Lewis acid catalyzed reaction of methylenecyclopropanes with 1,2-diphenyldiselane or 1,2-di-p-tolyldisulfane

Article abstract of DOI:10.1021/jo9006514

(Chemical Equation Presented) Catalyzed by Lewis acid, 1,2-diphenyldiselane or 1,2-di-p-tolyldisulfane could add to methylenecyclopropanes smoothly. Compared with the reported free radical additions, the results were quite different. A four-membered carbon ring was constructed to give cyclobutane-1,1-diylbis(phenylselane) derivatives or cyclobutane-1,1-diylbis(p- tolylsulfane) derivatives as products, which are useful intermediates in organic synthesis.

Full text of DOI:10.1021/jo9006514

SCHEME 1. Addition of PhSeSePh to MCPs
Lewis Acid Catalyzed Reaction of
Methylenecyclopropanes with
1,2-Diphenyldiselane or 1,2-Di-p-tolyldisulfane
Lei Yu,* Jundong Meng, Ling Xia, and Rong Guo
School of Chemistry and Chemical Engineering,
Yangzhou UniVersity, Shouxihu Campus,
Yangzhou 225002, People’s Republic of China
Because of their wide applications in drug chemistry and
organic synthesis, selenium-containing organic compounds are
important and have attracted chemists for a long period.7
Ordinarily, the addition of 1,2-diphenyldiselane to an unsaturated
carbon carbon bond is a convenient way of introducing
selenium.8 In the investigation field of MCPs, the reactions with
1,2-diphenyldiselane have already been reported in the litera-
tures, via heat-promoted9 or visible-light-irradiated10 free radical
additions, affording a facile path for the synthesis of but-3-ene-
1,3-diylbis(phenylselane) derivatives (Scheme 1). Herein, we
wish to report the Lewis acid catalyzed additions of 1,2-
diphenyldiselane to MCPs. Compared with the reported inves-
tigations, the reaction products were quite different (Scheme
1).
yulei@yzu.edu.cn
ReceiVed March 28, 2009
Catalyzed by Lewis acid, 1,2-diphenyldiselane or 1,2-di-p-
tolyldisulfane could add to methylenecyclopropanes smoothly.
Compared with the reported free radical additions, the results
were quite different. A four-membered carbon ring was
constructed to give cyclobutane-1,1-diylbis(phenylselane)
derivatives or cyclobutane-1,1-diylbis(p-tolylsulfane) deriva-
tives as products, which are useful intermediates in organic
synthesis.
Initially, we examined the addition of 1,2-diphenyldiselane
to MCP 1a catalyzed by AlCl3. When 1a, 1,2-diphenyldiselane.
and AlCl3 were stirred in cyclohexane under nitrogen atmo-
sphere protection, a novel cyclobutane structure unit containing
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Menezes, P. H.; Stefani, H. A. Org. Lett. 2004, 6, 1135. (c) Prediger, P.; Moro,
A. V.; Nogueira, C. W.; Savegnago, L.; Menezes, P. H.; Rocha, J. B. T.; Zeni,
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Methylenecyclopropanes (MCPs), which are highly strained
but readily accessible molecules,1 are useful building blocks in
organic synthesis.2 Because of the intramolecular ring strain,
MCPs are highly activated and can undergo a series of particular
and interesting reactions under mild conditions, providing novel
methods for the construction of important organic skeletons.
During the past decade, much attention has been paid to
reactions involving MCPs. These include electrophilic addi-
tions,3 free radical additions,4 and transition metal catalyzed
reactions.5 Lewis acid catalyzed reactions of MCPs have also
been widely investigated, involving the addition of alcoholic
or acidic nucleophiles,6a aromatic amides,6b imines,6c activated
aldehydes or ketones,6d arenes,6e,f acyl chlorides,6g and so
on.6h-k
(1) For preparation of MCPs, see: Brandi, A.; Goti, A. Chem. ReV. 1998,
98, 589.
(2) For reviews, see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem. ReV. 2003, 103, 1213. (b) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal.
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2003, 44, 985.
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(e) Yu, L.; Huang, X.; Xie, M. Synlett 2006, 423.
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10.1021/jo9006514 CCC: $40.75  2009 American Chemical Society
Published on Web 05/21/2009
J. Org. Chem. 2009, 74, 5087–5089 5087

TABLE 1. Lewis Acid Catalyzed Addition of PhSeSePh to 1a
under Different Conditionsa
TABLE 2. Synthesis of Cyclobutane-1,1-diylbis(phenylselane)
Derivatives (2)
entry
R1, R2
yield of 2 (%)a
1
2
3
4
5
6
7
8
9
p-BrC6H4, H (1a)
C6H5, H (1b)
p-ClC6H4, H (1c)
C7H15, H (1d)
C9H19, H (1e)
-CH2CH2CH(Ph)CH2CH2- (1f)
-(CH2)5- (1g)
-(CH2)6- (1h)
C6H5, C5H11 (1i)
C6H5, C6H5 (1j)
62 (2a)
57 (2b)
50 (2c)
73 (2d)
68 (2e)
71 (2f)
47 (2g)
40 (2h)
53 (2i)
yield of
2a (%)d
entry LAb (equiv)
temp; timec
rt; 24 h
rt; 20 h
rt; 18 h
50 °C; 4 h
rt; 1 h
solvent
1
2
3
4
5
6
7
8
AlCl3 (1)
AlCl3 (1.5)
AlCl3 (2)
AlCl3 (2)
TiCl4 (0.5)
TiCl4 (0.5)
TiCl4 (0.5)
TiCl4 (1)
cyclohexane 24
cyclohexane 31
cyclohexane 46
cyclohexane 17
DCM
15
38
62
35
-25 °C to rt; overnight DCM
-75 °C to rt; overnight DCM
-75 °C to rt; overnight DCM
-75 °C to rt; overnight DCM
10
<10 (2j)
a Isolated yields.
9
10
11
TiCl4 (10)
FeCl3 (1)
traces
rt; 24 h
cyclohexane traces
traces
BF3OEt2 (0.5) -75 °C to rt; overnight ether
a 0.22 mmol of 1a (10% excess), 0.2 mmol of 1,2-diphenyldiselane,
and 1 mL of solvent were employed. b LA ) Lewis acid. Purity of
AlCl3 was 99%. c The reaction was monitored by TLC (eluent,
petroleum ether). d Isolated yields based on (PhSe)2.
FIGURE 1. Structure of 1,1-diphenyl-4-chrolo-1-butene (3).
SCHEME 2. Possible Mechanism for the Lewis Catalyzed
Addition of PhSeSePh to MCPs
compound 2a could be separated in 17-46% yield depending
on the reaction conditions (entries 1-4, Table 1). Further
screening demonstrated that TiCl4 should be a better catalyst
(entries 5-9, Table 1), and the yield of 2a was enhanced to
62% yield by stirring the substrates with 50% TiCl4 in
dichloromethane (DCM) from -75 °C to rt (entry 7, Table 1).
Four-membered carbon ring structures are widely present in
natural products.11 They are of important value12 but not easy
to build due to the high ring strain. Containing a four-membered
carbon ring and selenium element, cyclobutane-1,1-diylbis(phe-
nylselane) derivatives are useful intermediates that serve
important roles in organic synthesis and drug chemistry.13
Hence, we tried to examine the application scope of this reaction
under the optimized conditions outlined above, and the results
are listed in Table 2. It is obvious that the corresponding product
2 could be synthesized smoothly when R1 and R2 are alkyl,
aryl, or H (entries 1-9, Table 2). When R1 and R2 were both
aryl, the yield decreased and the HCl adduct 1,1-diphenyl-4-
chrolo-1-butene 3 (Figure 1) could be obtained in 38% yield as
a result of the reaction of TiCl4 with MCPs (entry 10, Table
2).14 The structures of 2 were confirmed by single-crystal X-ray
diffraction determination of 2i, and the molecular structure of
2i in crystal is shown in Supporting Information. For comparison
to MCPs, methylenecyclobutanes (MCBs) are also highly
strained molecules. However, when (4-bromophenyl) methely-
enecyclobutane was employed, only a series of unidentified
mixtures were observed instead of the desired ring enlargement
product.
On the basis of the above experimental results, a possible
mechanism of this reaction is outlined in Scheme 2. The reaction
of 1,2-diphenyldiselane with TiCl4 affords the phenylselenyl
cation, which adds to MCPs 1 and gives the intermediate 4 as
the episelenium ion.3c The latter could be transformed to the
intermediate carbon cation 5, which rearranges to give the stable
cyclobutyl cation 6.15 Further nucleophilic attack of PhSe- to
6 provides the final product 2. The relief of the ring strain of
MCPs should be the necessary thermodynamic driving force
of this reaction. When simple olefins (e.g., cyclohexene) were
employed, no reaction was observed.
1,2-Di-p-tolyldisulfane has reaction properties similar to those
of 1,2-diphenyldiselane, and the addition of 1,2-di-p-tolyldis-
ulfane to carbon-carbon unsaturated bonds is a facile method
for the synthesis of sulfur-containing organic compounds, which
are useful intermediates in organic synthesis and drug design.16
Therefore, we next examined the addition of 1,2-di-p-tolyldis-
ulfane to MCPs catalyzed by Lewis acid. Under similar
(11) (a) Smith, A. B.; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem.
Soc. 2000, 122, 11254. (b) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa,
N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem.
Soc. 2003, 125, 8228.
(12) For reviews, see: Namyslo, J. C.; Kaufmann, D. E. Chem. ReV. 2003,
103, 1485.
(13) For typical examples for the application of cyclobutane-1,1-diyl bis(phe-
nylselane) derivatives, see: (a) Griffin, R. J.; Arris, C. E.; Bleasdale, C.; Boyle,
F. T.; Calvert, A. H.; Curtin, N. J.; Dalby, C.; Kanugula, S.; Lembicz, N. K.;
Newell, D. R.; Pegg, A. E.; Golding, B. T. J. Med. Chem. 2000, 43, 4071. (b)
Krief, A. Top. Curr. Chem. 1987, 135, 1. (c) Halazy, S.; Krief, A. Tetrahedron
Lett. 1980, 21, 1997. (d) Krief, A. Tetrahedron 1980, 36, 2531.
(14) Xu, B.; Shi, M. Org. Lett. 2003, 5, 1415.
(15) (a) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95, 5311.
(b) Crandall, J. K.; Conover, W. W. J. Org. Chem. 1978, 43, 3533. (c) Halazy,
S.; Krief, A. J. Chem. Soc: Chem. Commun. 1979, 1136. (d) Halazy, S.;
Zutterman, F.; Krief, A. Tetrahedron Lett. 1982, 23, 4385.
5088 J. Org. Chem. Vol. 74, No. 14, 2009

TABLE 3. Synthesis of Cyclobutane-1,1-diylbis(p-tolylsulfane)
tolyldisulfane to MCPs catalyzed by Lewis acid. A plausible
mechanism has been proposed based on the above experimental
results and previous reports. The novelty in this paper is the
formation of the four-membered carbon ring, which is of
synthetic value but not easy to obtain due to its high ring strain.
Further investigations on the applications of these derivatives
are being undertaken in our laboratory.
Derivatives (7)
entry
R1, R2
yield of 7 (%)a
1
2
3
4
5
6
p-BrC6H4, H (1a)
C6H5, H (1b)
C7H15, H (1d)
C9H19, H (1e)
-CH2CH2CH(Ph)CH2CH2- (1f)
-(CH2)5- (1g)
75 (7a)
68 (7b)
72 (7c)
88 (7d)
70 (7e)
54 (7f)
Experimental Section
General Procedure for the Lewis Acid Catalyzed Additions of
1,2-Diphenyldiselane or 1,2-Di-p-tolyldisulfane to MCPs. In a
Schlenk tube, 0.22 mmol of 1 and 0.2 mmol of 1,2-diphenyldiselane
(or 1,2-di-p-tolyldisulfane) were dissolved in 0.5 mL of DCM under
nitrogen atmosphere. The mixture was kept at -75 °C, and 0.5
mL of TiCl4 solution (0.2 mol/L) was added dropwise at this
temperature. The reaction liquid turned red immediately and was
stirred overnight. The temperature rose gently to room temperature.
Water (5 mL) was then added, and the mixture was extracted with
DCM (3 × 5 mL). The combined organic layer was dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum, and
the residue was isolated by preparative TLC (eluent, petroleum
ether/EtOAc 10:1) to give the corresponding product 2 or 7.
Compound 2a. Oil. IR (film): 2950, 1435, 1232, 1071, 1009,
a Isolated yields.
SCHEME 3. Difunctional Reaction of MCP 1g with
(ArS)-(ArSe) Binary System Catalyzed by Lewis Acid
911, 822, 741, 692 cm-1. H NMR (600 MHz, CDCl3, TMS): δ
1
7.23-7.71 (m, 14H), 3.76-3.78 (m, 1H), 2.57-2.62 (m, 1H),
2.22-2.25 (m, 1H), 2.06-2.09 (m, 1H), 1.93-1.96 (m, 1H). 13C
NMR (150 MHz, CDCl3): δ 22.2, 31.7, 49.0, 55.6, 121.0, 128.0,
128.5, 128.7, 128.8, 129.2, 129.3, 130.2, 131.1, 136.7, 137.9, 138.6.
MS (EI, 70 eV): m/z (%) 522 (1) [M+], 365 (14) [M+ - PhSe],
340 (76) [M+-p-BrC6H4CHCH2], 183 (88), 128 (100). HRMS (ESI):
m/z calcd for C22H19BrNaSe2 (M + Na)+ 544.8898, found 544.8889.
Compound 7a. Oil. IR (film): 2960, 1628, 1483, 1394, 1241,
conditions as above, the desired products cyclobutane-1,1-
diylbis(p-tolylsulfane) derivatives 7 could be synthesized con-
veniently from the corresponding MCPs in acceptable to good
yields (Table 3).
Allowing the introduction of two different functional groups
at the same time, difunctional reactions are important in organic
synthesis.17 Previously, Ogawa and co-workers developed a
series of free radical mediated difunctional reactions employing
a (ArS)2-(ArSe)2 binary system, which could introduce ArS and
ArSe groups simultaneously.8b-d,g Encouraged by these works,
we tried to examine our reaction of MCP 1f with (ArS)2 and
(ArSe)2. However, when the corresponding substrates were
stirred together in the presence of TiCl4, only traces of the
difunctional product 8 were observed (Scheme 3).
915, 811, 738 cm-1 1H NMR (600 MHz, CDCl3, TMS): δ
.
7.10-7.47 (m, 12H), 3.74-3.77 (m, 1H), 2.48-2.51 (m, 1H), 2.37
(s, 3H), 2.34 (s, 3H), 1.97-2.08 (m, 3H). 13C NMR (150 MHz,
CDCl3): δ 20.7, 21.2, 21.3, 30.1, 48.4, 66.9, 120.8, 128.3, 129.3
(d), 129.6, 129.9, 131.0, 135.6, 137.1, 137.8, 138.5, 139.5. MS (EI,
70 eV): m/z (%) 454 (2) [M+], 333 (9) [M+ - CH3C6H4S], 272
(100) [M+ - p-BrC6H4CHCH2]. HRMS (EI): m/z calcd for
C24H23BrS2 454.0425, found 454.0421.
Acknowledgment. This work was supported by the National
Natural Scientific Foundation of China (No. 20633010 and
20773106). We thank Prof. C. G. Yan and Miss L. T. Du for
X-ray diffraction analysis.
In conclusion, we have developed a convenient method for
the synthesis of substituted cyclobutane-1,1-diylbis (phenylse-
lane) derivatives or cyclobutane-1,1-diylbis(p-tolylsulfane) de-
rivatives via the addition of 1,2-diphenyldiselane or 1,2-di-p-
Supporting Information Available: Single-crystal X-ray
diffraction data of 2i have been deposited with the CCDC
(deposition no. CCDC 729806). General experimental proce-
dures and spectroscopic data for all compounds, including
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) For selected articles about sulfur contained organic compounds’ ap-
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Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702. (b) Rauhut,
C. B.; Melzig, L.; Knochel, P. Org. Lett. 2008, 10, 3891. (c) Shi, M.; Jiang, M.;
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JO9006514
J. Org. Chem. Vol. 74, No. 14, 2009 5089