Nickel-catalyzed reductive coupling of aryl halides with secondary alkyl bromides and allylic acetate

Article abstract of DOI:10.1021/ol3013342

A room-temperature Ni-catalyzed reductive method for the coupling of aryl bromides with secondary alkyl bromides has been developed, providing C(sp ²)-C(sp³) products in good to excellent yields. Slight modification of this protocol allows efficient coupling of activated aryl chlorides with cyclohexyl bromide and aryl bromides with allylic acetate.

Full text of DOI:10.1021/ol3013342

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3352–3355
Nickel-Catalyzed Reductive Coupling
of Aryl Halides with Secondary Alkyl
Bromides and Allylic Acetate
Shulin Wang, Qun Qian, and Hegui Gong*
Department of Chemistry, Shanghai University, 99 Shang-Da Road,
Shanghai 200444, China
hegui_gong@shu.edu.cn
Received May 14, 2012
ABSTRACT
A room-temperature Ni-catalyzed reductive method for the coupling of aryl bromides with secondary alkyl bromides has been developed,
providing C(sp2)ÀC(sp3) products in good to excellent yields. Slight modification of this protocol allows efficient coupling of activated aryl
chlorides with cyclohexyl bromide and aryl bromides with allylic acetate.
The construction of secondary alkylÀaryl CÀC bonds
has achieved significant success using Ni-catalyzed cross-
coupling of secondary alkyl halides with aryl metallic
reagents.1,2 Recently, transition-metal-catalyzed coupling
of secondary alkyl-metallics with aryl halides has also
attracted considerable attention.3 Both strategies require
the catalytic system to prevail over the challenges residing
in alkyl coupling partners, e.g., β-elimination and slow
reductive elimination.3e,4
efficient production of aryl and alkyl CÀC bonds. These
include Co-, Fe-, and Pd-catalyzed in situ Kumada and
Negishi processes5 and Co- and Ni-catalyzed reductive
coupling protocols.6,7 The nickel methodsare pioneered by
Durandetti’s electrochemical and Weix’s elegant chemical
reductive conditions for activated and unactivated halides,
respectively.7 However, secondary alkyl halides generally
delivered the products in less than 70% yields.8 Although
Weix’s Ni-catalyzed reductive method discloses that the
coupling of iodobenzene with 2-bromoheptane is high
yielding, an expensive phosphine ligand is inevitable at
elevated temperature. use of equimolar secondary alkyl
and aryl bromides, on the other hand, results in less than
60% yields solely using bipyridine ligands.
Direct coupling of aryl and alkyl halides that does not
need preprepared organometallic reagents has also led to
(1) For selected reviews, see: (a) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656–2670. (b) Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674–688. (c) Hu, X. Chem. Sci. 2011, 2, 1867.
(2) For selected examples, see: (a) Powell, D. A.; Maki, T.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 510–511. (b) Lou, S.; Fu, G. C. J. Am.
Chem. Soc. 2010, 132, 1264–1266. (c) Strotman, N. A.; Stefan Sommer,
S.; Gregory C. Fu, G. C. Angew. Chem., Int. Ed. 2007, 46, 3556–3558.
(d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341.
(e) Oelke, A. J.; Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 2966–
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2969. (f) Gong, H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 12177–12183.
(g) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756.
(3) For examples, see: (a) Smith, S. C.; Fu, G. C. Angew. Chem., Int.
Ed. 2008, 47, 9334. (b) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 7532. (c) Thaler, T.; Haag, B.; Gavryushin, A.; Schober, K.;
Hartmann, E.; Gschwind, R. M.; Zipse, H.; Mayer, P.; Knochel, P.
Nature Chem. 2010, 2, 125. (d) Joshi-Pangu, A.; Ganesh, M.; Biscoe,
M. R. Org. Lett. 2011, 13, 1218. (e) Jana, R.; Pathak, T. P.; Sigman,
M. S. Chem. Rev. 2011, 111, 1417.
Figure 1. Structures of ligands.
We herein report highly efficient reductive coupling of
equimolar secondary alkyl bromides with aryl bromides at
(4) Breitenfeld, J.; Vechorkin, O.; Corminboeuf, C.; Scopelliti, R.;
Hu, X. Organometallics 2010, 29, 3686–3689.
r
10.1021/ol3013342
Published on Web 06/14/2012
2012 American Chemical Society

Table 1. Optimization for the Reaction of 1 and PhBra
Table 2. Scope and Limitation of Aryl Bromidesa
entry Ni/ligand/temp (°C)
additive (mol %)
none
yieldb (%)
1c
2c
Ni(acac)2/3a/80
Ni(acac)2/3a/80
NiI2/3a/80
NiI2/4a/80
NiI2/5a/80
NiI2/5b/80
NiI2/6a/80
NiI2/6b/80
NiI2/6c/80
NiI2/6c/80
NiI2/6c/25
NiI2/6c/25
NiI2/6c/25
32
53
60
<30
47
54
57
54
59
69
92
89
46
MgCl2 (100)
3c
MgCl2 (100)
4c
MgCl2 (100)
5c
MgCl2 (100)
6c
MgCl2 (100)
7c
MgCl2 (100
8c
MgCl2 (100)
9c
MgCl2 (100)
10d
11d
12d
13d
MgCl2 (100)/Py (1:1)e
MgCl2 (100)/Py (1:1)e
Py (100)e
MgCl2 (100)/Py (10:1)e
a Reaction conditions: 1 (0.15 mmol, 100 mol %), PhBr (0.15 or 0.16
mmol), Ni source (10 mol %), ligand (10 mol %), Zn (200 mol %),
MgCl2 (100 mol %), pyridine (100 mol %), DMA (1 mL). b Isolated
yields. c 1.2 equiv of PhBr. d 1 equiv of PhBr. e Py = pyridine.
ambient temperature. Simple modification of the reaction
conditions allowed efficient coupling of electron-deficient
aryl chlorides with cyclohexyl bromide as well as allylation
of aryl bromides with allylic acetate. The present work
should serve a complementary means to the concurrent
methods for the coupling of aryl and alkyl electrophiles.
In the course of our early effort on the Ni-catalyzed
reductive coupling of two electrophiles,9 we initially dis-
covered that use of Cl-PyBox 3a ligand alone provides the
desired alkylaryl product 2a in nearly 32% yield under
Ni(acac)2/Zn/DMA (DMA = N,N-dimethylacetamide)
conditions for the coupling of 1 equiv of 1 with 1.2 equiv
of PhBr at 80 °C (Table 1, entry 1).10 The yield could be
boosted to 53% by addition of 1 equiv of MgCl2 (entry 2).
Use of NiI2 raised the yield to 60% (entry 3). Other
tridentate and bidentate ligands such as 4a, 5a,b, and
6aÀc were inferior (Figure 1 and entries 4À9).10 Inspired
a Reaction conditions: 1 (0.15 mmol, 100 mol %), PhBr (100 mol %),
NiI2 (10 mol %), 6c (10 mol %), Zn (200 mol %), MgCl2 (100 mol %),
pyridine (100 mol %), DMA (1 mL). b Isolated yields. c Not detected.
by Weix and Gosmini’s reductive coupling procedures
where pyridine necessitates the coupling of organo halides,
we reasoned that a combination of a bidentate ligand and
pyridine should be effective for this coupling event.7b,11
However, only moderate improvement was observed when
1 equiv of pyridine was used (entry 10). A dramatic
increase of the yield to 92% was eventually observed by
lowering the temperature to 25 °C (entry 11).10 With no
MgCl2, thereaction still proved tobehighlyeffective (entry
12). Employment of 1 equiv of pyridine seemed to be
critical as only 46% of yield was obtained using 10%
pyridine (entry 13). With no or a low ratio of pyridine,
significant homocoupling of 1 was observed, suggesting
that pyridine can promote the reactivity of phenylbromide.
With the optimized conditions in hand, the limitation
and scope of the aryl bromides were examined for the
(5) (a) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem.
Soc. 2009, 131, 15592–15593. (b) Czaplik, W. M.; Mayer, M.; von
Wangelin, A. J. Angew. Chem., Int. Ed. 2009, 48, 607–610. (c) Amatore,
M.; Gosmini, C. Chem. Commun. 2008, 5019. (d) Duplais, C.; Krasovskiy,
A.; Wattenberg, A.; Lipshutz, B. H. Chem. Commun. 2010, 562. (e) Czaplik,
W. M.; Mayer, M.; Jacobi von Wangelin, A. Synlett 2009, 2931.
(6) Amatore, M.; Gosmini, C. Chem.ÀEur. J. 2010, 16, 5848.
ꢀ ꢀ
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(7) (a) Durandetti, M.; Nedelec, J.-Y.; Perichon. J. Org. Chem. 1996,
61, 1748–1755. (b) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am.
Chem. Soc. 2010, 132, 920–921. (c) Yan, C.-S.; Peng, Y.; Xu, X.-B.;
Wang, Y.-W. Chem.;Eur. J. 2012, 18, 6039–6048. (d) Everson, D. A.;
Jones, B. A.; Weix, D. J. J. Am. Chem. Soc. 2012, 134, 6146–6159.
(8) Although the cobalt/phosphine-catalyzed method gave a high
yield for bromocyclohexane, it is limited to activated aryl halides (ref 6).
(9) (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011,
13, 2138. (b) Dai, Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Chem.;Eur.
J. 2012, 16, 808. (c) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org.
Lett. 2012, 14, 3044. (d) Yin, H.; Zhao, C.; You, H.; Lin, Q.; Gong, H.
Chem. Commun. 2012, in press (DOI: 10.1039/C2CC33232A).
(11) Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C. Angew. Chem.,
Int. Ed. 2011, 50, 10402.
(10) See the Supporting Information for details.
Org. Lett., Vol. 14, No. 13, 2012
3353

coupling with 1 (Table 2). In general, aryl iodides were less
effective (entries 1 and 2). Aryl bromides bearing electron-
donating substituents, e.g., 2b,c,eÀk, delivered much better
yields than those substituted with electron-withdrawing
groups, e.g., 2d,l (entries 3À13). The reaction conditions also
tolerate acidic phenol and free amines as evident in 2c and 2i.
The sterically more hindered 2,6-dimethylbromobenzene did
not generate desired product 2m (entry 14). 2-Bromopyridine
only gave rise to a low yield for 2n, probably due to the
deactivated aromatic ring (entry 15). In addition to the be-
nzene rings, 1-bromonaphthalene was also compatible, giv-
ing 2o in 73%. 8-Bromoquinoline gave the coupling product
in 96% yield, implying that coordination of the 1-nitrogen to
nickel center played an important role (entries 16À17).
Extension of the coupling strategy to the less reactive
aryl chlorides was also performed (Scheme 1). It was
determined that only aryl chlorides bearing electron-with-
drawing groups were effective at 50 °C. The presence of
Bu4NBr was indispensable, without which no products
was detected.13 The modified reaction conditions allowed
the coupling of 4-cyano- and 4-(methoxycarbonyl)phenyl
chlorides with cyclohexyl bromide to generate 21 and 22 in
72% and 79% yields, respectively. These results offset the
shortcomings of low coupling efficiency using electron-
deficient aryl bromides (vide supra).
Scheme 1. Coupling of Activated Ar-Cl with Cyclohexyl
Bromidea,b
a Reaction conditions: ArCl (0.15 mmol, 100 mol %), cyclohexyl
bromide (100 mol %), NiI2 (10 mol %), 6c (10 mol %), Zn (200 mol %),
Bu4NBr (100 mol %), MgCl2 (100 mol %), pyridine (100 mol %), DMA
(1 mL). b Isolated yields.
Scheme 2. Coupling of Ar-Br with Allylic Acetatea,b
a Reaction conditions: ArBr (0.15 mmol, 100 mol %), allylic acetate
(100 or 200 mol %), NiI2 (10 mol %), 6c (10 mol %), Zn (200 mol %),
Bu4NBr (100 mol %), MgCl2 (100 mol %), pyridine (100 mol %), DMA
(1 mL). b Isolated yields. c Not available. d The yield in parentheses was
achieved at 25 °C.
Figure 2. Coupling of aryl bromides with secondary alkyl bro-
mides. (a) Reaction conditions: Ar-X (0.15 mmol, 100 mol %),
PhBr (100 mol %), NiI2 (10 mol %), 6c (10 mol %), Zn
(200 mol %), MgCl2 (100 mol %), pyridine (100 mol %), DMA
(1 mL). (b) Isolated yields. (c) 1-Chloro-2,3-dihydro-1H-indene
was used. (d) Not detected.
Finally, it was interesting to identify that the modified
coupling conditions for activated aryl chlorides were
highly effective for the coupling of aryl bromides with
allylic acetate (Scheme 2). With 2 equiv of allylic acetate
at 60 °C, aryl bromides containing electron-rich substi-
tuents gave allylated products 23 and 24 in fairly good
yields, which were less effective than those with electron-
withdrawing groups as evident in 25. High coupling
yield for 25 was even obtained at room temperature.
Use of 1 equiv of allylic acetate, significantly eroded the
coupling yields, e.g., 40% for 23 and 70% for 25. The Ni-
catalyzed conditions seem to be more effective than the
analogous Co-catalyzed reductive and Fe-catalyzed
domino Kumada methods.14
An investigation of the scope of the alkyl halides and
other aromatic systems is summarized in Figure 2. The
cyclic and the open-chain secondary bromides were both
efficient, providing 7À19 in good to excellent yields.
Notably, benzylic chloride such as 1-chloro-2,3-dihydro-
1H-indene also delivered 16 in excellent yield even with
electron-deficient aryl bromide. The coupling of primary
bromide with aryl bromides and iodides was not satisfac-
tory. No or low yields were observed for 20 using PhBr or
PhI, respectively. This is possibly due to less stable primary
alkyl radical is involved.12
In summary, we have developed a highly efficient pro-
tocol for the coupling of secondary alkyl halides with aryl
(12) Coupling of (bromomethyl)cyclopropane with 8-bromoquino-
line only generated ring-opening product, and 1 equiv of TEMPO
completely inhibited the reaction of 1 with PhBr, indicating a possible
radical process for alkyl halides.
(13) The role of MgCl2 and BuNBr may possibly account for activa-
tion of Zn by removing salts on the surface.
3354
Org. Lett., Vol. 14, No. 13, 2012

halides, which provides a complementary solution to the
unresolved issue in the previous studies on the coupling of
aryl bromides with secondary alkyl bromides. Extension of
the couplingstrategytothe allylation of arylbromides with
allylic acetate is also highly effective, which may offer a
convenient synthetic strategy for functionalization of aro-
matic rings.
support was provided by the Chinese NSF (Nos. 2097209
and 21172140), the Program for Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions
of Higher Learning, Shanghai Education Committee (No.
10YZ04), and Shanghai Leading Academic Discipline
Project (No. S30107).
Supporting Information Available. Spectral data of new
compounds and experimental details. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. Dr. Hongmei Deng (Shanghai
University) is thanked for use of the NMR facility. Financial
ꢀ
(14) (a) Gomes, P.; Gosmini, C.; Perichon, J. Org. Lett. 2003, 5,
1043–1045. (b) Mayer, M.; Czaplik, W. M.; Jacobi von Wangelin, A.
Adv. Synth. Catal. 2010, 352, 2147.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3355