Direct coupling reaction between alcohols and silyl compounds: Enhancement of Lewis acidity of Me3SiBr using InCl3

Article abstract of DOI:10.1021/jo061512k

The combination of InCl₃ and Me₃SiBr provided an enhanced Lewis acid system that can be used to promote a wide range of direct coupling reactions between alcohols and silyl nucleophiles in non-halogenated solvents, such as hexane or MeCN. The enhanced Lewis acidity of this system was measured by the ¹³C NMR in terms of the coordination to an alcohol. Moreover, the interaction between Me₃SiBr and the In(III) species was revealed by ²⁹Si NMR spectral analysis. Highly chemoselective allylations toward a hydroxyl moiety over ketone and acetoxy ones have been demonstrated.

Full text of DOI:10.1021/jo061512k

Direct Coupling Reaction between Alcohols and Silyl Compounds:
Enhancement of Lewis Acidity of Me3SiBr Using InCl3
Takahiro Saito, Yoshihiro Nishimoto, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka,
Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
ReceiVed July 20, 2006
The combination of InCl3 and Me3SiBr provided an enhanced Lewis acid system that can be used to
promote a wide range of direct coupling reactions between alcohols and silyl nucleophiles in
non-halogenated solvents, such as hexane or MeCN. The enhanced Lewis acidity of this system was
measured by the 13C NMR in terms of the coordination to an alcohol. Moreover, the interaction between
Me3SiBr and the In(III) species was revealed by 29Si NMR spectral analysis. Highly chemoselective
allylations toward a hydroxyl moiety over ketone and acetoxy ones have been demonstrated.
Introduction
compounds, such as carbonyls, ethers, and alkenes, the C-C
bond formation by direct substitution of their hydroxyl groups
would be a quite important process to provide useful building
blocks in organic synthesis. However, the low leaving ability
of the hydroxyl group often retards the direct substitution.5
Lewis acid-promoted carbon-carbon bond formation is one
of the most important processes in organic syntheses. Classically,
Friedel-Crafts, ene, Diels-Alder, Mukaiyama, and Hosomi-
Sakurai reactions have been mediated by typical Lewis acids,
such as AlCl3, TiCl4, BF3‚OEt2, or SnCl4, in which the elements
used as Lewis acids have all its own characteristic features.1
Among them, group 13 elements, aluminum, and boron are the
most traditional and representative Lewis acids, but any practical
utilizations of indium species had been scarcely exploited
because of its lower Lewis acidity.2 Over the past decade, indium
species, however, have been paid much attention owing to their
moderate Lewis acidity and water tolerance, applying to catalytic
reactions under protic conditions.3 In a series of these reactions,
the protection of alcohols has been reported, but there are few
reports for the application for C-C bond formation using
alcohols.4 Since alcohols are common and important compounds
for natural products and key precursors for other functionalized
(3) (a) Frost, C. G.; Hartley, J. P. Mini-ReV. Org. Chem. 2004, 1, 1-7.
(b) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans. 1 2000,
3015-3019. (c) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 16-
22. (d) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347-2356. (e) Araki, S.;
Hirashita, T. In Main Group Metals in Organic Synthesis; Yamamoto, H.,
Oshima, K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Chapter 8, pp
323-386.
(4) (a) Chauhan, K. K.; Frost, C. G.; Love, I.; Waite, D. Synlett 1999,
1743-1744. (b) Ranu, B. C.; Dutta, P.; Sarkar, A. J. Chem. Soc., Perkin
Trans. 1 2000, 2223-2225. (c) Mineno, T. Tetrahedron Lett. 2002, 43,
7975-7978. (d) Chapman, C. J.; Frost, C. G.; Hartley, J. P.; Whittle, A. J.
Tetrahedron Lett. 2001, 42, 773-775. (e) Lee, S.-g.; Park, J. H. J. Mol.
Catal. A: Chem. 2003, 194, 49-52.
(5) For recent reports of transition-metal-catalyzed C-C bond formation
through direct substitution of allylic or propargylic alcohols with nucleo-
philes other than allylic ones, see: (a) Ozawa, F.; Okamoto, H.; Kawagishi,
S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124,
10968-10969. (b) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.;
Uemura, S. J. Am. Chem. Soc. 2002, 124, 11846-11847. (c) Luzung, M.
R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 15760-15761. (d) Manabe,
K.; Kobayashi, S. Org. Lett. 2003, 5, 3241-3244. (e) Kinoshita, H.;
Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085-4088. (f) Kimura,
M.; Mukai, R.; Tanigawa, N.; Tanaka, S.; Tamaru, Y. Tetrahedron 2003,
59, 7767-7777. (g) Kayaki, Y.; Koda, T.; Ikariya, T. Eur. J. Org. Chem.
2004, 4989-4993.
* To whom correspondence should be addressed. Tel: +81-6-6879-7384.
Fax: +81-6-6879-7387.
(1) For an excellent and comprehensive use of Lewis acids in organic
synthesis, see: Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH: Weinheim, Germany, 2000; Vols. 1 and 2.
(2) Olah, G. A.; Kobayashi, S.; Tashiro, M. J. Am. Chem. Soc. 1972,
94, 7448-7461.
10.1021/jo061512k CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/04/2006
8516
J. Org. Chem. 2006, 71, 8516-8522

In-Si-Catalyzed Direct Substitutions of Alcohols
TABLE 1. Allylation by Using Combined Lewis Acida
yield
(%)
entry
catalyst (mol %)
InCl3 (5)
InCl3 (5)
InCl3 (5) + Me3SiBr (10) hexane
Me3SiBr (10) hexane
InCl3 (5) + Me3SiBr (10) CH2Cl2
InCl3 (5) + Me3SiBr (10) toluene
InCl3 (5) + Me3SiBr (10) MeCN
InCl3 (5) + Me3SiBr (10) Et2O
InCl3 (5) + Me3SiBr (10) THF
solvent
conditions
1b
2
3
4
5
6
7
8
9
ClCH2CH2Cl 80 °C, 3 h
hexane
51
0
77
0
66
66
22
2
reflux, 8 h
rt, 2 h
rt, 8 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
FIGURE 1. Lewis acid-mediated allylation of alcohol.
0
a Reactions were carried out in a solvent (1 mL) with allylsilane 2 (2.0
mmol) and alcohol 1a (1.0 mmol). b See ref 15a.
Direct substitution of alcohols with allylsilane was first
demonstrated by Cella,6 which some groups have also devel-
oped.7 All examples, however, have required excessive amounts
of Lewis acids. To avoid the excessive use of acid, the hydroxy
moieties have to be transformed into their corresponding good
leaving groups, such as halogens or related moieties, before
treatment with nucleophiles (Figure 1).8-11 The development
of an efficient and practical method for the catalytic substitution
of alcohols is in demand and still a challenging goal.
version promoted by the combination catalyst of InCl3 and
Me3SiBr.16 Herein, we wish to report the systematic studies,
including NMR observation, of combined active species and
some characteristic applications to chemoselective reactions.
Results and Discussion
Although a few examples of catalytic allylations of alcohols
with allyltrimethylsilane were reported using such acids as HN-
1. Catalytic Allylation of Alcohols with Allyltrimethylsi-
lane. We have previously reported the direct allylation of
1-phenylethanol (1a) with allyltrimethylsilane (2) in 1,2-
dichloroethane at 80 °C in the presence of a catalytic amount
of InCl3 (Table 1, entry 1).15a When the solvent was changed
to hexane, no reaction was observed even under reflux condi-
tions (entry 2). To our delight, however, the combined use of
InCl3 and Me3SiBr as a catalyst was found to give the desired
product 3a in 77% yield at room temperature (entry 3). Since
Me3SiBr did not exhibit any catalytic ability on its own, the
combination was essential for the allylation (entry 4).17 It is
noteworthy that halogenated solvent was no longer requisite
because only moderate yield was obtained in CH2Cl2 (entry 5).
While the reaction in toluene gave 3a in 66% yield (entry 6),
the use of coordinative solvents resulted in low yields (entries
7-9). In particular, strong coordination of Et2O and THF
completely shut down the reaction. Other Lewis acids, such as
BF3‚OEt2, AlCl3, GaCl3, Yb(OTf)3,18 Sc(OTf)3, ZnCl2, BiCl3,19
12
(SO2F)2 and B(C6F5)3,10 these procedures are limited to the
employment of alcohols possessing strong cation-stabilizing
aromatic substituents.13,14 We have recently overcome this
problem by developing the InCl3-catalyzed direct substitution
of various alcohols.15 In any case of direct allylations, including
ours, the use of environmentally hazardous halogen-containing
solvents, such as dichloromethane or 1,2-dichloroethane, is
essential. In this context, the development of a new direct
substitution method of alcohols and the replacement of the
halogenated solvent are both very important objectives. Re-
cently, we have preliminarily developed a non-halogenated
(6) Cella, J. A. J. Org. Chem. 1982, 47, 2125-2130.
(7) (a) Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 43, 514-
517. (b) Toshimitsu, A.; Nakano, K.; Mukai, T.; Tamao, K. J. Am. Chem.
Soc. 1996, 118, 2756-2757. (c) Pilli, R. A.; Robello, L. G. Synlett 2005,
2297-2300. (d) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002,
1823-1826. (e) Gullickson, G. C.; Lewis, D. E. Aust. J. Chem. 2003, 56,
385-388. (f) Mu¨hlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005,
127, 9348-9349.
(8) (a) Dau-Schmidt, J.-P.; Mayr, H. Chem. Ber. 1994, 127, 205-212.
(b) Mayr, H.; Dau-Schmidt, J.-P. Chem. Ber. 1994, 127, 213-217. (c) Mayr,
H.; Pock, R. Tetrahedron 1986, 42, 4211-4214. (d) Yamamoto, Y.; Onuki,
S.; Yumoto, M.; Asao, N. Heterocycles 1998, 47, 765-780. (e) Yamamoto,
Y.; Onuki, S.; Yumoto, M.; Asao, N. J. Am. Chem. Soc. 1994, 116, 421-
422. (f) Yamamoto, Y.; Maruyama, K.; Matsumoto, K. J. Chem. Soc., Chem.
Commun. 1984, 548-549.
(16) Saito, T.; Yasuda, M.; Baba, A. Synlett 2005 1737-1739.
(17) Mukaiyama and we have reported the InCl3-Me3SiCl combined
Lewis acid catalyst for Hosomi-Sakurai, Friedel-Crafts, and Mukaiyama
aldol reaction in which the Lewis acidity of the silicon center would be
enhanced by the coordination of chlorine on silicon to the indium. See: (a)
Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002, 58, 8227-
8235. (b) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem.
2002, 1578-1581. (c) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett.
1998, 39, 6291-6294. (d) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron
1999, 55, 1017-1026. (e) Mukaiyama, T.; Ohno, T.; Nishimura, T.; Han,
J. S.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1991, 64, 2524-2527. (f)
Mukaiyama, T.; Ohno, T.; Han, J. S.; Kobayashi, S. Chem. Lett. 1991, 20,
949-952. For other reports of combination of indium and silicon, see: (g)
Lee, P. H.; Seomoon, D.; Kim, S.; Nagaiah, K.; Damle, S. V.; Lee, K.
Synthesis 2003, 2189-2193. (h) Lee, P. H.; Lee, K.; Sung, S.-y.; Chang,
S. J. Org. Chem. 2001, 66, 8646-8649. (i) Sakai, N.; Annaka, K.;
Konakahara, T. Tetrahedron Lett. 2006, 47, 631-634. (j) Bandini, M.;
Fagioli, M.; Melloni, A.; Umani-Ronchi, A. Synthesis 2003, 397-402.
(18) For a report of the combination of Yb(OTf)3-Me3SiCl or Yb-
(OTf)3-Me3SiOTf, see: Yamanaka, M.; Nishida, A.; Nakagawa, M. Org.
Lett. 2000, 2, 159-161.
(9) Schwier, T.; Rubin, M.; Gevorgyan, V. Org. Lett. 2004, 6, 1999-
2001.
(10) Rubin, M.; Gevorgyan, V. Org. Lett. 2001, 3, 2705-2707.
(11) Kim, S. H.; Shin, C.; Pae, A. N.; Koh, H. Y.; Chang, M. H.; Chung,
B. Y.; Cho, Y. S. Synthesis 2004, 1581-1584.
(12) Kaur, G.; Kaushik, M.; Trehan, S. Tetrahedron Lett. 1997, 38,
2521-2524.
(13) For example, HN(SO2F)2, B(C6F5)3, and InBr3 did not catalyze the
reaction of the acid-sensitive alcohol such as 1-phenylethanol.
(14) For reports of other catalytic substitution of alcohol, see: (a) Georgy,
M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180-
14181. (b) Marquet, J.; Moreno-Man˜as, M. Chem. Lett. 1981, 10, 173-
176.
(15) (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int.
Ed. 2004, 43, 1414-1416. (b) Yasuda, M.; Somyo, T.; Baba, A. Angew.
Chem., Int. Ed. 2006, 793-796. (c) Yasuda, M.; Yamasaki, S.; Onishi, Y.;
Baba, A. J. Am. Chem. Soc. 2004, 126, 7186-7187. (d) Yasuda, M.; Onishi,
Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66, 7741-7744.
(19) Recently, direct allylation of 1-phenylethanol (1a) was achieved
using BiCl3 in CH2Cl2. See: De, S. K.; Gibbs, R. A. Tetrahedron Lett.
2005, 46, 8345-8350.
J. Org. Chem, Vol. 71, No. 22, 2006 8517

Saito et al.
FIGURE 2. Screening of In(III) species and Me3SiX for the allylation of 1-phenylethanol (1a).
TABLE 2. Allylation of Various 1-Arylethanols by Using
and B(C6F5)3, hardly exhibited catalytic activity in hexane even
when combined with Me3SiBr.20
Combined Lewis Acida
To determine the optimal combination, screening of indium
and silyl species was undertaken using the reaction of 1-phen-
ylethanol (1a) with allylsilane 2 in hexane, and the results are
illustrated in Figure 2. A combination of InCl3 and Me3SiBr
gave the highest yield (77%), while the allylation with InBr3-
Me3SiCl17h,i and InBr3-Me3SiOTf systems was also effective.21
The use of Me3SiI resulted in lower yields of 3a along with
some side products because of its very high reactivity. In
contrast, the combination of InCl3 and Me3SiOTf could not
complete the allylation, and the starting alcohol was considerably
recovered. In general, Lewis acidity of Me3SiX is arranged in
the following order: Me3SiCl < Me3SiBr , Me3SiOTf <
Me3SiI.22 Therefore, the higher activity of the Me3SiOTf system
than that of Me3SiCl or Me3SiBr had been expected, but this
system exhibited only low activity. It is noteworthy that the
activity of the combined Lewis acid does not necessarily depend
on the Lewis acidity of the silicon. We believe that the
appropriate combination between indium and silicone species
is essential for the allylation, and that low oxophilicity and high
halophilicity of indium are the reasons of the reactivity observed.
On the whole, the combination of InCl3 and Me3SiBr can act
as the most active catalyst in this allylation system.
Allylation of 1-arylethanols 1 bearing various substituents
was investigated under the optimized conditions, and the results
are summarized in Table 2. The yield of allylated product 3a
increased up to 87% by slow addition of 1a to the solution of
3 equiv of allylsilane 2 at 50 °C (entries 1 and 2). The alcohols
1b and 1c bearing the electron-donating groups were allylated
in excellent yield (entries 3 and 4). The phenolic OH could
tolerate the allylation conditions, in which MeCN solvent was
required because of the poor solubility of 1d in hexane (entry
5). In this case, the high reactivity of 1d showed that the reaction
was unaffected by coordination of MeCN. Alcohols 1e-h
possessing halogen substituents also gave the allylated products
3e-h in high yields (entries 6-9). OTf-substituted alcohol 1i
could provide the desired product 3i, although severe conditions
were required (entry 10). A strong electron-withdrawing NO2
yield
(%)
entry
X
conditions
1
2b,c
3
H (1a)
rt, 2 h
77
87
91
>99
>99
92
>99
90
87
71
50 °C, 2 h
50 °C, 3 h
50 °C, 3 h
rt, 1 h
Me (1b)
OMe (1c)
OH (1d)
F (1e)
Cl (1f)
Br (1 g)
I (1h)
4c
5c,d
6
rt, 3 h
7c
reflux, 3 h
50 °C, 3 h
reflux, 3 h
50 °C, 6 h
reflux, 3 h
8
9
10c,e
11f
OTf (1i)
NO2 (1j)
19
a Reactions were carried out in hexane (1-2 mL) with allylsilane 2 (2.0
mmol), alcohol 1 (1.0 mmol), Me3SiBr (0.1 mmol), and InCl3 (0.05 mmol).
b A hexane solution of alcohol was added dropwise. c Allylsilane (3 mmol).
d MeCN was used as a solvent. e Me3SiBr (1.0 mmol). f Me3SiBr (0.2
mmol).
moiety strongly disturbed the reaction to give only 19% yield
(entry 11). Because the reactivity pattern observed is similar to
that of the allylation using benzylic chlorides8a or ethers8b
reported by Mayr, our system would also proceed via the SN1
mechanism.
Further, a variety of alcohols were subjected to allylation
using the InCl3-Me3SiBr system (Table 3). The tertiary and
primary benzylic alcohols 4a and 4b gave the corresponding
products 5a and 5b in 75 and 68% yields, respectively (entries
1 and 2). Benzhydrol (4c) was quantitatively transformed to
the allylated product 5c (entry 3). The yield of allylation of the
alcohol bearing ferrocenyl moiety 4d was increased to 94% in
MeCN (entry 4) as compared to the reaction in other solvents
(e.g., 12 and 58% yields in hexane and toluene, respectively16).
2-Cyclohexen-1-ol (4e) provided the desired product 5e in 81%
(entry 5). The allylation of 1-methyl-2-cyclohexen-1-ol (4f) took
place at the 3-position to give 5f in 98%. This result apparently
suggests the involvement of an allylic carbocation. The two
aliphatic alcohols, exo-norborneol (4g) and 1-adamantanol (4h),
gave the allylated products 5g and 5h, respectively (entries 7
and 8). Unfortunately, a simple aliphatic alcohol, such as
(20) See Supporting Information.
(21) Recently, direct allylation of alcohol using InBr3 was reported, but
only a dimeric ether was obtained by sole use of InBr3 (see ref 11).
(22) Dilman, A. D.; Ioffe, S. L. Chem. ReV. 2003, 103, 733-772.
8518 J. Org. Chem., Vol. 71, No. 22, 2006

In-Si-Catalyzed Direct Substitutions of Alcohols
TABLE 3. Scope of Allylation of Alcohol by Using Combined
Lewis Acida
TABLE 4. Coupling of Alcohol with Various Nucleophilesa
a Reactions were carried out in hexane (1-2 mL) with nucleophile 6
(2.0 mmol), alcohol 1a or 4c (1.0 mmol), Me3SiBr (0.1 mmol), and InCl3
(0.05 mmol). b Nucleophile (3 mmol). c Me3SiBr (0.2 mmol).
highly substituted products 7b, 8b, 7c, and 8c in exclusive
γ-addition manner (entries 3-6). Alkynylsilane 6d provided the
corresponding adducts 7d and 8d (entries 7 and 8). Selective
formation of allenes from propargylsilane 6e took place through
exclusive γ-addition (entries 9 and 10). The transformation of
allenylmethylsilane 6f into the dienes 7f and 8f was the first
demonstration under neutral conditions (entries 11 and 12).
3. Application to Chemoselective Reactions. Next, for an
application of the direct substitution of hydroxyl moieties, we
demonstrated saving steps in the allylation of hemiacetal. In
the total synthesis of pinolidoxin by Fu¨rstner and co-workers,
ribose derivative 9 was transformed into the allylated adduct
after the acetylation of both hydroxyl moieties, in which the
deprotection of another acetoxy moiety was required after the
allylation of the target acetal moiety.24 In contrast, in our catalyst
system, the direct transformation from the hemiacetal 9 into 10
could be achieved in a single step with high stereoselectivity,
in which the protection of the primary alcohol moiety was never
required (eq 1). We could have saved the protection and
deprotection steps by the use of the indium and silicon system,
although the yield is in a range similar to that of the multistep
one.
a Reactions were carried out in hexane (1-2 mL) with allylsilane 2 (2.0
mmol), alcohol 4 (1.0 mmol), Me3SiBr (0.1 mmol), and InCl3 (0.05 mmol).
b A hexane solution of alcohol was added dropwise. c Allylsilane (3 mmol).
d Allylsilane (4 mmol). e Me3SiBr (0.5 mmol). f MeCN was used as a
solvent.
2-octanol (4i), was not applicable for the reaction system (entry
9). Even the direct allylation of a hemiacetal, which has a high
reactivity due to the formation of an oxocarbenium ion, has
been reported to require an excess amount of acids.23 In contrast,
our system catalytically promoted the allylation of hemiacetal
4j in high yield (entry 10).
2. Substitution of Alcohols with Various Silyl Nucleophiles.
A series of silyl nucleophiles 6, including allylic, allenyl,
alkynyl, and propargyl moieties, were allowed to react with
1-phenylethanol (1a) or benzhydrol (4c) in non-halogenated
solvent using the combination of InCl3 and Me3SiBr (Table 4).
Methallylation of 1a and 4c with 6a furnished the desired
products 7a and 8a in high yields, although 20 mol % of Me3-
SiBr was required in the case of 1a (entries 1 and 2). It is
interesting that γ-substituted allylsilanes 6b and 6c gave the
On the basis of this result, we tried to compare the reactivity
between hydroxyl moieties and acetoxy ones. Gevorgyan et al.
reported that a B(C6F5)3 catalyst readily promoted the allylation
of an acetoxy moiety, while the reaction toward hydroxyl
moieties hardly took place.10 Apparently, acetylation is again
an important step in increasing the leaving ability of a hydroxyl
(23) For a review on the substitution of OH in hemiacetal, see: (a)
Harmange, J-.C.; Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711-
1754. For a recent report of the stereoselective reaction, see: (b) Schmitt,
A.; Reissig, H.-U. Eur. J. Org. Chem. 2001, 1169-1174. (c) Schmitt, A.;
Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893-3901. (d) Schmitt, A.;
Reissig, H.-U. Chem. Ber. 1995, 128, 871-876. (e) Smith, D. M.; Woerpel,
K. A. Org. Lett. 2004, 6, 2063-2066.
(24) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C.
W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069.
J. Org. Chem, Vol. 71, No. 22, 2006 8519

Saito et al.
TABLE 5. Effect of Lewis Acids on the Chemical Shifts, δ(13C), of
the r-Carbon in 1-Octanola
SCHEME 1. Higher Reactivity toward Alcohol over Acetate
entry
Lewis acid
none
Me3SiCl
Me3SiBr
InCl3
InBr3
InCl3 + Me3SiCl
InCl3 + Me3SiBr
InBr3 + Me3SiCl
InBr3 + Me3SiBr
δ(13C)/ppm
∆δ(13C)/ppm
1
2
3
4
5
6
7
8
9
62.7
62.8
64.0
65.2
65.2
66.0
66.3
67.4
70.2
0
+0.1
+1.3
+2.5
+2.5
+3.3
+3.6
+4.7
+7.5
SCHEME 2. Competitive Reaction between Alcohol and
Ketone
a 1-Octanol and Lewis acids (1.0 M each) in MeCN at room temperature.
of 1-octanol in the mixture with InX3 and Me3SiX, as noted in
Table 5.29 Reasonable downfield shifts of the R-carbon which
represent the strength of their acidity were observed in the
presence of Lewis acids, such as Me3SiCl, Me3SiBr, InCl3, or
InBr3 (entries 2-5), which indicates that these species act as
moderate Lewis acids. In comparison to these values, combined
Lewis acid systems caused larger downfield shifts (entries 6-9),
and particularly, the combination of InBr3 and Me3SiBr showed
the largest value examined (+7.5 ppm, entry 9). This result
indicates that this combination would act as the most effective
catalyst. However, this InBr3-Me3SiBr system gave a slightly
lower yield relative to that of the InCl3-Me3SiBr system perhaps
because of the instability of stronger Lewis acid (Figure 2).
Therefore, the suitable combination, InCl3/Me3SiBr, should be
chosen to accomplish the reaction.
Next, 29Si NMR studies were performed. Upon mixing with
equimolar amounts of Me3SiBr and InCl3 (1.0 M each), a facile
halogen exchange gave a broadened signal of Me3SiCl at around
33.0 ppm ((iii) in Figure 3).30 In the combination of Me3SiCl
and InBr3, only the signal corresponding to Me3SiCl was
broadened ((iv) in Figure 3). Therefore, this broadening plausibly
indicates the range of interaction between Me3SiCl and In(III)
halide 15, as shown in Scheme 3.17a,e,31 A mixing of Me3SiBr
and InBr3, which caused the most downfield shift of the
R-carbon of the alcohol, noted in Table 5, gave the most
broadened signal of Me3SiBr ((v) in Figure 3). This interaction
is weakened at low temperature because the signal became
sharp.20 In the case of AlCl3 and BF3‚OEt2, halogen exchange
with Me3SiBr also took place at room temperature. The
generated Me3SiCl and Me3SiF, however, do not seem to
moiety. As aforementioned, 1-phenylethanol (1a) was success-
fully allylated with the InCl3-Me3SiBr system. We interestingly
found the fact that no reaction took place in the allylation of
1-phenylethyl acetate (11) by our catalytic system, as shown in
Scheme 1.25 Under the conditions optimized for the direct
allylation of 1-phenylethanol (77% yield), no substitution of
the acetoxy moiety was observed. Consequently, the InCl3-
Me3SiBr system has reversed chemoselectivity to general
procedures.
Since the predominant reactivity toward hydroxy moieties
over acetoxy ones was demonstrated, we next focused on the
difference in the reactivity between the hydroxyl and ketone
moieties (Scheme 2). When we treated allyltrimethylsilane (2)
with an equimolar amount of 1-phenylethanol (1a) and p-
chloroacetophenone (12) in the presence of a catalytic amount
of InCl3 and Me3SiBr, the alcohol 1a was exclusively allylated
in contrast to complete recovery of the starting ketone 12. This
result is very interesting because we have already reported how
the InCl3/Me3SiCl system effected the allylation of ketones.17a,b
The combined catalyst apparently activated a hydroxyl moiety
far more strongly than a ketone. In contrast, Bu4NF, which is a
representative and effective catalyst for the allylation of carbonyl
compounds,26 promoted the exclusive allylation of ketone 12.
The catalyst systems of InCl3-Me3SiBr and Bu4NF were found
to be complementary to each other. On the other hand, a
representative Lewis acid, TiCl4, gave a complicated mixture,
including 45% of the double allylated product 14 of ketone, in
which alcohol 1a was completely consumed.27,28
(29) We did not use hexane as a solvent owing to the poor solubility of
InCl3. When AlCl3 or BF3‚OEt2 instead of InX3 was used in MeCN, these
NMR charts were complicated by the concomitant formation.
From these results, it is apparent that the combined system
of InCl3 and Me3SiBr makes possible the selective activation
of alcohols over ketones.
(30) In the presence of 1-octanol, the similar broadening of the
combination of Me3SiCl and InCl3 on 29Si NMR in MeCN was observed.
(31) For reports of silylium ion, see: (a) Kim, K.-C.; Reed, C. A.; Elliott,
D. W.; Mueller, L. J.; Tham, F.; Lin, L.; Lambert, J. B. Science 2002, 297,
825-827. (b) Lambert, J. B.; Zhao, Y. Angew. Chem., Int. Ed. Engl. 1997,
36, 400-401. (c) Lambert, J. B.; Lin, L. J. Org. Chem. 2001, 66, 8537-
8539. (d) Lambert, J. B.; Zhao, Y.; Zhang, S. M. J. Phys. Org. Chem. 2001,
14, 370-379. Gabba¨ı et al. reported a working model in which the mercury
atom on Me3SiCl is activated by coordination of bidentate mercury Lewis
acid and the interaction between Ga(III) and Cl on Sn(IV) was confirmed
by X-ray single-crystal analysis: (e) King, J. B.; Gabba¨ı, F. P. Organo-
metallics 2003, 22, 1275-1280. (f) Tschinkl, M.; Hoefelmeyer, J. D.;
Cocker, T. M.; Bachman, R. E.; Gabba¨ı, F. P. Organometallics 2000, 19,
1826-1828.
4. NMR Study. The enhanced Lewis acidity was confirmed
by monitoring the NMR chemical shifts, δ(13C), of the R-carbon
(25) 1-Phenylethyl acetate (11) and 1-phenylethanol (1a) were obtained
in 75 and 12% yields, respectively.
(26) Hosomi, A.; Shirahata, A.; Sakurai, H. Tetrahedron Lett. 1978, 33,
3043-3046.
(27) When an equimolar amount of titanium(IV) chloride was used, only
chlorination of alcohol was promoted.
(28) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 16, 1295-1298.
8520 J. Org. Chem., Vol. 71, No. 22, 2006

In-Si-Catalyzed Direct Substitutions of Alcohols
combined system, we propose a plausible mechanism using the
reaction of 1-phenylethanol (1a) with allyltrimethylsilane (2)
catalyzed by InCl3/Me3SiBr (Scheme 3). At first, the combined
Lewis acid 1532 activates the hydroxyl moiety by strong
coordination to the silicone center to promote the formation of
carbocation 16. Addition of allylsilane 2 to the cation 16 gives
the allylated product 3a with regeneration of the combined
catalyst,33 consequently completing the catalytic cycle of the
direct allylation of alcohols. When alcohol 1a reacted with the
cation 16, dimeric ether 17 would be produced.34 The ether may
be incorporated in this allylation when the combined Lewis acid
activated the ether. The optimized reaction conditions, however,
required an excess amount (2-fold) of silyl compounds. In
addition, in some cases, slow and dropwise addition of the
alcohol was essential for high yields (entry 2 in Table 2, entries
1 and 2 in Table 3). These results plausibly suggest that the
direct attack of 2 to the cation 16 is favorable for the effective
substitution of alcoholic hydroxyl moieties. An additional
important factor for the completion of the catalytic cycle is the
low oxophilicity and high halophilicity of indium halides
because high oxophilicity disturbs the regeneration of the
combined catalyst. Perhaps AlCl3 is the case of high oxophilicity
and has no catalytic ability.
To confirm the low oxophilicity of InCl3 for regenerating
the combined catalyst, the interaction between Me3SiOMe and
some Lewis acids was monitored with 29Si NMR.20 No
interaction was observed in the mixture of indium halide and
Me3SiOMe, while the reaction with AlCl3 or BF3‚OEt2 rapidly
took place to give Me3SiCl or Me3SiF, respectively. The strong
oxophilicity of Al and B species disturbs the regeneration of
the catalytic species in contrast to the indium-silicone system.
These results, including Figure 3, also represent the strong
halophilicity enough to enhance the Lewis acidity of the silicon
center.
FIGURE 3. 29Si NMR spectra of the mixture of Me3SiX and Lewis
acids in MeCN at room temperature (79 MHz, TMS external standard).
Conclusion
SCHEME 3. Plausible Mechanism
A direct allylation of alcohols was established by using InCl3
and Me3SiBr. This combination catalyst was essential for the
reaction in a non-halogenated solvent and applied to the reaction
of a wide range of alcohols and silyl nucleophiles, such as
methallyl-, cinnamyl-, prenyl-, alkynyl-, propargyl-, allenyl, and
allenylmethylsilane. We also demonstrated the predominant
allylation to a hydroxyl moiety over ketone and acetoxy ones.
It was proved that In(III) exhibited specific characteristics of
high halophilicity and low oxophilicity.
Experimental Section
Typical Procedure for Allylation of 1a (Table 1, Entry 3).
To a mixture of InCl3 (0.05 mmol) and 1-phenylethanol (1a, 1.0
mmol) in hexane (1 mL) were added allyltrimethylsilane (2, 2.0
mmol) and Me3SiBr (0.1 mmol) under nitrogen. The reaction
mixture was stirred under the reaction conditions noted in the text.
The resulting mixture was poured into Et2O (50 mL) and aqueous
NaHCO3 (30 mL). The solution was extracted with Et2O, and the
organic layer was dried over MgSO4. The evaporation of the ether
interact with aluminum or boron halides because of the
observation of the sharp signal ((vi) and (vii) in Figure 3). This
is perhaps the reason why the InCl3-Me3SiBr system is more
effective than AlCl3-Me3SiBr, as the catalytic activity depends
on the interaction.
(32) The halogen exchange between Me3SiBr and InCl3 was also
observed in hexane as well as MeCN.
(33) An SN1 mechanism is also supported by the result that racemization
took place in the direct allylation of enantiomerically pure 1-phenylethanol;
see Supporting Information.
(34) In fact, a small amount of ether 17 can be observed when the reaction
was quenched in the early stage.
5. Possible Mechanism. On the basis of the discussions
involving cation species and the strong Lewis acidity of the
J. Org. Chem, Vol. 71, No. 22, 2006 8521

Saito et al.
solution gave the crude product, which was analyzed by NMR.
The details of further purification performed for the new compounds
are described in Supporting Information.
Allylation by Slow Addition of 1a (Table 2, Entry 2). To a
mixture of InCl3 (0.05 mmol), Me3SiBr (0.1 mmol), and allyltri-
methylsilane (2, 3.0 mmol) in hexane (1 mL) was slowly added a
solution of 1-phenylethanol (1a, 1.0 mmol) in hexane (1 mL) for
10 min under nitrogen. The reaction mixture was stirred under the
reaction conditions noted in the text. The workup employed is the
same as that described in the typical reaction procedure.
Allylation of 9 (eq 1). To a mixture of InCl3 (0.05 mmol) and
alcohol 9 (1.0 mmol) in 1,2-dichloroethane (2 mL) were added
allyltrimethylsilane (2, 4.0 mmol) and Me3SiCl (0.5 mmol) under
nitrogen. The reaction mixture was stirred at 80 °C for 3 h. The
workup employed is the same as that described in the typical
reaction procedure.
Competitive Reaction between 1a and 12 Using the InCl3/
Me3SiBr System (Scheme 2). To a solution of 1-phenylethanol
1a (1 mmol) and p-chloroacetophenone 12 (1 mmol) in hexane (2
mL) were added allyltrimethylsilane (2, 2.0 mmol) and Me3SiBr
(0.1 mmol) under nitrogen. The reaction mixture was stirred under
reflux for 6 h. The resulting mixture was poured into Et2O (50
mL) and aqueous NaHCO3 (30 mL). The solution was extracted
with Et2O, and the organic layer was dried over MgSO4. The solvent
was evaporated, and the residue was purified by TLC (hexane/
AcOEt, 95/5, Rf ) 0.72 and 0.22) affording 3a (65%) and 12 (99%).
Competitive Reaction between 1a and 12 Using Bu4NF
(Scheme 2).26 To a mixture of Bu4NF (0.05 mmol), 4 Å molecular
sieves (25 mg), 1-phenylethanol 1a (1 mmol), and p-chloroaceto-
phenone 12 (1 mmol) in THF (4 mL) was added allyltrimethylsilane
(2, 3.0 mmol) under nitrogen. The reaction mixture was stirred
under reflux for 3 h. After treatment of the reaction mixture with
MeOH (5 mL) and 1 N HCl (5 mL) at room temperature for 30
min, the solution was extracted with Et2O, and the organic layer
was dried over MgSO4. The solvent was evaporated, and the residue
was purified by TLC (hexane/AcOEt, 80/20, Rf ) 0.28 and 0.44)
affording 1a (99%) and 13 (99%).
Competitive Reaction between 1a and 12 Using TiCl4 (Scheme
2).28 To a solution of a 1-phenylethanol 1a (1 mmol) and
p-chloroacetophenone 12 (1 mmol) in dichloromethane (2 mL) was
added TiCl4 (3 mmol) dropwise with a syringe at 0 °C. After stirring
for 5 min, allyltrimethylsilane (2, 3 mmol) was added to the mixture.
The reaction mixture was stirred at 0 °C f room temperature for
30 min. The resulting mixture was poured into Et2O (50 mL) and
water (30 mL). The solution was extracted with Et2O, and the
organic layer was dried over MgSO4. The solvent was evaporated,
and the residue was purified by TLC (hexane/AcOEt, 95/5, Rf )
0.67) affording 14 (45%).
Acknowledgment. This research has been carried out at
Handai Frontier Research Center and was supported by the
Sumitomo Foundation and a Grant-in-Aid from the Ministry
of Education, Culture, Sports, Science and Technology. T.S.
acknowledges a Research Fellowship of the Japan Society for
the Promotion of Science for Young Scientists.
Supporting Information Available: Reaction procedure, NMR
study, and spectroscopic details of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO061512K
8522 J. Org. Chem., Vol. 71, No. 22, 2006