Inter- and intramolecular radical couplings of ene-ynes or halo-alkenes promoted by an InCl3/MeONa/Ph2SiH2 system

Article abstract of DOI:10.1021/ol051114o

(Chemical Equation Presented) An effective generation of indium hydride (HInCl₂) under nonacidic conditions is achieved by transmetalation between Ph₂SiH₂ and InCl₂OMe. The presented system achieves the titled coupling reactions in a radical manner. In particular, the nonacidic character enables the applications to acid-sensitive inter- and intramolecular ene-yne couplings.

Full text of DOI:10.1021/ol051114o

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3093-3096
Inter- and Intramolecular Radical
Couplings of Ene-ynes or Halo-alkenes
Promoted by an InCl3/MeONa/Ph2SiH2
System
Naoki Hayashi, Ikuya Shibata, and Akio Baba*
Department of Applied Chemistry, Center for Atomic and Molecular Technologies
(CAMT), Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received May 12, 2005
ABSTRACT
An effective generation of indium hydride (HInCl2) under nonacidic conditions is achieved by transmetalation between Ph2SiH2 and InCl2OMe.
The presented system achieves the titled coupling reactions in a radical manner. In particular, the nonacidic character enables the applications
to acid-sensitive inter- and intramolecular ene-yne couplings.
The use of radical reactions in modern organic synthesis is
now well-established.1 Despite the disadvantages of toxicity
and difficulty in the removal of tin residues,2 the majority
of examples still rely on the use of tri-n-butyltin hydride
because of its high versatility.3,4 An alternative promising
radical reagent, dihalogenoindium hydride (HInX2), has been
recently found by us and other groups and can be generated
from indium(III) trihalides (InCl3 or InBr3) and metal
hydrides.5-8 At first, Bu3SnH had to be employed as a
hydride source,5 and then it was replaced by NaBH4,6
DIBAL-H,7 and then Et3SiH.8 While the advances have been
(4) For examples of Bu3SnH-initiator systems (Bu3SnH-Et3B, Bu3-
SnH-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.
(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) 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.
(8) Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981-
4983.
(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 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.
(3) 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.
10.1021/ol051114o CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/14/2005

Scheme 1
Table 1. Effects of Solvents and Silanes
entry
X
solvent
Si-H
yield (%)
1
2
3
4
5
6a
7b
8c
9d
10
11e
1
1
1
1
1
1
1
1
1
2
2
THF
Ph2SiH2
Et3SiH
66
0
8
0
0
0
0
0
0
MeCN
MeCN
hexane
CH2Cl2
THF
THF
THF
THF
THF
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
significant, all suffer from the strong reducing ability of the
hydride sources themselves and from the actions of byprod-
ucts. In the case of NaBH4, the generation of BH3 during
transmetalation becomes a serious problem in the reaction
with alkynes. We have recently developed an InCl3/Et3SiH
system that can achieve intramolecular cyclization of enynes.
This result strongly indicates the higher potentiality of indium
hydride over tributyltin hydride because such cyclization has
usually required transition metal catalysts under harsh
conditions. However, in the course of expanding the ap-
plication to various substrates, we met with serious problems
since enyne 3c and halo-alkene 5c gave no desired products,
although all starting substrates were consumed (Scheme 1,
eq 1). This is because Et3SiCl is the byproduct in transmeta-
lation of InCl3 with Et3SiH (eq 2). We have already reported
that enhanced Lewis acidity can be achieved by the
combination of silyl chloride and InCl3 (eq 3),9 which may
work to decompose substrates 3c and 5c or their products.
To overcome this serious problem we made an attempt using
an alkoxyindium that is generated in situ (eq 4). If the
alkoxyindium were transmetalated to dichloroindium hydride,
alkoxy silanes (Si-OR) would be the byproduct instead of
Et3SiCl. Thus, the formation of a strong acid system, InCl3/
Et3SiCl, can be avoided.
Herein we report a new method for generation of indium
hydride from alkoxy indium and expand the scope of
application to acid-sensitive reactions. In addition, the first
examples of intermolecular radical reaction between alkynes
and alkenes are presented.
Initially, we investigated the optimized conditions for the
radical reduction of ethynylbenzene (1) using InCl3/NaOMe/
hydrosilane system as summarized in Table 1. A mixture of
InCl3 (1 equiv) and NaOMe (1 equiv) was stirred in THF at
room temperature for 0.5 h to generate indium alkoxides.
To the resulting mixture were sequentially added Ph2SiH2
(1 equiv), the alkyne, and Et3B (0.1 equiv), and the mixture
was stirred at room temperature for 2 h to give the reduction
95
79
THF
a Without NaOMe. b AlCl3 was used instead of InCl3. c BF3 was used
instead of InCl3. d Without InCl3. e Without Et3B.
product, styrene, in 66% yield after the usual workup (Table
1, entry 1).10
The solvent and hydrosilane used were THF and Ph2SiH2,
respectively. Other solvents such as acetonitrile and hexane
promoted the reaction in low yields (entries 2-5), while
acetonitrile was the most effective solvent in the case of
the transmetalation between InCl3 and Et3SiH to give
HInCl2 and Et3SiCl.8 Other hydrosilanes (Ph3SiH, PhSiH3)
gave lower yields than Ph2SiH2 in THF. No reaction oc-
curred without the addition of NaOMe in THF (entry 6)
perhaps because of the sluggish transmetalation between
InCl3 and Ph2SiH2. Other metal alkoxides such as NaOtBu,
KOtBu, and NaOAc were less effective. Using typical Lewis
acids such as AlCl3 or BF3 instead of InCl3 also gave no
product (entries 7 and 8). Of course, no reduction took place
without InCl3 (entry 9). These results indicate that the
transmetalation between the In-OR bond and the Si-H bond
takes place under the optimized conditions. When 2 equiv
of Ph2SiH2 was used, product 2 was obtained in a higher
yield (entry 10). In addition, although the yield was slightly
lower, this reaction proceeded well without Et3B (entry
11).11
In the next stage, we carried out intramolecular radical
cyclizations of enynes under the optimized conditions
(Scheme 2, eqs 5-7). Heterocycles including oxygen or
nitrogen were obtained in good yields. Particularly, enyne
(10) For the generation of the In-C bond after the hydroindation, we
can detect â-iodostyrene by quenching with I2.
(11) We have already reported that the radical reaction of HInCl2 from
InCl3/Bu3SnH proceeded without any initiators because homolytic cleavage
of the In-H bond takes place easily. Hence, the InCl3/NaOMe/hydrosilane
system caused effective transmetalation to give HInCl2. On the contrary,
the previously reported system InCl3/Et3SiH required Et3B because of the
low concentration of indium hydride due to the slow transmetalation between
InCl3 and Et3SiH.
(9) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002, 58,
8227-8235.
3094
Org. Lett., Vol. 7, No. 14, 2005

Scheme 2. Cyclization of Enynes
Scheme 4. Plausible Cyclization Mechanisms
3c, which had afforded no cyclization product by the InCl3/
Et3SiH system, gave 4c in 81% yield (eq 7). Even in the
case of 3b bearing terminal alkene and alkyne moieties, a
similar cyclization took place in an acceptable yield. These
results indicate the low acidity of this system and the
characteristic interaction between the alkyne moiety with an
indium species.12
This low-acid system was found to be applicable to a
radical dehalogenation as effectively as already reported
indium hydride systems.6,8 Among the dehalogenation reac-
tions, Scheme 3 exemplifies intramolecular cyclizations of
halo-alkenes bearing acid-sensitive moieties. It is particularly
notable that the adduct 6c was obtained in 89% yield from
5c, which had been decomposed by the system of InCl3/Et3-
SiH in acetonitrile (eq 10). That the use of 50 mol % InCl3
was sufficient for this high yield suggests the possibility of
a catalytic reaction, although it is not completely achieved
in this stage.
Plausible cyclization mechanisms are illustrated in Scheme
4. The in situ-formed InCl2OMe is transmetalated with
Ph2SiH2 to give HInCl2, which affords an indium radi-
cal (•InCl2) by the easy cleavage of the In-H bond. No
direct reaction between InCl3 and Ph2SiH2 is taking place,
and also the participation of the transmetalation of InCl2-
OMe with Ph2SiH2 could be plausibly proposed on the
basis of the fact that no reaction proceeds without NaOMe.
The choice of solvent is important for the control of
the reaction. In THF, the formation of InCl2OMe and/or
the transmetalation between In-OMe and Si-H bonds
may be promoted effectively. Even if a small amount of
silyl chloride is generated, the strong coordination ability
of THF disturbs the interaction between the silyl chlo-
ride and indium species to depress the formation of a
strong Lewis acid. The resulting indium radical (•InCl2) adds
to the C-C triple bond to give vinyl radical A, which reacts
with the remaining alkene moiety to give cyclized radical
B. Finally, the radical B is hydrogenated by HInCl2.
Scheme 3. Cyclization of Halo-alkenes
In the reaction with organic halides, a similar radical chain
mechanism is plausible. When the reaction of the resulting
InCl2X and NaOMe is effectively achieved in situ, a catalytic
cycle is completed.
(12) Tin hydride is more reactive toward alkene than indium
hydride. Leusink, A. J.; Noltes, J. G. Tetrahedron Lett. 1966, 7, 335-
340.
Org. Lett., Vol. 7, No. 14, 2005
3095

desired product 8a was obtained in a moderate yield by using
excess alkene (Scheme 5, eq 11). More active secondary
alkyl iodide 7b reacted with methyl methacrylate to give 8b
in the presence of a catalytic amount (10 mol %) of InCl3
(eq 12). The intermolecular radical reaction of alkyne with
alkene was also enabled by detailed investigations to give
products 10a and 10b in 44 and 45% yields, respectively
(eqs 13 and 14). To the best of our knowledge, this is the
first example of intermolecular radical coupling between
alkynes and alkenes. When Bu3SnH was used instead of our
system, no intermolecular coupling product was obtained.
This failure may result from the higher reactivity of tin
hydride toward alkene because the hydrostannation product
of alkene was obtained in the intermolecular coupling of
alkyne with alkene.
Scheme 5. Intermolecular Radical Reactions
In conclusion, we developed an effective method for the
generation of indium hydride by using alkoxyindium formed
in situ. This system was able to prevent decomposition of
acid-sensitive substrates to achieve intermolecular ene-yne
couplings. The detailed mechanism is under investiga-
tion.
Acknowledgment. This research has been carried out at
the “Handai Frontier Research Center” and was supported
by the center of excellence (21COE) program “Creation of
Integrated EcoChemistry” of Osaka University and a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, 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.
Next, intermolecular radical reactions were carried out.
In the reaction of phenyl iodide (7a) with acrylonitrile, the
OL051114O
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Org. Lett., Vol. 7, No. 14, 2005