Regioselective carboindation of simple alkenes with indium tribromide and ketene silyl acetals

Article abstract of DOI:10.1021/ol1012108

(Equation Presented). The regioselective carboindation of simple alkenes with indium tribromide and ketene silyl acetals was accomplished. Various alkenes such as ethylene, 1-alkenes, and cyclic alkenes were applicable for this reaction system. The alkyli

Full text of DOI:10.1021/ol1012108

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3390-3393
Regioselective Carboindation of Simple
Alkenes with Indium Tribromide and
Ketene Silyl Acetals
Yoshihiro Nishimoto, Hiroki Ueda, Yoshihiro Inamoto, 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 May 26, 2010
ABSTRACT
The regioselective carboindation of simple alkenes with indium tribromide and ketene silyl acetals was accomplished. Various alkenes such
as ethylene, 1-alkenes, and cyclic alkenes were applicable for this reaction system. The alkylindium product from the carboindation of cyclohexene
revealed an anti addition mechanism.
The carbometalation of alkenes has an important role in
organic chemistry, because the resulting alkylmetals are
fundamental materials for diverse organic transformations.1
In particular, the use of simple and easily accessible alkenes
in the petrochemical industry would be quite practical.
However, almost all carbometalations of simple alkenes, in
contrast to other unsaturated compounds such as alkynes and
allenes, are restricted to the addition of feasible alkylmetal
nucleophiles like Grignard and organolithium reagents, which
strictly narrows the scope of both alkenes and nucleophiles.2
In addition, preparation of the starting alkylmetal substrates
is considerably taxing. Therefore, the development of car-
bometalation that can introduce functional groups has been
highly desired. Especially, carbometalation with metal eno-
lates has significant value, because it could furnish organo-
metallic compounds bearing carbonyl groups. However, there
are only a few examples of intramolecular reactions perhaps
to avoid undesired over-reactions.3,4 Herein, we describe the
intermolecular carbometalation of simple alkenes using
indium tribromide and ketene silyl acetals, wherein no
preparation of organoindium nucleophiles is required.
(2) For reviews, see: (a) Semmelhack, M. F. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991;
Vol. 4. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c) Negishi,
E.; Kondakov, D. Y. Chem. Soc. ReV. 1996, 25, 417. (d) Marek, I. J. Chem.
Soc., Perkin Trans. 1 1999, 535. (e) Fallis, A. G.; Forgione, P. Tetrahedron
2001, 57, 5899. (f) Ojima, I. In ComprehensiVe Organometallic Chemistry
III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford, UK, 2007;
(1) For reviews, see: (a) Knochel, P. In ComprehensiVe Organometallic
Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford,
UK, 2007; Vol. 9. (b) Hiyama, T. In ComprehensiVe Organometallic
Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier: Oxford,
UK, 2007; Vol. 11.
Vol. 10.
(3) (a) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63,
2442. (b) Kitagawa, O.; Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T.
J. Org. Chem. 1998, 63, 9470. (c) Kitagawa, O.; Fujiwara, H.; Suzuki, T.;
Taguchi, T.; Shiro, M. J. Org. Chem. 2000, 65, 6819
.
10.1021/ol1012108  2010 American Chemical Society
Published on Web 06/30/2010

A variety of allylindations of alkynes has been examined
due to high compatibility of indium species with functional
groups, in which effective activation of alkynes by generated
allylindium halide species is plausible.5 In contrast to alkynes,
carboindation of alkenes has been strictly limited to the
reaction with cyclopropenes or norbornenes bearing directing
groups (L) like a hydroxy one (eq 1).6 These facts indicate
that the activation of alkenes by allylindium halide species
is insufficient and that stronger Lewis acidity is required
for the activation. The introduction of organic ligands is the
analysis, which showed that indium added selectively at the
terminal olefin carbon (Figure 1). The geometry around the
Figure 1. X-ray crystallographic analysis and dimeric structure of
alkylindium 3aa. (In the dimeric structure, one molecule is shown
in black and the other is shown in red.)
indium atom is a distorted trigonal bipyramid, in which one
alkyl group and two bromine atoms occupy equatorial
positions, and a carbonyl oxygen atom and a bromine atom
of another molecule occupy axial positions. Bromine bridges
are used to construct the alkylindium dimer.
reason for decreasing the Lewis acidity. Therefore, the
formation of organoindium nucleophiles should be avoided
to achieve a practical carboindation of alkenes, which
promotes the type of reaction as shown in eq 2. In eq 2, it
is an important point that the activation of alkenes by indium
trihalide is followed by the reaction of nucleophiles. Quite
recently, we reported the carboindation of terminal alkynes
on the basis of a similar strategy.7 It was very surprising
and fortunate that the same concept could be applied to a
variety of alkenes, including internal ones, because the
reactivity of alkene had been considered to be far lower than
that of alkynes. To the best of our knowledge, this is the
first example of the carboindation of simple alkenes.
First, we treated InBr3 (1 mmol) with 1-octene 1a (3
mmol) and dimethylketene silyl acetal 2a (1.5 mmol) in
CH2Cl2 (2 mL) at room temperature. To our delight, the
desired carboindation smoothly proceeded in 2 h. After the
solvent was evaporated and the residue was washed with
hexane, the carboindation product 3aa was isolated as a white
solid in 70% yield based on InBr3 (eq 3). The structure of
3aa was successfully confirmed by X-ray crystallographic
This carboindation strongly depended on the counteranion
of indium(III). InBr3 gave the desired ester 4aa quantitatively
after the treatment with 1 M HBr of CH3COOH solution
(Scheme 1). InI3 also gave 4aa in 69% yield, while InF3,
Scheme 1. Effect of Indium Trihalides
(4) For a pioneering work of carbometalation of alkenes with zinc
enamides, see: (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. 1997,
36, 2491. (b) Nakamura, E.; Kubota, K.; Sakata, G. J. Am. Chem. Soc.
1997, 119, 5457. For a review, see: (c) Pe´rez-Luna, A.; Botuha, C.; Ferreira,
F.; Chemla, F. New J. Chem. 2008, 32, 594.
(5) For carboindation of alkynes and allenes, see: (a) Araki, S.; Imai,
A.; Shimizu, K.; Butsugan, Y. Tetrahedron Lett. 1992, 33, 2581. (b) Araki,
S.; Imai, A.; Shimizu, K.; Yamada, M.; Mori, A.; Butsugan, Y. J. Org.
Chem. 1995, 60, 1841. (c) Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1997,
62, 2318. (d) Ranu, B. C.; Majee, A. Chem. Commun. 1997, 1225. (e)
Fujiwara, N.; Yoshinori, Y. J. Org. Chem. 1999, 64, 4095. (f) Klaps, E.;
Schmid, W. J. Org. Chem. 1999, 64, 7537. (g) Salter, M. M.; Sardo-Inffiri,
S. Synlett 2002, 2068. (h) Lee, P. H.; Kim, S.; Lee, K.; Seomoon, D.; Kim,
H.; Lee, S.; Kim, M.; Han, M.; Noh, K.; Livinghouse, T. Org. Lett. 2004,
6, 4825. (i) Miura, K.; Fujisawa, N.; Hosomi, A. J. Org. Chem. 2004, 69,
2427. (j) Yanada, R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama, M.;
Yanada, K.; Takemoto, Y. AdV. Synth. Catal. 2005, 347, 1632. (k) Goeta,
A.; Salter, M. M.; Shah, H. Tetrahedron 2006, 62, 3582. (l) Miura, K.;
Fujisawa, N.; Toyohara, S.; Hosomi, A. Synlett 2006, 1883.
InCl3, and In(OTf)3 had no effect on the carboindation. Other
Lewis acids, such as boron, aluminum, and gallium trihalides,
gave no product because these harder Lewis acids strongly
interact with oxygen moieties in preference to alkenes.8 This
compatibility with functional groups is an advantage of
indium halides. These results showed that InBr3 has the most
suitable π-electrophilic Lewis acidity.
(6) For carboindation of activated alkenes, see: (a) Araki, S.; Nakano,
H.; Subburaj, K.; Hirashita, T.; Shibutani, K.; Yamamura, H.; Kawai, M.;
Butsugan, Y. Tetrahedron Lett. 1998, 39, 6327. (b) Araki, S.; Kamei, T.;
Igarashi, Y.; Hirashita, T.; Yamamura, H.; Kawai, M. Tetrahedron Lett.
1999, 40, 7999. (c) Araki, S.; Shiraki, F.; Tanaka, T.; Nakano, H.; Subburaj,
K.; Hirashita, T.; Yamamura, H.; Kawai, M. Chem.sEur. J. 2001, 7, 2784.
(7) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew. Chem.,
Int. Ed. 2009, 48, 4577.
As shown in Table 1, various types of 1-alkenes were
applicable to this reaction system. Styrene 1b gave the
(8) The results of other Lewis acids are shown in the Supporting
Information.
Org. Lett., Vol. 12, No. 15, 2010
3391

13-15). The reaction of the monosubstituted ketene silyl
acetal 2e with 1b at 50 °C yielded 4be in a 61% yield
(entry 16), while unsubstituted ketene silyl acetal was
found be inapplicable to this reaction system perhaps due
to its low nucleophilicity.9 Notably, the carboindation of
vinylsilane 1n proceeded with reverse regioselectivity to
furnish the product 4na (eq 4).
Table 1. Scope and Limitations of Alkenes 1 and Silyl Ketene
Acetals 2a
Selective carbometalation of ethylene remains a chal-
lenging problem because of a lack of polarity despite the
fact that ethylene is obviously the most fundamental
alkene. Notably, when InBr3 was treated with 2a under 1
and 10 atom of ethylene in CH2Cl2 at room temperature,
carboindation of ethylene took place in 61% and 94%
yields, respectively, without polymerization of ethylene
(Scheme 2).
Scheme 2. Carboindation of Ethylene
After an extensive survey of diverse multisubstituted
alkenes, we found that cyclic ones were applicable to this
reaction system, although acyclic ones could not been used
in this stage. Norbornene 1p gave stereoselectively the exo
product 4pa in 30% yield (eq 5).10 Cyclopentene 1q and
cyclohexene 1r also gave the desired products in 50% and
20% yields, respectively (eqs 6 and 7). To gain insight into
the reaction mechanism, we examined the X-ray crystal-
lographic analysis of alkylindium 3ra, which was obtained
as a white solid in 18% yield from the reaction under the
same conditions as eq 7 without the acid treatment.11 The
a InBr3 (1 mmol), 1 (1.5 mmol), 2 (1.5 mmol), CH2Cl2 (2 mL), 2 h.
b 2a (3 mmol). c 1d was added slowly for 10 min. d 1 (3 mmol). e Quench
by 1 M HCl of diethyl ether solution. f 1m (E/Z ) 88:12), 4ma (E/Z )
92:8). g Yields based on InBr3 were determined by 1H NMR spectroscopy.
h Diastereomer ratio 66:34. i Diastereomer ratio 57:43.
desired product 4ba in a quantitative yield (entry 1).
Reactions with other aromatic alkenes, 1c-e, successfully
proceeded with the exception of the nitro-substituted one,
1f (entries 2-5). Electron-rich alkene 1c quantitatively
yielded 4ca even at -20 °C. Vinyl naphthalene 1g and
4-phenyl-but-1-ene 1h also underwent carboindation to
furnish the corresponding esters in 74% and 70% yields,
respectively (entries 6 and 7). The use of vinyl cyclohex-
ane 1i resulted in a low yield due to its steric hindrance
(entry 8). Chloride and ether moieties tolerated the reaction
conditions (entries 9 and 10). In the reaction with 1,3-
diene 1l, a 1,2-addition selectively took place (entry 11).
When using 1,5-diene 1m, a carboindation of the terminal
alkene moiety occurred to give the predictable product
4ma in 95% yield (entry 12). Diverse disubstituted ketene
silyl acetals 2b-d gave satisfactory results (entries
structure indicates that carboindation proceeds in an anti
addition manner (Figure 2). Complex 3ra as well as 3aa
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Org. Lett., Vol. 12, No. 15, 2010

found to cause the bromination of alkylindium under mild
conditions (Scheme 4).13 Even alkenes bearing functional
Scheme 4. Bromination of Alkylindium
Figure 2. X-ray crystallographic analysis and dimeric structure of
alkylindium 3ra. (In the dimeric structure, one molecule is shown
in black and the other is shown in red.)
has a distorted trigonal bipyramidal structure, and bromine
bridges are used to construct the alkylindium dimer.
groups afforded the corresponding alkyl bromides 5a-c. This
method provided convenient access to functionalized com-
pounds that have been traditionally difficult to synthesize.
A plausible mechanism for the formation of alkylindium
3 is illustrated in Scheme 3. InBr3 effectively activates alkene
In summary, we have accomplished the carboindation of
simple alkenes using InBr3 and ketene silyl acetals, in which
InBr3 directly activates an alkene without the generation of
organoindium species via transmetalation between InBr3 and
a ketene silyl acetal. Successful application of internal
alkenes is a cornerstone of carboindation. In addition,
PhI(OAc)2 smoothly transformed produced alkylindiums to
the corresponding alkyl bromides. The mechanistic study is
currently underway in our laboratory.
Scheme 3. Plausible Mechanism
1 irrespective of the oxygen atoms of ketene silyl acetal
2. The positive charge, which is stabilized by the R1 group,
on the internal carbon atom of the double bond was
increased to accept the nucleophilic attack of 2 from the
opposite side of InBr3, and then alkylindium product 3
and Me3SiBr are generated. In the carboindation of
vinylsilane 1n, the stability of the positive charge at the
ꢀ-position to the silyl group reversed the regioselectivity
(eq 4). This anti addition is supported by the structure of
3ra. At this stage, syn addition via an indium enolate
species followed by isomerization to alkylindium 3ra was
ruled out because transmetalation between InBr3 and 2
was not observed under the reaction conditions. No
transmetalation is an important point in terms of the fact
that an organoindium species would not be so highly
π-electrophilic to activate alkenes.7,12 In addition, InBr3
would have a low oxophilicity and a high π-electrophilicity
in contrast to harder Lewis acids such as In(OTf)3, which
interact preferentially with oxygen moieties of ketene silyl
acetals or produced esters.
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research on Priority Areas (No. 18065015,
“Chemistry of Concerto Catalysis” and No. 20036036, “Syn-
ergistic Effects for Creation of Functional Molecules”) and for
Scientific Research (No. 19550038) from Ministry of Education,
Culture, Sports, Science and Technology, Japan. We thank Dr.
Nobuko Kanehisa (Osaka University) for the valuable advice
regarding X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures, and characterization data for all new compounds,
and CIF of 3aa, 3ra, and s1. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL1012108
(10) The stereochemistry of 4qa was confirmed by X-ray analysis of
the amide obtained by the reaction of 4qa with aniline.
(11) Reaction conditions: InBr3 (2 mmol), 1s (12 mmol), 2a (6 mmol),
CH2Cl2 (4 mL), rt, 6 h. Experimental procedures are shown in the Supporting
Information.
(12) (a) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem.
2007, 72, 8588. (b) Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2007,
9, 4931. (c) Nishimoto, Y.; Saito, T.; Yasuda, M.; Baba, A. Tetrahedron
2009, 65, 5462.
Finally, we developed the transformation of alkylindium
compounds to the corresponding alkyl bromides. After
examining various bromination reagents, PhI(OAc)2 was
(13) A bromonium ion generated from the reaction of PhI(OAc)2 with
a bromide ion probably caused the bromination of alkylindiums. NBS, Br2,
and PhIBr2 as well as PhI(OAc)2 gave the corresponding alkyl bromides,
although yields were low or moderate.
(9) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
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