Communications
DOI: 10.1002/anie.201008007
Cross-Coupling Reactions
Copper-Catalyzed Cross-Coupling Reaction of Organoboron
Compounds with Primary Alkyl Halides and Pseudohalides**
Chu-Ting Yang, Zhen-Qi Zhang, Yu-Chen Liu, and Lei Liu*
Cross-coupling reactions of organocopper reagents with alkyl
tions in a fundamental sense, but also provides practically
useful reactivities. It may thus complement palladium- and
nickel-catalyzed Suzuki–Miyaura coupling reactions of alkyl
halides.[9–11]
À
halides are among the most useful C C bond-forming
reactions in organic synthesis.[1] One drawback of these
reactions has been the need to use an excess of the organo-
copper reagent for high conversion of the starting material.[2]
This requirement causes serious waste of the precious
organometallic species, in particular in the case of cuprate
We began our study by examining the coupling of n-
dodecyl p-toluenesulfonate with an aryl boronate ester 1. We
initially used CuI as the catalyst and tested several different
bases (Table 1, entries 1–7). Although the yield of the desired
product was very low with most bases, LiOtBu provided a
good yield of 83% at 1108C (Table 1, entry 7). Interestingly,
when the temperature was lowered to 608C, the yield
increased slightly to 87% (Table 1, entry 8). The reaction
also proceeded at room temperature, but more slowly
(Table 1, entry 9). The use of other Li bases, Cu catalysts,
and solvents did not improve the reaction (Table 1,
entries 10–17). Other organoboron substrates, 2–4, could
also be used (Table 1, entries 18–20). Alkyl iodides, bromides,
mesylates, and even chlorides are also acceptable coupling
partners (Table 1, entries 21–24). The amount of the CuI
catalyst could be decreased to 2 mol% (Table 1, entry 25);
however, no product was formed with Pd and Ni salts
(Table 1, entries 26 and 27). Thus, we could rule out the
possible involvement of Pd or Ni contamination in the
catalysis. In the absence of a catalyst, the reaction did not
occur (Table 1, entry 28). The reaction was also sensitive to
water (Table 1, entry 29). Finally, under the present condi-
tions, the reaction of cyclohexyl p-toluenesulfonate with 1
gave only a trace amount of the desired product. Thus, with
this catalyst system, secondary alkyl electrophiles do not
undergo the coupling reaction.
The above results indicate that CuI is a competent catalyst
for the cross-coupling of organoboron reagents with primary
halides and pseudohalides. To test the scope of this method,
we examined a variety of substrates (Table 2). We found that
alkyl halide and pseudohalide reagents with different chain
lengths and branching could participate in the reaction (to
give 5aa–5af). A variety of substituents were well-tolerated
on the alkyl reagent, including an olefin (product 5ag), an
ether (product 5ah), an aryl group (product 5aj), an ester
(product 5ak), a cyano group (product 5al), and an amide
(product 5am). This feature compares favorably with pre-
vious examples of the copper-catalyzed coupling of primary
alkyl halides with Grignard reagents, in which nearly all
reported alkyl groups were hydrocarbons.[3–5] Furthermore,
for the synthesis of 5ab, we changed the catalyst from CuI to
CuOtBu generated in situ through the equimolar reaction of
anhydrous CuI with LiOtBu in THF at room temperature
under nitrogen. The yield with CuOtBu was 90%, which is
slightly higher than that observed with CuI (86%). Finally,
reagents (R2CuLi), which contain two transferable
R
groups.[3] To solve this problem, several research groups
have developed copper-catalyzed alkylation reactions of
Grignard reagents.[3–5] It was found that these catalytic
reactions are much easier to carry out and considerably less
expensive. Additives, such as 1-methyl-2-pyrrolidinone and 1-
phenylpropyne, were originally used to promote the alkyla-
tion reactions,[4] and the slow addition of the Grignard reagent
was found to provide similar results in a recent study.[5]
Although primary alkyl halides (as well as mesylates and
tosylates) are mostly used in these catalytic alkylation
reactions, some studies have indicated that secondary and
even tertiary alkyl halides may also be possible coupling
partners.[3,6]
Our interest in copper-catalyzed cross-coupling[7]
prompted us to consider the possibility of using organoboron
compounds in such alkylation reactions. The advantages of
replacing Grignard reagents with organoboron reagents are
well-known, including the better commercial availability of
the reagents and the higher functional-group tolerance.[8]
However, whereas certain complexes of Pd,[9] Ni,[10,11] and
Fe[12] have been reported to be competent catalysts for the
coupling of alkyl halides with organoboron compounds, until
now the catalysis of such transformations by Cu complexes
has not been reported.[13] Therefore, we were surprised to find
that in the presence of LiOtBu as a base, CuI could efficiently
catalyze the cross-coupling of aryl boronate esters with
À
primary halides and pseudohalides containing a C X bond
(X = I, Br, Cl, OTs, and OMs; Ts = p-toluenesulfonyl, Ms =
methanesulfonyl). This new transformation not only expands
the concept and utility of copper-catalyzed alkylation reac-
[*] C.-T. Yang, Z.-Q. Zhang, Y.-C. Liu, Prof. Dr. L. Liu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education)
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
E-mail: lliu@mail.tsinghua.edu.cn
[**] We are grateful for support in the form of national “973” grants from
the Ministry of Science and Technology (No. 2011CB965300).
Supporting information for this article is available on the WWW
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3904 –3907