Indium(i)-catalyzed alkyl-allyl coupling between ethers and an allylborane

Article abstract of DOI:10.1039/c0cc03673k

An efficient method for alkyl-allyl cross-coupling between ethers and a 9-BBN-derived allylborane catalyzed by indium(i) triflate has been developed. The allylborane proved to be essential to obtain the desired products in high yields. The reaction displayed good substrate scope including high functional group tolerance. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c0cc03673k

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Indium(I)-catalyzed alkyl–allyl coupling between ethers
and an allylboranew
Hai Thanh Dao, Uwe Schneider and Shu¯ Kobayashi*
Received 5th September 2010, Accepted 1st November 2010
DOI: 10.1039/c0cc03673k
An efficient method for alkyl–allyl cross-coupling between ethers
and a 9-BBN-derived allylborane catalyzed by indium(I) triflate
has been developed. The allylborane proved to be essential to
obtain the desired products in high yields. The reaction displayed
good substrate scope including high functional group tolerance.
Csp3–Csp3 cross-coupling is a challenging task in organic
synthesis.1 While main group metal-catalyzed alkyl–allyl
Scheme 1 Dual activation concept for nucleophilic substitution with
coupling reactions are relatively underexplored, this trans-
formation is typically conducted under Lewis acid catalysis
between secondary benzylic or allylic halides2 or acetates3 and
allyl silicon,2a,3 tin2a or indium2b nucleophiles. Ether substrates
are more desirable than the corresponding halides, because they
are readily available and more stable building blocks for complex
synthesis. Straightforward modification of these synthetic
handles through catalytic C–C coupling under mild conditions
is therefore worthwhile. However, the activation of aliphatic
ethers is considerably more challenging because of the relatively
strong CÀO bond and the poor leaving ability of the OR
component.4,5 Thus, there have been only sporadic examples
for reactions of aliphatic ethers employing Lewis acids.2a,4,6
Non-toxic boron reagents are of high importance for C–C
bond-forming reactions.7 In this context, allylic boron compounds
have been extensively studied for uncatalyzed allylations with
Csp2-type electrophiles such as carbonyl compounds and imines.8
Recently, metal-catalyzed activation of allylic boron reagents for
these transformations has also been explored by us and others.9
Although boron-based reagents might provide interesting reactivity
because of their intrinsic properties, there are only limited examples
using these reagents for coupling with Csp3-type electrophiles.10
In our earlier report,11 we disclosed a general catalytic
method for allylation of acetals and ketals with allylboronates.
To the best of our knowledge, this work represents the first
activation of allylboronates for C–C bond formation with
non-carbonyls facilitated by a main group metal catalyst.
We subsequently aimed at promoting the more challenging
coupling reaction with ethers (Scheme 1).
allylic boron reagents.
Scheme 2 Alkyl–allyl cross-coupling with allylboronate 2a.
energy barrier, we then used Lewis acid co-catalysts in addition to
InOTf; however, all attempts were unsuccessful.14 We reasoned
that, in the presence of these stronger Lewis acids, activation of the
CÀO bond might have occurred to afford the corresponding
metal methoxide species, but that, in contrast to InOMe, these
intermediates might not be able to deliver the required
methoxide to activate allylboronate 2a.
Bearing in mind this difficulty, we next changed our strategy
from ether activation to facilitating activation of the boron-based
reagents. We envisioned that
a more Lewis-acidic boron
compound might result in a faster transmetalation, and thus
acceleration of the catalytic cycle. To our delight, when
9-BBN-derived allylborane 2b was employed, the desired C–C
bond-forming reaction with 1a proceeded smoothly to provide the
allylated product 3a in full conversion with a high isolated yield
(Table 1). This result may be explained by the significantly more
Lewis-acidic boron atom of 2b compared with that of allyl-
boronate 2a. As for solvents, excellent conversions were observed
in nonpolar solvents such as DCM, CDCl3, toluene, benzene and
hexane, while no reaction occurred in Lewis-basic or polar
solvents such as THF or MeCN. Strikingly, reactions employing
various other conventional allyl reagents including borate 2c,
Grignard reagent 2d, silanes 2e–g and stannane 2h did not provide
any desired product or only afforded very low yields of 3a even
after extended reaction times. These results highlight the remark-
able reactivity of allylborane 2b compared with other allyl
reagents. It is noted that metal triflates other than InOTf were
found to be significantly less efficient, or did not afford the desired
In initial experiments, we conducted the reactions of ethers 1
with allylboronate 2a under the same conditions as those reported
in the acetal allylation (Scheme 2).11 Although certain indium(I)
triflate-catalyzed12 transformations afforded the desired cross-
coupling products 3, the substrate scope was limited and yields
were low.13 We thought that these disappointing results might be
ascribed to the strong CÀO bond of ethers. To overcome this high
Department of Chemistry, School of Science and Graduate School of
Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of new materials. See DOI: 10.1039/
c0cc03673k
c
692 Chem. Commun., 2011, 47, 692–694
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Table
allyl reagents
1
Alkyl–allyl cross-coupling: allylborane 2b vs. other
Table 2 Substrate scope and limitationsa
a Conversion of 1a to 3a was determined by 1H NMR spectroscopic
analysis of aliquots of the reaction mixtures. b Conversion was less
than 20% after 14 h. c InOTf (1 mol%), DCM (0.5 M), rt, 90 min;
isolated yield of 3a after purification on silica gel (PTLC): 86%. d No
trace of 3a even after 14 h. e Grignard reagent (1 M in ether) was used.
f Conversion was less than 5% after 18 h.
product.15 Reactions using strong Lewis acids such as Al(OTf)3
and In(OTf)3 might suffer from side reactions, while other metal
triflates such as Mg(OTf)2 and Zn(OTf)2 might not activate the
CÀO bond successfully, or the corresponding methoxide inter-
mediates might not be able to deliver the required Lewis base to
activate allylborane 2b.
Next, we investigated the scope and limitations of this catalytic
system (Table 2). Gratifyingly, it was found that the present
alkyl–allyl cross-coupling showed good substrate generality with
various primary, secondary and tertiary benzylic, allylic and
propargylic ethers, providing the corresponding allylated products
in moderate to excellent yields (entries 1–18). It is noted that
secondary ethers underwent smooth allylation at room tempera-
ture in a short reaction time, while harsher conditions and longer
reaction times were needed for the allylation of primary substrates.
For tertiary and other reactive ethers, lower temperatures were
necessary to prevent side reactions such as the Friedel–Crafts
reaction, elimination and other related transformations.
Although unactivated non-benzylic ethers were not suitable
in this indium(I) catalysis (entry 19), compounds such as
homobenzylic ether 1t and tertiary ether 1u16 gave the desired
products in good yields (entries 20 and 21). Importantly,
a heteroaromatic moiety and functional groups such as
aromatic bromo or methoxy and aliphatic chloro groups were
tolerated under these mild conditions.
a
Isolated yields of 3 after purification on silica gel (PTLC) or column
chromatography. b Neat, 60 1C, 48 h.
Lewis acid to activate the CÀO bond of ethers 1, we propose a
transmetalative SN1 mechanism, in which indium(I) plays a
dual role,11 as shown in Scheme 3. First, InOTf acts as a Lewis
acid to activate the CÀO bond to form carbenium ion species
A and InOMe. The in situ formed InOMe then triggers B-to-In
Although we cannot definitely exclude the possibility that
the Lewis-acidic boron atom of 2b may act as a stoichiometric
c
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Scheme 3 Proposed reaction mechanism.
transmetalation of borane 2b to generate the allylic indium(I)
species B, which reacts with A to give the desired cross-coupling
product 3. The substantially improved reactivity switching from
allylboronate 2a to allylborane 2b can be explained by: (1) the
Lewis acidity of the boron atom of borane 2b is much higher than
that of boronate 2a; thus, allylborane 2b would have a significantly
higher affinity toward the in situ formed methoxide to generate the
ate complex C, which might drive the equilibrium of the first step
to the right side, that is, the formation of A. (2) Ate complex C
might undergo faster transmetalation than the corresponding ate
complex D derived from 2a.17 However, at this stage, we cannot
rule out a nontransmetalative pathway, which would involve the
direct reaction of ate complex C with electrophile A.18
In conclusion, we have developed an efficient indium(I)-
catalyzed alkyl–allyl coupling reaction between ethers and an
allylborane, which is therefore clearly distinguished from our
earlier work with allylboronates.9e,9f,9h,11 In addition, this
transformation represents a rare example of (1) a main group
metal-catalyzed alkyl–allyl cross-coupling using boron-based
reagents, and (2) the use of an allylborane for CÀC bond
formation with non-carbonyl electrophiles.19 We believe that
these findings will significantly expand the utility of allylboranes in
various domains of organic synthesis. Further investigations
include mechanistic studies and the development of new
transformations by means of non-toxic boron reagents.
This work was partially supported by a Grant-in-Aid for
Science Research from JSPS, the Global COE Program, The
University of Tokyo, MEXT, Japan, ERATO (JST) and NEDO.
10 For an example of an in situ formed boron reagent for nucleophilic
substitution of alcohols, see: G. W. Kabalka, Z. Wu and Y. Ju,
Org. Lett., 2004, 6, 3929.
11 U. Schneider, H. T. Dao and S. Kobayashi, Org. Lett., 2010, 12, 2488.
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13 The reactions did not occur at all in the absence of InOTf.
14 Combination of InOTf (10 mol%) with 10 mol% of In(OTf)3,
InCl3, or GaCl3 provided messy reaction mixtures.
15 Conditions: catalyst (5 mol%), DCM (0.5 M), rt, 3 h; catalysts and
corresponding yields: InOTf (85%), In(OTf)3 (45%), Ga(OTf)3
(41%), Hf(OTf)4 (35%), AgOTf (26%), Cu(OTf)2 (26%), Al(OTf)3
(25%), Fe(OTf)2 (12%), Zn(OTf)2 (NR), Mg(OTf)2 (NR),
TMSOTf (43%), HOTf (12%); conditions for TMSOTf and
HOTf: catalyst (10 mol%), DCM (0.5 M), À78 1C to rt, 3 h.
16 The assumed intermediate in the reaction with 1u, adamantyl
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´
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5 With only a few exceptions, allylation of allylic and benzylic
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c
694 Chem. Commun., 2011, 47, 692–694
This journal is The Royal Society of Chemistry 2011