Synthesis of 2,4-substituted 3-oxo-1-phenylcyclopentane-1-carboxylic acids

Article abstract of DOI:10.1134/S1070428006120050

A procedure has been developed for the synthesis of 2,4-substituted 3-oxo-1-phenylcyclopentan-1-carboxylic acids, and substituent effects on particular steps of the synthesis have been studied.

Full text of DOI:10.1134/S1070428006120050

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 12, pp. 1786–1788. © Pleiades Publishing, Inc., 2006.
Original Russian Text © A.O. Martirosyan, S.P. Gasparyan, V.E. Oganesyan, G.K. Arutyunyan, V.V. Martirosyan, M.V. Aleksanyan, 2006, published in
Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 12, pp. 1798–1800.
Synthesis of 2,4-Substituted 3-Oxo-1-phenylcyclo-
pentane-1-carboxylic Acids
A. O. Martirosyan, S. P. Gasparyan, V. E. Oganesyan, G. K. Arutyunyan,
V. V. Martirosyan, and M. V. Aleksanyan
Institute of Fine Organic Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Erevan, 375014 Armenia
Received December 20, 2005
Abstract—A procedure has been developed for the synthesis of 2,4-substituted 3-oxo-1-phenylcyclopentan-1-
carboxylic acids, and substituent effects on particular steps of the synthesis have been studied.
DOI: 10.1134/S1070428006120050
differs from that described in [1]. In the second step,
instead of alkylation with tert-butyl 3-chloropropan-
oate, we performed cyanoethylation with acrylonitrile
and methacrylonitrile under conditions of phase-
transfer catalysis (Scheme 1).
We previously developed a convenient procedure
for the synthesis of 3-oxo-1-phenylcyclopentane-1-
carboxylic acid via successive alkylation of phenyl-
acetonitrile with tert-butyl chloroacetate and tert-butyl
3-chloropropanoate under conditions of phase-transfer
catalysis, followed by the Dieckmann cyclization [1].
2,4-Substituted 3-oxo-1-phenylcyclopentane-1-carbox-
ylic acids are important starting compounds for the
preparation of analogs of the antitumor antibiotic
Sarcomycin [2–4] and antiviral antibiotic Amidino-
mycin [5]. With a view to improve the procedure for
the preparation of such compounds and examine the
effect of the R1, R2, and R3 substituents on the reaction
course, we have developed another version which
First, phenylacetonitrile was treated with tert-butyl
bromoacetate, 2-bromopropionate, 2-bromo-2-methyl-
propionate, and 2-bromo-3-methylbutanoate in 40%
aqueous sodium hydroxide in the presence of benzyl-
triethylammonium chloride (BTEAC). The alkylation
smoothly occurred to give compounds IIa–IId, regard-
less of the R1 and R2 substituent. The cyanoethylation
of IIa–IId with acrylonitrile and methacrylonitrile was
performed under analogous conditions. In this case, the
Scheme 1.
R2
R1
COOBu-t
CN
Br
BTEAC, 40% aq. NaOH
CN
+
COOBu-t
R2
R1
I
IIa–IId
R2
COOBu-t
R1
CH2=C(R3)CN
COOH
R1
R3
O
H+, H2O
Δ
BTEAC, 40% aq. NaOH
HO
OH
CN
R3
CN
HO
R2
R1
O
O
R3
O
IIIa–IIId
IVa–IVd
Va–Vc
II, R1 = R2 = H (a), Me (c); R1 = Me, R2 = H (b); R1 = H, R2 = i-Pr (d); III, IV, R1 = R2 = H, R3 = Me (a); R1 = Me, R2 = R3 = H (b);
R1 = R3 = Me, R2 = H (c); R1 = R3 = H, R2 = i-Pr (d); V, R1 = H, R3 = Me (a); R1 = Me, R3 = H (b); R1 = R3 = Me (c).
1786

SYNTHESIS OF 2,4-SUBSTITUTED 3-OXO-1-PHENYLCYCLO-...
1787
Compound IIb (R1 = CH3, R2 = H). Yield 70%,
bp 137–138°C (3 mm), mp 44–45°C, Rf 0.48 (C).
1H NMR spectrum, δ, ppm: 0.95 d and 1.24 d (3H,
CH3, J = 8.0 Hz), 1.23 s and 1.34 s (9H, t-Bu), 2.50–
2.90 m (1H, CH), 3.79 d and 4.02 d (1H, CH, J =
8.0 Hz), 7.10–7.20 m (5H, C6H5). Found, %: C 73.40;
H 7.50; N 5.85. C15H19NO2. Calculated, %: C 73.47;
H 7.75; N 5.71.
Compound IIc (R1 = R2 = CH31). Yield 30%,
bp 145–148°C (5 mm), Rf 0.50 (C). H NMR spec-
trum, δ, ppm: 1.05 s (3H, CH3), 1.25 s (3H, CH3),
1.44 s (9H, t-Bu), 4.25 s (1H, CH), 7.20–7.30 m
(5H, C6H5). Found, %: C 74.20; H 7.95; N 5.20.
C16H21NO2. Calculated, %: C 74.13; H 8.10; N 5.40.
substituent effect was obvious, and no reaction oc-
curred with compound IIc (R1 = R2 = Me) even at
elevated temperature. The hydrolysis of IIIa–IIId with
hydrochloric acid was also smooth, but the subsequent
pyrolysis of the corresponding tricarboxylic acids IVa–
IVd strongly depended on the R2 substituent: it did
not occur with compound IVd (R1 = R3 = H, R2 =
Me2CH). Our attempt to effect Dieckmann cyclization
of compound IIId having the same substituents (R1 =
R3 = H, R2 = i-Pr) was also unsuccessful.
Thus we succeeded in synthesizing three new
Sarcomycin analogs: 4-methyl-, 2-methyl-, and 2,4-di-
methyl-3-oxo-1-phenylcyclopentane-1-carboxylic
1
acids Va–Vc. Analysis of their H NMR spectra
Compound IId (R1 = H, R2 = (CH3)2CH]. Yield
showed that carboxylic acids Va and Vb are mixtures
of cis and trans stereoisomers at a ratio of ~1:1. Pro-
tons in the methyl groups of the trans and cis isomers
of Va give rise to two doublets centered at δ 1.05 and
1.13 ppm (J = 7.0 Hz); the corresponding signals of
the trans and cis isomers of Vb appear at 0.65 and
1.15 ppm (J = 7.0 Hz). 2,4-Dimethyl-3-oxo-1-phenyl-
cyclopentane-1-carboxylic acid (Vc) is a mixture of
approximately equal amounts of four possible stereo-
isomers (δ, ppm: 0.60 d.d and 1.15 d.d, J = 7.0 Hz, for
trans- and cis-2-CH3; 1.05 d.d and 1.13 d.d, J = 7.0 Hz
for trans- and cis-4-CH3, respectively). The observed
difference in the chemical shifts of the methyl protons
originates from magnetically anisotropic effect of the
aromatic ring [6].
1
25%, mp 152–153°C, Rf 0.53 (C). H NMR spectrum,
δ, ppm: 1.11 d (6H, CH3, J = 7.0 Hz), 1.25 s (9H,
t-Bu), 2.10–2.80 m (2H, CHCHCO), 4.06 d (1H,
CHCN, J = 10.0 Hz), 7.20–7.35 m (5H, C6H5). Found,
%: C 74.30; H 8.30; N 5.00. C17H23NO2. Calculated,
%: C 74.70; H 8.40; N 5.10.
tert-Butyl 3,5-dicyano-3-phenylpentanoates IIIa–
IIId (general procedure). Acrylonitrile or methacrylo-
nitrile, 0.3 mol, was added at 35°C to a mixture of
0.3 mol of compound IIa–IId, 100 ml of 40% aqueous
sodium hydroxide, 150 ml of benzene, and 1.15 g
(5 mmol) of benzyltriethylammonium chloride. The
mixture was heated for 4 h at 50°C, the organic phase
was separated, washed with water, dried over anhy-
drous sodium sulfate, and evaporated, and the residue
was recrystallized from hexane or carbon tetrachloride.
Stereoisomers of compounds Va–Vc are unstable.
In acidic or basic medium, an isolated individual
stereoisomer is converted into a mixture of all possible
isomers through the corresponding enol form.
Compound IIIa (R1 = R2 = H, R3 = CH3). Yield
1
58%, mp 67–68°C, Rf 0.40 (C). H NMR spectrum, δ,
ppm: 1.28 s (9H, t-Bu), 1.45 d (3H, CH3, J = 7.0 Hz),
2.20–2.80 m (3H, CH2CH), 2.95 s (2H, 5-CH2), 7.25–
7.45 m (5H, C6H5). Found, %: C 72.50; H 7.10;
N 9.70. C18H22N2O2. Calculated, %: C 72.48; H 7.38;
N 9.39.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Mercury-300 instrument at 300 MHz. Thin-layer chro-
matography was performed on Silufol UV-254 plates
using acetone–hexane mixtures (A, 1:1; B, 1:2; C,
1:3; D, 3:2).
Compound IIIb (R1 = CH3, R2 = R3 = H). Yield
1
95%, mp 93–94°C, Rf 0.42 (C). H NMR spectrum, δ,
ppm: 1.28 s (9H, t-Bu), 1.45 d (3H, CH3, J = 7.0 Hz),
1.95–2.50 m (4H, C4H2, C5H2), 2.94 q (1H, C2H, J =
7.0 Hz), 7.25–7.45 m (5H, C6H5). Found, %: C 72.15;
H 7.50; N 9.63. C18H22N2O2. Calculated, %: C 72.48;
H 7.38; N 9.39.
tert-Butyl 3-cyano-3-phenylpropanoates IIa–IId
were synthesized by the procedure described in [1].
Compound IIa (R1 = R2 = H). Yield 60%, bp 141–
143°C (4 mm), mp 57–58°C, Rf 0.45 (C). H NMR
spectrum, δ, ppm: 1.20 s (9H, t-Bu), 2.62 d (2H, CH2,
J = 7.0 Hz), 4.05 t (1H, CH, J = 7.0 Hz), 7.20–7.30 m
(5H, C6H5). Found, %: C 71.17; H 7.60; N 5.89.
C14H17NO2. Calculated, %: C 71.46; H 7.28; N 5.95.
1
Compound IIIc (R1 = R3 = CH3, R2 = H). Yield
1
36%, mp 137–138°C, Rf 0.30 (C). H NMR spectrum,
δ, ppm: 1.15 d (3H, CH3, J = 7.0 Hz), 1.25 s (9H,
t-Bu), 1.52 d (3H, CH3, J = 7.0 Hz), 1.90–2.60 m (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006

MARTIROSYAN et al.
1788
CH2CH), 2.9 q (1H, C2H, J = 7.0 Hz), 7.05–7.20 m
(5H, C6H5). Found, %: C 69.00; H 7.28; N 8.80.
C19H24N2O2. Calculated, %: C 68.67; H 7.20; N 8.40.
Compound IIId (R1 = R3 = H, R2 = (CH3)2CH].
Yield 95%, mp 115–117°C, Rf 0.49 (B). 1H NMR spec-
trum, δ, ppm: 1.18 s (9H, t-Bu), 1.05 d and 1.21 d (6H,
CH3, J = 7.0 Hz), 1.60–2.90 m (6H, CH2CH2, CHCH),
7.35–7.55 m (5H, C6H5). Found, %: C 73.80; H 8.10;
N 8.30. C20H26N2O2. Calculated, %: C 73.60; H 7.97;
N 8.58.
pound IVa–IVc, 0.1 mol, was heated for 30 min at
250–270°C under nitrogen. The resulting material was
cooled and dissolved in 50 ml of 8% aqueous sodium
hydrogen carbonate. The solution was washed with
several portions of diethyl ether, the aqueous phase
was acidified with 10% hydrochloric acid to pH 2–3,
the oily material was extracted into diethyl ether, and
the extract was washed with water and dried over an-
hydrous sodium sulfate. The solvent was distilled off,
and the residue was recrystallized from carbon tetra-
chloride.
1,4-Substituted 2-phenylbutane-1,2,4-tricarbox-
ylic acids IVa–IVd (general procedure). A mixture of
0.1 mol of compound IIIa–IIId and 150 ml of concen-
trated hydrochloric acid was heated for 8 h at the
boiling point. The mixture was cooled and extracted
with diethyl ether, the extract was washed with water
and dried over anhydrous sodium sulfate, the solvent
was distilled off, and the residue was recrystallized
from water.
Compound Va (R1 = H, R3 = CH3). Yield 68%,
1
mp 102–103°C, Rf 0.59 (A). H NMR spectrum, δ,
ppm: 1.05 d.d and 1.13 d.d (3H, 4-CH3, J = 7.0 Hz),
1.85–3.60 m (5H, 2-H, 4-H, 5-H), 7.20–7.45 m (5H,
C6H5), 10.05 s (1H, COOH). Found, %: C 72.00;
H 6.40. C13H14O3. Calculated, %: C 71.50; H 6.40.
Compound Vb (R1 = CH3, R3 = H). Yield 80%,
1
mp 147–148°C, Rf 0.68 (A). H NMR spectrum, δ,
Compound IVa (R1 = R2 = H, R3 = CH3). Yield
ppm: 0.65 d and 1.15 d (3H, 2-CH3, J = 7.0 Hz), 2.20–
2.80 m (4H, CH2CH2), 3.14 q (1H, 2-H, J = 7.0 Hz),
7.25–7.50 m (5H, C6H5), 10.15 s (1H, COOH). Found,
%: C 71.90; H 6.60. C13H14O3. Calculated, %: C 71.50;
H 6.40.
1
84%, mp 175–176°C, Rf 0.49 (D). H NMR spectrum,
δ, ppm: 0.82 d and 1.05 d (3H, CH3, J = 7.0 Hz), 1.60–
2.90 m (3H, CH2CH), 3.16 s (2H, CH2), 7.35–7.50 m
(5H, C6H5), 11.65 s (3H, COOH). Found, %: C 59.80;
H 5.70. C14H16O6. Calculated, %: C 60.00; H 5.71.
Compound IVb (R1 = CH3, R2 = R3 = H). Yield
90%, mp 161–162°C, Rf 0.5 (A). 1H NMR spectrum, δ,
ppm: 0.92 d and 1.13 d (3H, CH3, J = 7.0 Hz), 1.85–
2.40 m (4H, CH2CH2), 2.97 q (1H, CH, J = 7.0 Hz),
7.25–7.40 m (5H, C6H5), 11.98 s (3H, COOH). Found,
%: C 60.25; H 5.74. C14H16O6. Calculated, %: C 60.00;
H 5.71.
Compound Vc (R1 = R3 = CH3). Yield 68%,
1
mp 172–173°C, Rf 0.42 (B). H NMR spectrum, δ,
ppm: 0.60 d and 1.15 d (3H, 2-CH3, J = 7.0 Hz),
1.05 d.d and 1.13 d.d (3H, 4-CH3, J = 7.0 Hz), 2.05–
3.00 m (3H, 5-H, 4-H), 3.24 q (1H, 2-H, J = 7.0 Hz),
7.35–7.50 m (5H, C6H5), 10.17 s (1H, COOH). Found,
%: C 72.10; H 6.60. C14H16O3. Calculated, %: C 72.40;
H 6.90.
Compound IVc (R1 = R3 = CH3, R2 = H). Yield
60%, mp 185–186°C, Rf 0.52 (D). H NMR spectrum,
REFERENCES
1
δ, ppm: 0.89 d and 1.17 d (6H, CH3, J = 7.0 Hz), 1.75–
2.85 m (3H, CH2CH), 3.22 q (1H, CH, J = 7.0 Hz),
7.25–7.40 m (5H, C6H5), 11.15 s (3H, COOH). Found,
%: C 61.30; H 6.00. C15H18O6. Calculated, %: C 61.20;
H 6.10.
Compound IVd (R1 = R3 = H, R2 = (CH3)2CH].
Yield 95%, mp 110–111°C, Rf 0.50 (D). 1H NMR spec-
trum, δ, ppm: 1.05 d and 1.19 d (6H, CH3, J = 7.0 Hz),
1.60–3.50 m (6H, CH2CH2, CHCH), 7.30–7.50 m
(5H, C6H5), 12.45 s (3H, COOH). Found, %: C 62.00;
H 7.00. C15H18O6. Calculated, %: C 62.30; H 6.60.
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