Communications
DOI: 10.1002/anie.200805588
Indium Reagents
LiCl-Mediated Preparation of Functionalized Benzylic Indium(III)
Halides and Highly Chemoselective Palladium-Catalyzed Cross-
Coupling in a Protic Cosolvent**
Yi-Hung Chen, Mai Sun, and Paul Knochel*
The development of palladium-catalyzed cross-coupling reac-
tions has revolutionized the formation of carbon–carbon
bonds.[1] These coupling reactions have found many applica-
tions in natural product synthesis,[2] material science,[3] and
medicinal chemistry.[4] The Suzuki reaction, which involves
organoboron compounds, has been widely used because of
the ready availability of boronic esters and their excellent
compatibility with many functional groups during the cross-
coupling reaction.[5] Typically, functional groups bearing
acidic protons, ketones, and aldehydes are compatible with
these coupling reactions. However, the low reactivity of
Scheme 1. Preparation of benzylic indium reagents 2 by the direct
insertion of In0 in the presence of LiCl followed by activation with
iPrMgCl·LiCl and palladium-catalyzed cross-coupling. FG=functional
group, SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl.
boronic acids may require harsh reaction conditions or
sophisticated ligand systems. Furthermore, some classes of
boronic acid derivatives such as functionalized benzylic
boronic acids are more difficult to prepare.[6]
Indium organometallic reagents have attracted consider-
able attention because of their unique compatibility with
aqueous media.[7] Palladium-catalyzed cross-coupling reac-
tions of organoindium reagents with aryl halides and triflates
were pioneered by Sarandeses and co-workers.[8] The stan-
dard method for the preparation of organoindium reagents
involves a Li/In or Mg/In transmetalation. Recently, the
preparation of arylindium(III) reagents by direct metal
insertion in the presence of LiCl was reported by us and
Papoian and Minehan.[9] Herein, we report a general way to
prepare benzylic InIII reagents[10] by the direct insertion of In0
into benzylic chlorides and bromides, as well as the use of
these reagents in highly chemoselective cross-coupling reac-
tions in protic cosolvents.
20–30 min for the benzylic bromides but required 408C and 6–
15 h for benzylic chlorides. A broad range of sensitive
functional groups such as CN, CO2Et, COR, CHO, and
CH2OH were tolerated (see Table 1).
The palladium-catalyzed cross-coupling reactions of the
In reagents 2 with aryl iodides were very sluggish and not
preparatively useful. However, the addition of a protic
solvent (such as ethanol) to these In reagents prior to the
cross-coupling dramatically increased their reactivity. This
compatibility of organoindium species with aqueous media
has been reported previously.[7] Palladium-catalyzed cross-
coupling reactions of indium organometallic reagents with
aryl halides in aqueous media was first reported by Oshima
and co-workers.[8k] The reaction in a protic cosolvent still
required high temperature (reflux) to afford the cross-
coupling product. However, we found that a transmetalation
of 2 with iPrMgCl·LiCl[11] (1.1 equiv, À608C, 30 min) provided
a more-reactive InIII reagent 3. These mixed InIII reagents
underwent smooth cross-coupling with various aryl iodides 4
at 25–308C and with aryl bromides at 408C to give products 5,
with selective transfer of the aryl group.
Various functionalized benzylic chlorides and bromides 1
were treated with In powder (1.2–2.5 equiv) in THF in the
presence of LiCl (1.2–2.5 equiv), which allowed the smooth
formation of the corresponding benzylic InIII reagents 2
(Scheme 1). The insertion reactions proceeded at 08C within
[*] Dr. Y.-H. Chen, M. Sun, Prof. Dr. P. Knochel
Department Chemie & Biochemie
The treatment of ethyl (3-chloromethyl)benzoate (1a)
with activated In powder (99.99% from Chempur, 2.5 equiv)
and LiCl (2.5 equiv) in THF at 408C for 12 h provided the
corresponding InIII reagent 2a. After the addition of
iPrMgCl·LiCl (1.1 equiv, À608C, 30 min), ethanol or water
was added to give a 6:1 (THF/cosolvent) ratio. Ethyl 4-
bromobenzoate (4a; 0.7 equiv) was then added and the
resulting reaction mixture was warmed to 25–308C. The cross-
coupling was carried out in the presence of Pd(OAc)2
(2 mol%) and SPhos[12,13] (4 mol%) at 408C for 4 h, which
afforded the desired product 5a (84% yield with ethanol as
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E-mail: paul.knochel@cup.uni-muenchen.de
[**] Y.-H.C. thanks the Humboldt Foundation for financial support. We
thank Dr. Sheng-Kai Wang (The Scripps Research Institute) for
valuable suggestions. We thank the Fonds der Chemischen
Industrie, the DFG, and the European Research Council (ERC) for
financial support. We thank Chemetall for the generous gift of
chemicals.
Supporting information for this article is available on the WWW
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 2236 –2239