Reactions of 2,3,5-trichloro-4,4-ethylenedioxy-2-cyclopentenone with some ambident nucleophiles. Sterically loaded functionalized 6-azabicyclo[3.1.0]hex- 5-enes

Article abstract of DOI:10.1007/s11178-005-0054-9

2,3,5-Trichloro-4,4-ethylenedioxy-2-cyclopentenone reacted with sodium azide in tetrahydrofuran to give the expected 3-azido derivative which was converted into 1,3-dichloro-4,4-ethylenedioxy-6-azabicyclo-[3.1.0]hex-5-en-2-one and 3-amino-2,5-dichloro-4,4

Full text of DOI:10.1007/s11178-005-0054-9

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1521–1525. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1569–1573.
Original Russian Text Copyright © 2004 by Shavaleeva, Ivanova, Usmanova, Akhmetvaleev, Miftakhov.
Reactions of 2,3,5-Trichloro-4,4-ethylenedioxy-2-cyclopentenone
with Some Ambident Nucleophiles. Sterically Loaded
Functionalized 6-Azabicyclo[3.1.0]hex-5-enes
G. A. Shavaleeva, N. A. Ivanova, F. G. Usmanova, R. R. Akhmetvaleev, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
fax: (3472)356066; e-mail: bioreg@anrb.ru
Received January 17, 2004
Abstract—2,3,5-Trichloro-4,4-ethylenedioxy-2-cyclopentenone reacted with sodium azide in tetrahydrofuran
to give the expected 3-azido derivative which was converted into 1,3-dichloro-4,4-ethylenedioxy-6-azabicyclo-
[
3.1.0]hex-5-en-2-one and 3-amino-2,5-dichloro-4,4-ethylenedioxy-2-cyclopentenone on heating in
chloroform. The reaction of 2,3,5-trichloro-4,4-ethylenedioxy-2-cyclopentenone with potassium thiocyanate,
depending on the conditions, afforded the corresponding 3-thiocyanato derivative or symmetric sulfide.
Treatment of the title compound with hydroxylamine resulted in opening of the dioxolane ring with
2
simultaneous formation of oxime via replacement of chlorine at the neighboring sp -carbon atom.
In the past decade, the synthesis and transforma-
tions of azirines have attracted persistent attention
azirine structure (e.g., azirinomycin [11], enantiomeric
dizidazirines [12], and antazirine [13]). The most
practical and general procedures for the synthesis of
azirines are based on thermal and photochemical
decomposition of vinyl azides, which involve inter-
[
1–10]. This interest originates from both specific
chemical properties of highly strained cyclic imines
and isolation of a series of natural antibiotics having an
Scheme 1.
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
a
d
+
N
O
O
O
O
Cl
N3
H N
O
O
O
2
O
I
II
V
VI
b
a
e
O
O
O
Cl
Cl
Cl
Cl
Cl
c
N
O
O
O
PhS
PhSO2
O
O
O
III
IV
VII
f
V
I
a: NaN
3
, THF, 20°C (82% from I; 71% from II); b: PhSNa, THF–MeOH (85%); c: m-ClC
, ∆, (V, 70%; VI, 10%); e: Zn–THF–NH
6
H
4
CO
3
2 2
H, CH Cl (79%);
d: CHCl
3
4
2
Cl, ∆ (20%); f: 20% hydrochloric acid, Me CO (60%).
1
070-4280/04/4010-1521 © 2004 MAIK “Nauka/Interperiodica”

1
522
SHAVALEEVA et al.
mediate formation of vinylnitrenes. While continuing
our studies on the chemical behavior of a new series of
functionalized trichlorocyclopentenones derived from
hexachlorocyclopentadiene [14], we examined the
reaction of 2,3,5-trichloro-4,4-ethylenedioxy-2-cyclo-
pentenone (I) with azide ion with a view to obtain the
corresponding vinyl azide. Here, we took into account
shifts are likely to result from the deshielding effect on
3-H of the cis-oriented chlorine atom at C and aniso-
tropic effect of the azirine ring on the carbonyl group.
1
We examined some reactions of compound V. Its
decomposition (e.g., on storage in solution) leads to
slow accumulation of amino derivative VI. Acid
hydrolysis of V in a mixture of 20% hydrochloric acid
with acetone gave initial trichloroketone I, and reduc-
3
that the chlorine atom at C in molecule I can readily
be replaced via reactions with heteronucleophiles
tive dechlorination with Zn–NH Cl in THF afforded
4
according to the Ad E pattern.
N
partially dechlorinated azirine VII (Scheme 1).
Experiments showed that trichlorocyclopentenone I
smoothly reacted with sodium azide in tetrahydrofuran
to give the corresponding vinyl azide II in a good yield
The reaction of trichlorocyclopentenone I with
another ambident nucleophile, potassium thiocyanate,
resulted in formation of different products, depending
on the reactant ratio. From equimolar amounts of
enone I and KSCN in THF we obtained the corre-
sponding thiocyanato derivative VIII as the major
product, whereas treatment of I with excess KSCN
gave sulfide IX. The reaction of compound I with
hydroxylamine in the presence of sodium hydroxide
was accompanied by opening of the dioxolane ring
with formation of oxime X. The structure of sulfide IX
was proved by independent synthesis from cyclo-
pentenone I and sodium sulfide. According to the
(
Scheme 1). It should be noted that analogous reaction
with a stronger Michael acceptor, sulfone IV (which
was prepared by oxidation of known sulfide III [15])
afforded azide II in a lower yield. Compound II was
fairly stable on storage in a refrigerator, but on heating
in chloroform or under UV irradiation it underwent
decomposition with formation of several new products.
In some experiments, by heating of azide II in boiling
chloroform, followed by standard treatment and
column chromatography on silica gel, we isolated crys-
talline bicyclic azirine V and amine VI (Scheme 1).
1
H NMR data, symmetric sulfide IX is a mixture of
racemic and meso forms at a ratio of 6:5 (or vice
13
The C NMR spectrum of azirine V revealed an
appreciable upfield shift of the carbonyl carbon signal
versa); the spectrum contained two singlets from 5-H
1
13
(
δ 175.10 ppm), while the CHCl signal in the H
at δ 4.60 and 4.61 ppm. In the C NMR spectra, we
C
NMR spectrum was displaced downfield (δ 6.10 ppm),
also observed two signals at δ 153.66 and 153.89 ppm
C
5
5'
as compared to compounds I and II. The observed
(C and C ).
Scheme 2.
O
Cl
Cl
KSCN (1 equiv), THF, ∆
8%
4
O
NCS
O
VIII
O
O
O
O
O
Cl Cl
S
KSCN (excess), THF
or Na S, THF
Cl
Cl
2
Cl
Cl
O
50% or 62%
Cl
O
O
O
I
IX
O
NH OH, THF
Cl
Cl
2
3
0%
HON
OCH CH OH
2 2
X
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

REACTIONS OF 2,3,5-TRICHLORO-4,4-ETHYLENEDIOXY-2-CYCLOPENTENONE
1523
Undoubtedly, previously unknown bicyclic azirines
V and VII attract interest from the viewpoints of their
synthetic utility and potential biological activity.
evaporated, the residue was dissolved in 10 ml of
water, and the solution was extracted with chloroform
(3×20 ml). The combined extracts were dried over
MgSO and concentrated, and the residue was sub-
4
EXPERIMENTAL
jected to column chromatography on silica gel using
petroleum ether–ethyl acetate (9:1) as eluent to isolate
0.25 g (82%) of azide II.
The IR spectra were obtained on a UR-20 spec-
trometer from samples prepared as thin films (neat) or
dispersed in Nujol. The NMR spectra were recorded
on a Bruker AM-300 spectrometer at 300 MHz for
b. Sodium azide, 0.08 g (1.15 mmol), was added at
2
0°C to a solution of 0.20 g (0.57 mmol) of sulfone IV
in 5 ml of THF. The mixture was stirred for 1.5 h,
diluted with water, and extracted with ethyl acetate
1
13
H and 75.47 MHz for C using CDCl or acetone-d
3
6
(
V, VI) as solvent and TMS as internal reference. The
(
3×20 ml). The extract was washed with water and
mass spectra (electron impact, 20 or 70 eV) were
measured on an MKh-1306 instrument; ion source
temperature 75–100°C. The progress of reactions was
monitored by TLC on Silufol plates using pentane–
ethyl acetate or petroleum ether–ethyl acetate as
eluent; spots were visualized by treatment with an al-
a saturated solution of sodium chloride, dried over
MgSO , and evaporated, and the residue was subjected
4
to chromatography on silica gel using petroleum ether–
ethyl acetate (9:1) as eluent to isolate 0.10 g (71%)
of compound II. Colorless crystals, mp 95–97°C. IR
–
1
1
spectrum, ν, cm : 2160, 1752, 1620. H NMR spec-
kaline solution of KMnO [16].
4
trum, δ, ppm: 4.27–4.43 m (4H, CH O), 4.48 s (1H,
2
1
3
5
5
-H). C NMR spectrum, δ , ppm: 61.43 (C ), 66.28
2
,5-Dichloro-4,4-ethylenedioxy-3-phenylsulfonyl-
-cyclopentenone (IV). A solution of 1.50 g
4.73 mmol) of sulfide III in 15 ml of methylene
chloride was added dropwise at 0°C to a suspension of
.38 g (15.60 mmol) of 50% m-chloroperoxybenzoic
C
4 2
and 66.66 (CH O), 107.03 (C ), 119.51 (C ), 156.72
2
(
2
3
(
C ), 185.77 (C=O). Found, %: C 33.81; H 2.10;
Cl 28.22; N 16.50. C H Cl N O . Calculated, %:
7
5
2
3
3
C 33.63; H 2.02; Cl 28.36; N 16.61.
5
acid in 20 ml of methylene chloride. The mixture was
stirred for 1.5 h, filtered from excess m-chloroperoxy-
benzoic acid, diluted with 30 ml of methylene chloride,
and washed with water. The aqueous phase was
extracted with 30 ml of methylene chloride, and the
extract was combined with the organic phase, washed
Decomposition of azide II in chloroform. A solu-
tion of 0.45 g (2.02 mmol) of azide II in 5 ml of
chloroform was heated for 2 h under reflux. By
chromatography on silica gel we isolated 0.31 g (70%)
of azirine V and 0.04 g (10%) of amine VI.
1
,3-Dichloro-4,4-ethylenedioxy-6-azabicyclo-
with a solution of NaHCO until neutral reaction, and
3
[3.1.0]hex-5-en-2-one (V). Colorless crystals, mp 126–
dried over MgSO , The solvent was distilled off under
4
127°C (from ethyl acetate–petroleum ether, 7:3) IR
–
1
1
reduced pressure, and the residue was recrystallized
from ethyl acetate. Yield 1.30 g (79%), colorless crys-
spectrum, ν, cm : 2020, 1680, 1600. H NMR spec-
trum (acetone-d ), δ, ppm: 4.88–4.98 m (2H, CH O),
6
2
–
1
13
tals, mp 122°C. IR spectrum, ν, cm : 1765, 1600,
5
.08–5.13 m (2H, CH O), 6.20 s (1H, 3-H). C NMR
2
1
3
1
1
(
040, 1335, 1160. H NMR spectrum, δ, ppm: 4.43
spectrum, δ , ppm: 44.86 (C ), 85.48 (C ), 68.95 and
C
5
6
2H, CH O, J = 6.20 Hz), 4.50 (2H, CH O, J =
71.55 (CH O), 114.09 (C ), 166.38 (C ), 175.10
2
2
2
6
7
.56 Hz), 4.58 s (1H, 5-H), 7.60 t (2H, m-H, J =
.56 Hz), 7.72 t (1H, p-H, J = 7.56 Hz), 8.04 t (2H,
(C=O). Found, %: C 38.60; H 2.20; Cl 31.53; N 6.50.
C H Cl NO . Calculated, %: C 38.87; H 2.27; Cl 31.94;
N 6.31. Mass spectrum (EI, 70 eV), m/z: 222 [M] ,
7
5
2
3
1
3
+
o-H, J = 7.56 Hz). C NMR spectrum, δ , ppm: 63.36
C
5
4
o
(
(
(
C ), 67.51 (CH O), 109.31 (C ), 128.62 (C ), 129.30
C ), 134.95 (C ), 138.96 (C ), 140.77 (C ), 155.45
C ), 187.57 (C ). Found, %: C 44.52; H 3.03; Cl 20.16;
147, 103, 119, 114.
2
i
p
m
2
3
-Amino-2,5-dichloro-4,4-ethylenedioxy-2-cyclo-
3
1
pentenone (VI). Colorless crystals, mp 260°C. IR
S 9.24. C H Cl O S. Calculated, %: C 44.72; H 2.89;
Cl 20.31; S 9.18.
–1
1
13
10
2
5
spectrum, ν, cm : 3350, 1680, 1620, 1590. H NMR
spectrum, δ, ppm: 3.05–3.10 m (4H, CH O), 3.14 br.s
2
1
3
3
-Azido-2,5-dichloro-4,4-ethylenedioxy-2-cyclo-
(1H, CHCl), 3.94 br.s (2H, NH ). C NMR spectrum,
2
5
pentenone (II). a. Sodium azide, 0.16 g (2.40 mmol),
was added to a solution of 0.30 g (1.20 mmol) of
ketone I in 6 ml of THF, and the mixture was stirred
for 12 h at room temperature. The mixture was
δ
C
, ppm: 62.21 (C ), 66.52 and 66.69 (CH
2
O), 101.18
(C ), 106.08 (C ), 163.22 (C ), 183.06 (C=O). Found,
%: C 37.60; H 3.20; Cl 31.58; N 6.45. C Cl NO
Calculated, %: C 37.53; H 3.15; Cl 31.65; N 6.25.
4
7
2
H
7
.
3
7
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

1
524
SHAVALEEVA et al.
1
-Chloro-4,4-ethylenedioxy-6-azabicyclo[3.1.0]-
hex-5-en-2-one (VII). To a solution of 0.15 g
0.60 mmol) of compound V in 3 ml of THF we added
.18 g (2.75 mmol) of Zn and 0.003 g (0.06 mmol) of
ammonium chloride, and the mixture was heated for
h at the boiling point under stirring. The mixture was
water, and the solution was extracted with chloroform
(3×20 ml). The combined extracts were dried over
(
0
MgSO , filtered, and concentrated, and the product
4
was isolated by column chromatography on silica gel
using pentane–ethyl acetate (1:4) as eluent. Yield
2
0.33 g (65%). Yellow oily substance, R 0.5 (pentane–
f
–
1
cooled and filtered, the filtrate was evaporated, the
residue was dissolved in 5 ml of water, and the solu-
tion was extracted with methylene chloride (3×10 ml).
The combined extracts were dried over MgSO4,
filtered, and evaporated, and the residue was purified
by column chromatography on silica gel using pen-
tane–ethyl acetate (1:1) as eluent. Yield 0.03 g (20%),
ethyl acetate, 1:4). IR spectrum, ν, cm : 1740, 1610,
1
1580, 1470, 1270, 1200, 1003. H NMR spectrum, δ,
ppm: 4.18–4.45 m (8H, CH O), 4.61 s and 4.68 s (2H,
2
1
3
5-H, 5'-H). C NMR spectrum, δ
, ppm: 61.84 and
C
5
5'
61.97 (CH O), 67.20 and 67.27 (C , C ), 108.77 and
2
108.83 (C , C ), 137.67 and 138.09 (C , C ), 153.66
and 153.89 (C , C ), 186.25 (C , C ). Found, %:
4
4'
2
2'
3
3'
1
1'
C 37.52; H 2.15; Cl 31.30; S 7.20. C H Cl SO .
colorless oily substance, R 0.13 (from pentane–ethyl
14 10
4
6
f
–1
Calculated, %: C 37.53; H 2.25; Cl 31.65; S 7.15.
acetate, 1:1). IR spectrum, ν, cm : 2272, 1738, 1648,
1
1
588. H NMR spectrum (acetone-d ), δ, ppm: 4.02 s
6
b. Following the above procedure, by reaction of
compound I with 4 equiv of potassium thiocyanate we
obtained 0.25 g (50%) of sulfide IX.
13
(
2H, 2-H), 4.81–5.01 m (4H, CH O). C NMR spec-
2
2
trum (acetone-d ), δ , ppm: 30.15 (C ), 68.47 and
6
C
1
4
5
7
1
0.99 (CH O), 87.49 (C ), 114.82 (C ), 168.85 (C ),
2
2
,4-Dichloro-5-(2-hydroxyethoxy)-4-cyclo-
pentene-1,3-dione 1-oxime (X). A solution of 0.15 g
2.10 mmol) of hydroxylamine hydrochloride and
.08 g (2.10 mmol) of sodium hydroxide in 3 ml of
78.39 (C=O). Found, %: C 44.80; H 3.20; Cl 18.98;
N 7.50. C H ClNO . Calculated, %: C 44.82; H 3.22;
7
6
3
(
0
Cl 18.90; N 7.47.
,5-Dichloro-4,4-ethylenedioxy-3-thiocyanato-2-
cyclopentenone (VIII). Potassium thiocyanate, 0.20 g
2
water was added to a solution of 0.25 g (1.05 mmol) of
ketone I in 5 ml of THF. The mixture was stirred for
2
h and evaporated, the residue was dissolved in 10 ml
(
2.10 mmol), was added to a solution of 0.50 g
of water, and the solution was extracted with
methylene chloride (3×20 ml). The combined extracts
(
2.10 mmol) of trichlorocyclopentenone I in 5 ml of
THF, and the mixture was heated for 12 h under reflux
with stirring. The solvent was distilled off, the residue
was dissolved in 10 ml of water, and the solution was
extracted with chloroform (3×20 ml). The combined
extracts were dried over MgSO , filtered, and evapo-
rated, and the residue was subjected to chromatog-
raphy on silica gel using pentane–ethyl acetate (1:1).
Yield 0.24 g (48%), colorless oily substance, R 0.4
(
2
were dried over MgSO , filtered, and concentrated, and
4
the product was isolated by chromatography on silica
gel using pentane–ethyl acetate (1:1) as eluent. Yield
0
.07 g (30%). Colorless oily substance, R 0.27 (pen-
f
4
–1
tane–ethyl acetate, 1:1). IR spectrum, ν, cm : 3600,
1
3
3
200, 1940, 1720, 1580. H NMR spectrum, δ, ppm:
.89–4.02 m (4H, CH O), 4.07 br.s (1H, CHCl), 4.11–
2
f
13
–1
4.40 m (1H, OH), 12.30 br.s (1H, NOH). C NMR
pentane–ethyl acetate, 1:4). IR spectrum, ν, cm :
2
2'
1
spectrum, δ , ppm: 42.68 (C ), 60.37 (C ), 75.97
C
380, 1720, 1680, 1480, 1380. H NMR spectrum, δ,
1' 4 1 5
(
C ), 115.08 (C ), 148.09 (C ), 167.88 (C ), 185.26
(C=O). Found, %: C 35.10; H 2.90; Cl 29.45; N 5.80.
Cl NO . Calculated, %: C 35.03; H 2.94; Cl 29.54;
N 5.84.
ppm: 4.24 br.s (1H, 5-H), 4.18–4.21 m (4H, CH O).
2
13
5
C NMR spectrum, δ , ppm: 62.28 (C ), 66.29 and
C
4
C
7
H
7
2
4
6
(
6.60 (CH O), 101.41 (CH), 106.26 (C ), 150.90
C ), 163.10 (C ), 182.94 (C=O). Found, %: C 36.00;
2
2
3
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 02-03-32594a).
H 1.80; Cl 26.52; N 5.90; S 12.15. C H Cl NSO .
Calculated, %: C 36.11; H 1.89; Cl 26.65; N 5.60;
S 12.05.
8
5
2
3
Bis(2,4-dichloro-5,5-ethylenedioxy-3-oxo-1-
cyclopentenyl) sulfide (IX). a. Sodium sulfide, 0.08 g
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004