The reactions of thiols and diphenyldisulfide with terminally substituted methylenecyclopropanes

Article abstract of DOI:10.1016/S0040-4039(02)00384-2

In the reactions of thiols with terminally substituted methylenecyclopropanes, we found that the Markovnikov adducts were produced exclusively along with cyclopropyl ring-opened products via a radical reaction mechanism. The substituent effects and the re

Full text of DOI:10.1016/S0040-4039(02)00384-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2781–2784
The reactions of thiols and diphenyldisulfide with terminally
substituted methylenecyclopropanes
Bo Xu,a Yu Chenb and Min Shia,*
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
bDepartment of Chemistry, East China Normal University, 3663 Zhong Shan Bei Lu, Shanghai 200062, China
Received 6 December 2001; revised 13 February 2002; accepted 21 February 2002
Abstract—In the reactions of thiols with terminally substituted methylenecyclopropanes, we found that the Markovnikov adducts
were produced exclusively along with cyclopropyl ring-opened products via a radical reaction mechanism. The substituent effects
and the reaction with diphenyldisulfide were also examined. © 2002 Elsevier Science Ltd. All rights reserved.
Methylenecyclopropanes (MCPs) are highly strained
but readily accessible molecules that have served as
useful building blocks in organic synthesis.1 Recently,
much attention has been paid to transition-metal cata-
lyzed reactions of MCPs with various reactants. The
reaction patterns of MCPs were both interesting and
troublesome. Three kinds of reaction patterns of MCPs
have been disclosed based on the concept of synthons
(Scheme 1). MCPs can react with polar reactants such
as ROH,2 R2NH,3 malonate derivatives,4 carbon diox-
ide,5 aldehydes,6 and imines7 in the presence of a Pd
metal catalyst to give type I products. MCPs can also
react with nonpolar reactants such as R3SiH,8 R3SnH,9
R2B–BR2,10 R3Si–BR2,11 R3Si–CN12 and olefins13 in the
presence of Pd or Rh metal catalysts to afford type II
and/or type III products depending on the reaction
conditions (Scheme 1). However, these reactions usually
need severe reaction conditions such as very high tem-
perature (120°C) and prolonged reaction time (3 days).
Little attention has been paid to the free radical reac-
tions of MCPs.14
tuted methylenecyclopropanes, the anti-Markovnikov
adducts were formed exclusively with retention of the
cyclopropyl ring (Scheme 2). However, during our own
examination of the reactions of thiophenol with termi-
nally substituted MCPs, we found that the reaction
products are different from those reported before and
that these reactions are completed within 24 h at room
temperature in the absence of metal catalysts and radi-
R
+
R'
I
R
R'
R
Metal
*
*
R'
II
R
*
*
It is well known that many reactions involving thiols
and disulfides proceed via a free radical mechanism.
Moreover, metal-catalyzed reactions of thiols15 and
disulfides16 have also been explored in recent years
although their scope and limitations are not very clear.
Gilchrist17 in 1968 and Kozhushkov18 in 1998 reported
that in the reactions of thiols with terminal unsubsti-
R'
III
Scheme 1.
SR3
R1
+
R3SH
R1
R2
R2
Keywords:
thiol;
methylenecyclopropane;
radical
reaction;
Markovnikov adduct; terminally substituted; diphenyldisulfide.
* Corresponding author. E-mail: mshi@pub.sioc.ac.cn
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00384-2

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B. Xu et al. / Tetrahedron Letters 43 (2002) 2781–2784
cal initiators (Table 1). As can be seen from Table 1,
Markovnikov adducts were produced along with the
cyclopropyl ring-opened products. The substituents can
affect the selectivity of the products. Aryl and alkyl
disubstituted MCPs gave exclusively Markovnikov
adducts 3 in very high yields (Table 1, entries 2 and 3).
Dialkyl substituted MCPs and MCPs with only one
aryl substituent produced Markovnikov adducts 3
along with cyclopropyl ring opened products 2 as the
major products (Table 1, entries 1, 4–7).
In order to gain more mechanistic insights into this
thiol addition reaction, we carried out the same reac-
tion in the presence of an excess of di-tert-butyl nitrox-
ide (1.2 equiv.) (a free radical scavenger) (Scheme 3),
but we found that no reaction occurred at all. The
Table 1. The free radical reactions of thiophenol with methylenecyclopropanesa
Product
Entry
1
Substrate
Time/h
24
Yield/%b
SPh
SPh
1a
2a, 32%
3a, 41%
SPh
1b
24
24
2
3
3b, 95%
SPh
1c
3c, 90%
SPh
SPh
4
5
1d
2
3
Ph
H
Ph
Ph
H
2d (E/Z= 2.4/1), 21%
3d, 53%
SPh
SPh
1e
Ph
H
Ph
Ph
3e, 4%
2e (E/Z= 1.3/1), 58%
SPh
SPh
1f
6
24
24
H
2f (E/Z mixture), 40%
3f, 45%
SPh
1g
SPh
7
H
10
10
10
2g (E/Z= 1/3.3), 61%
3g, 31%
a)All reactions were carried out with 0.5 mmol MCPs (1a-1g) and 1.0 mmol thiophenol in toluene at r.t.
b)All yields were isolated yields.

B. Xu et al. / Tetrahedron Letters 43 (2002) 2781–2784
2783
The two processes compete with each other (k1 and k2).
The stabilities of methylenecyclopropyl radicals have
been disclosed before.20 Groups which can conjugate
with the radicals greatly slow down the rearrangement.
Thus, in the reaction of 1a or 1e–f with thiophenol, two
products were formed at the same time (k2ꢀk1). How-
ever, in the reaction of 1b and 1c with thiophenol, only
products 3b and 3c were isolated, respectively (k2ꢁk1).
N
O
.
+
No reaction
PhSH
PhSH
Di-tert-butyl nitroxide
R2
R1
O
O2
In addition, the reactions of mercaptoethanol (an
aliphatic thiol) with MCPs are, in general, slower than
those of thiophenol. Higher reaction temperatures are
required to give the analogous products 7 and 8 in
moderate yields (Scheme 5).
S Ph
OH
Ph
+
Ph
Ph
Ph
4, 76%
Scheme 3.
On the other hand, we also examined the reaction of
diphenyldisulfide with terminally substituted MCPs.
The reaction is very sluggish even at higher temperature
giving the cyclopropyl ring-opened product 9 in 10%
yield as the sole product (Scheme 6). We believe that
the reaction pattern of disulfides with MCPs is very
similar to those of thiols.
reactions were probably initiated by adventitious oxy-
gen because a trace of PhSSPh was also detected in all
cases.15 Furthermore, if the reaction was carried out
under air, product 4, derived from a radical ‘TOCO
reaction’, was obtained in 76% yield (Scheme 3).19
Based on the results obtained and the distribution of
products, a stepwise radical mechanism is proposed in
Scheme 4. In contrast to the addition to terminal
unsubstituted methylenecyclopropanes, the thiophenol
radical attacks C1 of the double bond to generate the
cyclopropyl radical 5, which undergoes the well-estab-
lished rapid ring opening rearrangement to give the
corresponding homoallylic radical 6. The radicals 5 and
6 abstract hydrogen to give 2 and 3, respectively.
SPh
130 oC, 48 h
SPh
+
PhSSPh
Ph
Ph
Ph
Ph
9, 10%
Scheme 6.
PhSH
k1
1
SPh
R2
SPh
R2
+
PhS
SPh
PhS
+
2
R2
R1
R2
R1
R1
R1
6
2
5
k2
PhSH
SPh
+
PhS
R2
R1
3
Scheme 4.
60 oC, 24 h
SEt
SEt
+
+
EtSH
Ph
Ph
H
H
Ph
H
7e, 8%
1e
8e (E/Z= 1.6/1), 55%
60 oC, 24 h
SEt
SEt
+
+
EtSH
H
10
10
10
1g
7g, 8%
8g (E/Z= 1/5.2), 30%
Scheme 5.

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B. Xu et al. / Tetrahedron Letters 43 (2002) 2781–2784
In conclusion, we disclose a novel reaction pattern of
thiols and disulfides with terminally substituted MCPs.
The substituents can significantly affect the reaction
products. Markovnikov adducts 3 were exclusively
formed along with a cyclopropyl ring-opened product
via a radical reaction mechanism which is totally differ-
ent from terminal unsubstituted MCPs. Efforts to eluci-
date the scope and limitations of this radical reaction
system are underway.
6. Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2001, 40, 1298.
7. Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 6203.
8. Bessmertnykh, A. G.; Blinov, K. A.; Grishin, Yu. K.;
Donskaya, N. A.; Tveritinova, E. V.; Yur’eva, N. M.;
Beletskaya, I. P. J. Org. Chem. 1997, 62, 6069.
9. Lautens, M.; Meyer, C.; Lorenz, A. J. Am. Chem. Soc.
1996, 118, 10676.
10. Ishiyama, T.; Momota, S.; Miyaura, N. Synlett 1999,
1790.
11. Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc.
2000, 122, 11015.
Acknowledgements
12. Chatani, N.; Takaya, H.; Hanafusa, T. Tetrahedron Lett.
1988, 29, 3979.
We thank the State Key Project of Basic Research
(Project 973) (No. G2000048007) and the National
Natural Science Foundation of China (20025206) for
financial support. We also thank the Inoue Photochiro-
genesis Project (ERATO, JST) for chemical reagents.
13. The reactions of MCPs with unsaturated carbon bonds
has been extensively studied; please see the review: Lau-
rens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
14. The intramolecular cascade free radical reactions involv-
ing the addition of the double bonds of MCPs fragments:
(a) Santagostino, M.; Kilburn, J. D. Tetrahedron Lett.
1995, 36, 1365; (b) Destabel, C.; Kilburn, J. D. J. Chem.
Soc., Chem. Commun. 1992, 596.
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