Design and synthesis of novel polyheterofunctionalyzed cyclopentenones

Article abstract of DOI:10.1016/j.tet.2012.06.048

Novel highly functionalized chlorocyclopentenones derivatives with N-, O-, and C-substituents were synthesized.

Full text of DOI:10.1016/j.tet.2012.06.048

Tetrahedron 68 (2012) 7122e7128
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Tetrahedron
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Design and synthesis of novel polyheterofunctionalyzed cyclopentenones
,
Victor A. Egorov y, Fanuza A. Gimalova y, Gullira M. Khalikova y, Mansur S. Miftakhov y
*
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, Prosp. Octyabrya 71, 450054 Ufa, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel highly functionalized chlorocyclopentenones derivatives with N-, O-, and C-substituents were
Received 12 March 2012
Received in revised form 21 May 2012
Accepted 12 June 2012
synthesized.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 19 June 2012
Keywords:
Functionalized cyclopentenones
Synthesis
Antiviral carbocycles
1. Introduction
Chlorocyclopentenones 6 and 7 are core structures, which can
be modified.9 In this paper we have planned synthesis new com-
The number of virus diseases in the world continues to increase
the search for compounds possessing antiviral activity remains
important. As a model for the so design and construction of new
antiviral carbocycles known neuraminidase inhibitors Tamiflu 11e3
and Peramavir 24,5 as well as polyheterofunctionalyzed chlor-
ocyclopentenone derivatives 3e5, synthesized in our laboratory,
were chosen. These derivatives exhibit highly activity against the
virus of Tobacco mosaic and Solanaceae.6e8
pounds, which include the most important pharmacophore ele-
ments of structures 1e5. In particular, our efforts were directed to
the introduction of an amino function into structures 6 and 7
generating an enaminochlorvinylketone fragment containing in 3
and 4 as well the formation of
in 1 and 3 etc.
a,
b-unsaturated carboxyl function as
O
O
CO2H
O
CO2H
Cl
Cl
Cl
CO2H
Cl
HO
Et
Et
OMe
OMe
Et
NH2
NH2
Me2N
O
O
O
Cl
Cl
N
H
O
O
NHAc
Et
NHAc
NH
1
3
2
7
6
Firstly, the reactions of 6 and 7 with C-nucleophiles were
studied. To introduce a carboxyl function into the structure of 6 and
7 the reaction with the Li-derivative of ethyl acetate was used to
produce hydroxyethers 8 and 9a,b in good yields. Diastereomeric
chlorohydrines 9a and 9b are formed in a 2:1 ratio, which was
determined by integration of the intensity of the singlet CHCl sig-
nals in the 1H NMR spectrum of a mixture of these compounds. The
assignment is based on the differences in the shifting effect of
a vicinal atom O neighboring the CHCl group: owing to the trans-
effect the H atom in 9b resonates at lower field. The pure major
trans-chlorohydrine 9a diastereomer was isolated by column
chromatography on SiO2. Individual cis-chlorohydrine 9b was
obtained by the isomerization of a mixture of 9a and 9b catalyzed
by 10% water/H2SO4. Under these sufficiently mild conditions the
O
O
Cl
Cl
C
Cl
Cl
OMe
OMe
OMe
OMe
N
PhO
N
H
4
OH
5
O
* Corresponding author. E-mail addresses: AMONNIKA@mail.ru (V.A. Egorov),
bioreg@anrb.ru (M.S. Miftakhov).
y
Fax: þ347 235 60 66.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.048

V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
7123
dioxolane protective group 9a is stable. Obviously the isomeriza-
tion of 9a/9b, occurs via the tertiary carbonium cation A. The
formation of the thermodynamically more stable compound 9b,
stabilized by an intramolecular H-bond, is a driving force for the
isomerization process (Scheme 1).
compared with 9b in the initial mixture. Methyl ether 14 was
formed by reacting dichlorocyclopentenone with methox-
ycarbonylmethylidenphosphorane and following hydrolysis of the
dioxolane protective group of compound 13. Under similar condi-
tions trichloroketone 6 did not react with the above phosphorane,
7
HO
CO2Et
Cl
O
53%
O
Cl
Cl
R
O
8
LDA, CH3COOEt
THF, - 78 oC -> rt
HO
CO2Et
Cl
HO
CO2Et
Cl
O
Cl
Cl
O
Cl
+
6, R = Cl
7, R = H
74%
O
O
:OH2
CO2Et
Cl
Cl
Cl
O
O
9b
9a
2 : 1
Cl
10% H2SO4
Δ
O
Cl
O
A
Scheme 1. Reaction of the compounds 6 and 7 with the Li-derivative of ethyl acetate.
Complete hydrolysis of the dioxolane protecting group 8 and
9a,b was achieved in 98% H2SO4 at 0 ꢀC, which results in the for-
mation of hydroxyketones 10 and 12, respectively, as well as the
dehydration dienone product 11. Evidently, the hydrolysis of 9a,b
leads to an increase in the amount of cis-chlorohydrine 12b as
presumably, due to steric hindrance. The E-configuration of double
bond assumed for 11, 13 and 14 is caused by the spatial difficulties
as well as owing to the presence of a small coupling constant of
vinyl H with methylene ring proton (J 1.7e1.8 Hz, forming a W), and
the absence of NOEdeffect among them (Scheme 2).
CO2Et
CO2Et
HO
Cl
Cl
+
O
Cl
O
Cl
HO
10 (20%)
HO
11 (71%)
98% H2SO4
0 oC
8, 9a,b
CO2Et
Cl
CO2Et
Cl
Cl
Cl
+
98%
Cl
O
Cl
CO2Me
O
12a
12b
5
:
4
CO2Me
Cl
Cl
MeO2CCH=PPh3
C6H6, 95%
98% H2SO4
0 oC, 98%
7
O
Cl
O
O
Cl
14
13
Scheme 2. The synthesis of the hydroxyketones 10, 12 and dienones 11, 14.

7124
V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
The spatial hindered E-configuration of double bond in com-
The reaction of chlorocyclopentenone 7 with NaN3 gave a high
yield of azide 23, the latter entered into ‘click’ reaction10,11 with
phenylacetylene to form a regioisomeric mixture of triazoles 24a,b
in the ratio w1:1 (Scheme 5).
pounds 12e13 is confirmed by the comparison of spectral data of
the mentioned E-isomers with the corresponding Z-isomers pro-
duced by a photoisomerization.
δH = 6.33 ppm
δH = 6.07 ppm
H
CO2Me
MeO2C
H
δC = 31.9 ppm
δC = 40.4 ppm
Cl
Cl
Cl
O
Cl
O
14-Z
14-E
Vinyl H atom in the compound 14-E is deshielded by the
neighboring chlorine atom and resonates at the lower field.
Downfield chemical shift of the methylene carbon in the compound
14-Z is associated with the decreasing 13C-steric compression ef-
fects in comparison with the methylene carbon in 14-E.
At the final stage of the formation of the target compounds
10e14, they were subjected to substitution reactions of the sp2-Cl
with amines and ‘equivalents’, as showed on Scheme 3.
In summary, we have demonstrated reactions of basic chlor-
ocyclopentenones 6 and 7 and its derivatives with some C-, N-
and O-nucleophiles, azide anion and methoxycarbonyltriphenyl-
phosphorane. The AdNE-type substitution of sp2-Cl is a key re-
action of chlorocyclopentenones with hetero nucleophiles. The
last reacts with chlorocyclopentenones regioselectively to form
corresponding substitution products of C3eCl. Thus, the pur-
poseful modification of basic chlorocyclopentenones 6 and 7
CO2Me
Cl
morpholine
13
or NH2CH2CH2OH
O
15, R = N(CH2)2O(CH2)2 (92%)
16, R = NHCH2CH2OH (92%)
R
O
CO2Me
CO2Et
CO2Et
Cl
Cl
R
50% H2SO4
MeOH
morpholine
or HNEt2
15
O
N
Cl
O
Cl
O
19
11
17, R = N(CH2)2O(CH2)2 (83%)
18, R = NEt2 (52%)
O
Scheme 3. Reactions of dichlorocyclopentenenones 11 and 13 with amines.
The introduction of N-function was carried out under standard
conditions of N-ketovinylation.9 Dichlorocyclopentene derivative
13 smoothly reacted with morpholine and ethanolamine in a ben-
zene solution to form substitution products of the most activated
atom Cl at C(9)dcompounds 15 and 16. Similar reactions of
dichlorocyclopentenenone 11 with morpholine and diethylamine
led to AdNE-substitution products 17 and 18. Evidently, in this case
the regioselectivity of the reaction was controlled by the keto-
function conjugated with a cycle double bond. The hydrolysis of
ketal 15 by 50% H2SO4 leads to compound 19.
resulted in compounds 14e24, which are of interest for
pharmacology.
2. Experimental
2.1. General
NMR spectra were recorded on a Bruker AM-300 spectrometer
at 300 MHz (1H) and 75.47 MHz (13C), using TMS as the internal
standard. IR spectra were recorded on IR Prestige-21 Fourier
Transform Shimadzu spectrophotometer from samples prepared as
thin films or dispersed in Nujol. Mass spectra were recorded on
a Thermo Finnigan MAT 95XP (the temperature of the ionizing
chamber was 200 ꢀC, the temperature of the sample injection was
The reactions of 12 and 14 with methionine and diethylamine
in MeOH led to enol ethers of 20 and 21 instead of expected N-
derivatives. Compounds 11 and 14 did not react with guanidine.
However, guanidine adduct 22 was obtained from 6 (Scheme 4).

V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
7125
HO
CO2Et
Cl
MeO
O
O
Et2NH
MeOH, 41%
Cl
Cl
H2NC(NH)NH2*HCl
O
Cl
6
20
CO2Me
O
KOH, MeOH, rt, 83%
H2N
12, 14
HN
NH
MeO
methionine
MeOH, 21%
22
O
Cl
21
Scheme 4. Synthesis of the enol ethers 20, 21 and adduct 22.
O
O
Cl
Cl
NaN3, DMF, rt
O
O
Cl
N3
O
O
7
23
O
O
Cl
N
Cl
N
O
O
+
N
N
MeCN, iPr2EtNH
CuI, 62%
O
O
N
N
Ph
24a
24b
~1 : 1
Ph
Scheme 5. Synthesis of the triazoles 24a,b.
5e270 ꢀC, the temperature was raised at the rate of 22 ꢀC minꢁ1
)
The combined organic layers were washed with brine, dried with
MgSO4, filtered, and concentrated in vacuo. The residue was chro-
matographed on a column with SiO2 using EtOAc/petroleum ether
(1:10) as the eluent to obtain 0.30 g (53%) of compound 8 as a col-
orless oil; Rf (EtOAc/petroleum ether, 1:10) 0.36; nmax (liquid film)
3454, 2982, 2899, 1734, 1637, 1618, 1473, 1396, 1373, 1338, 1306,
and Shimadzu LCMS-2010 spectrometers (chemical ionization un-
der atmospheric pressure). Elemental analyses were performed
using a Euro EA 3000 CHNS analyzer. The reaction course was
monitored by TLC on ‘Sorbphil’ plates (Russia) with visualization of
compounds by charring or in the alkaline solution of potassium
permanganate. The products were isolated by column chromatog-
raphy on silica gel (30e60 g of adsorbent per 1 g of compound);
freshly distilled solvents were used as eluents.
1207,1132, 1095,1031, 951, 833, 808 cmꢁ1
; dH (300 MHz, CDCl3) 1.27
(3H, t, 3J 7.0 Hz, CH3), 2.43 (1H, d, 2J 13.9 Hz, CH2), 2.56 (1H, d, 2J
13.9 Hz, CH2), 2.58 (1H, d, 2J 15.8 Hz, CH2), 2.86 (1H, d, 2J 15.8 Hz,
CH2), 3.97 (1H, m, OCH2), 4.00e4.04 (1H, m, OCH2), 4.15e4.20 (4H,
m, OCH2CH2O), 4.23 (1H, br s, OH); dC (75.47 MHz, CDCl3) 14.1
2.2. Ethyl (8,9-dichloro-7-hydroxy-1,4-dioxaspiro[4.4]non-8-
en-7-yl)acetate (8)
(CH3), 42.3 (CH2), 49.6 (CH2), 61.3 (OCH2), 66.2 and 66.4 (OCH2
-
CH2O), 77.1 (C-70), 111.9 (C-50), 133.3 (C-80), 138.2 (C-90), 171.5
(CO2Et); m/z: 296 (5 Mþ), 261 (18), 251 (10), 243 (6), 217 (29), 209
(100), 173 (54), 165 (18), 145 (16), 113 (16), 86 (28%); HRMS (EI): Mþ,
found 296.0213. C11H14O5Cl2 requires 296.0213.
The solution of n-BuLi in hexane (3.1 mL, 2.76 M, 8.67 mmol)
was added dropwise under argon to the solution of i-Pr2NH (1.2 mL,
8.62 mmol) in anhydrous THF (10 mL) cooled to ꢁ10 ꢀC. The re-
action mixture was stirred for 15 min followed by a dropwise ad-
dition of a solution of anhydrous EtOAc (0.84 mL, 8.60 mmol) in THF
(3 mL). After 15 min, the reaction mixture was cooled to ꢁ78 ꢀC
followed by a dropwise addition of the compound 7 (0.40 g,
1.91 mmol) solution in THF (3 mL), the mixture was stirred for 1 h at
ꢁ78 ꢀC and for 2 h at room temperature. Then, the saturated so-
lution of NH4Cl (3 mL) was added and with stirring continued for
10 min, THF was evaporated, and the residue extracted with CHCl3.
2.3. Ethyl-(6,8,9-trichloro-7-hydroxy-1,4-dioxaspiro[4,4]non-
8-en-7-yl)-acetate (9a,b)
Compound (9a,b) was obtained similarly to compound 8 from
compound 6 (0.40 g, 1.64 mmol) and 0.72 mL (7.39 mmol) of EtOAc.
The product was purified by column chromatography with SiO2
using EtOAc/petroleum ether (1:10) as the eluent to obtain 0.4 g

7126
V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
(74% yield) of compound 9a,b as mixture of cis,trans-isomers in
a ratio 2:1 (as determined by 1H NMR). White powder, mp
120e122 ꢀC. nmax (liquid film) 3400, 2890, 2880, 1745, 1732, 1600,
1375, 1348, 1234, 1205, 1072, 1022, 720 cmꢁ1; m/z 295 (80
[MꢁCl]þ), 261 (38), 253 (100), 209 (64), 181 (36), 133 (42%); HRMS
(EI): (MꢁCl)þ, found 295.0135. C11H13Cl2O5 requires 295.0140.
This mixture was subjected to repeated chromatography on
silica gel to isolate 0.2 g (37%) of individual trans-chlorohydrin 9a;
mixed fractions of 9a and 9b were converted into individual cis-
chlorohydrin 9b by heating in 10% H2SO4 solution. Yield 0.15 g
(28%). trans-Isomer (9a). Rf (EtOAc/petroleum ether, 1:10) 0.41; dH
(300 MHz, CDCl3): 1.26 (3H, t, 3J 7.3 Hz, CH3), 2.72 (1H, d, 2J 16.0 Hz,
42.71; H, 3.98; Cl, 28.02]; dH (300 MHz, CDCl3): 1.27 (3H, t, 3J 7.1 Hz,
CH3), 2.69 (1H, d, 2J 16.0 Hz, CH2) and 2.99 (1H, d, 2J 16.0 Hz, CH2),
2.85 (1H, d, 2J 18.4 Hz, CH2) and 2.97 (1H, d, 2J 18.4 Hz, CH2), 4.20
(2H, q, 3J 7.0 Hz, OCH2), 4.48 (1H, s, OH); dC (75.47 MHz, CDCl3) 13.9
(CH3), 41.8 (CH2), 48.6 (CH2), 61.6 (OCH2), 75.3 (C-10), 134.1 (C-30),
163.4 (C-20), 170.5 (CO2Et), 193.2 (C]O); m/z 252 (11 Mþ), 234 (19),
207 (9), 189 (9), 171 (16), 165 (100), 137 (14), 88 (26), 60 (12%);
HRMS (EI): Mþ, found 251.9951. C9H10Cl2O4 requires 251.9956.
2.7. Ethyl (2E)-(2,3-dichloro-4-oxocyclopent-2-en-1-ylidene)
acetate (11)
2
CH2), 2.86 (1H, d, J 16.0 Hz, CH2), 3.60 (1H, s, OH), 4.12e4.22 (6H,
Rf (EtOAc/petroleum ether, 1:1) 0.37; nmax (liquid film) 2981,
m, OCH2), 4.64 (1H, s, CHCl), 6.05 (1H, s, OH); dC (75.47 MHz, CDCl3)
13.9 (CH3), 38.7 (CH2), 61.2 (OCH2), 66.2 (CHCl), 66.0 and 67.0
(OCH2CH2O), 77.4 (C-70), 110.5 (C-50), 133.3 (C-80), 136.8 (C-90), 169.7
(CO2Et). cis-Isomer (9b). Rf (EtOAc/petroleum ether, 1:10) 0.40; dH
(300 MHz, CDCl3): 1.29 (3H, t, 3J 7.2 Hz, CH3), 2.64 (1H, d, 2J 15.9 Hz,
CH2), 2.81 (1H, d, 2J 15.9 Hz, CH2), 4.12e4.22 (6H, m, OCH2), 4.40
(1H, s, CHCl), 6.05 (1H, s, OH); dC (75.47 MHz, CDCl3) 13.8 (CH3), 37.7
(CH2), 61.6 (OCH2), 66.9 (OCH2CH2O), 70.6 (CHCl), 79.3 (C-70), 109.2
(5-40), 131.5 (C-80), 136.8 (C-90), 172.9 (CO2Me).
2962, 2939, 2906, 2872, 1724, 1710, 1645, 1371, 1348, 1259, 1225,
1217, 1177, 984, 901 cmꢁ1 dH (300 MHz, CDCl3) 1.31 (3H, t, 3J 7.1 Hz,
;
CH3), 3.64 (1H, d, 2J 1.8 Hz, CH2), 4.23 (2H, q, 2J 7.1 Hz, OCH2), 6.30
(1H, t, J 1.8 Hz, ]CH); dC (75.47 MHz, CDCl3) 14.1 (CH3), 39.1 (CH2),
61.0 (OCH2), 115.0 (]CH), 139.6 (C-30), 145.4 (C-20), 156.1 (C-10),
164.8 (CO2Et),192.1 (C]O); m/z 234 (33 Mþ), 207 (22),199 (32), 189
(88), 171 (100), 162 (31), 149 (20), 143 (52), 133 (75), 119 (29), 84
(59), 69 (37), 56 (26), 49 (30%); HRMS (EI): Mþ, found 233.9845.
C9H8O3Cl2 requires 233.9850.
2.4. Ethyl (2,3,5-trichloro-1-hydroxy-4-oxocyclopent-2-en-1-
yl)acetate (12a,b)
2.8. Methyl (2E)-(8,9-dichloro-1,4-dioxaspiro[4,4]non-8-en-7-
yl)acetate (13)
The isomeric mixture (0.30 g) of compounds 9a and 9b (2:1) on
stirring was added in small portions to 1 mL of concentrated sul-
furic acid cooled to 0 ꢀC, and the reaction mixture was stirred for
w1 h at 0 ꢀC, then diluted with chloroform (20 mL), and the organic
phase separated and the acidic layer extracted with chloroform
(2ꢂ10 mL). The combined extracts were washed with 5% solution of
sodium hydrogen carbonate and saturated solution of sodium
chloride, dried over MgSO4, filtered through a small layer of silica
gel and evaporated to give 0.23 g (98% yield) of compound 12a,b as
a mixture of cis,trans-chlorohydrins (in the ratio w5:4, as de-
Methoxycarbonylmethylidentriphenylphosphorane (2.39 g,
7.17 mmol) was added to a solution of compound 7 in anhydrous
benzene (10 mL) and the reaction mixture was stirred for 48 h
(monitored by TLC). Benzene was evaporated, and the residue was
purified by column chromatography with SiO2 using EtOAc/ben-
zene (1:5) as the eluent to obtain 0.60 g (95% yield) compound 13.
Colorless crystals, mp 50e52 ꢀC; Rf (EtOAc/petroleum ether, 1:1)
0.52; nmax (liquid film) 2997, 2951, 2922, 2851, 1720, 1709, 1639,
1591, 1454, 1437, 1396, 1346, 1294, 1252, 1198, 1152, 1028, 1016, 947,
858 cmꢁ1
; dH (300 MHz, CDCl3) 3.35 (2H, dd, J 1.0 and J 2.2 Hz, CH2),
1
termined by H NMR). White powder, mp 132e133 ꢀC; Rf (EtOAc/
3.73 (3H, s, OCH3), 4.04e4.08 (2H, m, OCH2CH2O) and 4.18e4.23
(2H, m, OCH2CH2O), 6.05 (1H, m, ]CH); dC (75.47 MHz, CDCl3) 41.9
(CH2), 51.4 (OCH3), 66.3 (OCH2CH2O), 111.8 (]CH), 112.20 (C-50),
134.1 (C-80), 142.9 (C-90), 150.9 (C-70), 166.4 (CO2Me); m/z 264 (14
Mþ), 229 (100), 197 (17), 157 (22), 133 (13), 129 (4), 83 (6%); HRMS
(EI): Mþ, found 263.9950. C10H10O4Cl2 requires 263.9951.
petroleum ether, 1:5) 0.31; nmax (liquid film) 3400, 2960, 2900,
1745, 1732, 1600, 1396, 1375, 1348, 1234, 1205, 1148, 1097, 1072,
1022, 740 cmꢁ1; m/z 286 (0.1 Mþ), 251 (100), 223 (11), 199 (12), 178
(6), 129 (4), 107 (5), 60 (7%). HRMS (EI): Mþ, found 285.9568.
C9H9Cl3O4 requires 285.9561. trans-Isomer 12a. dH (300 MHz, CDCl3)
1.31 (3H, t, 3J 7.1 Hz, CH3), 2.82 (1H, d, 2J 16.8 Hz) and 2.92 (1H, d, 2J
16.8 Hz, CH2), 4.17e4.28 (2H, m, OCH2), 4.69 (1H, s, CHCl), 6.0 (1H, s,
OH); dC (75.47 MHz, CDCl3) 13.8 (CH3), 38.3 (CH2), 61.9 (CHCl), 62.1
(OCH2), 79.6 (C-10), 133.1 (C-20), 161.7 (C-30), 169.3 (CO2Et), 186.9
(C]O). cis-Isomer 12b. dH (300 MHz, CDCl3): 1.28 (3H, t, 3J 7.1 Hz,
CH3), 2.85 (1H, d, 2J 16.3 Hz, CH2) and 3.09 (1H, d, 2J 16.3 Hz, CCH2),
3.92 (1H, s, OH), 4.17e4.28 (2H, m, OCH2), 4.83 (1H, s, CHCl); dC
(75.47 MHz, CDCl3) 13.9 (CH3), 40.2 (CH2), 61.9 (OCH2), 65.5 (CHCl),
75.8 (C-10), 133.1 (C-20), 162.0 (C-30), 171.9 (CO2Et), 187.9 (C]O).
2.9. Methyl (2E)-(2,3-dichloro-4-oxocyclopent-2-en-1-
ylidene)acetate (14-E)
Compound (14-E) was obtained similarly to 10 by sustaining the
solution of compound 13 (0.38 g, 1.43 mmol) in 98% H2SO4 (3 mL) at
0
ꢀC during 2 h. The yield 98% (0.31 g). Yellow powder, mp
88e89 ꢀC; Rf (EtOAc/petroleum ether, 1:10) 0.43; nmax (liquid film)
2880, 1728, 1703, 1637, 1556, 1445, 1438, 1377, 1352, 1261, 1220,
1217,1190,1165, 988, 962, 881 cmꢁ1
; dH (300 MHz, CDCl3): 3.68 (2H,
2.5. Hydrolysis of compound 8
d, J 1.6 Hz, CH2), 3.82 (3H, s, OCH3), 6.35 (1H, t, J 1.6 Hz, ]CH); dC
(75.47 MHz, CDCl3) 39.2 (CH2), 52.1 (OCH3), 115.0 (]CH), 139.8 (C-
30), 145.3 (C-10), 156.1 (C-20), 165.4 (CO2), 192.0 (C]O); m/z 220 (22
Mþ), 185 (50), 157 (100), 133 (55), 84 (42), 63 (19), 49 (40%); HRMS
(EI): Mþ, found 219.9670. C8H6O3Cl2 requires 219.9689.
Compound 8 (0.3 g,1.01 mmol) was carried out similar to 9 (0 ꢀC,
H2SO4, 15 min). The product was chromatographed on a silica gel
column using EtOAc/petroleum ether (1:10) as the eluent to obtain
0.06 g (w20% yield) compound 10 and 0.19 g (71% yield) enone 11.
Sustaining the reaction mixture for 30e40 min produces only
0.26 g (in 98% yield) of enone 11.
2.10. Methyl (2Z)-(2,3-dichloro-4-oxocyclopent-1-en-1-
ylidene) acetate (14-Z)
2.6. Ethyl (1-hydroxy-2,3-dichloro-4-oxocyclopent-2-en-1-yl)
acetate (10)
The irradiation of 14-E (0.06 mg, 0.27 mmol) was carried out at
room temperature in dry benzene (24 mL) with the use of an UV-
lamp ORK-21. After completion of the irradiation (2 h) benzene
was evaporated to obtain of a mixture of 14-E and 14-Z (0.06 g) in
ratio 2:3 (as determined by 1H NMR). The more polar isomer 14-Z
Colorless amorphic crystals; Rf (EtOAc/petroleum ether, 1:5)
0.20; [found: C, 43.02; H, 3.88; Cl, 28.60. C9H10Cl2O4 requires for C,

V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
7127
was easily separated by column chromatography with SiO2 using
EtOAc/petroleum ether (1:10) as the eluent. Light-yellow oil; Rf
(EtOAc/petroleum ether, 1:10) 0.26; dH (300 MHz, CDCl3): 3.33 (2H,
s, CH2), 3.83 (3H, s, OCH3), 6.07 (1H, s, ]CH); dC (75.47 MHz, CDCl3):
40.4 (CH2), 52.4 (OCH3), 118.1 (]CH),135.8 (C-30),140.6 (C-10),154.0
(C-20), 165.3 (CO2), 191.0 (C]O).
52% (0.06 g); Rf (EtOAc/petroleum ether, 1:1) 0.30; nmax (liquid film)
2974, 2951, 2935, 2878, 1714, 1697, 1638, 1562, 1435, 1384, 1350,
1276, 1211, 1159, 1093, 1026, 979, 877, 788, 655 cmꢁ1
; dH (300 MHz,
CDCl3) 1.22 (3H, t, 3J 7.1 Hz, CH3), 3.49 (2H, d, J 1.8 Hz, CH2), 3.59 (2H,
q, 3J 7.0 Hz, OCH2), 3.75 (3H, s, OCH3), 6.08 (1H, t, J 1.8 Hz, ]CH); dC
(75.47 MHz, CDCl3) 14.0 (CH3), 38.8 (CH2), 45.1 (NCH2), 51.8 (OCH3),
114.1 (]CH), 118.0 (C-30), 148.5 (C-10), 163.9 (C-20), 166.0 (CO2),
192.7 (C]O); m/z 257 (50 Mþ), 242 (75), 222 (18),198 (50),182 (30),
149 (22), 84 (97), 49 (100%). HRMS (EI): Mþ, found 257.0830.
2.11. Methyl (2E)-[9-(morpholin-4-yl)-8-chloro-1,4-
dioxaspiro[4,4]non-8-en-7-ylidene]acetate (15)
C12H16ClNO3 requires 257.0813.
A mixture of compound 13 (0.10 g, 0.38 mmol) and morpholine
(0.5 mL, 5.75 mmol) in benzene (3 mL) was stirred 48 h at room
temperature. The mixture was diluted with benzene (10 mL),
washed with brine, dried with MgSO4, filtered through a small layer
of silica gel and evaporated to give 0.11 g (92% yield) of colorless
crystals, mp 116e117 ꢀC; Rf (EtOAc/petroleum ether, 1:1) 0.26; nmax
(liquid film) 2953, 2922, 2852, 1689, 1570, 1560, 1440, 1346, 1280,
2.15. Methyl (2E)-[2-chloro-3-(morpholin-4-yl)-4-
oxocyclopent-2-en-1-ylidene]-acetate (19)
To the solution of compound 15 (0.10 g, 0.377 mmol) in MeOH
(5 mL) 1 mL of solution (50%) sulfuric acid was added, and the
mixture was stirred for 1 h at the room temperature (monitored by
TLC). Then solid NaHCO3 was added until pH 6.0, MeOH was
evaporated, the residue was dissolved in CH2Cl2. The solution fil-
tered through a small layer of silica gel and the filtrate evaporated
to give 0.08 g (93% yield) of colorless crystals, mp 86e87 ꢀC; Rf
(EtOAc/petroleum ether, 1:1) 0.48; nmax (liquid film) 2920, 2880,
1719, 1703, 1694, 1582, 1337, 1258, 1165, 1152, 1113, 1028, 848, 830,
1163, 1124, 1109, 1038, 1020, 1001, 880, 827 cmꢁ1
; dH (300 MHz,
CDCl3) 3.16 (2H, d, J 1.7 Hz, CH2), 3.61e3.65 (4H, m, NCH2), 3.66 (3H,
s, OCH3), 3.71e3.74 (4H, m, OCH2), 4.06 (4H, br s, OCH2CH2O), 5.71
(1H, t, J 1.7 Hz, ]CH); dC (75.47 MHz, CDCl3) 42.1 (CH2), 48.1 (NCH2),
50.6 (OCH3), 63.7 (OCH2), 66.9 (OCH2CH2O), 101.2 (]CH), 107.4 (C-
50), 112.5 (C-80), 148.5 (C-70), 154.5 (C-90), 168.0 (CO2); m/z 315 (34
Mþ), 280 (100), 236 (4), 222 (3), 150 (4), 69 (3%); HRMS (EI): Mþ,
found 315.0880. C14H18ClNO5 requires 315.0868.
620 cmꢁ1
; dH (300 MHz, CDCl3) 3.46 (2H, d, J 1.7 Hz, CH2), 3.68e3.80
(8H, m, NCH2, OCH2), 3.70 (3H, s, OCH3), 5.91 (1H, t, J 1.7 Hz, ]CH);
dC (75.47 MHz, CDCl3) 39.8 (CH2), 47.9 (NCH2), 51.2 (OCH3), 67.1
(OCH2), 105.7 (]CH), 128.1 (C-20), 145.9 (C-10), 148.5 (C-30), 166.7
(CO2), 196.4 (C]O); m/z 271 (33 Mþ), 240 (24), 236 (100), 214 (7),
200 (8), 178 (29), 86 (5), 69 (8%). HRMS (EI): Mþ, found 271.0550.
2.12. Methyl (2E)-[9-(hydroxyethyl)amino-8-chloro-1,4-
dioxaspiro[4,4]non-8-en-7-ylidene]acetate (16)
Compound (16) was synthesized similarly to 15 from the com-
pound 13 (0.06 g, 0.23 mmol) and monoethanolamine (0.04 g,
0.68 mmol). Yield 92% (0.60 g) as colorless oil; Rf (EtOAc/petroleum
ether, 1:1) 0.17; nmax (liquid film) 3361, 2949, 2924, 2897, 1693,
1681, 1643, 1587, 1568, 1556, 1435, 1406, 1346, 1274, 1192, 1169,
C12H14ClNO4 requires 271.0606.
2.16. Ethyl (3,5-dichloro-1-hydroxy-2-methoxy-4-
oxocyclopent-2-en-1-ylidene)-acetate (20)
1138,1124,1039,1013, 948, 835 cmꢁ1
;
dH (300 MHz, CDCl3) 3.17 (2H,
Compound (20) was obtained from 11 (0.10 g, 0.45 mmol) and
diethylamine (0.07 mL, 0.69 mmol) in MeOH (3 mL) at the room
temperature for 24 h (monitored by TLC). Yield 41% (0.04 g) as
a mixture of trans,cis-chlorohydrins; Rf (EtOAc/petroleum ether,
1:1) 0.16; nmax (liquid film) 3389, 2955, 2932, 1726, 1707,1608,1393,
1373, 1348, 1302, 1253, 1217, 1192, 1086, 1072, 1022, 952, 907,
737 cmꢁ1; m/z 282 (7 Mþ), 264 (3), 247 (100 [MꢁCl]þ), 233 (11), 219
(16), 197 (20), 172 (12), 131 (19), 119 (14%). HRMS (EI): Mþ, found
282.0033. C10H12Cl2O5 requires 282.0062. cis-Isomer. dH (300 MHz,
CDCl3) 1.29 (3H, t, 3J 7.0 Hz, CH3), 2.81 (2H, d, J 3.4 Hz, CH2), 4.19 (1H,
d, 3J 7.0 Hz, OCH2) and 4.27 (1H, dd, 3J 7.0 and 2J 1.4 Hz, OCH2), 4.40
(3H, s, OCH3), 4.56 (1H, s, CHCl); dC (75.47 MHz, CDCl3) 13.8 (CH3),
38.3 (CH2), 60.8 (OCH3), 61.7 (OCH2), 64.1 (CHCl), 77.8 (C-10), 107.1
(C-30), 171.9 (CO2Et), 175.2 (C-20), 188.1 (C]O). trans-Isomer. dH
(300 MHz, CDCl3) 1.28 (3H, t, 3J 7.0 Hz, CH3), 2.83 (2H, d, J 6.2 Hz,
CH2), 4.19 (1H, d, 3J 7.0 Hz, OCH2) and 4.27 (1H, dd, 3J 7.0 and 2J
1.4 Hz, OCH2), 4.40 (3H, s, OCH3), 4.67 (1H, s, CHCl); dC (75.47 MHz,
CDCl3) 13.9 (CH3), 39.5 (CH2), 61.5 (OCH3), 61.4 (OCH2), 64.1 (CHCl),
74.3 (C-10), 107.4 (C-30), 169.7 (CO2Et), 175.5 (C-20), 189.3 (C]O).
d, J 1.7 Hz, CH2), 3.58e3.63 (2H, m, NCH2), 3.66 (3H, s, OCH3),
3.72e3.77 (3H, m, OH, OCH2), 4.06e4.10 (4H, m, OCH2CH2O), 4.88
(1H, m, NH), 5.59 (1H, t, J 1.7 Hz, ]CH); dC (75.47 MHz, CDCl3) 42.1
(CH2), 45.1 (NCH2), 50.8 (OCH3), 62.1 (OCH2), 64.9 (OCH2CH2O),
100.3 (]CH), 104.5 (C-50), 111.5 (C-80), 149.3 (C-70), 154.6 (C-90),
168.4 (CO2Me); m/z 289 (82 Mþ), 258 (68), 254 (88), 214 (100), 182
(33), 178 (9), 83 (4), 69 (6%); HRMS (EI): Mþ, found 289.0710.
C
11H12ClNO5 requires 289.0712.
2.13. Ethyl (2E)-[3-chloro-2-(morpholin-4-yl)-4-
(oxocyclopent-2-en-1-ylidene)acetate (17)
Compound (17) was obtained similarly to compound 15 from 11
(0.08 g, 0.34 mmol) and morpholine (0.09 mL, 1.02 mmol). Yield
83% (0.08 g) as yellow crystals, mp 86e87 ꢀC. Rf (EtOAc/petroleum
ether, 1:1) 0.23; nmax (liquid film) 2880, 1699, 1635, 1565, 1558,
1480, 1370, 1340, 1300, 1269, 1246, 1197, 1167, 1134, 1119, 1026, 975,
933, 885, 779 cmꢁ1 dH (300 MHz, CDCl3) 1.30 (3H, t, 3J 7.1 Hz, CH3),
;
3.49 (2H, d, J 1.7 Hz, CH2), 3.66 (4H, t, J 4.1 and 4.9 Hz, NCH2), 3.82
(4H, t, J 4.4 and 4.7 Hz, OCH2), 4.22 (4H, q, 3J 7.0 Hz, OCH2), 6.02 (1H,
t, J 1.7H, ]CH); dC (75.47 MHz, CDCl3) 14.3 (CH3), 38.7 (CH2), 50.2
(NCH2), 60.9 (OCH2), 67.3 (OCH2CH2O), 114.9 (]CH), 118.8 (C-30),
146.7 (C-10), 163.5 (C-20), 165.3 (CO2), 192.8 (C]O); m/z 286 (100%
MHþ). HRMS (EI): Mþ, found 285.0762. C13H16ClNO4 requires
285.0762.
2.17. Methyl (2E)-(3-chloro-2-methoxy-4-oxocyclopent-2-en-
1-yl)acetate (21)
Compound (21) was obtained from the mixture of 14 (0.20 g,
0.91 mmol), methionine (0.18 g, 0.91 mmol) and of KOH (0.05 g,
0.91 mmol) in MeOH (3 mL). Yield 21% (0.04 g); Rf (EtOAc/petro-
leum ether, 1:1) 0.31; nmax (liquid film): 3017, 2963, 2904, 1726,
2374, 1718, 1610, 1437, 1359, 1325, 1254, 1240, 1211, 1184, 1109, 978,
2.14. Ethyl (2E)-[3-chloro-2-(N,N-diethylamino)-4-
(oxocyclopent-2-en-1-ylidene)acetate (18)
950, 897, 907, 744, 661 cmꢁ1
; dH (300 MHz, CDCl3) 3.45 (2H, d, J
1.7 Hz, CH2), 3.85 (3H, s, OCH3), 4.00 (3H, s, OCH3), 6.35 (1H, t, J
1.7 Hz, ]CH); dC (75.47 MHz, CDCl3) 37.3 (CH2), 51.8 (OCH3), 59.9
(OCH3), 112.9 (]CH), 115.6 (C-30), 144.7 (C-10), 165.9 (CO2), 170.2 (C-
Compound (18) was obtained similarly to compound 15 from 11
(0.10 g, 0.45 mmol) and diethylamine (0.14 mL, 1.36 mmol). Yield

7128
V.A. Egorov et al. / Tetrahedron 68 (2012) 7122e7128
20), 193.8 (C]O); m/z 216 (100 Mþ), 185 (32), 153 (30), 129 (75), 123
(50), 59 (18%); HRMS (EI): Mþ, found 216.0184. C9H9ClO4 requires
216.0184.
requires 317.0562. Compound 24a. dH (300 MHz, CDCl3) 3.04 (2H, s,
CH2), 4.08 and 4.45 (4H, both m, OCH2CH2O), 7.41 (4H, m, C6H5) and
7.90e7.93 (1H, m, C6H5), 7.80 (1H, s, ]CH); dC (75.47 MHz, CDCl3)
46.8 (CH2), 66.8 (OCH2), 109.1 (C-5), 119.4 (]CH), 124.5 (C-50), 126.1,
127.5, 129.0, 129.2, 130.2, 132.6 (C6H5), 133.9 (C-8), 147.8 (C-40),
153.3 (C-9), 191.9 (C]O); Compound 24b. dH (300 MHz, CDCl3) 3.11
(2H, s, CH2), 3.91 and 4.09 (4H, both m, OCH2CH2O), 7.41 (4H, m,
C6H5) and 7.90e7.93 (1H, m, C6H5), 8.68 (1H, s, ]CH); dC
(75.47 MHz, CDCl3) 47.4 (CH2), 66.6 (OCH2), 109.4 (C-5), 125.89 (C-
40), 126.1, 127.5, 129.0, 129.2, 130.2, 132.6 (C6H5), 133.9 (C-8), 130.0
(]CH), 150.5 (C-9), 191.9 (C]O).
2.18. N-(7,9-Dichloro-8-oxo-1,4-dioxaspiro[4,4]non-6-en-6-yl)
guanidine (22)
Compound (22) was synthesized from compound 6 (0.20 g,
0.82 mmol), guanidine hydrochloride (0.08 g, 0.82 mmol) and KOH
(0.05 g, 0.905 mmol) in MeOH (5 mL). Yield 83% (0.18 g). [Found: C,
36.67; H, 3.56; Cl, 28.95; N 15.23. C8H9Cl2N3O3 requires C, 36.11; H,
3.41; Cl, 28.65; N, 15.79%]; Rf (CHCl3/methanol, 10:1) 0.11; nmax
(liquid film) 3417, 3373, 3354, 3335, 3154, 3091, 2953, 2853, 1685,
1640, 1595, 1458, 1381, 1257, 1178, 1112, 1045, 1014, 951, 908, 856,
Acknowledgements
719, 613 cmꢁ1
; dH (300 MHz, CDCl3) 3.86e3.99 (2H, m, OCH2CH2O),
The study was performed under the financial support of the
program of the Russian Foundation for Basic Research e Povolzhie
(grant 11-03-97013 r_a) and of the Federal target program ‘Scien-
tific and scientific-pedagogical staff of the innovation Russia’ for
2009e2013 (State contract No. 14.740.11.0367).
4.08 (2H, m, OCH2CH2O), 4.53 (3H, s, CHCl), 6.99 (1H, s, NH), 7.85
(2H, br s, NH2); dC (75.47 MHz, CDCl3) 63.0 (CHCl), 65.1 and 66.1
(OCH2), 108.2 (C-50), 133.8 (C-70), 158.7 (C-60), 166.9 (]CN), 179.0
(C]O).
2.19. 8-Chloro-9-[4(5)-phenyl-1H-1,2,3-(triazol-1-yl)]-1,4-
dioxaspiro[4,4]non-8-en-7-ones (24a,b)
References and notes
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The mixture of compound 7 (0.10 g, 0.45 mmol) and sodium
azide (0.032 g, 0.49 mmol) in DMF (0.1 mL) was stirred at room
temperature for 2 h. Then it was diluted with MeCN (0.5 mL) and
phenylacetylene added (0.055 g, 0.54 mmol) to the mixture, as well
as N-ethyldiisopropylamine (0.11 g, 0.9 mmol) and copper (I) iodide
(0.44 mg, 0.026 mmol). The mixture was then stirred at room
temperature for 2 h then was evaporated under reduced pressure.
The residue was subjected to chromatography on silica gel using
EtOAc/petroleum ether (1:1) as the eluent to afford 24a,b (regioi-
someric mixture, w1:1, as determined by 1H NMR) (0.109 g, 62%
yield) as a white solid. Mp 111e113 ꢀC; Rf (EtOAc/petroleum ether,
1:1) 0.11; nmax (liquid film) 2960, 2880, 1745, 1732, 1645, 1456, 1435,
1418, 1377, 1292, 1232, 1145, 1024, 972, 952, 856, 762, 694,
565 cmꢁ1; m/z 317 (42 Mþ), 281 (6), 226 (18), 187 (100), 119 (14), 86
(34), 69 (25%); HRMS (EI): Mþ, found 317.0560. C15H12ClN3O3
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