Nickel-mediated N-arylation with arylboronic acids: An avenue to Chan-Lam coupling

Article abstract of DOI:10.1021/ol3021836

An efficient use of NiCl₂·6H₂O, for the cross-coupling of arylboronic acids with various N-nucleophiles, has been demonstrated. The method is practical and offers an alternative to the corresponding Cu-mediated Chan-Lam process for the construction of the C-N bond.

Full text of DOI:10.1021/ol3021836

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Nickel-Mediated N‑Arylation with
Arylboronic Acids: An Avenue to
ChanꢀLam Coupling
Dushyant Singh Raghuvanshi, Amit Kumar Gupta, and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science,
Banaras Hindu University, Varanasi 221005, India
knsinghbhu@yahoo.co.in
Received June 8, 2012
ABSTRACT
An efficient use of NiCl2 6H2O, for the cross-coupling of arylboronic acids with various N-nucleophiles, has been demonstrated. The method is
practical and offers an alternative to the corresponding Cu-mediated ChanꢀLam process for the construction of the CꢀN bond.
3
Transition-metal-catalyzed carbon-heteroatom cross-
coupling reactions have made a great contribution to the
recent growth of organic synthesis. A great diversity of
carbonꢀnitrogen bonds can now be easily generated by
transition-metal-catalyzed protocols that find wide applica-
tions in the synthesis of substances such as natural products,
agrochemicals, materials, dyes, and pharmaceuticals.1 The
Pd and Cu catalyzed coupling of electrophilic aryl halides
and nucleophilic primary or secondary amines, pioneered
by Buchwald, Hartwig, and others, is a hallmark reaction
in this field.2ꢀ6 In 1998, the groups of Chan, Evans, and
Lam independentlydevelopedCu-mediatedoxidativeami-
nation of arylboronic acids with amines and other nucleo-
philes,7ꢀ9 providing a valuable alternative to traditional
cross-couplings in the construction of carbonꢀheteroatom
bonds. Many extensions and applications of this new
method have been reported, including the catalytic version
of the reaction,10 arylation of amines under base and
ligand-free conditions,11 tandem cross-coupling reactions,12
and solid-phase chemistry.13 The reaction has been applied
to a variety of substrates for carbonꢀheteroatom bond
formation, but in almost all cases, copper salts are the only
choice to promote the reaction and have been repeatedly
(1) (a) Yudin, A. K.; Hartwig, J. F. Catalyzed Carbon-Heteroatom
Bond Formation; Wiley-VCH: Weinheim, 2010. (b) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954. (c) Hartwig, J. F. Nature 2008,
455, 314. (d) Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1439. (e) Surry,
D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (f) Evano,
G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (g) Beccalli,
E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007,
107, 5318. (h) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (i)
Beletskaya, I. P. Pure Appl. Chem. 2005, 77, 2021. (j) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337. (k) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (l) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (m) Qiao, J.-X.; Lam, P. Y. S.
Synthesis 2011, 829.
(2) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(3) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348.
(4) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459.
(5) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670.
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Chem. Soc. 2001, 123, 7727.
(7) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Li, J. J. Name Reaction, 4th ed.;
Springer: Berlin, 2009; pp 101ꢀ104.
(8) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
(9) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(10) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233. (b)
Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (c) Lam, P. Y. S.;
Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415. (d) Finet, J.-P.; Fedorov, A. Y.; Combes, S.; Boyer, G.
Curr. Org. Chem. 2002, 6, 597.
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J.-B.; Zhang, G.-L.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett
2004, 1095. (c) Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667. (d)
Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.; Balasubrahmanyam,
V. Synthesis 2008, 795.
(12) Collot, V.; Bovyb, P. R.; Raulta, S. Tetrahedron Lett. 2000, 41,
9053.
r
10.1021/ol3021836
XXXX American Chemical Society

used in combination with different ligands, bases, and
solvents.1m,14 To the best of our knowledge, no other metal
is described in the literature to bring about the ChanꢀLam
reaction except for an unpublished report using stoichio-
metric amount of gold(III) acetate to afford merely a
26% product yield.1m Therefore, it is a highly exigent
and preferred endeavor to find a readily available, inex-
pensive, and efficient alternative transition metal catalyst
for the CꢀN cross-coupling of boronic acids.
salt could bring about the desired conversion (entry 5), and
therefore the studies were directed to look at the prospec-
tive of other nickel salts too. All the nickel salts tried, viz.
Ni(NO3)2 6H2O, NiSO4, Ni(OAc)2 4H2O, NiCl2, and
3
3
NiCl2 6H2O, invariably worked well (entries 5ꢀ9), but
3
the performance of NiCl2 6H2O was maximum, providing
3
the N-aryl product 3a in 78% yield at rt (entry 9). As
evident, the yield of 3a was not enhanced at all when
anhydrous NiCl2 was used (entry 8). The experiment under
identical conditions without the aid of a nickel salt ended
with no conversion (entry 10). To exclude the role of a
Cu contaminant in the present reaction, some control
experiments for the model reaction were carefully investi-
gated using 1, 5, and 10 ppm of Cu(OAc)2 (entry 11)
leading to no reaction at all, which conclusively discards
any possible role of Cu contaminant catalysis under the
Nickel-based catalysts are well-recognized in CꢀC
bond-forming reactions and have also been expanded for
CꢀN bond creation by means of halide amination.15ꢀ20 It
was therefore imperative to exploit the catalytic potential
of nickel along with other unexplored metals for Chanꢀ
Lam type N-arylation using arylboronic acid and N-nucleo-
philes as coupling partners. As a part of our ongoing
program to develop viable and efficient synthetic proto-
cols,21 we disclose herein our results on the Ni-catalyzed
N-arylation using the reaction of arylboronic acids with
amines, amides, and N-heterocycles under atmospheric
conditions.
Table 1. Optimization of the Reaction Conditionsa
To explore a new catalytic system for ChanꢀLam CꢀN
cross-coupling, a model reaction using easily accessible
phenylboronic acid and aniline was investigated in detail
by varying different parameters such as catalyst, ligand,
base, and solvent to develop appropriate reaction condi-
tions for this transformation (Table 1). At the outset,
different transition metal catalysts, viz. FeCl3, CoCl2,
CdCl2, RuCl3 xH2O, and Ni(NO3)2 6H2O, were screened
using 2,20-bipyridyl as ligand and DBU as a base in
acetonitrile to determine their catalytic efficacy (Table 1,
entries 1ꢀ5). We were astonished to see that only the nickel
entry
catalyst
FeCl3
base
solvent
yieldb (%)
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
KOH
t-BuOK
K3PO4
ꢀ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
CH2Cl2
CH3OH
ꢀ
nrc
nr
2
CoCl2
CdCl2
3
nr
4
RuCl3 xH2O
nr
3
3
3
5
Ni(NO3)2 6H2O
60
3
6
NiSO4
65
7
Ni(OAc)2 4H2O
68
3
8
NiCl2
77
9
NiCl2 6H2O
78 (76)d
nr
3
10
11e
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
ꢀ
(13) (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623. (b) Hayat, S.; Atta-Ur-Rahman;
Choudhary, M. I.; Khan, K. M.; Schumann, W.; Baye, E. Tetrahedron
2001, 57, 9951. (c) Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.;
Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179. (d) Chiang, G. C. H.; Olsson,
T. Org. Lett. 2004, 6, 3079. (e) Kantam, M. L.; Venkanna, G. T.; Sridhar,
C.; Sreedhar, B.; Choudary, B. M. J. Org. Chem. 2006, 71, 9522.
(14) Kaboudin, B.; Abedi, Y.; Yokomatsu, T. Eur. J. Org. Chem.
2011, 6656.
(15) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054.
(16) (a) Lipshutz, B. H.; Ueda, H. Angew. Chem., Int. Ed. 2000, 39,
4492. (b) Lipshutz, B. H.; Nihan, D. M.; Vinogradova, E.; Taft, B. R.;
Boskovic, Z. V. Org. Lett. 2008, 10, 4279.
(17) (a) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39, 5359. (b)
Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829. (c)
Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41, 2875.
(d) Gradel, B.; Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2001, 42, 5689. (e) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem.
2002, 67, 3029. (f) Omar-Amrani, R.; Thomas, A.; Brenner, E.;
Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311.
(18) (a) Chen, C.; Yang, L.-M. Org. Lett. 2005, 7, 2209. (b) Chen, C.;
Yang, L.-M. J. Org. Chem. 2007, 72, 6324. (c) Gao, C.-Y.; Yang, L.-M.
J. Org. Chem. 2008, 73, 1624.
Cu(OAc)2
nr
NiCl2 H2O
65f
70g
14h
nr
3
NiCl2 6H2O
3
NiCl2 6H2O
3
NiCl2 6H2O
3
NiCl2 6H2O
44
3
NiCl2 6H2O
48
3
NiCl2 6H2O
52
3
NiCl2 6H2O
nr
3
NiCl2 6H2O
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
45
3
NiCl2 6H2O
48
3
NiCl2 6H2O
nr
3
NiCl2 6H2O
40
3
NiCl2 6H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
77i
78j
60k
42l
58m
3
NiCl2 6H2O
3
NiCl2 6H2O
3
NiCl2 6H2O
3
NiCl2 6H2O
3
a Reaction conditions: Phenylboronic acid (1 mmol), aniline
(2 mmol), catalyst (20 mol %), 2,20-bipyridyl as ligand (20 mol %), base
(2 equiv) at rt for 20 h. b Isolated yield based on arylboronic acid.
c No reaction. d Reaction performed at 60 °C. e Reaction using 1, 5, and
10 ppm Cu(OAc)2. f 1,10-Phenanthroline as ligand. g Tetramethylethy-
lenediamine as ligand. h Reaction performed without ligand. i 20 mol %
(19) Kuhl, S.; Fort, Y.; Schneider, R. J. Organomet. Chem. 2005, 690,
6169.
(20) Matsubara, K.; Ueno, K.; Koga, Y.; Hara, K. J. Org. Chem.
2007, 72, 5069.
(21) (a) Gupta, A. K.; Kumari, K.; Singh, N.; Raghuvanshi, D. S.;
Singh, K. N. Tetrahedron Lett. 2012, 53, 650. (b) Gupta, A. K.; Rao,
G. T.; Singh, K. N. Tetrahedron Lett. 2012, 53, 2218. (c) Kumari, K.;
Raghuvanshi, D. S.; Jouikov, V.; Singh, K. N. Tetrahedron Lett. 2012,
53, 1130. (d) Raghuvanshi, D. S.; Singh, K. N. Synlett 2011, 373. (e)
Raghuvanshi, D. S.; Singh, K. N. Tetrahedron Lett. 2011, 52, 5702. (f)
Allam, B. K.; Singh, K. N. Tetrahedron Lett. 2011, 52, 5851. (g) Allam,
B. K.; Singh, K. N. Synthesis 2011, 1125.
of NiCl2 6H2O, 40 mol % of 2,20-bipyridyl were used. j 25 mol % of
3
NiCl2 6H2O, 25 mol % of 2,20-bipyridyl were used. k 10 mol % of
3
3
NiCl2 6H2O, 10 mol % of 2,20-bipyridyl were used. l 1.0 equiv of aniline
was used. m 1.5 equiv of aniline was used.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Coupling of Arylboronic Acid with a Range of N-Nucleophilesa
a Reaction conditions: Arylboronic acid (1 mmol), N-nucleophile (2 mmol), NiCl2 6H2O (20 mol %), 2,20-bipyridyl (20 mol %), CH3CN (1 mL), rt,
3
20 h. b Isolated yield based on arylboronic acid. c Reaction carried out at 60 °C for 28 h. d Phenylboronic acid (20 mmol), benzylamine (40 mmol),
NiCl2 6H2O (20 mol %), 2,20-bipyridyl (20 mol %), CH3CN (20 mL). e No reaction.
3
Org. Lett., Vol. XX, No. XX, XXXX
C

investigated reaction conditions. The outcome approves
the sole contribution of NiCl2 6H2O as a catalyst in the
present study.
different boronic acids, viz. phenylboronic acid, o/m/p-
tolylboronic acids, and 4-(trifluoromethyl)boronic acid
(Table 2). The findings reveal that all sorts of aromatic
amines undergo reaction smoothly, although the anilines
containing a nitro group required a higher temperature
and longer reaction time (Table 2, entries 1ꢀ10). Aliphatic
amines also work well (entries 11ꢀ13), though diethyla-
mine and dibutylamine were surprisingly reluctant (entries
14, 15). Pyrazole was found to couple sluggishly to a small
extent even at higher temperature (entry 16). To our
delight, poorly nucleophilic amides also underwent this
CꢀN cross-coupling reaction proficiently (entries 17, 18),
albeit N-methylbenzamide showed no reactivity (entry 19).
The versatility of the reaction was further demonstrated
for the coupling of different amines and benzamide with
o/m/p-tolylboronic acids and 4-(trifluoromethyl)boronic
acid (entries 21ꢀ34); nonetheless, the reaction of benza-
mide with 4-(trifluoromethyl)boronic acid and that of
o-tolylboronic acid with amines necessitated a longer
reaction time and higher temperature (entries 29, 32ꢀ34).
More importantly, a scale-up experiment for the cou-
pling of phenylboronic acid with benzylamine on a
20 mmol (gram) scale was carried out to show the practic-
ability of the method, which gave rise to a 70% isolated
product yield (Table 2, entry 12), exhibiting this protocol
to be appropriate for industrial applications.
3
Subsequent investigation on the role of ligands for the
aforementioned reaction revealed 2,20-bipyridyl as the
most favored one to push the reaction forward (entries 9,
12, and 13). In the absence of a ligand under the same set of
conditions, considerably lower conversion was observed
(entry 14). As the nature of the base is assumed to have a
marked impact on the overall process, different bases such
as Et3N, KOH, t-BuOK, K3PO4, and DBU were also
examined. Whereas triethylamine did not afford any pro-
duct (entry 15), the other bases, viz. KOH, t-BuOK,
and K3PO4, gave rise to 44%, 48%, and 52% product
yields respectively (entries 16ꢀ18). The use of 1,8-di-
azabicyclo-[5.4.0]-undec-7-ene (DBU) in acetonitrile en-
hanced the product yield significantly (78%, entry 9),
which may be attributed to the very strong basicity of
DBU in acetonitrile (pKa 24.33).22 For maximum conver-
sion, 2 equiv of the base were needed, and no reaction was
observed in the absence of base (entry 19). To advance the
process further, the optimized catalytic reaction was also
probed in different solvents, such as DMSO, dichloro-
methane, and methanol at rt, in addition to acetonitrile,
which categorically approved acetonitrile as the most
appropriate choice (entries 9, 20ꢀ22). The absence of the
solvent diminished the product yield considerably (entry
23). In another endeavor, a 20 mol % catalyst loading with
a 1:1 molar ratio of metal to ligand was found to be
optimal, and no improvement was noticed on raising the
ratio from 1:1 to 1:2 (entries 9, 24ꢀ26). When the reaction
temperature was elevated to 60 °C (entry 9), no remarkable
change was observed in the product yield. Regarding
the reactant ratio, 2 equiv of aniline were needed and
found sufficient to gain the utmost conversion (entry 9);
a lower reactant ratio decreased the product yield (entries
27, 28).
In conclusion, nickel-catalyzed CꢀN bond formation
has been developed employing a range of N-nucleophiles
and arylboronic acids. The protocol embodies the first
time use of Ni salts, is efficient and versatile, and renders a
new way of ChanꢀLam coupling. Further assessment re-
garding the scope and limitations of the reaction is currently
underway.
Acknowledgment. We are thankful to the Council of
Scientific and Industrial Research (CSIR), New Delhi for
financial assistance.
With the stipulated conditions in hand, the scope of this
method was extended to the reaction of a wide range
of diverse NꢀH substrates including o/m/p substituted
arylamines, alkylamines, amides, and N-heterocycles with
Supporting Information Available. Detailed experimen-
tal procedure and spectral data of all the products along
with copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Ishikawa, T. Superbases for Organic Synthesis; John Wiley &
Sons: Chichester, U.K., 2009.
The authors declare no competing financial interest.
D
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