Some reactions of 5-benzyl-2,3,5-trichloro-4,4-dimethoxy-cyclopent-2-en-1- one and its derivatives

Article abstract of DOI:10.1134/S107042800804009X

5-Benzyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one and 2-benzyl-2,4,5-trichlorocyclopent-4-ene-1,3-dione were subjected to dehydrochlorination by the action of 1,4-diazabicyclo[2.2.2]octane, selective dechlorination at C⁵ by the action

Full text of DOI:10.1134/S107042800804009X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 4, pp. 524–527. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © F.A. Gimalova, V.A. Egorov, M.S. Miftakhov, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 4, pp. 529–532.
Some Reactions of 5-Benzyl-2,3,5-trichloro-4,4-dimethoxy-
cyclopent-2-en-1-one and Its Derivatives
F. A. Gimalova, V. A. Egorov, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received August 1, 2007
Abstract—5-Benzyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one and 2-benzyl-2,4,5-trichlorocyclo-
pent-4-ene-1,3-dione were subjected to dehydrochlorination by the action of 1,4-diazabicyclo[2.2.2]octane,
selective dechlorination at C5 by the action of CrCl2, and AdNE replacement of the chlorine atom at C3 by the
action of secondary amines. The reduction of 2-benzyl-2,4-dichloro-5-morpholinocyclopent-4-ene-1,3-dione
with sodium tetrahydridoborate in methanol and ethanol gave different products.
DOI: 10.1134/S107042800804009X
In the preceding communication [1] we described
a novel iodine-catalyzed carbonyl–arene-like intramo-
lecular carbocyclization of 2-benzyl-2,4,5-trichlorocy-
clopent-4-ene-1,3-dione (II) obtained from dimethoxy
ketone I. In the present article we report on some reac-
tions of these compound with a view to obtain prod-
ucts interesting from the viewpoint of pharmacology.
gave dichlorocyclopentenone derivatives III and IV,
respectively (Scheme 1). Dimethoxytrichlorocyclopen-
tenone I was subjected to dehydrochlorination by the
action of 1,4-diazabicyclo[2.2.2]octane (DABCO). Al-
though compound I is less activated than II, it is more
stable under the severe dehydrochlorination conditions
(heating in boiling toluene). The reaction occurred at
a low rate and gave highly electrophilic cross-con-
jugated styrene derivative V as a mixture of E and Z
Selective dechlorination of trichloro ketones I and
II at C5 (C2) using CrCl2 under standard conditions [2]
Scheme 1.
O
Ph
Cl
CrCl2, Me2CO, HCl
O
OMe
Cl
OMe
Cl
Ph
Cl
III
O
O
OMe
OMe
Ph
Cl
Cl
Cl
DABCO, PhMe, Δ
I
Ph
OMe
+
OMe
OMe
Cl
Cl
OMe
E-V
Z-V
O
O
Cl
Ph
Cl
Cl
CrCl2, Me2CO, HCl
Ph
Cl
O
Cl
O
II
IV
524

SOME REACTIONS OF 5-BENZYL-2,3,5-TRICHLORO-4,4-DIMETHOXY-...
525
Scheme 3.
isomers in a moderate yield (Scheme 1). According to
the spectral data, sterically more favorable Z isomer
predominated in the product mixture. Isomer E-V is
less favorable because of coplanar arrangement of the
carbonyl group and benzene ring at the double bond.
The ratio Z-V:E-V was estimated at 3:1 on the basis of
intensities of signals from the methoxy groups, olefinic
proton, and ortho-protons in the benzene ring, which
Cl
O
NaBH4, MeOH, 0°C
O
N
IX
Cl
Ph
HO
(4R,5*S)-X
Cl
1
O
appeared separately in the H NMR spectrum. For
example, the olefinic proton in E-V resonated at
δ 7.75 ppm due to strong deshielding effect of the
magnetically anisotropic carbonyl group, while the cor-
responding signal of Z-V was located at δ 7.11 ppm.
O
N
+
Cl
Ph
HO
(4S,5*S)-X
Taking into account that amino derivatives of tri-
chlorocyclopentenones structurally related to com-
pounds I and II exhibit biological activity [3], cyclo-
pentenones I–III were brought into reactions with
morpholine, diethylamine, and pyrrolidine to obtain
new benzyl-substituted vinylogous amides VI–IX of
the cyclopentenone series (Scheme 2).
Cl
1'
Ph
3
1
4
2'
NaBH4, EtOH, 0°C
2
O
N
IX
O
HO
XI
the reduction of IX with NaBH4 in ethanol at 0°C gave
no expected compounds X. We succeeded in isolating
(in a poor yield) and identifying 2-hydroxytetrahydro-
furan XI which was likely to be formed as a result of
a tandem transformation. The structure of XI and pos-
sible paths of formation of this compound will be the
subject of a separate publication.
Scheme 2.
Cl
O
R2NH, MeOH
Cl
I
R2N
Ph
MeO
OMe
VI, VII
VI, R2N = morpholino; VII, R = Et.
EXPERIMENTAL
Cl
O
The IR spectra were recorded on Specord M-80 and
Shimadzu IR Prestige-21 spectrometers from samples
prepared as thin films (neat) or dispersed in mineral
NH, MeOH
Ph
III
N
1
oil. The H and 13C NMR spectra were measured on
MeO
OMe
a Bruker AM-300 spectrometer at 300 and 75.47 MHz,
respectively, using CDCl3 as solvent and tetramethyl-
silane as internal reference. The mass spectra (electron
impact, 70 eV) were obtained on a Thermo Finnigan
MAT 95XP mass spectrometer (ion source temperature
200°C, sample injection temperature 5–270°C, tem-
perature ramp 22 deg/min). Thin-layer chromatog-
raphy was performed using Silufol and Sorbfil plates;
spots were detected by calcination or treatment with
an alkaline solution of potassium permanganate.
VIII
Cl
O
NH
, MeOH
O
Cl
Ph
II
N
O
O
IX
Morpholino-substituted derivative IX was reduced
with sodium tetrahydridoborate. When the reaction
was carried out in methanol at 0°C, a mixture of two
diastereoisomeric hydroxycyclopentenones (4R,5*S)-X
and (4S,5*S)-X was obtained, the latter slightly pre-
vailing (Scheme 3). In the 13C NMR spectrum of iso-
mer mixture (4R,5*S)-X/(4S,5*S)-X, the signal from
C4 was characteristic: δC 76.68 and 70.73 ppm for
(4S,5*S)-X and (4R,5*S)-X, respectively. Interestingly,
5-Benzyl-2,3-dichloro-4,4-dimethoxycyclopent-2-
en-1-one (III). Compound I, 0.5 g (1.49 mmol), was
dissolved in 10 ml of acetone, 15 ml of a freshly pre-
pared aqueous acidic solution of CrCl2 [2] was added
under stirring, and the mixture was stirred for ~1 h at
room temperature and evaporated. The aqueous layer
was treated with chloroform (3×10 ml), the extracts
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 4 2008

GIMALOVA et al.
526
were combined, washed with a solution of sodium
chloride, dried over MgSO4, and evaporated, and the
residue was purified by column chromatography on
silica gel using ethyl acetate–petroleum ether (1:9) as
eluent. Yield 0.4 g (89%), colorless crystals, mp 43–
(1.16 mmol) of morpholine in 5 ml of methanol was
added dropwise under stirring to a solution of 0.20 g
(0.60 mmol) of compound I in 8 ml of methanol, and
the mixture was stirred for 3 h at room temperature
(until the initial compound disappeared according to
the TLC data). The solvent was removed, the residue
was treated with 10 ml of cold water and extracted
with chloroform (4×20 ml), and the combined extracts
were washed with a saturated aqueous solution of
sodium chloride, dried over MgSO4, and evaporated.
The residue was purified by column chromatography
on silica gel using ethyl acetate–petroleum ether (1:4)
as eluent. Yield 0.22 g (96%), colorless crystals,
1
44°C. H NMR spectrum, δ, ppm: 2.95 s and 3.55 s
(3H each, OCH3); 3.28 d (2H, CH2, J = 4.9 Hz); 3.36 t
(1H, 5-H, J = 4.8, 4.5 Hz); 7.07 m (1H), 7.22 m (2H),
and 7.89 m (2H) (C6H5). 13C NMR spectrum, δC, ppm:
32.40 (CH2); 52.96 (OCH3); 57.76 (C5); 102.68 (C4);
127.39, 128.67, 129.45, 139.62 (Carom); 135.06 (C2);
151.58 (C3); 191.23 (C=O). Found, %: C 55.42;
H 5.16; Cl 18.79; N 3.34. C18H21Cl2NO4. Calculated,
%: C 55.97; H 5.48; Cl 18.36; N 3.63.
1
mp 153–155°C (from Et2O). H NMR spectrum, δ,
ppm: 3.20 s and 3.71 s (3H each, OCH3), 3.33 m and
3.53 m (2H each, CH2N), 3.38 d (2H, CH2, J =
2.7 Hz), 7.17–7.22 m (5H, Ph). 13C NMR spectrum, δC,
ppm: 46.13 (CH2); 48.94 (CH2N); 51.16 and 53.13
(OCH3); 66.57 (CH2O); 77.27 (C5); 104.26 (C4);
107.51 (C2); 126.93, 127.60, 130.53, 135.34 (Carom);
158.53 (C3); 186.48 (C=O).
2-Benzyl-4,5-dichlorocyclopent-4-ene-1,3-dione
(IV) was synthesized in a similar way from 0.5 g
(1.73 mmol) of compound II. The product was purified
by column chromatography on silica gel using ethyl
acetate–petroleum ether (1:9) as eluent. Yield 0.18 g
1
(40%), colorless oily substance. H NMR spectrum, δ,
ppm: 4.01 m (2H, CH2), 4.62 d (1H, 2-H, J = 4.2 Hz),
7.29 m (5H, C6H5). 13C NMR spectrum, δC, ppm: 41.65
(CH2); 52.85 (C2); 127.95, 128.85, 129.24, 138.78
(Carom); 135.03 (C5); 151.55 (C4); 191.09 (C1, C3).
5-Benzyl-2,5-dichloro-3-diethylamino-4,4-di-
methoxycyclopent-2-en-1-one (VII) was synthesized
in a similar way from 0.1 g (0.297 mmol) of compound
I and 0.1 ml (0.90 mmol) of diethylamine. Yield 0.08 g
(72%), colorless crystals, mp 109–110.5°C (from
(E,Z)-5-Benzylidene-2,3-dichloro-4,4-dimethoxy-
cyclopent-2-en-1-one (V). Compound I, 0.3 g
(0.89 mmol), was dissolved in 10 ml of toluene, 0.2 g
(1.79 mmol) of DABCO was added, and the mixture
was heated for 48 h under reflux, cooled to room tem-
perature, washed with a saturated solution of sodium
chloride, dried over MgSO4, and evaporated. The resi-
due was purified by column chromatography on silica
gel using ethyl acetate–petroleum ether (1:10) as
eluent. Yield 0.08 g (30%), oily substance (a mixture
of Z and E isomers at a ratio of ~3:1). IR spectrum, ν,
cm–1: 798, 879, 1028, 1097, 1114, 1149, 1190, 1228,
1
EtOAc–petroleum ether, 1:5). H NMR spectrum, δ,
ppm: 1.01 m (6H, CH3); 3.14 s and 3.72 s (3H each,
OCH3), 3.39 s (2H, CH2), 7.17 br.s (5H, Ph). 13C NMR
spectrum, δC, ppm: 13.66 (CH3); 44.91 (CH2N); 46.15
(CH2); 50.89 and 53.06 (OCH3); 77.19 (C5); 102.76
(C4); 104.38 (C2); 126.91, 127.61, 130.61, 135.40
(Carom); 158.49 (C3); 186.15 (C=O). Found, %: C 58.42;
H 6.41; Cl 18.49; N 3.47. C18H23Cl2NO3. Calculated,
%: C 58.07; H 6.23; Cl 19.05; N 3.76.
5-Benzyl-2-chloro-4,4-dimethoxy-3-(pyrrolidin-
1-yl)cyclopent-2-en-1-one (VIII) was synthesized in
a similar way from 0.21 g (0.73 mmol) of compound
III and 0.12 ml (1.46 mmol) of pyrrolidine. Yield
1
1263, 1452, 1602, 1633, 1712. H NMR spectrum, δ,
ppm: E isomer: 3.19 s (6H, OCH3), 7.49 d (2H, o-H,
J = 1.72 Hz), 7.75 s (1H, =CH), 8.03 m (2H, m-H),
8.15 m (1H, p-H); Z isomer: 3.38 s (6H, OCH3), 7.11 s
(1H, =CH), 7.47 d (2H, o-H, J = 1.88 Hz), 8.05 d (2H,
m-H, J = 1.89 Hz), 8.17 d (1H, p-H, J = 1.69 Hz).
13C NMR spectrum, δC, ppm: E isomer: 51.88 (OCH3);
104.85 (C4); 125.72 (C5); 128.82, 131.65, 133.21,
137.92 (Carom); 132.04 (C2); 138.89 (=CH); 158.82 (C3);
183.24 (C=O); Z isomer: 51.88 (OCH3); 104.85 (C4);
125.72 (C5); 128.04, 129.39, 131.02, 137.92 (Carom);
132.04 (C2); 138.89 (=CH); 158.82 (C3); 183.24 (C=O).
1
0.16 g (49%), mp 65–67°C. H NMR spectrum, δ,
ppm: 1.88 m (4H, CH2); 2.77 d.d (1H, PhCH2, J =
6.4, 14.35 Hz); 2.91 d.d (1H, PhCH2, J = 6.4, 5.2 Hz);
3.09 s and 3.23 s (3H each, OCH3); 3.47 s (1H, 5-H);
3.87 m (4H, CH2N); 7.19 t (1H, J = 7.2 Hz), 7.29 m
(2H), and 7.37 d (2H, J = 7.34 Hz) (C6H5). 13C NMR
spectrum, δC, ppm: 24.98 (CH2CH2N); 32.60 (PhCH2);
50.26 (CH2N); 52.16 and 52.43 (OCH3); 53.11 (C5);
102.28 (C4); 106.23 (C2); 126.51, 128.15, 129.11,
136.45 (Carom); 158.37 (C3); 189.62 (C1).
5-Benzyl-2,5-dichloro-4,4-dimethoxy-3-morpho-
2-Benzyl-2,4-dichloro-5-morpholinocyclopent-4-
linocyclopent-2-en-1-one (VI). A solution of 0.1 ml
ene-1,3-dione (IX) was synthesized in a similar way
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 4 2008

SOME REACTIONS OF 5-BENZYL-2,3,5-TRICHLORO-4,4-DIMETHOXY-...
527
from 0.22 g (0.76 mmol) of compound II and 0.13 ml
(1.48 mmol) of morpholine. The residue was purified
by column chromatography on silica gel using ethyl
acetate–petroleum ether (1:5) as eluent. Yield 0.18 g
(Carom); 163.60 (C3); 188.38 (C=O); (4R,5*S) isomer:
44.79 (PhCH2); 49.06 (CH2N); 66.24 (CH2O); 70.74
(C4); 73.60 (C5); 99.48 (C2); 127.58, 128.56, 130.62,
135.11 (Carom); 163.55 (C3); 188.82 (C=O).
1
(70%), colorless powder, mp 95–96°C. H NMR spec-
4-Chloro-3-morpholino-5-(2-phenylethyl)tetra-
hydrofuran-2-ol (XI). A solution of 0.1 g (0.29 mmol)
of compound IX in 3 ml of ethanol was added
dropwise under stirring to a suspension of 0.022 g
(0.58 mmol) of NaBH4 in 5 ml of ethanol, cooled to
0°C. The mixture was stirred at that temperature until
the initial diketone disappeared (TLC) and was then
treated as described above for the synthesis of com-
pounds X. Purification by column chromatography on
silica gel using ethyl acetate–petroleum ether (1:4) as
eluent gave 0.06 g (60%) of compound XI as an oily
trum, δ, ppm: 3.30 d (1H, PhCH2, J = 12.9 Hz), 3.48 d
(1H, PhCH2, J = 12.9 Hz), 3.54 t (4H, CH2N, J = 4.75,
4.30 Hz), 3.77 m (4H, CH2O); 6.93 m (2H) and 7.17 m
(3H) (Ph).
(4RS,5*S)-5-Benzyl-2,5-dichloro-4-hydroxy-3-
morpholinocyclopent-2-en-1-one (X). A solution of
0.1 g (0.29 mmol) of compound IX in 3 ml of metha-
nol was added dropwise under stirring to a suspension
of 0.011 g (0.29 mmol) of NaBH4 in 5 ml of methanol,
cooled to 0°C. The mixture was stirred at that tempera-
ture until the initial diketone disappeared (TLC) and
treated with a calculated amount of water (0.03 ml),
methanol was distilled off, the residue was dissolved in
chloroform, the solution was dried over MgSO4 and
evaporated, and the residue was subjected to column
chromatography on silica gel using ethyl acetate–pe-
troleum ether (1:4) as eluent to isolate 0.06 g (60%) of
a mixture of diastereoisomeric compounds X as an oily
1
substance. H NMR spectrum, δ, ppm: 2.01 m and
2.39 d.d (1H each, 1′-H, J = 13.8, 9.6 Hz), 2.64 m and
2.74 m (2H each, CH2N), 3.10 t (1H, 3-H, J =
11.7 Hz), 3.19 d.d (1H, 2′-H, J 13.7, 3.4 Hz), 3.45 t
(1H, CHCl, J = 10.77, 8.6 Hz), 3.68 m (6H, 5-H, 2′-H,
CH2O), 4.29 m (1H, 2-H), 7.15–7.32 m (5H, Ph).
13C NMR spectrum, δC, ppm: 34.49 and 35.21 (CH2);
45.23 (C3); 47.37 (CH2N); 62.36 (C4); 67.01 and 67.56
(CH2O); 76.91 (C5); 94.94 (C2); 126.24, 128.44, 128.99,
138.55 (Carom). Found: [M]+ 311.126. C16H22ClNO3.
Calculated: M 311.804.
1
substance. H NMR spectrum, δ, ppm: (4S,5*S) iso-
mer: 3.22 d (1H, PhCH2, J = 13.03 Hz), 3.39 d (1H,
PhCH2, J = 13.77 Hz), 3.30 m (4H, CH2N), 3.73 m
(4H, CH2O), 4.50 m (1H, OH), 4.98 s (1H, 4-H), 7.17–
7.28 m (5H, Ph); (4R,5*S) isomer: 3.22 d (1H, PhCH2,
J = 13.03 Hz), 3.39 d (1H, PhCH2, J = 13.77 Hz),
3.30 m (4H, CH2N), 3.73 m (4H, CH2O), 4.50 m
(1H, OH), 4.71 s (1H, 4-H), 7.13–7.28 m (5H, Ph).
13C NMR spectrum, δC, ppm: (4S,5*S) isomer: 40.26
(PhCH2); 49.08 (CH2N); 66.65 (CH2O); 73.14 (C5);
76.69 (C4); 98.78 (C2); 126.92, 128.08, 131.22, 136.19
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