Reactions of zinc enolates formed from 1-aryl-2-bromo-2-phenylethanone or 2-bromoindanone and zinc, with dimethyl 2-(1-arylmethylene)malonates

Article abstract of DOI:10.1007/s11176-006-0017-z

Zinc enolates formed from 1-aryl-2-bromo-2-phenylethanones and zinc react with dimethyl 2-(1-arylmethylene)malonates to afford dimethyl 2-(1,3-diaryl-3-oxo-2-phenylpropyl)malonates. The latter react with cyclohexylamine, piperidine, or morpholine to give the corresponding monosubstituted amides. The zinc enolate derived from 2-bromoindanone and zinc reacts with dimethyl 2-(4-bromobenzylidene)malonate, yielding dimethyl 2-[(4-bromophenyl)(1-oxoindan-2-yl)methyl]malonate. The final products largely form as a single diastereomer.

Full text of DOI:10.1007/s11176-006-0017-z

Russian Journal of General Chemistry, Vol. 75, No. 12, 2005, pp. 1935 1938. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 12, 2005,
pp. 2026 2029.
Original Russian Text Copyright
2005 by Shchepin, Korzun, Vakhrin, Shurov, Silaichev, Ezhikova, Kodess.
Reactions of Zinc Enolates Formed
from 1-Aryl-2-bromo-2-phenylethanone
or 2-Bromoindanone and Zinc,
with Dimethyl 2-(1-Arylmethylene)malonates
V. V. Shchepin*, A. E. Korzun*, M. I. Vakhrin*, S. N. Shurov*,
P. S. Silaichev*, M. A. Ezhikova**, and M. I. Kodess**
* Perm State University, Perm, Russia
** Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
Received March 29, 2005
Abstract Zinc enolates formed from 1-aryl-2-bromo-2-phenylethanones and zinc react with dimethyl
2-(1-arylmethylene)malonates to afford dimethyl 2-(1,3-diaryl-3-oxo-2-phenylpropyl)malonates. The latter
react with cyclohexylamine, piperidine, or morpholine to give the corresponding monosubstituted amides. The
zinc enolate derived from 2-bromoindanone and zinc reacts with dimethyl 2-(4-bromobenzylidene)malonate,
yielding dimethyl 2-[(4-bromophenyl)(1-oxoindan-2-yl)methyl]malonate. The final products largely form as a
single diastereomer.
Condensations of dialkyl -benzylidenemalonic acid
esters with carbonyl compounds under the action of
bases have been exemplified in the literature [1]. Ho-
wever, the reported condensation procedures feature a
number of drawbacks, such as long reaction time
(>20 h), low product yields (<25 %), and formation
of a mixture of mono- and dialkyl esters of malonic acid.
In the present communication we report the
results of research on the reaction of zinc enolates
IIa IId generated from -bromoketones Ia Id and
zinc under Reformatskii reaction conditions, with
dimethyl 2-(1-arylmethylene)malonates IIIa and
IIIb. The reaction probably occurs by the following
scheme.
Ph
OZnBr
Ar1
<
>
<
Zn
>
PhCHBrCOAr1
>
<
H
>
<
Ia Id
IIa IId
O
O
Ar1
H
Ph
H
CO2Me
Ph
Ar1
CO2Me
H2O
IIa IId
CO2Me
ZnBr
H
Zn(OH)Br
H
H
H
Ar2
CO2Me
Ar2
Ar2
CO2Me
CO2Me
IIIa, IIIb
IVa IVe
Va Ve
I, II, Ar1 = 4-MeC6H4 (a), 4-EtC6H4 (b), 4-BrC6H4 (c), 4-ClC6H4 (d). III, Ar2 = 4-BrC6H4 (a), 4-ClC6H4 (b). IV, V,
Ar1 = 4-MeC6H4, Ar2 = 4-BrC6H4 (a), 4-ClC6H4 (b). Ar1 = 4-EtC6H4, Ar2 = 4-BrC6H4 (c); Ar1 = 4-BrC6H4, Ar2 =
4-ClC6H4 (d), Ar1 = 4-ClC6H4, Ar2 = 4-BrC6H4 (e).
Zinc enolates IIa IId regiospecifically add across
the double bond of electrophilic substrates IIIa and
IIIb to give intermediates IVa IVd whose hydrolysis
gives rise to dimethyl 2-(1,3-diaryl-3-oxo-2-phenyl-
propyl)malonates Va Ve as final reaction prod-
ucts. The structure of compounds Va Ve was proved
by elemental analysis and H NMR and IR spec-
1
troscopy. The IR spectra of compounds Va Ve
1070-3632/05/7512-1935 2005 Pleiades Publishing, Inc.

1936
SHCHEPIN et al.
contain ketone and ester carbonyl absorption bands at
These data suggest that, in principle, both the dia-
stereomers can form, but the reaction presumably
occurs stereoselectively and provides a mixture en-
riched with one of the isomers; recrystallizion of the
mixture leaves this latter as a single isolable product.
The other compounds of this series are represented by
a single diastereomer that is similar to the major
isomer of compound Vc.
1
1675 1690 and 1735 1745 cm , respectively. The
1H NMR spectra provide evidence to show that the
resulting products are present as one of the two pos-
1
sible diastereomers. Thus, the H NMR spectrum of
dimethyl 2-[1-(4-bromophenyl)-3-oxo-2-phenyl-3-(4-
ethylphenyl)propyl]malonate (Vc) in DMSO displays
the following characteristic proton signals, , ppm
(J, Hz)]: 3.35 s, 3.43 s (6H, 2OMe), 4.00 d (1H, H1,
J1,2 8.6), 4.39 d.d (1H, H2, J2,3 10.6, J2,1 8.6), 5.57 d
(1H, H3, J3,2 10.6) [major isomer (90%); 3.16 s, 3.33 s
(6H, OMe), 3.79 d (1H, H1, J1,2 8.3), 4.30 d.d (1H,
H2, J2,3 11.2, J2,1 8.3), 5.62 d (1H, H3, J3,2 11.2)
Further we turned to the reactions of ester Va with
cyclohexylamine, piperidine, and morpholine. It was
shown that the reactions in xylene under reflux at a
3:1 amine:ester ratio result in exclusive formation of
monosubstitution products, specifically, methyl 3-(4-
bromophenyl)-2-(cyclohexylcarbamoyl)-5-oxo-5-p-
tolyl-4-phenylpentanoate (VI), methyl 3-(4-bromo-
phenyl)-5-oxo-2-[(piperidin-1-yl)carbonyl]-5-p-tolyl-
4-phenylpentanoate (VIIa), and methyl 3-(4-bromo-
phenyl)-2-[(morpholin-4-yl)carbonyl]-5-oxo-5-p-tolyl-
4-phenylpentanoate (VIIb).
1
[minor isomer (10%] (the full H and 13C NMR spec-
tra of the major isomer are given in Experimental).
CH3
18
17
15
16
14
13
11
12
10
4
1
O
1
The elemental analyses and H NMR and IR spec-
CO2Me
H
3
9
6
H
tra of the products are given in Experimental.
H
2
5
CO2Me
Under the above conditions we also studied the
reaction of zinc enolate IX generated from 2-bromo-
indanone (VIII) and zinc, with electrophilic substrate
IIIa.
7
8
Br
Vc
O
Ph
CO2Me
H
NH2
H
O
H
N
Me
O
H
Br
Va
VI
Ph
X
NH
CO2Me
H
H
H
N
X
Me
O
Br
VIIa, VIIb
VII, X = CH2 (a), O (b).
It was found that the reaction involves intermediate
X and gives rise to dimethyl 2-[(4-bromophenyl)[(1-
oxoindan-2-yl)methyl]malonate (XI). The IR spec-
trum of compound XI contains characteristic ketone
and ester carbonyl absorption bands at 1710 and
1
1
1755 cm 1, respectively. The H NMR spectra in
DMSO display the following characteristic proton
signals, , ppm (J, Hz)]: 3.37 s, 3.66 s (6H, OMe),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 12 2005

REACTIONS OF ZINC ENOLATES FORMED FROM 1-ARYL-2-BROMO-2-PHENYLETHANONE
1937
OZnBr
Br
O
Zn
VIII
IX
O
IX
H2O
IIIa
CO2Me
ZnBr
O
1
Zn(OH)Br
CO2Me
H
3
H
H
2
CO2Me
CO2Me
Br
Br
X
XI
3.95 d.d (1H, H2, J1,2 10.8, J2,3 4.8), 4.39 d (1H, H1,
J1,2 10.8) [major isomer (90%)]; 3.31 s, 3.52 s (6H,
OMe), 3.80 d.d (1H, H2, J1,2 11.8, J2,3 3.6), 4.72 d
(1H, H1, J1,2 3.6) [minor isomer (10%)]. This data,
too, provide evidence showing that the reaction results
in preferential formation of one diastereomer.
Dimethyl 2-[1-(4-bromophenyl)-3-(4-methyl-
phenyl)-3-oxo-2-phenylpropyl]malonate (Va). Yield
1
76%, mp 174 175 C. IR spectrum, , cm : 1685
1
(ketone C=O), 1740 (ester C=O). H NMR spectrum,
, ppm (J, Hz): 2.25 s (3H, 4-MeC6H4), 3.38 s, 3.50 s
(6H, COOMe), 3.89 d [1H, CH(COMe)2, J 7], 4.30 m
(1H, 4-BrC6H4CH), 5.20 d (1H, CHC6H5, J 10),
6.90 m (9H, C6H5, 4-BrC6H4), 7.05 d, 7.75 d (4H,
4-MeC6H4, J 8). Found, %: C 65.63; H 4.92; Br 15.71.
C27H25BrO5. Calculated, %: C 65.66; H 4.95; Br
15.69.
EXPERIMENTAL
The IR spectra were measured on a UR-20 spec-
trometer for individual compounds in mineral oil. The
1H NMR spectra were measured on a Tesla BS-567A
spectrometer (100 MHz) in CDCl3 against internal
HMDS (Va, Vb, Vd, and Ve), Bruker DRX-400
spectrometer (400 MHz) in DMSO-d6 (Vc), and
Mercury-Plus-300 spectrometer (300 MHz) in CDCl3
(VI, VIIa, and VIIb) or DMSO-d6 (XI) against
internal TMS. The 13C NMR spectrum of compound
Vc was recorded on a Bruker DRX-400 spectrometer
(100 MHz).
Dimethyl 2-[1-(4-chlorophenyl)-3-(4-methyl-
phenyl)-3-oxo-2-phenylpropyl]malonate (Vb). Yield
1
68%, mp 165 167 C. IR spectrum, , cm : 1680
1
(ketone C=O), 1745 (ester C=O). H NMR spectrum,
, ppm (J, Hz): 2.22 s (3H, 4-MeC6H4), 3.38 s, 3.44 s
(6H, COOMe), 3.91 d [1H, CH(COOMe)2, J 7],
4.32 m (1H, 4-ClC6H4CH), 5.18 d (1H, CHC6H5,
J 10), 6.90 m (9H, C6H5, 4-ClC6H4), 7.00 d, 7.72 d
(4H, 4-MeC6H4, J 8). Found, %: C 69.72; H 5.45;
Cl 7.65. C27H25ClO5. Calculated, %: C 69.75; H 5.42;
Cl 7.63.
Dimethyl 2-(1,3-diaryl-3-oxo-2-phenylpropyl)-
malonates Va Ve. Dimethyl 2-(1-arylmethylene)-
malonate, 0.08 mol, and 0.015 mol of 1-aryl-2-bromo-
2-phenylethanone were added to 2 g of fine zinc
turnings in 7 ml of diethyl ether and 7 ml of ethyl
acetate. The mixture was heated until reaction began,
after which the reaction let to occur spontaneously.
When the reaction was complete, the mixture was
refluxed for 15 20 min. After cooling, the resulting
material was hydrolyzed with 10% HCl and treated
with diethyl ether. The organic layer was washed to
neutral with 10% sodium bicarbonate, dried with
sodium sulfate, and the solvents were distilled off.
The final reaction products were purified by double
recrystallization from methanol.
Dimethyl 2-[1-(4-bromophenyl)-3-(4-ethylphe-
nyl)-3-oxo-2-phenyl]malonate (Vc). Yield 69%, mp
1
136 138 C. IR spectrum, , cm : 1675 (ketone C=O),
1
1735 (ester C=O). H NMR spectrum, , ppm (J, Hz):
1.15 t (3H, H18, J 7.6), 2.63 q (2H, H17, J 7.6), 3.35 s,
3.43 s (6H, 2OMe), 4.00 d (1H, H1, J1,2 8.6), 4.39 d.d
(1H, H2, J2,3 10.6, J2,1 8.6), 5.57 d (1H, H3, J3,2 10.6),
6.93 t.t (1H, H12, J 7.4, 1.3), 7.02 d.d (2H, H11, J 8.0,
7.4), 7.15 d.d (2H, H10, J 8.0, 1.3), 7.20 d (2H, H7,
J 8.6), 7.25 d (2H, H6, J 8.6), 7.32 d (2H, H15, J 8.6),
1
8.03 d (2H, H14, J 8.6). H NMR spectrum (100 MHz,
CDCl3), , ppm (J, Hz): 1.11 t (3H, CH2Me, J 7),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 12 2005

1938
SHCHEPIN et al.
2.52 q (2H, CH2Me, J 7), 3.38 s, 3.44 s (6H,
COOMe), 3.90 d [1H, CH(COOMe)2, J 7], 4.29 m
(1H, 4-BrC6H4CH), 5.20 d (1H, CHC6H5, J 10),
6.98 m (9H, C6H5, 4-BrC6H4), 7.10 d, 7.77 d (4H,
4-EtC6H4, J 8). 13C NMR spectrum (100 MHz,
DMSO-d6), C, ppm: 14.96 (C18), 28.06 (C17), 46.28
(C2), 52.04, 52.11 (2OMe), 54.26 (C3), 55.82 (C1),
119.55 (C8), 126.76 (C12), 128.00 (C15), 128.24 (C11),
128.89 (C14), 129.15 (C10), 130.29 (C6), 131.71 (C7),
133.51 (C9), 136.76 (C5), 138.54 (C13), 149.71 (C16),
167.58, 167.99 (2COOMe), 197.32 (C4). Found, %: C
64.22; H 5.23; Br 15.24. C28H27BrO5. Calculated, %:
C 64.25; H 5.20; Br 15.27.
Methyl 3-(4-bromophenyl)-5-oxo-4-phenyl-2-
(piperidin-1-ylcarbonyl)-5-p-tolylpentanoate (VIIa)
was prepared similarly to compound VI, using pipe-
ridine instead of cyclohexylamine. Yield 40%, mp
1
221 222 C. IR spectrum, , cm : 1620 (amide C=O),
1
1680 (ketone C=O), 1740 (ester C=O). H NMR spec-
trum, , ppm (J, Hz): 1.10 1.50 m, 3.15 3.30 m (10H,
C5H10N), 2.24 s (3H, 4-MeC6H4), 3.35 s (3H,
COOMe), 4.05 d (1H, CHCOOMe, J 7.2), 4.29 m
(1H, 4-BrC6H4CH), 5.48 d (1H, CHC6H5, J 9.6),
7.00 7.40 m, 7.69 d (13H, C6H5, 4-BrC6H4, 4-
MeC6H4). Found, %: C 66.23; H 5.74; Br 14.22; N
2.47. C31H32BrNO4. Calculated, %: C 66.19; H 5.73;
Br 14.20; N 2.49.
Dimethyl 2-[3-(4-bromophenyl)-1-(4-chlorophe-
nyl)-3-oxo-2-phenylpropyl]malonate (Vd). Yield
1
Methyl 3-(4-bromophenyl)-2-(morpholin-4-yl-
carbonyl)-5-oxo-4-phenyl-5-p-tolylpentanoate
(VIIb) was prepared similarly to compound VI, using
morpholine instead of cyclohexylamine. Yield 40%,
72%, mp 165 166 C. IR spectrum, , cm : 1685
1
(ketone C=O), 1745 (ester C=O). H NMR spectrum,
, ppm (J, Hz): 3.41 s, 3.45 s (6H, COOMe), 3.90 d
[1H, CH(COOMe)2, J 7], 4.29 m (1H, 4-ClC6H4CH),
5.17 d (1H, CHC6H5, J 10), 6.89 m (9H, C6H5,
4-ClC6H4), 7.38 d, 7.69 d (4H, 4-BrC6H4, J 8).
Found, %: C 58.96; H 4.21; Br 15.05; Cl 6.67.
C26H22BrClO5. Calculated, %: C 58.94; H 4.19;
Br 15.08; Cl 6.69.
1
mp 221 222 C. IR spectrum, , cm : 1620 (amide
1
C=O), 1675 (ketone C=O), 1750 (ester C=O). H
NMR spectrum, , ppm (J, Hz): 2.28 s (3H,
4-MeC6H4), 3.10 3.55 m (8H, C4H8NO), 3.40 s (3H,
COOMe), 4.27 4.40 m (2H, CHCOOMe, 4-BrC6H4
CH), 5.38 d (1H, CHC6H5, J 9.6), 6.90 7.16 m,
7.81 d (13H, C6H5, 4-BrC6H4, 4-MeC6H4). Found,
%: C 66.80; H 5.33; Br 13.88; N 2.44. C30H30BrNO5.
Calculated, %: C 63.83; H 5.36; Br 14.16; N 2.48.
Dimethyl 2-[1-(4-bromophenyl)-3-(4-chlorophe-
nyl)-3-oxo-2-phenylpropyl]malonate (Ve). Yield
1
46%, mp 154 156 C. IR spectrum, , cm : 1690
1
(ketone C=O), 1745 (ester C=O). H NMR spectrum,
, ppm (J, Hz): 3.42 s, 3.47 s (6H, COOMe), 3.87 d
[1H, CH(COOMe)2, J 7], 4.29 m (1H, 4-BrC6H4CH),
5.16 d (1H, CHC6H5, J 10), 6.92 m (9H, C6H5,
4-BrC6H4), 7.20 d, 7.75 d (4H, 4-ClC6H4, J 8). Found,
%: C 58.97; H 4.17; Br 15.05; Cl 6.66. C26H22BrClO5.
Calculated, %: C 58.94; H 4.19; Br 15.08; Cl 6.69.
Dimethyl 2-[(4-bromophenyl)(1-oxoindan-2-yl)-
methyl]malonate (XI) was prepared similarly to
compounds Va Ve. Yield 53%, mp 148 149 C. IR
1
spectrum, , cm : 1710 (ketone C=O), 1755 (ester
1
C=O). H NMR spectrum, , ppm (J, Hz): 2.89 m,
3.06 m, 3.09 m (3H, CHCH2), 3.37 s, 3.66 s (6H,
COOMe), 3.95 d.d (1H, 4-BrC6H4CH, J 10.8, 4.8),
4.39 d [1H, CH(COOMe)2, J 10.8], 7.10 7.50 m (8H,
C6H4, 4-BrC6H4). Found, %: C 58.46; H 4.47; Br
18.56. C21H19BrO5. Calculated, %: C 58.48; H 4.44;
Br 18.53.
Methyl 3-(4-bromophenyl)-2-(cyclohexylcar-
bamoyl)-5-oxo-5-p-tolyl-4-phenylpentanoate (VI).
Cyclohexylamine, 6.3 mmol, was added to a solution
of 2.1 mmol of compound Va in 10 ml of °-xylene.
The mixture was heated for 6 h. The solvent was
distilled off to leave the corresponding amide that was
twice recrystallized from methanol. Yield 42%, mp
ACKNOWLEDGMENTS
1
242 243 C. IR spectrum, , cm : 1630 (amide C=O),
1680 (ketone C=O), 1755 (ester C=O), 3330 (NH).
1H NMR spectrum, , ppm (J, Hz): 0.82 1.72 m (10H,
cyclo-C6H10), 2.27 s (3H, 4-MeC6H4), 3.57 3.72 m
(1H, NHCH), 3.65 s (3H, COOMe), 3.78 d (1H,
CHCOOMe, J 4.5), 4.24 d.d (1H, 4-BrC6H4CH,
J 10.8, 4.5), 5.59 d (1H, CHC6H5, J 10.8), 6.75
7.30 m, 7.85 8.00 m (14H, C6H5, 4-BrC6H4,
4-MeC6H4, NH). Found, %: C 66.70; H 5.91; Br
13.84; N 2.43. C32H34BrNO4. Calculated, %: C 66.67;
H 5.94; Br 13.86; N 2.43.
The work was financially supported by the Russian
Foundation for Basic Research (project nos. 04-03-
96036 and 04-03-975-05).
REFERENCES
1. Fahmy, A.F., Mohamed, M.M., Arify, A.A., El Ka-
dy, M.Y., and El Hashash, M.A., Rev. Roum. Chim.,
1980, vol. 25, no. 1, p. 125.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 12 2005