New nitrogen- and sulfur-containing derivatives of chlorocyclopentenones

Article abstract of DOI:10.1134/S1070428011030067

Reactions of 2,3,5-trichloro-4,4-ethylenedioxy- and 2,3,5-trichloro-5-(1,1- dimethylprop-2-en-1-yl)-4,4-dimethoxycyclopent-2-en-1-ones with amino acids gave products of AdNE substitution at the C³ atom, the corresponding vinylogous amides. Sodi

Full text of DOI:10.1134/S1070428011030067

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 3, pp. 366–370. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.A. Egorov, G.M. Khalikova, F.A. Gimalova, A.V. Grachev, M.S. Miftakhov, 2011, published in Zhurnal Organicheskoi Khimii,
2011, Vol. 47, No. 3, pp. 373–376.
New Nitrogen- and Sulfur-Containing Derivatives
of Chlorocyclopentenones
V. A. Egorova, G. M. Khalikovaa, F. A. Gimalovaa, A. V. Grachevb, and M. S. Miftakhova
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
b Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received May 11, 2010
Abstract—Reactions of 2,3,5-trichloro-4,4-ethylenedioxy- and 2,3,5-trichloro-5-(1,1-dimethylprop-2-en-1-yl)-
4,4-dimethoxycyclopent-2-en-1-ones with amino acids gave products of AdNE substitution at the C3 atom, the
corresponding vinylogous amides. Sodium carbamodithioates generated in situ from amines, carbon disulfide,
and sodium hydride in tetrahydrofuran reacted with di- and trichlorocyclopentenones in a similar way.
Cyanosilylation of 2,3,5-trichloro-4,4-ethylenedioxycyclopent-2-en-1-one with trimethylsilyl cyanide smoothly
occurred in toluene at 25°C in the presence of glycine as catalyst.
DOI: 10.1134/S1070428011030067
A promising line in the development of antiviral
agents implies design and synthesis of inhibitors of
neuraminidase which is an enzyme residing on the
surface of virus species and responsible for decom-
position of terminal sialic acids in glycoproteins and
for promotion of separation of mature viruses from
infected cells, etc. [1, 2]. Among neuraminidase in-
hibitors, the most potent is diaminocyclohexenecar-
boxylic acid derivative I which is known under the
trade name Tamiflu. A number of novel procedures for
the synthesis of compound I were proposed in the
recent years [3–5]. Another promising representative
of carbocyclic neuraminidase inhibitors is strongly
functionalized cyclopentanecarboxylic acid II (BCX-
1812); it is now under final step of clinical trial [6].
We set ourselves the task of synthesizing new
antiviral agents of the cyclopentane series containing
functionally important fragments like I and II. As key
COOH
O
COOH
Cl
COOH
HO
Et
Et
NH2
NH
N
Et
O
NH2
OMe
HN
NHAc
MeO
O
Et
NHAc
I
II
III
O
O
Cl
Cl
O
Cl
O
Cl
Cl
R
MeO
S
Cl
CH2
CH2
OMe
OMe
OMe
OMe
NH
N
OR'
Cl
OR'
Me
COOMe
IV
V
VIa–VId
R = CH2=CHCH2, R′ = Me (a); R = CH2=C=CH, R′ = Me (b); R = CH2=CHCMe2, R′ = Me (c); R = H, R′R′ = CH2CH2 (d).
366

NEW NITROGEN- AND SULFUR-CONTAINING DERIVATIVES
367
Scheme 1.
O
O
COOMe
NH2
Cl
Cl
Cl
Cl
KOH, MeOH, Et3N
O
+
Me
MeO
S
S
O
O
Cl
NH
O
O
Me
VId
VII
O
Cl
O
Cl
O
Me
COOMe
NH2
KOH, MeOH, Et3N
MeO
Me
VId
+
Me
NH
O
Me
VIII
O
Cl
O
Cl
COOMe
NH2
KOH, MeOH, Et3N
MeO
Me
O
VId
+
Me
NH
O
Me
Me
IX
O
O
Me
Cl
Cl
O
Me
Me
Cl
Me
COOMe
NH2
Me
Cl
KOH, MeOH, Et3N
CH2
MeO
Me
+
OMe
OMe
CH2
Me
NH
OMe
OMe
Cl
Me
VIc
X
Scheme 2.
O
O
Cl
S
Cl
NaH, THF
NH
+
+
CS2
O
S
O
O
N
O
Cl
O
O
XI
XII
O
Cl
Me
S
Me
NaH, THF
XI
+
+
CS2
S
O
Ph
NH2
N
Ph
O
H
XIII
O
Cl
S
Cl
S
NaH, THF
NH
VIa
+
+
CS2
CH2
O
N
OMe
MeO
O
XIV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

EGOROV et al.
368
Scheme 3.
Me3SiO
CN
HO
COOH
Cl
Concd. H2SO4
0 to 25°C
Toluene, 25°C
Cl
Cl
Cl
glycine (10 mol %)
VId
+
Me3SiCN
O
Cl
Cl
O
O
XV
XVI
as internal reference. The mass spectra (atmospheric
pressure chemical ionization) were obtained on
a Shimadzu LCMS-2010 instrument. The progress of
reactions was monitored by TLC on Silufol and Sorbfil
plates; spots were detected by calcination or by treat-
ment with an alkaline solution of potassium perman-
ganate. The products were isolated by column chroma-
tography on silica gel (30–60 g of sorbent per gram of
substrate); freshly distilled solvents were used as
eluents.
starting compounds we selected trichlorocyclopen-
tenone derivatives VI which were synthesized by us
previously [7] from hexachlorocyclopentadiene. Com-
pounds VIa–VId are convenient substrates for further
functionalization. Our search in this direction was
substantiated by the fact that compounds III and IV
obtained from chlorocyclopentenones VIa and VIb
exhibited antiviral activity. For example, compound III
showed a strong activity against tobacco mosaic
viruses [8], whereas compound IV was highly active
against H1N1 viruses.
N-(7,9-Dichloro-8-oxo-1,4-dioxaspiro[4.4]non-6-
en-6-yl)-L-methionine methyl ester (VII). A solution
of 0.29 g (1.43 mmol) of L-methionine methyl ester
hydrochloride in 5 ml of methanol, 0.08 g (1.43 mmol)
of potassium hydroxide, and 0.11 ml (0.82 mmol) of
triethylamine were added under stirring to a solution of
0.2 g (0.82 mmol) of ketone VId in 5 ml of methanol.
The mixture was stirred until the initial compound
disappeared (TLC) and evaporated, and the aqueous
phase was acidified with 1 N hydrochloric acid to pH 4
and extracted with chloroform (4×10 ml). The extracts
were combined, washed with a solution of sodium
chloride, dried over MgSO4, and evaporated, and the
residue was subjected to chromatography on silica gel
using ethyl acetate–petroleum ether (1:10) as eluent.
Yield 0.25 g (84%), yellowish oily substance. IR spec-
trum, ν, cm–1: 3292, 3280, 2954, 2920, 1730, 1699,
1604, 1527, 1425, 1290, 1271, 1211, 1168, 1124, 1028,
999, 968, 949, 878, 813, 714, 669, 543. 1H NMR spec-
trum, δ, ppm: 2.08 s (3H, SMe), 2.12 m (2H, CH2),
2.55 t (2H, SCH2, J = 7.8 Hz), 3.77 s (3H, CO2Me),
4.15–4.30 m (5H, OCH2CH2O, NCH), 4.34 s (1H,
Therefore, we performed functionalization of ring
carbon centers in some trichlorocyclopentenones VI
and their derivatives with a view to reveal signatures
responsible for biological activity. The results thus
obtained will be taken into account in the design of
particular structures. Following the procedures de-
scribed previously for compounds IV and V [9], we
synthesized derivatives VII–X that are new conjugates
of trichlorocyclopentenones VIc and VId with
L-methionine, D-leucine, and D-valine (Scheme 1). By
reactions of chlorocyclopentenones XI and VIa with
sodium carbamodithioates generated in situ from
carbon disulfide and amines (morpholine, α-methyl-
benzylamine) by the action of NaH we obtained new
dithiocarbamate derivatives XII–XIV (Scheme 2).
In order to introduce a carboxy or amino func-
tionality into chlorocyclopentenones VI we examined
the reaction of compound VId with trimethylsilyl
cyanide. The reaction smoothly occurred in toluene at
25°C in the presence of glycine as catalyst and
afforded α-siloxy nitrile XV which was converted into
trichlorocyclopentenone XVI by acid hydrolysis
(Scheme 3).
13
CHCl), 6.07 d (1H, NH, J = 8.8 Hz). C NMR spec-
trum (CDCl3), δC, ppm: 15.05 (SMe), 29.47 (CH2),
31.73 (SCH2), 52.66 (CO2Me), 54.49 (CHN), 66.15
(OCH2), 61.74 (CHCl), 106.57 (C5′), 106.62 (C7′),
158.41 (C6′), 171.29 (CO2Me), 184.50 (C8′). Found, %:
C 41.86; H 4.53; Cl 19.95; N 4.01; S 8.79.
C13H17Cl2NO5S. Calculated, %: C 42.17; H 4.63;
Cl 19.15; N 3.78; S 8.66.
EXPERIMENTAL
The IR spectra were recorded on Specord M-80 and
Shimadzu IR Prestige-21 spectrometers from samples
prepared as thin films or dispersed in mineral oil. The
13
1H and C NMR spectra were measured on a Bruker
AM-300 instrument at 300 and 75.47 MHz, respec-
tively, from solutions in CDCl3 using tetramethylsilane
Compounds VIII–X were synthesized in a simi-
lar way.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

NEW NITROGEN- AND SULFUR-CONTAINING DERIVATIVES
369
N-(7,9-Dichloro-8-oxo-1,4-dioxaspiro[4.4]non-6-
en-6-yl)-D-leucine methyl ester (VIII) was synthe-
sized from 0.2 g (0.82 mmol) of ketone VId and 0.26 g
(1.43 mmol) of D-leucine methyl ester hydrochloride.
Yield 0.16 g (55%). IR spectrum, ν, cm–1: 3350, 3310,
2951, 1734, 1710, 1611, 1437, 1406, 1211, 1166, 1124,
25.23 (25.12) (CH3), 42.35 (43.40) (C1″), 45.44 (45.32)
(CH2), 52.51 (52.31) and 52.73 (OMe), 53.68 (53.43)
(CO2Me), 54.02 (CH), 84.62 (C4′), 99.69 (C2′), 101.94
(C5′), 112.80 (112.59) (=CH2), 143.31 (143.41) (=CH),
158.70 (C1′), 172.56 (CO2Me), 187.35 (C=O). Mass
spectrum: m/z 422 (Irel = 100%) [M + H]+.
1
1037, 991, 706, 699, 617. H NMR spectrum, δ, ppm:
7-Chloro-8-oxa-1,4-dioxaspiro[4.4]non-6-en-6-yl
morpholine-4-carbodithioate (XII). A solution of
0.12 ml (1.44 mmol) of morpholine in 3 ml of anhy-
drous THF was added under stirring at room tempera-
ture to a suspension of 0.07 g (1.44 mmol) of sodium
hydride (preliminarily washed with anhydrous hexane)
in 5 ml of anhydrous THF. The mixture was stirred for
30 min, 0.09 ml (1.44 mmol) of carbon disulfide was
added, the mixture was stirred for 20 min, 0.20 g
(0.96 mmol) of compound XI was added, and the mix-
ture was stirred at room temperature until the initial
compound disappeared (TLC). The mixture was
quenched by adding a required amount of a saturated
solution of ammonium chloride and evaporated, the
residue was dissolved in chloroform, the solution was
filtered through a thin layer of silica gel, and the
0.88 d (3H, CH3, J = 6.0 Hz), 0.91 d (3H, CH3, J =
7.5 Hz), 1.66 m (3H, CH, CH2), 3.71 s (3H, CO2Me),
4.14–4.31 m (5H, NCH, OCH2CH2O), 4.38 s (1H,
CHCl), 5.76 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 22.35 (Me), 24.48 (CH), 41.91 (CH2), 52.44
(CO2Me), 54.22 (NCH), 61.86 (CHCl), 66.64
(OCH2CH2O), 106.73 (C7′, C5′), 158.19 (C6′), 172.17
(CO2Me), 184.0 (C8′). Found, %: C 47.25; H 5.55;
Cl 20.66; N 4.20. C14H19Cl2NO5. Calculated, %:
C 47.74; H 5.44; Cl 20.13; N 3.98.
N-(7,9-Dichloro-8-oxo-1,4-dioxaspiro[4.4]non-6-
en-6-yl)-D-valine methyl ester (IX) was synthesized
from 0.2 g (0.82 mmol) of ketone VId and 0.23 g
(1.43 mmol) of D-valine methyl ester hydrochloride.
Yield 0.08 g (~30%). IR spectrum, ν, cm–1: 3309,
2963, 1739, 1715, 1616, 1265, 1209, 1146, 1030, 999,
949, 874, 810, 712. 1H NMR spectrum, δ, ppm: 0.98 d
(3H, CH3, J = 7.6 Hz), 1.03 d (3H, CH3, J = 7.8 Hz),
2.17 m (1H, CH), 3.75 m (1H, NCH), 3.79 s (3H,
CO2Me), 4.22–4.34 m (4H, OCH2CH2O), 4.37 s (1H,
CHCl), 5.72 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 18.06 (Me), 29.67 (CH), 52.58 (CO2Me), 60.29
(CHCl), 61.50 (NCH), 66.39 (OCH2CH2O), 107.09
(C5′), 133.40 (C7′), 150.45 (C6′), 171.24 (CO2Me),
182.44 (C8′). Found, %: C 46.77; H 5.41; Cl 21.56;
N 4.32. C13H17Cl2NO5. Calculated, %: C 46.17;
H 5.07; Cl 20.97; N 4.14.
1
filtrate was evaporated. Yield 0.29 g (91%). H NMR
spectrum, δ, ppm: 2.82 s (2H, CH2), 3.72 s (4H,
OCH2CH2O), 4.01 m (4H, CH2N), 4.14 m (4H, OCH2).
13C NMR spectrum, δC, ppm: 65.89 (OCH2CH2O),
109.83 (C5′), 143.13 (C7′), 157.06 (C6′), 185.36 (C=O),
193.01 (C=S). Mass spectrum, m/z (Irel, %): 336
[M + H]+, 293, 279.
Compounds XIII and XIV were synthesized in
a similar way.
7-Chloro-8-oxo-1,4-dioxaspiro[4.4]non-6-en-6-yl
(1-phenylethyl)dithiocarbamate (XIII) was synthe-
sized from 0.2 g (0.96 mmol) of compound XI, 0.14 g
(1.15 mmol) of α-methylbenzylamine, 0.07 g
(1.44 mmol) of NaH, and 0.09 ml (1.44 mmol) of CS2.
N-[2,4-Dichloro-4-(1,1-dimethylprop-2-en-1-yl)-
5,5-dimethoxy-3-oxocyclopent-1-en-1-yl]-D-leucine
methyl ester (X) was synthesized as a 3:1 mixture of
diastereoisomers (according to the 1H NMR data) from
0.2 g (0.64 mmol) of allyl ketone VIc and 0.2 g
(1.11 mmol) of D-leucine methyl ester hydrochloride.
Yield 0.145 g (54%). IR spectrum, ν, cm–1: 3292,
2960, 1744, 1705, 1589, 1522, 1377, 1247, 1207,
1178, 1149, 1082, 1064, 1024, 924, 820, 746, 721.
1H NMR spectrum, δ, ppm: 0.97 d (3H, CH3, J =
6.0 Hz), 1.01 d (3H, CH3, J = 6.0 Hz), 1.19 s and
1.26 s (6H, CH3), 1.66 m (1H, CH), 1.74 m (2H, CH2),
3.33 s (3.24) and 3.49 s (3.46) (6H, OMe), 3.79 s (3H,
CO2Me), 4.99–5.04 m (3H, =CH2, NCH), 5.76 d (1H,
NH, J = 8.6 Hz), 6.07 d.d (1H, =CH, J = 10.5,
17.5 Hz). 13C NMR spectrum, δC, ppm: 21.80 and
22.64 (CH3), 24.17 (24.31) (CH), 24.68 (24.80) and
1
Yield 0.31 g (89%). H NMR spectrum (CD3OD), δ,
ppm: 1.61 d (3H, CH3, J = 6.85 Hz), 2.62 s (2H, CH2),
4.03 m and 4.44 m (2H each, OCH2CH2O), 4.99 q (1H,
CH, J = 6.84 Hz), 7.23 m (1H, NH), 7.33 m (5H,
C6H5). 13C NMR spectrum, δC, ppm: 25.06 (CH3),
47.76 (CH2), 58.23 (CH), 67.30 (OCH2CH2O), 111.53
(C5′); 126.46, 127.08, 129.15, 129.45, 129.88, 141.99
(Carom); 144.99 (C7′), 153.50 (C6′), 195.81 (C=O),
199.45 (C=S). Found, %: C 51.43; H 4.43; Cl 9.95;
N 4.0; S 17.89. C16H16ClNO3S2. Calculated, %:
C 51.95; H 4.36; Cl 9.58; N 3.79; S 17.34.
4-Allyl-2,4-dichloro-5,5-dimethoxy-3-oxocyclo-
pent-1-en-1-yl morpholine-4-carbodithioate (XIV)
was synthesized from 0.2 g (0.70 mmol) of compound
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011

EGOROV et al.
370
VIa, 0.06 g (1.05 mmol) of NaH, 0.07 ml (1.05 mmol)
of CS2, and 0.09 ml (1.05 mmol) of morpholine. Yield
0.23 g (80%). IR spectrum, ν, cm–1: 2947, 2922, 2854,
2717, 2461, 2360, 2332, 1732, 1719, 1674, 1431,
1269, 1230, 1211, 1188, 1149, 1115, 1070, 1018, 974,
(0.291 mmol), was added in portions under stirring to
3 ml of concentrated sulfuric acid cooled to 0°C. The
mixture was stirred for 1 h at 0°C, allowed to warm up
to room temperature, and treated with chloroform
(3×5 ml). The extracts were combined, dried over
MgSO4, and evaporated, and the residue was subjected
to column chromatography on silica gel using ethyl
acetate–petroleum ether (1:10) as eluent. Yield 0.033 g
(~50%). IR spectrum, ν, cm–1: 3462, 2993, 1737, 1693,
1682, 1597, 1573, 1244, 1203, 1170, 1124, 1010, 985,
1
926, 910, 874, 820, 714, 681. H NMR spectrum, δ,
ppm: 2.81 d.d (1H, CH2, J = 7.3, 15.1 Hz) and 3.16 d.d
(1H, CH2, J = 6.9, 15.1 Hz), 3.42 s (3H, OCH3), 3.59 s
(3H, OCH3), 3.81 t (4H, CH2N, J = 4.6 Hz), 4.17 m
(4H, OCH2), 5.17 m (2H, =CH2), 5.84–5.96 m (1H,
=CH). 13C NMR spectrum, δC, ppm: 40.84 (CH2),
43.09 (NCH2), 52.10 (OCH3), 63.67 (C4′), 66.19
(OCH2), 104.37 (C5′), 119.83 (=CH2), 130.91 (C2′),
157.0 (C1′), 131.54 (=CH), 184.68 (C=O), 189.50
(C=S). Found, %: C 43.37; H 4.45; Cl 17.85; N 3.46;
S 15.94. C15H19Cl2NO4S2. Calculated, %: C 43.69;
H 4.64; Cl 17.20; N 3.40; S 15.55.
1
926, 841, 827, 727. H NMR spectrum: δ 5.14 ppm, s
(1H, CHCl). 13C NMR spectrum, δC, ppm: 61.41
(CHCl), 79.72 (C1), 132.67 and 159.44 (C2, C3),
169.49 (CO2H), 188.12 (C4). Found, %: C 28.88;
H 0.86; Cl 43.93. C6H3Cl3O4. Calculated, %: C 29.36;
H 1.23; Cl 43.33.
REFERENCES
6,8,9-Trichloro-7-trimethylsiloxy-1,4-dioxaspiro-
[4.4]non-8-ene-7-carbonitrile (XV). Ketone VId,
0.2 g (0.82 mmol), was dissolved in 5 ml of toluene,
0.01 g (0.08 mmol) of glycine and 0.122 g
(1.23 mmol) of trimethylsilyl cyanide were added, and
the mixture was stirred for 24 h at room temperature.
The mixture was then filtered through a layer of silica
gel, the sorbent was washed with methylene chloride,
and the solution was evaporated. Yield 0.26 g (95%).
IR spectrum, ν, cm–1: 3325, 2960, 1635, 1458, 1377,
1260, 1246, 1217, 1180, 1155, 1130, 1109, 1059, 1031,
953, 920, 874, 846, 808, 758, 718, 690, 638, 570. Mass
spectrum, m/z (Irel, %): 243 (28) [M + H – Me3SiCN]+,
232 (100) [M + H – Me3Si – Cl]+. Major stereoisomer:
1H NMR spectrum, δ, ppm: 0.34 s (9H, SiCH3), 4.17–
4.24 m (4H, OCH2CH2O), 4.26 s (1H, CHCl). 13C NMR
spectrum, δC, ppm: 1.06 (SiMe), 66.74 and 67.42
(OCH2CH2O), 67.92 (CHCl), 74.84 (C7), 110.31 (C5),
116.41 (CH), 132.29 (C8), 136.62 (C9); minor stereo-
isomer: 1H NMR spectrum, δ, ppm: 0.35 s (9H, SiCH3),
4.17–4.24 m (4H, OCH2CH2O), 4.58 s (1H, CHCl).
13C NMR spectrum, δC, ppm: 1.06 (SiMe), 67.09 and
67.35 (OCH2CH2O), 69.23 (CHCl), 78.10 (C7), 108.81
(C5), 114.64 (CH), 133.69 (C8), 135.33 (C9).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 3 2011