Cobalt-Catalyzed Negishi Cross-Coupling Reactions of (Hetero)Arylzinc Reagents with Primary and Secondary Alkyl Bromides and Iodides

Article abstract of DOI:10.1002/anie.201411960

We report a cobalt-catalyzed cross-coupling of di(hetero)arylzinc reagents with primary and secondary alkyl iodides or bromides using THF-soluble CoCl₂·2 LiCl and TMEDA as a ligand, which leads to the corresponding alkylated products in up to 88% yield. A range of functional groups (e.g. COOR, CN, CF₃, F) are tolerated in these substitution reactions. Remarkably, we do not observe rearrangement of secondary alkyl iodides to unbranched products. Additionally, the use of cyclic TBS-protected iodohydrins leads to trans-2-arylcyclohexanol derivatives in excellent diastereoselectivities (up to d.r.=99:1).

Full text of DOI:10.1002/anie.201411960

Angewandte
Chemie
DOI: 10.1002/anie.201411960
Cross-Coupling
Cobalt-Catalyzed Negishi Cross-Coupling Reactions of
(Hetero)Arylzinc Reagents with Primary and Secondary Alkyl
Bromides and Iodides**
Jeffrey M. Hammann, Diana Haas, and Paul Knochel*
Abstract: We report a cobalt-catalyzed cross-coupling of
di(hetero)arylzinc reagents with primary and secondary alkyl
iodides or bromides using THF-soluble CoCl2·2LiCl and
TMEDA as a ligand, which leads to the corresponding
alkylated products in up to 88% yield. A range of functional
groups (e.g. COOR, CN, CF3, F) are tolerated in these
substitution reactions. Remarkably, we do not observe rear-
rangement of secondary alkyl iodides to unbranched products.
Additionally, the use of cyclic TBS-protected iodohydrins
leads to trans-2-arylcyclohexanol derivatives in excellent
diastereoselectivities (up to d.r. = 99:1).
Scheme 1. a) Preparation of TMP2Zn·2MgCl2·2LiCl (1). b) Cobalt-cata-
lyzed cross-coupling reactions.
T
ransition-metal-catalyzed cross-coupling reactions are val-
À
uable tools for C C bond-forming reactions and have found
many applications for the synthesis of biologically active
molecules.[1] Pd- or Ni-catalyzed cross-coupling reactions
dominate this field, but have several drawbacks, for example,
the toxicity[2] and high price of the metal, as well as the
requirement of sophisticated ligands to achieve a broad
reaction scope.[3] Recently, cross-coupling reactions with
cobalt catalysts were found to be a valuable alternative.[4]
However, despite the spectacular advances of Co-catalyzed
coupling reactions between C(sp2) and C(sp3) centers by using
magnesium reagents,[5] no Co-catalyzed Negishi-type[6] cou-
pling reactions using arylzinc reagents have been described.[7]
Recently, we have reported a range of synthetic methods
for preparing polyfunctional unsaturated zinc reagents.[8] In
particular, the directed metalation[9] of polyfunctional hetero-
cycles and aromatic substrates has a broad reaction scope, and
sterically hindered bases,[10] such as TMPZnCl·LiCl[11] and
TMP2Zn·2MgCl2·2LiCl[12] (1; TMP = 2,2,6,6-tetramethylpi-
peridyl) have given a straightforward entry to a range of
unsaturated diorganozinc compounds.
À
C H
zincation
using
TMP2Zn·2MgCl2·2LiCl
(1;
Scheme 1).[14]
In preliminary experiments, we have examined the cross-
coupling of the diarylzinc reagent (2a), which was generated
by a directed metalation of ethyl 3-fluorobenzoate (3a)[15]
using TMP2Zn·2MgCl2·2LiCl[10] (1, 0.6 equiv), with cHex-I in
the presence of various metal catalysts (Table 1). The addition
of the zinc species to cHex-I in the presence of [Co(acac)2] or
FeCl2 [16] resulted in the exclusive formation of the protonated
Table 1: Optimization of the conditions for the Co-catalyzed cross-
coupling.
Entry
Catalyst
(mol%)
Ligand
(mol%)
Yield[c]
[%]
Herein, we report a Co-catalyzed Negishi-type cross-
coupling reaction of primary and secondary alkyl iodides and
bromides[13] with diarylzinc reagents prepared by a directed
1
2
FeCl2 (20)
FeCl2 (20)
4-fluorostyrene (50)
TMEDA (30)
0
13
3
4
5
6
[Co(acac)2] (20)
[Co(acac)2] (20)
CoCl2 (20)
4-fluorostyrene (50)
TMEDA (30)
4-fluorostyrene (50)
TMEDA (30)
0
18
42
84
[*] M.Sc. J. M. Hammann,[+] M.Sc. D. Haas,[+] Prof. Dr. P. Knochel
Department of Chemistry
CoCl2 (20)
7
8
9
10
CoCl2·2LiCl (20)
CoCl2·2LiCl (20)
CoCl2·2LiCl (20)
CoCl2·2LiCl (10)
TMEDA (30)
4-fluorostyrene (50)
L1 (30)
94 (87)[d]
38
40
33
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Munich (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[+] These authors contributed equally to this work.
TMEDA (30)
[**] We would like to thank the Deutsche Forschungsgemeinschaft
(DFG) for financial support. We also thank Rockwood Lithium
GmbH for the generous gift of chemicals.
[a] MgCl2 and LiCl are omitted for the sake of clarity. [b] The use of
TMPZnCl.LiCl did not lead to a satisfactory conversion into the desired
product. [c] Determined by GC with undecane (C11H24) used as an
internal standard. [d] Yield of isolated product. acac=acetylacetonate.
L1=trans-N,N,N’,N’-tetramethylcyclohexane-1,2-diamine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411960.
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zinc species when using 4-fluorostyrene (50 mol%).[17] Mod-
erate yields of 4a (13–18%) were obtained using N,N,N’,N’-
tetramethylethane-1,2-diamine (TMEDA, 30 mol%) as
ortho,ortho’ substituents present in the diarylzinc species
(2a) did not disturb the cross-coupling and most of the
reactions were complete within 6 h at 08C. Primary alkyl
bromides have also been used successfully coupled, but with
somewhat lower yields (entries 2–4). Functional groups such
as an ester or a nitrile are well-tolerated in such cross-
coupling reactions. Interestingly, secondary alkyl iodides
reacted smoothly to provide the alkylation products 4a and
4e–j in 55–79% yield (entries 4–10). In no case did we
observe rearrangement products (branched to unbranched;
see entry 5 and Table 3).[20] When an oxygen substituent was
present in position 2 to the carbon–iodine bond, excellent
diastereoselectivities were observed (up to d.r. = 99:1, see
entries 8–10) and the products were isolated in 55–69% yield.
Additionally, this cross-coupling can also be performed with
heterocyclic alkyl iodides, thereby leading to the expected
products 4g and 4j in 79% and 55% yield, respectively (see
entries 7 and 10).
a
ligand (entries 1–4). Switching to cobalt(II) chloride
(20 mol%) and 4-fluorostyrene (50 mol%) or TMEDA
(30 mol%) in THF at 08C furnished the desired cross-
coupling product 4a in 42% and 84% yield, respectively
(entries 5 and 6). Significant improvements were achieved by
using the THF-soluble CoCl2·2LiCl (20 mol%)[18] and
TMEDA (30 mol%),[19] which afforded the coupling product
4a in 87% yield of the isolated product (entry 7). Further
variation of the ligand[5b] or lowering the amount of the cobalt
catalyst from 20 mol% to 10 mol% led only to a decrease in
the yield (entries 7–10).
With these optimized reaction conditions in hand, we have
performed a range of alkylations using primary alkyl iodides,
which led to the polyfunctional alkylated benzoates (4b–d) in
58–77% yield (Table 2, entries 1–3). Remarkably, the
The reaction scope of this Co-catalyzed alkylation is quite
broad and a range of diarylzinc reagents prepared by
a directed deprotonation using TMP2Zn·2MgCl2·2LiCl (1,
0.6 equiv) provided the isolated alkylated products 5a–o in
51–88% yield (Table 3). Thus, this sequential one-pot metal-
ation/cross-coupling procedure could be extended to various
1,2- and 1,3-disubstituted aromatic compounds. The zincation
of 2-fluorobenzonitrile or 3-fluorobenzonitrile using
1 (0.6 equiv) proceeds within 12 h at 258C, and the subse-
quent coupling reactions with secondary alkyl iodides pro-
vides the desired products 5a–e in 52–86% yield (entries 1–
4). Remarkably, diheteroarylzinc reagents generated by
directed zincation using 1 undergo the alkylation reactions
in good yields to afford the expected products 5a–o (51–88%
yield, entries 6–14). Thus, zincated benzofurans or benzothio-
phenes reacted with secondary alkyl iodides such as cHex-I,
iPr-I, or nBu-I to furnish the corresponding cross-coupling
products 5 f–i in 61–76% yield (entries 6–9). The metalation
of benzofuran with TMP2Zn·2MgCl2·2LiCl (1, 0.6 equiv) was
complete within in 12 h at 258C, thereby providing the
corresponding zinc reagent. This species undergoes the Co-
catalyzed cross-coupling with nBu-I to afford the substituted
benzofuran 5h in 63% yield (entry 8). This alkylated
benzofuran (5h) is a key intermediate for the synthesis of
amiodarone, an active antiarrhythmic agent.[21,22] Similarly,
3,6-dimethoxypyridazine was zincated using 1 (0.6 equiv, 4 h,
RT), and the cross-coupling with 2-iodopropane or cHex-I
afforded the desired polyfunctional hetereocycles 5j, k in 69
and 61% yield, respectively (entries 10 and 11). Coumarin is
also an excellent substrate, with its zincation complete within
1 h at 258C. After alkylation with various primary and
secondary alkyl iodides, the substituted coumarins 5l–
n were obtained in up to 88% yield (entries 12–14) Similarly,
the regioselective zincation of thiochromone (À408C, 1 h)[23]
at the a-position to sulfur followed by a Co-catalyzed
alkylation with 2-iodobutane led to the desired product 5o
in 51% yield (entry 15).
Table 2: Scope of various primary and secondary alkyl iodides or
bromides.
Entry
1
Product/yield [%]
Entry
6
Product/yield [%]
4b: 63% (X=I)
4 f: 79% (X=I, d.r. =
50:50)[d]
2
3
4
5
7
4c: 58% (X=I)
38% (X=Br)
4g: 79% (X=I)
8
4d: 71% (X=I)
51% (X=Br)
4h: 68% (X=I, d.r.=
99:1)[e]
9
4a: 61% (X=Br)
2% (X=Cl)[b]
4i: 69% (X=I, d.r.=99:1)[f]
10
4e: 70% (X=I, d.r.=
4j: 55% (X=I, d.r.=99:1)[g]
50:50)[c]
[a] MgCl2 and LiCl are omitted for the sake of clarity. [b] The yield was
determined by GC. [c] The starting material was 99:1 syn/anti. [d] The
starting material was 75:25 cis/trans. [e] The starting material was 75:25
cis/trans. [f] The starting material was 99:1 trans/cis. [g] The starting
material was 99:1 trans/cis. TBS=tert-butyldimethylsilyl.
In summary, we have reported a new Co-catalyzed cross-
coupling of polyfunctional diaryl- and diheteroarylzinc
reagents with primary and secondary alkyl iodides (or
bromides) using the highly soluble cobalt salt CoCl2·2LiCl.
2
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5l: 76
4
5
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13
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7
8
15
5g: 61
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is observed. This cross-coupling is also compatible with
various functional groups and hetereocyclic scaffolds. Further
applications to the synthesis of natural products are under-
way.
Received: December 12, 2014
Published online: && &&, &&&&
Keywords: cobalt · cross-coupling · heterocycles · metalation ·
.
zinc
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Cross-Coupling
J. M. Hammann, D. Haas,
P. Knochel*
&&&& — &&&&
Cobalt-Catalyzed Negishi Cross-Coupling
Reactions of (Hetero)Arylzinc Reagents
with Primary and Secondary Alkyl
Bromides and Iodides
Cobalt and zinc—a lovely couple! The
soluble CoCl2·2LiCl complex allows effi-
cient cross-coupling between polyfunc-
tional diaryl- and diheteroarylzinc
reagents, obtained by directed zincation
using TMP2Zn·2MgCl2·2LiCl, and various
primary or secondary alkyl iodides or
bromides to afford the alkylated products
in up to 88% yield. In no case was
rearrangement of the secondary alkyl
iodide (to its linear isomer) observed.
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