New synthesis of allylidenecyclobutanes by the reaction of cyclobutylmagnesium carbenoids with vinyl sulfones

Article abstract of DOI:10.1016/j.tetlet.2011.08.018

The reaction of cyclobutylmagnesium carbenoids, which were generated from 1-chlorocyclobutyl p-tolyl sulfoxides with EtMgCl via the sulfoxide-magnesium exchange reaction at low temperature, with carbanions derived from vinyl sulfones with n-BuLi or LDA re

Full text of DOI:10.1016/j.tetlet.2011.08.018

Tetrahedron Letters 52 (2011) 5563–5566
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New synthesis of allylidenecyclobutanes by the reaction of
cyclobutylmagnesium carbenoids with vinyl sulfones
⇑
Masashi Ishigaki, Mio Inumaru, Tsuyoshi Satoh
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162 0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of cyclobutylmagnesium carbenoids, which were generated from 1-chlorocyclobutyl p-tolyl
sulfoxides with EtMgCl via the sulfoxide–magnesium exchange reaction at low temperature, with carba-
nions derived from vinyl sulfones with n-BuLi or LDA resulted in the formation of allylidenecyclobutanes
in moderate to good yields. The actual reactive species of the sulfones in this reaction were proved to be
Received 27 June 2011
Revised 27 July 2011
Accepted 3 August 2011
Available online 19 August 2011
the lithium a-sulfonyl carbanion of allyl sulfones derived from the vinyl sulfones by double bond migra-
tion with the bases used. Mono- and di-substituted allylidenecyclobutanes can be obtained by using a
variety of vinyl sulfones.
Keywords:
Magnesium carbenoid
Cyclobutylmagnesium carbenoid
Cyclobutane
Ó 2011 Elsevier Ltd. All rights reserved.
Allylidenecyclobutane
Vinyl sulfone
Introduction
magnesium carbenoid 2 via the sulfoxide–magnesium exchange
reaction.7 In an another flask, vinyl sulfone 38 in THF at low tem-
Small ring strained molecules such as cyclopropanes and cyclob-
utanes, and their derivatives, have been known as versatile interme-
diates in organic synthesis for long time.1 Small ring compounds
reveal characteristic reactivity by their strain release. Innumerable
studies for the chemistry, synthesis, and synthetic uses of cyclopro-
panes have been carried out; however, those for cyclobutanes are
still limited.2 Alkylidenecyclobutanes are also very interesting
highly strained cyclobutane derivatives and often used in organic
synthesis3; however, adequate methods for their synthesis are still
lacking.4
perature was treated with n-BuLi (or LDA) and this solution was
transferred to the solution of cyclobutylmagnesium carbenoid 2
through a cannula and the whole reaction mixture was slowly
allowed to warm to 0 °C to afford allylidenecyclobutane 4 in mod-
erate to good yield. This is an unprecedented new method for the
synthesis of allylidenecyclobutanes 4 from easily available 1-chlo-
rocyclobutyl p-tolyl sulfoxides 1.6 Preliminary results of this study
and mechanistic discussion of this reaction are reported in this
Letter.
We recently started to investigate the chemistry and synthetic
uses of cyclobutylmagnesium carbenoid (carbenacyclobutane)
and many interesting reactions have appeared.5,6 Synthesis of alky-
lidenecyclobutanes by the reaction of cyclobutylmagnesium carb-
R1CH2
R2
R3
SO2Tol
enoids with lithium
a-sulfonyl carbanions as nucleophiles was
R
Cl
R
Cl
3
one of the most interesting results from the investigations.6 In con-
tinuation of our studies concerning the reaction of cyclobutylmag-
nesium carbenoids with nucleophiles, we recently found that the
reaction of cyclobutylmagnesium carbenoids with the carbanions
derived from vinyl sulfones with n-BuLi (or LDA) resulted in the
formation of allylidenecyclobutanes in moderate to good yields
(Scheme 1).
EtMgCl
THF
STol
MgCl
R
R
n-BuLi (or LDA)
O
2
1
4
R3
R
H
Thus, treatment of 1-chlorocyclobutyl p-tolyl sulfoxide 1 in THF
with EtMgCl at À90 °C resulted in the generation of cyclobutyl-
R
R2
R1
⇑
Corresponding author. Tel.: +1 81 3 5228 8272; fax: +1 81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.018

5564
M. Ishigaki et al. / Tetrahedron Letters 52 (2011) 5563–5566
occur relatively easily,10 vinyl sulfone 5 must be isomerized to allyl
sulfone 7 by n-BuLi in the reaction medium. -Hydrogen of allyl
sulfone 7 was easily deprotonated to give lithium -sulfonyl carb-
anion 8. Carbenoid 2a was attacked from back side of the chlorine
EtMgCl (2.5 eq)
THF, -90 °C
C2H5OCH2
C2H5OCH2
Cl
C2H5OCH2
Cl
a
MgCl
C2H5OCH2
S(O)Tol
a
2a
1a
atom by a-sulfonyl carbanion 8 to give cyclobutylmagnesium chlo-
ride intermediate 9,11 from which b-elimination must have oc-
curred to afford allylidenecyclobutane 6.
H3C
H3C
H
n-BuLi
SO2Tol
The double bond migration of vinyl sulfone 5 to allyl sulfone 7
was confirmed from the experiment shown in Scheme 3. Thus,
treatment of vinyl sulfone 5 with n-BuLi at À70 °C for 10 min fol-
C2H5OCH2
C2H5OCH2
H
5
H
-90 to 0 °C, 69%
H3C
H
lowed by CH3OD gave a-deuterio allyl sulfone 10 in 85% yield with
6
over 99% deuterium content. In order to make sure that this reac-
tion proceeds via -sulfonyl carbanion of allyl sulfones, cyclobutyl-
magnesium carbenoid 2a was reacted with 3 equiv of lithium
-sulfonyl carbanion generated from allyl sulfone 7 under the
a
Scheme 2.
a
same conditions described above. As expected, this reaction gave
allylidenecyclobutane 6 in 71% yield, which was almost the same
as that of the reaction with vinyl sulfone 5 (69%, see Scheme 2).
As we recognized that this reaction is unprecedented and would
become a new method for the synthesis of allylidenecyclobutanes,
generality was investigated and the results are summarized in Ta-
ble 1. The result shown in entry 1 has been mentioned above. The
reaction of 1b with the carbanion derived from 5 gave allylidene-
cyclobutane 11a in somewhat better yield (77%, entry 2). When
the vinyl sulfone has a phenyl group at the b-position, yield of
the reaction markedly diminished (entries 3 and 4).
Disubstituted allylidenecyclobutanes 11d and 11e were synthe-
sized from 1a and 1b with 2,2-diethylvinyl sulfone in moderate
yields (entries 5 and 6). Interestingly, only the geometrical isomer
depicted in Table 1 was obtained and the structures of 11d and
11e were determined from their NOESY spectra. The vinyl sulfones
synthesized from cyclopentanone and cyclohexanone gave allylid-
enecyclobutanes bearing a cyclopentene- and cyclohexene ring,
respectively, in moderate to good yields (entries 7–10). In order to
make sure that this reaction is not affected by the substituents on
the 3-position of the cyclobutane ring, we investigated the reaction
starting from 1-chlorocyclobutyl p-tolyl sulfoxide bearing no substi-
tuent 1c and the vinyl sulfone having higher molecular weight, 2-
benzyl-3-phenyl-1-propenyl p-tolyl sulfone, whichwas synthesized
Results and discussion
As a representative example for this investigation, the reaction
using 1-chlorocyclobutyl p-tolyl sulfoxide 1a and 2-methyl-1-pro-
penyl p-tolyl sulfone 59 is reported (Scheme 2). In our previous stud-
ies, we reported the reactions of cyclobutylmagnesium carbenoids
with carbon nucleophiles, including lithium a-sulfonyl carbanions,
followed by electrophiles to give multi substituted cyclobutanes.6
Based on the experiences of these studies, we treated cyclobutyl-
magnesium carbenoid 2a, generated from 1a with EtMgCl in THF
at À90 °C, with 3 equiv of an anion generated from vinyl sulfone 5
with n-BuLi. The temperature of the reaction mixture was slowly al-
lowed to warm to 0 °C.
This reaction cleanly gave a product, which has C14H24O2 as the
molecular formula, in 69% yield as colorless oil. The product had
three olefin protons (d 4.74, 2H, broad singlet and d 5.83, 1H, quin-
tet, J=2.3 Hz) and one olefinic methyl group (d 1.85, broad singlet).
The structure of this product was easily assigned to be allylidene-
cyclobutane 6 as shown in Scheme 2. We investigated to find bet-
ter conditions for this reaction; however, the conditions mentioned
above were found to be the best.
A plausible mechanism of this quite interesting reaction is
proposed as follows (Scheme 3). Thus, as the double bond migra-
tion of vinyl sulfones to allyl sulfones by a base was reported to
H2C
H
n-BuLi
H3C
H3C
H
n-BuLi
H2C
H3C
H
H3C
SO2Tol
SO2Tol
SO2Tol
double bond
migration
H
5
8
7
SO2Tol
CH2
CH3
MgCl
C2H5OCH2
C2H5OCH2
H
C2H5OCH2
C2H5OCH2
MgCl
Cl
C2H5OCH2
C2H5OCH2
H
H
H3C
2a
6
9
H3C
H3C
H
n-BuLi
H2C
H3C
D
SO2Tol
CH3OD
SO2Tol
THF, -70°C , 10 min
10
5
H2C
CH2SO2Tol
n-BuLi
H3C
C2H5OCH2
C2H5OCH2
MgCl
Cl
C2H5OCH2
C2H5OCH2
H
7
H
H
71%
H3C
2a
6
Scheme 3. A plausible mechanism for the reaction of cyclobutylmagnesium carbenoid 2a with the carbanion generated from vinyl sulfone 5 with n-BuLi giving
allylidenecyclobutane 6.

M. Ishigaki et al. / Tetrahedron Letters 52 (2011) 5563–5566
5565
Table 1
Synthesis of allylidenecyclobutanes 11 from 1-chlorocyclobutyl p-tolyl sulfoxides 1 with vinyl sulfones
Vinyl sulfone (3 eq)
EtMgCl (2.5 eq)
THF, -90°C
R
R
Cl
R
R
Cl
n-BuLi
Allylidenecyclobutane 11
MgCl
S(O)Tol
-90 to 0°C
2
1a R= CH2OC2H5
1b R= CH2O(CH2)3Ph
1c R= H
Entry
1
Vinyl sulfone
11
Yield (%)
1
2
1a
1b
6 (69)
11a (77)
H3C
H3C
H
R
H
H
SO2Tol
R
H3C
H
3
4
1a
1b
11b (39)
11c (47)
Ph
H
R
R
H
H
H
H
H
H3C
SO2Tol
Ph
5
6
1a
1b
11d (49)
11e (59)
C2H5
C2H5
R
R
H
CH3
H
SO2Tol
C2H5
7
8
1a
1b
11f (58)
11g (66)
H
R
R
H
SO2Tol
9
10
1a
1b
11h (83)a,b
11i (53)b
H
R
R
H
H
SO2Tol
PhH2C
PhH2C
H
H
H
11
1c
11j (64)c
SO2Tol
PhH2C
Ph
a
b
c
Five equivalents of vinyl sulfone were used.
Carbanion was generated with LDA at 0 °C for 1.5 h.
About 30:1 mixture of two geometrical isomers; the configuration not determined.
Table 2
Synthesis of disubstituted allylidenecyclobutanes 14 from 1 with fully substituted vinyl sulfones 12
H2C
H3C
R1
SO2Tol
H3C
H3C
R1
n-BuLi
SO2Tol
Li
13
THF, -78 °C
10 min
12
EtMgCl (2.5 eq)
R1
R
R
S(O)Tol
Cl
R
MgCl
Cl
R
R
H
H
R
-90 to 0 °C
H3C
1
2
14
Entry
Sulfoxide/1
12
14
R
R1
Yield (%)
1
2
1a CH2OC2H5
1b CH2O(CH2)3Ph
12a CH3
12a CH3
14a (79)
14b (83)
3
4
1a CH2OC2H5
1b CH2O(CH2)3Ph
12b Ph
12b Ph
14c (20)
14d (26)
5
6
1a CH2OC2H5
1b CH2O(CH2)3Ph
12c COOt-Bu
12c COOt-Bu
14e (32)a
14f (33)a
7
8
1c H
1c H
12b Ph
12c COOt-Bu
14g (17)
14h (28)a
a
Carbanion 13 was generated with LDA at 0 °C.
from dibenzyl ketone. As shown in entry 11, the reaction gave the
Finally, we examined this reaction with the
a
-sulfonyl carba-
desired product 11j in 64% yield without any problem.
nions generated from the vinyl sulfones bearing a substituent at

5566
M. Ishigaki et al. / Tetrahedron Letters 52 (2011) 5563–5566
E. S.; Ibragimov, A. G. Tetrahedron Lett. 2007, 48, 8583; (f) Jiang, M.; Liu, L.-P.;
the a-position and the results are summarized in Table 2. Thus, at
Shi, M. Tetrahedron 2007, 63, 9599; (g) Jiang, M.; Shi, M. Tetrahedron 2008, 64,
10140; (h) Jiang, M.; Shi, M. Tetrahedron 2009, 65, 798; (i) D’yakonov, V. A.;
Tuktarova, R. A.; Trapeznikova, O. A.; Khalilov, L. M.; Popod’ko, N. R. ARKIVOC
2011, 20.
first, 3-methyl-2-butenyl p-tolyl sulfone 12a (R1 = CH3, 3 equiv;
synthesized from acetone and ethyl p-tolyl sulfone) was treated
with n-BuLi in THF at À78 °C for 10 min. This solution was trans-
ferred into a solution of cyclobutylmagnesium carbenoid 2a
(R = CH2OCH2CH3) through a cannula and the temperature of the
reaction mixture was slowly allowed to warm to 0 °C. Gratifyingly,
we obtained the desired allylidenecyclobutane 14a in 79% yield
(entry 1).12 The same reaction starting from 1b gave the desired
14b in better yield of 83% (entry 2).
4. Some
selected
recent
papers
concerning
the
synthesis
of
alkylidenecyclobutanes: (a) Narasaka, K.; Hayashi, K.; Hayashi, Y. Tetrahedron
1994, 50, 4529; (b) Takahashi, Y.; Ohaku, H.; Morishima, S.; Suzuki, T.; Miyashi,
T. Tetrahedron Lett. 1995, 36, 5207; (c) Shepard, M. S.; Carreira, E. M. J. Am.
Chem. Soc. 1997, 119, 2597; (d) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima,
T.; Tamaru, Y. J. Am. Chem. Soc. 1997, 119, 10869; (e) Hojo, M.; Murakami, C.;
Nakamura, S.; Hosomi, A. Chem. Lett. 1998, 331; (f) Fujiwara, T.; Iwasaki, N.;
Takeda, T. Chem. Lett. 1998, 741; (g) Barbero, A.; Cuadrado, P.; Garcia, C.;
Rincon, J. A.; Pulido, F. J. J. Org. Chem. 1998, 63, 7531; (h) Gauvry, N.; Bhat, L.;
Mevellec, L.; Zucco, M.; Huet, F. Eur. J. Org. Chem. 2000, 2717; (i) Park, K.-H.;
Kurth, M. J. J. Org. Chem. 2000, 65, 3520; (j) Chowdhury, M. A.; Senboku, H.;
Tokuda, M. Tetrahedron Lett. 2003, 44, 3329; (k) Chen, L.; Shi, M.; Li, C. Org. Lett.
2008, 10, 5285; (l) Iwasaki, M.; Yorimitsu, H.; Oshima, K. Synlett 2009,
2177.
Other results are summarized in entries 3–8. Vinyl sulfone bear-
ing a phenyl group at the a-position 12b again gave allylidenecyc-
lobutanes 14c and 14d in low yields. Vinyl sulfone bearing a tert-
butyl ester group 12c can be used in this reaction; however, at
present, the yields were not satisfactory (entries 5 and 6). The reac-
tion of 1c with the carbanions derived from 12b and 12c also gave
the desired product; however, the yields again were not satisfac-
tory (entries 7 and 8).
In conclusion, we found that the reaction of the lithium carba-
nions derived from easily synthesized vinyl sulfones with cyclobu-
tylmagnesium carbenoids, derived from 1-chlorocyclobutyl p-tolyl
sulfoxide with EtMgCl via the sulfoxide–magnesium exchange
reaction, resulted in the formation of allylidenecyclobutanes in
variable yields. The chemistry presented herein is unprecedented
and will contribute to the synthesis of various kinds of allylidene-
cyclobutanes in relatively short steps.
5. Nakaya, N.; Sugiyama, S.; Satoh, T. Tetrahedron Lett. 2009, 50, 4212.
6. (a) Satoh, T.; Kasuya, T.; Miyagawa, T.; Nakaya, N. Synlett 2010, 286; (b) Satoh,
T.; Kasuya, T.; Ishigaki, M.; Inumaru, M.; Miyagawa, T.; Nakaya, N.; Sugiyama, S.
Synthesis 2011, 397.
7. (a) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561; (b) Satoh, T. In The Chemistry of
Organomagnesium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley and
Sons: Chichester, 2008; pp 717–769; (c) Satoh, T. Yakugaku Zasshi 2009, 129,
1013.
8. (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford,
1993; (b)Patai, S., Rappoport, Z., Eds.The Synthesis of Sulphones Sulphoxides
and Cyclic Sulphides; John Wiley and Sons: Chichester, 1994.
9. 2-Methyl-1-propenyl p-tolyl sulfone
5 was synthesized from acetone and
methyl p-tolyl sulfone as follows. Methyl p-tolyl sulfone was treated with LDA
followed by acetone to give adduct. The hydroxyl group in the adduct was
acetylated with Ac2O-pyridine-DMAP to afford an acetate, which was treated
with N-lithio piperidone to give 5 via b-elimination. Each step gave almost
quantitative yield. Other vinyl sulfones except 12c were synthesized from
ketones with corresponding sulfones in the same manner in high overall yields.
10. (a) O’Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840; (b) Hine, J.;
Skoglund, M. J. J. Org. Chem. 1982, 47, 4766.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 and 22590021 from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and TUS
Grant for Research Promotion from Tokyo University of Science,
which is gratefully acknowledged.
11. Yajima, M.; Nonaka, R.; Yamashita, H.; Satoh, T. Tetrahedron Lett. 2009, 50,
4754.
12. Experimental procedure for the synthesis of 14a: Ethylmagnesium chloride
(2 mol/L solution in THF; 0.13 mL; 0.25 mmol) was added to a solution of 1a
(34.5 mg; 0.1 mmol) in 1 mL of dry THF in a flame-dried flask at À90 °C under
Ar atmosphere dropwise with stirring. In an another flame-dried flask, n-BuLi
(1.65 mol/L solution in hexane; 0.18 mL; 0.3 mmol) was added to a solution of
vinyl sulfone 12a (67.3 mg; 0.3 mmol) in 1 mL of dry THF at À70 °C with
stirring to give light yellow solution. After being stirred for 15 min, this
References and notes
solution was cooled to À90 °C and was transferred to
a solution of the
1. Greenberg, A.; Liebman, J. F. Strained Organic Molecules; Academic Press: New
York, 1978.
cyclobutylmagnesium carbenoid through a cannula. The reaction mixture was
stirred and slowly allowed to warm to 0 °C. The reaction was quenched by
adding satd aq NH4Cl solution. The whole was extracted with CHCl3 and the
organic layer was dried over MgSO4 and concentrated. The product was
purified by silica gel column chromatography to give 14a (19 mg; 79%) as
2. Some recent reviews for the chemistry, synthesis and synthetic uses of
cyclobutanes: (a) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. 1988, 27, 797; (b)
Bach, T. Synthesis 1998, 683; (c) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003,
103, 1449; (d) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485; (e)
Sadana, A. K.; Saini, R. K.; Billups, W. E. Chem. Rev. 2003, 103, 1539; (f) Leemans,
E.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2011, 111, 3268.
3. Some selected recent papers concerning the synthetic uses of
alkylidenecyclobutanes: (a) Frimer, A. A.; Weiss, J.; Gottlieb, H. E.; Wolk, J. L.
J. Org. Chem. 1994, 59, 780; (b) Zhang, W.; Dowd, P. Tetrahedron Lett. 1995, 36,
8539; (c) Baldwin, J. E.; Shukla, R. Org. Lett. 1999, 1, 1081; (d) Pizem, H.; Sharon,
O.; Frimer, A. A. Tetrahedron 2002, 58, 3199; (e) D’yakonov, V. A.; Finkelshtein,
colorless oil. IR (neat) 2975, 2931, 2865, 1606, 1445, 1375, 1112, 877 cmÀ1 1H
;
NMR (CDCl3) d 1.19 (6H, t, J = 7.0 Hz), 1.63 (3H, m), 1.90 (3H, br s), 2.51 (2H, m),
2.71 (2H, m), 3.43 (4H, s), 3.51 (4H, q, J = 7.0 Hz), 4.77 (1H, br s), 4.82 (1H, br s);
13C NMR (CDCl3) d 15.08 (CH3 Â 2), 15.51 (CH3), 22.75 (CH3), 36.71 (CH2), 37.94
(C), 38.33 (CH2), 66.64 (CH2 Â 2), 73.64 (CH2 Â 2), 110.81 (CH2), 129.05 (C),
133.69 (C), 144.42 (C). MS m/z (%) 238 (M+, 13), 133 (100), 105 (19), 91 (18).
Calcd for C15H26O2: M, 238.1933. Found: m/z 238.1935.