Ni-catalyzed Sonogashira coupling of nonactivated alkyl halides: Orthogonal functionalization of alkyl iodides, bromides, and chlorides

Article abstract of DOI:10.1021/ja906040t

(Chemical Equation Presented) Ni-catalyzed Sonogashira coupling of nonactivated, β-H-containing alkyl halides, including chlorides, is reported. The coupling is tolerant to a wide range of functional groups, including ether, ester, amide, nitrile, keto, h

Full text of DOI:10.1021/ja906040t

Published on Web 08/11/2009
Ni-Catalyzed Sonogashira Coupling of Nonactivated Alkyl Halides:
Orthogonal Functionalization of Alkyl Iodides, Bromides, and Chlorides
Oleg Vechorkin, Delphine Barmaz, Vale´rie Proust, and Xile Hu*
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Fe´de´rale de Lausanne (EPFL), SB-ISIC-LSCI, BCH 3305, Lausanne CH 1015, Switzerland
Received July 20, 2009; E-mail: xile.hu@epfl.ch
Table 1. Sonogashira Coupling of Alkyl Iodides and Bromidesa
Substituted alkynes are recurring units in numerous natural
products, bioactive molecules, and organic materials.1 They are also
versatile synthetic intermediates.2 During the last decades, Sono-
gashira coupling has become one of the most widely used methods
for the incorporation of alkynyl functionality into organic com-
pounds.3 It enables the efficient coupling of an organic halide or
pseudohalide with a terminal alkyne, normally using a Pd catalyst
and a Cu cocatalyst. The electrophilic coupling partners for
Sonogashira reactions, however, are generally limited to aryl and
vinyl halides and triflates. Coupling of nonactivated, ꢀ-H-containing
alkyl halides has been challenging because of their reluctance to
undergo oxidative addition and the tendency of metal-alkyl
intermediates to undergo unproductive ꢀ-H elimination. Moreover,
in Sonogashira coupling, the organometallic reagents available for
transmetalation are the in situ-generated Cu-alkynyl species. They
are present in substoichiometric amounts (a few mol %) with respect
to the substrates, which further disfavors the competition between
C-C coupling and ꢀ-H elimination.4 Consequently, in contrast to
the recent progress of other cross-coupling reactions of nonactivated
alkyl halides,5 there are only two prior reports of successful
Sonogashira coupling of such substrates. In their important pioneer-
ing studies, Fu et al.4 and later Glorius et al.6 demonstrated the
coupling of alkyl iodides and bromides, but not chlorides, using
Pd(N-heterocyclic carbene) catalysts. Here we describe a Ni-
catalyzed Sonogashira coupling of nonactivated alkyl halides that
includes chlorides. The difference in reactivities of alkyl-X (X )
I, Br, Cl) bonds has allowed us to develop coupling protocols
selective for specific C-X bonds, leading to orthogonal function-
alization of alkyl halides.
The coupling of octyl iodide with octyne was used as a test
reaction. After exploring a wide range of conditions,7 we found
that 7-hexadecyne could be produced in 83% yield in dioxane using
a 5 mol % loading of our previously reported NiII pincer complex
[(MeNN2)NiCl] (1)8,9 as the catalyst, 3 mol % CuI as the cocatalyst,
a For coupling of iodides, no NaI was added; for coupling of
and 1.4 equiv of Cs2CO3 as the base (Table 1, entry 1). The best
bromides, 20 mol % NaI was added. b Isolated yields relative to the
alkyl halide. c Using 1.5 equiv of alkyne.
results were obtained at 100 °C. Other combinations of solvents,
bases, and cocatalysts led to lower coupling yields.7 Replacing 1
by HMeNN2, [(MeNN2)2Li2], or Ni(dme)Cl2 (dme ) dimethoxy-
ethane) completely shut down the catalysis, confirming the role of
complex 1 as the catalyst.7 The reaction did not occur under metal-
free conditions.7
The coupling of alkyl bromides under these conditions is also
possible but requires an iodide salt as an additive. The best results
were obtained using 20 mol % NaI.7 The coupling presumably
occurs after the alkyl bromides are converted into their corre-
sponding iodides in situ by Br/I exchange. Alkyl bromides
containing ester, ether, acetal, and olefin groups were readily
converted into substituted alkynes (Table 1, entries 9-13).
Coupling of alkyl-Br is selective in the presence of Ar-Br
bonds (entry 14).
The optimized conditions are applicable to the coupling of other
alkyl iodides with terminal alkynes (Table 1). Branching at the
ꢀ-position of the iodide was tolerated (entry 3). Substrates contain-
ing reactive functional groups such as ester, amide, aromatic enone,
and heterocycle were successfully coupled (entries 4-7). Moreover,
an array of terminal alkynes with alkyl, aryl, TMS, OTMS, and
alkyl-Cl substituents could be used (entries 1-7). Unfortunately,
coupling of secondary alkyl iodides was not successful.
Compared with alkyl bromides and iodides, alkyl chlorides
are even more challenging substrates. In fact, we are not aware
of any prior example of Sonogashira coupling of nonactivated
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12078 J. AM. CHEM. SOC. 2009, 131, 12078–12079
10.1021/ja906040t CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
alkyl chlorides. Gratifyingly, in combination with an in situ
catalytic Cl/I exchange process, complex 1 also catalyzes the
coupling of alkyl chlorides (Table 2). n-Bu4NI (20 mol %) was
used as an additive, and the reactions were conducted at 140 °C
(entry 1). The reaction gave only 4.1% yield under metal-free
conditions.7 Even at such a relatively elevated temperature,
functional groups such as ester, keto, furan, ether, acetal, nitrile,
and heterocycle were tolerated (entries 3-12). The coupling of
alkyl-Cl bonds is selective over aryl-Cl/Br bonds (entries 13
and 14). Alkynes containing alkyl, aryl, Si(i-Pr)3, and acetate
groups were all viable coupling partners.
Table 2. Sonogashira Coupling of Alkyl Chlorides
While the mechanism of these reactions is still under investigation,
we propose that a (MeNN2)NiII-alkynyl complex is the key intermedi-
ate. This complex reacts with alkyl halide to form the coupling product
via sequential oxidative addition and reductive elimination, similar to
the KCT coupling catalyzed by the same complex.7,9
In summary, we have developed the first Ni-based methods for
Sonogashira coupling of nonactivated, ꢀ-H-containing alkyl halides.
This also appears to be the first time that alkyl chlorides have been
used in Sonogashira reactions. The coupling tolerates a wide range
of functional groups in both coupling partners. Substituted alkynes
could also be prepared in comparable yields by reactions of alkyl
halides with alkynyl anions in liquid ammonia solutions.10 However,
the latter methods require a strong base and thus have limited
functional-group tolerance for both alkyl halides and terminal
alkynes. Therefore, the current Sonogashira protocols are advanta-
geous for the preparation of highly functionalized alkynes. By
judicious choices of coupling conditions, different alkyl-X bonds
can be differentiated, leading to orthogonal functionalization of alkyl
iodides, bromides, and chlorides.
Acknowledgment. We thank the EPFL for financial support.
Supporting Information Available: Experimental details, additional
entries, and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Isolated yields relative to alkyl chloride.
One of the useful features in this Ni-catalyzed Sonogashira
coupling is that it can be selective among alkyl halides,
depending on the reaction conditions (additive and temperature).
It is therefore possible to carry out sequential coupling reactions
on substrates containing more than one type of alkyl-X bond
(eq 1). Furthermore, the current protocol for Sonogashira
coupling of alkyl chlorides can be combined with our Kumada-
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iodides,9 leading to the multiple functionalization of substrates
with both alkyl-Cl and alkyl-Br or alkyl-I units (eqs 2-4).
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