Nickel-catalyzed Negishi cross-coupling reactions of secondary alkylzinc halides and aryl iodides

Article abstract of DOI:10.1021/ol200098d

A general Ni-catalyzed process for the cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides has been developed. This is the first process to overcome the isomerization and β-hydride elimination problems that are associated with the use of secondary nucleophiles, and that have limited the analogous Pd-catalyzed systems. The impact of salt additives was also investigated. It was found that the presence of LiBF₄ dramatically improves both isomeric retention and yield for challenging substrates.(Figure Presented)

Full text of DOI:10.1021/ol200098d

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1218–1221
Nickel-Catalyzed Negishi Cross-Coupling
Reactions of Secondary Alkylzinc Halides
and Aryl Iodides
Amruta Joshi-Pangu, Madhu Ganesh, and Mark R. Biscoe*
Department of Chemistry, The City College of New York, 160 Convent Avenue,
New York, New York 10031, United States
mbiscoe@ccny.cuny.edu
Received January 12, 2011
ABSTRACT
A general Ni-catalyzed process for the cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides has been developed. This is the
first process to overcome the isomerization and β-hydride elimination problems that are associated with the use of secondary nucleophiles, and
that have limited the analogous Pd-catalyzed systems. The impact of salt additives was also investigated. It was found that the presence of LiBF4
dramatically improves both isomeric retention and yield for challenging substrates.
Transition metal-catalyzed cross-coupling reactions of
C(sp2) organometallic nucleophiles with C(sp2) electro-
philes have been thoroughly studied and developed over
the past few decades.1a More recently, the use of C(sp3)
nucleophiles and C(sp3) electrophiles has been demon-
strated in Pd-, Cu-, Ni-, Fe-, Co-, and Ag-catalyzed
cross-coupling reactions.1 However, a general procedure
that enables the cross-coupling of secondary nucleophiles
and aryl halides has not yet been demonstrated.2,3 The
recent Pd-catalyzed methods developed by Molander/
Dreher3c and Buchwald3d constitute the only comprehen-
sive efforts toward establishing a general protocol for such
cross-coupling reactions. Unfortunately the Pd-catalyzed
systems often suffer from isomerization of secondary alkyl
nucleophiles on account of facile β-hydride elimination
and slow reductive elimination.1a Isomerization is less
problematic when using electronically or sterically acti-
vated arenes since these substrates experience accelerated
reductive elimination relative to β-hydride elimination.4
Suchsubstitution effectshavebeenshown for both Pd- and
Ni-catalyzed systems.3j However, the utility of the process
is reduced if the scope of electrophiles is limited to such
activated substrates. The use of symmetric, cyclic (e.g.,
cyclohexyl or cyclopentyl) nucleophiles precludes isomer-
ization, but an ideal process should accommodate a large
range of nucleophiles. Based upon the success of Ni
catalysis in cross-coupling reactions involving an alkyl
component,1b we postulated that a new Ni-catalyzed
process could surmount the problems inherent to the
analogous Pd-catalyzed systems. Herein, we report a
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds., Wiley-VCH: New York, 2004. (b) Rudolph, A.; Lautens,
M. Angew. Chem., Int. Ed. 2009, 48, 2656 and references cited therein.
(c) Vechorkin, O.; Hu, X. Angew. Chem., Int. Ed. 2009, 48, 2937 and
references cited therein..
(2) Original pioneering study: Tamao, K.; Kiso, Y.; Sumitani, K.;
Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268.
(3) For recent examples of secondary nucleophiles in Pd catalysis,
see: (a) Campos, K. R.; Klapars, A.; Walsman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538. (b) Luo, X.; Zhang, H.;
Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571.
(c) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A.
J. Am. Chem. Soc. 2008, 130, 9257. (d) Han, C.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 7532. (e) Thaler, T.; Haag, B.; Gavryushin, A.;
Schober, K.; Hartman, E.; Gschwing, R. M.; Zipse, H.; Mayer, P.;
Knochel, P. Nat. Chem. 2010, 2, 125. (f) Nakao, Y.; Takeda, M.;
Matsumoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 45, 4447.
(g) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.-Y.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108. For recent examples
of secondary nucleophiles in Ni catalysis, see: (h) Melzig, L.; Gavryushin,
A.; Knochel, P. Org. Lett. 2007, 9, 5529. (i) Smith, S. W.; Fu, G. C. Angew.
Chem., Int. Ed. 2008, 47, 9334. (j) Phapale, V. B.; Guisan-Ceinos, M.;
Bunuel, E.; Cardenas, D. J. Chem.;Eur. J. 2009, 15, 12681.
(4) The presence of an ortho-substituent or an electron-withdrawing
group on the electrophilic component of Pd-catalyzed cross-coupling
reactions has been shown to accelerate reductive elimination. See:
(a) Crabtree, R. H. The Organometallic Chemistry of the Transition
Metals, 3rd ed.; John Wiley and Sons: New York, 2001. (b) Torraca, K. E.;
Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
10770. (c) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
r
10.1021/ol200098d
Published on Web 02/10/2011
2011 American Chemical Society

general Ni-catalyzed process that enables the cross-
coupling of unactivated, acyclic secondary alkylzinc
halides with aryl and heteroaryl iodides without competi-
tive isomerization of the nucleophile. This process is the
first to overcome the problem of β-hydride elimination
observed in Pd-catalyzed systems, thus enabling the
direct and rapid preparation of arenes bearing second-
ary alkyl substituents.
oxidative addition of aryl halides to nickel, however, has
not been explored.
Using 10 mol % NiCl2 glyme and 15 mol % ligand, we
3
investigated the use of bidentate and tridentate nitrogen-
based ligands more extensively (Figure 2). The ratios of
s-BuPh to n-BuPh products were generally high with un-
hindered bipyridine, phenanthroline, and terpyridine
ligands, but were greatest with terpyridine derivatives
(i.e. >200:1). Additionally, the formation of homocoupling
product8 was completely suppressed when terpyridine
ligands were employed. Electronic perturbations, intro-
duced by modifying terpyridine (8), did not improve the
efficiency of the catalytic process. Additionaly, the inclu-
sion of ortho-substituents on the ligands destroyed the
activity of the catalyst (see the Supporting Information).
Figure 1. Proposed catalytic cycle for the Ni-catalyzed cross-
coupling of secondary alkyl nucleophiles and aryl halides.
Figure 1 shows a plausible catalytic cycle for the Ni-
catalyzed cross-coupling reaction of a secondary nucleo-
phile and an aryl halide.5 After transmetallation, the
secondary alkyl ligand of complex IIa may undergo
isomerization (IIb) and racemization (IIa0) (if optically
active) through a β-hydride elimination/reinsertion se-
quence. Dissociation of the olefin after β-hydride elimina-
tion would result in the formation of a nickel hydride
complex (IIc), which may lead to catalyst deactivation or
aryl halide reduction. According to this model, the ele-
mentary steps of the catalytic cycle must out-compete β-
hydride elimination tocreate anefficient catalytic process.6
From an initial screen of different ligand classes (see the
Supporting Information), bidentate and tridentate nitro-
gen-based ligands appeared most promising in effecting
the Ni-catalyzed cross-coupling of iodobenzene and
s-BuZnI. Indeed, the Cardenasgroup hasshown the ability
of bidentate nitrogen ligands to support the oxidative
addition of aryl halides to nickel,3j and the Fu group has
repeatedly shown the ability of tridentate nitrogen-based
ligands to support Ni-catalyzed cross-coupling reac-
tions involving alkyl nucleophiles and electrophiles.7 The
ability of the tridentate terpyridine scaffold to support the
Figure 2. Ligand screen for the Ni-catalyzed cross-coupling of
iodobenzene and s-BuZnI.
Thus, 8 was employed in ensuing optimization studies.
Upon increasing the reaction concentration from 0.07 to
0.60 M, the yield improved to 93% (Table 1) as the
competitive reduction of iodobenzene was suppressed. At
such a concentration, we were additionally able to lower
the nickel and ligand loadings to 2 mol %, reduce the
alkylzinc iodide to1.5 equiv, and replaceNiCl2 glyme with
3
NiCl2,9 while obtaining >500:1 selectivity for the desired
branched product over the isomerization product. The
addition of cosolvents such as DME, DMF, DMA, and
NMP resulted in significantly decreased yields and in-
creased formation of isomerized, linear product.
(5) While a Ni(0)-Ni(II) catalytic cycle cannot be conclusively ruled
out, structural and computational studies support a Ni(I)-Ni(III)
catalytic cycle for such Ni-catalyzed reactions when bi- and tridentate
nitrogen are employed as the supporting ligand. See ref 3h. (a) Anderson,
T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126, 8100. (b) Jones,
G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.;
Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A.
J. Am. Chem. Soc. 2006, 128, 13175.
(6) Phapale, V. B.; Cardenas, D. J. Chem. Soc. Rev. 2009, 38, 1598.
(7) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726.
(b) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (c) Fischer,
C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. (d) Son, S.; Fu, G. C.
J. Am. Chem. Soc. 2008, 130, 2756. (e) Smith, S. W.; Fu, G. C. J. Am.
Chem. Soc. 2008, 130, 12645. (f) Lundin, P. M.; Esquivias, J.; Fu, G. C.
Angew. Chem., Int. Ed. 2009, 48, 154.
Using the conditions described above, we explored the
generality of this process with respect to the aryl iodide
employed. Additionally, we subjected each aryl iodide to
(8) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547.
(9) NiCl2 ($0.43/g from Strem) is considerably less expensive than
NiCl2 glyme ($13.12/g from Strem) and Pd(OAc)2 ($27.12/g from
Strem).
3
Org. Lett., Vol. 13, No. 5, 2011
1219

Table 1. Optimization of Conditions for the Ni-Catalyzed Cross-Coupling Reaction of Iodobenzene and s-BuZnIa
entry
L
variation from conditions of Figure 2
yield (%)
s-Bu/n-Bu
1
2
3
4
5
6
7
8
3
6
8
8
8
8
0.15 M in THF
93
53
80
91
96
98
93
200/1
70/1
0.15 M in THF
0.15 M in THF
0.45 M in THF
60/1
200/1
300/1
>500/1
>500/1
0.45 M in THF, 2% NiCl2 glyme, 2% L
3
0.45 M in THF, 2% NiCl2, 2% L
0.60 M in THF, 2% NiCl2, 2% L, 1.5 equiv of RZnI
a Yields and selectivities determined by GC with dodecane as an internal standard.
and utility of this method, we concentrated on functiona-
lized substrates that have been traditionally difficult to
employ in cross-coupling reactions. In most cases, excel-
lent yields of the desired product were isolated. Aldehydes,
esters, arylboronic esters, phenols, anilines, alkynes, and
heterocycles were all successfully tolerated in these reac-
tions. Thus, this process is remarkably general with respect
to the functional groups of the aryl iodide component. The
use of ortho-substituted aryl iodides generally led to low
conversion and significant aryl iodide reduction. However,
the analogous Pd-catalyzed cross-coupling process is par-
ticularly facile when an ortho-substituent is present on the
aryl halide to accelerate reductive elimination.3d Thus, our
Ni-catalyzed system appears to be highly complementary
to the Pd-catalyzed process.
Scheme 1. Ni-Catalyzed Cross-Coupling Reactions of i-PrZnI
and s-BuZnI with Aryl and Heteroaryl Iodides
Scheme 2. Ni-Catalyzed Cross-Coupling Reactions of 1-Iodo-
3,5-Dimethylbenzene with Different Secondary Alkylzinc Io-
didesa
a ArI (1 mmol), RZnI (1.5-2.5 mmol); average isolated yield
of 2 runs; all products are formed with >100:1 branched to linear
ratio. b With LiBF4 (1 equiv) as additive. c 70:1 s-Bu to n-Bu; see
ref 11. d Volatile products: GC yields are 80% (i-Pr) and 82%
(s-Bu).
reactions with i-PrZnI and s-BuZnI to gather insight into
the general sensitivity of the method to R-branching on the
nucleophile. We observed no dependence on the electronic
properties of the aryl iodide or on the use of an R-branched
nucleophile (Scheme 1). The ratio of branched (retention)
product to linear (isomerization) product was greater than
100:1 in each of these reactions.10,11 In a few instances,
exogenous LiBF4 was employed toeliminate the formation
of small amounts of linear byproduct (discussed below).
Thus, β-hydride elimination can be successfully avoided by
using these general conditions. To demonstrate the scope
a ArI (1 mmol), RZnI (1.3-1.5 mmol); average isolated yield of
2 runs.
To verify that secondary alkylzinc nucleophiles can be
employed in this Ni-catalyzed cross-coupling reaction
in a general fashion with isomeric retention, we perfor-
med cross-coupling reactionswith acyclic alkylzinc nucleo-
philes other than i-PrZnI and s-BuZnI (Scheme 2). Notably,
we successfully employed a secondary alkylzinc reagent
bearing an ester, as well as a secondary alkylzinc reagent
with R-branching on both alkyl substituents. These reac-
tions occurred in good to excellent yields without detect-
able isomerization of the nucleophile.
(10) The >100:1 ratio of retention to isomerization is conservative.
GC analyses show that the majority of these reactions favor retention by
a ratio of >500:1.
(11) The use of exogenous LiBF4 improved isomeric retention in the
cross-coupling of iodofuraldehyde and s-BuZnI, but greatly reduced the
yield.
During our initial investigation into the Ni-catalyzed
cross-coupling of aryl iodides and secondary alkylzinc
nucleophiles, we observed that both yield and selectivity
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Org. Lett., Vol. 13, No. 5, 2011

were greatly influenced by the presence of lithium chloride
in the reaction mixture. When alkylzinc reagents were
prepared with LiCl according to the procedure of
Knochel,12 yields of cross-coupling products were low
and ca. 5-10% linear product was observed. This obser-
vation, as well as the reported ability of exogenous salts to
facilitate Negishi reactions13 and certain Ni-catalyzed
cross-couplings,14 inspired us to investigate the effect of
salt additives on this process. While the majority of sub-
strates included in Scheme 1 underwent cross-coupling
with >100:1 branched to linear product ratio, four of
the substrates did show more significant formation of
linear alkyl products when the conditions derived in
Table 1 were employed. The greatest extent of isomeriza-
tion was observed in the cross-coupling of methyl 4-iodo-
benzoate and s-BuZnI, where the s-Bu (14) and n-Bu (15)
products were formed in a ratio of 33:1, respectively. Thus,
we employed this substrate in our model study on the effect
of different salt additives on yield and selectivity. The
results of this study are shown in Scheme 3. In all instances,
complete conversion of PhI was observed. The presence of
LiCl and LiI showed a dramatic inhibitory effect on the
cross-coupling reaction, which became more pronounced
as the salt concentration was increased. This coincided
with a shift in the reaction selectivity toward the linear
product (15) and the homocoupling product. While in-
creasing the concentration of halide salts had an adverse
effect in most cases, the use of exogenous zinc halides had a
marginally beneficial effect on both yield and selectivity.
product was completely suppressed. In addition to suppres-
sing the isomerization of the secondary nucleophile, the
addition of LiBF4 also helped to diminish arene formation
from aryl iodide reduction. Thus, if necessary, LiBF4 can
be employed as an additive in instances where isomeriza-
tion or reduction byproduct is undesirably high. Since the
addition of lithium halide salts has been shown to facilitate
Pd-catalyzed Negishi cross-coupling reactions,13 it is sur-
prising that the addition of lithium halide salts is so
deleterious to the outcome of the Ni-catalyzed process.
These salt effects are particularly important to consider
when preparing alkylzinc reagents via methods involving
the concurrent formation of salt byproduct.
Because we are interested in developing methods of high
operational simplicity as well as generality, we performed
each of these reactions on the benchtop, using readily
available disposable vials with screw-top septa. The reac-
tion vials were evacuated and backfilled with argon prior
to the addition of the alkylzinc reagent, sealed with elec-
trical tape, and allowed to stir in the absence of additional
argon pressure. When the optimized conditions described
in Table 1 were applied to the cross-coupling reaction of
iodobenzene and s-BuZnI without any precaution to ex-
clude air or moisture, the observed yield only fell to 86%.
Thus, while we recommend that these reactions be per-
formed under an inert atmosphere of nitrogen or argon if
possible, the described system appears not to be especially
sensitive to air and moisture.
In summary, we have developed the first general proce-
dure for the cross-coupling of secondary nucleophiles and
aryl/heteroaryl iodides. This process solves the problem of
isomerization inherent to analogous Pd-catalyzed reac-
tions. Accordingly, the use of nickel catalysis should be
preferred in most cases where potential isomerization of
the nucleophile is a concern. We are currently pursuing
kinetic studies on this transformation, through which we
hope to elucidate the mechanism involved and the role of
salt additives.
Scheme 3. Effect of Exogenous Salts on Yield and Isomerization
(14:15)a
Acknowledgment. We thank The City College of New
York (CCNY) and PSC-CUNY for financial support.
We gratefully acknowledge the National Science Founda-
tion for an instrumentation grant (CHE-0840498). Acknow-
ledgment is additionally made to the donors of the American
Chemical Society Petroleum Research Fund (50307-DNI1)
for partial support of this research.
a Yields and selectivities determined by GC with dodecane as an
internal standard. b 3 equiv added.
By far, the greatest positive effect was observed when
LiBF4 was employed as an additive. With LiBF4, the
reaction yield increased to 95% and the formation of linear
Supporting Information Available. Experimental pro-
cedures and spectral data for all products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(12) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117. For salt-free conditions, see: Huo, S. Org.
Lett. 2003, 5, 423.
(13) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O’Brien,
C. J.; Organ, M. G. Chem. Commun. 2010, 46, 4109.
(14) (a) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 3500. (b) Anderson, T. J.; Vicic, D. A. Organometallics 2004, 23,
623. (c) Colon, I.; Kelsey, D. R. J. Org. Chem. 1986, 51, 2627.
Org. Lett., Vol. 13, No. 5, 2011
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