Upload
others
View
3
Download
0
Embed Size (px)
Citation preview
SO
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.
2.4 References:
1. Sawamura, M.; Hamashima, M.; Ito, Y., Tetrahedron, 1994,5O, 4439. '
2. Kundu, N.G.; Mahanty, J.S.; Spears, C.P.; Andrei, G.; Snoeck, R.; Balzarini, J.; De
Clerq, E., Bioorg. Med. Chem., 1995,5, 1627.
3. Wads, A.; Ohki, K.; Nagai, S.; Kanotomo, S., J. Heterocycl. Chem., 1991,28, 509.
4. Kovalev, LP.; Kolmogorov, Y.N.; Ignatentenko, A.V.; Vinogradov, M.G.;
Nikishin. G.I., Izv. A k d Nauk S S R , Ser. Khim., 1989, 1098. Chem. Abstr.,
1 125445 1 x.
5. Sawamura, M.; Hamashima, M.; Shinoto, H.; Ito, Y , Tetrahedron Lett., 1995, 36,
6475.
6 . Keller, E.; Feringa, B.L., Tetrahedron Lett., 1996,37, 1879.
7. Kovalev, I.P.; Kolmogorov, Y.N.; Ignatentenko, A.V.: Vinogradov, M.G.;
Nikishin, G.I., Izv. Akad. Nauk SSSR, Ser. Khim., 1989, 1215. Chem. Abstr.,
1 1254452~.
8. Basavaiah, D.; Gowriswari, V.N.L.; Bharathi, T.K., Tetrahedron Lett., 1988, 28,
4591.
9. Nitta, M.; Soeda,H; Iino, Y., Bull.Chem.Soc.Jpn., 1990, 63, 932. Chem. Abstr.,
ll3:1l5036k
10. Kobayashi, T.; Iino, Y.; Nitta, M., Nippon Kagaku Kaishi, 1987, 1237. Chem.
Abstr.. 109:6602p.
11. Iino, Y.; Nitta, M., Bull. Chem. Soc. Jpn., 1988, 61, 2235. Chem. Abstr..
1 1 1 :23590s.
12. Nitta, M.; Akie, T.; Iino, Y., J. Org. Chem., 1994, 59, 1309.
13. Wyss, C.; Barn, R.; Lehmann, C.; Sauer, S.; Giese, B., Angew. Chem., Int. Ed.
Engl., 1996,35,2529.
146
14. Mohrle, H.; Wille, R.; Middelhaure, B.; Mortz, D.; Wunderlich, H., Z.
Naha$vsch., B: Chem. Sci., 1997,52,859. Chem. Abstr.. 127:220427a
15. Stetter, H.; Guenther, L., Chem. Ber., 1985, 118, 11 15. Chem. Abstr.,
102:220174z
16. Jaeger, D.A.; Shinozaki, H.; Goodson, P.A.,J. Org Chem., 1991,56,2482.
17. Belanger, P.C.; Duftesne, C., Can. J. Chem., 1986,64, 15 14.
18. Hickrnott, P.W.; Simpson, R., J. Chem. Res.. Syhop., 1992,304.
19. Cordero, F.M.; Brandi, A.; Desarlo, F.; Viti, G., Chem. Commun., 1994, 1047.
20. Cordero, F.M.; Brandi, A.; Cristillis, S.; Desarlo, F.: Viti, G., Tetrahedron, 1994,
50, 12713.
21. Hickmott, P.W.; Rae, B.; Carter, B.G.; Highcock, R.M, S. Afr. J. Chem., 1990,43,
136. Chem. Abstr., 115: 48898~.
22. Bunce, R.A.; Wamsley, E.J.; Pierce, J.D.; Shellhamnler, Jr. A.J.; Drumright, R.E.,
J. Org. Chem., 1987,32,464.
23. .Posner, G.H.; Asirvatham, E.; Webb, K.S.; Jew, S.S., Tetrahedron Lett., 1987, 28,
5071.
24. Occhiato, E.G.; Scarpi, D.; Meuchi, G.; Guarna, A., Tetrahedron: Asymmehy,
1996, 7, 1929.
25. Vogel's Textbook of Practical Organic Chemistry, revised by Fumiss, B.S.;
Hannaford, A.J.; Rogers, V.; Smith, P.W.G.; Tatchell, A. R., Fourth edition,
ELBS, p815.
26. Gill, N.S.; James, K.B.; Lions, F.; Pons, K.T., J. Am. Chem. Soc., 1952,4923.
27. Stothers, J. B.; Tan, C.T., Can. Chem., 1974,52,308.
28. Watansbe, Y.; Sakamoto, F.; Shim, S.C.; Mitsudo, T.-A., BUN. Chem. Soc. Jpn.,
1981.54,3875.
147
29. Global energy minimisations were performed with PCModel version for Windows
(Serena Software) in the MMX mode.