Direct synthesis of water-tolerant alkyl indium reagents and their application in palladium-catalyzed couplings with aryl halides

Article abstract of DOI:10.1002/anie.201005798

A direct result: Alkyl indium reagents are synthesized by the insertion of indium into alkyl halide mediated by CuCl. The synthetic utility of these reagents is demonstrated by their palladium-catalyzed coupling with aryl halides (see scheme). The reagents are compatible with various functional groups, and this makes the protocol generally useful in organic synthesis. DMA=N,N-dimethylacetamide, TBS=tert-butyldimethylsilyl.

Full text of DOI:10.1002/anie.201005798

DOI: 10.1002/anie.201005798
Organoindium Reagents
Direct Synthesis of Water-Tolerant Alkyl Indium Reagents and Their
Application in Palladium-Catalyzed Couplings with Aryl Halides**
Zhi-Liang Shen, Kelvin Kau Kiat Goh, Yong-Sheng Yang, Yin-Chang Lai,
Colin Hong An Wong, Hao-Lun Cheong, and Teck-Peng Loh*
Organometallic reagents involving magnesium and zinc have
found widespread applications in organic synthesis and have
revolutionized the field of organometallic chemistry.[1] How-
ever, the incompatibility of organomagnesium and organo-
zinc reagents with certain functional groups, such as carbonyl
and hydroxyl, have limited their utility in organic synthesis. In
comparison, the recent development of an organoindium
reagent has shown that organoindium compounds exhibit
great tolerance towards various functional groups, such as
carbonyl, nitrile, and alcohol.[2–6] Among the many organo-
indium compounds, allylic indium reagent has been exten-
sively studied by Araki, Chan, Li, Lloyd-Jones, our group, and
others.[7] In recent years, Knochel,[2,3] Minehan,[4] Chupak,[5]
Yamamoto,[8] and their co-workers have independently
reported efficient methods for the synthesis of benzyl and/
or aryl indium reagents (mainly activated by using LiCl as
reaction additive). However, until now there has been no
straightforward method to prepare the synthetically more
useful alkyl indium reagent by using readily available alkyl
halides, probably because of the low reactivity of indium and
alkyl halide, which makes the direct preparation of alkyl
indium reagent from alkyl halide extremely difficult.
Current methods for the synthesis of triorganoindium
reagent (R3In) suffer from drawbacks in terms of the require-
ment to use other reactive organometallic reagents (trans-
metalation of preprepared RMgX/RLi with InX3 under
anhydrous conditions and with the protection of inert gas)
and thus show limited functional-group compatibility.[9]
Therefore, a direct and clean method for the synthesis of
alkyl indium reagent from readily available alkyl halide under
mild reaction conditions and with wide functional-group
tolerance is highly desirable. In connection with our recently
developed radical-type alkylation reactions in aqueous media
using unactivated alkyl halide and In/CuI,[10] herein we
describe an efficient method for the synthesis of water-
tolerant alkyl indium reagent by direct insertion of indium
metal into alkyl halide with activation by CuCl at room
temperature. The synthetic utility of the alkyl indium reagent
was demonstrated by palladium-catalyzed coupling with aryl
halide in N,N-dimethylacetamide (DMA) with great func-
tional-group compatibility.[9,11,12]
Initially, 1-(2-iodoethyl)benzene (1a) was chosen as the
substrate to investigate the formation of alkyl indium reagent
2a (see Table 1) in THF at room temperature, by using CuI as
reaction additive. Gratifyingly, 50% conversion from the
substrate 1a to the desired alkyl indium reagent 2a was
observed. Inspired by this promising result, various copper
salts were screened to investigate their efficiency in the
formation of the alkyl indium reagent 2a.
Table 1: Optimization of reaction conditions.[a]
Entry
Reagent
Yield [%][b]
1
2
3
4
5
6
7
8
In (2 equiv)
<5
<5
50
89
99
86
74
77
88
93
80
48
<5
In/CuCN (2 equiv/2 equiv)
In/CuI (2 equiv/2 equiv)
In/CuBr (2 equiv/2 equiv)
In/CuCl (2 equiv/2 equiv)
In/CuCl (1.5 equiv/1.5 equiv)
In/CuCl (1 equiv/1 equiv)
In/CuBr2 (2 equiv/2 equiv)
In/CuBr2 (2 equiv/1 equiv)
In/CuCl2·2H2O (2 equiv/1 equiv)
In/Cu(OAc)2 (2 equiv/1 equiv)
In/CuCO3 (2 equiv/1 equiv)
In/CuSO4·5H2O (2 equiv/1 equiv)
9
10
11
12
13
[a] 1 mmol 1-(2-iodoethyl)benzene (1a, 1 equiv) was used in all the
reactions. X = I and/or the anion of the copper salt. [b] The yield was
determined by 1H NMR spectroscopy using p-xylene as internal stan-
dard.
As shown in Table 1, most of the copper salts screened did
promote the reaction at room temperature. Among them,
good to excellent yields were obtained when CuCl,
CuCl2·2H2O, CuBr, CuBr2, and Cu(OAc)2 were employed
as reaction additives. Nevertheless, only with the use of CuCl
as reaction additive was the substrate 1a fully consumed and
exclusively produced the desired alkyl indium reagent 2a in
almost quantitative yield (Table 1, entry 5). 1H NMR analysis
(CDCl3 as solvent) showed that the chemical shift of the
a-CH2 proton of 1a moved upfield from d = 3.2 to 1.7 ppm
(see the Supporting Information, pages S3 and S15), which
[*] Z. L. Shen, K. K. K. Goh, Y. S. Yang, Y. C. Lai, C. H. A. Wong,
H. L. Cheong, Prof. Dr. T. P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University
(NTU), the Ministry of Education (No. M45110000), and A*STAR
SERC Grant (No. 0721010024) for the funding of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005798.
indicated the formation of an alkyl indium reagent.[13]
A
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Table 2: Substrate scope study using various aryl halides.[a,b]
relatively low yield was obtained when the reaction was
performed with a decrease in additive loading (Table 1,
entries 6 and 7). A trace amount of the desired product was
detected when indium was solely used under these conditions
(Table 1, entry 1).
Importantly, the alkyl indium reagent 2a is thermally
stable in organic solvents (such as THF, 1,4-dioxane, and
DMA) and tolerant to water,[14,15] though it may decompose
completely when subjected to purification by silica-gel
column chromatography. In addition, no competitive
b-hydride elimination, homocoupling, or formation of ethyl-
benzene was observed under the optimized conditions
(Table 1, entry 5). Moreover, the reaction was completely
performed under an air atmosphere; no protection of the
reaction with inert gas was needed. All these features make
the alkyl indium reagent more convenient to prepare and
easier to handle than its lithium, magnesium, and zinc
counterparts. In comparison, when In/LiCl (2 equiv/2 equiv)
was used as reaction promoter, which was developed by
Knochel and others in the synthesis of benzyl and aryl indium
reagents,[2,3] the formation of two main types of alkyl indium
reagent was observed (see the Supporting Information
page S3 for details of a 1H NMR comparison of the two
reactions using CuCl and LiCl). This further demonstrates the
advantage of using CuCl as reaction additive in the generation
of a single alkyl indium reagent.
With the optimized reaction conditions in hand, we
continued to study the palladium-catalyzed coupling of alkyl
indium reagent with aryl halide. The first palladium-catalyzed
coupling of organoindium reagent involving triorganoindium
complex (R3In) was reported by Sarandeses and co-workers
and the reaction was carried out in THF.[9,11] However, the
palladium-catalyzed coupling of alkyl indium reagent 2a with
4’-iodoacetophenone (3a) proceeded sluggishly in THF
(<20% yield). After optimization of the reaction conditions
by using various solvents and palladium catalysts, it was
gratifying to find that the coupling reaction proceeded more
efficiently at 1008C using [PdCl2(PPh3)2] as catalyst, DMA as
solvent, and LiCl as additive (see the Supporting Information
page S4 for details of reaction conditions optimization). A
good yield of 91% was obtained when the reaction was
carried out under the above optimal conditions (Table 2,
substrate 3a). To demonstrate the general applicability of the
alkyl indium reagent in palladium-catalyzed coupling with
aryl halide, a variety of alkyl and aryl halides were screened.
As shown in Table 2, the coupling reactions of alkyl
indium reagent 2a with various aryl halides proceeded
efficiently to afford the desired products in moderate to
good yields. It is important to note that functional groups,
including COR, NO2, CN, CHO, and COOR, can be well
tolerated in the coupling reaction, which makes the protocol
more general and synthetically more useful. Especially note-
worthy, substrate 3e containing a hydroxyl group also reacted
well under optimal conditions to give the product in a
moderate yield of 51%. Heterocyclic halides such as
3-iodopyridine (3g), 5-iodofuraldehyde (3h), and 2-bromo-
pyridine (3m) can also be used as coupling partners under the
optimized conditions. Finally, it is gratifying to observe that
[a] See the Supporting Information for detailed reaction conditions.
[b] Yield of isolated product based on 3 as limiting reagent.
aryl chloride 3l can be employed as well leading to the desired
product in 53% yield.
In addition, a range of alkyl halides was also screened to
investigate the substrate scope of the reaction. All alkyl
iodides can be effectively converted into the corresponding
alkyl indium reagents at room temperature (> 90% conver-
sion), as indicated by crude 1H NMR analysis of the first-step
reaction mixture. The subsequent coupling reactions of
4’-iodoacetophenone (3a) with various alkyl indium reagents
proceeded well to furnish the target products in moderate to
good yields.
As shown in Table 3, alkyl iodides possessing function-
alities such as OH (1 f), OTBS (1g; TBS = tert-butyldime-
thylsilyl), COOR (1h), COR (1i), CHO (1j), and CN (1k)
Table 3: Substrate scope study using various alkyl iodides.[a,b]
[a] See the Supporting Information for detailed reaction conditions.
[b] Yield of isolated product based on 3a as limiting reagent.
512
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Angew. Chem. Int. Ed. 2011, 50, 511 –514

were all tolerated under the reaction conditions, and afforded
the expected products in moderate to good yields. The
successful use in the reaction of substrate 1 f which bears a
hydroxyl group makes the method a good alternative to the
use of other organometallic reagents, such as organomagne-
sium and organozinc reagents, because of their low tolerance
to hydroxyl groups. Especially noteworthy, because of the low
reactivity of alkyl bromide and alkyl chloride, dihalides 1l and
1m containing Cl and Br functionalities only reacted at the
reaction can be carried out under an air atmosphere and even
in the presence of water. The palladium-catalyzed coupling of
the alkyl indium reagent with various aryl halides proceeded
efficiently in DMA to afford the desired products in moderate
to good yields. The great compatibility of the alkyl indium
reagent and the subsequent coupling reactions with functional
groups, including COR, COOR, CHO, CN, OH, OTBS, NO2,
=
C C, Br, and Cl, render this method general and useful:
1) protection of sensitive functional groups, either in the alkyl
indium reagent or in the electrophile, is unnecessary; and
2) the versatile functional groups can thus be kept for late-
stage modifications, which confers the method great potential
for use in organic synthesis. Further studies pertaining to
determination of the structure of the alkyl indium reagent and
its synthetic utility in organic synthesis are currently in
progress.
À
À
À
C I bond while leaving the C Cl and C Br bonds intact. This
finding indicates that the formation of alkyl indium reagent
À
À
can be selectively achieved at the C I bond, and the C Cl and
À
C Br bonds can be kept for late-stage modification in organic
synthesis. The use of substrate 1n further broadened the
substrate scope to alkyl halides containing an alkene func-
tionality. As for secondary iodide, the reaction of 4’-iodoace-
tophenone (3a) with organoindium reagent derived from iPrI
(1o) also proceeded as expected, albeit in a moderate yield of
47%.
Experimental Section
General procedure for the synthesis of alkyl indium reagent and its
palladium-catalyzed coupling with aryl halide (Tables 2 and 3): Alkyl
iodide (1 mmol), indium (2 mmol), CuCl (2 mmol), and analytical-
grade THF (3 mL) were added sequentially to an 8 mL sample vial.
The mixture was stirred vigorously at room temperature for 24 h.
After reaction, the mixture was allowed to stand for around 10 min,
then the upper clear solution was carefully separated from the bottom
black precipitate by a syringe. The residual precipitate was washed
with THF (3 mL) and the THF layer was carefully separated by
syringe. The combined organic layers were concentrated in vacuo.
The residue was dissolved in DMA (3 mL) and transferred to another
8 mL sample vial. Aryl halide (0.7 mmol), LiCl (2 mmol), and
[PdCl2(PPh3)2] (0.05 mmol, 0.05 equiv) were added to the vial
sequentially. The reaction mixture was stirred at 1008C for 24 h.
After reaction, the mixture was directly purified by silica-gel column
chromatography with EtOAc/hexane as eluent to afford the desired
product.
However, alkyl bromide, as a result of its low reactivity
relative to alkyl iodide, cannot be converted into the
corresponding alkyl indium reagent under the same condi-
tions.[16] Fortunately, when the reaction involving 1-(2-bro-
moethyl)benzene (1p) was carried out in DMA at 1008C in
the presence of In/CuCl, > 90% conversion of the alkyl
bromide to the corresponding alkyl indium reagent was
observed. Thus, several alkyl bromides were tested in the
protocol to further broaden the general applicability of this
method in the synthesis of alkyl indium reagent from alkyl
bromide and further coupling with aryl halide. As shown in
Table 4, the alkyl bromides 1p–t can be employed for the
synthesis of alkyl indium reagents as well, and the subsequent
coupling reactions with aryl iodide 3a also proceeded
efficiently to furnish the desired products in moderate to
good yields.
Received: September 15, 2010
Published online: December 5, 2010
Table 4: Substrate scope study using various alkyl bromides.[a,b]
Keywords: cross-coupling · indium · organoindium reagents ·
.
palladium · synthesis design
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for the synthesis of water-tolerant alkyl indium reagent
through CuCl-mediated direct insertion of indium into alkyl
halide in THF at room temperature is described. The syn-
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Communications
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1H NMR spectrum of the alkyl indium reagent 2a). A slight
1
chemical shift of THF in the H NMR spectra was also visible
(OCH2 moved downfield from d = 3.76 to 3.86 ppm), which
might be because of its coordination to the indium center. In
addition, the ratio of THF to alkyl group (R = PhCH2CH2) in the
1H NMR spectra is approximately 1:1 (see the Supporting
Information, page S15). Furthermore, it was interesting to find
that the alkyl indium reagent 2a could decompose when THF
was completely removed under reduced pressure or when it was
purified by silica-gel column chromatography. Therefore, the
presence of THF might play an important role in the stabiliza-
tion of the alkyl indium reagent 2a by coordinating with the
indium center. Thus, the following structure was proposed for
the alkyl indium reagent 2a.
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stabilized by the coordination of THF/pathalan with the indium
center. In addition, the authors stated that removal of reaction
solvents (THF and acetonitrile) may lead to the decomposition
of the allylic indium species.
[14] No visible hydrolysis of the alkyl indium reagent 2a was
observed when it was stirred in THF/H2O (1:1) for 2 h. In
addition, the fact that an excellent yield (93%) was obtained for
the formation of 2a when hydrate-containing CuCl2·2H2O was
used as reaction additive (Table 1, entry 10) also proved that the
alkyl indium reagent was not sensitive to water.
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[13] Currently, we propose that the structure of the alkyl indium
reagent is RInX2 by analogy with the aryl and benzylic indium
reagents that were previously developed by Knochel. In
addition, the coordination of THF with the alkyl indium reagent
[16] The following solvents were screened for the conversion of 1-(2-
bromoethyl)benzene to the corresponding alkyl indium reagent:
THF, 658C, 24 h, < 5% yield; 1,4-dioxane, 1008C, 24 h, 38%
yield; DMA, 1008C, 24 h, > 90% yield; DMF, 1008C, 24 h,
> 90% yield. Considering that the subsequent palladium-
catalyzed coupling reaction should be carried out in DMA,
this was chosen as reaction solvent for the formation of the alkyl
indium reagent from alkyl bromide.
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