: 278 (M+

+1, 100 %).

3 h

16h

Ph

H

63


groups. 1H NMR: (CDCl3, 200 MHz): δ 7.39 (s, 5H, ), 7.20 (d, J

= 8.79 Hz, 1H, ), 7.12 (t, J = 7.33 Hz, 1H, ), 6.71 (t, J = 7.33 Hz,

1H, ArH), 6.60 (d, J = 7.81 Hz, 1H, ), 5.13 (d, J = 8.31 Hz, 1H,

NCHO), 4.29 – 4.19 (m, 1H, SCHPh), 4.06 – 3.94 (dd, 8.30 &

15.63 Hz, 1H, OCH2CH2N), 3.73 (d, J = 8.30 Hz, 1H,

OCH2CH2N), 3.54 (t, J = 7.32 Hz, 2H, NCH2CH2O). Mass: 270

(M+

+1, 100 %).

3 i

16i

H

Et

71


groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,

ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.11 (dd, J= 3.7 and 9.1

Hz, 1H), 4.23 – 4.02 (m, 2H), 3.79 – 3.72 (m, 1H), 3.09 – 3.01

(dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.48 (dd, J = 6.3 and 12.0 H,

1H), 1.96 – 1.71 (m, 1H), 1.56 – 1.43 (m, 1H), 0.99 – 0.91 (m,

3H); Mass: 222 (M+

+1, 100 %).

3 j

16j

H

Pr

61


groups; 1H NMR: (CDCl3, 200 MHz): δ 7.18 – 6.96 (m, 2H,

ArH), 6.67 - 6.48 (m, 2H, ArH), 5.17 – 5.10 (dd, J= 3.7 and 9.1

Hz, 1H), 4.20 – 4.04 (m, 2H), 3.94 – 3.82 (m, 1H), 3.86 – 3.71 (m,

1H), 3.09 – 3.01 (dd, J = 3.7 and 10.0 Hz, 2H), 2.58 – 2.47 (dd, J =

6.3 and 12.0 H, 1H), 1.88 – 1.72 (m, 1H), 1.59 – 1.32 (m, 5H),

0.98 (t, J = 7.1 Hz, 3H); Mass: 236 (M+

+1, 100 %).

3k

16k


groups. 1H NMR: (CDCl3, 200 MHz): δ 7.34 (s, 3H, ), 7.31 (d, J

65

H

Ph

46

= 3.9 Hz, 2H, ), 7.21 – 7.17 (dd, J = 1.5 & 7.8 Hz, 1H, ), 6.92 –

6.84 (m, 1H, ArH), 6.60 (d, J = 7.31 Hz, 1H, ), 6.33 (d, J = 8.31

Hz, 1H, NCHO), 5.48 – 4.41 (dd, J = 3.9 & 9.3 Hz, 1H), 4.82 (t, J

= 7.8 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 3.76 (t, J = 8.3 Hz, 1H),

3.20 – 3.12 (dd, J = 3.5 % 12.1 Hz, 1H), 2.66 – 2.55 (dd, J = 9.2 &

12.2 Hz, 1H); Mass (m/z): 270 (M+

+1, 100 %).

3l

16l

H

*

39


groups. 1H NMR: (CDCl3, 200 MHz): δ 7.95 (d, J = 8.3 Hz, 2H,

ArH), 7.56 (d, J = 8.3 Hz, 2H), 7.21 (s, 1H), 6.90 (t, J = 8.2 Hz,

1H), 6.67 (t, J = 8.2 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 5.49 – 5.42

(dd, J = 4.0 & 9.2 Hz, 1H), 4.9 (t, J = 6.8 Hz, 1H), 4.57 (t, J = 9.3

Hz, 1H), 3.74 (t, J = 7.8 Hz, 1H), 3.32 – 3.14 (m, 1H), 3.07 (s,

3H), 2.67 – 2.56 (dd, J = 9.3 & 18.0 Hz, 1H); Mass: 347 (M+

+1,

100 %), 304 (60 %).

3m

16m

H

**

41


groups. 1H NMR: (CDCl3, 200 MHz): δ 7.26 (m, 4H, ArH), 6.89

(d, J = 8.3 Hz, 2H), 6.62 (t, J = 7.5 Hz, 1H), 6.36 (d, J = 8.1 Hz,

1H, ArH), 5.47 – 5.40 (dd, J = 4.0 & 9.0 Hz, 1H), 4.77 (t, J = 7.5

Hz, 1H), 4.49 (t, J = 8.6 Hz, 1H), 3.80 – 3.74 (m, 4H), 3.29 (d, J =

4.3 Hz, 1H), 3.19 – 3.11 (dd, J = 4 & 11 Hz, 1H), 2.65 – 2.54 (dd,

J = 9.4 & 12.0 Hz, 1H).Mass: 300 (M+, 100%)

* =, 4 – methylsulfonyl phenyl, ** = 4 –methoxy phenyl

66

2.4 POSSIBLE MECHANISM OF REDUCTIVE CYCLIZATION:

(i) Addition of LAH: Addition of the LAH in both the ways, that is normal

addition (substrate was added to the LAH) or reversible addition (LAH was

added to the substrate). In the both the ways, same product (16a) was

obtained.

(ii) Use of more than 1.1 equivalents of LAH leads to alcohol (17a) as the

product. Once the cyclized product is formed, it is stable and no further

reduction occurs with LAH. After isolating product by using 1.1 eq. of LAH

and aq. sodium sulfate workup it was treated with 3.0 eq to 4.0 eq of LAH, no

reaction was took place. Even same thing was done before work up it lead to

alcohol 17a. Compound 17a is more stable with LAH, once it cyclizes.

N

S

OEt

O

N

S

O

O

(3a)

(16a)

N

S

OH

(17a)

2 - 4 eq. of LAH

THF

N

S

(16a)

1.1 eq. of LAH

2 - 4 eq. of LAH

X

OH

Scheme 2.6

Formation of tricyclic compound 16a can be rationalized through initial reduction

of 3a to amino alcohol 24 which may instantaneously cyclize to the cyclic compound 25.

In contrast, compound 24 may react with excess of LAH to form the diol 26 which may

reduce further with LAH to give amino alcohol 17a or get cyclized to afford 16a. In the

presence of excess of LAH, therefore, the yield of 16a decreases as the yield of alcohol

25 increases. In order to substantiate this mechanism as well as to develop a new method

67

to synthesize the hitherto unknown fused 1,3-oxazolo tricyclic compound 16a, reactions

were carried out as shown below (Scheme – 2.7).

N

S

OEt

O

THF, LAH(1.1 eq)

r.t, 1.0 h N

S

N

S

OH

OM

N

S

OH

OOOM

N

S

OHN

S

O

LAH

(3a)(24)

O

(25)

(26)(16a)(17a)

Scheme – 2.7

Optimization:

With a view to optimize conditions, the reactions of 3a with LAH were studied

under different conditions and different equivalents of LAH gave a mixture of 16a and

17a and in certain conditions almost zero yields of 16a. These results are shown in

Table- 2.6

N

S

O N

S

O

OEt

O

(3a) (16a)

N

S

OH

(17a)

LAH

Equation – 2.11

Table – 2.6: Reduction of 3a with different equivalents of LAH

68

S.No. LAH a eq. Ratio of products

b (%)

3a 16a 17a

01. 0.5 60 40 0

02. 1.0 4 96 0

03. 1.1 0 100 0

04. 2.0 0 97 0

05. 4.0 0 91 9

06. 6.0 0 72 28

aAll reactions were carried out in dry THF under inert atmosphere at room temperature

(ca, 25 °C

) for 0.45 hrs, bproduct ratios were determined by HPLC; column: Inertsil ODS;

mobile phase: 0.01M KH2PO4 and ACN (30:70); λmax. 235 nm; retention time: 3a, 4.37

min.; 17a, 8.2 min.

Results from above experiments indicate that only 1.1 eq. of LAH are needed for

to get desired oxazolo product.

The above reaction was also been studied with reducing agents other than LAH.

These experiments showed some interesting results which are given in Table 2.7. The

expected product 16a was not formed in these reductions.

The compound 3a was treated with sodium metal (4.0 equivalents) in ethanol in

order to obtain 16a. However, the product obtained was 2-(3-oxo-3,4-dihydro-2H-

benzo[b][1,4]thiazin-4-yl)acetic acid (27). Equation –2.12

N

S

OEt

O

Na / EtOH

N

S

OH

80 °C, 6.0 hO O

(3a)

O

(27)

Equation – 2.12

69

The structure of compound 27 is supported by its spectral and analytical data. Thus, its

IR (KBr) spectrum showed peaks at 1732 cm-1

(acid carbonyl stretching), at 1671 cm-1

(amide carbonyl stretching). Its 1H NMR (in CDCl3) showed signals at δ 7.39 (d, J = 7.7

Hz, 1H), 7.29 – 7.26 (m, 1H), 7.06(t, J = 7.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.23 (bs,

1H, D2O exchangeable), 4.70 (s, 2H), 3.48 (s, 2H); while mass spectrum showed m/z 224

(M+1

, 25 %) molecular ion at 223 (M+, 50 %) and other peaks at 178 (25 %), 150 (100

%), 136 (60 %) etc.

Compound 3a was reacted with sodium borohydride and borane dimethyl sulfide

(2.2 equivalents) in THF at 50 oC to yield 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)-

1-ethanol (17a) instead of 16a. (Equation –2.13) 17a was confirmed by its spectral and

analytical data. Thus, its IR (KBr) showed peak at 3396 cm-1

due to alcohol stretching,

and no peaks at carbonyl stretching frequency. Its 1H NMR (in CDCl3) showed signals at

δ 7.07 – 6.96 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.69 (m, 1H), 3.84 (t, J = 6.0 Hz, 2H),

3.66(t, J = 6.0 Hz, 2H), 3.47(m, 2H), 3.05 (t, J = 6.0 Hz, 2H); mass spectrum showed m/z

at 196 (M+1

60 %), 195 (M+, 60 %) and other peaks at 164 (90 %), 136 (100 %).

N

S

O

O

OEt(3a)

N

S

OH(17a)

NaBH4 / BMS

Equation –2.13

When 3a was reacted with borane (2.2 equivalents) for 24 hrs in THF, it gave

ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)acetate (28). (Equation –2.14) 28 was

characterized by its spectral data. Thus, its IR (KBr) showed peak at 1744 cm-1

due to

ester carbonyl stretching. Its 1H NMR (CDCl3, 200 MHz): showed signals at δ 7.06 –

6.91 (m, 2H), 6.63 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 8.3,1H), 4.24 – 4.14 (q, J = 7.0 Hz,

2H), 4.00 (s, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.06(t, J = 6.4 Hz, 2H), 1.25 (t, J = 7.0 Hz,

2H); mass spectrum showed peaks at m/z 238 (M+1

75 %) and other peaks at 237 (M+, 60

%), 64 (100 %), 136 (80 %). All these experiments was explained in the following

70

Table – 2.7

N

S

OEt

O

BH3 (2.2 eq)

N

S

OEt

O

r.t., 24 hO

(3a) (28)

Equation –2.14

Table –2.7: Reaction of 3a with different reducing reagents, reaction conditions

and results.

S.No. Reagent Conditions Results

Name Equalents Solvent Temp.

(°C)

Time

(hrs)

3a 16a 17a

1. Na 4.0 EtOH 80 6.0 *

2. Na 8.0 EtOH 80 6.0 *

3. NaBH4 1.1 Diglyme 80 6.0 √

4. NaBH4 2.2 Diglyme 80 6.0 √

5. NaBH4 AlCl3 1.1 / 0.4 Diglyme r.t 12.0 √

6. NaBH4 / AlCl3 2.2 / 0.8 Diglyme r.t 12.0 √

7. NaBH4 / AlCl3 2.2 / 0.8 Diglyme 75 12.0 √

8. NaBH4 / LiCl 1.1 /1.1 THF r.t 12.0 √

9. NaBH4 / I2 1.1 / 0.4 THF r.t 4.0 √

10. NaBH4 / NiCl2 1.1 / 1.1 MeOH r.t 4.0 √

11. NaBH3 / H2SO4 2.4 / 1.2 THF 40 12.0 √

12. BMS / NaBH4 1.1 / 0.5 THF r.t 6.0 √

13. BMS 1.1 THF r.t 6.0 √

14. BMS 1.1 THF 50 6.0 √

15. BMS 2.4 THF 50 6.0 √

16. L-Selectride 1.1 THF r.t 4.0 Not clean

71

17. 9 BBN 1.1 THF r.t 6.0 √

18. BH3 1.1 THF r.t 6.0 √

19. BH3 2.2 THF r.t 24.0 **

20. DIBAL-H 1.1 THF r.t 24.0 √

* Ester was hydrolyzed, ** only amide keto was reduced.

Experimental procedure:

i) Preparation of 2a:

To a solution of 2-aminothiophenol (1) (50.0 gms, 400 mmol) in aq.

sodium hydroxide (8 %, 200 mL) at 15 oC was added a solution of chloroacetic acid (37.8

g gms, in 100 ml of water, 400 mmol) while the temperature was kept below 40 oC. Oil

starts separating out from the solution in about 60 min, time, and the resulting mixture

was stirred and refluxed for 4 hrs, during which time the oil changes to granular solid.

Then the mixture was cooled to room temperature, the solid was filtered and washed with

cold water. The solid was triturated with acetonitrile on the filter funnel and dried to

obtain 2a as colorless solid (50.0 g, 76 %).

ii) Preparation of 2a - h (General procedure):

First method: To a solution of 2-aminothiophenol (1) (5.0 g, 40.0 mmol) in water was

added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl acetate

(1.2 eq) at room temperature. The reaction mixture was stirred for one hr at room

temperature and then poured into dil. HCl (100 mL, 50 % v/v). The separated solid was

filtered, washed with water and dried to obtain 2a-h (Table-2.3).

Second method: To a solution of 2-aminothiophenol (0.250 g, 2.0 mmol) in water was

added of sodium hydroxide (0.12 g, 3.0 mmol), followed by ethyl 2-bromo-2-alkyl

acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using

household microwave oven for 5.0 min. The mixture was cooled and stirred with cold dil.

HCl (100 mL, 50 % v/v). The separated solid was filtered, washed with water and dried

to obtain 2a-h (Table-2.3).

72

iii) Preparation of 3a – j (General procedure): To a solution of 2a – h (1.0 eq) and

potassium carbonate (3.0 eq), in dry dimethylformamide, was added ethyl 2-bromo-2-

alkyl acetate (1.2 eq) drop wise at room temperature. After stirring for 24 hrs the mixture

was poured in to water and extracted with ethyl acetate. The organic layer was washed

with water, dried and concentrated under reduced pressure to obtain 3a – o as crude

product, which was purified through column chromatography yielding pure compounds

3a – j (Table 2.2)

iv) Preparation of 5: A mixture of 4 (20.0 gms, 147 mmol) in ethanol (200 mL) was

refluxed for 3.0 hrs in the presence of a trace of con. H2SO4 (catalytic amount). Then the

solvent was removed from the reaction mixture under reduced pressure and the residue

was dissolved in ethyl acetate (200 mL). The ethyl acetate layer was washed with aq.

NaHCO3 solution followed by water (2 X100 mL), dried over Na2SO4 and concentrated

under reduced pressure to give 5 (24.0 g, 99 %) as thick liquid.

v) Preparation of 6: To a solution of 5 (20.0 gms, 122 mmol) in carbon tetrachloride

(200 mL), was added N-bromosuccinimide (23.8 gms, 134 mmol) and catalytic amount

of benzoyl peroxide. The mixture was stirred for 24.0 hrs at 60 oC. Then, the mixture was

filtered, washed with CCl4 and filtrate was concentrated under reduced pressure to yield a

crude residue which was dissolved in ethyl acetate. The ethyl acetate layer was washed

with water, dried over Na2SO4 and concentrated under vacuum, to obtain 6 (25.0 gms, 86

%) as gummy solid.

vi) Preparation of 3k: A solution of 2a (2.0 gms, 12.12 mmol), 6 (3.33 gms, 14.54

mmol) and anh. potassium carbonate (2.5 gms, 18.18 mmol) was stirred in DMF at 80 oC

for 12 hrs. At the end of this period, the reaction mixture was cooled to room temperature

and poured in to water. The mixture was extracted with ethyl acetate. The ethyl acetate

layer was washed with water, dried and concentrated under reduced pressure to obtain the

crude product, which was purified through column chromatography to yield a pure low-

melting solid of 3k (1.2 gms, 32 %).

73

vii) Preparation of 8: To a suspension of aluminum chloride (25.7 gms, 193.5 mmol) in

methylene chloride (150 mL) was added acetyl chloride (15.2 mL, 193.5 mmol) slowly at

0°C

. The reaction mixture was then stirred at 25° o

C until clear solution was obtained. A

solution of 7 (20.0 gms, 161.0 mmol) in dichloromethane (50 mL) was added slowly to

this mixture at 25 oC with vigorous stirring. The stirring was continued for 4.0 hrs at 25

oC, then the mixture was poured into crushed ice (200 g) and extracted with chloroform

(3X100 mL). Combined organic layer was washed with water (2X100 mL), dried over

anhydrous Na2SO4 and concentrated under vacuum to give 8 (24.0 gms, 92 %) as pale

yellow powder.

viii) Preparation of 9: A mixture of 8 (22.0 gms, 132 mmol), elemental sulfur (5.0

gms, 159 mmol) and morpholine (13.8 gms, 159 mmol) was stirred for 24 hrs at 130 °C.

The reaction mixture was cooled to 25 °C followed by slow addition of 6N HCl (100 mL)

and then allowed to proceed for 24 hrs at 140 °C with vigorous stirring. After cooling to

room temperature the reaction mixture was poured into water (100 mL) and extracted

with ethyl acetate (3 X100 ml) followed by the extraction of the combined organic layer

with 10 % sodium hydroxide solution (2X100 mL). The aqueous layer was collected,

combined and acidified with 6N HCl. The separated solid was filtered, washed with

water and dried under vacuum to give 9 (17.0 gms, 71 %) as brown colour powder.

ix) Preparation of 10: A solution of 9 (16.0 gms, 87.9 mmol) in ethanol (200 mL) was

refluxed in the presence of con. H2SO4 (catalytic amount) for 4 hrs. At the end of this

period, the solvent was removed from the reaction mixture and the residue was dissolved

in ethylacetate (200 mL). The ethyl acetate layer was washed with aq. NaHCO3 solution

followed by water (100 mL X2), dried over Na2SO4 and concentrated under vacuum to

give 10 (18.0 g, quantitative) as thick liquid.

x) Preparation of 11: To a solution of 10 (6.0 gms, 28.57 mmol) in acetone (50 mL),

was added Oxone (36.89 gms, 59.99 mmol in 30 mL of water) at 25 °C. The mixture was

stirred for 4.0 hrs at 25 oC

Acetone was removed from the reaction mixture under

vacuum; the residue was neutralized with aq. NaHCO3 solution and extracted with ethyl

74

acetate. The ethyl acetate layer was washed with water, it was dried and concentrated to

obtain 11 (6.2 g, 90 %) as low-melting solid.

xi) Preparation of 12: To a solution of 11 (6.0 gms, 24.79 mmol) in carbon tetrachloride

(60 mL), was added N-bromosuccinimide (4.65 gms, 27.27 mmol) and catalytic amount

of benzoyl peroxide. The resulting mixture was stirred for 24.0 hrs at 60 °C. Then the

mixture was filtered, washed with CCl4 and filtrate was concentrated under reduced

pressure. The crude residue was dissolved in ethyl acetate. The ethyl acetate layer was

washed with water, dried over Na2SO4 and concentrated under vacuum, to yield 12 (6.3 g,

80 %) as low-melting solid.

Analytical data:

IR (Neat): 1738 cm-1

(ester carbonyl stretching); 1H NMR (CDCl3, 200 MHz): δ 7.96

– 7.92 (d, J = 8.30 Hz, 2H), 7.77 – 7.73 (d, J = 8.3 Hz, 2H), 5.36 (s, 1H), 4.31 – 4.19 (m,

2H), 3.06 (s, 3H), 1.32 –1.25 (t, J = 7.8 Hz, 3H); MS: m/z 321 (M+, 10 %), 250 (50 %),

241 (70 %), 185 (70 %), 170 (100 %), 162 (40 %), 107 (80 %), 90 (50 %).

xii) Preparation of 3l: A mixture of 2a (2.0 gms, 12.12 mmol), 12 (4.7 gms, 14.5 mmol)

and anh. potassium carbonate (2.5 gms, 18.18 mmol) in DMF was stirred at 80 °C for 24

hrs. The reaction mixture was cooled to room temperature and poured into water (100

ml). The mixture was extracted with ethyl acetate (3 x 50 mL). Ethyl acetate layer was

washed with water, dried and concentrated under reduced pressure to yield a crude

product, which was purified through column chromatography giving the pure product 3l

(0.25 gms, 5 %) as low-melting solid.

xiii) Preparation of 14: To a cooled solution of 4-methoxyphenylacetic acid (35) (5.0 g,

30.12 mmol) in ethanol (60 mL), was added thionyl chloride (45.0 mL, 60.24 mmol)

dropwise at 0 °C. Then the reaction mixture was refluxed for four hours and the solvent

removed under low pressure. The crude residue was dissolved in ethyl acetate and

washed with aq. NaHCO3 solution (100 mL of 10 % in water) followed by water (300

ml). The organic layer was dried and concentrated under reduced pressure to yield 14 (5.7

g, 98 %).

75

xiv) Preparation of 15: To a solution of ethyl 4-methoxyphenylacetate (5.0 g, 25.77

mmol) in carbon tetrachloride, was added N-bromosuccinimide (5.0 g, 28.35 mmol) and

the mixture was refluxed for three hours using electric bulb in the presence of catalytic

amount of benzoyl peroxide. Then the mixture was diluted with some more CCl4 and

washed with water, it was dried and concentrated to obtain 15 (6.8 gms, 97 %).

xv) Preparation of 3 m: To a mixture of 2a (0.5 gms, 3.03 mmol) potassium carbonate

(1.25 gms, 9.09 mmol), dry dimethylformamide (10 mL), was added 16 (0.99 gms, 3.63

mmol) in DMF (5.0 mL) drop wise at room temperature. After stirring at 60 oC, for 12

hrs, the mixture was poured in to water (50 ml) at room temperature. The separated solid

was filtered, washed with water and dried to obtain 3m ( 69 %).

xvi) Preparation of 16a – m (General procedure): To a solution of 3a - o (2.0 mmol) in

dry THF (25 mL) at 0 °C, lithium aluminumhydride (2.2 mmol) was added in several

portions over a period of 30 min. and stirred for 1.0 hr at room temperature. The resulting

mixture was quenched with aqueous sodium sulfate solution. The reaction mixture was

filtered and the filtrate concentrated. The crude product was purified by column

chromatography using ethyl acetate and pet. ether (5:95) to give 16a – m (Table-2.6).

xvii) Preparation of 18: To an ice cold solution of 16a (5.0 g, 25.77 mmol) in acetic

anhydride (80 mL) was added fuming nitric acid (1.78 g, 28.34 mmol) drop wise at –5

oC, and the mixture was stirred for 3 hrs at 0

°C. The reaction mixture was poured in to

crushed ice, the separated solid was filtered, washed with water and dried. The crude

product was purified through column chromatography by using ethyl acetate in petroleum

ether to obtain 18 (1.0 gms, 18 %) as yellowish crystalline solid.

xviii) Preparation of 3n: Method A: To a solution of 3a (1.0 g, 3.95 mmol) in dioxane

was added Lawsson’s reagent [2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-

dithiadiphosphetane) (0.8 g, 1.97 mmol) and the mixture was refluxed for 6 hrs. The

solvent was removed and the crude residue was purified through column

chromatography, to give 3n as yellow solid (1.0 g, 95 %).

xiv) Reduction of 3n with LAH: To a solution of 3n (0.534 g, 2.0 mmol) in dry THF

(10 mL) at 0 °C, lithium aluminumhydride (0.0836 g, 2.2 mmoles) was added in several

76

portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The resulting

mixture was then quenched with aq. sodium sulfate solution. The mixture was filtered

and the filtrate concentrated. The crude product was purified by column chromatography

using ethyl acetate and pet. ether (5:95) to obtain 16p.

xv) Experimental procedures of reactions which are explained in Table – 2.8:

a) (i) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.092

g, 4.0 mmol) in of dry toluene (20 mL) and the mixture was heated until sodium melted.

Then, the mixture was cooled to 60 °C and this was added 25a (0.25 g, 1.0 mmol) in

ethanol (5.0 ml), followed by more ethanol (20 mL) as rapidly as possible. The reaction

mixture was refluxed for 6.0 hrs, and the solvent was removed by distillation. The crude

residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water; it

was dried and concentrated under reduced pressure to give 27 (0.17 g, 81 %).

(ii) Reduction of 3a with Sodium: In the flask are placed sodium metal (0.184 g, 4.0

mmol) in dry toluene (20 mL) and was heated until sodium melted. Then the mixture was

cooled to 60 °C and to this was added 3a (0.25 g, 1.0 mmol) in ethanol (5.0 ml), followed

by more ethanol (20 mL) as rapidly as possible. The reaction mixture was refluxed for

6.0 hours, and the solvent was removed by distillation. The crude residue was dissolved

in ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated

under reduced pressure to obtain 27. (0.180 g, 86 %)

b) Reduction of 3a with Sodium borohydride: To a stirred solution of 3a (0.251 g, 1.0

mmol) in diglyme (10.0 mL), was added sodium borohydride (0.041 g, 1.1 mmol) pinch

by pinch at room temperature. The mixture was stirred for six hours at 80 °C. Then the

reaction mixture was quenched with ice-cold water (5 ml) and extracted with ethyl

acetate (2X25 mL), It was washed with satd. sodium chloride solution, dried and

concentrated. Instead of expected product, starting material was recovered. The same

reaction was done with 2.2 eq. of sodium borohydride yet no product could be isolated.

c) Reduction of 3a with sodium borohydride and aluminum chloride:

First Method: To a solution of sodium borohydride (0.041 g, 1.1 mmol) in diglyme

(11 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and

77

aluminum chloride (0.053 g, 0.4 mmol, 2.0 ml of 2M solution in diglyme) was added

through dropping funnel at room temperature. The mixture was stirred for 12.0 hours at

room temperature.

Second Method: To a solution of sodium borohydride (0.083 g, 2.2 mmol) in diglyme

(22 mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and

aluminum chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added


room temperature.

Third Method: To a solution of sodium borohydride (0.083 g, 2.2 mmol) in diglyme (22

mL), was added 3a (0.251 g, 1.0 mmol). Vigorous stirring was initiated and aluminum

chloride (0.106 g, 0.8 mmol, 4.0 ml of 2M solution in diglyme) was added through

dropping funnel at room temperature. The mixture was stirred for 12.0 hours at 75 °C.

In all the above methods, no product could be isolated and starting material was

recovered unchanged.

d) Reduction of 3a with Sodium borohydride and Lithium chloride: To a solution of

sodium borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0

mmol). Vigorous stirring was initiated and lithium chloride (0.046 g, 1.1 mmol) was

added at room temperature. The mixture was stirred for 12.0 hours at room temperature.

No product could be isolated and starting material was recovered unchanged.

e) Reduction of 3a with sodium borohydride and iodine: To a solution of sodium

borohydride (0.041 g, 1.1 mmol) in THF (15 mL) was added 3a (0.251 g, 1.0 mmol).

Vigorous stirring was initiated and iodine (0.101 g, 1.1 mmol) in THF (10 ml) was added


room temperature. Processing the reaction mixture gave back starting material was

unchanged.

f) Reduction of 3a with Sodium borohydride and Nickel chloride: To a solution of

25a (0.251g, 1.0 mmol) in methanol (15 mL) was added sodium borohydride (0.041 g,

1.1 mmol) at 0 °C, and followed by nickel chloride (0.262 g, 1.1 mmol) at same

78

temperature. The mixture was stirred for 12.0 hours at room temperature. On processing

the reaction mixture, starting material was recovered unchanged.

g) Reduction of 3a with sodium borohydride and sulfuric acid: To a solution of 3a

(0.251 g, 1.0 mmol) in THF (15 mL), was added sodium borohydride (0.120 g, 2.4 mmol)

at 0 °C, followed by sulfuric acid (0.117 g, 1.2 mmol) at the same temperature. The

mixture was stirred for 12 hrs at 40 °C. On processing the reaction mixture, starting

material was recovered unchanged.

h) Reduction of 3a with borane dimethylsulfide complex and Sodium borohydride:

To a solution of 3a (0.251 g, 1.0 mmol) in toluene (15 mL) was added dropwise borane

dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. After 30 min of stirring,

sodium borohydride (0.019 g, 0.5 mmol) was added in parts at 0 °C. The mixture was

stirred for 6.0 hours at room temperature. Reaction mixture was quenched by adding

methanol and solvent was removed from the mixture. The crude residue was purified

through column chromatography to give reduced product i.e. alcohol 3a (0.175 g, 89 %).

i) Reduction of 3a with borane dimethylsulfide complex:

First Method: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop

wise borane dimethylsulfide complex (1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture

was stirred for 6.0 hours at room temperature. On processing the reaction mixture,

starting material was recovered unchanged.

Second Method: To a solution 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop


was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol

and solvent was removed from the mixture. The crude residue was purified through

column chromatography to give reduced product i.e. alcohol 17a (0.155 g, 79 %).

Third Method : To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL) was added drop


was stirred for 6.0 hours at 50 °C. Reaction mixture was quenched by adding methanol

and solvent was removed from the mixture. The crude was purified through column

chromatography to obtain reduced product i.e. alcohol 17a. (0.150 g, 77 %)

79

j) Reduction of 3a with Selectride: To a solution of ethyl 2-(3,4 dihydro-3oxo-2H-

benzo[b][1,4]thiazin –4-yl)acetate (3a) (0.251 g, 1.0 mmol) in THF (15 mL) was added

drop wise L- selectride(1.0 ml of 10 M, 1.1 mmol) at 20 °C. The mixture was stirred for

4 hrs at room temperature. On processing the reaction mixture, starting material was

recovered unchanged.

k) Reduction of 3a with 9BBN: To a solution of 3a (0.251 g, 1.0 mmol) in THF (15 mL)

was added drop wise 9BBN (2.2 ml of 0.5 M, 1.1 mmol) at 20 °C. The mixture was

stirred for 6.0 hours at room temperature. Reaction mixture was quenched with methanol

and water. Then, the mixture was extracted with ethyl acetate. Ethyl acetate layer was

washed with water, dried and concentrated to yield alcohol product i.e. 3a (0.165 g, 86

%).

l) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in THF

(15 mL) was added dropwise borane in THF (1.1 ml of 10 M, 1.1 mmol) at 20 °C. The

mixture was stirred for 6.0 hours at room temperature. On processing the reaction

mixture, starting material was recovered unchanged.

m) Reduction of 3a with borane in THF: To a solution of 3a (0.251 g, 1.0 mmol) in

THF (15 mL) was added dropwise borane in THF (2.2 ml of 10 M, 2.2 mmol) at 20 °C.

The mixture was stirred for 24.0 hours at room temperature. Reaction mixture was

quenched with methanol and water. Then, the mixture was extracted with ethyl acetate.

Ethyl acetate layer was washed with water, dried and concentrated to give 28. (0.190 g,

80 %)

n) Reduction of 3a with DIBAL-H: To a solution of 3a (0.251 g, 1.0 mmol) in THF

(15 mL) was added drop wise DIBAL - H in THF (1.0 ml of 10 M, 1.1 mmol) at 20 °C.

The mixture was stirred for 24.0 hours at room temperature. On processing the reaction

mixture, starting material was recovered unchanged.

REFERENCE

01. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc., 1982,

74, 1321.

02. Unger, G. Chem. Ber.; 1897, 40, 2496.

80

03. Koos, M., Monatsh. Chem.; 1994, 125 (8/9) 1011.

(Chem. Abstr. 1994, 122: 81258)

04. Goudie, R. S.; Preston, P. N. J. Chem. Soc. C. 1971, 1718.

05. Hiroyuki, T.; Yasuo, S.; Hitoshi, I.; Yuiro, Y.; Kanji, Meguro. Chem. Pharm.

Bull. 1990, 38 (5), 1238. (Chem. Abstr. 1990, 113: 132112)

06. Erker, T.; Bartsch, H. Liebihgs Ann. Chem. 1992, 4, 403.

(Chem. Abstr. 1992, 116:214473)

07. Hiroshi, S.; Norihiro, U.; Tadashi, K.; Mikio, H. Chem. Pharm. Bull. 1984, 42

(7), 2571.

08. Nair, M. D.; David, J.; Nagarajan, K. Indian. J. Chem. Sect. B, 1985, 24, 940.

09. Saverio, F.; Vito, C.; Gennara, C.; Tetrahedron; 1997, 54 (16), 5849.

10. Zhong, W.; Zhang, Y. Tetrahedron Lett. 2001, 42 (17), 4125.

11. Mikio, H.; Tadashi, K.; Hiroshi, S.; Yutaka, I. Chem. Pharm. Bull. 1979, 27 (9),

1973.

12. Takamizawa, A., Chem. Pharm. Bull., 1972, 20, 892.

13. Wilkins, R.; Rohert, W. C. III. Can. J. Chem. 1979, 57, 444.

(Chem. Abstr. 1979, 90: 186884).

14. Norio, K.; Yuichi, H.; Koichi, S. Heterocycles. 1984, 22 (2), 277.

(Chem. Abstr. 1984, 100: 191811)

15. Niels, J.; Hans; Kolind, A. Synthesis. 1990, 10, 911.

16. Fujita, M.; Ota, A.; Ito, S.; Yamamoto, K.; Kawashima, Y. Synthesis.1990, 8,

599.

17. Babudri, F.; Florio, S.; Indelicati, G.; Trapani, G. J. Org. Chem. 1983, 48 (22),

4082.

18. Unger, G. Chem. Ber. 1897, 40, 2496, (1897). (Ref: 12)

19. Olagbemiro, T. O.; Nyakutse, C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E.

Bull. Soc. Chim. Belg. 1987, 96 (6), 473. (Chem. Abstr. 108:112387, 1987).

81

20. Trapani, G.; Reho, A.; Morlacchi, F.; Latrofa, A.; Marchini, P.; Venturi, F.;

Cantalamessa, F. Farmaco Ed Sci. 1985, 40 (5), 369.

(Chem. Abstr. 1985, 103: 87826).

21. Coutts, R. T., Sharon, J. M., Mah, E. and Pound, N. J.; Can. J. Chem. 1970, 48,

3727.

22. Langlet, B.; Till, S. Vet – Akd. Handlingar, 22, II, No 1, S 17.

23. Tawada, H.; Sugiyama, Y.; Ikeda, H.; Yamamoto, Y.; Meguro, K. Chem. Pharm.

Bull. 1990, 48 (5), 1248.

24. Shimizu, H.; Ueda, N.; Kataoka, T.; Hori, Mikio. Chem. Pharm. Bull. 1984,

42(7), 2571. (Chem. Abstr. 1984, 108:229556.

25. Iruvin Pachter, S. J.; Milton, C.; Kloetzel, M. C. J. Amer. Chem. Soc. 1952, 74,

321.

26. Bergmann; Ikan. J. Amer. Chem. Soc. 1958, 80, 3135.

27. Rahim Abdur, M.; Rao Praveen, P. N.; Knwas Edward, E. Bioorg. Med. Chem.

Lett. 2002, 12 (19), 2753.

28. Reichardt, C.; Schaefer, G.; Milart, P. Collect. Czech. Chem. Commun. 1990, 55

(1), 97. (Chem. Abstr. 1990, 113:25538.)

29. (a) Joseph, W. C.; Reuben G. J.; Quentin F. S.; Calvert W. W.; Otto K. B. J.

Amer. Chem. Soc. 1948, 70, 2837. (b) Charles, D. H.; Gene, L. O. J. Amer.

Chem. Soc. 1954, 76, 50. (c) Org. Synth. Coll. Vol. 1963, IV, 176. (d) Reichardt,

C.; Schaefer, G.; Milart, P. Collect. Czech. Chem. Commun. 1990, 55 (1), 97.

(Chem. Abstr. 1990, 113:25538.) (e) Shah, K. S.; Conard, P. D. Jr.; Paul E. F.;

Jeffrey, J. H.; William, K. H.; Karen, A. B.; Gilbert, O. C.; Amy, L. Kissinger.;

Bonnie, M. A. J. Med. Chem. 1992, 35 (21), 3745.

30. Davies, l. W.; Marcoux, Jean F.; Corley, E. G.; Journet, M.; Cai Dong, W.;

Palucki, M.; Wu Jimmy, R. D.; Larson Kai, R.; Pye Philip, J.; Di Michele, L.;

Peter Dorner; Paul, J. Reider. J. Org. Chem. 2000, 65 (5), 8415.

82

31. (a) Harry, H. Wasserman.; Dennis, J. H.; Temper, A. W.; James, S. W. J.

Org. Chem. 1981, 46 (15), 2999. (b) Nacci, V.; Fironi, I.; Garofalo, A.; Cagnotto,

Alfrendo. Farmaco. 1990, 45 (5), 545. (Chem. Abstr. 1990, 114:42752)

83

CHAPTER – III

STUDIES ON SYNTHESIS OF

“OXAZOLO OXAZINES”

3.1 Introduction:

Oxazolooaxzines were not very well documented in literature. Survey of literature

shows that not much work seems to have been done i.e. hexahydrooxazolo[2,3-

c][1,4]oxazine (29) as byproduct was reported by Jean-Charless Quirion, David S.

Grierson et. al. in Tetrahedron Letters.1

N

O

Ph

HO

O

N

O

Ph

O

OH

(29)

Compound (29) was prepared by condensation of phenylglycinol with

glutaraldehyde to give piperidine intermediate which was reacted with second molecule

of glutaraldehyde to give compound 29. (Equation – 3.1)

84

N O

Ph

NH2

PhOH

CHO CHO

+

CHO CHO

N

O

Ph

O

OH

(30)

(31) (32) (29)

Equation – 3.1

Apart from above another oxazolooxazine (33) was reported by Kukharev, B. F.

Stankevich, V. K. et. al. in Arkivoc (it’s an online journal), 2003.2

It was prepared by the

condensation of N-(2-hydroxybenzylidine)-1,2-aminoethanol (34) with

paraformaldehyde. Equation – 3.2

N

O

O

(33)

N

OH

OHNHO

OH + CH2O

N

O

O(34) (35) (33)

Equation – 3.2

3.2 Present Work:

The survey of literature revealed that synthesis of oxazolo oxazines is a

difficult task to accomplish. Therefore, it was considered worth while to attempt the

synthesis of new compounds containing oxazolooxazines. It is conceivable that the

oxazolo moieties can be synthesized from 2-nitrophenol on reaction with ethyl 2-bromo-

2-alkyl/aryl and followed by ring closure in the presence of 10 % palladium carbon and

hydrogen under pressure to obtain benzooxazines in the first step. These benzooxazines

can be used as building blocks for the synthesis of fused oxazolo ring units.

3.3 Results and Discussion:

85

Commercially available o-nitrophenol (36a i.e. R = R1 = H) was treated with

ethyl 2-bromoacetate in the presence of potassium carbonate to obtain ethyl 2(2-nitro

phenoxy) acetate (37a, i.e. R = R1 = H) in quantitative yield (Equation 3.2). Compound

37a is a compound known in literature.3 However, it was further characterized in the

present work by its spectral and analytical data. Thus, its IR (neat) spectrum showed (Fig

3.1) the absence of any peak above 3000 cm-1

indicating the disappearance of –OH group

of starting material. Further, the IR showed a peak at 1737 cm-1

assignable to ester

carbonyl stretching in the product 37a. It’s 1H NMR (in CDCl3) showed signals (Fig 3.2)

at δ 7.84 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.7 Hz, 2H), O – CH2 at

4.77 (s, 2H), 4.28 – 4.18 (q, J = 7.3 Hz, 2H, -CH2CH3-), 1.25 (t, J = 7.3 Hz, 3H, -

CH2CH3-). Its mass spectrum (Fig 3.3) showed peaks at m/z 266 (M+1

, 100%) and other

peaks at m/z 179 (10 %), 152 (10 %) etc.

The above reaction of 36a with ethyl 2-bromoacetate has been found to be a

general and has been extended to other phenols 37b-e and the products obtained have

been assigned structures 37b-e on the basis of their spectral and analytical data (Table

3.1).

NO2

OH

NO2

OCH2CO2EtR Rethyl bromoacetate,

K2CO3, DMF, 80 °C, 4 h(36a - e) (37 a -e)

R1R1

Equation – 3.3

85

Table –3.1: Synthesis of 37 (b-e) from 36 (b-e) and their spectral data.

S. No. R R1 Yield Spectral Data: 1

H NMR (200 MHz, CDCl3); IR

(KBr / Neat) / cm-1

.

37b F H 93.0 % IR (Neat): Absence of any absorption due to –OH

group and a strong band at 1748 cm-1

due to ester

carbonyl stretching; 1H NMR (CDCl3, 200 MHz): δ

8.01 – 7.94 (dd, J = 5.8 and 8.8 Hz, 1H), 6.84 – 6.75

(ddd, J = 2.44, 7.33 and 11.24 Hz, 1H), 6.71 – 6.55

(dd, J = 2.45 – 9.77 Hz, 1H), 4.76 (s, 2H), 4.33 – 4.22

(q, J = 7.32 Hz, 2H), 1.33 – 1.25 (t, J = 7.32 Hz, 3H);

Mass: m/z 244 (M+

+1, 100 %), 170 (30 %).

37c Me H 92.0 % IR (Neat): Absence of any absorption due to –OH


due to ester


7.81 (d, J = 7.82 Hz, 1H), 6.88 (d, J = 8.30 Hz, 1H),

6.77 (s, 1H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.32 Hz,

2H), 2.39 (s, 3H), 1.32 – 1.24 (t, J = 7.32 Hz, 3H);

Mass: m/z 240 (M+

+1, 100 %), 166 (40 %).

37d H Me 91.0 % IR (Neat): Absence of any absorption due to –OH


due to ester


7.67 (s, 1H), 7.32 (d, J = 8.79 Hz, 1H), 6.91 (d, J =

8.31 Hz, 1H), 4.74 (s, 2H), 4.31 – 4.22 (q, J = 7.32

Hz, 2H), 2.35 (s, 3H), 1.28 (t, J = 7.3 2Hz, 3H);

Maas: m/z 240 (M+

+1, 100 %), 166 (30 %).

37e MeS H 87.0 % IR (Neat): Absence of any absorption due to –OH


due to ester


86

7.88 (d, J = 8.31 Hz, 1H), 6.88 (d, J = 8.31 Hz, 1H),

6.75 (s, 3H), 4.75 (s, 2H), 4.32 – 4.21 (q, J = 7.33 Hz,

2H), 2.50 (s, 3H), 1.32 – 1.25 (t, J = 7.33 Hz, 3H);

Maas: m/z 272 (M+

+1, 100 %), 266 (40 %), 197 (20

%) etc.

87

The compound 37e, referred in Table 3.1, above is not known in literature. It was

needed in the present work and it was prepared as follows:- Commercially available 3-

fluro-5-nitro phenol (36b, i.e. R = F, R1 = H), was reacted with sodium thiomethoxide in

HMPA to give 5-methylsulfanyl-2-nitrophenol (36e). Structure of 36e was confirmed by

spectral and analytical data. Thus, its IR (KBr) showed a band at 3419 cm-1

indicating

the presence of a hydroxy group. Its 1H NMR (in CDCl3) showed signals at δ 10.89 (s,

1H, D2O exchangeable), 8.00 – 7.84 (dd, J = 2.44 and 8.79 Hz, 1H), 6.86 – 6.76 (m, 2H),

2.53 (s, 3H). Its mass spectrum showed peaks at m/z 186 (M+1

, 100 %). Compound 36e

was reacted with ethyl 2-bromoacetate in the presence of potassium carbonate to yield

37e as a yellow solid. (Equation – 3.4)

NO2

OHF

NO2

OH

NO2

OCH2CO2Et

MeS

MeS

NaSMe

HMPA, r.t, 5 h

ethylbromoacetate,

K2CO3, DMF, 80 oC,

4.0 h

(36b) (36e)

(37e)

Equation – 3.4

Reduction of 37a (i.e. R = R1 = H) with iron powder in acetic acid

4 gave 3-oxo,

2H 1,4-benzoxazine (38a i.e. R = R1 = H) in 63 % yield. This compound could also be

prepared from 37a by reduction with hydrogen in the presence of 10 % palladium carbon5

in 72 % yield. The structure of 38a was confirmed from its analytical and spectral data.

Thus, its IR (KBr) showed (Fig 3.4) peak at 1704 cm-1

due to the amide carbonyl

stretching vibration as distinct from the absorption at 1756 cm-1

in 37a due to the ester

carbonyl function. The –NH- stretching vibration of the product appeared at 3430 cm-1

.

Its 1H NMR (in CDCl3) showed signals (Fig 3.5) at δ 9.6 (s, 1H, D2O Exchangeable,

88

NH), 6.98 - 6.89 (m, 4H, Ar - H), 4.6 (s, 2H, O – CH2). Its mass spectrum (Fig 3.6)

showed peaks at 151 (M+1

, 20 %), 150 (M+, 100 %). (Equation – 3.5)

NO2

OCH2CO2Et

NH

O

O

Fe / AcOH

10 % Pd /CH2 Pressure

(36)(38)

R

R1

R

R1

Equation – 3.5

The formation of 38a from 37a is probably due to the reduction of the nitro group to

amino group followed by intramoleculor cyclization leading to cyclic amide formation

with the alcohol moiety as shown below.

NO2

OCH2CO2Et

NH

O

O(37)

(38)

R

R1

R

R1NH2

OCH2CO2Et

(37l)

R

R1

Equation – 3.6

In the above reaction involving formation of 38 from 37, 37l is an intermediate.

89

Table – 3.2 Syntheses of 37 (b-e) from 38 (b-e) and their spectral data:

Sub. Pdt R R1 Yield (%) Spectral Data: 1

H NMR (200 MHz, CDCl3); IR

(KBr / Neat) / cm-1

.

37b 38b F H 65.0 IR (KBr): 3429 cm-1

(amide –NH- stretching) 1694

cm-1

(amide carbonyl stretching); 1H NMR (in DMSO

d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 -

6.76 (m, 4H, Ar - H), 4.56 (s, 2H, O – CH2); Mass: m/z

(M+1

, 20 %), 168 (M+

+1, 100 %).

37c 38c Me H 59.0 IR (KBr): 3043 cm-1


cm-1


d6) δ 10.52 (s, 1H, D2O Exchangeable, NH), 6.73 (s,

3H, Ar - H), 4.49 (s, 2H, O – CH2), 2.18 (s, 3H,

ArCH3; Mass: m/z (M+1

, 20 %), 164 (M+, 100 %).

37d 38d H Me 57.0 IR (KBr): 3436 cm-1


cm-1


d6) δ 10.61 (s, 1H, D2O Exchangeable, NH), 6.81 (m,

1H, Ar - H), 6.77 – 6.66 (m, 2H, Ar - H), 4.47 (s, 2H,

O – CH2), 2.18 (s, 3H, ArCH3; Mass: m/z 164 (M+1

,

100 %), 163 (M+, 50 %).

37e 38e SMe H 53.0 IR (KBr): 3455 cm-1


cm-1


d6) δ 10.69 (s, 1H, D2O Exchangeable, NH), 6.87 –

6.84 (m, 3H, Ar - H), 4.55 (s, 2H, O – CH2), 2.42 (s,

3H, ArCH3; Mass: m/z 196 (M+

+1,100 %), 195 (M+,

60 %).

90

Apart from compounds 38a – e, compound 38f, an additional derivative in the

present series, was prepared from compound 38e by oxidation of sulfanyl group with

oxone reagent. It is versatile oxidizing agent used for oxidizing sulfanyl to sulfonyl

groups and used in place of hydrogen peroxide in acetone – water solution. (Equation

– 3.7) The structure of 38f was confirmed from its analytical and spectral data. Thus, its

IR (KBr) showed diagnostic peak at 1697 cm-1

due to amide carbonyl stretching and

twin peaks at 1299 cm-1

due to sulfonyl group. Its 1H NMR (in DMSO d6) signals

showed at δ 11.14 (s, 1H, D2O Exchangeable, NH), 7.53 – 7.48 (dd, J = 1.47 and 8.30

Hz, 1H, ArH), 7.45 (s, 1H, ArH), 7.07 (d, J = 7.91 Hz, 1H), 4.69 (s, 2H, O – CH2), 3.1

(s, 3H, SCH3). Its mass spectrum showed peaks at m/z 228 (M+, 100 %).

Oxone, acetone

methanol, r.t, 3.0 h

(38e) (38f)

NH

O

O

S

NH

O

O

SO

O

Equation – 3.7

Another intermediate 38g required in the present work, was prepared from

commercially available 2-amino-5-nitrophenol (39) by reacting it with chloroacetyl

chloride in the presence of triethylamine in dichloromethane yielding N1-(2-hydroxy-4-

nitrophenyl)-2-chloroacetamide (40) followed by cyclization with aq.

sodiumhydroxide in the presence of catalytic amount of tetrabutyl ammonium hydrogen

sulfate (TBAHS) giving 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-one (38g).

(Equation – 3.7) The structure of 38g is supported by its analytical and spectral data.

Thus, its IR (KBr) showed diagnostic amide carbonyl band at 1696 cm-1

. Its 1H NMR

(in DMSO d6) showed signals at δ 11.34 (s, 1H, D2O Exchangeable, NH), 7.93 – 7.87

(dd, J = 1.96 and 8.79 Hz, 1H, ArH), 7.76 (s, 1H, ArH), 7.06 (d, J = 8.30 Hz, 1H), 4.73

(s, 2H, O – CH2). Its mass spectrum showed peaks at m/z 195 (M+, 100 %).

91

O2N OH

NH2

O2N OH

NCl

O

H

ClCH2COCl

Et3N, CH2Cl2 r.t 6.0 h

aq. NaOH, TBAHS

CH2Cl2 r.t, 2.0 h

(40)

(38g)

(39)

NH

O

O

O2N

Equation – 3.7

The compound 38a was treated with ethyl 2-bromoacetate in the presence of

potassium carbonate6 in DMF at 80

°C. Processing of the reaction mixture gave a product

which was found to be 3,4 dihydro-3-oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester

(41a, i.e. 341, R = R = H) (Equation – 3.9). 41a had been characterized by spectral and

analytical methods. Thus, its IR (KBr) spectrum showed no absorption above 3000 cm-1

indicating absence of –NH- group. However, IR spectrum showed (Fig 3.7) two

diagnostic sharp strong bands, one at 1739 cm-1

(ester carbonyl stretching) and 1681 cm-1

(amide carbonyl stretching). Its 1H NMR (CDCl3, 200 MHz): showed signals (Fig 3.8) at

δ 7.02 – 7.01 (m, 3H, Ar - H), 6.77 – 6.73 (m, 1H, Ar - H), 4.67(s, 2H, O- CH2 - CO),

4.65 (s, 2H, N – CH2), 4.29 – 4.19 (q, J = 7.1 Hz, 2H, O – CH2 – CH3),1.31 – 1.24 (t, J =

7.1 Hz, 3H, O – CH2 – CH3). Its mass spectrum (Fig 3.9) showed peaks at m/z 236 (M+

+1, 100 %) and at 190 (10 %) when recorded in the Q+1 mode

N

O

O

O

OEt

K2CO3, BrCHCO2Et

DMF 80 °C, 12.0 hrs

(38) (41)

R1

R

NH

O

OR1

R

Equation – 3.9

6 or 7 substituted 3,4-dihydro-3oxo-2H-1,4-benzoxazine –4-acetic acid ethyl esters could

also be prepared using the above method. Apart from 41a – g, 41h was synthesized by

the reduction of nitro group of 41g with sodium borohydride in the presence of nickel (II)

92

chloride (to enhance speed of the reaction) in methanol leading to 7-nitro-3,4 dihydro-3-

oxo-2H-1,4-benzoxazine –4-acetic acid ethyl ester (41h) (Equation – 3.10).

N

OO2N

O

OEt

O

N

OH2N

O

OEt

O

NaBH4, NiCl2

MeOH, r.t 4.0 h

(41g)(41h)

Equation – 3.10

Structures of all products (41a – h) were assigned based on spectral and analytical data

(Table 3.3).

93

Table – 3.3: Synthesis of 41from 38 by alkylation.

Sub. Pdt. R R1 R

2 Yield (%) Spectral Data: 1

HNMR (200 MHz,

CDCl3); IR (KBr/Neat)/cm-1

.

38b 41b F H H 74.0 IR (KBr): 1741 cm-1

(ester carbonyl

stretching) and 1688 cm-1

(amide carbonyl

stretching); 1H NMR (CDCl3, 200 MHz): δ

6.78 – 6.64 (s, 3H), 4.68 (s, 2H), 4.63 (s, 2H),

4.29 – 4.19 (q, J = 7.25 Hz, 2H),1.31 – 1.24

(t, J = 7.25 Hz, 3H); Mass: m/z 254 (M+

+1,

100 %), 152 (30 %). Elemental Analysis:

Mol. F: C12H12NO4F, Cal. C: 56.900, H:

4.779, N: 5.533; Experimental, C: 56.551, H:

4.940, N: 5.403.

38c 41c Me H H 74.0 IR (KBr): 1744 cm-1

(ester carbonyl


(amide carbonyl


6.82 – 6.77 (m, 2H), 6.64 – 6.60 (d, J = 7.82

Hz, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 4.27 –

4.17 (q, J = 7.32 Hz, 2H), 2.27 (s, 3H), 1.33 –

1.26 (t, J = 7.32 Hz, 3H); Mass: m/z 250 (M+

+1, 100 %), 249 (M+, 75 %), 204 (40 %), 148

(40 %).

38d 41d H Me H 72.0 IR (KBr): 1742 cm-1

(ester carbonyl


(amide carbonyl


6.89 (d, J = 8.30 Hz, 1H), 6.80 (d, J = 8.30

Hz, 1H), 6.53 (s, 1H), 4.62 (s, 4H), 4.30 –

4.19 (q, J = 7.33 Hz, 2H), 2.29 (s, 3H), 1.31 –

1.24 (t, J = 7.33 Hz, 3H); Mass: m/z 250

94

(M+1

, 100 %), 204 (40 %), 176 (50 %), 148

(80 %).

38e 41e SMe H H 69.0 IR (KBr): 1739 cm-1

(ester carbonyl


(amide carbonyl

stretching); 1H NMR (DMSO d6, 200 MHz):

δ 7.00 – 6.99 (m, 3H), 4.70 (s, 4H), 4.16 –

4.13(q, J = 7.32 Hz, 2H), 2.45 (s, 3H), 1.24 –

1.17 (t, J = 7.32 Hz, 3H); Mass: m/z 282

(M+1

, 100 %), 281 (M+1

, 80 %), 236 (30 %),

180 (30 %).

38f 41f SO2Me H H 76.0 IR (KBr): 1747 cm-1

(ester carbonyl


(amide carbonyl


δ 7.60 – 7.55 (m, 2H), 7.35 (d, J = 8.30 Hz,

1H), 4.85 (s, 2H), 4.80 (s, 2H), 4.22 – 4.11

(q, J = 7.33 Hz, 2H), 3.22 (s, 3H), 1.25 – 1.18

(t, J = 7.32 Hz, 3H); Mass: m/z 314 (M+

+1,

100 %), 212 (30 %).

38g 41g NO2 H H 75.0 IR (KBr): 1736 cm-1

(ester carbonyl


(amide carbonyl


δ 7.96 (d, J = 1.95 Hz, 1H, Ar - H), 7.90 (d, J

= 1.96 Hz, 1H), 6.84 (d, J = 8.79 Hz, 1H),

4.78 (s, 2H), 4.71 (s, 2H), 4.32 – 4.21 (q, J =

7.33 Hz, 2H), 1.30 (t, J = 7.32 Hz, 3H); Mass:

m/z 281 (M+

+1, 100 %), 179 (30 %).

38g 41h NH2 H H IR (KBr): 1744 cm-1

(ester carbonyl


(amide carbonyl


95

δ 6.56 – 6.52 (d, J = 8.30 Hz, 1H), 6.36 – 6.28

(m, 2H), 4.61 (s, 2H), 4.58 (s, 2H), 4.27 –

4.17 (q, J = 7.33 Hz, 2H), 1.30 – 1.23 (t, J =

7.32 Hz, 3H); Mass: m/z 251 (M+

+1, 100 %),

177 (25 %) .

38a 41i H H Et IR (KBr): 1740 cm-1

(ester carbonyl


(amide carbonyl


7.07 – 6.90 (m, 3H), 6.87 – 6.80 (m, 1H), 5.37

– 5.29 (dd, J = 5.37 & 9.94 Hz, 1H), 4.72 –

4.53 (dd, 15.04 & 21.21 Hz, 2H), 4.28 – 4.12

(m, 2H), 2.37 – 2.19 (m, 1H), 2.17 – 1.91 (m,

1H), 1.23 – 1.16 (t, J = 7.25 Hz, 3H), 0.93 –

0.86 (t, J = 7.52 Hz, 3H); Mass: m/z 264 (M+

+1, 100 %).

38a 41j H H Pr IR (KBr): 1740 cm-1

(ester carbonyl


(amide carbonyl


7.07 – 6.90 (m, 3H, Ar H ), 6.87 – 6.80 (m,

1H, Ar H), 5.37 – 5.34 (dd, J = 5.37 & 9.94

Hz, 1H, NCH), 4.72 – 4.53 (dd, 15.04 &

21.21 Hz, 2H, OCH2CO), 4.28 – 4.12 (m, 2H,

OCH2CH3), 2.37 –1.91 (m, 2H,

NCHCH2CH2), 1.3 (t, J = 7.52 Hz, 2H,

NCHCH2CH2), 1.23 – 1.21 (t, J = 7.25 Hz,

3H, OCH2CH3), 0.98 – 0.88 (t, J = 7.52 Hz,

3H, NCHCH2CH2CH3); Mass: m/z 278 (M+

+1, 100 %).

38a 41l H H Ph 58.0 IR (KBr): 1746 cm-1

(ester carbonyl

96

stretching) and 1681cm-1

(amide carbonyl


7.36 – 7.31 (m, 5H, Ar H), 7.03 – 6.92 (m,

2H, Ar H), 6.80 – 6.70 (m, 2H, Ar H), 6.40 (s,

1H, Benzylic H), 4.76 (dd, J = 15.04 & 19.87

Hz, 2H, OCH2CO), 4.33 – 4.17 (m, 2H, OCH2

CH3), 1.19 (t, J = 7.2 Hz, 3H, OCH2 CH3);

Mass: m/z 312 (M+

+1, 100 %).

38a 41m H H Ar 71.0 IR (KBr): 1744 cm-1

(ester carbonyl

stretching) and 1691cm-1

(amide carbonyl


7.31 (d, J = 8.60 Hz, 2H, Ar H), 6.98 (d, J =

8.00 Hz, 2H, Ar H), 6.91 – 6.80 (m, 4H, Ar

H), 6.31 (s, 1H, Benzylic H), 4.79 – 4.61 (dd,

J = 15.05 & 20.95 Hz, 2H, OCH2 CO), 4.29 –

4.19 (m, 2H, OCH2 CH3), 3.78 (s, 3H), 1.19

(t, J = 7.3 Hz, 3H, OCH2 CH3); Mass: m/z

342 (M+

+1, 10 %) and 193 (100 %).

Ar = 4-methoxy phenyl

97


Treatment of 41a (41, R = R1 = H) with 1.1 eq. of LAH in THF followed by usual

workup gave a product as syrupy liquid. The compound was found to be homogenous on

TLC and different from the starting material. Its IR spectrum (Neat) did not show any

diagnostic peaks due to the presence of –NH- and -CO- groups (Fig 3.10). Its 1H NMR

(in CDCl3) showed signals (Fig 3.11) at δ 6.98 – 6.88 (m, 2H, Ar - H), 6.79 – 6.72 (m,

2H, Ar - H), 4.89 – 4.84 (dd, J= 3.42 and 6.84 Hz, 1H, O CH), 4.44 – 4.37 (dd, J= 2.93

and 10.75 Hz, 1H, OCH2), 4.14 – 3.94 (m, 2H, O CH2 & N CH2), 3.74 – 3.56 (m, 2H, O

CH2 & N CH2), 3.50 – 3.42 (m, 1H, O CH2). Its mass spectrum (Fig 3.12) showed

molecular ion peak at m/z 178 (M+

+1, 100 %). Elemental Analysis: Mol. F: C10H11NO2,

Cal. C: 67.766, H: 6.261, N: 7.908; Experimental, C: 67.763, H: 6.694, N: 8.179. Based

on this data, the product was assigned as 1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-

d][1,4]oxazine (42a). (Equation – 3.11)

N

O

O N

O

O

OEtO

LAH

THF, 0 - r.t1.0 hr

R

R1 R1

R

(41) (42)

R2 R2

Equation – 3.11

It is noteworthy that the product expected from LAH reduction in the above

reaction was 43, which however, did not form. (Equation – 3.12)

N

O

O N

O

O

OEtOH

LAH

THF, 0 - r.t1.0 min(41a)

(43)

Equation – 3.12

The above reaction (Equation – 3.11) of 41a yielding 42a is general one. It has

been extended to other N-substituted benzoxazinones (41) yielding (42). Structures of all

98

these compounds have assigned on analogy and on the basis of spectral and analytical

data (Table 3.4).

Structure confirmation: To confirm the structure of the compound 42 further

especially its stereochemistry, single crystal X-ray diffraction study was carried out.7

For

single crystal X-ray diffraction study to be carried out, it is essential that the compound

should be solid crystalline substance. Since the product 42a obtained in the present study

was a syrupy liquid and other analogs also had low melting points, compound 42a was

nitrated hoping that the resulting derivative 44a would be a solid amenable for X-ray

studies. Nitration of 42a with nitric acid in acetic anhydride yielded 7-nitro-1,2,3a,4-

tetrahydrobenzo[b][1,3]oxazolo[3,2-d][1,4]oxazine (44). (Equation – 3.13)

N

O

O N

O

O

O2N

(42a) (44)

HNO3

Ac2O

Equation –3.13

N

O

O

O2N

Ha

Ha

Hb

Ha

Hb

H

187

64

213

5

10

9

Hb

11

12

3

(44)

Thus, its IR (KBr) spectrum (Fig. 3.13) showed the absence of any diagnostic

peaks due to –NH- and -CO- groups. Its 1H NMR (CDCl3, 200 MHz) showed signals

(Fig. 3.14) at δ 7.89 – 7.84 (dd, J = 8.8 and 2.4 Hz, 1H, ArH), 7.77 (d, J = 2.4 Hz, 1H,

ArH), 6.56 (d, J = 8.8 Hz, 1H, ArH), 4.92 – 4.86 (dd, J = 8.4 and 3.4 Hz, 1H), 4.63 – 4.56

(dd, J = 10.0 and 4.0 Hz, 1H), 4.35 – 4.25 (dd, J = 9.0 and 3.2 Hz, 1H), 4.15– 4.03 (dt, J

= 6.4 and 8.8 Hz, 1H), 3.75 – 3.70 (m, 1H), 3.56 – 3.30 (m, 2H). The data of 400 MHz

1H NMR depicted in Table – 3.4. Carbon 13 and COSY data is also shown in Table 3.4.

99

The mass spectrum of 44 showed the molecular ion peak at 223 (M+1

, 100 %) in Q+1

mode.

In the steady state 1D nOe experiment on irradiating the C-8 proton at 6.57 ppm.

The spectrum showed enhancement of signals at 3.72 and 3.49 ppm corresponding to C-

11 Ha and Hb protons respectively. With this information, the position of the aromatic C-

8 proton was fixed at 6.57 ppm. The splitting of C-8 proton is doublet due to C-7 proton

coupling. Hence the position of Nitro group is fixed at C-6. NMR assignments of (44)

are listed in the following page

Table 3.4: The NMR assignments of (44)

Position 1H δδδδ (ppm) J (Hz)

# COSY

(Fig. 3.17)

13C

(Fig. 3.15)

DEPT

(Fig. 3.16)

2 1H 4.88 dd, 8.4, 4.4 (3Ha, 3.36)

(3Hb, 4.61)

82.34 CH

3 Ha 3.36 dd, 10.0, 8.4 (2H, 4.88) 65.70 CH2

Hb 4.61 dd, 10.0, 4.4 (2H, 4.88)

5 1H 7.78 d, 2.4 112.13 CH

6 138.19

7 1H 7.87 dd, 8.8, 2.4 (8H, 6.57) 119.82 CH

8 1H 6.57 d, 8.8 (7H, 7.87) 111.07 CH

9 139.11

10 141.58

11 Ha 3.49 dt, 7.6, 8.8 (12Ha, 4.12)

(12Hb, 4.32)

(11Hb, 3.72)

46.73 CH2

100

Hb 3.72 ddd, 7.6,6.4,2.8 (12Ha, 4.12)

(12Hb, 4.32)

(11Hb, 3.49)

12 Ha 4.12 dt, 6.4, 8.8 (11Ha, 3.49)

(11Hb, 3.72)

(12Hb, 4.32)

65.92 CH2

Hb 4.32 ddd, 7.6,6.4,2.8 (11Ha, 3.49)

(11Hb, 3.72)

(12Hb, 4.12)

The possible major fragments produced in the e.i mass spectrum (Fig.

3.20) of 44 are shown below:-

N

O

O

O2N

m/z = 223

N

O

O

m/z = 177

N O

O2N

m/z = 206

+

(45) (46) (47)

Melting point (150 °C) was confirmed by thermal analysis (Fig. 3.21)

Single crystal X-ray diffraction study: Single Crystal suitable for X-ray

diffraction have been grown from the recrystallisation of 44 in the mixture of solvents

such as ethyl acetate and petroleum ether. The compound crystallizes as yellow flakes in

monoclinic space group P21/c with cell dimensions a = 12.164 (2), b = 22.079 (2), c =

7.374 (2), β = 100.82 (2) A0 and V = 1945.2

0 (6), Z = 8. There are independent

molecules in the asymmetric unit. Molecule –A adopted envelope conformation while

molecule-B assumed half chair conformation. The molecules inside the lattice are

stabilized by Van der wall interactions. The intensity data was collected on Rigaku AFC-

7S single crystal diffractometer using Cu Kα (λ = 1.5405 A0). The structure has been

solved with direct methods and refined using the TEXSAN software. The final R factors

are: R (Rw) = 0.067 (0.076) with 2683 observed reflections (I>1.50\σ(I)). All the bond

101

parameters were normal. The results from the various physicochemical techniques

confirm the molecular structure.

Crystal Photograph of Compound 44

102

Crystal Structure of Compound 44

103

Table – 3.4 Synthesis of 41 (a-i) from 42 (a-i) by reduction with LAH:

Sub Pdt R R1 R

2 Yield (%) Spectral Data : 1

H NMR (200 MHz,

CDCl3); IR (KBr / Neat) / cm-1

.

41b 42b F H H 99.0

IR: Did not show any diagnostic peaks

due to –NH- and -CO- groups. 1H

NMR: δ 6.76 – 6.60 (m, 3H), 4.85 –

4.80 (dd, J= 3 and 6 Hz, 1H), 4.38 –

4.31 (dd, J= 3 and 11 Hz, 1H), 4.07 –

3.90 (m, 2H), 3.75 – 4.60 (m, 2H), 3.49

– 3.34 (m, 1H); MS: m/z 196 (M+ +1,

100 %), 195 (80%). Elemental

Analysis: Mol. F: C10H10FNO2, Cal. C:

61.517, H: 5.166, N: 7.179;

Experimental, C: 60.221, H: 5.468, N:

6.924.

41d 42d Me H H 86.0


due to –NH- and -CO- groups; 1H

NMR: δ 6.71 – 6.49 (m, 3H), 4.85 –

4.81 (dd, J= 3 and 6 Hz, 1H), 4.40 –

4.29 (dd, J= 2.9 and 11 Hz, 1H), 4.02 –

3.88 (m, 3H), 3.69 – 3.59 (m, 1H), 3.46

– 3.45 (m, 1H), 2.23 (s, 3H); MS: m/z

192 (M+ +1, 95 %), 191 (M

+, 100 %).

41e 42e H Me H 94.0



NMR: δ 6.74 (d, J = 7.8 Hz, 1H), 6.56

– 6.52 (m, 2H), 4.85 – 4.78 (dd, J= 3

and 7 Hz, 1H), 4.38 – 4.31 (dd, J= 2.9

and 11 Hz, 1H), 4.08 – 3.90 (m, 2H),

104

3.69 – 3.52 (m, 2H), 3.46 – 3.34 (m,

1H), 2.26 (s, 3H); MS: m/z 192 (M+ +1,

95 %), 191 (M+, 100 %).

41f 42f SMe H H 99.0



NMR: δ 6.93 – 6.88 (m, 2H), 6.71 –

6.67 (m, 1H), 4.85 – 4.81 (dd, J= 3 and

8 Hz, 1H), 4.40 – 4.34 (dd, J= 3.0 and

11 Hz, 1H), 4.13 – 3.91 (m, 2H), 3.70 –

3.55 (m, 2H), 3.45 – 3.37(m, 1H), 2.41

(s, 3H); MS: (m/z) 224 (M+ +1, 80 %),

223 (M+, 100 %).

41g 42g SO2Me H H 39.0 IR: Did not show any diagnostic peaks


NMR: δ 7.45 – 7.40 (dd, J = 1.9 & 8.4

Hz, 1H), 7.36 – 7.35 (d, J = 1.9 Hz, 1H),

6.65 – 6.61 (d, J = 8.4 Hz, 1H), 4.83 –

4.77 (dd, J = 3.8 & 8.0 Hz, 1H), 4.55 –

4.48 (dd, J = 4 & 10 HZ, 1H), 4.21 –

4.16 (m,1H), 4.08 – 4.00 (m, 1H), 3.67 –

3.61 (m, 1H), 3.44 – 3.24 (m, 2H), 2.94

(s, 3H); MS: m/z 256 (M+ +1, 100 %).

41j 42j H H Et 45 IR: Did not show any diagnostic peaks


NMR (CDCl3, 200 MHz): δ 6.95 – 6.71

(m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.69

& 4.88 Hz, 1H), 4.35 – 4.28 (dd, J =

2.68 and 11.23 Hz, 1H), 4.10 – 4.03 (dd,

J = 6.35 and 7.57 Hz, 1H), 3.91 – 3.83

105

(dd, J = 5.12 and 11.47 Hz, 1H), 3.76 –

3.70 (dd, J = 4.39 & 6.59 Hz, 1H), 3.69

– 3.59 (dd, J = 4.15 and 7.81 Hz, 1H),

1.87 – 1.76 (m, 1H), 1.71 – 1.57 (m,

1H), 1.11 – 1.04 (t, J = 7.33 Hz, 3H);

MS: m/z 206 (M+ +1,100 %), 136 (10

%).

41k 42k H H Pr 42 IR: Did not show any diagnostic peaks


NMR (CDCl3, 200 MHz): δ 6.96 – 6.71

(m, 4H, Ar H), 4.92 – 4.88 (dd, J = 2.68

& 4.88 Hz, 1H), 4.35 – 4.28 (dd, J =

2.68 and 11.48 Hz, 1H), 4.10 – 4.02 (dd,

J = 7.24 and 11.48 Hz, 1H), 3.93 –

3.85(dd, J = 4.88 and 11.48Hz, 1H),

3.82 – 3.73 (m, 1H), 3.63 – 3.57 (dd, J =

4.15 and 7.81 Hz, 1H), 1.82 – 1.70 (m,

1H), 1.59 – 1.41 (m, 3H), 1.07 – 1.00 (t,

J = 7.33 Hz, 3H); MS: m/z 206 (M+

+1,100 %), 136 (10 %).

41l 42l H H Ph 48 IR: Did not show any diagnostic peaks


NMR (CDCl3, 200 MHz): δ 7.42 – 7.32

(m, 5H, Ar H), 6.96 – 6.91 (dd, J = 1.88

& 6.25 Hz, 1H, Ar H), 6.81 – 6.67 (ddd,

J = 1.88, 6.98 & 9.13 Hz, 2H, Ar H),

6.50 – 6.45 (dd, J = 1.88 & 7.52 Hz, 1H,

Ar H), 5.25 – 5.19 (dd, J = 2.76 & 7.52

Hz, 1H, OCH2CHO), 4.73 (t, J = 7.26

106

Hz, 1H, N CH Ph), 4.56 – 4.47 (m, 2H,

O CH2CH), 3.79 (t, J = 8.06 Hz, 1H,

OCH2CHN), 3.61 – 3.52 (dd, J = 7.52 &

2.90 Hz, 1H, OCH2CHN); MS: m/z 254

(M+ +1,100 %). Elemental Analysis:

Mol. F: C16H15NO2, Cal. C: 75.856, H:

5.973, N: 5.532; Experimental, C:

75.721, H: 6.659, N: 5.258.

41m 42m H H Ar 39 IR: Did not show any diagnostic peaks

due to –NH- and -CO- groups; ; 1H

NMR (CDCl3, 200 MHz): δ 7.34 (d, J =

8.59 Hz, 2H, Ar H), 6.93 (d, J = 8.59

Hz, 2H, Ar H), 6.78 – 6.69 (ddd, J =

1.88, 7.52 & 9.67 Hz, 2H, Ar H), 6.51 –

6.47 (dd, J = 1.88 & 7.25 Hz, 1H, Ar H),

5.23 – 5.18 (dd, J = 3.76 & 7.52 Hz, 1H,

NCHO), 4.67 (t, J = 7.52 Hz, 1H,

Benzylic H), 4.55 - 4.42 (ddd, J = 4.03,

10.30 & 14.50 Hz, 2H, OCH2CHO),

3.82 (s, 3H, OCH3), 3.80 – 3.72 (dd, J =

6.17 & 8.05 Hz, 1H, CHCH2O), 3.59 –

3.50 (dd, J = 7.52 & 10.48 Hz, 1H,

CHCH2O); MS: m/z 284 (M+ +1,100

%), 151 (30%). Elemental Analysis:

Mol. F: C17H17NO3, Cal. C: 72.054, H:

6.051, N: 4.946; Experimental, C:

70.797, H: 5.763, N: 6.028.

Ar = 4-methoxy phenyl

108

It was considered desirable to study the effect of substitution on the cyclization

reaction yielding oxazolooxazines. All the compounds reported in Table 3.5 have

substitutions at 1, 7 and 8 positions. It would be interesting to study the course of

cyclization if there are substitutions with aryl moiety at position 3. Therefore,

preparation of 42j, which was needed in the present work, was carried out as follows:-

CO2MeBr

N

O

O

O

O

NO2

OH

NO2

O CO2Me

Ph

NH

O

O

Ph Ph

K2CO3, Acetone

60 °C, 12 hrs

10 % Pd /C

AcOH / H2gas

ethylbromoacetate,

K2CO3, DMF, r.t,

12 h

(37g)

(38i) (41j)

(36a)

N

O Ph

(42j)

O

LAH / THF

r.t, 60 min

Scheme – 3.1

Commercially available 2-nitrophenol (36a) was reacted with 4 in the presence of

potassium carbonate as base in acetone to give ethyl 2- (2-nitrophenoxy)-2 –

phenylacetate (37g), which was characterized by its spectral and analytical data. Thus, its

IR (Neat) showed a diagnostic peak at 1737 cm-1 due to ester carbonyl stretching. Its 1H

NMR (in CDCl3) showed signals at δ 7.91 – 7.86 (dd, J = 1.07 & 8.32 Hz, 2H, Ar H),

7.64 – 7.59 (m, 5H, Ar H), 7.52 – 7.38 (m, 4H), 7.08 (t, J = 7.79 Hz, 1H, Ar H), 6.98 (d, J

= 8.3 Hz, 1H, Ar H), 5.76 (s, 1H), 3.71 (s, 3H). Its mass spectrum showed peaks at 288

(M+, 20 %), 149 (M

-1, 100 %). 37g was cyclized in the presence of 10 % palladium

charcoal under hydrogen atmosphere in acetic acid to give 2-phenyl -3,4-dihydro-2H-

benzo[b][1,4]oxazin-3-one (38i). This was confirmed by analytical and spectral data.

Thus, its IR (KBr) showed peaks at 1681cm-1

indicating amide carbonyl stretching. Thus,

its 1H NMR (CDCl3) showed signals at δ 9.25 (bs, 1H, D2O exchangeable, NH), 7.45 –

7.43 (m, 2H), 7.35 – 7.32 (m, 3H), 7.04 – 6.91 (m, 3H), 6.89 – 6.78 (m, 1H), 5.69 (s, 1H).

Its mass spectrum showed the molecular ion peaks at m/z 226 (M+1

, 100 %) in Q+1

109

mode. The compound 38i was N- alkylated with ethyl 2-bromoacetate in the presence of

potassium carbonate as a base in DMF at room temperature to give 41j. The structure of

41j was assigned based on following spectral data. Thus, its IR (KBr) showed peaks at

1748 cm-1

indicating ester carbonyl stretching as diagnostic peak. Its 1H NMR (CDCl3)

showed signal at δ 7.45 – 7.42 (m, 2H, Ar H), 7.34 – 7.21 (m, 3H, Ar H), 6.96 – 6.91 (m,

3H, Ar H), 6.71 – 6.67 (m, 1H, Ar H), 5.74 (s, 1H, Benzylic H), 4.90 (d, J = 17.46 Hz,

1H, NCH2CO), 4.42 (d, J = 17.46 Hz, 1H, NCH2CO), 4.26 – 4.15 (q, J = 7.25 Hz, 2H,

OCH2CH3), 1.22 (t, J = 7.25 Hz, 3H, OCH2CH3). Its mass spectrum showed peaks at 312

(M+1

, 100 %), 311 (10 %) when spectrum used in the Q+1 mode. The compound 41j was

reduced with lithium aluminumhydride in THF followed by simple processing to obtain a

product as syrupy liquid. The compound was found to be homogenous on TLC. Its IR

spectrum (Neat) did not show any diagnostic peaks due to –NH- and -CO- groups. Its 1H

NMR (in CDCl3, 400 MHz) showed signals at δ 7.51 – 7.47 (m, 2H, ArH), 7.44 – 7.35

(m, 3H, ArH), 7.02 – 6.96 (dd, J = 7.80 and 12.55 Hz, 2H, ArH), 6.77 – 6.75 (d, J = 7.80

Hz, 2H, ArH), 4.72 – 4.70 (d, J = 7.32 Hz, 1H), 4.26 – 4.22 (m, 1H), 4.15 – 4.13 (d, J =

7.32 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.80 – 3.76 (m, 1H), 3.45 – 3.39 (m, 1H). Its mass

spectrum showed the molecular ion peak at m/z 254 (M+.

, 100 %). Based on this data, the

product was assigned as by 4-phenyl-1,2,3a,4-tetrahydrobenzo[b][1,3]oxazolo[3,2-

d][1,4]oxazine structure 42j. (Scheme – 3.1)

3.4 Experimental Section

i) Preparation of 37a-f (General procedure): To a suspension of 36 a-e (30 mmol) and

potassium carbonate (12.4 gms, 90.0 mmol) in dry dimethyl formamide (80 mL) was

added ethyl bromoacetate (4.0 mL, 36.0 mmol) at 25 °C and the mixture was stirred for

4.0 hrs at 80 °C. The reaction mixture was cooled to room temperature and water (200

mL) was added. The mixture was extracted with ethyl acetate (3 X 50 mL). The organic

layer was washed with water, dried over sodium sulfate and the solvent was evaporated

under reduced pressure yielding 37a-f. (Table-3.1)

110

ii) Preparation of 36f: To a solution of 5-fluoro-2-nitro phenol (40b) 5.0 g (31.80 mmol)

in HMPA (50 mL) was added sodium thiomethoxide (4.68 g, 66.87 mmol) at 25 °C and

the mixture was stirred for 12.0 hrs at room temperature. The reaction mixture was

poured into water (200 mL) acidified with cold 6N HCl (100 mL). The separated solid

was filtered washed with water and dried to obtain 36f. Yield = 5.6 gms (95 %).

iii) Preparation 38a: To a solution of 37a (5.0 gms, 22.22 mmol) in dioxane (60 mL)

was added 10 % palladium-carbon (1.0 g). The reaction mixture was stirred under 60 psi

of hydrogen pressure at room temperature for 6 hrs. The mixture was then filtered

through a bed of Celite and the bed was washed with dioxane. The combined filtrates

were concentrated under reduced pressure to give 38 a. Yield = 2.5 gms (75 %).

iv) Preparation of 38a – h (General procedure): To a solution of 37a - h in methanol

(10 mL / 1 gm) was added acetic acid (15 eq.) followed by iron powder (5.0 eq). Then

the reaction mixture was refluxed for 5 hrs at 80 °C. Solvent was removed from the

reaction mixture by distillation and the crude residue was neutralized with NaHCO3

solution. The mixture was extracted with ethyl acetate & combined organic layers were

washed with water. Finally, the organic layer was dried and concentrated under reduced

pressure to obtain 38 a-h. (Table-3.2)

v) Preparation of 38 g: To a solution of 38 f (2.5 gms, 12.82 mmol) in acetone (30 mL)

was added oxone (15.74 Gms, 25.6 mmol in 50 mL water) at 25 °C and the mixture was

stirred for 3.0 hrs at room temperature. Acetone was removed from the reaction mixture

by the distillation and residual water layer was diluted with more water. The separated

solid was filtered, washed and dried to obtain 38 g yield = 2.2 gms (76 %).

vi) Preparation of 38 h: To an ice cold solution of 2-amino-5-nitro-phenol (39) (10 g,

64.93 mmol), in dichloromethane (100 mL), was added triethylamine (18.0 mL, 129.86

mmol) followed by chloroacetylchloride (8.8 g, 77.92 mmol) at 0 °

C. The mixture was

111

stirred for 6 hrs at room temperature and then made basic (to pH = 14) with aqueous

sodium hydroxide solution. The resulting mixture was stirred for 6.0 hours at room

temperature and acidified with dil hydrochloric acid; the separated solid was filtered,

washed with ethanol and dried to obtain 38 h as brown solid. Yield = 6.0 gms (48 %).

vii) Preparation of 41a-g (General procedure): To a suspension of 38 a-g and

potassium carbonate (3.0 eq) in dry dimethyl formamide (10 mL / 1.0 gm) was added

ethyl bromoacetate (1.2 eq) at 25 °C and the mixture was stirred for 12.0 hrs at room

temperature. The reaction mixture was poured into cold water; the separated solid was

filtered, washed and then dried to obtain 41 a-g. (Table-3.3).

viii) Preparation of 41h: To a suspension of 41g (2.0 gms, 7.1 mmol) in methanol (40

mL) was added nickel chloride (5.06 gms, 21.3 mmol) at 0 °C and followed by pinch by

pinch of sodiumborohydride (1.08 gms, 28.57 mmol) at 0 °C. The reaction mixture was

stirred for 4 hrs at room temperature, then the solvent was removed from the mixture

under reduced pressure. Then the crude residue was dissolved in ethyl acetate, and

organic layer was washed with water dried and concentrated to give 41h.

ix) Preparation of 42a-h (General Procedure): To a solution of 41a-h (2.0 mmol) in


portions over a period of 20 min. and stirred for 1.0 hr at room temperature. The reaction


filtered and the filtrate concentrated. The crude residual product was purified by column

chromatography using ethyl acetate and pet. ether (5:95) to give 42a-h. (Table-3.4).

x) Preparation of 44: To an ice cold solution of 47a (6.0 g, 33.8 mmol) in acetic

anhydride (100 mL) was added fuming nitric acid (2.34 g, 37.18 mmol) drop wise at –5

°C, and the mixture was stirred for three hours at 0

°C. The reaction mixture was poured

in to crushed ice; the separated solid was filtered, washed with water and dried well. The

112

crude was purified through column chromatography using ethyl acetate & petroleum

ether to give 44 as yellowish crystalline solid, Yield: 1.5 g (44 %).

xi) Preparation of 37f: To a solution of 2-nitrophenol (36f) (4.0 g, 28.7 mmol) and

potassium carbonate (12.0 g) in acetone was added ethyl α-bromo phenylacetate (7.9 g,

34.5 mmol) at room temperature and the mixture was refluxed for 12.0 hrs. Then the

reaction mixture was filtered, washed with acetone and filtrate was concentrated under

reduced pressure. Crude residue was dissolved in ethyl acetate and washed with water.

Ethyl acetate layer was dried and concentrated under reduced pressure to give 37f in 82

% yield.

xii) Preparation of 38h: Palladium carbon (3.0 gm of 10 % ) was charged in 1000 mL

hydrogenation flask, made wet with acetic acid (50 mL) and to this 37f (15.0 gm, in150

mL of acetic acid) was added at room temperature. Then the flask was arranged for Parr

hydrogenation for 6.0 hrs at 60 psi H2 pressure. The reaction mixture was filtered

through a pad of Celite to remove palladium carbon and the filter bed washed with acetic

acid. The filtrate was stirred with 2000 mL of water and the separated white solid was

filtered, washed with water and dried to obtain 38h. (8.0 gms, 67 %)

xiii) Preparation of 41i: To a solution of 38h(1.0 gm, 4.42 mmol) and potassium

carbonate (1.8 gm, 13.2 mmol), in 20 mL of dry dimethylformamide was added ethyl

bromoacetate (0.6 mL, 5.3 mmol) drop wise at room temperature. After 12.0 hrs stirring

the mixture was poured in to water and the separated solid was filtered, washed with

water and dried to give 83 % of 41i.

xiv) Preparation of 42i: To a solution of 41i (2.0 mmol) in dry THF (10 mL) at 0 °C,

lithium aluminumhydride (2.2 mmol) was added in several portions over a period of 20

min. and stirred for 1.0 hr at room temperature. The reaction mixture was quenched with

aqueous sodium sulfate solution. The reaction mixture was filtered and the filtrate

113

concentrated. The crude product was purified by column chromatography using ethyl

acetate and pet. ether (5:95) to give 42i.

3.5 Reference:

01. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe

Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques Royer,

David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc. 1983, 105,

7754.

02. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A.

I. Arkivoc, 2003, xiii, 166.

03. (a) Sicker Dieter, Praetotius Birgitt, Mann Gerhard, Meyer Lutz.; Synthesis; 1989, 3,

211. (b) Atkinson, J. Morand Peter, Arnason John T, Niemeyer Harmann M., Bavo

Hector R., J. Org. Chem., 1990, 56 (5), 1788. (c) Banzatti Carlo, Heidempergher

114

Franco, Melloni Piero; J. Heterocycl. Chem.; 1983, 20, 259. (d) Sicker, Dieter;

Praetorius, Birgitt; Mann, Gerhard; Meyer, Lutz; Synthesis; 1988, 3, 211.

04. Finger, J. Amer. Chem. Soc.; 1959, 81, 94.

05. (a) Schlaeger, Leeb. Monatsh. Chem., 1950, 81, 714. (b) Blout, Silverman, J.

Amer. Chem. Soc., 1944, 66, 1442.

06. (a) Hogale, M. B.; Nikam, B. P. J. Indian Chem. Soc. 1988, 60 (10), 735. (b)

Caliendo, G.; Grieco, P.; Perissutti, E.; Santagada, V.; Santini, A. Eur. J. Med.

Chem. Ther. 1975, 33 (12), 957. (c) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, Akira,;

Takayama, Kazuhisa.; Yoden, T. Chem. Pharm. Bull. 1996, 44 (1), 103.

07. S. Vishnu Vardhan Reddy, A. Sivalakshmidevi, K. Vyas. Venugopal Rao

Veeramaneni, Koteswar Rao Yeleswarapu, A. Venkateswarlu and P. K. Dubey.

Acta Cyrstallographia Section E, 2003, E59, 0369.

CHAPTER – IV


“OXAZOLO [3,2-a]QUINOXALINES”

115

4.1 Introduction:

Oxazolo quinoxalines are not well documented in literature. Not much work have been

done in this area. One oxazolo quinoxaline, i.e. N, N’-[(4”, 5”-dimethyl)-1”, 2”-

phenylene]-2,2’-dimethyl-bisoxazolidine (49) seems to be well-known.1

N

N

O

O

(49)

2,3-Butanedione (50) was condensed with ethanol amine (52) in benzene1 for 5 hrs at

room temperature. Processing of the reaction mixture and separation of products gave 49

along with 52, 53 and 54. (Equation 4.1)

O

O

H2NOH

Benzene

Roomtemperature5.0 hrs

N

N

OH

OH

NH

O

O

HN

HN

O

NH

O

OH

OH

CH3

CH3N

N

O

O(50)

(51)

(52) (53) (54) (49)

Equation – 4.1

4.2 Present Work:

Survey of literature revealed that preparation of oxazoloquinoxalines has not been

carried out very extensively. Therefore, it was considered desirable to prepare new

compounds containing oxazoloquinoxalines. It is conceivable that these oxazolo

moieties can be synthesized from 1,2-diaminobenzene by ring closure with chloroacetic

116

acid to obtain quinoxalin-2-one in the first step. The latter can be used as a building block

for the synthesis of fused oxazolo ring units.


Commercially available o-phenylenediamine (55a) was treated with ethyl 2-

bromoacetate in the presence of triethylamine2 as a base in dichloromethane and

tetrahydrofuran as solvent to obtain 1,2,3,4-tetrahydro-2-quinoxalinone (56a R = H) in

67.0 % yield. (Equation – 4.2)

NH2

NH2 NH

HN

O

BrCH2CO2Et

TEA, CH2Cl2 THF

(56a)(55)

Equation – 4.2

Compound 56a is known in literature. However, it was further characterized in

the present work by analytical and spectral data. Thus, its IR (KBr) spectrum showed

(Fig 4.1) a peak at 3367 cm-1

(due to –NH stretching) and at 1681 cm-1

(due amide

carbonyl stretching) as diagnostic peaks. Its 1H NMR (DMSO d6): showed signals (Fig

4.2) at δ 10.21 (bs, 1H, D2O Exchangeable, NH), 6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H,

D2O Exchangeable, NH), 3.34 (s, 2H, NCH2CO), and its mass spectrum (Fig 4.3) showed

the molecular ion peak at m/z 149 (M++1, 100 %

) as the base peak in the spectrum.

In addition to the method given above, several other methods have also been

reported in literature for the preparation of 2-quinoxalinones. Thus, for example,

condensation3 of o-phenylenediamine and ethyl 2-halo-2-alkylacetate in the presence of

zinc dust, or the addition4 of chloroacetic acid in the presence of ammonia, or the

addition5 of 2-chloroacetamide in the presence of aqueous sodium hydroxide at 100

°C,

from N-(2-nitrophenyl)glycine in the presence of tin hydrochloride,6 o-phenylenediamine

and chloro acetic acid in the presence of sodium carbonate.7and from other methods.

8

Table – 4.1: Some known methods to prepare compounds 56a - g

117

S.No Reactant Conditions Product Ref:

1. NH2

NH2

Ethyl 2-bromo acetate,

Triethylamine, THF NH

HN

O

2

2. NH2

NH2

Chloro acetic acid,

Diluted Ammonia NH

HN

O

3

3. NH2

NH2

Chloro acetamide

Diluted Ammonia NH

HN

O

4

4. NH2

NH2

Bromo acetic acid

Zinc dust, HCl NH

HN

O

5

5. NH2

NH2

Ethyl 2-bromo-2,21-

dimethyl acetate NH

HN

O

6

6. NH2

NH2

Trichloromethane

Acetone, NaOH, PTS NH

HN

O

7

7. NH2

NH2

1,1,1-trichloro-2-

methylpropan-2-ol,

NaOH, PTS NH

HN

O

7

8. NH2

NH2

1,1,1-trichloro

compound, KOH NH

HN

O

8

9. NH2

NH2

3-phenyloxirane-2,2-

dicarbonitrile, ethanol NH

HN

O

Ph

9

118

10. NH2

NH2

Ethyl αααα-bromo phenyl

acetate, K2CO3, KI,

NaOEt NH

HN

O

Ph

10

11. NH2

NH2

Ethyl bromo acetae

Pot. tert. butoxide NH

HN

O

11

12.

NO2

HN

OH

O

Tin, HCl

NH

HN

O

12

13.

NO2

HN

OEt

O

H2 Pressure / 10 %

Palladium Carbon. NH

HN

O

2

14. HN

NO2

Pd(dba)2, Carbon

monoxide. NH

HN

O

13

15.

NH

N

O

Ph

Palladium carbon,

Hydrogen pressure NH

HN

O

Ph

14

Keeping this in view two simple but new methods were developed for the

synthesis of quinoxalines. In the first method o-phenylenediamine was treated with ethyl

2-bromo acetate in DMF in the presence of microwave irradiation for 5.0 min to obtain

56a in 72 % yield. (Equation – 4.3)

119

NH

HN

ONH2

NH2

BrCH2CO2Et, DMF

4 - 5 min

BrCH2CO2Et, NaOH,

Water, 80 °C, 1.0 hr,

(55) (56a)

Equation – 4.3

Substituted 1,2,3,4-tetrahydro-2-quinoxalinone (56a-i) were prepared in the above

two methods. The structures for these products were assigned on the basis of analogy

and on the basis of analytical and spectral data. (Table –4.2)

NH

HN

O

R1R

NH2

NH2

(55) (56 a-i)

Equation – 4.4

122

Table – 4.2: Synthesis of 56 (a-h) from o-phenylenediamine.

S. No. R R1

Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat)

/ cm-1

.

56a H H 72 IR (KBr): 3367 (Amide NH band), 1681 cm-1

(Amide Keto). 1H

NMR (In DMSO d6): δ 10.21 (bs, 1H, D2O Exchangeable, NH),

6.78 – 6.54 (m, 4H, ArH), 5.93 (bs, 1H, D2O Exchangeable,

NH), 3.38 (s, 2H, NCH2CO); Mass: 149 (M+ +1, 100%).

56b. H Me 69 IR (KBr): 1665 cm-1

(Amide Keto); 1H NMR (In DMSO d6): δ

12.17 (bs, 1H, D2O Exchangeable, NH), 7.72 (d, J = 7.81 Hz,

1H, ArH), 7.5), 7.70 – 7.21 (m, 3H, ArH), 2.95 (m, 1H,

NHCHCH3), 2.55 (s, 3H, CHCH3); Mass: 162 (M+, 10%), 161

(100 %).

56c. Me Me 73 IR (KBr): 3422 cm-1

(amide NH band), 1667 cm-1

(Amide

carbonyl stretching); 1H NMR (CDCl3, 200 MHz): 10.57 (bs,

1H, D2O Exchangeable, NH), 7.29 (d, J = 7.33 Hz, 1H, Ar H),

7.18 (d, J = 7.79 Hz, 1H, Ar H), 7.00 (d, J = 7.79 Hz, 2H, Ar H),

1.34 (s, 6H, C(CH3)2; Mass: m/z 194 ((M+ +1, 20 %).

56d. H Et 65 IR (KBr): 3440 cm-1

(amide NH band), 1659 cm-1

(Amide

carbonyl stretching); 1H NMR (In CDCl3): δ 11.99 (bs, 1H,

D2O Exchangeable, NH), 8.10 (d, J = 7.81 Hz, 1H, ArH), 7.78 –

7.71 (m, 1H, ArH), 7.59 – 7.52 (m, 2H, ArH), 3.32 – 2.21 (m,

1H, CHCH2CH3), 1.72 – 1.56 (m, 2H, CHCH2CH3), 1.44 – 1.36

(t, = 7.33 Hz, 3H, CH2CH3); Mass: 177 ((M+ +1, 10 %), 175

(M+, 100 %).

56e. H Pr 68 IR (KBr): 3384 (amide NH band), 1668 cm-1

(Amide carbonyl

stretching); 1H NMR (In DMSO d6): δ 12.16 (bs, 1H, D2O

Exchangeable, NH), 7.70 (d, J = 7.82 Hz, 1H, ArH), 7.45(t, J =

7.81 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 2.75 (t, J = 7.33

Hz, 1H, CHCH2CH2CH3), 2.53 (t, J = 5.36 Hz, 2H,

123

CHCH2CH2CH3), 1.73 (t, J = &.32 Hz, 2H, CHCH2CH2CH3),

0.95 (t, J = 7.32 Hz, 3H, CHCH2CH2CH3); Mass: 191 (M+1

, 50

%), 189 (M+, 100 %).

56f. H iPr 59 IR (KBr): 3433 (amide NH band), 1665cm

-1 (Amide carbonyl


Exchangeable, NH), 7.71 (d, J = 7.82 Hz, 1H, ArH), 7.45(d, J =

7.33 Hz, 1H, ArH), 7.29 – 7.22 (m, 2H, ArH), 3.49 – 3.42 (m,

1H, CH(CH3)2), 1.23 (s, 3H, CH(CH3)2), 1.19 (s, 3H,

CH(CH3)2); Mass: 191 (M+1

, 10 %), 189 (M+, 100 %), 188 (40).

56g. H Ph 63 IR (KBr): 3425 (amide NH band), 1664cm-1

(Amide carbonyl


Exchangeable, NH), 8.32 – 8.27 (m, 2H, ArH), 8.29 – 8.27 (d, J

= 7.33 Hz, 1H, ArH), 7.59 –7.49 (m, 4H, ArH), 7.74 (d, J = 7.81

Hz, 1H, ArH), 7.51 (s, 3H, CHPh); Mass: 224 ((M+ +1, 10 %),

223 (M+, 100 %), 194 (10).

124

Compound 56a was treated with benzyl bromide in the presence of sodium carbonate in

aq.ethanol15

to give 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a). (Equation 4.5)

NH

HN

O NH

N

O

CH2Ph

Na2CO3

aq. EtOH

80 °C, 12 hrs (57a)(56a)

PhCH2Br

Equation – 4.5

Substituted 4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinones (57b and 57c) were prepared

in the above method. (General Equation 4.6) The structures for these products were

assigned on the basis of analogy and on the basis of analytical and spectral data. (Table –

4.3)

NH

HN

O NH

N

O

Bn

Na2CO3

aq. EtOH

(56b &c)(56c & h)

R RBnBr

Equation – 4.6

125

Table – 4.3: Synthesis of 57 from 56

Sub. Pdt. R Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr / Neat)

/ cm-1

.

56a 57a H 79.0 IR (KBr): (Fig 4.4) 3438 (NH band stretching), 1684 cm-1

(Amide carbonyl stretching); 1H NMR (in CDCl3): (Fig 4.5) δ

9.29 (bs, 1H, D2O Exchangeable, NH), 7.31- 7.25 (m, 5H, Ar

H), 6.94 – 6.82 (m, 1H, Ar H), 6.79 – 6.72 (m, 3H, Ar H), 4.41

(s, 2H, PhCH2), 3.81 (s, 2H, NCH2); Mass: m/z (Fig 4.6) 239

(M+1

, 100 %) and 238((M+ +1, 30 %).

56h 57b Ph 59 IR (KBr): 3431 (NH band stretching), 1682 cm-1

(Amide

carbonyl stretching); 1H NMR (in CDCl3): δ 8.69 (bs, 1H, D2O

exchangeable, NH proton), 7.29 – 7.17 (m, 10H, ArH), 6.96 –

6.92 (m, 1H, ArH), 6.77 – 6.71 (m, 3H, ArH), 4.97 (s, 1H, NCH

(Ph)), 4.67 (d, J = 15.62 Hz, 1H, NCH2Ph), 4.09 (d, J = 15.62

Hz, 1H, NCH2Ph); Mass: 315 ((M+ +1, 100 %).

56c 57c DiMe 74.0 % IR (KBr): 3445 (NH band stretching), 1680 cm-1

(Amide

carbonyl stretching); 1H NMR (in CDCl3): δ 8.06 (bs, 1H, D2O

Exchangeable, NH), 7.32- 7.21 (m, 5H, Ar H), 6.82 – 6.78 (m,

1H, Ar H), 6.71 (d, J = 3.43 Hz, 2H, Ar H), 6.51 (d, J = 7.79 Hz,

1H, Ar H), 4.51 (s, 2H, PhCH2), 1.51 (s, 6H, NC(CH3)2); Mass:

m/z 267 ((M+ +1, 100 %).

126

4-benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57a) was treated with ethyl 2-

bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for 12 hrs. (Equation

4.7) Processing of the reaction mixture gave a product which was found to be ethyl 2-(4-

benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58a) which was characterized by

spectral methods. Thus, in its IR spectrum (Fig 4.3.1) peaks were found at 1749 cm-1

(due to ester carbonyl stretching) and at 1678 cm-1

(due to amide carbonyl stretching)

were observed. Its 1H NMR (In CDCl3) showed (Fig 4.3.2) signals at δ 7.32 (m, 5H,

ArH), 6.98 (t, J = 7.33 Hz, 1H), 6.87 – 6.70 (m, 3H), 4.67 (s, 2H), 4.38 (s, 2H), 4.29 –

4.18 (q, J = 7.33 Hz, 2H), 3.81 (s, 2H), 1.28 (t, J = 7.33 Hz, 3H). Its mass spectrum (Fig

4.3.3) showed peaks at m/z 325 (M+1

, 100 %) and at 324 (M+, 30 %) in the Q+1 mode.

NH

N

ON

N

O

O

OEt

K2CO3 / BrCHCO2Et

DMF 80 0C, 12.0 hrs

(57a)(58a)

BnBn

Equation – 4.7

Substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl) acetates

could also be prepared using the above method. Structures of all the products (58a – h)

have been assigned on the basis of analogy and on the basis of spectral & analytical data

(Table – 4.4).

NH

N

ON

N

O

O

OEt

K2CO3, BrR1CHCO2Et

DMF 80 0C, 12.0 hrs

(57a - h)

(58a - i)

R R

R1

Bn Bn

Equation – 4.8

127

Table – 4.4: Synthesis of 58 (a-h) from 57 (a-c)

Sub. Pdt. R R1 Yield % Spectral Data:

1H NMR (200 MHz, CDCl3); IR (KBr /

Neat) / cm-1

.

57a 58a H H 78 IR (KBr): 1749 (Ester carbonyl stretching), 1677 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m,

5H, ArH), 6.98 (t, J = 7.33 Hz, 1H, ArH), 6.87 – 6.70 (m,

3H, ArH), 4.67 (s, 2H, NCH2Ph), 4.38 (s, 2H, NCH2CON),

4.29 – 4.18 (q, J = 7.33 Hz, 2H, CO2CH2CH3), 3.81 (s, 2H,

NCH2CO2Et), 1.28 (t, J = 7.33 Hz, 3H, CO2CH2CH3);

Mass: 325 (M+1

, 100 %), 324 (M+, 10 %).

57b 58b Ph H 81 IR (KBr): 1749 (Ester carbonyl stretching), 1679 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.98 –

7.16 (m, 10H, ArH), 7.02 – 6.94 (m, 2H, ArH), 6.88 – 6.71

(m, 2H), 5.15 (s, J = 1H, NCHPh), 5.05 (m, 2H, NCH2Ph),

4.64 (d, J = 15.14 Hz, 1H, NCH2CO2Et), 4.40 (d, J = 17.10

Hz, 1H, NCH2CO2Et), 4.28 – 4.06 (m, 2H, CO2CH2CH3),

1.15 (t, J = 7.33 Hz, 3H, CO2CH2CH3); Mass: 401 ((M+ +1,

100 %), 309 (10 %).

57a 58c H Me 63 IR (KBr): 1741 (Ester carbonyl stretching), 1682 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.32 (m,

5H, ArH), 7.21 – 6.95 (m, 2H, ArH), 6.89 – 6.79 (m, 2H,

ArH), 5.49 – 5.56 (m, 2H, NCH2Ph), 5.28 – 5.25 (m, 2H,

NCH2CON), 4.26 – 4.13 (m, 2H, CO2CH2CH3), 3.73 – 3.72

(m, 2H, NCH2CO2Et), 1.75 (d, J = 8.0 Hz, 3H, CHCH3), 1.30

– 1.16 (m, 3H, CO2CH2CH3); Mass: 339 (M+1

, 100 %), 338

(M+, 30 %).

57a 58d H Et 57 IR (KBr): 1739 (Ester carbonyl stretching), 1683 cm-1

(Amide carbonyl stretching ); 1H NMR (In CDCl3): δ 7.31

(m, 5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.77 (m, 3H,

128

ArH), 5.36 – 5.28 (m, 1H, NCHCH2CH3), 4.49 – 4.42 (d, J =

15.44 Hz, 1H, NCH2Ph), 4.32 – 4.24 (d, J = 15.44 Hz, 1H,

NCH2Ph), 4.22 – 4.13 (m, 2H, CO2CH2CH3), 3.75 (s, 2H,

NCH2CON), 2.32 – 2.22 (m, 1H, NCHCH2CH3), 2.14 – 2.03

(m, 1H, NCHCH2CH3), 1.19 (t, J = 7.33 Hz, 3H,

CO2CH2CH3), 0.89 (t, J = 7.33 Hz, 3H, NCHCH2CH3);

Mass: 261 (M+ -1, 100 %).

57a 58e H Hex 49 IR (KBr): 1740 (Ester carbonyl stretching), 1685 cm-1

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.31 (m,

5H, ArH), 6.96 – 6.92 (m, 1H, ArH), 6.81- 6.76 (m, 3H,

ArH), 5.48 (s, 1H), 4.36 (d, J = 15.44 Hz, 1H, NCH2Ph),

4.27 (d, J = 15.44 Hz, 1H, NCH2Ph), 4.25 – 4.14 (m, 2H,

CO2CH2CH3), 3.75 (s, 2H, NCH2CON), 2.23 – 2.03 (m, 1H,

NCHCH2CH3), 1.23 – 1.16 (m, 11H), 0.82 (m, 3H); Mass:

407 (M+, 100 %).

57a 58f H Ph 56 IR (KBr): 1748 (Ester carbonyl stretching), 1683 cm-1

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.34 –

7.31 (m, 10H), 6.97 – 6.79 (m, 2H), 6.75 – 6.68 (m, 2H),

6.24 (s, 1H), 4.54 – 4.30 (m, 2H), 3.86 – 3.82 (m, 2H), 3.77

(s, 3H); Mass: m/z 387 (M+1

, 100 %) and 253 (10 %).

57b 58g Ph Ph 61 IR (KBr): 1744 (Ester carbonyl stretching), 1678 cm-1

(Amide carbonyl stretching); 1H NMR (CDCl3): δ 7.35 –

7.08 (m, 15H, ArH), 6.99 – 6.91 (m, 1H, ArH), 6.83 – 6.80

(m, 1H), 6.76 – 6.64 (m, 2H), 6.06 (s, 1H), 5.14 (d, J = 7.60

Hz, 1H, NCHPh), 4.83 – 4.70 (dd, J = 10.8 & 15.1 Hz, 1H,

NCH2CO2Et), 4.22 (t, J = 5.1 Hz, 1H, NCH2CO2Et), 3.82 (s,

3H), 3.60 (s, 1H); Mass: 463 ((M+ +1, 100 %), 371 (20 %),

265 (30 %).

57c 58h DiMe H 65 IR (KBr): 1739 (Ester carbonyl stretching), 1678 cm-1

129

(Amide carbonyl stretching ); 1H NMR (CDCl3): δ 7.33-

7.21 (m, 5H, Ar H), 6.87 – 6.80 (m, 4H, Ar H), 4.69 (s, 2H,

NCH2), 6.71 – 6.59 (m, 2H), 4.53 (s, 2H, PhCH2), 4.30 –

4.19 (q, J = 7.32 Hz, 2H, OCH2CH3), 1.51 (s, 6H,

NC(CH3)2), 1.25 (t, J = 7.33 Hz, 3H, OCH2CH3); Mass: m/z

353 ((M+ +1, 100 %), 337.

130


Treatment of 58a with 1.1 eq. of LAH in THF followed by simple processing


homogenous on TLC. Its IR spectrum (Neat) (Fig 4.10) did not show any diagnostic

peaks due to –NH- and -CO- groups. Its 1H NMR (in CDCl3) showed (Fig 4.11) signals

at δ 7.32 (m, 5H, ArH), 6.95 – 6.61 (m, 4H, ArH), 4.90 – 4.84 (dd, J = 3.90 & 7.32 Hz,

1H), 4.61 – 4.53 (d, J = 15.63 Hz, 1H), 4.33 – 4.26 (d, J = 15.13 Hz, 1H), 4.21 – 4.11 (m,

1H), 4.06 – 3.94 (m, 2H), 3.66 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J = 7.33 & 10.74 Hz, 1H).

Its mass spectrum (Fig 4.12) showed peaks at m/z 267 ((M+ +1, 90 %) and m/z 266 (M

+,

100 %) in the Q+1 mode. Based on this data, the product was assigned as 5-benzyl-

1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59a). (Equation – 4.9)

N

N

O N

N

O

OEtO

LAH

THF, 0 °C

to r.t 1.0 hr

(58a) (59a)

BnBn

Equation – 4.9

The above reaction of 58a yielding 59a general. It has been extended to other

substituted ethyl 2-(4-benzyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetates (58a-h)

yielding (59a-h). (Equation – 4.10)

131

N

N

O N

N

R1

O

OEtO

LAH

R1

RR

THF, 0 - r.t1.0 min

(58a-h) (59a-h)

BnBn

Equation – 4.10

Table –4.5: Synthesis of 59 (a-h) from 58 (a-h) with LAH was explained by data:

Sub. Pdt. Yiel

d

%

Analytical Data: (IR cm-1

), 1H NMR (δδδδppm) (CDCl3,

200 MHz) & Mass S.No R R1

58a 59a H H 75 IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H), 6.95 –

6.61 (m, 4H), 4.90 – 4.84 (m, 1H), 4.61 – 4.26 (dd, J =

15.63 and 15.13 Hz, 2H), 4.21 – 4.11 (m, 1H), 4.03 –

3.94 (m, 2H), 3.65 – 3.37 (m, 4H), 2.72 – 2.63 (dd, J =

7.33 and 10.74 Hz, 1H); Mass (m/z): 267 ((M+ +1, 90

%), 266 (M+, 100 %).

8b 59b Ph H 69 IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.33 – 7.14 (m, 10H), 6.81 –

6.71 (m, 2H), 6.63 – 6.56 (m, 2H), 5.02 (d, J = 3.90 Hz,

1H), 4.89 – 4.51 (m, 2H), 4.30 – 3.96 (m, 3H), 3.66 –

3.34 (m, 3H); Mass: (m/z) 343 ((M+ +1, 90 %), 342 (M

+,

100 %).

132

58c 59c H Me 54 IR: Did not show any diagnostic peaks due to –NH- and

-CO- groups. 1H NMR: δ 7.32 – 7.25 (m, 5H, Ar H),

6.82 – 6.63 (m, 4H, Ar H), 5.03 – 4.97 (dd, J = 4.36 and

7.24 Hz, 1H), 4.60 – 4.45 (m, 2H), 4.26 – 4.13 (m, 2H),

4.03 – 3.91 (m, 2H), 3.57 – 3.41 (m, 2H), 2.68 – 2.59

(m, 1H), 1.39 (d, J = 6.17 Hz, 3H); Mass: (m/z) 281

((M+ +1, 90 %), 280 (M

+, 100 %).

58d 59d H Et 66 IR: Did not show any diagnostic peaks due to –NH- and


6.81 – 6.64 (m, 4H, Ar H), 5.00 – 4.94 (dd, J = 4.36 and

6.75 Hz, 1H), 4.55 (d, J = 15.08 Hz, 1H), 4.25 (d, J =

15.08 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.85 – 3.75 (m, 1H),

3.67 – 3.60 (m, 2H), 3.49 – 3.41 (dd, J = 4.0 and 11.0

Hz, 1H), 2.72 – 2.63 (dd, J = 6.99 and 11.01 Hz, 1H),

1.90 – 1.71 (m, 1H), 1.68 – 1.56 (m,1H), 1.02 (t, J = 7.30

Hz, 3H); Mass: (m/z) 295 ((M+ +1, 90 %), 294 (M

+, 100

%).

58e 59e H Hex 49 IR: Did not show any diagnostic peaks due to –NH- and


6.81 – 6.63 (m, 4H, Ar H), 4.99 – 4.94 (dd, J = 4.31 and

6.71 Hz, 1H), 4.58 – 4.51 (d, J = 15.04 Hz, 1H), 4.24 (d,

J = 15.04 Hz, 1H), 4.06 (d, J = 7.52 Hz,1H), 3.85 – 3.82

(m, 1H), 3.64 – 3.58 (dd, J = 4.83 and 7.79 Hz, 2H), 3.48

– 3.41 (dd, J = 4.30 and 11.02 Hz, 1H), 2.72 – 2.63 (dd, J

= 16.98 and 10.98 Hz, 1H), 1.83 – 1.64 (m, 1H), 1.55 –

1.47 (m,1H), 1.32 – 1.26 (m, 8H), 0.98 – 0.88 (m, 3H);

Mass: (m/z) 351 ((M+ +1, 90 %), 350 (M

+, 100 %).

133

58f 59f H Ph 58 IR: Did not show any diagnostic peaks due to –NH- and


6.77 – 6.56 (m, 2H, Ar H), 6.41 – 6.37 (m, 1H), 5.27 –

5.21 (dd, J = 11.57 and 7.79 Hz, 1H), 4.77 (t, J = 8.32

Hz, 1H), 4.23 (d, J = 14.77 Hz, 1H), 3.72 (t, J = 8.33 Hz,

1H), 3.58 – 3.51 (dd, J = 4.60 and 15.31 Hz, 1H), 2.67 –

2.58 (dd, J = 7.74 and 10.48 Hz, 1H); Mass: (m/z) 343

(M+ +1, 90 %), 342 (M

+, 100 %).

58g 59g Ph Ph 49 IR: Did not show any diagnostic peaks due to –NH- and


6.65 – 6.44 (m, 2H, Ar H), 5.30 (d, J = 6.45 Hz, 1H),

4.88 (m, 1H), 4.53 – 4.43 (m, 2H), 4.05 (d, J = 16.65 Hz,

1H), 3.84 (d, J = 6.45 Hz, 1H), 3.69 (t, J = 8.06 Hz, 1H);

Mass: (m/z) 419 ((M+ +1, 90 %), 418 (M

+, 100 %).

58h 59h Di

Me

H 63 IR: Did not show any diagnostic peaks due to –NH- and


6.65 (m, 1H, Ar H), 6.52 (t, J = 7.3 Hz, 2H, Ar H), 6.37

(d, J = 7.2 Hz, 1H, Ar H), 4.62 (d, J = 14 Hz, 2H), 4.29 –

4.09 (m, 2H), 3.61 – 3.49 (m, 2H), 0.97 (s, 6H); Mass:

(m/z) 295 ((M+ +1, 50 %), 294 (M

+, 100 %), 223 (90

%).

135

It was considered desirable to study the effect of substitution in the cyclization

reaction yielding oxazolooxazines. All the compounds which are N-benzyl derivatives

are reported in Table 4.5. It would be interesting to study the course of cyclisation in N-

ethyl substituted derivatives instead of N-benzyl substituted derivatives. Therefore,

preparation of 59i, was needed in the present work was carried as follows: - Compound

56a was treated with ethyl bromide in the presence of sodium carbonate in aq.ethanol8 to

give 4-ethyl-1,2,3,4-tetrahydro-2-quinoxalinone (57d) and its structure was confirmed

from spectral and analytical data. Thus, its IR (KBr) showed a peak at 3443 cm-1

indicating presence of – NH – group and another at 1686 cm-1

indicating presence of

amide carbonyl group. Its 1H NMR (In CDCl3) showed signals at δ 10.32 (bs, 1H, D2O

exchangeable Amide NH proton), 6.89 – 6.60 (m, 4H), 3.82 (s, 2H), 3.67 (s, 2H), 3.32 –

3.22 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). Its mass spectrum showed peaks at m/z

177 (M+1

, 100 %) and at m/z 176 (M+, 10 %) in the Q+1 mode. Compound 57d was

treated with ethyl 2-bromoacetate in the presence of K2CO3 as base in DMF at 80 °C for

12.0 hrs. Processing of the reaction mixture gave a product which was found to be ethyl

2-(4-ethyl-2-oxo-1,2,3,4-tetrahydro-1-quinoxalinyl)acetate (58i) characterized by spectral

methods. Thus, its IR showed peaks at1748 cm-1

due to carbonyl carbon stretching and

another peak at 1684 cm-1

due to amide carbonyl stretching. Its 1H NMR (In CDCl3)

showed signals at δ 7.04 – 6.90 (m, 2H), 6.83 – 6.67 (m, 3H), 4.65 (s, 2H), 4.30 – 4.21

(m, 2H), 3.83 (s, 2H), 3.37 – 3.27 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.21 (t, J =

7.0 Hz, 3H). Its mass spectrum showed peaks at 277 (M+1

, 100 %) in the Q+1 mode.

Treatment of compound 58i with 1.1 eq. of LAH in THF yielded syrupy product. The

compound was found to be homogenous on TLC. Its IR spectrum (Neat) did not show

any diagnostic peaks due to of –NH- and -CO- groups. Its 1H NMR (in CDCl3) show

signals at δ 6.77 – 6.65 (m, 3H), 6.63 – 6.57 (m, 1H), 4.90 – 4.84 (dd, J = 4.0 and 8.7 Hz,

1H), 4.17 – 4.09 (m, 1H), 4.05 – 3.93 (q, J = 7.3 Hz, 2H), 3.64 – 3.24 (m, 3H), 2.72 –

2.63 (dd, J = 7.3 and 10 Hz, 1H), 1.17 (t, J = 7.3 Hz, 3H). Based on this data, the product

was assigned as 5-ethyl-1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-a]quinoxaline (59i).

136

NH

HN

O NH

N

ONa2CO3

aq. EtOH

N

N

O

O

O

N

N

O

LAH

THF

Ethyl bromoacetate

K2CO3, DMF

80 °C

(56a)(57d)

(58i) (59i)

EtBr

Scheme – 4.1

When N-ethyl derivative 58i was subjected to reduction with LAH it gave the

final product 59 in lower yield than the corresponding N-benzyl derivatives. This

indicates that for good yields N-benzyl protection is preferable than N-ethyl protection.

Another advantage with N-benzyl derivatives is that it is easy to remove the benzyl group

from tricyclic oxazolo quinoxaline to yield the parent ring system which can be utilized

for further chemical reactions.

4.4 Experimental procedure:

i) Preparation of 56a - h (General procedure):

Method A: To a solution of o-phenylenediamine (55, 5.0 gms, 46.0 mmol) in

water was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl

acetate (1.2 eq) at room temperature. The reaction mixture was stirred for one hour at 80

°C, cooled to room temperature and neutralized with aq. HCl (50 %, v/v). The separated

solid was filtered, washed with water and dried to obtain 56a-h (Table-4.1).

137

Method B: To a solution of o-phenylenediamine (55, 0.5 gms, 4.6 mmol) in DMF

was added powdered sodium hydroxide (1.5 eq) followed by ethyl 2-bromo-2-alkyl

acetate (1.2 eq) at room temperature. The mixture was irradiated with microwaves using

household microwave oven for 5.0 min. Then, the mixture was cooled, and neutralized

with aq. HCl (50 %, v/v). The separated solid was filtered, washed with water and dried

to obtain 56a-h (Table-4.1).

ii) Preparation of 57a - c (General procedure): To a solution of compounds 57a -h and

sodium carbonate (2.0 eq) in aqueous ethanol (10 mL ethanol: 1.0 mL water for 1.0 gm

of substrate) was added benzyl bromide (1.2 eq.) and the mixture refluxed for 12 hrs.

The reaction mixture was cooled to room temperature and poured into water. The

separated solid was filtered, washed with water and dried to obtain 57a-c (Table-4.2).

iii) Preparation of 57d: To a solution of compounds 56a (2.0 gms, 13.51 mmol) and

sodium carbonate (2.75 gms, 27.07 mmol) in aqueous ethanol (20 mL ethanol: 2.0 mL

water) was added ethyl bromide (1.26 mL, 16.21 mmol) and refluxed for 12 hrs. The

reaction mixture was cooled to room temperature and poured into water. The separated

solid was filtered, washed with water and dried to obtain 57d (1.78 gm, 75 %).

iv) Preparation of 58a – i (General procedure): To a solution of 57 a – d (1.0 eq) and


alkyl acetate (1.2 eq) drop wise at room temperature. After 12.0 hrs stirring at 80 °C, the

mixture was poured in to water. The separated solid was filtered, washed with water and

dried to give 58a –i (Table-4.3).

v) Preparation of 59a – i (General procedure): To a solution of 58a - i (2.0 mmol) in




138

filtered and the filtrate concentrated. The separated crude product was purified by column

chromatography using ethyl acetate and pet. ether (5:95) to give 59a – m (Table-4.4).

4.5 References:

01. Noberto Farfan, Rosa Santillan, Julian Guzaman, Belinda Castillo and Aurelio

Ortiz. Tetrahedron; 1994, 50 (33), 9951.

02. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B.

Carter, J. Med. Chem., 1994, 37, 758.

03. Motylewski, et. al. Chem. Ber. 41, 800 (1908).

04. Perkin, Riley, J. Chem. Soc., 1923, 123, 2406.

05. Holley, J. Amer. Chem. Soc., 1952, 74, 3069.

06. Ploechl; Chem. Ber.; 1886, 19, 10.

07. Borthakur N, Bhattacharyya A. K., Rastogi R. C., Indian J. Chem. Sect. B., 1981,

20 (9), 822.

08. (a) Harsanyi k et. al; Chem. Ber.; 1972, 105, 805. (b) Cuiban F; Bull. Soc. Chim.

Fr.; 1963, 356. (c) Taylor, Thompson; J. Org. Chem.; 1961, 26, 3511. (d) Bell,

Childress; J. Org. Chem.; 1964, 29, 506. (e) Heller.; J. Prakt. Chem.; 1925, 111,

19. (f) Hinsberg, Justus Liebigs Ann Chem., 1896, 292, 246. (g) Lai John T.,

Synthesis.; 1982, 1, 72. (h) Clark – Lewis. Aust J Chem.; 1970, 23, 1249. (i) Clark –

Lewis.; Aust J Chem.; 1964, 17, 877. (j) Soederberg Bjoern C. G., Wallace Jeffery

M, Tamariz Joaquin; Org. Lett.; 2002, 4 (8), 1339. (k) Taylor Edward C.,

Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem., 1980, 45 (12), 2512. (l)

139

Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.

Soc. Chim. Belg., 1987, 96 (6), 473. (m) De La Fuente, Julio R., Canete Alvaro,

Zanocco Antonio L., Saitz Claudio, Jullian Carolina., J. Org. Chem., 2000, 65 (23),

7949.

09. Taylor Edward C., Maryanoff Cynthia A., Skotnicki Jerauld S., J. Org. Chem.,

1980, 45 (12), 2512.

10. Olagbemiro, T. O., Nyakutse, C. A., Lajide, L., Agho, M. O., Chukwu, C. E., Bull.

Soc. Chim. Belg., 1987, 96 (6), 473.

11. Ruth, E. TenBrink, Wha, B. Im, Vimala, H. Sethy, Andrew, H. Tang and Don, B.

Carter, J. Med. Chem., 1994, 37, 758.

12. Ploechi; Chem. Ber., 1886, 19, 10.

13. Bjorn C. G. Sederberg, Jeffery M. Wallace and Joaquin Tamariz; Org. Lett.;

2002, 4 (28), 1339.

14. De La Fuente, Julio R., Canete Alvaro, Zanocco Antonio L., Saitz Claudio, Jullian

Carolina., J. Org. Chem., 2000, 65 (23), 7949.

15. (a) Laurinvicius Valdas, Krutinatiene Bogumila, Liauksminas Virgnijus,

Puodziunatie Benedikta Janciene., Monatsh Chem., 1999, 130 (10), 1269.

(b) Smith., J. Org. Chem., 1959, 24, 205.

140

CHAPTER –V


“OXAZOLO QUINOLINES”

5.1 INTRODUCTION:

Hexahydro-oxazolo[3,2-a]pyridine (60) or tetrahydro-oxazolo[3,2-a]pyridine (61)

is a fused heterocycle, in which piperidine or tetrahydropyridine is fused with 1.3-oxazole

in an angular fashion. These moieties are frequently found to be an integral part of many

biologically active molecules, synthetically important compounds and natural products.1-8

N O

N O

(60) (61)

141

A number of such structures and their use in different therapeutic areas have been

listed below in Table – 5.1. Hexahydro-oxazolo[3,2-a]pyridine (60) is an integral part of

Atisine (62),1 which is a natural product (aconite alkaloid). Oxazole derivative 64 was

used as starting material for synthesis of Salsolidine9 which is an isoquinoline alkaloid

found to posses anti tumor activity.

Table – 5.1: Some known Oxazolopyridines / Isoquinolines.

S.No. Structure of derivative Importance Ref.

1.

N O

OH

(62)

Atisine Alkaloid 1

2.

N

O

(63)

2

3.

N

O

Ph

O

O

(64)

Starting material for

(R)-(+) Salsolidine

Anti tumor

3

4.

N O

Ph

CO2Et

HO

(65)

4

5.

N

O

(66)

5

142

6.

N O

Ph

(67)

6

7.

N O

Ph

NC

(68)

(-)-Pumiltoxin

Natural product

7

Oxazolo[2,3-a]tetrahydroisoquinoline (64) was synthesized starting from 6,7-

dimethoxy-1-methyl-isochroman (69) which gives 70 in the presence of bromine in CCl4.

The latter on stirring with D-phenylglycinol (71) in the presence of triethylamine as base

at -78 °C gives compound 64.3 This compound 64 is useful as key intermediate for the

synthesis of isoquinoline alkaloid i.e. Saisolidine (72). (Equation - 5.1)

O

O

O CHO

O

O

Br

N

O

Ph

O

O

Br2, CCl4

80°

PhOH

NH2

Et3N

NH

O

O

Me

(R)-(+) Saisolidine

(69)(70)

(64) (72)

(13)

Equation - 5.1

3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-carbonitrile (68)6-7

was prepared

by condensation of phenylglycinol (71) with glutaraldehyde (73) in the presence of

potassium cyanide to give compound 68 via piperidine intermediate (681). (Equation -

5.2)

143

NH2

PhOH CHO CHO

N O

Ph

NC

KCN

(71) (73)

(68)

N O

Ph

NC

(681)

Equation - 5.2

Synthesis of compound 65 was achieved starting from 68. Reacting it with

alumina (Al2O3) and DEAD (diethyl acetylenedicaboxylate) in ethanol was refluxed to

give 8-Hydroxy-1-phenyl-1,2,4,5-tetrahydro-3aH-oxazolo[3,2-a]quinoline-6-carboxylic

acid ethyl ester (65).4 (Equation - 5.3)

N O

Ph

N OH

Ph

NC HCN

DEAD N O

Ph

Al2O3

CO2Et

HO

(68) (74)(65)

Equation - 5.3

5.2 Present Work:

Survey of literature thus, revealed that different oxazolo isoquinolines have

shown diverse types of biological activities and these are used in synthesis of some other

natural products. Therefore, it was considered desirable to prepare new compounds

containing oxazolo quinolines. Not much information is found in literature in the area of

oxazolo quinolines. It is conceivable that these oxazolo moieties can be synthesized from

2-nitro benzaldehyde by condensation with phenylacetic acid and followed by reductive

cyclization in the presence of hydrogen gas over palladium carbon to yield quinolines in

the first step. These can be used as building blocks for the further structural modification

leading to fused oxazolo ring units.


144

Commercially available 2-nitrobenzaldehyde (75) was reacted with

triphenylphosphine ylide (76) in benzene to obtain ethyl (E)-3-(2-nitrophenyl)-2-

propenoate (77 a, i.e. R = H) in 90.0 % yield (Equation – 5.4). 77a is a compound

known9 in literature. However, it was further characterized in the present work by

spectral and analytical data. Thus, its IR spectrum the absence of absorption at 1650 cm-1

typical of the aromatic aldehyde group. However, the IR spectrum showed (Fig 5.1) a

peak at 1716 cm-1

, which was assigned to ester carbonyl stretching. Its 1H NMR (in

CDCl3) showed signals (Fig 5.2) at δ 8.14 – 8.02 (m, 2H), 7.65 – 7.63 (m, 1H), 7.58 –

7.49 (m, 2H), 6.36 (d, J = 15.7 Hz, 1H), 4.34 – 4.23 (q, J = 7.30 Hz, 2H), 1.31 (t, J = 7.30

Hz, 3H). Its mass spectrum (Fig 5.3) showed the molecular ion peak at 222 ((M+ +1, 100

%), and other peaks at m/z 192 (30 %), 176 (40 %, indicative of loss of ethoxy).

CHO

NO2 NO2

+ Ph3P=CHCO2Et OEt

O

Benzene

80 0C, 6.0 hrs

(75) (76)(77a)

Equation – 5.4

In order to prepare the intermediate 77b, 2-nitrobenzaldehyde (75) was reacted

with phenylacetic acid (4) in the presence of triethylamine and acetic anhydride10

to give

(E)-2-phenyl-3-(2-nitrophenyl)-2-propenoic acid (77b) in 65.0 % yield. (Equation – 5.5)

The structure of 77b was confirmed by its analytical and spectral data. Thus, its IR

showed a peak at 1683 cm-1

indicative of carbonyl group, which has been assigned to

COOH group. Its 1H NMR (in DMSO d6) showed signals at 12.96 (bs, 1H, D2O

exchangeable), 8.10 - 8.05 (m, 1H, Ar H), 7.47 – 7.43 (m, 1H, Ar H), 7.20 (s, 1H), 7.08 –

7.07 (m, 1H, Ar H), 6.97 – 6.93 (m, 1H, Ar H). Its mass spectrum showed peaks at 254

(M+ +1) and 240 (100 %).

145

CHO

NO2

CO2HNO2

Ac2O, Et3N

CO2H

+

(75) (77b)(4)

Equation – 5.5

In order to prepare another intermediate 77c, 2-nitrobenzaldehyde (75) was

reacted with 4-methoxyphenylacetic acid (13) in the presence of triethylamine and acetic

anhydride to give (E)-2-(4-methoxyphenyl)-3-(2-nitrophenyl)-2-propenoic acid (77c) in

65.0 % yield. (Equation – 5.6) The structure of 77c was confirmed by its analytical and

spectral data. Thus, its IR showed peak at 1686 cm-1

due to the carbonyl stretching. Its

1H NMR (in DMSO d6) showed signals at 8.17 (s, 1H, Ar H), 8.10 – 8.08 (dd, J = 2.42 &

5.37 Hz, 1H, Ar H), 7.37 - 7.33 (m, 2H, ArH), 7.07 (d, J = 8.86 Hz, 2H, ArH), 6.99 –

6.95 (m, 1H, Ar H), 6.76 (d, J = 8.60 Hz, 2H, ArH), 3.76 (s, 3H). Its mass spectrum

showed peak at 300 (M+1

, 100 %).

CHO

NO2

CO2HNO2

Ac2O, Et3N

CO2H

+

(75) (77c)(13)

OMe

OMe

Equation – 5.6

Ethyl (E)-3-(2-nitrophenyl)-2-propenoate (77 a) was reduced with hydrogen gas

over 10 % palladium on charcoal in acetic acid at room temperature11

to give 1,2,3,4-

tetrahydro-2-quinolinone (78a) in 97.0 % yield, (Equation – 5.7) which was characterized

by analytical and spectral data. Thus, its IR (KBr) spectrum showed (Fig 5.4) a peak at

3440 cm-1

which may be assigned to –NH- stretching vibration, and a strong peak at 1680

cm –1

in the carbonyl region which may be assigned to the amide carbonyl grouping. Its

1H NMR (in CDCl3) showed (Fig 5.5) three aromatic signals at δ 8.79 (bs, 1H, D2O

exchangeable), 7.14 (d, J = 7.0 Hz, 2H), 6.99 (d, J = 7.0 Hz, 1H), 6.81 (d, J = 7.0 Hz,

146

1H), and other signals at 2.97 (t, J = 7.0 Hz, 2H), 2.68 (d, J = 7.0 Hz, 2H). Its mass

spectrum (Fig 5.6) showed peaks at m/z 148 (M+ +1, 100 %).

NH

OCO2EtNO2

10 % Pd-C

H2, 60 PSI

(77a) (78a)

Equation – 5.7

Substituted 2-quinolinones (78 b and c) were prepared in the similar manner as

above.12

The structures for these products were assigned on the basis of analogy and on

the basis of analytical and spectral data. (Table –5.2)

NH

OCO2HNO2

10 % Pd-C

H2, 60 PSI

(77b-c)

RR

(78b-c)

Equation – 5.8

Table 5.2: Synthesis of 78 from 77 and their spectral Data:

Sub. Pdt. R Yield % Spectral Data: 1H NMR (200 MHz, CDCl3); IR (KBr) /

cm-1

.

77b 78b H 65.0 IR (KBr): 3210 cm-1

(amide –NH- band), 1680 cm-1

(amide

carbonyl stretching); 1H NMR (DMSO d6, 200 MHz):

δ10.31 (bs, 1H, D2O exchangeable, NH), 7.23 – 7.14 (m, 7H,

Ar H), 6.90 – 6.87 (m, 2H, Ar H), 3.80 (t, J = 7.3 Hz, 1H,

PhCH), 3.15 (d, J = 7.30 Hz, 2H, Ph CH2); Mass: m/z 224

(M+1

, 100 %).

77c 78c OMe 67.0 IR (KBr): 3208 cm-1

(amide –NH- band), 1678 cm-1

(amide

carbonyl stretching); 1H NMR (DMSO d6, 200 MHz): δ 8.39

(bs, 1H, D2O exchangeable, NH), 7.18 – 7.15 (m, 5H, Ar

H),7.03 – 6.95 (m, 1H), 6.87 – 6.75 (m, 2H, Ar H), 3.85 –

3.72 (m, 1H, PhCH), 3.77 (s, 3H, OMe), 3.23 (d, J = 7.70

147

Hz, 2H, Ph CH2); Mass: m/z 254 (M+1

, 100 %).

1,2,3,4-tetrahydro-2-quinolinone (78a) was treated with ethyl 2-bromoacetate in

the presence of potassium carbonate in DMF at 80 °C for 9 hrs. Processing of the reaction

mixture gave a product (68 %) which was found to be 79a in 50 % yield (Equation 5.9) it

was characterized by spectral methods. Thus, its IR spectrum showed no absorption

above 3000 cm-1

indicating absence of any –NH- grouping. However, the IR spectrum

(Fig 5.7) showed two strong sharp bands, one at 1743 cm-1

and the other at1688 cm-1

.

The former has been assigned to ester carbonyl grouping and other assigned to amide

carbonyl grouping. Thus, its 1H NMR spectrum (Fig 5.8) displayed signals at δ 7.21-

17(m, 2H, Ar - H), 7.03 (d, J = 7.3 Hz, 1H, Ar-H), 6.75 (d, J = 7.3 Hz, 1H), 4.66 (s, 2H,

N-CH2), 4.27 – 4.16 (q, J = 7.30 Hz, 2H, O – CH2CH3), 2.95 (t, J = 6.4 Hz, 2H), 2.72 (t, J

= 6.4 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H, O – CH2CH3) while the mass spectrum (Fig 5.9)

showed m/z 234 (M+ +1, 100 %).

NH

ON O

CO2Et

(78a) (79a)

K2CO3

BrR1CHCO2Et

Equation – 5.9

150

Substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl esters (79a-k)

could also be prepared using the above method. Structures of all products 79a – k

(Equation 5.10) have been assigned on the basis of analogy and on the basis of spectral &

analytical data (Table – 5.3).

NH

ON O

CO2Et

RR

R1

(78a-c) (79a-k)

K2CO3

BrR1CHCO2Et

Equation – 5.10

Table 5.3 Synthesis of 79 (a-k) from 78 (a-c) and data:


1H NMR (200 MHz, CDCl3); IR

(KBr) / cm-1

.

78b 79b Ph H 54 IR (KBr): no absorption above 3000 cm-1

indicating

absence of –NH- grouping. Ester carbonyl appeared at

1748 cm-1

and amide carbonyl appeared at 1681 cm-1

;

1H NMR (CDCl3): δ 7.26 (s, 5H), 7.17 (d, J = 10 Hz,

2H), 7.01 (t, J = 7.32 Hz, 1H), 6.80 (d, J = 8.10 Hz,

1H), 4.84 – 4.61 (q, J = 17.46 Hz, 2H), 4.28 – 4.18 (q,

J = 7.25 Hz, 2H), 3.96 (t, J = 6.72 Hz, 1H), 1.25 (t, J =

7.25 Hz, 3H); Mass: m/z 310 (M+ +1, 100 %).

78b 79c Ph Me 49 IR (KBr): no absorption above 3000 cm-1

indicating


1742 cm-1


;

1H NMR (CDCl3): δ 7.30 – 6.79 (m, 9H), 5.07 – 4.97

(m, 1H), 4.26 – 4.08 (m, 2H), 3.80 – 3.74 (m, 1H), 3.39

– 3.20 (m, 1H), 3.18 – 3.04 (m, 1H), 1.57 – 1.43 (m,

3H), 1.28 – 1.12 (m, 3H); Mass: m/z 324 (M+1

, 100

%).

78b 79d Ph Et 51 IR (KBr): no absorption above 3000 cm-1

indicating

151


1738 cm-1


;

1H NMR (CDCl3): δ 7.28 – 6.78(m, 9H), 5.15 – 5.08

(m, 1H), 4.28 – 4.10 (m, 2H), 3.91 – 3.83 (m, 1H), 3.33

– 2.88 (m, 1H), 2.35 – 2.19 (m, 1H), 2.15 – 2.00 (m,

1H), 1.28 – 1.20 (m, 3H), 1.10 – 0.97 (m, 3H); Mass:

m/z 338 (M+ +1, 100 %).

78c 79f Ar H 57 IR (KBr): no absorption above 3000 cm-1

indicating


1735 cm-1


;

1H NMR (CDCl3): δ 7.26 – 7.16 (m, 5H, ArH), 7.05 –

7.01 (m, 1H), 6.85 – 6.77 (m, 2H), 4.84– 4.59 (q, J =

17.46 Hz, 2H, NCH2), 4.28 – 4.17 (q, J = 6.98 Hz, 2H,

O – CH2CH3), 3.95 – 3.88 (m, 1H), 3.75 (s, 3H, OCH2),

3.25 – 3.20 (m, 2H), 1.25 (t, J = 6.98 Hz, 3H, O –

CH2CH3); Mass: m/z 340 (M+, 100 %).

78c 79g Ar Me 56 IR (KBr): no absorption above 3000 cm-1

indicating


1739 cm-1


;

1H NMR (CDCl3): δ 7.26 – 7.08 (m, 5H, ArH), 7.03 –

6.74 (m, 4H), 5.38 – 5.31 (m, 1H), 4.27 – 4.10 (m, 2H,

O – CH2CH3), 3.95 – 3.89 (m, 1H), 3.73 (s, 3H, OCH2),

3.35 – 3.03 (m, 2H), 1.69 – 1.62 (m, 3H), 1.26 (t, J =

7.33 Hz, 3H, O – CH2CH3); Mass: m/z 354 (M+, 100

%).

78c 79h Ar Et 62 IR (KBr): no absorption above 3000 cm-1

indicating


1737 cm-1

and amide carbonyl appeared at 1676cm-1

;

1H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.06 –

152

7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H),

4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H,

OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.20

(t, J = 6.98 Hz, 3H, O – CH2CH3), 0.88 (t, J = 7.3 Hz,

3H); Mass: m/z 368 (M+, 100 %).

78c 79i Ar Pr 49 IR (KBr): no absorption above 3000 cm-1

indicating


1737 cm-1


;

1H NMR (CDCl3): δ 7.26 – 7.12 (m, 4H, ArH), 7.05 –

7.02 (m,1H), 6.98 – 6.74 (m, 3H), 5.47 – 5.12 (m, 1H),

4.28 – 4.10 (m, 2H), 3.99 – 3.81 (m, 1H), 3.73 (s, 3H,

OCH2), 3.35 – 3.08 (m, 2H), 2.35 – 2.04 (m, 2H), 1.21

– 1.18 (t, J = 6.98 Hz, 3H, O – CH2CH3), 0.92 – 0.85

(m, 3H); Mass: m/z 411 (M+, 100 %).

78c 79j Ar Hex 46 IR (KBr): no absorption above 3000 cm-1

indicating


1737 cm-1


;

1H NMR (CDCl3): δ 7.26 – 7.10 (m, 4H, ArH), 7.05 –

7.02 (m,1H), 6.91 – 6.74 (m, 3H), 5.53 – 5.46 (m, 1H),

4.27 – 4.10 (m, 2H, O – CH2CH3), 3.98 – 3.81 (m, 1H),

3.73 (s, 3H, OCH2), 3.36– 3.12 (m, 2H), 2.34 – 2.05

(m, 2H), 1.23 – 1.14 (m, 11), 0.98 – 0.84 (m, 3H);

Mass: m/z 424 (M+, 100 %).

78c 79k Ar Ph 49 IR (KBr): no absorption above 3000 cm-1

indicating


1747 cm-1


;

1H NMR (CDCl3): δ 7.34 – 7.26 (m, 5H, ArH), 7.22 –

7.06 (m, 4H, ArH), 7.02 – 6.86 (m, 2H, ArH), 6.83 –

6.72 (m, 2H, ArH), 3.86 – 3.83 (m, 1H), 3.80 (s, 3H),

153

3.75 (s, 3H), 3.40 – 3.20 (m, 2H). Mass: m/z 402 (M+

100 %), 369 (20 %), 342 (20 %)

Ar = 4-methoxyphenyl

154


Treatment of 79a with 1.1 eq. of LAH in THF followed by simple processing


homogenous on TLC. Its IR spectrum (Neat) did not show any diagnostic peaks due to

of –NH- and -CO- groups (Fig 5.10). Its 1H NMR (400 MHz, in CDCl3) showed (Fig

5.11) signals at δ 7.12 – 7.10 (m, 1H), 7.08 – 6.99 (m, H), 6.68 – 6.64 (m, 1H), 6.52 –

6.50 (d, J = 7. 0 Hz, 1 H), 4.850 – 4.82 (dd, J = 1.9 & 7.9 Hz, 1H), 4.22 – 4.17 (m, 1H),

4.01 – 3.95 (m, 1H), 3.51 – 3.46 (m, 1H), 3.38 – 3.34 (m, 1H), 2.84 – 2.74 (m, 1H), 2.29

– 2.23 (m, 1H), 1.69 – 1.43 (m, 2H). Its mass spectrum showed (Fig 5.12) peaks at m/z

175 (M+, 30 %), 174 (40 %), 149 (70 %), 135 (40 %), 125 (75 %), 97 (100 %). Based on

this data, the product was assigned as 1,2,4,5-tetrahydro-3aH-[1,3]oxazolo[3,2-

a]quinoline (80a). (Equation – 5.11)

N O

LAH, THF

0 °C - r.t, 1.0 hr N O

CO2Et(79a) (80a)

Equation – 5.11

The above reaction of 79a yielding 80a seems to be general one. It has been

extended to other substituted 1,2,3,4-tetrhydro-2-oxo-quinolinone-1-acetic acid ethyl

esters (79a-k) yielding 80a-k. (Equation – 5.12)

N O

RLAH, THF

0 °C - r.t, 1.0 hr N

R

O

R1R1 CO2Et

(79a-k) (80a-k)

Equation – 5.12

155

Table 5.3 Synthesis of 80 (a-k) from 79 (a-k) by reduction with LAH and their spectral

characteristics.


1H NMR (200 MHz, CDCl3); IR

(KBr / Neat) / cm-1

.

79c 80c Ph Me 65 IR: Did not show any diagnostic peaks due to –NH-

and -CO- groups. 1H NMR (CDCl3): δ 7.43 – 7.21

(m, 5H, ArH), 7.17 – 6.99 (m, 2H, ArH), 6.70 (t, J =

7.32 Hz, 1H, ArH), 6.56 (d, J = 7.81 Hz, 1H, ArH),

4.92 (d, J = 8.79 Hz, 1H), 4.27 (t, J = 6.83 Hz, 1H),

4.03 – 3.90 (m, 1H), 3.57 (t, J = 5.86 Hz, 1H), 3.43 (t,

J = 7.81 Hz, 1H), 3.19 – 2.93 (m, 1H), 2.87 – 2.69

(m, 1H), 1.44 (s, 3H); Mass: m/z 266 (M+, 100 %).

79d 80d Ph Et 52 IR: Did not show any diagnostic peaks due to –NH-


(m, 5H), 7.16 – 7.01 (m, 2H), 6.98 – 6.83 (m, 1H),

6.67 – 6.59 (m, 1H), 5.00 – 4.87 (m, 1H), 4.26 – 4.22

(m, 1H), 3.85 – 3.81 (m, 1H), 3.65 – 3.61 (m, 1H),

3.38 (m, 1H), 3.07 – 3.00 (m, 1H), 2.88 – 2.75 (m,

1H), 1.89 – 1.86 (m, 1H), 1.64 – 1.61 (m, 1H), 1.00 –

0.85 (m, 3H); Mass: m/z 280 (M+, 100 %).

79f 80f Ar H 58 IR: Did not show any diagnostic peaks due to –NH-


(m, 4H), 7.07 (d, J = 7.52 Hz, 1H), 6.93 (d, J = 8.3

Hz, 1H), 6.69 (t, J = 7.30 Hz, 1H), 6.55 (d, J = 7.82

Hz, 1H), 4.86 (d, J = 8.79 Hz, 1H), 4.31 – 4.23 (m,

1H), 3.99 – 3.90 (m, 1H), 3.82 (s, 3H), 3.57 – 3.52

(m, 1H), 3.46 – 3.34 (m, 1H), 3.5 (d, J = 13.70 Hz,

1H), 2.91 (d, J = 3.90 Hz, 1H), 2.75 – 2.64 (m, 1H);

Mass: m/z 282 (M+, 100 %), 270 (30 %), 240 (20 %)

156

and 216 (30 %).

79g 80g Ar Me 49 IR: Did not show any diagnostic peaks due to –NH-


(m, 4H), 7.09 – 7.02 (m, 1H), 6.95 – 6.78 (m, 2H),

6.72 – 6.57 (m, 1H), 4.97 – 4.92 (d, J = 9.80 Hz, 1H),

4.32 (t, J = 7.4 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.94 –

3.88 (m, 1H), 3.82 (s, 3H), 3.55 – 3.57 (m, 1H), 3.34

– 3.23 (m, 1H), 3.09 – 3.01 (m, 1H), 2.98 – 280 (m,

1H), 2.77 – 2.65 (m, 1H), 1.41 – 1.27 (m, 3H); Mass:

m/z 296 (M+, 100 %).

79h 80h Ar Et 52 IR: Did not show any diagnostic peaks due to –NH-


(m, 4H), 7.09 – 7.03 (m, 1H), 6.96 – 6.84 (m, 2H),

6.73 – 6.60 (m, 1H), 4.96 – 4.80 (m, 2H), 4.28 (t, J =

7.8 Hz, 1H), 4.03 – 3.87 (m, 1H), 3.82 (s, 3H), 3.77 –

3.59 (m, 1H), 3.48 – 3.38 (m, 1H), 3.09 – 3.01 (m,

1H), 2.99 – 266 (m, 2H), 1.98 – 1.81 (m, 1H), 1.77 –

1.46 (m, 1H), 1.02 – 0.95 (m, 3H); Mass: m/z 310

(M+, 100 %).

79j 80j Ar Hex 45 IR: Did not show any diagnostic peaks due to –NH-


(m, 4H), 7.14 – 7.05 (m, 1H), 7.02 – 6.80 (m, 2H),

6.72 – 6.59 (m, 1H), 4.95 – 4.85 (m, 2H), 4.26 – 4.23

(m, 1H), 3.81 (s, 3H), 3.61 (t, J = 7.8 Hz, 1H), 3.42 –

3.34 (m, 1H), 3.27 – 3.04 (m, 1H), 2.97 – 271 (m,

2H), 1.86 – 1.79 (m, 1H), 1.58 – 1.55 (m, 1H), 1.34

(m, 6H), 0.93 – 0.81 (m, 3H); Mass: m/z 366 (M+,

100 %).

Ar = 4-methoxyphenyl

157

158

5.4 Experimental procedure:

i) Preparation of 77a: A mixture of 2-nitrobenzaldehyde (75, 5.0 gms, 33 mmol) and

triphenylphosphine ylid (76, 13.8 gms, 39 mmol) in benzene (150 mL) was refluxed for

24 hours at 80 °C. Then the mixture was cooled to r.t, adsorbed over silica gel and

purified through column chromatography to give pure 77a as thick liquid (5 gms, 71 %).

ii) Preparation of 77b and c (General procedure): A mixture of 2-nitrobenzaldehyde

(75, 20.0 gms, 131.11 mmol), phenylacetic acid (197.35 mmol of 4 or 13), acetic

anhydride (67.0 mL, 657 mmol) and triethylamine (18.0 mL, 131.11) were refluxed at 90

°C for 15 min. The solution was cooled, the separated solid was filtered and washed with

mixture of water-acetic acid to give 77a & b, yield of 77a 28 gms (79 %); yield of 77b

32 gms (82 %)

iii) Preparation of 78a-c (General procedure): 10 % palladium carbon (1.0 gm/10.0

gms of substrate) was charged in hydrogenation flask, made wet with acetic acid (10

mL/1.0 gm of substrate) and to this 78a-c (1.0 gm, in10 mL of acetic acid) was added at

room temperature. Then the flask was arranged for parr hydrogenation for 6 hrs at 60 psi

H2 pressure. The reaction mixture was filtered through a pad of Celite to remove

palladium carbon and the filter bed washed with acetic acid. The filtrate was stirred with

water (100 ml/1.0 gm substrate) and the separated white solid was filtered, washed with

water and dried to give 78a-c. (Table-5.1)

iv) Preparation of 79a-k (General procedure): To a solution of 78 a – c (1.0 eq) and


alkyl acetate (1.2 eq) drop wise at room temperature. After 24.0 hrs stirring, the mixture

was poured in to water and the separated solid was filtered, washed with water and dried

to give 79a-k. (Table-5.2)

159

v) Preparation Of 80a – k (General procedure): To a solution of 79a – k (2.0 mmol) in




filtered and the filtrate concentrated. The crude product was purified by column

chromatography using ethyl acetate and pet. Ether (5:95) to give 80a – k (Table-5.3).

5.5 References:

01. (a) Pellettier, S. W., Walter A. Jacobs. J. Amer. Chem. Soc. 1954, 76, 4496.

(b) Pellettier, S. W., David M. Locke. J. Amer. Chem. Soc. 1965, 87 (4) 761.

(c) Pellettier, S. W., Parthasarathi, P. C. J. Amer. Chem. Soc. 1965, 87 (4) 777.

(d) Pellettier, S. W., Naresh V. M., Haridutt K. D., Janet Finer-Moore, Jacek

Nowacki, and Balawant S. J., J. Org. Chem., 1983, 48 (11), 1787. (e) Naresh V.

M., Pellettier, S. W., Tetrahedron; 1978, 34, 2421.(f) Pellettier, S. W. and

Walter A. J., J. Amer. Chem. Soc. 1956, 78, 4144.

02. Crist N. Filer, Felix E. Granchelli, Albert H. Soloway and John L. Neumeyer.

J. Org. Chem., 1978, 43 (4), 672.

160

03. (a) Spath, E.; Dengel, F. Chem. Ber., 1938, 71B, 113. (b) Masatoshi, Y.;

Kuniko, H.; Shigetaka, I. and Nazmul, Q. Tetrahedron Letters; 1988, 29 (52),

6949.

04. (a) Trevor, A. Crabb and Asmita V. Patel. Heterocycles. 1994, 37 (1), 431.

(b) Marie-Christine Lallemand; Mathieu Gaillard; Nicole Kunesch and Henri-

Philippe Husson. Heterocycles. 1998, 47 (2), 747. (c) Kukharev, B. F.;

Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.; Albanov, A. I. Arkivoc,

2003, xiii, 166.

05. Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.; Bayandin, V. V.;

Albanov, A. I. Arkivoc, 2003, xiii, 166.

06. (a) Jean-Charles Quirion, David S. Grierson, Jacques Royer and Henri-Philippe

Husson. Tetrahedron Letters; 1988, 29 (27), 3311. (b) Lue Guerrier, Jacques

Royer, David S. Grierson and Henri-Philippe Husson. . J. Amer. Chem. Soc.

1983, 105, 7754. (c) Mercedes Amat, Nuria Llor, Carmen Escolano, Marta

Huguet, Maria Perez, Elies Molins and Joan Bosch. Tetrahedron Asymmetry;

2003, 14, 293. (d) Teran, J. L. Gnecco, D. Galindo, A. Juarez, J. Bernes, S. and

Enriquez, R. G. Tetrahedron Asymmetry; 2001, 12, 357.

07. (a) Mercedes, A.; Nuria, L.; Carmen, E.; Marta, H.; Maria, P.; Elies, M and

Joan, B.; Tetrahedron Asymmetry; 2003, 14, 293. (b) Jean-Charles, Q.; David S.

G.; Jacques, R and Henri-Philippe H.; Tetrahedron Letters; 1988, 29 (27), 3311.

(c) Lue, G.; Jacques, R.; David S. G and Henri-Philippe Husson. . J. Amer.

Chem. Soc. 1983, 105, 7754.

08. (a) Martin, E.; Asuncion M.; Lusia, M. M.; Luis S. R.; Pilar, P. P.; Manual, M.;

Esther, C. and Arturo S. F. Bioorg Med Chem Lett. 2000, 10 (4), 419. (b)

Esther C.; Pilar P. P.; Manual M. and Arturo S. F.; Tetrahedron; 1993, 49 (44),

10079. (c) Esther C.; Pilar, P. P.; Mar, S.; Manuel, M.; Lourdes, M.; and Arturo

S. F.; Tetrahedron Asymmetry; 1996, 7 (7), 1985. (d) Esther C.; Pilar, P. P.; Mar

S.; Miguel, A. S.; Garcia-Granda and Arturo S. F.; J. Org. Chem., 1996, 61 (9),

1890.

161

09. Mali R. S., Yadav V. J., Synthesis, 1984, 10, 862.

10. Bakunin, Peccerillo, Gazz. Chim. Ital.; 1935, 65, 1145. (ii) Org. Synth. Coll.

vol.; 1963, V, 730

11. (a) Schlaeger, Leeb. Monatsh. Chem., 1950, 81, 714. (b) Blout, Silverman, J.

Amer. Chem. Soc., 1944, 66, 1442.

12. (a) Loudon, Ogg., J. Chem. Soc.,1955, 739. (b) Hino, Katsuhiko, Nagai

Yasutaka, Uno, Hiyoshi.; Chem. Pharm. Bull.; 1987, 35 (7), 2819.

CONCLUSIONS & HIGHLITS

A simple method has been developed for the synthesis of Novel tricyclic oxazolo

or oxazine derivatives,

This method represents a good example of reductive cyclization with lithium

aluminumhydride.

The oxazolo compounds are structural mimics of some known biologically active

molecules.

Preparation of starting materials (benzothiazin-3-ones and quinoxaline-2-ones) in

this work was made by the method of high-speed parallel synthesizer using

microwaves and water as solvent.

Intense use has been made of chromatographic methods to isolate products in a

state of high purity.

Intense use has been made of spectroscopic methods and X-ray diffraction

technique to assign structures for products to the highest accuracy and detail.

162

APPENDIX – LIST OF PUBLICATIONS

1. Novel Method for the preparation of Tricyclic [6:6:5] systems by Reductive

Cyclization with Lithium Aluminum Hydride (LAH).

B. B. Lohray, V. B. Lohray, A. Sekar Reddy, V. Venugopal Rao.

Indian .J. Chem., Vol. 39B, April 2000, pp. 297 – 299.

2. 7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new

heterocycle.

S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas. Venugopal Rao

Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu Akella and

Pramod Kumar Dubey.

32nd

National Seminar on Crystallography, October 24 – 26, 2002. Jammu,

INDIA. (Poster Presentation)

3. 7-nitro-1,2,3a,4-tetrahyfrobenzo[b][1,3]oxazolo[3,2-d]oxazine: A new

heterocycle. S. Vishnuvardhan Reddy, A. Sivalaxmi Devi, K. Vyas.

Venugopal Rao Veeramaneni, Koteswar Rao Yeleswarapu, Venkateswarlu

Akella and Pramod Kumar Dubey.

Acta Cyrstallographia E, 2003, E359

4. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2H-

benzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.



Pharmacophore, January 16-17, 2004, Hyderabad. INDIA.

(Poster Presentation)

5. Novel method for the preparation of poly cyclic [6:6:5], [6:6:6] and [6:6:7:6]

systems by reductive cyclization with LAH.



IUPAC – BNP – 2004. January 26 – 31, 2004, New Delhi, INDIA.

163

(Poster Presentation)

6. One pot and High-Speed Parallel Synthesis of Substituted 3,4-dihydro-2H-

benzo[b][1,4]thiazine-3-ones And 1,2,3,4-tetrahydro-2-quinoxalinones.



(J. Org. Chem., Will be communicated)

7. Novel method for the preparation of tri cyclic [6:6:5] oxazolooxazines,

oxazolothiazines, oxazoloquinoxalines and oxazoloquinolines by reductive

cyclization with LAH.




8. Novel method for the preparation of poly cyclic [6:6:6] [6:7:5]and [6:6:7:6]

systems by reductive cyclization with LAH.




Ph.D THESIS by Venugopal Rao Veeramaneni

Documents