Cyclopropylmethylation of benzylic and allylic chlorides with cyclopropylmethylstannane catalyzed by gallium or indium halide

Article abstract of DOI:10.1021/ol100240b

"Figure Presented" Benzylic and allylic chlorides easily coupled with cyclopropylmethylstannane in the presence of GaCl₃ or InBr ₃ catalyst, in which an intermediate of an active butenylgalllum or -indium species was confirmed by NMR

Full text of DOI:10.1021/ol100240b

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1520-1523
Cyclopropylmethylation of Benzylic and
Allylic Chlorides with
Cyclopropylmethylstannane Catalyzed
by Gallium or Indium Halide
Kensuke Kiyokawa, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Center for Atomic and Molecular Technologies,
Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received January 30, 2010
ABSTRACT
Benzylic and allylic chlorides easily coupled with cyclopropylmethylstannane in the presence of GaCl3 or InBr3 catalyst, in which an intermediate
of an active butenylgallium or -indium species was confirmed by NMR spectroscopy and X-ray analysis. An ionic reaction process is plausible
for this coupling.
Cyclopropane functional compounds are versatile synthetic
intermediates because of their unique reactivity.1 Moreover,
cyclopropyl rings also exist in many natural compounds
that show biological activity.2 For their preparation, the
Simmons-Smith reaction3 and transition-metal-catalyzed
cyclopropanation with diazo compounds4 have been widely
used.5 Although butenyl metal species are useful reagents
for construction of cyclopropyl ring systems, their low
nucleophilicity has limited their synthetic applications.6 Only
a few examples have been reported. For example, an
equimolar amount of TiCl4 promoted the coupling of
butenyltrimethylsilane and acid chlorides.7 Similar types of
reactions have been achieved using butenyltributylstannanes
in the presence of Lewis acids.8 In addition, in situ generated
butenylgallium, -indium, and -aluminum species from bute-
nyl Grignard reagents have been coupled with R-halocar-
bonyl compounds9 in a radical manner.10 Recently, we
confirmed the generation of active indium species by
(1) (a) Paquette, L. A. Chem. ReV. 1986, 86, 733–750. (b) Wong,
H. N. C.; Hon, M.-Y.; Tse, C. W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T.
Chem. ReV. 1989, 89, 165–198. (c) Reissig, H.-U.; Zimmer, R. Chem. ReV.
2003, 103, 1151–1196.
(6) Reactions of butenylstannane with inorganic electrophiles have been
reported, see: (a) Peterson, D. J.; Robbins, D.; Hansen, J. R. J. Organomet.
Chem. 1974, 73, 237–250. (b) Nicolaou, K. C.; Claremon, D. A.; Barnette,
W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979, 101, 3704–3706. (c) Ueno, Y.;
Ohta, M.; Okawara, M. Tetrahedron Lett. 1982, 23, 2577–2580. (d)
Herndon, J. W.; Harp, J. J. Tetrahedron Lett. 1992, 33, 6243–6246.
(7) (a) Sakurai, H.; Imai, T.; Hosomi, A. Tetrahedron Lett. 1977, 18,
4045–4048. (b) Hatanaka, Y.; Kuwajima, I. Tetrahedron Lett. 1986, 27,
719–722.
(2) (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589–8627. (b) Gnad,
F.; Reiser, O. Chem. ReV. 2003, 103, 1603–1623. (c) Wessjohann, L. A.;
Brandt, W. Chem. ReV. 2003, 103, 1625–1647.
(3) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323–
5324. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968,
24, 53–58.
(4) Brookhart, M.; Studabaker, W. B. Chem. ReV. 1987, 87, 411–432.
(5) For stereoselective cyclopropanation reaction, see: (a) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977–
1050.
(8) (a) Sugawara, M.; Yoshida, J. Chem. Commun. 1999, 505–506. (b)
Sugawara, M.; Yoshida, J. Tetrahedron 2000, 56, 4683–4689.
10.1021/ol100240b  2010 American Chemical Society
Published on Web 03/10/2010

transmetalation between cyclopropylmethylstannane11 and
indium halide and its radical coupling reaction with R-io-
docarbonyl compounds, although a catalytic trial failed.12
In this communication, we report the GaCl3- or InBr3-
catalyzed cyclopropylmethylation of alkyl chlorides, which
are readily available but less reactive than iodides or
bromides, with cyclopropylmethylstannane (Scheme 1).
Contrary to our previous report, this reaction proceeded by
an ionic mechanism, which apparently enabled the catalytic
coupling. In addition, the generated butenylgallium inter-
mediate was isolated and confirmed by its complexation with
a phosphine ligand.
Table 1. Reaction of 1-Chloro-1-(4-methylphenyl)ethane (2a)
with Cyclopropylmethylstannane 1a
yield (%)b
entry
catalyst
solvent
3a
4a
1
2
3
4
5
6
7
8
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
toluene
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
81
69
58
59
52
0
57
55
55
73
45
71
0
19
18
19
26
19
0
14
14
15
20
13
21
InBr3
InCl3
InI3
Scheme 1
.
Reactivity of Butenylgallium or Butenylindium
Species
InBr3
InBr3
InBr3
GaCl3
GaBr3
InBr3
InBr3
GaCl3
GaCl3
9
10c
11d
12c
13d
a All entries were carried out at 0 °C for 2 h using 1.0 mmol of 1, 1.0
mmol of 2a, and 0.05 mmol of catalyst. b Determined by 1H NMR. c TEMPO
(0.05 mmol) was added. d Galvinoxyl (0.05 mmol) was added.
First, we chose the reaction of 1-chloro-1-(4-methylphe-
nyl)ethane (2a) with cyclopropylmethylstannane 1 for the
investigation of the catalysts (Table 1).13 No reaction took
place without catalyst loading (entry 1). Use of 5 mol % of
InBr3 in CH2Cl2 effectively promoted the coupling reaction
to afford the cyclopropylmethylated product 3a in 81% yield
along with 19% yield of the ring-opening product 4a (entry
2). Other indium halides, InCl3 or InI3, gave yields lower
than that of InBr3 (entries 3 and 4). Hydrocarbon solvents
such as hexane and toluene were also effective (entries 5
and 6), whereas no reaction was observed in MeCN, perhaps
because the interaction between the indium catalyst and the
substrates was disturbed by its strong coordination ability
(entry 7). In addition, it was found that gallium halide was
also an efficient catalyst (entries 8 and 9). The reactions were
not affected by the addition of a radical inhibitor, such as
TEMPO or galvinoxyl, which had completely disturbed the
reactions with R-haloesters, as previously reported12 (entries
10-13). These data strongly indicated that the reaction
proceeded in an ionic manner. All previous reactions of
organic halides with organoindium species proceed via a
radical mechanism. For example, the reduction by indium
hydride14 and the coupling between R-halocarbonyl com-
pounds with vinyl-, allyl-, or alkynylindium species15 are
both known to be radical reactions.16 Organogallium spe-
cies9,15,17 also reacted with organic halides in a radical
manner. An ionic reaction with organic halides has never
been reported for either the organoindium or the organogal-
lium species, as far as we know.
(9) Usugi, S.; Tsuritani, T.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Bull. Chem. Soc. Jpn. 2002, 75, 841–845.
(10) (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 2547–2549. (b) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima,
K.; Omoto, K.; Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041–11047.
(c) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415–3434. (d)
Yorimitsu, H.; Oshima, K. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, Chapter 1.2.
(11) (a) Brown, R. S.; Eaton, D. F.; Hosomi, A.; Traylor, T. G.; Wright,
J. M. J. Organomet. Chem. 1974, 66, 249–254. (b) San Filippo, J., Jr.;
Silbermann, J. J. Am. Chem. Soc. 1982, 104, 2831–2836. (c) Alnajjar, M. S.;
Smith, G. F.; Kuivila, H. G. J. Org. Chem. 1984, 49, 1271–1276. (d) Lucke,
A. J.; Young, D. J. Tetrahedron Lett. 1991, 32, 807–810. (e) Lucke, A. J.;
Young, D. J. J. Org. Chem. 2005, 70, 3579–3583.
We next explored the scope of this system using either
InBr3 or GaCl3 catalyst (Table 2). Various secondary benzylic
chlorides furnished cyclopropylmethylated products in mod-
erate to high yields (entries 1-12).18 In the case of 2c and
2e, which bear two types of chlorine atoms, selective
coupling was achieved at benzylic positions. 3-Chlorocy-
(14) Baba, A.; Shibata, I. Chem. Rec. 2005, 5, 323–335.
(15) Takami, K.; Usugi, S.; Yorimitsu, H.; Oshima, K. Synthesis 2005,
824–839.
(12) Yasuda, M.; Kiyokawa, K.; Osaki, K.; Baba, A. Organometallics
2009, 28, 132–139.
(13) The reaction using unmethylated cyclopropylmethylstannane failed.
An equimolar use of indium halide was required. The reaction of
unmethylated cyclopropylmethylstannane (2 mmol) with benzhydryl chloride
(1 mmol) in the presence of InBr3 (1 mmol) in dichloromethane gave
cyclopropylmethylated product in 58% yield (ring-opening product, 28%
yield).
(16) A halogen substitution reaction using alkylindium species toward
haloalkenes was reported, see: Nomura, R.; Miyazaki, S.-i.; Matsuda, H.
J. Am. Chem. Soc. 1992, 114, 2738–2740.
(17) A gallium hydride also reacts with organic halides in a radical
manner, see: Mikami, S.; Fujita, K.; Nakamura, T.; Yorimitsu, H.;
Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1853–1855
.
Org. Lett., Vol. 12, No. 7, 2010
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Table 2. GaCl3 or InBr3-Catalyzed Cyclopropylmethylation of
Various Alkyl Chlorides 2a
Figure 1.
1H NMR spectra of (i) 1, (ii) the mixture of GaCl3 and
1, and (iii) the mixture of InBr3 and 1 in CD2Cl2.
product ratio of 5a/6a was ∼5:1. On the other hand, a 1:2
mixture of GaCl3/1 preferentially gave 6a (integration ratio
of 5a/6a ≈ 1:10) with no other highly substituted species
(see Supporting Information). The integration ratio was
somewhat different in the case of InBr3 (5b/6b ≈ 1:1) (Figure
1iii). The addition of benzhydryl chloride (2b) to the stirred
mixture of 1 and GaCl3 (1/GaCl3 ) 1:1) for 30 min in
dichloromethane-d2 gave the coupling product in 86% yield
(InBr3, 71% yield). These results demonstrated that the active
species in the reaction was a mono- and dibutenyl metal
species.12
a All entries were carried out with 1.0 mmol of 1, 1.0 mmol of 2a, and
0.05 mmol of catalyst. b Determined by 1H NMR. c 1.5 mmol of 1 and
0.75 mmol of catalyst were used. d 0.5 mmol of catalyst was used.
Scheme 2
.
Complexation and Isolation of the Butenylgallium
Species
clohexene (2h) was also transformed to the corresponding
product 3h (entries 13 and 14). Primary benzylic chloride,
p-chlorobenzyl chloride (2i), gave the product when an
equimolar amount of metal halide was used (entries 15 and
16). GaCl3 catalyzed the reaction with ꢀ-chloro ester 2j to
afford the ester 3j, while the starting ester was recoverd in
the case of InBr3 (entries 17 and 18).
Furthermore, we attempted to isolate the butenylgallium
species by complexation using external ligands. The addition
of DPPE to a 1:1 mixture of GaCl3/1 in CH2Cl2 gave a
crystal, which was determined by X-ray crystal structural
analysis to be butenylgallium complex 7 (Scheme 2). The
structure is shown in Figure 2. The four-coordinated gallium
center had a butenyl group, a phosphorus in DPPE, and two
chlorines. Each phosphine moiety in DPPE coordinated to
the other molecule’s gallium centers. The angles for
Cl1-Ga-Cl2 (107.02°) and C-Ga-Cl (115.58° and 113.48°)
indicated that the gallium center exhibited a distorted
tetrahedral structure. This stable structure was different from
that of TBP of the indium species.12
To confirm the active gallium species, a mixture of an
1
equimolar amount of GaCl3 and 1 was monitored by H
NMR. Similar signals were observed with two doublets for
the vinylic protons (a), two triplets for the allylic protons
(c), and two singlets for the methyl protons (b) (Figure 1ii).
On the basis of the reported facts,12 they were assigned the
designations of mono- and dibutenylgallium species 5a and
6a. The integration ratio of the peaks was ∼2.5:1, and the
(18) Benzylic bromides were also applicable in a similar range to the
chlorides. For example, the reaction of 1-bromo-1-phenylethane (1 mmol)
with 1 (1 mmol) in the presence of GaCl3 (0.05 mmol) in dichloromethane
gave 3d (62%) and 4d (22%).
1522
Org. Lett., Vol. 12, No. 7, 2010

alcohols as substrates would be ideal for synthetic organic
chemistry because alcohols are plentiful and readily available.
The reaction of 1 with benzhydrol (12) in the presence of
InBr3 and trimethylsilyl chloride furnished corresponding
cyclopropylmethylated product 3b in 49% yield. It is
assumed that a reaction using trimethylsilyl chloride chlo-
rinated alcohol in the presence of InBr3,20,21 followed by
coupling with cyclopropylmethylstannane, would proceed in
the manner discussed above.
Scheme 4. Cyclopropylmethylation of Alcohol
Figure 2. X-ray structure of 7 (all hydrogens are omitted for clarity).
A plausible reaction mechanism is shown in Scheme 3.
Transmetalation between 1 and GaCl3 gives butenylgallium
species. Then the resulting gallium species activates alkyl
chloride by formation of an intermediate 9, perhaps via the
alkyl cation species. Finally, cyclization takes place with the
release of gallium chloride to form a cyclopropyl ring. When
the isomerization from 9 to 10 via a hydride shift occurs,
the ring-opening product is formed.7a,8b,19 The interaction
of the butenylgallium species and alkyl chloride may be a
key step in this ionic mechanism to complete the catalytic
cycle. The reaction using InBr3 as a catalyst proceeds in a
similar manner.
In conclusion, we have developed GaCl3- or InBr3-
catalyzed cyclopropylmethylation of benzylic and allylic
chlorides with cyclopropylmethylstannane. NMR spectros-
copy and X-ray crystal structural analysis revealed the
generation of butenylgallium and -indium species. Further
investigation of the mechanism and synthetic application of
this transformation is now underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas [No.
18065015 (“Chemistry of Concerto Catalysis”) and No.
20036036 (“Synergistic Effects for Creation of Functional
Molecules”)] and for Scientific Research (No. 21350074)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We thank Dr. Nobuko Kanehisa (Osaka
University) for the valuable advice regarding X-ray crystal-
lography. K.K. thanks the Global COE Program “Global
Education and Research Center for Bio-Environmental
Chemistry” of Osaka University.
Scheme 3. Plausible Reaction Mechanism
Supporting Information Available: Experimental details,
characterization data and CIF of 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL100240B
(19) Ogasawara, M.; Okada, A.; Murakami, H.; Watanabe, S.; Ge, Y.;
Takahashi, T. Org. Lett. 2009, 11, 4240–4243.
(20) We have reported indium-catalyzed direct chlorination of alcohols
using chlorodimethylsilane-benzil system, see: Yasuda, M.; Yamasaki, S.;
Onishi, Y.; Baba, A. J. Am. Chem. Soc. 2004, 126, 7186–7187.
(21) Chlorination of alcohols using trimethylsilyl chloride catalyzed by
BiCl3 has been reported, see: Labrouille`re, M.; Roux, C. L.; Gaspard-
Iloughmane, H.; Dubac, J. Synlett 1994, 723–724.
Finally, this reaction system was applied to the direct use
of alcohol instead of chloride, as shown in Scheme 4. Using
Org. Lett., Vol. 12, No. 7, 2010
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