Ring-opening reactions of cyclopropanes. Part 6. A facile synthesis of dialkyl sulfenylbutanedioates

Article abstract of DOI:10.1055/s-1999-3617

The reaction of cyclopropanes 1 with sulfenyl chlorides 2 readily affords 2-sulfenylbutanedioates 3 and/or their 3-sulfenyl analogues 5, which are compounds of applicative and biological interest.

Full text of DOI:10.1055/s-1999-3617

1944
PAPER
Ring-Opening Reactions of Cyclopropanes. Part 6.1 A Facile Synthesis of
Dialkyl Sulfenylbutanedioates
M. Liliana Graziano,* M. Rosaria Iesce, Flavio Cermola
Dipartimento di Chimica Organica e Biologica dell’Università di Napoli Federico II, Via Mezzocannone 16, I-80134 Napoli, Italy
Received 26 March 1999; revised 7 July 1999
The most general method for the synthesis of sulfenylbu-
Abstract: The reaction of cyclopropanes 1 with sulfenyl chlorides
tanedioates is the addition of thiols to maleates.3b,3c,4 Here
2 readily affords 2-sulfenylbutanedioates 3 and/or their 3-sulfenyl
we report the synthesis of dialkyl sulfenylbutanedioates
analogues 5, which are compounds of applicative and biological in-
by reaction of sulfenyl chlorides 2 with ethyl 2,2-
dimethoxycyclopropanecarboxylates 1 (Scheme 1). The
choice of these acceptor–donor substituted cyclopropanes
was made by considering their facile regioselective ring
opening at the C1–C2 bond by various electrophiles
which leads to interesting hetero- and carbocycles.7
Sometimes, this reaction competes with thermal rear-
rangement into 1,1-dimethoxyalkenes 4.7a,8 The investiga-
tion also proved interesting since a survey of the relevant
literature on the reaction between sulfenyl halides and cy-
clopropanes highlighted a paucity of data on the ring
cleavage by these electrophilic reagents. In fact, the reac-
tion with alkyl- or aryl-substituted cyclopropanes is
generally quite sluggish;9 it occurs with various me-
terest.
Key words: cyclopropanes, sulfenyl chlorides, sulfenylbutanedio-
ates, electrophilic bimolecular substitution, selectivity
a-Sulfenylated esters have received considerable atten-
tion because the flexibility of sulfur on a carbon adjacent
to a carbonyl group allows great diversity in structural
modification and elaboration.2 Among these com-
pounds, sulfenylbutanedioates such as arylthio,3
phosphonomethylthio4 and carboxyalkylthio-derivatives5
have particular applicative and biological interest as they
are used as bactericides,3e enzyme inhibitors,4 corrosion
inhibitors5a,b and components of detergent mixtures5c or as
intermediates for agrochemicals3d,f and bioproducts.3c
Some of them have been identified by mass spectrometry
in the degradation products of widely used pesticides.6
thyl
2-(trimethylsiloxy)cyclopropanecarboxylates,10a
vinylcyclopropanes10b or alkylidenecyclopropanes10c in
the presence of a Lewis acid or in acidic media. Only cy-
R1
R2SCl
2
EtO2C
R2S
R1
EtO2C
R2S
R1
+
R1=Me, Et
OMe
EtO2C
OMe
MeCl
1
CO2Me
CO2Me
anti-3
syn-3
major pathway
for R1=H
R2SCl
2
R1
OMe
OMe
R1 SR2
CO2Me
EtO2C
EtO2C
5
4
MeCl
1
R1
2
R2
Ph
3
R1
R2
Ph
5
R1
R2
a
b
c
H
Me
Et
a
b
c
a
b
c
d
e
f
Me
Me
Me
Me
Et
Et
Et
Et
a
b
c
d
e
f
H
H
H
H
Me
Me
Me
Me
Ph
4-NO2C6H4
Me
CO2Me
4-NO2C6H4
Me
CO2Me
Ph
4-NO2C6H4
Me
CO2Me
4-NO2C6H4
Me
CO2Me
Ph
4-NO2C6H4
Me
CO2Me
d
g
h
g
h
Scheme 1
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ring-Opening Reactions of Cyclopropanes. Part 6
1945
clopropane rings that form part of highly strained molec-
ular framework, such as quadricyclene, undergo
uncatalyzed arenesulfenylation.11
EtO2C
Ph
Me
EtO2C
Ph
Me
MCPBA
CCl4
S
CO2Me
S
CO2Me
O
syn-3a
The reaction of 1a–c with equimolecular amounts of 2a–
d was performed under strictly anhydrous conditions12 in
carbon tetrachloride at the reaction temperatures and for
the times reported in Table 1. 1-Ethyl 4-methyl syn-2-
sulfenylbutanedioates 3 were obtained in addition to small
amounts of their anti-isomers starting from trans-cyclo-
propanes 1b,c; for 1b 3-sulfenyl analogues 5 were also
formed and these were the only reaction products starting
from 3-unsubstituted 1a.15 Control experiments showed
that compounds 5 were formed by the sulfenylation of
alkenes 4a,b that derive from the isomerization of 1a,b
(Scheme 1).15
syn-6
∆, C6H6
PhSOH
H
Me
EtO2C
CO2Me
Z-7
EtO2C
Ph
Me
EtO2C
Me
MCPBA
CCl4
S
CO2Me
Ph
S
CO2Me
As shown in Table 1, the reaction times depend on both
reagents; they increase from 1a to 1c and by decreasing
electrophilicity of 2 from methanesulfenyl chloride (2c)
up to acyl derivative 2d. However, the formation of 3 and/
or 5 depends only on the starting cyclopropane; thus, 1a
leads to 3-sulfenylbutanedioates 5a–d via 4a, 1b to both
2-sulfenyl- and 3-sulfenyl derivatives 3a–d and 5e–h and,
finally, 1c only to 3e–h. This trend is evidently linked to
the tendency of 1 to isomerize into 4, which is 1a>1b>1c
and, hence, for 1a,b the isomerization competes with the
addition of the sulfenyl chloride to the cyclopropane
ring.16 Reasoning that the isomerization might be favored
by the presence of trace amounts of HCl deriving from
easily hydrolyzable sulfenyl chloride 2,14 we attempted to
optimize the reaction, when using 1a,b, by adding pyri-
dine.17 This expedient proved to be effective for 1b, lead-
ing only to 3 with a similar diastereomeric ratio as is found
in the absence of base; for 1a it was unsuccessful, and the
only effect we observed was an increase of the reaction
times, showing that the isomerization rate was higher than
that of the reaction with 2.
O
anti-3a
anti-6
∆, C6H6
PhSOH
H
CO2Me
Me
EtO2C
E-7
Scheme 2
All attempts to extend the reaction to C3 disubstituted cy-
clopropanes 1 failed, even in the presence of a Lewis ac-
id.27
In conclusion, we report here a facile synthetic method for
dialkyl sulfenylbutanedioates 3 and/or 5, unsubstituted or
alkyl-substituted on the carbon bearing the sulfenyl group
or on the adjacent one. Formation of 3 occurs regio- and
stereoselectively via electrophilic ring opening of 1 while
5 result from the sulfenylation of the alkenes 4 formed by
isomerization of the cyclopropane 1. The reaction can be
performed using various sulfenyl chlorides and product
distribution depends on the reaction conditions and/or the
substitution at C3 of cyclopropane 1.
All of the products were separated and purified by column
chromatography followed by HPLC. The structures were
assigned on the basis of the analytical and spectroscopic
data and, for 5a–d, they were confirmed by comparing the
spectral data with those of authentic samples, which were
prepared by the sulfenylation of the alkene 4a with 2a–d.
The configuration of syn- and anti-3 was determined on
the basis of the vicinal coupling constants.18 Confirmation
of stereochemistry was performed chemically by stereo-
selectively obtaining the known20 alkenes Z-7 and E-7 via
the oxidation21 of syn-3a and anti-3a followed by the ther-
mal decomposition of the related sulfoxides syn-6 and
anti-6, respectively (Scheme 2).22
IR spectra were recorded on a Perkin Elmer 1760/X-FT spectropho-
tometer using CHCl3 as solvent. 1H and 13C NMR spectra were re-
corded with a Varian Gemini-200HC spectrometer using CDCl3 as
solvent and TMS as internal standard. J Values are given in Hz.
DEPT techniques were employed to determine the multiplicity in
the 13C NMR spectra and gated decoupling methods to obtain quan-
titative noise-decoupled spectra. Elemental analyses were per-
formed using a Carlo Erba EA 1108-Elemental analyzer. HPLC was
performed on a Shimadzu LC-9A instrument equipped with a LCA-
Shimadzu UV detector using a Merck Lichrosorb Si-60 (10 mm)
column and t-BuOMe/hexane (3:17) as eluent with 3 mL/min flow
rate of elution unless otherwise stated. CCl4, CH2Cl2, pyridine and
C6H6 (benzene) used in the reactions were anhydrous. Silica gel
[0.063–0.20 mm (Macherey–Nagel)] and light petroleum (bp 40–
60 °C) were used for column chromatography. Cyclopropanes
1a,b,81c,13 alkenes 4a,b8 and sulfenyl chloride 2a28 were prepared
according to literature methods. 2c29 was prepared in CCl4 or
CH2Cl2 depending on the reaction solvent to be used. Products 2b,
The high syn diastereoselectivity observed for 3 can be in-
terpreted in terms of a SE2-type attack at the corner of
trans-1b,c which, with inversion of configuration at C1,
affords syn-3 via the unstable23 chloride syn-8; only to a
lesser extent does the edge attack occur, and this leads,
with retention at the same carbon, to anti-3 via the corre-
sponding anti-8 (Scheme 3).24
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

1946
M. L. Graziano et al.
PAPER
R1
H
R1
H
EtO2C
R2S
R1
OMe
OMe
Cl
syn-3
R2S
EtO2C
OMe
OMe
OMe
Cl OMe
syn-8
CO2Et
R2
H
H
S
MeCl
syn-8
Cl
corner
attack
H
R1
R1
H
R1
EtO2C
R2S
OMe
OMe
Cl
anti-3
EtO2C
OMe
EtO2C
OMe
Cl OMe
anti-8
H
OMe
H
SR2
anti-8
MeCl
S
R2
Cl
edge
attack
only for R1=H
Scheme 3
2d, m-chloroperoxybenzoic acid (MCPBA) and TiCl4 were pur-
chased from Fluka.
Table 1 Reaction of Cyclopropanes 1a–c with Sulfenyl Chlorides
2a–d
Cyclo- Sulfenyl Conditionsa
propane Chloride Temp/Time
Product Distribution (%)b
Sulfenylation of Cyclopropanes 1; General Procedure
An equimolecular amount of 2a–d was added to a 0.2 mol/L solu-
tion of 1a–c (1 mmol) in dry CCl4 and the resulting mixture was kept
under strictly anhydrous conditions at the temperature reported in
Table 1 until complete conversion of cyclopropane 1 (1H NMR).
Then, the solvent was removed under reduced pressure and the res-
idue chromatographed on silica gel. For the residues obtained start-
ing from cyclopropane 1a, elution with light petroleum/Et2O (9:1)
gave the esters 5a–d. For the residues obtained starting from cyclo-
propane 1c, elution as above led to a mixture of syn- and anti-3e–h,
which were separated by HPLC.30 For the residues obtained in the
reaction of cyclopropane 1b with 2a,d, elution as above gave sub-
sequent fractions containing the esters 5e,h and a mixture of 5e,h
and syn- and anti-3a,d.30 Each compound was separated and puri-
fied by HPLC except for anti-3d, which was obtained in mixture
with its isomer in ca. 9:1 molar ratio (1H NMR). The work-up as
above of the residue derived from 1b and 2b afforded only 5f and
syn-3b; that of 1b with 2c led to ester 5g.
3 (syn/anti)
5
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1a
1b
1b
1b
1b
1c
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
–20°C/30 min
r.t./ 2 d
–20°C/5 min
r.t./3 d
r.t./2 h
r.t./2 d
–20°C/5 min
r.t./7 d
r.t./2 d
r.t./7 d
–20°C/15 min
r.t./16 d
r.t./12 h
r.t./24 h
r.t./8 d
–20°C/10 min
r.t./15 d
–
–
–
–
a 80
b 65
c 70
d 60
e 55
f 60
g 10c
h 40
–
–
–
–
a 70
–
a 10 (85:15)
b 10 (100:0)
-
d 22 (90:10)
e 60 (85:15)
f 50 (85:15)
g 10 (90:10)
h 55 (85 :15)
–
a 75 (90:10)
b 30 (100:0)
c 30 (100:0)
d 65 (90:10)
g 50 (90:10)
2a/pyd
2a/pyd
2b/pyd
2c/pye
2d/pyd
2c/pye
–
–
–
–
The yield of each compound is reported in Table 1 and the spectral
and analytical data are listed in Tables 2 and 3.
–20°C/30 min
a Equimolecular amounts of 1 and 2; solution of 1 in CCl4 (0.2 mol/L).
bYields and isomeric ratios were evaluated by chromatography.
c To obtain 5g in higher yield (70%) it is convenient to carry out the
methanesulfenylation on the alkene 4b.
Sulfenylation of 4a with 2a–d
The reactions were carried out as above at the temperatures and
times reported for 1a (Table 1). Then, the solvent was removed and
chromatography of the residues on silica gel (light petroleum/Et2O
9:1) led to the esters 5a–d in similar yields as those starting from 1a.
d 1/2/py 1:1:1.2; solution of 1 in CH2Cl2 (0.2 mol/L).
e 1/2c/py 1:1:3; solution of 1 in CH2Cl2 (0.2 mol/L).
Sulfenylation of 4b with 2c
The reaction was carried out at –20 °C for 15 min as above for 1b.
Then, the solvent was removed and chromatography of the residue
on silica gel (light petroleum/Et2O 9:1) followed by HPLC led to the
ester 5g (70%).
The reactions of 1b with 2a,b,d were carried out as for 1a and were
similarly worked up. For 2a,d chromatography of the residues, elut-
ing as above, gave subsequent fractions containing syn-3a,d and a
mixture of syn- and anti-3a,d; each compound was separated and
purified by HPLC. For 2b, the work-up as above gave only the syn-
3b.
Sulfenylation of Cyclopropanes 1 in the Presence of Pyridine
The reaction of 1a with 2a was carried out at r.t. as above using 2a/
pyridine in a 1:1.2 molar ratio and dry CH2Cl2 as solvent. After
completion of the reaction (1H NMR), the solution was washed with
H2O, dried (Na2SO4) and evaporated. Chromatography of the resi-
due (light petroleum/ Et2O 9:1) gave the ester 5a.
The reactions of 1b,c with 2c were carried out at –20 °C as for 1a
using 2c/pyridine in a 1:3 molar ratio and were similarly worked up.
For 1b chromatography of the residue as above, followed by HPLC,
gave syn-3c.30 Chromatography of the residue obtained starting
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ring-Opening Reactions of Cyclopropanes. Part 6
1947
Table 2 1-Ethyl 4-Methyl 2-Sulfenylbutanedioates (3) Prepared
Prod-
ucta
IR
tR (min) 1H NMR (CDCl3) d, J (Hz)
13C NMR (CDCl3) d
(CHCl3)
n (cm–1)
syn-3a
1735
10.4
1.18 (t, J = 7.3, 3H, OCH2CH3), 1.44 (d, J = 7.3,
13.8 (q, CH2CH3), 15.2 (q, CH3), 40.6 (d, CHCH3),
51.9 (q, OCH3), 53.2 (d, CHS), 61.1 (t, OCH2),
128.4, 128.9 and 133.6 (3d, CH of Ar), 132.3 (s,
C1 of Ar), 171.2 and 174.8 (2s, 2 ¥ CO2)
3H, CH3), 2.88 (dq, J = 10.3, 7.3, 1H, CHCH3),
3.64 (s, 3H, OCH3), 3.75 (d, J = 10.3, 1H, CHS),
4.11 (q, J = 7.3, 2H, OCH2), 7.20–7.55 (m, 5H,
ArH)
anti-3a
syn-3b
1735
1734
8.2
1.20 (t, J = 7.0, 3H, OCH2CH3), 1.26 (d, J = 6.7,
3H, CH3), 2.98 (dq, J = 9.8, 6.7, 1H, CHCH3), 3.74 52.0 (q, OCH3), 53.5 (d, CH-S), 61.3 (t, OCH2),
(s, 3H, OCH3), 3.87 (d, J = 9.8, 1H, CHS), 4.14 (q, 128.3, 128.9 and 133.5 (3d, CH of Ar), 132.8 (s,
14.0 (q, CH2CH3), 15.6 (q, CH3), 42.1 (d, CHCH3),
J = 7.0, 2H, OCH2), 7.25–7.55 (m, 5H, ArH)
C1 of Ar), 171.3 and 174.1 (2s, 2 ¥ CO2)
17.7b
1.21 (t, J = 7.1, 3H, OCH2CH3), 1.42 (d, J = 7.3,
14.0 (q , CH2CH3) , 15.1 (q, CH3), 40.7 (d,
3H, CH3), 3.04 (m, J = 9.3, 7.3, 1H, CHCH3), 3.71 CHCH3), 52.1 and 52.2 (d and q, CHS and OCH3),
(s, 3H, OCH3), 4.02 (d, J = 9.3, 1H, CHS), 4.18 (q, 61.6 (t, OCH2), 123.9 and 130.3 (2 d, CH of Ar),
J = 7.1, 2H, OCH2), 7.60 and 8.16 (2 d, J = 8.2, 4H, 143.5 and 146.7 (2s, C1 and C4 of Ar), 170.6 and
C6H4)
174.1 (2s, 2 ¥ CO2)
syn-3c
syn-3d
1729
1733
9.3b
14.1b
14.7b
9.8
1.28 (t, J = 7.1, 3H, OCH2CH3), 1.37 (d, J = 7.3,
3H, CH3), 2.12 (s, 3H, SCH3), 2.90 (dq, J = 10.6,
7.3, 1H, CHCH3), 3.34 (d, J = 10.6, 1H, CHS), 3.69 (t, OCH2), 171.4 (s, 2 ¥ CO2)
(s, 3H, OCH3), 4.20 (q, J = 7.1, 2H, OCH2)
13.4 (q, SCH3), 14.1 (q, CH2CH3), 15.2 (q, CH3),
39.5 and 49.4 (2d, 2 ¥ CH), 52.0 (q, OCH3), 61.2
1.27 (t, J = 7.1, 3H, OCH2CH3), 1.32 (d, J = 7.3,
14.0 and 14.7 (2q, CH2CH3 and CH3), 41.2 (d,
3H, CH3), 3.08 (m, J = 8.4, 7.3, 1H, CHCH3), 3.71 CHCH3), 50.2 (d, CHS), 52.2 and 54.8 (2q, 2 ¥
and 3.85 (2s, 6H, 2 ¥ OCH3), 4.21 (q, J = 7.1, 2H, OCH3), 61.9 (t, OCH2), 169.6, 170.3 and 173.9 (3s,
OCH2), 4.35 (d, J = 8.4, 1H, CHS)
3 ¥ CO2)
anti-3dc 1734
1.27 (t, J = 7.0, 3H, OCH2CH3), 1.31 (d, J = 7.2,
14.0 and 14.5 (2q, CH2CH3 and CH3), 41.4 (d,
3H, CH3), 3.24 (m, J = 7.2, 5.7, 1H, CHCH3), 3.71 CHCH3), 50.7 (d, CHS), 52.6 and 54.6 (2q, 2 ¥
and 3.86 (2s, 6H, 2 ¥ OCH3), 4.21 (q, J = 7.0, 2H, OCH3), 62.0 (t, OCH2), 169.9, 170.3 and 173.6 (3s,
OCH2), 4.42 (d, J = 5.7, 1H, CHS)
3 ¥ CO2)
syn-3e
anti-3e
syn-3f
anti-3f
syn-3g
1734
1735
1735
1735
1735
0.91 (t, J = 7.3, 3H, CH2CH3), 1.17 (t, J = 7.1, 3H, 10.3 (q, CH2CH3), 13.8 (q, OCH2CH3), 22.4 (t,
OCH2CH3), 1.80–2.20 (m, 2H, CH2), 2.80 (m, 1H, CH2), 46.8 (d, CHCH2), 51.2 and 51.4 (d and q,
CHCH2), 3.66 (s, 3H, OCH3), 3.78 (d, J = 11.2, 1H, CHS and OCH3), 61.0 (t, OCH2), 128.6, 128.9 and
CHS), 4.10 (q, J = 7.1, 2H, OCH2), 7.28–7.55 (m, 133.6 (3d, CH of Ar), 132.2 (s, C1 of Ar), 171.3
5H, ArH)
and 174.0 (2s, 2 ¥ CO2)
6.8
0.90 (t, J = 7.3, 3H, CH2CH3), 1.19 (t, J = 7.1, 3H, 11.7 (q, CH2CH3), 14.0 (q, OCH2CH3), 24.4 (t,
OCH2CH3), 1.55–1.75 (m, 2H, CH2), 2.85 (m, 1H, CH2), 49.4 (d, CHCH2), 51.8 (d, CHS), 52.9 (q,
CHCH2), 3.75 (s) and 3.78 (d, J = 11.2d) (4H,
OCH3 and CHS), 4.25 (q, J = 7.1, 2H, OCH2),
7.28–7.55 (m, 5H, ArH)
OCH3), 61.3 (t, OCH2), 128.5, 128.9 and 133.7
(3d, CH of Ar), 130.0 (s, C1 of Ar), 170.6 and
173.5 (2s, 2 ¥ CO2)
12.9
0.91 (t, J = 7.3, 3H, CH2CH3), 1.20 (t, J = 7.1, 3H, 10.5 (q, CH2CH3), 13.9 (q, OCH2CH3), 22.5 (t,
OCH2CH3), 1.75–2.10 (m, 2H, CH2), 2.92 (m, 1H, CH2), 46.8 (d, CHCH2), 49.8 (d, CHS), 51.9 (q,
CHCH2), 3.71 (s, 3H, OCH3), 4.03 (d, J = 10.8, 1H, OCH3), 61.7 (t, OCH2), 123.9 and 130.2 (2d, CH
CHS), 4.16 (q, J = 7.1, 2H, OCH2), 7.64 and 8.20
(2d, J = 8.2, 4H, C6H4)
of Ar), 143.2 and 146.5 (2s, C1 and C4 of Ar),
170.6 and 173.4 (2s, 2 ¥ CO2)
10.2
0.94 (t, J = 7.1, 3H, CH2CH3), 1.24 (t, J = 7.1, 3H, 11.6 (q, CH2CH3), 14.1 (q, OCH2CH3), 24.4 (t,
OCH2CH3), 1.55–1.75 (m, 2H, CH2), 2.89 (m, 1H, CH2), 49.1 (d, CHCH2), 51.4 (d, CHS), 52.0 (q,
CHCH2), 3.74 (s, 3H, OCH3), 3.99 (d, J = 10.5, 1H, OCH3), 61.9 (t, OCH2), 123.9 and 130.4 (2d, CH
CHS), 4.20 (q, J = 7.1, 2H, OCH2), 7.57 and 8.15
(2d, J = 8.2, 4H, C6H4)
of Ar), 143.6 and 146.7 (2s, C1 and C4 of Ar),
169.9 and 173.0 (2s, 2 ¥ CO2)
15.0b,e
0.90 (t, J = 7.3, 3H, CH2CH3), 1.28 (t, J = 7.1, 3H, 10.3 (q, CH2CH3), 13.2 (q, SCH3), 14.1 (q,
OCH2CH3), 1.70–2.10 (m) and 2.11 (s) (5H, CH2
and SCH3), 2.85 (m, 1H, CHCH2), 3.40 (d, J =
11.4, 1H, CHS), 3.69 (s, 3H, OCH3), 4.20 (q, J =
7.1, 2H, OCH2)
OCH2CH3), 22.2 (t, CH2), 45.4 (d, CH), 47.0 (d,
CHS), 51.7 (q, OCH3), 61.1 (t, OCH2), 171.4 and
174.4 (2s, 2 ¥ CO2)
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

1948
M. L. Graziano et al.
PAPER
Table 2 (continued)
Prod-
ucta
IR
tR (min) 1H NMR (CDCl3) d, J (Hz)
13C NMR (CDCl3) d
(CHCl3)
n (cm–1)
anti-3g 1734
9.9b,e
0.91 (t, J = 7.3, 3H, CH2CH3), 1.28 (t, J = 7.1, 3H, 11.7 (q, CH2CH3), 13.6 (q, SCH3), 14.1 (q,
OCH2CH3), 1.50–1.70 (m, 2H, CH2), 2.16 (s, 3H, OCH2CH3), 24.6 (t, CH2), 48.2 and 48.5 (2d, 2 ¥
SCH3), 2.90 (m, 1H, CHCH2), 3.34 (d, J = 11.4, 1H, CH), 51.7 (q, OCH3), 61.2 (t, OCH2), 170.4 and
CHS), 3.74 (s, 3H, OCH3), 4.22 (q, J = 7.1, 2H,
OCH2)
173.5 (2s, 2 ¥ CO2)
syn-3h
1735
11.3
0.92 (t, J = 7.3, 3H, CH2CH3), 1.27 (t, J = 7.1, 3H, 11.0 (q, CH2CH3), 14.0 (q, OCH2CH3), 22.6 (t,
OCH2CH3), 1.70–1.90 (m, 2H, CH2), 2.91 (m, 1H, CH2), 47.7 and 48.6 (2d, 2 ¥ CH), 51.9 and 54.7
CHCH2), 3.71 and 3.86 (2s, 6H, 2 ¥ OCH3), 4.20
(2q, 2 ¥ OCH3), 61.9 (t, OCH2), 170.3, 173.4 and
(q, J = 7.1, 2H, OCH2), 4.33 (d, J = 9.2, 1H, CHS) 173.9 (3s, 3 ¥ CO2)
anti-3h 1734
11.7
0.97 (t, J = 7.3, 3H, CH2CH3), 1.27 (t, J = 7.1, 3H, 11.9 (q, CH2CH3), 14.0 (q, OCH2CH3), 23.3 (t,
OCH2CH3), 1.55–1.90 (m, 2H, CH2), 3.02 (m, 1H, CH2), 48.3 and 49.1 (2d, 2 ¥ CH), 51.9 and 54.6
CHCH2), 3.70 and 3.85 (2s, 6H, 2 ¥ OCH3), 4.20
(2q, 2 ¥ OCH3), 62.0 (t, OCH2), 170.2, 170.3 and
(q, J = 7.1, 2H, OCH2), 4.37 (d, J = 6.7, 1H, CHS) 173.1 (3s, 3 ¥ CO2)
a Satisfactory microanalyses obtained: C 0.34; H 0.13; N 0.28.
b Using a differential refractometric detector RID-10A (Shimadzu).
c Obtained in mixture with syn-isomer in 9:1 molar ratio (1H NMR).
d
Measured by recording the spectrum in C6D6 where the signals of CH and OCH3 are split at d 4.05 and 3.39, respectively.
e 2.5 mL/ min flow rate of elution and t-BuOMe/hexane (3:22) as eluent.
from 1c, eluting as above, gave subsequent fractions containing syn-
3g and a mixture of syn- and anti-3g.30 Each compound was sepa-
rated and purified by HPLC.
(3) (a) Fleming, I.; Iqbal, J. Tetrahedron Lett. 1983, 24, 327.
(b) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363.
(c) Robillard, R.; Ingold, K. U. Tetrahedron Lett. 1986, 27,
2817.
The reaction times and yields are reported in Table 1. The analytical
and spectral data for syn-3c are reported in Table 2.
(d) Feng, L.; Chen, J.; Kong, L.; Wang, L.; Wei L., Zhang, Z.
Chemosphere 1996, 32, 2077.
(e) Feng, L.; Zhang, W.; Wang, L.; Wei L. Chemosphere
1996, 32, 2505.
(f) Chen, J.; Zhao, Y.; Feng, L.; Han, S.; Wang, L.; Zhang, Z.
Toxicol. Environ. Chem. 1997, 60, 211.
1-Ethyl 4-Methyl (E)- and (Z)-3-Methylbutenedioates 720
A solution of syn-3a (70 mg, 0.25 mmol) in CH2Cl2 (5 mL) was
treated with MCPBA (48 mg, 0.25 mmol) and the resulting mixture
kept at r.t. under stirring. After completion of the reaction (2 h, 1H
NMR), the mixture was poured onto 10% aq NaHCO3 (2 mL). The
organic layer was washed with brine (2 mL) and dried (Na2SO4).
After removal of the solvent, the residue was chromatographed on
silica gel (light petroleum/Et2O 1:1) and gave the diastereomeric
mixture of sulfoxide syn-631 (60 mg with a purity of 90%, 1H NMR).
The latter (60 mg) was dissolved in dry C6H6 (6 mL) and refluxed.
After 12 h, the solvent was removed and chromatography of the res-
idue on silica gel (light petroleum/Et2O 9:1) afforded Z-alkene 7 (25
mg, 58% based on syn-3a) which was identified by comparing its
1H NMR spectrum with that reported.20
(4) Farrington, G. K.; Kumar, A.; Wedler, F. C. J. Med. Chem.
1985, 28, 1668.
(5) (a) Onodera, S.; Yamada, M.; Katsura, I. Jpn. Kokai Tokkyo
Koho JP 08277480, 1996; Chem. Abstr. 1997, 126, 134438c.
(b) Yamada, M.; Onodera, S.; Katsura, I.; Hatanaka, T.;
Yonekura, A.; Kawamura, T. Jpn. Kokai Tokkyo Koho JP
0924389, 1997; Chem. Abstr. 1997, 126, 229346k.
(c) Yamada, M.; Onodera, S.; Katsura, I. Jpn. Kokai Tokkyo
Koho JP 08283783, 1996; Chem. Abstr. 1997, 126, 76519s.
(6) Rengasamy, S.; Parmar, B. S. J. Agric. Food Chem. 1989, 37,
430.
The same procedure was carried out for anti-3a (50 mg, 0.18 mmol)
(7) (a) Ref. 1 and preceding issues of the series.
(b) Shimada. S.; Hashimoto, Y.; Nagashima, T.; Hasegawa,
M; Saigo, K. Tetrahedron 1993, 49, 1589.
(c) For a review on vicinally donor–acceptor substituted
cyclopropanes see: Reissig, H.-U. Top. Curr. Chem. 1988,
144, 73.
1
and led to the sulfoxide anti-631 (43 mg with a purity of 90%, H
NMR) which, treated as syn-6, afforded E-7 (20 mg, 67% based on
1
anti-3a). This was identified by comparing its H NMR spectrum
with that reported.20
(8) Graziano, M. L.; Scarpati, R. J. Chem. Soc., Perkin Trans. 1
1985, 289.
Acknowledgement
(9) See for example: Rappe, C.; Gustafsson, R. Acta Chem.
Scand. 1968, 22, 2927.
The authors gratefully acknowledge financial support by MURST
and CNR (Rome). NMR Spectra were run at the Centro di Metodo-
logie Chimico-fisiche, Università di Napoli Federico II.
Bengston, G.; Keyaniyan, S.; de Meijere, A. Chem. Ber. 1986,
119, 3607.
Klein, L. L.; Yeung, C. M.; Weissing, D. E.; Lartey, P. A.;
Tanaka, S. K.; Plattner, J. J.; Mulford, D. J. J. Med. Chem.
1994, 37, 572.
References
(1) Graziano, M. L.; Iesce, M. R.; Cermola, F. J. Chem. Res.
1996, (S) 82, (M) 0622.
(2) Trost, B. M. Chem. Rev. 1978, 78, 363.
(10) (a) Reissig, H.-U.; Reichelt, I. Tetrahedron Lett. 1984, 25,
5879.
Reissig, H.-U.; Lorey, H. Liebigs Ann. Chem. 1986, 1914.
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ring-Opening Reactions of Cyclopropanes. Part 6
1949
Table 3 1-Ethyl 4-Methyl 3-Sulfenylbutanedioates (5) Prepared
Prod- IR
tR (min)
1H NMR (CDCl3) d, J (Hz)
13C NMR (CDCl3) d
uct a
(CHCl3)
n (cm-1)
5a
1734
1.24 (t, J = 7.0, 3H, CH3), 2.73 (dd, J = 16.5, 6.2)
14.0 (q, CH3), 36.6 (t, CH2), 45.6 (d, CH), 52.4 (q,
and 2.94 (dd, J = 16.5, 9.3) (2H, CH2), 3.69 (s, 3H, OCH3), 60.9 (t, OCH2), 128.7, 129.0 and 134.1 (3d,
OCH3), 4.01 (dd, J = 9.3, 6.2) and 4.13 (q, J = 7.0) CH of Ar), 131.6 (s, C1 of Ar), 170.4 and 171.5 (2s,
(3H, CH and OCH2), 7.30–7.55 (m, 5H, ArH)
2 ¥ CO2)
5b
1734
1.26 (t, J = 7.3, 3H, CH3), 2.80 (dd, J = 17.1, 6.2)
14.1 (q, CH3), 36.3 (t, CH2), 44.4 (d, CH), 52.8 (q,
and 3.06 (dd, J = 17.1, 8.8) (2H, CH2), 3.75 (s, 3H, OCH3), 61.3 (t, OCH2), 124.0 and 130.4 (2d, CH of
OCH3), 4.17 (q, J = 7.3) and 4.25 (dd, J = 8.8, 6.2) Ar), 142.7 and 146.7 (2s, C1 and C4 of Ar), 169.9
(3H, OCH2 and CH), 7.57 and 8.16 (2d, J = 8.2, 4H, and 170.9 (2s, 2 ¥ CO2)
C6H4)
5c
5d
5e
5f
1734
1734
1733
1733
1735
1734
1.26 (t, J = 7.3, 3H, CH3), 2.18 (s, 3H, SCH3), 2.67 13.7 and 13.9 (2q, CH3 and SCH3), 35.8 (t, CH2),
(dd, J = 17.1, 5.5) and 3.01 (dd, J = 17.1, 9.9) (2H, 41.9 (d, CH), 52.2 (q, OCH3), 60.8 (t, OCH2), 170.5
CH2), 3.64 (dd, J = 9.9, 5.5, 1H, CH), 3.77 (s, 3H,
OCH3), 4.15 (q, J = 7.3, 2H, OCH2)
and 171.6 (2s, 2 ¥ CO2)
1.26 (t, J = 7.0, 3H, CH3), 2.93 (dd, J = 17.2, 5.7)
and 3.07 (dd, J = 17.2, 7.6) (2H, CH2), 3.77 and
3.86 (2s, 6H, 2 ¥ OCH3), 4.15 (q, J = 7.0, 2H,
OCH2), 4.38 (dd, J = 7.6, 5.7, 1H, CH)
14.0 (q, CH3), 36.9 (t, CH2), 43.0 (d, CH), 53.0 and
54.6 (2q, 2 ¥ OCH3), 60.9 (t, OCH2), 169.4, 170.0
and 170.3 (3s, 3 ¥ CO2)
10.9
1.23 (t, J = 7.0, 3H, OCH2CH3), 1.58 (s, 3H, CH3), 14.1 (q, CH2CH3), 22.6 (q, CH3), 43.0 (t, CH2), 51.5
2.63 and 3.06 (2d, J = 16.6, 2H, CH2), 3.66 (s, 3H, (s, C-S), 52.2 (q, OCH3), 60.7 (t, OCH2), 128.8 and
OCH3), 4.11 (q, J = 7.0, 2H, OCH2), 7.30–7.55 (m, 129.9 (2d, CH of Ar), 137.4 (s + d, CH and C1 of
5H, ArH)
Ar), 170.1 and 172.6 (2s, 2 ¥ CO2)
14.8b
14.8b,c
16.2b
1.24 (t, J = 7.2, 3H, OCH2CH3), 1.63 (s, 3H, CH3), 14.0 (q, CH2CH3), 22.8 (q, CH3), 42.8 (t, CH2), 52.1
2.68 and 3.04 (2d, J = 16.4, 2H, CH2), 3.71 (s, 3H, (s, C-S), 52.5 (q, OCH3), 60.9 (t, OCH2), 123.5 and
OCH3), 4.12 (q, J = 7.2, 2H, OCH2), 7.64 and 8.19 137.1 (2d, CH of Ar), 138.8 and 148.5 (2s, C1 and
(2d, J = 8.2, 4H, C6H4)
C4 of Ar), 169.5 and 172.1 (2s, 2 ¥ CO2)
5g
5h
1.25 (t, J = 7.0, 3H, OCH2CH3), 1.60 (s, 3H, CH3), 12.6 (q, SCH3), 14.1 (q, CH2CH3), 22.1 (q, CH3),
2.10 (s, 3H, SCH3), 2.55 and 3.16 (2d, J = 16.3, 2H, 42.2 (t, CH2), 46.9 (s, C-S), 52.4 (q, OCH3), 60.7 (t,
CH2), 3.75 (s, 3H, OCH3), 4.13 (q, J = 7.0, 2H,
OCH2)
OCH2), 170.2 and 172.5 (2s, 2 ¥ CO2)
1.26 (t, J = 7.0, 3H, OCH2CH3), 1.79 (s, 3H, CH3), 14.1 (q, CH2CH3), 23.6 (q, CH3), 42.0 (t, CH2), 52.9
2.98 and 3.21 (2d, J = 15.6, 2H, CH2), 3.78 and 3.79 (s, C-S), 53.1 and 54.0 (2q, 2 ¥ OCH3), 60.8 (t,
(2s, 6H, 2 ¥ OCH3), 4.15 (q, J = 7.0, 2H, OCH2)
OCH2), 169.1, 169.6 and 172.4 (3s, 3 ¥ CO2)
a Satisfactory microanalyses obtained: C 0.18; H 0.10; N 0.22.
b Using a differential refractometric detector RID-10A (Shimazdu).
c 2 mL/ min flow rate of elution and t-BuOMe/hexane (1:7) as eluent.
(b) Magerramow, A.M.; Gyul’akhmedov, L. M.; Sadovaja, N.
K.; Koz’min, A. S. Zh. Org. Khim. 1990, 26, 2333; Chem.
Abstr. 1991, 115, 231785u.
(16) By heating at 130 °C 1a isomerizes quantitatively into 4a
within 4 h while 1b isomerizes into 4b within 10 h.8 Control
experiments showed that under above conditions 1c was
recovered unchanged even after 10 h.
(c) Dunkelblum, E. Tetrahedron 1974, 30, 3991.
(11) Beaulieu, P. L.; Kabo, A.; Garratt D. G. Can. J. Chem. 1980,
58, 1014.
(17) CH2Cl2 was used as solvent since in CCl4 a pyridine–sulfenyl
chloride complex precipitated.14 However, control
(12) Both cyclopropanes 18,13 and sulfenyl chlorides 214 hydrolyze
very easily; in particular, the former lead to the corresponding
ethyl methyl butanedioates, which may be present
occasionally in the reaction mixtures.
experiments showed that the reaction of 1b with 2a in the
absence of pyridine carried out in this solvent gave the same
results as in CCl4.
(18) The values for the syn isomers are larger than those for their
anti counterparts.19 Since the diastereomeric pairs 3e and 3g
exhibited the same value for both isomers, configuration was
assigned on the basis of straightforward comparison of 1H
NMR spectral data with those of pairs 3f,h; in particular, syn-
3e,g show signals due to chain methylenes in the d range 1.7–
2.2 and anti-3e,g in the d range 1.5–1.7 as observed for syn-
3f,h and anti-3f,h, respectively. In the reactions of 1b with
2b,c only one isomeric 2-sulfenyl-3-methylbutanedioate was
(13) Graziano, M. L.; Iesce, M. R. Synthesis 1985, 762.
(14) Capozzi, G.; Modena, G.; Pasquato, L. In The Chemistry of
Sulphenic Acids and Their Derivatives; Patai, S. Ed.; Wiley:
New York, 1990; chapter 10, p 403.
(15) For all reactions 1H NMR of a sample of the CCl4 solution,
recorded in CDCl3, indicated the presence of MeCl. This
could not be quantified owing to its volatility.
Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York

1950
M. L. Graziano et al.
PAPER
(26) Coxon, J. M.; Steel, P. J.; Wittington, B. I. J. Org. Chem.
obtained in moderate amount; thus, configuration of syn-3b
and syn-3c was assigned on the basis of the general
stereochemical course which leads to syn-3 as by far the main
products.
1990, 55, 4136.
(27) Control experiments showed that ethyl 2,2-dimethoxy-3,3-
dimethylcyclopropanecarboxylate8 was recovered unchanged
under the above reaction conditions, even after prolonged
times. When the sulfenylation was carried out in the presence
of either catalytic10a or equimolecular amount of TiCl4 at –70
or 0 °C, ethyl methyl 3,3-dimethylbutanedioate and/or
mixtures of unidentified products were obtained. It is to be
noted that the low reactivity of C3 disubstituted
cyclopropanes 1 was already observed.7a,8,13
(28) Mueller, W. M.; Butler, P. E. J. Am. Chem. Soc. 1968, 90,
2075.
(29) Brintzinger, H.; Pfaunstiel, K.; Koddebusch, H.; Kling, K.
Chem. Ber. 1950, 83, 87.
(30) In the reactions of 1b,c with 2c a prevailing unidentified
product was present which did not interfere in the
chromatographic procedures as it is more polar than the
reaction products.
(31) Spectral data are consistent with the structural assignment.
Selected IR data: n (S=O) = 1057 and 1059 cm-1 for syn-6 and
anti-6, respectively.
(19) Sato, T.; Otera, J.; Nozaki, H. J. Org. Chem. 1990, 55, 6116.
Sato, T.; Otera, J. J. Organomet. Chem. 1994, 473, 55.
Villa, M. J.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1994,
2953.
(20) Bornstein, D.; Weisz, A.; Mandelbaum, A. Org. Mass
Spectrom. 1986, 225.
(21) Kresze, G. In Houben-Weyl, Klamann, D., Ed.; Thieme:
Stuttgart, 1985; Band E11, p 669.
(22) It is well-known that the thermal decomposition of sulfoxides
bearing a b-hydrogen atom leads stereoselectively to alkenes
via a concerted syn-intramolecular mechanism: Braverman, S.
In The Chemistry of Sulphenic Acids and Their Derivatives;
Patai, S., Ed.; Wiley: New York, 1990; chapter 8, p 311.
(23) Schmitz, E.; Eichhorn, I. In The Chemistry of the Ether
Linkage; Patai, S., Ed.; Interscience: London, 1967; p 342.
Similar unstable chlorides may also be formed in the addition
of 2 to 4a,b, as shown by the presence of MeCl in the related
CCl4 solutions.15
(24) These modes of attack on the cyclopropane ring have been
found both in bromination25 and in reactions with other
electrophiles26. However, for cyclopropanes 1 hitherto only a
SE2-type attack has been observed as reported in ref 7a.
(25) Lambert, J. B.; Chelius, E. C.; Schulz, W. J. Jr.; Carpenter, N.
E. J. Am. Chem. Soc. 1990, 112, 3156.
Article Identifier:
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Synthesis 1999, No. X, 1944–1950 ISSN 0039-7881 © Thieme Stuttgart · New York