Angewandte
Communications
Chemie
Cross-Coupling
A Robust and Broadly Applicable Cobalt-Catalyzed Cross-Coupling of
Functionalized Bench-Stable Organozinc Pivalates with Unsaturated
Halides
Jeffrey M. Hammann+, Ferdinand H. Lutter+, Diana Haas, and Paul Knochel*
Abstract: We report a robust and broadly applicable CoCl2-
catalyzed cross-coupling between functionalized aryl and
heteroaryl zinc pivalates and various electron-poor aryl and
heteroaryl halides (X = Cl, Br, I). Couplings with (E)- or (Z)-
bromo- or iodo-alkenes proceed with retention of configura-
tion. Also, alkynyl bromides react with arylzinc pivalates
providing arylated alkynes.
ity and a broad reaction scope is essential for an extensive use
in industrial and academic research.[16] Also, many Co-
catalyzed cross-couplings are limited to electron-deficient
N-heterocyclic halides and ortho-activated electron-poor
aromatic halides.[17] Herein, we report a practical, robust
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and broadly applicable Co-catalyzed Csp Csp cross-cou-
pling between various aryl or heteroarylzinc pivalates and
electron-poor aryl or heteroaryl iodides, bromides and
chlorides. Recently, we have noticed that sodium formate
was an excellent promoter for cross-couplings between ortho-
activated heterocyclic halides and arylzinc chlorides.[17] These
results encouraged us to examine the use of arylzinc pivalates
as nucleophilic cross-coupling partners. The pivalate anion[10]
like sodium formate may accelerate the coupling reaction. To
our delight, this hypothesis was confirmed.
T
ransition metal-catalyzed cross-coupling reactions are
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indispensable tools for the construction of Csp Csp bonds,
which is of great importance for the synthesis of pharma-
ceuticals and agrochemicals.[1] Boron organometallics have
been extensively used for such couplings[2] in medicinal
chemistry,[3] allowing late-stage functionalizations of biolog-
ically active molecules.[4] Their air and water stability has
made boronic esters,[5] boronic acids,[6] as well as trifluoro-
boronates,[7] highly attractive for the pharmaceutical industry.
However, some of these boron derivatives are sensitive or
difficult to prepare in high yields and in general require an
additional base to achieve satisfactory cross-couplings.[8] In
comparison, organozinc reagents display an excellent func-
tional group compatibility and a better reactivity in coupling
reactions.[9] No additional base is required and the trans-
metalation from Zn to Pd or other transition metals is very
fast. Nevertheless, standard organozinc reagents (RZnX, X =
Hal), are highly air and moisture sensitive, thus limiting their
synthetic applications. Recently, we demonstrated that orga-
nozinc pivalates (RZnOPiv)[10] afford, after solvent evapo-
ration, solid organozinc compounds with greatly improved air
and moisture stability, allowing them to be weighed out on the
benchtop.
Thus, the treatment of the bromobenzonitrile (1a) with p-
anisylzinc chloride (3a’) in the presence of CoCl2 (5 mol%)[16]
in THF (408C, 16 h)[18] gave the desired product (2a) in 41%
yield (see Scheme 1). During this reaction, extensive homo-
Scheme 1. Cobalt-catalyzed cross-coupling of 4-bromo-2-fluorobenzo-
nitrile (1a).
These organozinc pivalates readily undergo Pd-catalyzed
cross-couplings.[11] However, since palladium[12] and nickel,[13]
the favored transition metal catalysts for couplings, are
expensive[14] and/or toxic,[15] we envisioned the performance
of cross-couplings with organozinc pivalates using industrial
friendly transition metal catalysts. Cobalt-catalyzed couplings
are of special interest since cobalt salts are much less toxic
than palladium salts[15] and additionally are ca. 800 times
coupling as well as hydrolysis of the organometallic species
was observed explaining the low yield. However, using p-
anisylzinc pivalate (3a) prepared from 4-bromoanisole (4) by
Mg-insertion in the presence of LiCl[19] followed by a trans-
metallation with Zn(OPiv)2 (> 95% yield), we observed
a very clean cross-coupling affording the biphenyl (2a) in
80% yield showing the clear superiority of ArZnOPiv over
ArZnCl.[20] Remarkably, although ortho-fluoro electron-defi-
cient aromatics are known to readily undergo Co-catalyzed
cross-couplings with Grignard reagents,[16c] using 4-bromo-2-
fluorobenzonitrile (1a) only a regio- and chemoselective
coupling of bromide occurs. With these results in hand, we
have further optimized the reaction conditions and showed
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cheaper.[14] Although several Co-catalyzed Csp Csp cross-
À
couplings have been reported, all these methods lack general-
[*] J. M. Hammann,[+] F. H. Lutter,[+] Dr. D. Haas, Prof. P. Knochel
Department of Chemistry, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstr. 5-13, Haus F, 81377 Munich (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[22]
[23]
that MnCl2,[21] CrCl2 or FeCl2 were unsuitable catalysts
[+] These authors contributed equally to this work.
(Table 1, entries 2–4).
[16]
We found that CoCl2 is superior to other cobalt salts,
Supporting information for this article can be found under:
such as Co(acac)2, Co(acac)3, CoBr2 and CoCl2·2LiCl[17,24]
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Hammann, Jeffrey M.
