Ligand-Free Copper-Catalyzed Negishi Coupling of Alkyl-, Aryl-, and Alkynylzinc Reagents with Heteroaryl Iodides

Article abstract of DOI:10.1002/anie.201502379

Reported herein is an unprecedented ligand-free copper-catalyzed cross-coupling of alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 C) is required for aryl-heteroaryl and alkynyl-heteroaryl couplings.

Full text of DOI:10.1002/anie.201502379

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International Edition: DOI: 10.1002/anie.201502379
German Edition: DOI: 10.1002/ange.201502379
Cross-Coupling
Ligand-Free Copper-Catalyzed Negishi Coupling of Alkyl-, Aryl-, and
Alkynylzinc Reagents with Heteroaryl Iodides**
Surendra Thapa, Arjun Kafle, Santosh K. Gurung, Adam Montoya, Patrick Riedel, and
Ramesh Giri*
Abstract: Reported herein is an unprecedented ligand-free
copper-catalyzed cross-coupling of alkyl-, aryl-, and alkynyl-
zinc reagents with heteroaryl iodides. The reaction proceeds at
room temperature for the coupling of primary, secondary, and
tertiary alkylzinc reagents with heteroaryl iodides without
rearrangement. An elevated temperature (1008C) is required
for aryl–heteroaryl and alkynyl–heteroaryl couplings.
rearranged products.[5] Heteroaryl halides are known to
cause considerable problems by binding to the catalysts
competitively over the ligands, thus eventually leading to
catalyst inhibition and deactivation (Scheme 2).[6]
N
egishi coupling represents one of the most versatile
À
transformations utilized for constructing carbon–carbon (C
C) bonds in a variety of synthetic targets.[1] Over the course of
the last three decades, tremendous progress has been made in
the context of scope for this reaction and a wide variety of
substrates can now be coupled effectively. Despite significant
progress in the substrate scope, two classes of coupling
partners, alkylzinc reagents and heteroaryl halides, still pose
significant challenges.[2] Direct cross-coupling of alkylzinc
reagents with heteroaryl halides only makes the transforma-
tion more challenging. As such, examples of couplings
between alkylzinc reagents and heteroaryl halides to generate
alkylated heteroarenes are limited.[3] Alkyl substrates con-
taining b-hydrogen atoms generally derail the reaction path-
way by b-hydride elimination after transmetalation and
generate olefins as side products (Scheme 1).[4] In addition,
Scheme 2. Complications resulting from heteroaryl halides.
Inspired by the ubiquitous presence of alkylated and
arylated heteroarenes in pharmaceuticals and drug candi-
dates,[7] tremendous efforts have been dedicated to designing
effective catalysts to overcome these limitations. In palla-
dium- and nickel-based catalytic systems, the complication
associated with alkylzinc reagents bearing b-hydrogen atoms
is generally addressed by the application of bidentate and/or
custom-designed, sterically hindered ligands (Scheme 3).[3g,8]
Scheme 1. Complications resulting from b-hydride elimination.
Scheme 3. Coupling of heteroaryl halides with alkylzinc reagents con-
taining b-hydrogen atoms.
secondary and tertiary alkylzinc reagents containing b-hydro-
gen atoms pose further challenges because of the rearrange-
ment by a b-hydride elimination/migratory reinsertion pro-
cess, thus affording a mixture of both the desired and
This strategy renders reductive elimination faster than b-
hydride elimination, thereby affording the desired pro-
ducts.[3g] Recently, seminal work by the groups of Lipshutz,[3l]
Organ,[3g] Knochel,[3c,e] Biscoe,[3b] and Buchwald[3f] have
further shown that these sterically hindered ligands also
enable the efficient cross-coupling of alkylzinc reagents with
heteroaryl halides using palladium and nickel catalysts to
generate alkylated heteroarenes. Despite having this strategy
already at our disposal, the availability of a simple reaction
protocol which allows us to conduct similar transformations in
the absence of custom-designed ligands would no doubt have
a significant impact on the cost-effective and sustainable
syntheses of pharmaceuticals and drug candidates. Herein, we
report one such simple reaction protocol that enables us to
[*] S. Thapa, A. Kafle, Dr. S. K. Gurung, A. Montoya, P. Riedel,
Prof. R. Giri
Department of Chemistry & Chemical Biology
The University of New Mexico
Albuquerque, NM 87131 (USA)
E-mail: rgiri@unm.edu
[**] We thank the University of New Mexico (UNM) for financial
support, and upgrades to the NMR (NSF grants CHE08-40523 and
CHE09-46690) and MS Facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502379.
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execute, for the first time, a copper-catalyzed coupling of
alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides
without requiring the addition of a ligand (Scheme 3).[9] The
reaction proceeds efficiently at room temperature with
primary, secondary, and tertiary alkylzinc reagents without
b-hydride elimination and rearrangement. The reaction pro-
tocol can be extended to the coupling of aryl- and alkynylzinc
reagents with heteroaryl iodides at an elevated temperature
(1008C).
1 equivalent of ZnI2, a byproduct of the reaction, indicated
that the cross-coupling was experiencing a mild product
inhibition (entry 2), potentially a result of reverse trans-
metalation from [R-Cu] to ZnI2 as the concentration of the
latter increases during the reaction.[11c] Addition of LiCl,
which is generally considered to generate more reactive
organozinc species,[17] effectively eliminated the inhibition
and furnished the coupled product in 98% GC yield
(entry 3).[18] Alternatively, addition of 2 equivalents of
NaOAc, which would convert ZnI2 into Zn(OAc)2, also
afforded the product in 96% GC yield (entry 4).
The reaction did not furnish the coupled product in the
absence of CuI, and provided only a trace amount of the
product even after heating the reaction for 12 hours at 1208C
(Table 1, entries 5 and 6). Use of [CuOtBu], purified by
sublimation, as a catalyst also afforded the product in a similar
yield (entry 7). While lowering the loading of CuI to 1 mol%
at room temperature slightly decreased the yield (entry 8),
the reaction could be conducted with as low as 0.1 mol% CuI
at 608C with a turnover number (TON) of 780 and turnover
frequency (TOF) of 65 hÀ1 (entry 9). The reaction produced
the coupled products only in trace amounts when [Pd(dba)2]
and [(Ph3P)4Ni], known catalysts for the Negishi cross-
coupling, were utilized instead of CuI under the current
reaction conditions (entries 10 and 11), thus suggesting that
the reaction is unlikely to be catalyzed by low levels of
palladium and nickel contaminants. While the reactions in
1,4-dioxane and toluene did not produce the product, DMF
can be replaced with similar solvents such as DMA and
DMSO (entries 12–15).
Recently, we[10] and others[11] have demonstrated that
copper catalysts could effect couplings of different organo-
metallic reagents with aryl halides.[12] However, despite
literature evidence for facile transmetalation of alkyl- and
arylzinc reagents with copper salts,[13] as evidenced in allylic[14]
and 1,2-addition[15] reactions, catalytic cross-coupling with
organohalides has remained elusive.[16] In this regard, encour-
aged by the versatility and unique reactivity of copper
catalysts towards heteroaryl iodides, a reaction which pro-
ceeds without requiring ligands,[10] we reasoned that success-
ful execution of the coupling of alkylzinc reagents with
heteroaryl iodides under ligand-free conditions could address
the longstanding challenge entrenched in palladium and
nickel catalysis where specially designed, sterically hindered
ligands are required. Therefore, we initially attempted the
coupling of cyclohexylmethylzinc bromide with 7-chloro-4-
iodoquinoline. We were surprised to find that the reaction not
only proceeded without a ligand but also was completed after
3 hours at room temperature in DMF, thus affording the
alkylated heteroarene 3 in 64% yield (Table 1, entry 1).
Further analysis by seeding the reaction mixture with
After optimizing the reaction conditions, we surveyed the
substrate scope of the current cross-coupling. The reaction
proceeds well for the coupling of different heteroaryl iodides
with a variety of organozinc reagents to afford the desired
products in excellent yields (Tables 2–5). Iodides of a number
of nitrogen-containing heterocycles such as quinoline, iso-
quinoline, pyridine, and pyrazine can be utilized as coupling
partners. The reaction demonstrates a high level of efficacy
for the coupling of primary, secondary, and tertiary alkylzinc
reagents containing b-hydrogen atoms.[19]
Primary alkylzinc reagents containing both aliphatic
chains and aromatic rings can be utilized as coupling partners
(Table 2). The coupling can be performed with heteroaryl
iodides containing sensitive functional groups, such as Cl,
ester, amide, and cyano, in good yields (3, 5, 10, 12–17).
Primary alkylzinc reagents bearing terminal olefins can be
used as coupling partners (10–12). The reaction also tolerates
oxygen-containing functional groups as demonstrated by the
couplings of organozinc reagents derived from dioxanyl-
protected aliphatic aldehydes, which furnished the products in
good yields (13 and 14).
Table 1: Standard and control reactions.[a]
Entry
Modified reaction conditions
Yield [%][b]
1
without LiCl
64
10
98 (92)
96
2
3
1 equiv ZnI2 without LiCl
standard conditions
4
5
2 equiv NaOAc instead of LiCl
without CuI
0
6
7
8
without CuI, 1208C, 24 h
CuOtBu (sublimed) instead of CuI
1 mol% CuI
trace
97
85
9
0.1 mol% CuI at 608C, 12 h
0.1 mol% [Pd(dba)2] instead of CuI
0.1 mol% [(Ph3P)4Ni] instead of CuI
1,4-dioxane instead of DMF
toluene instead of DMF
DMSO instead of DMF
DMA instead of DMF
78
10
11
12
13
14
15
trace
trace
trace
0
96
95
The coupling of secondary alkylzinc reagents proceeded
smoothly with complete selectivity for the desired products
(Table 3). In addition to simple open-chain and cyclic
secondary alkylzinc reagents (products 18–24), more steri-
cally encumbered and strained 2-adamantyl- and cyclopro-
pylzinc reagents can also be coupled to afford the products in
high yields (25–29). The current reaction also proceeds with
open-chain tertiary alkylzinc reagents and affords the desired
[a] Reactions were run in 0.5 mL DMF. CuI (99.999%) was used.
[b] Yields determined by GC using pyrene as a standard. Value within
parentheses is yield of the product isolated from a 1.0 mmol scale
reaction. Reactions with 2-bromopyridine, 2-chloropyridine, and 2-pyridyl
triflate did not afford any product. dba=dibenzylideneacetone,
DMA=dimethylacetamide, DMF=N,N-dimethylformamide, DMSO=
dimethylsulfoxide.
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Table 2: Coupling with primary alkylzinc reagents.[a]
products with complete selectivity (30–33). In addition, the
tertiary adamantylzinc reagent can also be employed as
a coupling partner with different heteroaryl iodides (34 and
35).
The current reaction protocol can also be extended to the
coupling of arylzinc reagents with heteroaryl iodides
(Table 4).[20] However, the reaction requires an elevated
Table 4: Coupling with arylzinc reagents.[a]
[a] Reactions were run in 5.0 mL DMF. Yield is that of the product
isolated from a 1.0 mmol scale reaction. [b] 608C.
Table 3: Coupling with secondary and tertiary alkylzinc reagents.[a]
[a] Reactions were run in 5.0 mL DMF. Yield is that of the product
isolated from a 1.0 mmol scale reaction. TBS=tert-butyldimethylsilyl.
temperature (1008C) to afford the products in the best
yields. The reaction proceeds with a variety of heterocycles
including the ones containing chloride substituent. Electron-
neutral and electron-rich arylzinc reagents bearing substitu-
ents such as ortho-Me, OMe, and OTBS can be utilized as
coupling partners. More pleasingly, the reaction also tolerates
arylzinc reagents containing ortho-NR2 substituents and
affords the product in excellent yield (50). This latter aspect
enabled us to use the current transformation to synthesize
[a] Reactions were run in 5.0 mL DMF. Yield is that of the product
isolated from a 1.0 mmol scale reaction.
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[a] Reactions were run in 5.0 mL DMF. Yield is that of the product
isolated from a 1.0 mmol scale reaction.
In summary, we have developed an unprecedented
reaction protocol for copper-catalyzed cross-coupling of
alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides
without requiring the addition of ancillary ligands. The
reaction affords desired cross-coupled products with primary,
secondary, and tertiary alkylzinc reagents without b-hydride
elimination and rearrangement. Sterically hindered alkylzinc
reagents, ortho-amine-substituted arylzinc reagents, as well as
sensitive functional groups, such as TBS-protected phenols
and dioxanyl-protected aliphatic aldehydes are well tolerated.
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Keywords: copper · cross-coupling · heterocycles ·
synthetic methods · zinc
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8236–8240
Angew. Chem. 2015, 127, 8354–8358
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Received: March 13, 2015
Revised: April 28, 2015
Published online: May 28, 2015
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