Triethylsilane-indium(III) chloride system as a radical reagent

Article abstract of DOI:10.1021/ol047849v

(Chemical Equation Presented) A novel generation method of indium hydride (Cl₂InH) was found by the transmetalation of InCl₃ with Et₃SiH. In the intramolecular cyclization of enynes, the previously reported system (NaBH₄-InCl₃) has a problem of side reactions with the coexistent borane. In contrast, the problem was solved by the presented system, which affords effective hydroindation of alkynes.

Full text of DOI:10.1021/ol047849v

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4981-4983
Triethylsilane−Indium(III) Chloride
System as a Radical Reagent
Naoki Hayashi, Ikuya Shibata, and Akio Baba*
Department of Molecular Chemistry, Science and Technology Center for Atoms,
Molecules and Ions Control (STAMIC), Graduate School of Engineering,
Osaka UniVersity, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received October 18, 2004
ABSTRACT
A novel generation method of indium hydride (Cl2InH) was found by the transmetalation of InCl3 with Et3SiH. In the intramolecular cyclization
of enynes, the previously reported system (NaBH4 InCl3) has a problem of side reactions with the coexistent borane. In contrast, the problem
was solved by the presented system, which affords effective hydroindation of alkynes.
−
The use of radical reactions in modern organic synthesis is
now well-established.1 Despite the many well-documented
advantages of free-radical chain reactions in organic chem-
istry, the majority of examples still rely on the use of tri-
n-butyltin hydrides.2,3 Hence, a major area of current research
is the development of processes that seek to either alleviate
the problems associated with toxic tin residues or remove
the need for tin completely.4 With a potential similar to that
of Bu3SnH, dihalogenoindium hydrides (X2InH) have been
recently found by us and other groups to be novel reagents
that were generated by the transmetalation of indium(III)
trihalides (InCl3 or InBr3) with metal hydrides.5-7 At first,
Bu3SnH was employed as a hydride source,5 and then it was
have been significant, all suffer from the strong reducing
ability of the hydride sources themselves. All the hydrides
employed could reduce a variety of functionalities without
any assistance of Lewis acids or catalysts. In the case of
NaBH4-InCl3, although we could achieve intramolecular
cyclization and intermolecular coupling reactions initiated
by dehalogenation,6 the generation of BH3 during transmeta-
lation becomes a serious problem. Therefore, an alternative
hydride source that causes no side reactions should be
developed. Considering this background, Et3SiH is a good
candidate, and we already found weak ionic interactions
(4) For reviews see: (a) Studer, A.; Amrein, S. Synthesis 2002, 835-
849. ((TMS)3SiH): (b) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-
194. Cyclohexadienyl-silane: (c) Studer, A.; Amrein, S. Angew. Chem.,
Int. Ed. 2000, 39, 3080-3082. Tri-2-furanylgermane: (d) Nakamura, T.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 1999, 1415-1416.
Gallium hydride: (e) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo,
H.; Oshima, K. Tetrahedron 2003, 59, 6627-6635. Schwartz reagents: (f)
Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 3137-3138.
(5) We have already reported that indium hydrides act as both radical
and ionic reagents in the reaction with a variety of halides, carbonyls, imines,
and carbon-carbon multiple bonds. (a) Miyai, T.; Inoue, K.; Yasuda, M.;
Shibata, I.; Baba, A. Tetrahedron Lett. 1998, 39, 1929-1932. (b) Inoue,
K.; Sawada, A.; Shibata, I.; Baba, A. Tetrahedron Lett. 2001, 42, 4661-
4663.
6
replaced by NaBH4 and DIBAL-H.7 While the advances
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vols. 1 and 2. (b) Samir, Z. Z. Radical
Reactions in Organic Synthesis; Oxford University Press: Oxford, 2003.
(2) For tin hydride reviews, see: (a) Pereyre, M.; Quintard, J.-P.; Rahm,
A. Tin in Organic Synthesis; Butterworth: London, 1987. (b) RajanBabu
T. V. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L.,
Ed.; Wiley: New York, 1995; Vol. 7, p 5016.
(3) For examples of Bu3SnH-initiator systems (Bu3SnH-Et3B, Bu3SnH-
9BBN, Bu3SnH-CuCl, and Bu3SnH-ZnEt2), see: (a) Miura, K.; Ichinose,
Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc.
Jpn. 1989, 62, 143-147. (b) Perchyonok, V. T.; Schiesser, C. H.
Tetrahedron Lett. 1998, 39, 5437-5438. (c) Ooi, T.; Doda, K.; Sakai, D.;
Maruoka, K. Tetrahedron Lett. 1999, 40, 2133-2136. (d) Ryu, I.; Araki,
F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998, 39, 6335-6336.
(6) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002,
124, 906-907.
(7) Takami, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993-
2995.
10.1021/ol047849v CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/01/2004

between Et3SiH-InCl3.8 Herein we report the first application
of Et3SiH in a radical reaction via the generation of an indium
hydride.
Initially, we performed the reduction of alkyl halide 1a
by Et3SiH-InCl3 in optimized conditions of our previous
systems such as Bu3SnH-InCl35 and NaBH4-InCl36 (Table
1, entries 1 and 2). The reduction proceeded in moderate
Under the optimized conditions, radical cyclizations from
haloalkenes were performed effectively (Scheme 1, eqs 1
and 2). Intermolecular radical addition could be accomplished
effectively to give 4c (eq 3).
Scheme 1
Table 1. Reduction of Halides by a Mt-H-InCl3 System
In the next stage, we performed the reaction with alkynes.
For example, hydrostannation of alkynes is often accelerated
by radical initiators such as UV irradiation, AIBN, Et3B, and
ultrasound.10 An indium hydride is also expected to perform
hydroindation of alkynes due to its radical reactivity. When
NaBH4-InCl36 was allowed to react with alkynes, not only
hydroindation but also side reactions occurred by BH3
generated in situ.11 In contrast, Et3SiH, an alternative hydride
source that causes no side reactions, was used in the reactions
with alkynes (Table 2). In the reduction of 5a, product 6a
was obtained in 90% yield in MeCN (entry 1). Under the
a Et3B (0.1 mmol) was added. b InCl3 (1 mmol) was used. c Et3SiH (2
mmol) was used.
yield at room temperature in MeCN to afford 2a (entry 3).
In the presence of Et3B as a radical initiator, the yield of 2a
was slightly increased (entry 4), while in CH2Cl2, Et3B was
essential for the reaction (entries 5 and 6). When 2 mmol
Et3SiH was used, 2a was obtained in good yield (entry 7).
In the reaction of the less reactive aryl iodide 1b, a catalytic
amount of InCl3 was less effective (entry 8), but the use of
equimolar InCl3 afforded dehalogenation to give benzene
(2b) in 67% (entry 9). The use of InCl3 catalyst is essential
because no reduction took place in the absence of InCl3. As
Et3SiH has no radical reactivity,9 indium hydride is a
plausibly reactive species. In our Bu3SnH-InCl3 and NaBH4-
InCl3 systems, various alkyl halides were reduced with a
catalytic amount of InCl3 without any initiators.5,6 Although
the exact reason Et3B and equimolar InCl3 are necessary in
the Et3SiH-InCl3 system is not clear yet, this may be due
to the low concentration of indium hydride because the
transmetalation of Et3SiH-InCl3 is slow,8 especially in CH2-
Cl2.
Table 2. Reduction of Alkynes by a Et3SiH-InCl3-Et3B
System
(8) We have recently developed a Et3SiH-InBr3 system that alternatively
afforded ionic reactions such as reductive aldol reaction of enones. Shibata,
I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004,
43, 711-713.
(9) Banfi, L.; Narisano, E.; Riva, R. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; Vol. 7, pp
4522.
4982
Org. Lett., Vol. 6, No. 26, 2004

Scheme 2
Scheme 3
contrast, as shown Scheme 3, the transmetalation of Et3SiH-
InCl3 gives Et3SiCl as a byproduct, which has no reducing
ability to alkynes. The reaction of N-tosyl allylpropargy-
lamine (7b) gave nitrogen heterocycle 8b in 58% yield (eq
6).
In conclusion, the indium hydride generated from Et3SiH
and InCl3 is a promising alternative to the Bu3SnH system.
The reducing system has several advantages in terms of
convenience, low toxicity, and mild conditions, and InCl3
and Et3SiH in particular are readily available and easy to
handle.
same conditions, aliphatic alkyne 5b was reduced to alkene
6b in 59% yield (entry 2). Propargylic ether and internal
alkynes 5c and 5d were effectively reduced to 6c and 6d,
respectively (entries 3 and 4). Et3SiH-InCl3 also reduced
alkynyl ester 5e to 6e without affecting the ester moiety
(entry 5).
We next performed representative cyclization of enynes.
Allylpropargylmalonate (7a) underwent cyclization to give
exo-methylene compound (8a) in 53% yield at 0 °C for 2 h
(Scheme 2, eq 4).12 This reaction involves the cyclization
of the generated vinyl radical to the remaining alkene
(Scheme 3). The Et3SiH-InCl3 system is superior to
NaBH4-InCl3 in which linear compound 9a was obtained
as a major product (eq 5). This would be because of NaBH4-
InCl3, which resulted in the occurrence of hydroboration. In
Acknowledgment. This research has been carried out at
the “Handai Frontier Research Center” and was supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) (a) Leusink, A. J.; Budding, H. A. J. Organomet. Chem. 1968, 11,
533-539. (b) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1987, 60, 3465-3467. (c) Nakamura, E.; Machii, D.; Inubishi, T. J. Am.
Chem. Soc. 1989, 111, 6849-6850.
6
(11) When NaBH4-InCl3 was allowed to react with phenylacetylene
OL047849V
(5a), styrene (6a) was obtained in 68% yield in MeCN at -30 °C in the
presence of a radical initiator, Et3B. The reduction scarcely proceeded in
the absence of Et3B under the same conditions. One of the serious problems
of NaBH4-InCl3 system is the generation of BH3 in the transmetalation,
which was found to promote hydroboration. Indeed, even in the conditions
promoting no hydroindation, namely, in the presence of a radical scavenger
(p-dinitrobenzene) and in the absence of Et3B, 23% of the product 6a was
still obtained by the hydroboration of 5a at room temperature. This result
suggests that the NaBH4-InCl3-promoted reaction at room temperature
includes hydroboration besides the Cl2InH-promoted radical hydroindation.
From these reasons, the NaBH4-InCl3 must be carried out below -30 °C
to effect hydroindation as the sole reaction.
(12) Typical Experimental Procedure of the Reduction of Enyne. The
10 mL round-bottom flask charged with InCl3 (0.442 g, 2.0 mmol) was
heated at 110 °C under reduced pressure for 1 h. After the system was
filled with nitrogen, MeCN (4 mL) and Et3SiH (2.0 mmol) were added and
the mixture was stirred at 0 °C for 5 min. Then enyne 7a (1.0 mmol) and
1 M Et3B in hexane (0.1 mL) were added, and the resulting mixture was
stirred at 0 °C for 2 h. After deionized water was added, the reaction mixture
was extracted with ether (10 mL x 3). The combined organic layer was
dried over MgSO4 and concentrated. The crude mixture was purified by
column chromatography to give cyclization product 8a (0.127 g, 53%).
Org. Lett., Vol. 6, No. 26, 2004
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