VILSMEIER-HAACK REACTIONS OF TERTIARY ALCOHOLS: …shodhganga.inflibnet.ac.in/bitstream/10603/94/9/08_chapter2.pdf · of methyl Grignard to substituted acetophenones. Thus the hitherto

VILSMEIER-HAACK REACTIONS OF TERTIARY ALCOHOLS: SYNTHESIS OF FUNCTIONALIZED

PYRIDINES AND NAPHTHYRIDINES

2.1 Introduction

The Vilsmeier-Haack reaction is a widely used method for the formylation of

electron rich substrates, particularly aromatic compounds.' In &tion to simple formylation

reactions, Vilsmeier reactions are also employed in interesting synthetic transformations on

carbonyl compounds and their derivatives2 These versatile reagents can very easily be

prepared by the reaction of a N,Ndsubstituted formamide with an acid halide.

In continuation of our studies on the utility of Vilsmeier reagents in organic

synthesis, we have examined their reactions with tertiary alcohols. Our survey of

literature revealed that there are only a few reports on the synthetic utility of the iminium

salt intermediates derived from carbinols and their subsequent transformations to

synthetically useful compounds. Rao et al. has reported a one-pot synthesis of biphenyls

2 by the Vilsmeier reaction of homoallyl alcohols 1 (Scheme I).'

1 2 Scheme 1

The Vilsmeier reaction has been employed in the synthesis of aromatic aldehydes

from acyclic compounds. For example, the acyclic unsaturated alcohol 3 on treatment

with chloromethyleneiminium salts gave uvitaldehyde 4 (Scheme 2)'

CHO I

OHC

3 4 Scheme 2

Lelouche and co-workers have converted 0-tert-Butyldlmethylsilylated or

0-triethylsilylated alcohols 5 to their corresponding 0- formyl derivatives 6 in a one step

procedure using V~lsmeier reagents (Scheme 3)'

Me Me

___)

TBWSO OKX)

5 Scheme 3

In the present study, we have examined the reactivity of Vilsmeier reagents with

the tertiary alcohols derived from alkyl aryl ketones having active methyl or methylene

groups, which led to a convenient path for the synthesis of functionalized pyridines and

naphthyridlnes having the synthetically valuable formyl functionality. Pyridlnes are

important among heterocyclic compounds and are present in several biological systems.

They also find applications as agrochemicals and anticancer agents6 Extensive studles

have been camed out on the synthesis of these valuable compounds owing to their

importance as drugs and biologically active natural products.'

2.2 General Methods for the Preparation of Functionalized Pyridines

Functionalized pyridines are valuable precursors for the synthesis of a wide

variety of biologrcally active organic molecules. Jutz and co-workers have reported the

synthesis of 4-aryl pyridine carboxaldehydes 11 from 2-phenyl propene 7 employing the

Vilsmeier Haack protocol (Scheme 4)'

11

Scheme 4

Boruah and co-workers have reported the reactions of conjugated oximes with

Vilsmeier reagents. They found that the reaction of the steroidal oxime 12 with POCl,

and Dh4F at 65 'C afforded the pyrido-steroidal product 14 in good yields. When the

reaction was camed out at 0 OC, C-16 formylated product 13 was formed (Scheme 5).9

The Vilsmeier reaction on benzalacetone oximes afforded formylated chloropyndines.

Perumal and Amaresh, also have shown that oximes of a, P-unsaturated ketones can be

transformed to 3-pyr~dine carboxaldehydes under Vilsmier-Haak conditions.1°

AGO -:.;'.I 12 65C O

Scheme 5

The V~lsme~er Haack reaction of enamidines 16 obtained by the treatment of

substituted acetanilides 15 with PCIS gave 6-chloro-1-aryl-2-iminopyridine 17 and its

analogues (Scheme 6)."

16

Scheme 6

Meth-Cohn and Westwood have developed a general method for the preparation of

qlllnolines and fused pyridines from acyl anilides or related compounds." For example 5-

Substituted 2-acetamidothiophens 18 can be converted into 6-chlorothieno[2,3-blpyridine-5-

carbaldehydes 19 by treating with seven mol equivalent of POCI, and three mol equivalent

of &methyl formamide under reflux for 3 hours (Scheme 7). l3

POCWMF 3h, reflw

19

Scheme 7

Pyndines having aryl substituents at 3-,5-, and 6 positions were synthesized by

Powell et. al. by the hydrochloric acid medlated cyclization of 5-(dimethylamino)

aryl-substituted pentadienyl nitriles 21. This method allows for the incorporation of

electron-withdraw~ng substituents on the pyndine ring as well as the preparation of

desired unsubstituted aryi pyridines (Scheme 8).14

21

Scheme 8

The 4-aryl substituted glutarimides 23 on treatment with Vilsmeier Naack reagent

(POCl2 and DMF) and subsequent hydrolysis with sodium acetate followed by acid

bydrolysis gave the chlorosubstituted dicarboxaldehydes" 24. They could be fiuther

oxidised to the correspondmg pyridine derivatives 25 using ceric ammonium nitrate

(Scheme 9).

Scheme 9

Commtns e l . ul. have prepared 3-pyridine carboxaldehydes 28 from

3 -substituted 1 -(phenoxycarbonyl)-1,2-dihydro pyrimnes 26 by reaction with

Vilsmeier reagent followed by treatment with hot sulfur (Scheme 10).16

UR- DMF ""vR & N I I COOPh COOPh R- Br, a, MeO. Me, Fh

26 27 28

Scheme 10

Similarly N-acyl-2,3-dihydro pyridones react with one equivalent of Vilsmeier Haack

reagent to afford 1 -acyl-4-chloro-l,2-dihydro pyridines.17

Matsumoto and coworkers" have reported the synthesis of substituted pyridines

from a$-unsaturated carbonyl compounds through a sequence involving 1,4conjugate

addition of thophenol, condensation with a methylene ketone, the Pummerer

rearrangement to an unsaturated 1,5-dicarbonyl compound and treatment with ammonia

(Scheme 1 1 ).

33 Scheme 11

1,3-Diphenylpropenone 35 ( R = Ph ) reacted with malononitrile in methanolic

sodium hydroxide to afford 4,6-diphenyl-2-methoxypyridine-3-carbo~trile'9 36. When

the reaction was carried out in various alcohols the appropriate alkoxy group was

introduced at C-2 (Scheme 12). The proposed mechanism involves the ring opening of

the initially formed Z-amino-4,6-diphenyl-4H-pym and the subsequent pyridine ring

formation employ~ng the nitrogen of the 2-amino group.

R 'C6H5, CH=CH--C&, napthyl

Scheme 12

The 2-azahexa-l,3,5-triene generated by the aza-Wittig reaction of iminophosphoranes

37 derived fiom a-azidw,P-unsaturated esters and earyl propenals 38 undergo a thermal

6- electrocyclization to give 4-aryl pyridines 39 (Scheme 13).'O

39

Scheme 13

Kambe and co workers have reported the direct synthesis of 2-aminopyridine

derivatives 43 by the condensation reaction of malononitrile 42 with aromatic aldehydes

40 and alkyl ketones 41 in presence of ammonium acetate (Scheme 14).''

0- 0 I I

CHO + &-C-CH2-$ + NH40Ac

R" .. .* CN bemene --_____--- 40 41 42

43

Scheme 14

Oxime derivatives of 5-oxoalkanenitriles 44 underwent cyclization when refluxed

in presence of AcCl and Ac20 to give 2-(N-actey1amino)-6-methyl pyridines, which on

hydrolysis with aqueous NaOH afforded 2-aminod-methyl pyridines 45 in good yields

(Scheme 15).12

1. AcCV Am1 HCI

2. NaOW H20

Scheme 15

Another approach to substituted pyndines employs palladium-catalyzed

min no annul at ion of alkynes. Thus vinylic imine 46 underwent palladium catalysed

reaction with a variety of aryl acetylenes 47 to afford highly substituted pyndine

derivatives 48 (Scheme 16).23

47 Scheme 16

Oximinosulfonates 50 derived from meldrum's acid 49 by nitrosation undergoes

Diels-Alder cycloaddition with a host of 1,3dienes to afford the corresponding

tetrahydropyridine cycloadducts 51, which on subsequent oxidation using

N-chlorosuccinim~de and sodium methoxide gave substituted pyridines 52 in excellent

yields (Scheme 17 I.'"

R' ,OTs 2

NaQ. &OH- YO: then 13$, 0.9 equiv Tsa

O x 0

* pH7buffer. 15rrin

OX" 2 equiv &fin, w,, - 7 h

r -

3 equiv M O M ,

lequw. W. WOH-TW ( IZ1 )

1.t. COOMe

Scheme 17

Trifluoromethyl substituted P-diketones 53 underwent regoselective reaction

with ethyl p-aminocrotonate to afford 4-trifluoromethyl pyridine~.~' The mechanism

involves the Michael addition of the enamine to the en01 form of the trifluoromethyl

substituted S-diketone 54 and 1 or the addition of the enarnine to the more reactive

CFj-carbonyl of 53 producing an adduct 55, which upon subsequent cyclization and

dehydration gves the 4-trifluoromethyl pyridine 57 (Scheme 18).

56 Scbeme 18

2-(benzomazol- 1 -yl)acetonitrile 59 has been reported as a valuable precursor for

the synthesis of substituted pyridine~.~~ It reacts with a,fhnsaturated ketones 58 to

provide an efficient method for the regioselective preparation of both 2di(substituted

amino) pyndines 60 and 4,6-substituted pynd-2-ones 61. The formation of the pyridine

nucleus results from tandem [3+3] annulations involving a Michael addition followed by

cyclization (Scheme 19).

61

Scbeme 19

The discuss~on on the reported methods for the synthesis of functionalized

pyridines reveals that those having the aryl and formyl moieties on their skeleton are

very rare. The s w e y also reveals that their synthesis from tertiary alcohols have not

been reported till date. The formyl group present on these molecules make them

promising precursors for many synthetic transformations.

2.3 Results and Discussion

Reactions of aliphatic alkenes with chloromethyleneiminium salt are often

accompanied by multiple imino alkylations leadmg to the formation of conjugated

polyenaldehydes as end products. Jutz et. al. have shown that the interme&ate iminium

salts formed from 2-phenylpropene and isobutene cyclise to substituted pynhne or

naphthyridine in the presence of ammonium acetate. We envisioned that direct treatment

of tertiary alcohols with chloromethyleneiminium salts should lead to five carbon units

with terminal electrophlic centers. Treatment of such intermediates with ammonium

acetates would provide an easy access to valuable functionalized pyridines. We have

subjected the tertiary alcohols derived from alkyl aryl ketones like acetophenone to

Vilsmeier conditions. The reactivity of tertiary alcohols derived from a,P-unsaturated

ketones towards Vilsmeier reagents was also studied. In both cases, the corresponding

aryl pyri&ne carboxaldehydes were obtained in good yields. When the same reaction

protocol was extended to tertiary alcohols derived from aliphatic ketones and alicyclic

ketones, napthyridine derivatives were obtained in impressive yields.

2 . 1 Reactions of 2-Aryl-2-propanols with Chloromethyleneiminium Salt Followed by Ammonium Acetate

The 2-phenylpropan-2-01 63a can conveniently be prepared by the Grignard

reaction of the corresponding acetophenone 62a. The crude carbinol is then treated with

the chloromethyleneiminium salt derived from POCl, and DMF for two hours at 80 OC

using DMF as solvent. Excess solid ammonium acetate is then added to the reaction

mixture and agaln heated at 80 OC for two more hours. Subsequent work up using ,, , saturated potasslum carbonate solution, extraction with &ethyl ether and column

chromatography over sllica gel using hexane:etliyl acetate(l6:4) afforded a solid product

having mp 40-41 'C in 60 % yield (Scheme 20). The compound w& identified as

4-phenylnicotinaldehyde 64a on the basis of comparison of spectral and physical data

with the reported value^.^'.^

The reaction was extended to several 2-aryl-2-propanols derived by the addition

of methyl Grignard to substituted acetophenones. Thus the hitherto unreported

4-arylnicotinaldehydes 64 b-e were obtained in 60-66 % overall yields.

Scheme 20

64

The mechanism for the formation of aryl pyridine-3-carboxaldehydes from

tertiary alcohols can be rationalized as follows. The acid catalyzed dehydration of the

tertiary alcohol affords the intermediate alkene, adds sequentially to three moles of

X 1 Yield (%)

chloromethyleneiminium salt derived from POC13 and DMF to give a multiple

iminoalkylated enamine derivative 68. The enamine derivative undergoes cyclization in

the presence of ammonia to form an iminiurn salt substituted pyridine which on

subsequent hydrolysis affords 4-arylnicotinaldehyde 64s.

Scheme 21

The same protocol was extended to 2-(2-naphthy1)propan-2-01 71 derived from

2-acetyl naphthalene 70 to afford the corresponding 4-(2-napthy1)nicotinaldehyde 72 in

43% yield (Scheme 22). The structure of the product was confirmed by spectral data(see

experimental).

72

Scheme 22

Our attempts to extend this protocol for the synthesis of pyridines from aliphatic

ketones like ethyl methyl ketone and diethyl ketone, alicyclic ketones like

cyclohexanone and other systems such as a-tetralone and 2-acetylpyndine were less

successful and resulted in complex reaction mixtures.

1. MeMgl

2. POCI, I DMF

3. NH40Ac

73

Scheme 23

1. MeMgl

2. POC13 I DMF

3. NH40Ac

Scheme 24

Scheme 25

1. MeMgl

2. POCI3 / DMF

3. NH40Ac

Scheme 26

2.3.2 Reaction of 2-Methyl-4-phenyl-3-buten-2-01 with Chloromethyleneiminium Salt Followed by Ammonium Acetate

We have next examined the reactivity of 2-methyl-4-phenyl-3-buten-2-01 82

derived from benzalacetone 81 to Vilsmeier-Haack reagent. The wbinol was treated

with four equivalents of Vilsmeier reagent prepared by the addition of POC13 to DMF.

The reaction was carried out at 80 OC for two hours. Solid ammonium acetate was added

to the reaction mixture and again heated at 80 OC for two more hours. The mixture on

usual work up and chromatography on silica gel using hexane: ethyl acetate (16:4) as the

eluent afforded a pale yellow solid having mp 66-67 'C in 51% yield. The compound

was identified as 4-(phenylvinyl)nicotinaldehyde 83 on the basis of the spectral data

(Scheme 27). The 'H NMR (90 MHz, CDC13) shows a 5 proton multiplet at 6 7.5-7.7 due

to the phenyl group. The two doublets at 6 7.25 and 8.17 respectively (lH, J=15.8) are

due to two [runs vinylic protons on the alkene moiety. The singlet at 6 9 is due to the

proton at C-2 of the pyridine ring. The doublets at 6 7.4 and 8.7 (lH, J=5.3 Hz) are due

to protons at C-5 and C-6 of the pyridine ring respectively. The singlet at 6 10.3 arises

13 from the aldehyde proton on the pyridine . C NMR (22.4 MHz, CDC12) shows signals

at 6 119.87, 122.05, 127.12, 127.30, 128.67, 129.12, 135.66, 137.03, 145.98, 153.14,

154.89 due to vinyl~c and aromatic carbons. A strong peak at 6 191.59 is due to the

aldehyde carbon. The IR spectrum shows bands at 1680, 1620, 1590, 1490, 1440, 1410,

1310, 1230, 1190 cm-' respectively. Finally the structure was confirmed by the mass

spectrum(EIMS), having the molecular ion peak at mlz 208.

Scheme 27

Our efforts to introduce other substituents on the aryl functionality by treating the

carbinols derived from other sustituted benzalacetones did not give good yields of the

expected arylviny 1 pyridines.

2.3.3 Reactions of 2-Aryl-2-butanois with Chloromethyleneiminium Salt Followed by Ammonium Acetate

We have next studied the reactivity of chloromethyleneiminium salts with 2-aryl-2-

butanols in order to introduce alkyl substituents on the pyridne ring, in addition to the aryl

and formyl groups. Thus, the 2-phenyl-2-butanol 84a was treated with Vilsmeier reagent

formed from POCI? and DMF at 80 OC for 2 hours, to the reaction mixture added solid

ammonium acetate in excess and heated the mixture for 2 more hours. Work up followed by

chromatogaphy on silica gel with hexane:ethyl acetate(l6:4) as eluent afforded an yellow

solid in 55% yeld, mp 65 'C (Scheme 28). The compound was identified as 5-methyl-4-

phenyhw~naldehyde 85a on the basis of spectral data. The proton NMR spectrum

(200MHz C X i ? ) of 85a showed a singlet due to the methyl group at 6 2.17 ppm. The

aromatic protons of the phenyl group appeared as two multiplets between 6 7.22-7.31 ppm

and 7.45-7.60 ppm lntegrahng for two and three protons respectively! The singlets at 6 8.68

and 8.98 were attributed to the protons at C-6 and C-2 of the pyridme ring. The aldehyde

proton appeared as a singlet at 6 9.79 ppm. I3c NMR (50.32 MHz, CDCb) shows signals at

6 17.08 due to the methyl group on pyridine ring (PyCH3), 129.09, 129.36, 132.38, 134.21,

147.30, 152.06, 155.08 are aromatic carbons. A strong peak at 6 191.85 is due to the

aldehyde carbon. The lR spectrum shows bands at 3050,2850, 1680, 1575, 1435, 1380 and

1260 cm" respectively Finally the structure was confirmed by the mass spectrum(EIMS),

having the molecular ion peak at 197 (100, M+).

Scheme 28

We next attempted to introduce one more methyl group in the pyridine ring in the

place of the formyl group. Thus propiophenone on treatment with ethyl Grignard

followed by subsequent reaction with Vilsmeier reagent and ammonium acetate afforded

a complex reaction mixture.

1. EtMgl

2. POCI, I DMF

3. NH,OAc

Scheme 29

2.4 Reactions of Aliphatic and Alicyclic Tertiary Alcohols with Chloromethyleneiminium Salt: Synthesis of Functionalized Napthy ridines

We have also examined the reactions of tertiary alcohols with

chloromethyleneiminium salts. Jutz et. 01. have reported that the reaction of

2-methylpropene with excess of chloromethyleneiminium salt proceeds with multiple

iminoalkylations and cyclization of the iminoalkylated intermediate induced by

ammonium acetate leads to the formation of [2,7]-naphthyridine4carbaldehyde.

Considering the prevalence of [2,7]-naphthyridine moiety in biolo~cally active marine

natural alkaloids we became interested in this transformation. We envisaged that the

reaction of tertiary alcohols with chloromethyleneiminium salts would lead to the

formation of the corresponding alkene, which upon sequential multiple iminoalkylation

followed by ammonium acetate mediated cyclization may afford substituted

naphthyridines.

Our survey of literature revealed that the chemistry of [2,7] naphthyridine

derivatives has been little explored, partly due to the d~fficult and multistep synthesis of

these comp~unds.'~ In 1978, Baldwin and Ponticello have reported the synthesis of

naphthyridinones starting from methyl substituted pyridine carbonitriles. For example

I-hydroxy-[2,7]-napthyndine 90 was prepared by the reaction of DMF acetal with

4-methylnicotinon~tnle 88 followed by acid cyclization of the resulting enamines 89

(Scheme 30)."

89

Scheme 30

lsoolefins are known to undergo stepwise acetylations under Friedel-Crafts

conditions. Thus isobutylene 91 derived from t-butanol under the reaction conditions

underwent tetraacetylation in a mixture of AIC13 and AcCI followed by treatment with

liquid ammonia afforded 1,3,6,8-tetramethy1[2,7]napthyridine 92 and 2,4,6-trimethyl

pyridne 93 in 63 and 37% yields respectively (Scheme 31)"

92

Scheme 31

The same research group have reported a modified synthetic strategy which

enables regioselective introduction of one of the alkyl groups and also proves the

intermdacy of 4acetonylidene-2,4-drmethyl4H-pyran in the formdon of naphthwdine ring

system." This method involves a tetraacylation of 2-methyl-1-propene followed by hydrolysis

and then further acylation using a different acyl halide. Thus they treated the intermediate

4-ketyonylidene-2.6-dialkylpyran 94 with a different acyl halide in presence of AICI, and

treated the reaction mixture with NH3 to obtain the wrrespodng napthyndine derivative 97

regioselectively in quantitative yields (Scheme 32).

96

Scheme 32

Dibenzoyl pyridines 98 react with methyl amine derivatives 99 in 10% ethanolic

KOH under reflux to give [2,6]- and [2,7]-napthyridines lOOa andlOOb (Scheme 33).32

Ph Ph

%h pwphy#h 0' KOH

+ Ph-C*-NHz= 0, \ N N \ N \ / N ' Ph

Ph Ph Ph Ph Ph Ph

98 99 lOOa lOOb

Scheme 33

Substituted benzo[c]napthyndines are the key structures in the molecular

framework of many marine alkaloids. 4,5 Disubstituted benzo[c]napthyridines 104 have

been prepared by the dlrected ortho metallation of pyridines followed by a halogen dance

reaction and biaryl cross-coupling. The substituted pyridines 101 are subjected to

metallation-iodination sequence. Further lithiation, which is ortho directed by the

iodogroup, affords a 2-substituted-3-lithio-4-iodopyridine which was quenched with the

electrophile 4-pyndinecarbonitrile to form an imine which on cross-coupling with aryl

~ O ~ O N C acid under Suzda's procedure results in a spontaneous cyclization to give the

napthyndine derivative 104 in impressive yields (Scheme 34).33

1.R LII -70'~ / MF 1. LDA 13K70k I THF

2. Y-~o@C/T-IF 2.4-cyanopyridinel2h 3. b0

104 Scheme 34

Iminophosphoranes 105 prepared from 4-formyl pyridines by the sequential

treatment with ethyl azido acetate and triphenyl phosphine reacted with isocyanates in an

Aza-Wittig fashion to give carbodiimides 106 which undergo cyclization to substituted

napthyndines 107 (Scheme 35)"

COOEt COOEt COOEt

106

Scheme 35

Methylenedthydropynhes 108a and 108b can be converted to [2,7-napthyTidines

derivatives 109a and 109b by a cyclization reaction using phosphoric acid." The starting

materials can be prepared from 2(1H)-pyridenethiones by alkylation using methyl iodide

followed by reaction with active methylene compounds like malononitrile or ethyl

cyanoacetate in the presence of a base (Scheme 36).

R = Me. SBn

- 130 C

SMe I

108b 109b Scheme 36

The protocols depicted above reveals that the synthesis of [2,7]-napthyridines,

though of immense significance, are very few in number. None among the procedures

reported so far has employed the tertiary alcohols as starting materials for their synthesis.

The functionalized [2,7]-napthyridines being promising precursors in the synthesis of a

wide spectrum of natural products, a facile route to their synthesis would prove to be one

of substantial importance in organic synthesis.

2.4.1 Reaction of tert-Butanol with Chlorometbyleneiminium Salt Followed by Ammonium Acetate

(err-Butanol 110 was treated with six equivalents of Vilsmeier reagent at room

temperature for 15 hours, cooled to 0 OC, added solid ammonium acetate in excess and

again stirred at 0 'C for 1 more hour. The reaction mixture after usual work-up and

purification by chromatography afforded white crystalline solid in 18% yield having mp.

2 15-2 16 'c.'"' The compound was identified as [2,7]naphthyridine-4-carbaldehyde 111

(Scheme 37). The ' H NMR spectrum (300 MHz, CDC13) shows peaks at 9.60,9.54,9.17,

8.96,7.28 are due to the protons on the naphthyndine ring. The peak due to the aldehyde

group found at 10.42. The I3c NMR spectrum (75.48 MHz, CDCI3) shows signals at

117.22, 123.34, 123.93, 135.61, 150.32, 153.23, 155.56, 158.51 which are naphthyridine

ring carbons and a peak at 191.81 is due to the aldehyde carbon atom. The IR (KBr,v,,)

of the compound" shows peak at 2850 (C-H,, aldehyde), 1695 (C=O,, aldehyde), 1626

(C-C,, ring), 1433 (C-N,, ring). Mass spectrum of the compound shows the molecular

ion peak at miz 158

1. POCIS I DMq 6 equiv. )

H3c CH:, 2.r.t.,15h H3C 3. NH40Ao O'C, I h

Scheme 37

A plausible mechanism for this transformation is shown in Scheme 38.

Formation of 2-methylpropene 112 by the elimination of Hz0 followed by

iminoalkylation and elimination of HCI would afford the N,N-dimethylamino

substituted diene 113. Further sequential imino alkyalations involving four

equivalents of chloromethyleneiminium salt would finally lead to the tris iminium

salt 115 which on treatment with ammonium acetate followed by a&eous basic work

up would afford the [2,7]naphthyridine-4-carbaldehyde 111.

115

Scheme 38

2.4.2 Reaction of 2-Methyl-2-butanol with Chloromethyleneiminium Salt Followed by Ammonium Acetate

We have next studied the reaction of 2-methyl-2-butanol 116 with Vilsmeier reagent

prepared from POCI? and DMF. To the carbinol 116 after treatment with six equivalents of

Vilsmeier reagent at room temperature for 15 hours and subsequent cooling to 0 OC, was

added excess solid ammonium acetate and allowed to react for one more hour. Usual workup

and purification of the mixture gave a pale yellow solid in 11% yield. The compound was

identified as 5-methyl[2,7]naphthyridine4-carbaldehyde 117 (Scheme 39). The 'H NMR

spectrum (300 MHz, CDCI3) shows peaks at S 2.72 (s, 3H, CH3- ), and singlets at 6 8.65,

9.05, 9.28, 9.46 ppm. are due to protons on the naphthyridine ring. The aldehyde proton

shows peak at 6 10.90 ppm.; The I3c NMR spectrum (75.48 MHz, CDC13) shows signals

at 21.69 (the CH3 carbon), 118.90, 123.38, 126.07, 127.66, 150.02, 150.46, 152.12, 158.28

are due to naphthyid~ne ring carbons and a peak at 191.29 ppm. is due to the aldehyde

carbon; IR (KBr, v,,) 2962, 1683, 1601, 1261, 1097, 1023 cm-', Finally the structure was

confirmed by the mass spectrum, which shows the molecular ion peak at miz 172.

H 3 4 1. P0Cl3 I DMR: 6 equiv. 2.r.t., 15h

H3C CH3 3. NH40A= O'C, 1 h

Scheme 39

2-43 Reaction of 3-Methyl-3-pentanol with Chloromethyleneiminium Salt Followed by Ammonium Acetate

The reaction of 3-methyl-3-pentanol under similar conditions afforded a brown

oil in 90io yield, which was identified as 4,5-dimethyl[2,qnaphthyridine 119 (Scheme 40).

The 'H NMR (300 MHz, CDC1,) shows peaks at 6 2.91 due to the CH, substituents. Peaks

due to the ring protons appeared at 6 7.93 and 7.99 ppm. respectively. The structure was

confirmed by the mass spectrum, which shows the molecular ion peak at m/z 158.

1. POCi3 I DMF( 6 equiv. )

3. NH40Ao 0 k , 1 h CH3

CH3 CH3

Scheme 40

2.4.4 Reaction of 1-Methyl-1-cyclohexanol with Chloromethyleneiminium Salt Followed by Ammonium Acetate

We have examined the reactivity of 1-methyl-I-cyclohexanol 120 with

chloromethyleneiminium salt derived from POC13 and DMF. The carbinol was

prepared from cyclohexanone by Grignard reaction and the crude carbinol was added

to six equivalents Vilsmeier reagent at room temperature and the reaction was allowed

to proceed for 15 hours. The reaction mixture was then cooled to 0 OC and treated with

excess ammonium acetate for one hour. Subsequent work up and purification on

silicagel column afforded a brown oil in 8% yield. The structure of the compound

was elucidated as 8.9-dihydro-7H-benzo[de][2,7]naphthyridine 121 (Scheme 41). The

'H NMR(300 MHz, CDC13) 6 2.05, 2.99, 8.45, 9.17; I3c NMR (75.48 MHz, CDC13)

6 21.28, 25.59, 121.63, 127.59, 134.75 ,142.89, 149.09 ppm.; IR (neat, v,,) 2932,

1612, 1545, 1432, 1382, 1270, 11 19 cm-I; Finally the structure was confirmed by the

mass spectrum (EIMS), which shows the molecular ion peak at 170 (100, M+).

Scheme 41

2.5 Conclusions

The reactions of a variety of tertiary alcohols with chloromethyleneiminium salt

were examined. Our studies reveals that multiple imino alkylated intermehates could be

cyclized by the incorporation of ammonia as a nucleophile, to afford substituted

pyridines with aryl, alkyl and formyl functionalities. When this protocol was extended to

the stylyl carbinol derived from benzalacetone, functionalized pyridine with a styryl

substituent was obtained. Similarly, carbinols derived from aliphatic and alicyclic

ketones upon multiple iminoalkylation with excess of Vilsmeier reagent and subsequent

nucleophilic quenching led to the synthesis of functionalized naphthyrid$es.

2.6 Experimental

Diethyi ether was dried over anhydrous calcium chloride. It was further dried by

refluxing in sodium wire, distilled and collected shortly before the commencement of the

reaction. DMF was dried by azeotropic distillation using sodium dned benzene, distilled

under reduced pressure and kept over typ 4A molecular sieves. All the ketones for the

preparation of carbinols were obtained from Sisco-Chem Industries, Bombay. TLC

analysis were performed on silica gel coated glass plates and visualized in an iodine

chamber or developed using KMn04 spray. Proton NMR spectra were recorded on a

Varian 390 (90 MHz) or Joel EX 90 (90 MHz) or Bruker WM 300 (300 MHz) or Bruker

WM 200 (200 MHz) spectrometer in CDC13. 13c NMR spectra were recorded either on a

Joel (22.4 MHz) or a Bruker WM 300 (75.5 MHz) or on a Bruker WM 200 (50.3 MHz)

spectrometer in CDC13. Chemical shifts are given in ppm(6) relative to internal standard

of tetramethylsilane. Coupling constants (4 are given in Hz. IR spectra were recorded on

a Shimadzu IR-470 spectrometer and are given as cm". Electron impact mass spectra

were obtained on a Finnigen-Mat 312 instrument, GCMS were obtained on a Hewlett

Packard 5890 Serles I1 GC connected to a 5890 mass selective detector. Melting points

were uncorrected and were obtained on a Buchi-530 melting point apparatus.

2.6.1 General Procedure for the Preparation of 2-Aryl-2-propanols from Substituted Acetophenones

The methyl Gr~gnard reagent was prepared from 4.23g (30 mmol) methyl iodide,

0.84g (35 mmol) magnesium and a pinch of iodine crystal in ether. The methyl

magnesium iodide was cooled to 0-5 OC and the ketone (20 mmol) in ether was added

slowly over 15 min. The mixture was stirred at this temperature for half an hour and was

poured over cold saturated ammonium chloride. It was then extmted with ether (3 x 50 ml)

The combined organic layer was washed with water and dried over anhydrous sodturn

sulfate. Ether was removed and the crude carbinol was used as such for the next step.

2.6.2 Reactions of Substituted 2-Aryl-2-propanols with Vilsmeier Reagent Followed by Ammonium Acetate: Synthesis of 4-Arylnicotinaldehydes

Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL) and POC13

(7.46 mL, 80 mmol). The mixture was then stirred for 15 minutes at room temperature.

The 2-aryl propan-2-01s 63a-e and 71 (20 mrnol) obtained from the Grignard reaction was

dissolved in dry DMF and added in about 15 minutes at 0-5 OC. The reaction mixture was

stirred for 10 minutes at room temperature and heated to 80 OC for 2 hours with stirring.

After the heating excess solid ammonium acetate (25g) was added to the reaction mixture

and continued to heat with stining at 80 OC for two hours more. The mixture was then added

to cold saturated K2C03 solution (500 mL) and extracted with methyl ether (3 x 50 mL). The

orgamc layer was washed with water, dned over anhydrous Na2S04 and evaporated to afford

the crude product. It was chromatographed over silicagel using hexane: ethylacetate (8:2) as

eluent to give the 4-arylnicotinaldehyde~~~~~ 64a-e, 72.

4-phenyInicorinaldehyde 64a was obtained as a solid from

the reaction of 2-phenyl-2-propanol63a (2.71g, 20 mmol)

with vilsmeier reagent and subsequent treatment with 0 27. ammonium acetate. yield: 2.17g (60%), mp 40-41 C ,

$ 'H NMR (90 MHz, CDCl,) 6 7.35 (d, J = 5.3Hz, lH,

\ 5-H); 7.40-7.70 (m, 5H, phenyl); 8.80 (d, J = 5.3Hz, IH,

CI~HYNO 6-H); 9.15 (s, IH, 2-H); 10.05 (s, 1H, CHO) ppm.; FW 183 20

"C Nh4R2"'; IR (neat, v,,) 3050, 1685, 1580, 1470,

1440, 1390 cm-'; GCMS mlz (%): 183 (69, w), 182 (loo), 140 (31.6), 127 (29.5), 77 (24.2), 51 (23.2).

4-(4-methoxyphenyl)nrcotma[dehyde 64b was obtained

as a pale brown solid from the reaction of

244-methoxypheny1)-2-propanoI63b (3.32 g, 20 mmol)

with Vilsmeier reagent and subsequent treatment with

ammonium acetate. yield: 3.lg (66%), mp 82 OC;

O H C e u 'H NMR (90 MHz, CDC13) 6 3.80 (s, 3H, OCH3);

6.95 (d, J = 5.3Hz, IH, 5-H); 7.20-7.40 (m, 4H,

aromatic); 8.65 (4 J = 5.3Hz, lH, 6-H), 9.GO (s, lH, 2-H); H&O

10.00 (s, lH, CHO) ppm. L 3 ~ NMR (22.4 MHz, CDC13)

CI ,HIIN% S 54.71(WH3), 113.81, 123.96, 126.46:'127.89, 130.46, FW 213 23 149.11, 150.99, 152.60, 160.15 (aromatic), 190.67 (C*)

ppm.; IR (KBr,v,,) 2950,2830, 1680, 1600, 1580, 1510,

1465, 1380 cm"; GCMS: mlz (Oh) 213 (100, &),

212 (22.4), 170 (37.8), 142 (19.4).

4-(4-methy1phenyl)nicorinaldehyde 64c was obtained

as a brown liquid from the reaction of

2-(4-methylpheny1)-2-propanol63c (3g, 20 mmol) with

Vilsmeier reagent and the subsequent treatment with

ammonium acetate. yield: 2.4 g (61%); 'H NMR

(90 MHz, CDCI3) 6 2.40 (s, 3H, CH3); 7.20-7.40

(m, 4H, aromatic); 7.00 (d, J = 5.3Hz, IH, 5-H);

8.75 (d, J = 5.3Hz, IH, 6-H); 9.12 (s, IH, 2-H);

10.10 (s, lH, CHO) ppm. ')c NMR (22.4 MHz, CDC13)

6 21.00 (CH3), 125.00, 127.50, 128.00, 129.00, 132.00,

140.00, 150.00, 152.00, 153.00 (aromatic), 191.50

(C=O) ppm.; IR (neat, v,,) 3025, 2850, 1690, 1590,

1540,1510,1470,1390 cm-I; GCMS m/z (%): 197 (87.8,

M+), 182 (loo), 168(32.7), 154 (19.4), 115 (18.4).

4-(3-chlorophenyl)nicot~naldehyde 64d was obtained as

a pale yellow solid from the reaction of

244-chloropheny1)-2-propanol 63d (3.4g, 20 mmol)

with Vilsmeier reagent and the subsequent treatment

with ammonium acetate. yield: 2.7 g (63%), mp 75 OC; I H NMR (90 MHz, CMJ13) 6 7.5-7.7 (m, 4H, aromatic);

7.4 (d, J = 5Hz, lH, 5-H); 8.8 (d, J = ~ H z , lH, 6-H);

10. l (s, IH, CHO ) ppm.; I3c NMR (22.4 MHz, CDC13)

6 124.17, 127.87, 128.59, 130.38, 133.15, 135.24,

149.53, 150.13, 153.08, (aromatic), 190.13 (C=O) ppm.;

IR (KBr,v,,) 3050,2875, 1690 1580, 1470, 1390 cm-';

GCMS ndz (%): 217 (100, M+), 182 (73.5), 154 (21.4),

126 (23.5).

4-(4-bromophenyl)nicolinaldehyde 64e was obtained as

a brown solid from the reaction of 2-(4-bromopheny1)-

2-propanol 63e (4.3 g, 20 mmol) with Vilsmeier

reagent and the subsequent treatment with ammonium

acetate. yield: 3.15 g (60%), mp 80-82 OC; 'H NMR

(90 MHz,CDCI,) 6 7.27-7.57 (m, 4H, aromatic); 7.24

9 (d, J = 5.3Hz, lH, 5-H); 8.71 (d, J = 5.3Hz, lH, 6-U);

9.02 (s,lH, 2-H); 9.96 (s,lH, CHO) ppm.; I3c NMR

\ (22.4MHz,CDCl,)G 124.56, 124.99, 128.76, 131.42,

Br 132.52, 134.39, 150.54, 151.23, 153.99 (aromatic),

C1 2HsNOBr FW 262 10

191.09 (C-) ppm.; IR (neat, v,,) 2849, 1696, 1593,

1471, 1392 cm-'; EIMS m/z (%): 265 (61.9, ~ + + 2 ) ,

264 (55.8, hl++l), 263 (73.2, M'), 184 (24), 183 (loo),

155 (49.9), 154 (37.9), 127 (62.1), 106 (30.3),

77 (37.9), 64 (31.8), 50 (22.7).

4-(2-nophthy[)nicotina[dehyde 72 was obtained as an

yellow solid from the reacion of 2-(2-naphthy1)-2-

propanol 71 (3.72 g, 20 mmol) with Vilsmeier reagent

and the subsequent treatment with ammonium acetate.

yield: 2.02 g (43%), mp 103-104 OC; 'H NMR

(200 MHz, CDCI3), 6 7.4-7.9 (rn, 7H, aromatic), 7.45

(d, J = 5.7Hz, lH, 5-H); 8.2 (d, J = 5.7Hz, 1 H, H-6);

9.18 (s, IH, H-2); 10.1 (s, lH, CHO) ppm.; I3c NMR

(50.32 MHz, cDc13), 6 124.57, 126.21, 126.85, 127.05,

C I ~ I I N O 127.48, 127.96, 128.37, 128.44, 129.16, 132.04, 132.52, F W 233 26

132.90, 149.54, 151.72, 153.07 (aromatic), 190.88

(C=O) ppm.; IR (KBr, v,,) 3050, 2825, 1680, 1580,

1480, 1380 cm"; EIMS m/z (%) 233 (84.3, M'),

232 (60.6), 205 (70.1), 204 (61.9), 177 (22.4),

176 (34.8), 152 (18.3), 151 (26), 88 (18.2), 77 (21.2),

57 (18.2), 40 (100).

2.6.3 Reaction of 2-Methyl-4-phenyl-3-buten-2-01 with Vilsmeier Reagent Followed by Ammonium Acetate: Synthesis of Q(Phenylviny1)nicotinaldehyde

Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL) and POC13

(7.46 mL, 80 mmol). The mixture was then stirred for 15 minutes at room temperature. The

2-methyl-4-phenyl-3-buten-2-01 82 (20 mmol) obtained fiom the Grignard reaction was

dissolved in dry DMF and added in about 15 minutes at 0-5 OC. The reaction mixture was

stirred for 10 minutes at room temperature and heated to 80 OC for 2 hours with stining.

After the heating excess solid ammonium acetate (25g) was added to the reaction

mixture and continued to heat with stirring at 80 'C for two hours more. The mixture was

then added to cold saturated K2C03 solution (500 mL) and extracted with diethyl ether

(3 x 50 mL). The organic layer was washed with water, dned over anhydrous NazS04 and

evaporated to afford the crude product. It was chromatographed over silicagel using hexane:

ethylacetate(8:2) as eluent to give the 4-(pheny1vinyl)niwtinaldehyde 83 in good yield.

4-(phenylvmny~nrcorrnaldehyde 83 was obtained as a

pale yellow solid from the reaction of 2-methyl-4-

phenyl-3-buten-2-01 82 (3.24g 20 mmol) with

Vilsmeier reagent and the subsequent treatment with

ammonium acetate. yield: 2.lg (51%), mp 66 OC;

'H NMR (90 MHz, CDC13) 6 7.5-7.7 (m, 5H,

aromatic); 7.25 (d, J = 15.8Hz,lH, PhCH-=CH-);

7.40(d,JZ5.3Hz, IH, 5-H); 8.17(d, J = 15.8Hz, lH,

PhCH=CH-); 8.70 (4 J = 5.3Hz, IH, 6-H);

9.00 (s,lH, 2-H); 10.3 (s,lH, CHO) ppm; I3c NMR c14~1 lNO FW 209 24 (22.4MHz,CDCI3)6 119.87, 122.05, 127.12, 127.30,

128.67, 129.12, 135.66, 137.03, 145.98, 153.14,

154.89 (aromatic and vinylic), 191.59 (C=O) ppm.;

LR (KBr, v,,) 1680, 1620, 1590, 1490, 1440, 1410,

1310, 1230, 1190 cm-'; E M S m/z (%): 209 (23.8,

&+I), 208 (100, M'), 207 (45.4), 180 (19.4), 179 (M),

152 (21.1), 151 (39.6), 105 (18.2), 77 (39.4), 63 (21.2),

50 (34.8).

2.6.4 Preparation of 2-Aryl-2-butanols: General Procedure

The ethyl Grignard reagent was prepared from 4.648 (30 mmol) ethyl bromide,

0.84g (35 mmol) magnesium and a pinch of iodine crystal in ether. The ethyl magnesium

bromide was cooled to 0-5 OC and the ketone (20 mmol) in ether was added slowly over

15 min. The mixture was stirred at this temperature for half an hour and was poured over

cold saturated ammonium chloride. It was then extracted with ether (3 x 50 mL) the

combined organic layer was washed with water and dried over anhydrous sodium sulfate.

Ether was removed and the crude carbinol was used as such for the reaction with

chloromethyleneiminium salt.

2.6.5 Reactions of 2-Aryl-2-butanols with Vilsmeier Reagent Followed by Ammonium Acetate: Snthesis of 4-Aryl-5-methylnicotinaldehydes

Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL) and POCI,

(7.46 mL, 80 mmol). The mixture was then stirred for 15 minutes at room temperature.

The carbinol 84a-d (20 mmol) obtained from the Grignard reaction was dissolved in dry

DMF and added in about 15 minutes at 0-5 OC. The reaction mixture was stirred for 10

minutes at room temperature and heated to 80 OC for 2 hours with stirring. After the

heating add solid ammonium acetate to the reaction mixture in excess (25g) and the

mixture was further heated at 80 OC for 2 more hours. It was then added to cold saturated

K2C03 solution (300 mL) and extracted with diethyl ether (3 x 50mL). The organic layer

was washed with water, dried over anhydrous Na2S04 and evaporated to get the crude

product. It was chromatographed using hexane : ethylacetate, ( 8:2 ) as eluent to give the

4-aryl-5-methylnicotinaldehydes 85a-d.

5-methyl-4-phenyln~coi~nuldehyde 85a was obtained as

a pale brown solld from the reaction of 2-phenyl-2-

butanol 84a (3.03 g, 20 mmol), with Vilsmeier reagent

and the subsequent treatment with ammonium acetate.

\ CHO fl Yield: 2.17g (55%), mp 65 'c; 'H NMR (200 MHz,

C I ~ ~ I I N O CDC13) 6 2.17 (s, 3H, CH3), 7.22-7.31 and 7.45-7.60 FW 19723

(integrating for two and three protons aromatic),

8.68 (s, lH, 6-H), 8.98 (s, lH, 2-H), 9.79 (s, IH, CHO);

I3c NMR (50.32 MHz, CDCI,) 6 17.08 (CH3), 129.09,

129.36, 132.38, 134.21, 147.30, 152.06, 155.08

(aromatic), 191.85 (C=O) ppm.; IR (KBr, v,,) 3050,

2850,1680,1575,1435,1380,1260 an-'; EIMS mlz (%):

198 (17.2, M++1), 197 (100, Id), 196 (98.9), 168 (50.5),

167 (45), 139 (27.3), 115 (59.6), 63 (41.4), 51 (46.5).

4-(4-methoxyphenyl)-5-methylnicofinaldehyde 85b was

obtained as a brown liquid from the reaction of

2-(4-methoxypheny1)-2-butanol &Ib (3.6 g, 20 mmol),

with Vilsmeier reagent and the subsequent treatment

with ammonium acetate. yield: 2.588 (56.5%); 'H NMR

(90 MHz, CDCl3) 6 2.3 (s, 3H, CH3 ), 4.0 (s, 3% OCH3),

7.1-7.4 (m, 4J3, aromatic), 8.85 (s, 1K 6-H),

9.15 (s, lJ3, 2-H), 10.5 (s, IH, CHO).; I3c NMR

(75.47 MHz, CDC13) 6 16.20 (CH3), 55.32 (OCH3),

115.63, 131.94, 131.96, 139.73, 140.18, 144.67, 148.53,

154.06, 156.74 (aromatic), 195.16 (C=O) ppm.;

IR (neat, v,,) 2950, 2850, 1690, 1600, 1570, 1510,

1460, 1390 cm-'; EIMS d z (%): 228 (34, Mf+l),

227 (100, Id), 212 (18.3), 184 (58.1), 168 (19.8), 156

(25.1), 154 (19.5), 128 (26), 84 (27.3), 63 (24), 49 (69).

5-methyl-4-(4-methyIphenyl)nicotinaldelyde 85c was

obtained as a brown liquid from the reaction of

2-(4-methylpheny1)-2-butawl 84c (3.2Sg, 20 mrnol)

with Vilsmeier reagent and the subsequent treatment

with ammonium acetate. yield: 2.21g (52%); 'H NMR

(300 MHz, cDC13) 6 1.82 (s, 3H, PhCH3), 2.12 (s,3H,

PyCH3), 8.69 (s, lH, 6-H), 8.98 (s,lH, 2-H),

7.2-7.7 (m, 4H, aromatic), 9.8 (s, lH, CHO); "C NMR

(75.47 MHz, CDC13) 6 15.74 (Py CH3), 20.23 (CH3),

127.84, 127.95, 128.38, 129.66, 131.25, 137.71, 145.77,

151.02, 153.43 (aromatic), 190.67 (C*) ppm.;

IR (neat, vmx) 1692, 1581, 1463, 1387, 1268, 1157 cm-I;

EMS m/z (%) 212 (21.6, M++I). 211 (100, M>, 210

(68.5), 196 ( 7 7 3 , 182 (24.6), 168 (46.1), 167 (39.1),

139 (IS), 40 (19).

4-(4-ch1orophenyl)-5-methylnicotinaldehyde 85d was

obtained as a pale brown solid from the reaction of \

2-(4-ch1orophenyl)-2-butanol 84d (3.678, 20mmol)

with Vilsmeier reagent and the subsequent treatment

with ammonium acetate. yield: 2.48g (54%). mp 78 OC; 9 'H NMR (300 MHz, CDC13) 6 2.31 (s, 3H, CH,),

7.07-7.26 (m, 4H, aromatic), 8.53 (s, IH, 6-H), \ CHO 8.83 (s, lH, 2-H), 9.8 (s, lH, CHO); "C NMR (75.47

C ~ f l ~ d ' r ~ i MHz, CDCI3) 6 17.15 (Py G'H,), 129.03, 129.51, FW 231 68 130.69, 132.55, 132.68, 135.49, 147.71, 150.89,

155.15 (aromatic), 191.45 ppm.; IR (KBr, v-) 1690,

1494, 1391, 1265, 1092 cm-'; EMS m/z (%): 233 (32,

M++2), 232 (33.4, Id+]), 231 (100, M>, 230 (56.4),

196 (70.9), 192 (24.6), 168 (33.2), 167 (47),

140 (17.7), 139 (33.3), 119 (42.4), 63 (18.2), 44 (39.4).

2.6.6 General Procedure for the Preparation of Aliphatic and Alicyclic Tertiary Alcohols from Ketones

The methyl Grignard reagent was prepared from 4.23g (30 mmol) methyl i d d e ,

0.84g (35 mrnol) magnesium and a pinch of iodme crystal in ether. The methyl magnesium

i d d e was cooled to 0-5 OC and the ketone (20 mmol) in ether was added slowly over 15

min. The mixture was stirred at this temperature for half an hour and was poured over cold

saturated ammonium chloride. It was then extracted with ether (3 x 50 ml). The combined

organic layer was washed with water and dned over anhydrous d u r n sulfate. Ether was

removed and the crude carbinol was used as such for the next step.

.7 Reactions of Aliphatic and Alicyclic Tertiary Alcohols with Vilsmeier Reagent Followed by Ammonium Acetate: Synthesis of Substituted [2,7]Naphthyridines

Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL) and POC13

(1 1.2 mL, 120 mmol). The mixture was then stirred for 15 minutes at room temperature.

The tertiary alcohol (20 mmol) was dissolved in dry Dh4F and added in about 15 minutes

at 0-5 OC. The reaction mixture was stirred for 15 hours at room temperature and cooled

in ice, solid ammonium acetate was added to the reaction mixture in excess (25g) and the

mixture was again stirred for 2 hours more. The mixture was then added to cold saturated

K2C03 solution (500 mL) and extracted with diethyl ether (3 x 50 hL). The organic

layer was washed with water, dried over anhydrous Na2S04 and evaporated to get the

crude product. It was chromatographed using hexane: ethylacetate (4:6) as eluent to give

the substituted [2,7]naphthyridines.

(2.7]nuphthyr1dine-4-carbaldehyde 111 was obtained

from the reaction of rerf-butanol 110 (1.47g, 20 mrnol)

as a white crystalline solid with Vilsmeier reagent and

the subsequent treatment with ammonium acetate.

yield: 0.57g (IS%), mp 216-217 OC; 'H NMR

(300 MHz, CDCI3), 6 7.28 (d, J = 5.6Hz, IH, 5-H);

y?& \ /

8.96 (d, J = 5.6Hz, IH, 6-H); 9.17 (s, lH, 8-H);

9.54 (s, lH, I-H); 9.60 (s, lH, 3-H); 10.42 (s, IH, CHO); CH3 ')c NMR (75.48 MHz, CDC13), 6 117.22, 123.34,

W N 2 0 123.93, 135.61, 150.32, 153.23, 155.56, 158.51 (aromatic), FW 158 15

191.81 (C=O) ppm.; IR (KBr, v,,) 3356,2850, 1695,

1626,1585,1555, 1497, 1433, 1381, 1355, 1309, 1253,

1215, 1192, 1115, 1082, 1033,943,900, 840,711,789,

740, 676 cm-'; EIMS miz (%): 158 (100, M'),

157 ( 4 5 4 , 129 (73.7), 103 (25.3), 75 (22.2).

5-methyl[2,7]nuphthyrrdine-4-curbuldehyde 11 7 was

obtained as a pale yellow solid, from the reaction of

2-methyl-2-butanol 116 (1.76g, 20mmol) with

Vilsmeier reagent and the subsequent treatment with

ammonium acetate. yield: 0.3768 (1 I%), mp 181 "c; I H NMR(300 MHz, CDCI3), 6 2.72 (s, 3H, CH3),

8.65 (s, IH, 6-H), 9.05 (s, IH, 8-H), 9.28 (s, IH, 1 -H),

9.46 (s, IH, 3-H), 10.86 (IH, CHO); I3c NMR (75.48

MHz, CDCI,), 6 21.69 (C&), 118.90, 123.38, 126.07,

127.66, 150.02, 150.46, 152.12, 158.28 (aromatic),

191.29 (C=O) ppm.; IR (KBr, v,,) 2962, 1683, 1601,

1261, 1097, 1023 cm-'; EMS m/z (%): 172 (1 00, M'),

171 (56), 155 (72.9), 149 (30), 145 (21.9), 144 (61.4),

143 (44.8), 89 (36.4), 83 (19.7), 77 (19.7), 70 (25.8), .I

60 (39.4), 43 (75.8).

4,S-d;methyl[2,7]naphthyridine 119 was obtained as a

brown liquid from the reaction of 3-methyl-3-pentanol

118 (2.04g, 20mmol), with Vilsmeier reagent and the

subsequent treatment with a m m o ~ u m acetate.

yield: 0.2848 (9%); 'H NMR (300 MHz, CDCh),

6 2.91 (s, 6H, 2-C&), 7.93 (s, 2H, 2-H and 5-H),

7.98 (s, 2H, 1-H and 8-H). EIMS m/z (%): 158 (24.1,

M'), 151 (19.6), 150 (19.6), 113 (36.4), 98 (19.7),

85 (31.8), 55 (25.8), 45 (100).

8,9d;iydro-7H-benzo(de][2,7]mphthyrid;ne 121 was

obtained as a reddish brown liquid from the reaction of

I-methyl-I-cyclohexanol 120 (2.288 20mmol) with

Vilsmeier reagent and the subsequent treatment with

ammonium acetate. yield: 0.2688 (8%); 'H NMR

(300 MHz, cDc13) 6 2.049 (q, J = 6.2& 2H,

CHz-CHz-CHz); 2.995 (t, J = 6.2 HZ, 4H, CH2-CH2-CH2);

8.445 (s, ZH, 3-H and 6-H); 9.166 (s, ZH, 1-H and 8-H)

ppm; I3c NMR (75.48 MHz, CDC13) 6 21.28

(CH2-CH2-CHz); 25.59 (CH2-CH2-CHz); 12 1.63

(C-8a); 127.59 (C-4 and C-5); 134.75 (C-4a); 142.89

(C-3 and C-6) 149.09 (C-1 and C-8) ppm.; IR (neaf v,,)

2932, 1612, 1545, 1432, 1382, 1270, 1119 cm-';

EIMS mlz (%) 171(91.3, &+I), 170 (100, &),

169 (25.5), 84 (22.4), 73 (49.3), 49 (61.2), 44 (77.6).

2.7 References

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