derivative^,^,' dike tone^,^^ - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/962/8/08_chapter 2.pdf · The compound with higher Rf value crystallised as colourless crystals

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CHAPTER 2

SYNTHETIC ELABORATIONS ON PHENYL V I N n KETONE AND ITS DERIVATIVES

2.1 Introduction

In the previous chapter we have described the isolation and characterisation of

interesting bicyclic and spirocyclic alcohols from the reaction of chalcone and its

derivatives with cyclopentanone in the presence of Ba(OH)*. It is logical to extend this

versatile reaction to other a, punsaturated ketones. In the present chapter results from

reaction of phenyl vinyl ketone and its derivatives with the carbanion generated from

cyclopentanone are presented. Before describing the results from the above reaction, a

brief review on the synthetic manipulations of phenyl vinyl ketone leading to the

formation of heterocyclic and carbocyclic products is given. As it was done in the

previous chapter, emphasis will be on the generation of heterocycles and carbocycles,

that too, from recent literature.

Phenyl vinyl ketone has been employed extensively as a Michael acceptor for

the generation of a wide range of useful products such as amino acids,' nucleic acid

derivative^,^,' 1,5 and 1,6 dike tone^,^^ among several other interesting products. A

variety of complexes from transition m e t a ~ s ~ . ~ and rare earth metals6 are found to

promote these reactions. A base mediated dimerisation of 4-methyl phenyl vinyl ketone

following the Baylis-Hillman pathway has also been reported.8

2.1.1 Synthesis of Heterocycles from Phenyl Vinyl Ketone

The a, @unsaturated ketones react with with N-vinylimino phosphoranes in an

enamine-alkylation process followed by aza-Wittig reaction to furnish pyridine

derivatives. A wide range of with N-vinylimino phosphoranes can be prepared from the

corresponding azides and tertiary phosphines (the Staudinger reaction), thus increasing

the synthetic utility for the generation of nitrogen heterocycles. For example, phenyl

81

vinyl ketone 1 undergoes facile enamine alkylation with N-vinylimino phosphorane

derivatives, such as 2, followed by intramolecular aza-Winig type reaction to furnish

cyclohepta[b]pyridine derivative 3 (Scheme 2. I).'

Reagents and conditions: i. 10 % Pd-C, benzene, reflux.

Scheme 2.1

An interesting synthesis of substituted pyridines 610." has been achieved by the

condensation of phenyl vinyl ketone 1 with N-vinyliminophosphoranes 4 or 5

(Scheme 2.2)."

Reagents and conditions: i. benzene, N2 atm., reflux.

Scheme 2.2

Amino azulenes 7 undergo condensation with phenyl vinyl ketone 1 to generate

azulenopyridine derivative 8 in an extremely facile manner (Scheme 2.3).12

4

Reagents and conditions: i, dry toluene, reflux.

Scheme 2.3

82

A stereoselective synthesis of N-substituted 6-lactams 10 and 11 has been

reported from N-benzoylethyl peptide 9 which was prepared by the Michael addition of

phenyl vinyl ketone 1 with amino acid esters (Scheme 2.4).13

ii iii- 2-Tf

k H O R

Reagents and conditions: i. H2NCH(R)C02Me; ii. ZHNCH2C02H, N-cyclohexyl-N'- (2-morpholinoethyl)carbodiimide, methyl-p-toluene sulfonate; iii. hv, toluene, 25°C.

Scheme 2.4

2.1.2 Synthesis of Carbocycles from Phenyl Vinyl Ketone:

Phenyl vinyl ketone 1 underwent cyclotrimerisation induced by 2-pynolidinone

12 to furnish highly substituted cyclohexanol derivative 13 (Scheme 2.5).14 The product

13 was formed via three consecutive Michael additions followed by aldol condensation.

12

Scheme 2.5

83

In a biomimdc type reaction thiazoliurn salt catalysed addition of a-ketoacids

14 to phenyl vinyl ketone 1 resulted in the formation of diketone 15 which underwent

cyclisation to form cyclopentenone derivatives 16 (Scheme 2.6).15

Reagents and conditions: i. cat. thiazolium salt; ii. HjP04, pyridine.

Scheme 2.6

Several syntheses of carbocycles have been reported from Diels-Alder addition

reaction of 1 with dienes.I6." For example, diene ester 17 reacts with phenyl vinyl

ketone 1 to furnish bicyclo[2.2.2]octene 18, which underwent further reaction to give 20

via 19. 20 is found to serve as a non-peptide mimic of enkephalins (Scheme 2.7).17

ii, iii, iv, v

Reagents and conditions: i. Hydroquinone, N2 atm., 150 OC; ii. KOH, EtOH, reflux; iii. a. S02C12, reflw; b. NH3, THF, rt; iv. LAH, THF, reflw; v. a. LiNH,, THF; b. HCOOH, CH20, N2 atm., reflw; vi. a. BHI, THF, N2 atm., 0 OC; b. 4- OCHtC&MgBr, rt; c. TsOH, benzene, reflux; vii, a. H2Pd, EtOH; b. HBr, CH3COOH, N2 atm., reflux.

Scheme 2.7

84

In a similar manner, condensation of phenyl vinyl ketone 1 with dienamine 21

resulted in tricyclic product 22 (Scheme 2.8).18

Scheme 2.8

Reagents and conditions: i. Toluene, reflux; ii. ~ ~ 0 ' .

There were several reports of phenyl vinyl ketone acting as an efficient

dipolarophile for the generation of stereochemically well-defined heterocyclic

c ~ m ~ o u n d s . ' ~ ~ ~ ~ 1,3-dipolar cycloaddition of cyclic nitrone 23 to phenyl vinyl ketone 1

resulted in the formation of isooxazolidine derivative 24 which underwent further

reaction to give cis-substituted indolizidinamine 25 (Scheme ~ . 9 ) . ~ ' 25 was found to be

active as NK, receptor antagonists at micromolar levels in functional tests.

Reagents and conditions: i. CHzC12, rt; ii. Mo(C0)6, CHXN-HIO, reflux; iii. u- methoxy benzylamine, p-TsOH, C6H6, reflux; iv. NaBH4, O°C+rt.

Scheme 2.9

Reaction of the imine 26 generated from ethyl methyl ketone with phenyl vinyl

ketone 1 goes through several cascades involving double Michael addition, cyclisation

and hydrolysis to furnish bicyclic ketone 27 (Scheme 2.10).~' This fascinating reaction

is an example for the generation of complex compounds from simple starting materials

through atom efficiency.

Reagents and conditions: i. MeOH, reflux.

Scheme 2.10

Phenyl vinyl ketone 1 and triester 28 undergo sequential Michael-Michael and

ring closure reactions for the construction of highly functionalised five-membered ring

compounds such as 29 (Scheme 2.1 1).22

Reagents and conditions: i. NaOMe, MeOH, 0+2O0C

Scheme 2.11

Similarly, phenyl vinyl ketone 1 and cyclohexenone 30 and a variety of

aldehydes undergo interesting one pot 4-component annulation for a simple synthesis of

substituted heteroaromatics such as 31 (Scheme 2.12).'~

Reagents and conditions: i. LiSnBus; ii. R'CHO, benzene, reflw.

Scheme 2.12

86

An intensting synthesis of dioxa-spirononanes 34 and 35 via 33, starting from

phenyl vinyl ketone 1 and nitroketone 32 has been reported (Scheme 2 . 1 3 ) ~ ~ The

dioxa-spirononane skeleton of 35 is a structural moiety in several phemones.

Reagents and conditions: i. (-)DIP-CI, CH2C12, -2S°C; ii. NaOH, EtOW; iii. H2S04, n- hexane-water, O°C.

Scheme 2.13

It is clear from the literature survey that phenyl vinyl ketone is a good Michael

acceptor. This property can be fine tuned with the installation of substituents in the 4-

position of the phenyl ring. In the following we present our endeavours in the study of

the reaction of phenyl vinyl ketone and its derivatives with cyclopentanone leading to

the formation of complex products in a single pot reaction through cascade pathways.

2.2 Results and Discussion

P-Dimethylaminopropiophenone hydrochloride 36 was prepared by following

the literature procedure. Pyrolysis of the salt resulted in the formation of phenyl vinyl

ketone 1 with the elimination of dimethylamine hydrochloride (Scheme 2.14)~'

qbcoc%c~im+)cr --I-c P~COCII-C% + % ~ c ~ c ~ c I .

36 1 37

Reagents and conditions: i. cat. Hydroquinone, 1 80°c, 0.5h.

Scheme 2.14

2.2.1 Michael Addition of Cyclopentanone to Phenyl Vinyl Ketone under Basic

Condition:

The anion generated from cyclopentanone 38 in the presence of Ba(0Hk added

to phenyl vinyl ketone 1 in 1,4-fashion to furnish known 1,s-diketoneZ6 39 along with a

new product 40 having higher Rf value (Scheme 2.15).

The IR spectrum of 1,5-diketone 39 showed two carbonyl absorptions at 1730

cm-' and 1680 cm" assignable to cyclopentanone and aromatic ketone stretching

frequencies. The 'H NMR spectrum (Fig.2.1) of 39 showed the presence of aromatic

and aliphatic protons in the ratio of 1 :2.

1 38 39 40

Reagents and conditions: i. Ba(OH)2, EtOH, RT, 12h.

Scheme 2.15

The cyclopentanone protons appeared as multiplet between 1.9-2.3 ppm. The

"C NMR spectnun (Fig.2.2) revealed the presence of six aromatic carbons, six

aliphatic carbons and two carbonyl carbons. The carbonyl carbons appeared at 199 and

220 ppm assignable to acetophenone and cyclopentanone carbonyl carbons

respectively.

90

The compound with higher Rf value crystallised as colourless crystals from

column h t i o n s (mp. 113 OC). The mass spectrum and elemental analysis indicated

the molecular formula to be C23H2.103. The IR spectrum of 40 revealed the presence of

hydrogen bonded hydroxy group at v 3460 cm'l and two carbonyl groupsat v 1720 cm.

I and 1660 cm" assignable to cyclopentanone and aromatic ketone stretching

frequencies. The IH NMR spectrum (Fig.2.3) of 40 revealed the presence of aromatic

protons and aliphatic protons in the ratio 1: 1.4, indicating that two phenyl vinyl ketone

moeities and one cyclopentanone moeity were involved in the fonnatio? of the product.

The OH proton was observed as a singlet at 6 5.05 ppm. A double doublet at 6 5.12

ppm, with J = 9 and 3.5 Hz integrating for one hydrogen, indicated that it is an axially

orlented hydrogen having axial-axial and axial-equatorial coupling with adjacent

prochiral hydrogens. A double multiplet at 6 7.86 ppm, accounting for two hydrogens,

revealed the presence of only one benzoyl group in the molecule. On the basis of above

evidence and mechanistic considerations, the structure 40 has been assigned to the new

compound. Configuration of cyclopentanone on the splro carbon has been fixed on the

basis of unusually high downfield shift of Cg axial hydrogen (6 5.12 ppm). Molecular

models revealed that this hydrogen comes under the anisotropic environment of the

carbonyl group The IR spectral evidence showed the hydrogen bonding interaction

between hydroxy and C9 benzoyl group. This information fixed the orientation of the

benzoyl group to equatorial position.

The IH-'H COSY spectrum (Fig.2.4) showed the connectivities between CP-H

and Clo-H, at 6 2.02 ppm and Cl0-Heq at 6 1.7 pprn. An upfield shift of Cto-H

equatorial at 6 1.7 ppm indicated that it is located in the shielding zone of the carbonyl

group. The COSY spectrum also revealed the connectivities between hydrogens

present on C6 and C,. Similarly the connectivities between aromatic hydrogens present

on the two phmyl rings could be clearly observed. Spectral assignments for important

protons in 40 is given in Fig. 2.5.

. . , a ................ R * 5.06 (9)

............... * 1.86-1.88 (m)

c 2 .06( fJ = 13.5 Hz) ...........

PIT.......... c 1.74-1.75 (m)

c 1.69(dd.J= 10.5, 5.5Hz

.......................... r 5.13 (dd,J= 9, 3.5 Hz)

0

Fig. 2.5 'H NMR assignments of characteristic protons of 40

The proton decoupled I3c NMR spectrum (Fig. 2.6) revealed the presence of

nine aliphatic carbons, ten aromatic carbons and two carbonyl carbons. The carbon

attached to OH group appeared at 6 74 ppm and the spiro carbon appeared at 6 46 ppm.

The off-resonance I3c NMR spectrum revealed the number of protons attached to each

carbon atom. The assignment of carbon resonances in the aromatic region could be

carried out on the basis of 'H-"C COSY spectrum (Fig.2.7). The details of the carbon

assignments for 40 is given in Fig.2.8. On the basis of above spectral data and

mechanistic considerations, the structure of (40) has been assigned as (8S, 5R, 7R)-7-

benzoyl-8-hydroxy-8-phenylspiro[4.5]decan-l-one.

The NOESY spectrum (Fig.2.9) of 40 indicated the steric proximity of several

hydrogens in the molecule, especially C g hydrogen and o-hydrogens of the benzoyl

group. The information from the NOESY spectrum was helpful in assigning the ' H and

"C resonances of Cs phenyl and C p benzoyl group. Finally, the confirmation of the

97

structure of 40 came from the single crystal X-ray crystallography data (generated by

prof. H.K. Fun at Universiti Sains, Malaysia).

46.2 ppm

28.2 ppm

39.3 ppm

74.1 ppm

45.5 ppm

36.1 ppm

223.1 ppm

, I * .......................................................................... * . , , . 32.9 pprn . . : L.... ....................................................................... * 38.1 ppm

Fig. 2.8 'H NMR assignments of characteristic carbons of 40

Single crystals were obtained by slow evaporation from a solution of methanol-

chloroform (1:l). The ORTEP diagram, s h o w in Fig.2.10, reveals that the five-

membered ring adopts a half-chair conformation with C4 and C5 twisted out of its

mean plane by 0.229(2) and -0.234(2) A, respectively. The cyclohexane ring adopts

chair conformation. The C4-C5 bond, the benzoyl group and the phenyl ring are

equatorially attached to it. The hydroxyl group and the carbonyl oxygen 0 3 are

involved in 02-H2A.. . 03 intramolecular hydrogen bond.

2.2.1.1 Mechanism for the formation of spiroketoalcohol40

A plausible mechanism for the formation of spiroketoalcohol 40 is given in

Scheme 2.16.

40 41

Scheme 2.16

Base mediated Michael addition of cyclopentanone 38 to phenyl vinyl ketone 1

resulted in 1,Sdiketone 39 which on hnher reaction with one more unit of phenyl vinyl

ketone 1 furnished the bis-alkylated product 41. Cyclisation through intramolecular

aldol condensation resulted in the spiroketoalcohol 40. Bis-alkylation in 2 position of

cyclopentanone is expected to take place under equilibrium conditions (thermodynamic

control).

An alternative mechanism leading to condensation of two units of phenyl vinyl

ketone and cyclopentanone is given in Scheme 2.17. However, the formation of 43 was

led out on the basis of spectral data and X-ray analysis.

43 42

Scheme 2.17

It is interesting to note that only a single diastereomer in which cyclopentanone

is oriented a has been isolated from the reaction. Intramolecular hydrogen bonding

interations may be the driving force for the formation of single diastereomeric product

40. Several attempts to isolate the derivatives of spiroketoalcohol 40 starting from

either substituted phenyl vinyl ketone or substituted 1,5-diketones under similar

experimental conditions proved to be futile.

2.2.2 Reaction of Mannich base with Cyclopentanone Under Thermal Conditions

Previously, Pons and coworkers carried out the reaction of phenyl vinyl ketone

with cyclopentanone under thermal condition^.^^ Phenyl vinyl ketone was generated in

the reaction vessel by pyrolysing the Mannich base dimethylaminopropiophenone 44.

When we repeated this reaction of 44 with cycopentanone 38 following the reported

procedure (160 OC, neat) we isolated the 1,s-diketone 39 along with a new product 45

(Scheme 2.18).

Reagents and conditions: i. 160'~. 0.Sh.

Scheme 2.18

The product 45, with the lower Rt crystallized out of column fractions as

colorless crystals (mp. 94 O C ) . Mass spectrum and elemental analysis gave the

molecular formula as C~H2403. The IR spectrum of this product 45 showed the

presence of two keto groups at 1715 and 1665 cm-' assignable to cyclopentanone and

aromatic ketone stretching frequencies. The 'H NMR spectrum (Fig. 2.1 1) revealed the

presence of aromatic and aliphatic protons in the ratio of 1:1.4 which showed that this

product was formed by the condensation of two molecules of phenyl vinyl ketone with

cyclopentanone just as in the case of spiroketoalcohol isolated previously under basic

conditions. But interpretation of the most downfield signals in 'H NMR spectrum

accounted for the presence of two benzoyl moeities. Analysis of the signals appearing

between 6 1.4-3.9 ppm indicated the symmetrical nature of the molecule. The proton

decoupled "C NMR spectrum (Fig. 2.12) revealed the presence of four aliphatic

carbons, two carbonyl carbons and rest aromatic carbons. On the basis of above

spectral analysis the structure of (45) has been assigned as 2,s-(3-0x0-3-phenylpropy1)-

2.2.2.1 Stereochemistry o f Triketone

The stereochemistry of the triketone 45 was fixed on the following basis.

Stothers and s an^' have previously studied I3c NMR spectra of cis and trans-2,5-

dimethylcyclopentanones and utilised the values for establishing the stereochemical

assignments and conformational preferences. Watanabe and coworkers28 have

104

synthesized various 2,5-dialkylated cyclopentanones and assigned the stereochemistry

on the basis of their "C NMR spectral characteristics. Spectral assignments of the

relevant examples from the above two references are gathered in Table I.

Table I:'~c NMR assignments of 2,5-dialkyl ~ ~ c l o ~ e n t a n o n e s ~ ' ~ ~

It is clear from the Table that the "C NMR values of the tertiary carbon C2 (next

to cyclopentanone carbonyl) can be used for assigning the stereochemistry and

comparison of the peak heights in the I3c NMR of the mixture of isomers would help to

establish the ratio of stereoisomers. Based upon above information and on the basis of

X-ray crystal data as discussed in the following, we have assigned the stereochemistry

105

of the triketone 45 as trans. Complete 'H assignments are given in Fig. 2.13. The "C

NMR values of 45 are gathered in Table 11.

. . - 3.09-3.13 (m. 2

" ................. c 1 46 (m, lH)

" * 1.82-1.85 (m, 1

Fig. 2.13 'H NMR assignments of characteristic protons of triketone 45

"C NMR spectrum of the crude product from the reaction of Mannich base 44

and cyclopentanone 38 revealed the presence of both cis and trans triketones. For the

purpose of standardization, before taking "C NMR, the reaction mixture was passed

through a short silica gel column for removing the 1,5-diketone 39 and other coloured

impurities. The "C NMR (Fig. 2.14) of the mixture of isomers of 45 as obtained from

the reaction mixture revealed the trans:cis ratio to be 70:30. Final conformation of the

stereochemistry of the triketone was obtained by X-ray crystallographic studies

(recorded by H.K. Fun, Universiti Sains, Malaysia) of (2R.5R)-2,5-Di[3-(4-

methylpheny1)-3-oxopropyl] cyclopentan-l-one (56).

Single crystals were obtained by fractional crystallization from the solvent

mixture of hexane-ethylacetate. The ORTEP diagram, shown in Fig.2.15, reveals that

the cyclopentane ring adopts a half-chair conformation with C3 and C4 twisted from its

mean plane by 0.224(3) and -0.219(3)A, respectively. The carbonyl group and one of

the side chain (C6-C15) is attached in the equatorial position whereas the other side

chain is attached in a biaxial orientation. The carbonyl oxygen 0 2 is in the syn-

periplanar conformation with respect to C6 and 0 3 is in the syn-penplanar

conformation with respect to C16. Anti-periplanar conformation was observed across

108

the C6-C7-C8-C9 and C16-Cl7-Cl8-Cl9 linkages. The mean plane through the

cyclopentane ring form dihedral angles of 30.9(2) and 24.3(2)' respectively with the

phenyl rings B and C. The two phenyl ring planes form a dihedral angle of 53.8(2)'.

The crystal structure is further stabilised by a number of C-H. ..pi interactions involving

the two phenyl rings and methyl H atoms.

To ascertain the generality of the formation of triketones, several p-substituted

Mannich bases such as pchloro 46, p-bromo 47, p-methyl 48 and p-methoxy 49

substituted dimethylaminopropiophenones were heated with cyclopentanone 38 at

160°C for O.5h to furnish the corresponding 1,5-diketones 50-53 as well as the

triketones 54-57 (Scheme 2.19).

X = Cl 46 X =CI; 50 X = CI; 54 X = Br; 47 X =Br; 51 X = Br; 55 X=Me; 48 X = Me; 52 X = Me; 56 X = OMe; 49 X = OMe; 53 X = OMe; 57

Reagents and conditions: i. 160°c, 0.5h.

Scheme 2.19

In all the cases the tm-compound was obtained as major products. The 'H

NMR (Fig.2.16-2.19) and "C NMR (Fig.2.20-2.23) spectra obtained in each case is

given. The ')c NMR spectroscopic data of the triketones 45, 54-57 generated in this

study is given in Table 11.

Table 11: The "C NMR values (6 ppm) of the triketones obtained by the reaction

of Mannich bases 44,46-49 with cyclopentanone 38.

The ratio of the aans:cis isomers as obtained from the heights of peaks of "C

NMR spectra is given in Table 111.

11s

Table 111: Ratio of ham- and cbisomers formed in the reaction of Mannich b a a

44,46-49 with cyclopentanone 38.

2.2.2.2 Mechanism of formation of triketone:

The proposed mechanism for the formation of triketone 45 from the reaction of

phenyl vinyl ketone 1 with cyclopentanone 38 is given in Scheme 2.20.

I

45 58

Scheme 2.20

Initial reaction of phenyl vinyl ketone 1 with one mole of cyclopentanone 38 in

Michael fashion resulted in 1,5-diketone 39. Michael addition of the diketone 39 to a

second molecule of phenyl vinyl ketone 1 hrnished the 2,s-bisalkylated

H

C1

Br

Me

OMe

45

54

55

56

57

70

67

79

64

86

30

33

2 1

36

14

119

cyclopentanone 45 via 54, which is expected to be more stable than the 2,2-bisalkylated

~ roduc t due to relatively lower steric crowding. Under the reaction conditions

employed, that is heating neat at 160 'C, 2,s-bisalkylated product accumulated in the

reaction. Of the two diasteromeric bisalkylated product, the trans-isomer is more stable

than the cis-isomer (Table 111). Results from Molecular Mechanics ca l c~ la t ions~~ (Fig.

2.24) also support this observation. MMXE for trans-isomer = 40.9; MMXE for cis-

isomer = 41.7.

2.2.2.3 Support for the Mechanism of Formation of Triketone

In order to confirm the proposed mechanism for the formation of triketone, the

intermediate 1.5-diketone 50 having a chlorophenyl group, was subjected to reaction

with phenyl vinyl ketone derived from Mannich base 44 under same reaction

conditions, that is heating neat at 160 O C for 0.5 h. (Scheme 2.21)

44 50 59

Reagents and conditions i. 1 60°c, 0.5h.

Scheme 2.21

From this reaction the unsymmetrical triketone 59 was isolated in 24% yield as

a mixture of trans- and cis-isomers (73:27). Phenyl group resonances in "C NMR (Fig.

2.25) spectrum of the triketone 59 was highly diagnostic showing two different set of

signals, one for unsubstituted phenyl and the other for 4-chlorophenyl group. 'H NMR

(Fig. 2.26) spectnun of 59 also showed resonances due to aromatic hydrogens, vicinal

to two keto groups.

The reverse addition of substituted 4-chlorophenyi substituted Mannich base 46

~ i g . 2.24 h h h u m masy srmcturc WMW for CIS+) md ham-@) 2,5-di-(3oxcr-3-phenylpmpyl>1-c~~0p~~ (45)

123

with 1,s-diketone 39 was also carried out under similar conditions to isolate tram- and

cis- mixture of triketones 59 in 66% yield (Scheme 2.22).

46 39 59

Reagents and condition.: i. 160°c, 0.5h.

Scheme 2.22

Above reaction offered further confirmation of the proposed mechanism.

Increased yield of the target triketone from this reaction may be due to higher reactivity

of 4-chlorophenyl vinyl ketone as a Michael acceptor. Absence of symmetrical ketones

such as 54 and 45 from the above reaction indicated that the triketone does not undergo

equilibration with its precursors.

Synthesis of unsymmetrical triketones was extended to other cases wherein the

15diketones having different 4-substituted phenyl rings such as 39 and 51 were

X = Br; 47 Y = H;39 X = Br; Y = H; 60 X = Me; 48 X = Me; Y = H; 61 X = OMe; 49 X = OMe; Y = H; 62 X = H; 44 Y = Br; 51 X = H; Y = Br; 60

Reagents and conditions: i. 160°c, 0.5h.

Scheme 2.23

subjected to Michael addition with substituted phenyl vinyl ketones generated from

Table IV- The I3c NMR values (6 ppm) of the triketones obtained by the reaction

of 1,s-diketones with Mannich bases.

', **: "C assignments are interchangable.

appropriate Mannich bases 47,48,49 and 44 (Scheme 2.23). The 'H NMR spectra (Fig.

2.27-2.29) and the ''c NMR spectra (Fig. 2.30-2.32) obtained for the unsymmetrical

triketones 59-62 is given. The "C NMR spectroscopic assignment for unsymmetrical

triketones is given in the form of a table (Table IV). "C NMR spectra of the crude

131

products revealed the ratios of two isomers formed in the reaction (Table V). It can be

seen from the Table V that the h'ans isomer is the major product in all the cases.

The ratio of the 1rans:cis isomers as obtained from the heights of peaks of "C

NMR spectra is given in Table V.

Table V: Ratio of trans- and cis-isomen formed in the reaction of 1,Sdiketones

with Mannich bases.

Me 64

OMe 62 33

2.3 Experimental section

Reaction of Phenyl vinyl ketone with cyclopentanone under basic conditions:

Phenyl vinyl ketone was synthesised following the procedure used in Vogel's

To a stirred suspension of freshly activated Ba(0H)z (heated to 100°C for

2h and cooled in a desicator, 0.34278, 2mmol) in 7mL of absolute alcohol,

cyclopentanone (0.9248, I lmmol) was added dropwise at room temperature and stimng

was continued for 10 min. Phenyl vinyl ketone (1.32g, 10 mmol) was added drop wise

to the reaction mixture and stirred for 12 h at room temperature. TLC of the reaction

revealed the presence of two major products. The reaction mixture was diluted with

di~hlorome~hane, washed with ice water (2 x 10 ml). brine (2 x 10 mL), dried (Na2S04 )

and concentrated . The mixture was then separated by chromatography usiag silica gel

(100-200 mesh) with hexanc/ethylacetate solutions as eluent (99:l to 90:10) to give 39

and 40.

132

2-(3-Oxo-3-phenylp~~Ib1-eyclopentanone (39). Rf = 0.35. Yield = 80%. mp

=39'C. IR (KBr) v 3065,2953,2868,1730,1680,1597, 1450,1402, 1261, 1217, 1157,

1105, 1001,833,742,690,655 cm.'. I H NMR (200 MHz, CDClp) G 7.89-7.94 (m, 2H),

7.35-7.55 (m,3H), 3.03-3.1 1 (m,2H), 1.90-2.33 (m,6H), 1.68-1.89 (m,2H), 1.56-1.65 (m,

IH). I3c NMR (50 MHZ CDCI3) 6 220.6(C1.), 199.8(C3), 136.9(Cl-), 132.9(C4-),

128.5(Cz*), 128.O(C~-), 48.1(C2,), 38.0(C~), 36.1(Cz), 29.8(Cj), 24.3(C4.), 20.6(C3,).

(&S;SR,7R)-7-Benzoyl-&hydrory-8-phenylspiro4.S]decan-l-one (40). Rr = 0.42.

Yield = 7%. mp = 113-1 14°C. IR (KBr) v 3460,2800,2600, 1720, 1660, 1580, 1450,

1390, 1270, 1230, 1050, 1000 crn-I. 'H NMR (500 MHz, CDCI3) 6 7.86 (dt, J = 8.5,2

Hz, 2H), 7.52 (m, IH), 7.49 (m,2H), 7.39 (n, J = 8.5, 1.5 Hz, 2H), 7.20 (n, J = 7,2 Hz,

2H), 7.08 (tt, J = 7, 1.5 Hz, lH), 5.13 (dd, J = 9, 3.5 Hz, IH), 5.06 (s, IH), 2.43-2.50

(rn, IH), 2.30 (dt, J = 8.5,19Hz, lH), 2.07 (dd, J = 13.5, 4.5 Hz, lH), 2.03 (t, J = 13.5

Hz, IH), 2.00-2 01 (rn, IH), 1.88-1.99 (rn, 2H), 1.86-1.88 (m, IH), 1.79-1.82 (rn, IH),

175-1.78 (m, lH), 1.74-1.75 (rn, IH), 1.69 (dd, J = 13.5, 5 Hz, 1H). "CNMR(125

MHz, CDCI3) G 223.1(C1.), 206.4(Cy), 147,8(Cl.), 135.8(Cl), 133.6(C4-), 128.7(Cy),

128.4(Cy ), 128.1(Cc ), 126.5(C3, ), 124.5(C2 ), 74.1(C8 ), 46.2(C5 ), 45.5(C9 ),

39.1(C7), 38.1(C2 ), 36.qClo ), 32.9(C4 ), 28.2(C6 ), !8.3. (C3 ). HRMS m/z (M+) for

C23H2403 calcd. 348.440 obsd. 348.432

Crystal Data and Structure Refinement of (&S,SR,7R)-7-benzoyl-8-hydroxy-8-

Phenylspiro[4.5]decan-1-one (40)

Single crystals were obtained by slow evaporation from a solution of methanol-

chloroform (I:]). The X-ray data was collected on SMART (Siemens, 1996) and the

cell refinement and data reduction was done on SAINT(Siemens, 1996). The data

collection covered over a hemisphere of reciprocal space by a combination of three sets

Of exposures; each set had a different cp angle (0, 88 and 180') for the crystal and each

133

exposure of 30s covered 0.3' in o. The crystal-to-detector distance was 4 cm and the

detector swing angle was -30". Crystal decay was monitored by repeating thirty initial

frames at the end of data collection and andysing the intensity of duplicate reflections,

and was found to be negligible. The structure was solved by direct methods and refined

by full-matrix least squares techruques using the program SHELXTL (Sheldrick, 1997).

After checking the presence of H-atoms in the difference map, all of them were placed

at the geometrically calculated positions and riding model was used for their refinement.

The crystal data are summarized in Table VI. The refinement converged to a final R-

index of 0.054. The fractional atomic coordinates and equivalent isotrpic displacement

parameters for all the non-hydrogen atoms are listed in Table VII.

Reaction of Mannich base under thermal conditions:

P-Dimethylaminopropiophenone hydrochloride (log) was taken in a beaker and

minimum amount of water (15 mL) was added to dissolve the salt. The beaker was

kept in ice bath and 20% NaOH solution was added drop by drop checking the pH by

pH paper. At neutralisation point the solution became turbid and the addition of NaOH

was continued till pH = 10, when an oily layer of base separated. This oily layer was

extracted with CHzC12 and concentrated to give P-dimethylaminopropiophenone 44

(Yield = 97%). To this base (8.40, 0.0475 mol), cyclopentanone 38 ( 1 1.9g. 0.1424 mol)

was added and refluxed at 160°C (oil bath temperature) for 30 minutes. The reaction

mixture was cooled to room temperature and applied on to column directly, without

workup, using silica gel (100-200) and eluting with hexanelethylacetate (98:2 to 85:15)

to give two products 39 and 45.

2,s-Di-(3-0x0-3-pbenylpropyl)-1-cyclopentanone (45). Rr = 0.18. Yield = 7%. mp =

94'C. IR (KBr) v 2900,2820, 1710, 1660, 1430, 1350, 1240, 1140,980,730,670 cm".

'HNMR (400 MHz, CDCI,) b 7.96 (d, J = 8.3 Hz, 2H), 7.42-7.56 (m, 3H), 3.09-3.13

Table VI: Crystal data md structure refinement for C,H,,O,

Crysral data

Cull2.0, &I, = 318.12 htonoclinic P2l / c a = 13.4416(4) A LJ = 6.4787 (2) A c = 21.7352 (6) A p lM.OGS(1)' V = 1836.05 (9) A' z=4 "

D, = 1.260 M g m-' D , not measured

Data colkction Sicmcnr SMART CCD rum 2836 rcflectioru with

&clor dif6aclomelu >2~igm.(l) w scans Rw = 0.036 Absorvtion comction: none - 8 - = 28.29'

Table M: Fractioaal atomic coordinates and equivalent isotropic displacement parameters (A')

0 I 0 2 0 3 C l C 2 C3 GI cs C6 CI C8 c9 c t o C l I C12 C13 C14 CIS C16 C17 C l 8 CL9 C20 a I C11 cu

L 0.16423 (8) 0.08030 (6) 0.19419 (8) 0.14692 (8) 0.13198 (LO) o.13a1 (11) 0. I64 16 (9) o. 14 174 (8) 0.18180 (8) o . u w 1 (8) 0.08577 (8) 0.04663 (8) 0.07135 (8) 0.05737 (8) 0.02368 (9)

-om718 (11) -0.oosw (12)

0.02920 (12) 0.05989 (10) 0. I9884 (9) 0.24643 (8) 0.28011 (9) 032674 (10) aul290 (I I) 0.31220 (11) 0.26(57 (9)

136

(m, 2H), 2.10-2.22 (m, 2Hh1.82-1.85 (m, 2H),1.45-1.46 (m, 1H). "C NMR (100 MHz,

CDCl3) S 221.8(C1), 200.1(c3.), 137.O(C1-), 133.3(C4*), 128.9(C2"), 128.3(C1.),

48.7(Cz), 36.3(Cz,), 28.1(C1,), 24.9(C3). LRMS 348(Mt, 0.6), 331(5), 229(11),

228(54), 210(10), 133(9), 121(6), 109(12), 105(100), 95(12), 77(75), 76(26), 55(16),

51(18). HRMS mlz (M') for C23H2403 d ~ d . 348.440 obsd. 348.436.

General procedure for the reaction of substituted /3-dimetbylaminopropiophenone:

The substituted P-dimethylaminoproiophenones were prepared following the

general ptocedure described for the unsubstiluted case. To the substituted P-

dimethylaminopropiophenone (1 mol), cyclopentanone (3 rnol) was added and

refluxed at 160°C (oil bath temperature) for 20 rnin. The reaction mixture was

cooled to room temperature and separated by column chromatography using silica gel

(100-200) with hexanelethylacetate solutions (98:2 to 85:15) to yield two products in

each case.

Reaction of N,N-dimethylamino-4-cbloropropiophenone (46) with cyclopentanone

(38):

The geneml procedure was followed to yield 1,s-diketone 50 and triketone 54.

l-(4-Chloropbenyl)-3-(2-oxoqclopentyl)-l-propanone (50). Rr = 0.46. Yield =

72%. mp = 115'~. IR (nujol) v 2962,1734, 1676, 1587,1452, 1406, 1371, 1255, 1217,

1153, 1093, 1014,979,827,769,569,491 cm-I. 'H NMR (200 MHz, CDCI,) 6 7.90

(dd, J = 4.3, 1.9 Hz, 2H), 7.36 (dd, J = 7.28, 1.94Hz, 2H), 3.09 (ddd, J = 10.8,6.89, 1.9

Hz, 2H), 2.00-2.3 1(m, 6H), 1.77-1.87 (m, 2H), 1.61 -1.64 (m, IH). "C NMR (50 MHz,

CDC13) 6 220.5(Cl*), 198.5(Cl), 139.4(C.v). 135.3(Cl,,), 129.5(C~), 128.9(Cr),

47.0(C2,), 38.0(C5,), 36.1(Cl), 29.9(c3), 24.3(C4,), 20.6(C3.).

(2R,5R)-2,E~i[3-(4-cbloro~besyl)-3-oxop~clopentan-l-one (54). Rf = 0.21.

Yield = 7%. mp = 124OC. IR (nujol) v 2961, 1724, 1684, 1589, 1487, 1452, 1400,

137

1367, 1309, 1255, 1203, 1155, 1093, 987, 831, 769, 565, 518 cm-I. 'H NMR (200

MHz, CDCI3) S 7.90 (d, J = 8.3 Hz, ZH), 7.43 (d, J = 8 Hz, 2H), 3.10 (t, J = 8.3 Hz, 2H),

2.05-2.22 (m, 2H), 1.70-1.95 (m, 2H), 1.47-1.60 (m, IH). "C NMR (50 MHz, CDC13) S

220(C1), 198.51(C3.), 139.52(C11*), 135.17(C.v), 129.48(C~), 128.91(C3..), 48.32(C2),

36(C2*), 27.85(Cl<), 24.65(C3).

Reaction of N,N-dimethylamino-4-bromopropiophenoae (47) with cyclopentanone

(38):

The general procedure was followed to yield 1,5-diketone 51 and triketone 55.

l-(4-Bromopbenyl)-3-(2-0xocyclopentyI)-l-propanone (51). Rf = 0.44. Yield =

48%. mp =67'~. IR (nujol) v 3435, 3079, 2958,2878, 1944, 1736, 1676, 1488, 1454,

1407, 1266, 1158,984, 829,776, 574,500 em-'. 'H NMR (400 MHz, CDC13) 6 7.83

(dd, J = 4.88, 1.96 Hz, 2H). 7.59 (dd, J = 4.88, 1.95Hz, 2H), 3.02-3.16 (dm, J = 6.83

Hz, 2H), 1.98-2.35 (m,6H), 1.77-1.86 (m,2H), 1.57 (ddd, J=17 , 10, 7 Hz, 1H). "C

NMR (100 MHz, CDCI,) S 220.6(Cl,), 198.5(Cl), 135.3(Cl..), 131,7(Cr), 129.4(Cy),

127.9(C.v), 47.8(C2.), 37.9(Cs.), 35.9(C2), 29.7(c3), 23.9(Cs), 20.4(C3.).

(2R,5R)-2,5-Di[3-(4-bromophenyl)3-oxopropy]cyclopentan-l-one (55). Rf = 0.23.

Yield = 4%. mp = 126OC. IR (nujol) v 2960, 1726, 1680, 1587, 1480, 1462, 1378,

1250, 1210, 1158, 1093,823,769, 565 em". 'H NMR (400 MHz. CDC13) 6 7.83 (dd, J

= 6.8, 2 Hz, 2H), 7.59 (dd, J = 6.3, 2 Hz, 2H), 3.03-3.15 (m, 2H), 1.98-2.30 (m, 2H),

1.70-1.88 (m, 2H), 1.45-1.49 (m, IH). "C NMR (100 MHz, CDCL) 6 221.5(C1),

198.8(C3.), 135.5(C4*), 131.9(C2-), 129.6(Cy), 128.2 (CI*.), 48.3(Cz), 36.1(C~),

27.8(Cl.), 24.6(C3).

Reaction of NJY-dimethylamino-4-methylpropiophenone (48) with cyclopentanone

(38):

The general procedure was followed to yield 13-diketone 52 and triketone 56.

138

1 - ( 4 - M e t ~ ~ ~ ~ ~ e ~ ~ ~ b ~ 4 2 ~ 1 . o e y c l o p e n ~ I b 1 - p ~ p o n e (52). R, = 0.41. Yield = 65%.

mp = 71'~. IR (nujol) v 2958,2878, 1729, 1676, 1608, 1454, 1373, 1259, 1219, 1158,

984, 829, 769, 567,494,467,420 an-'. 'H NMR (300 MHz, CDC13) S 7.86 (d, J = 9.5

Hz, 2H), 7.25 (d, J- 10.9 Hz, 2H), 3.08 (ddd, J =9, 6.3, 3 Hz, 2H), 2.4 (s, 3H), 2.00-

2.30 (m, 6H), 1.75-1.83 (m, 2H), 1.54-1.59 (m, 1H). I3c NMR (75 MHz, CDCI,) S

220.9(C1,), 199.5(C1), 143.8(C4"), 134.4(C1.2), 129.7(C,), 128.2(Cy), 48.2(C2-), 38.1

(Cy), 36.1(C2), 29.9(Cj), 24.4(Cc), 21.6(C1-.), 20.7(C,t).

(2R,5R)-2,5-Di[3-(4-methylphenyl).3-oxoppyl]cyclopentan-1-one (56). Rf = 0.19.

Yield = 10%. mp = 10I0C. IR (nujol) v 2958, 2911, 2871, 1729, 1682, 1608, 1373,

1306, 1232, 11 85,984,823,782,567,460 cm-'. 'H NMR (300 MHz, CDCI3) S 7.86 (d,

J=5.2Hz,2H),7.25(d,J=4.7Hz,2H),3.08(ddd,J=5,3,1.8Hz,2H),2.40(~,3H),

2.00-2.33 (m, 2H), 1.81-1.86 (m, 2H), 1.69-1.76 (m, 1H). NMR (75 MHz, CDCl3)G

221.8(Cl), 199.4(C;,), 143.8(C4-), 134.4(Cl,,), 129.3(C2-), 128.2(C;,,), 47.4(C2),

36.1(C2,), 27.3(Cl,), 24.8(Cj), 21.6(C1.-). LRMS 376(M1, 0.8). 358(6), 243(11),

242(48), 147(12), 135(1 I), 134(59), 119(100), 96(1 I), 91(68), 65(23), 55(17), 40(8),

39(9), 27(7). HRMS ndz M' for C25Hz80; calcd. 376.493 obsd. 376.489.

Crystal Data and Structure Refinement of (ZR,SR)-2,5-di[3-(4-methylphenyl)-3-

o~opropyl]cyclopentan-l-one (56)

Single crystals were obtained by slow evaporation from a solution of hexane:ethyl

acetate (2: 1). The X-ray data was collected on SMART (Siemens, 1996) and the cell

refinement and data reduction was done on SAINT(Siemens, 1996). The data collection

covered over a hemisphere of reciprocal space by a combination of three sets of

exposures; each set had a different cp angle (0, 88 and 1809 for the crystal and each

exposure of 30s covered 0.3' in o. The crystal-to-detector distance was 4 cm and the

detector swing angle was -30'. Crystal decay was monitored by repeating thirty initial

139

fmnes at the end of data collection and analysing the intensity of duplicate reflections,

and was found to be negligible. The structure was solved by direct methods and refined

by full-matrix least- squares techniques using the program SHELXTL (Sheldrick,

1997). All the H-atoms were located from a difference map; both the methyl groups

were found to be disordered with two positions rotated from each other by 60' and they

were treated as idealised disordered methyl groups. The remaining H-atoms were also

placed at the geometrically calculated positios and riding model was used for their

refinement. The crystal data are summarized in Table VIII. The refinement converged

to a final R-index of 0.068. The fractional atomic coordinates and equivalent isotropic

displacement parameters for all the non-hydrogen atoms are listed in Table IX.

Reaction of N,N-dimethylamino-4-methoxypropiophenone (49) with

cyclopentanone (38):

The general procedure was followed to yield 1,Sdiketone 53 and triketone 57.

1-(4-Methoxyphenyl)-3-(2-oxocyclopentyl)-l-propanone (53). Rf = 0.39. Yield =

81%. mp = 67 '~ . IR (nujol) v 2880, 1710, 1650, 1580, 1550, 1480, 1440, 1360, 1290,

1240, 1220, 1160, 1140, 1080, 1000, 820, 780, 700 cm". 'H NMR (400 MHz, CDCI,)

67.95(dd,J=7.33,2.44Hz,2H),6.93(dd,J=6.84,1.93Hz,2H),3.86(s,3H),3.07

(ddd, J = 9.79, 6.3, 2.93 Hz, 2H), 1.98-2.34 (m, 6H), 1.76-1.84 (m, 2H), 1.54-1.62 (m,

IH). "C NMR (100 MHz, CDC13) 6 221 .O(Cl.), 198.5(Cl), 163.4(Cc), 130.3(C1-),

129.9(Cy), 113.7(Cy), 55.4(Cl,,,), 48.2(C2,), 38.I(Cs,), 35.8(C2), 29.9(C3), 24.5(Cc),

20.6(Cj,).

(~R,5R)-2,S-Di[3-(4-mcthoxyphenyl)-3-oxopropy1cyclopentan-- (57). Rf =

0.23. Yield = 3%. mp = 103-105OC. IR (nujol) 1724, 1678, 1602, 1510, 1255, 1178,

1028, 837 cm-'. 'H NMR (200 MHz, CDCl,) b 7.95 (dd, J = 6.9, 2.18 Hz, 2H), 6.93

(dd, J = 8.8, 1.86 Hz, 2H), 3.86 (s, 3H), 3.02-3.09 (m, 2H), 2.05-2.21(m, 2H), 1.70-1.90

Table VIII: Crystal data and structure refinement for C2,H2,03

Cqsfal h a

CutI?s03 M, = 376.47 Orthorhor~bis Pbca a = 11.7941 (5).A 0 = 7.6537 (3) A c = 46.737, (7,) 4- V ;4218.9(3) A' Z = 8 D. = 1.185 Mg m-' D, not munved

Mo h'o radiation A = 0.71073 A Cell parameters from 1910

reflections 8 = 1.74-25.0O0 p = 0.076 rnm-' T = 293 (2) K Plak 0.38 x 0.32 x 0.14 rnm Colourless

Dara collccrion Sicmcns ShlART CCD area 2485 rcflcctions with

dclator dilhcu~rncter >2sigmn(f) w SG~J~S Rht = 0.059 Absorption correction: none 6)- = '-5.00' 20844 mevlPcd teflccnons k = 0 - 14 3705 indcpcndcnt reflections k = 0 - 9

1 - 0 - 5s

Refinement on (A/u)- = 0.00 R[P > &(FZ) ] = 0.068 ~ p - = o . I ~ c A - ' W R ( ~ ) = 0.148 Apmin = -0.14 e A" S= 1.14 . Extinction correction: none 3705 refladons Scattering faclon lrom 253 pyyncten h U ~ n r r ~ i 0 ~ l Tiles for x e text Crysrdlog~ply (Vol. C) W=I~(U~(F:) + (0.034spY +

2.4171PJ whne P = (F.' + 2 ~ f N

T a b l e IX: Fractional atomic coordinates a n d equivalent isotropic

displacement parameters (A')

U- = (1/3)X,Z,@dd*.q.

01 1 =Jq OaeuPmq :saw (1s) (1) 6 2 9 s (1p.ouI (q

02 1 0.71SH(L9) L.IUl(3) 119292(:P.U?7Zm 03 I 0 . z ~ 0, I 01 o.<ms rm.as71 R) Cl I 0 . i ~ am: (4) 0Z9559 (SPOSCO (7) 0 I 0.CjlS (191 0.W7 0) 025925 (ZP.0123 (5) 0 1 0516; :t) 0.953 11) 0.7979 (bp.0582 (8) Cd I 0 % 2 ) 0.9022 (4) 0.311CZ (60.05S4 (1) C5 I 0.6535 (2) 0 4 032203 ( 5 P . W 0 U 1 0.5731 (2) L.Pl9 (2) 0.11- (5P.CZ86 (7) C] I 0.61t. :2) 0.9641 O ) 0.2UU ( 5 P . W (6) C1 I 0.6;€! D) 1.0389 0) 0 . l W (6PXLI7L (6) C9 I o.cz g) 0.993 p) 0.1- ( m . w l (6) CIO I OiWO Q) 1.0399 (41 0.13755 iiP.0592 (8) CII I 0.6i:i 3) awn (1) O.IIOI: (m.a76 (9) c12 I ona 0) a9035 ( 4 ) 0.10169 !~P.MIZ (8) C13 I 0%- (3) 0.1611 (1) 0.12775 (6P.059r (8 ) C14 I ozjr. 3 o.so3a 0) 0.1ss?S16~).&~ m c:s I 0525 0 ) 0 . ~ 5 (5) O.G* b7P.rnS (12) C16 I 0 .6 i~ i !2) 0 . 9 (4) 034731 LW.&P m C17 I 0.601i 2) 0,1589 (2) 03735 (m.0555 m CIS I 12) anss (1) OJW (SY.ISU (8 ) c19 I 0.5% n) a 7 ~ 9 y 0.42691 : ~ ~ 0 5 1 7 (s) C X 1 0 . c.r:9>.ijj 0.42795 (5P.ms (10) C11 I aam: 5) 0.- (9 0.41321 PP.016D (I I) 42 L adis 0) a7171 in a d a l 0 0 p . 0 ~ 3 (11) C3 I a.rd.3 3) 0.1223 (6) , 0.4773 mOW0 (11) e 4 I 0.62: 3) azm cn o..cnll m . m ~ s (11) C3 I 02U7 (4) 0 . m m O-ws 1~~.1216 116)

142

(m, ZH), 1.44-1.47 (m, 1H). 'k NMR (50 MHz, CDCI3) S 221.5(Cl), 198.4(Co.),

General procedure to obtain the unsymmetrical triketone:

To the substituted P-dimethylarninopropiophenone (1.1 mol), the 1,5-diketone (1

mol) was added and allowed to reflux at 160°C(oil bath temperature) for 20 minutes.

The reaction mixture was then cooled to room temperature and the product was purified

by column chromatography (silica 100-200 mesh) with hexanelethylacetate solutions

(85: 15) as eluent to yield the corresponding triketone

Reaction of l-(4-chlorophenyl)-3-(2-oxocyclopentyl)-l-propanone (50) with N,N-

dimethylaminopropiophenone:

(ZR,5R)-2-[3-(4-Chlorophenyl)-3-o~opropyl]-5-(3-oxo-3-~henyl~rop~l)c~clo~entan-

1-one (59). Rr= 0.24. Yield = 24%. mp = 126°C. IR (nujol) v 2900,2840, 1720, 1670,

1580, 1445, 1365, 1250, 1200, 1080, 980, 825, 730, 680 cm". 'H NMR (400 MHz,

CDCI3) G 7.94 (dd, J = 15, 8 Hz, 2H), 7.54-7.57 (m, 2H), 7.44-7.47 (m, 2H), 7.20-7.44

(m, 3H), 3.07-3.14 (m, 2H), 2.06-2.22 (m, 2H), 1.83-1.87 (m, 2H), 1.47 (m, 1H). I3c

NMR (100 MHz, CDCl3) G 221.6(C,), 199.8(C>,,-), 198.6(C3,), 139.5(C4-,), 136.8(Cl...),

135.1(C1,,), 133.1(G.,), 129.5(C3.*), 128.9(C3,.), 128.6(C2), 128.1(C2,), 48.4(C5),

48.3(Cz), 36.O(C2.), 27.8(Cl.), 24.6(C3). HRMS m/z M' for C23H23C103 calcd. 382.885

obsd. 382.879.

Reaction of I-(4-bromophenyl)-3-(2-ox0cyclopentyl)-l-propanone (51) with N,N-

dimethylaminopropiophenone:

(~,5R)-2-[3-(4-Bromophenyl)-3-oxopropyl~-5-(3-oxo-3-phenylpropyl)cyclopentan-

1-one (60). Rr = 0.19. Yield = 9%. mp = 113'C. 1R (nujol) v 2900, 2840, 1715, 1670,

1580, 1445, 1370, 13 10, 1250, 1200, 1150, 1065, 980, 830, 730, 680 cm". 'H NMR

143

(400 M H s CDClp) 8 7.96 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.3 HZ 2H), 7.54-7.60 (m,

3H), 7.43-7.47 (m, 2H), 3.04-3.18 (m, 2H), 2.03-2.29 (m, 2H), 1.78-1.88 (m, 2H), 1.45-

1.47 (m, 1H). NMR (100 MHz, CDCb) S 221.S(71), 199.8(C3.), 198.7(C 3.1..),

136.7(C4...), 135.4(C1...), 133.O(C1..), 131.8(C4..), 129.6(C3-t), 128.5(C2-), 128.2(C3-),

128.0(C2,,), 48.4(C2), 48.3(Cs), 35.9(Cz...*), 35.9(Cz), 27.8(Cl-,,), 27.2(Cl.-), 24.6(C4),

24.5(C3). HRMS mlz M' for C ~ H u B r 0 3 calcd. 427.356 obsd. 427.353,

Reaction of 1-(4-methylphen~l)-3-(2-oxoeyflopentyl)-l-propanone (52) with N,N-

dimethylaminopropiophenone:

(2R,5R)-2-~3-(4-Methylphenyl)-3-oxopropyl]-5-(3-oxo-3-

phenylpropyl)cyclopentan-I-one (61). Rr = 0.22. Yield = 22%. mp = 124'C. IR

(nujol) v 2900, 2840, 1720, 1690, 1670, 1600, 1450, 1370, 1250, 1200, 1180, 1000,

980, 830, 740,680 ern.'. 'H NMR (300 MHz, CDCI3) 6 7.93 (d, J = 10.3 Hz, 2H), 7.84

(d, J = 10.3 Hz, 2H), 7.50(dt, J = 19.8, 9.2 Hz, 3H). 7.22 (d, J = 10.3 Hz, 2H), 3.07 (dd,

J = 11.5, 3.4 Hz, 2H), 2.37 (s, 3H), 2.07-2.23 (m, 2H), 1.71-1.82 (m, 2H), 1.41-1.46 (m,

IH). I3c NMR (75 MHz, CDCI,) S 221.5(Cl), 199.8(C3,), 199.5(C3-.), 143.8(Cq),

136.8(C4,-,), 134.3(Cl-), 133.0(C1,,,,), 129.2(C2), 128.6(C3-), 128.2(C3.-..), 128.0(C2~~~~),

48S(Cs), 47.4(C2), 36.O(Cy), 35.9(C2,,,), 27.8(C1,), 27.2(C1,,,), 24.8(C1), 24.6(C4),

21.6(C1,,,-). HRMS m/z for C24H2f.03 calcd. 362.466 obsd. 362.460.

Reaction of I-(4-metboxypheny1)-3-(2-oxocyclopentyl)panone (53) with N,N-

dimethylaminopropiopbenone:

(2R,5R)-2-[3-(4-Methoxyphenyl)-3-oxopropyl]-5-(3-0~0-3-

~henylpropy1)cyclopentan-1-one (62). Rf = 0.21. Yield = 13%. mp = 87°C. IR

(nujol) v 2900,2820, 1700, 1660, 1585, 1440, 1360, 1290, 1240, 1160, 1020,980,825,

730, 680 cm". 'H NMR (400 MHz, CDC13) 8 7.96 (d, J = 9.28Hz, 2H), 7.93 (d, J =

6 .84H52H) ,7 . s s ( t ,~=6 .83 Hz, lH),7.4S(t,J=7.81 Hz,2H),6.92(d,J=9.28Hs

144

2H), 3.85 (s, 3H), 3.04-3.14 (m, 2H), 2.01-2.30 (m, 2H), 1.71-1.87 (m, 2H), 1.44-1.47

(m, 1H). "C NMR (100 MHz, CDCII) 6 221.6(C1), 199.8(C3-), 198.4(C3.), 163.4(C4.),

136.7(Cl.s), 132.9(Cc*), 130.3(Cr.), 129.8(C2-), 128.5(C,-*), 127.9(Cl-.), 113.6(C3s.),

55.4(c1-..), 48.5(Cz), 48.4(Cs), 35 .9(Cr) , 35.7(C2.), 27.7(Cl.), 27.2(Cl..-), 24.8(C4),

24.6(C,). HRMS m/z M' for C21H2604 calcd. 378.465 obsd. 378.459.

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146

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147

29. Global energy minimisations were performed with PCModel version for Windows

(Serena Software) in the MMX mode.