Nickel-catalyzed synthesis of diarylamines via oxidatively induced C-N bond formation at room temperature

Article abstract of DOI:10.1021/ol302688u

A nickel-catalyzed oxidative coupling of zinc amides with organomagnesium compounds selectively produces diarylamines under mild reaction conditions, with tolerance for chloride, bromide, hydroxyl, ester, and ketone groups. A diamine is bis-monoarylated. A bromoaniline undergoes N-arylation followed by Kumada-Tamao-Corriu coupling in one pot. The reaction may proceed via oxidatively induced reductive elimination of a nickel species.

Full text of DOI:10.1021/ol302688u

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5570–5573
Nickel-Catalyzed Synthesis
of Diarylamines via Oxidatively
Induced CÀN Bond Formation
at Room Temperature
Laurean Ilies, Tatsuaki Matsubara, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received September 28, 2012
ABSTRACT
A nickel-catalyzed oxidative coupling of zinc amides with organomagnesium compounds selectively produces diarylamines under mild reaction
conditions, with tolerance for chloride, bromide, hydroxyl, ester, and ketone groups. A diamine is bis-monoarylated. A bromoaniline undergoes
N-arylation followed by KumadaÀTamaoÀCorriu coupling in one pot. The reaction may proceed via oxidatively induced reductive elimination
of a nickel species.
Diarylamines form the core of many commercially
available drugs,1 and their synthesis,2 such as transition-
metal-catalyzed cross-coupling of amines witharyl halides,
has received much attention.3 There have also been reports
on a different retrosynthetic strategy, where a metal amide
is coupled with an organometallic reagent in the presence
of an oxidant under mild reaction conditions, typically in
the presence of a stoichiometric4,5 or catalytic amount6
of copper. We have recently demonstrated7 that an iron
catalyst can effect the oxidative reaction of zinc amides
with diarylzinc reagents; however, the reaction requires
a large amount of organometallic reagent and catalyst and
a high reaction temperature, and the substrate scope is
limited. We report here that a catalytic amount (5 mol %)
of a nickel salt effects the coupling of zinc amides with
organomagnesium reagents (1.2À3 equiv) at rt in the
presence of an organic dihalide as a mild oxidant to
produce diarylamines with high yields and with tolerance
of chloride, bromide, hydroxyl, ester, and ketone groups.
This reaction is a rare example of nickel-catalyzed oxida-
tively induced carbonÀnitrogen bond formation.8À10
As depicted in Scheme 1, a large amount of organometallic
reagent is necessary for amination under oxidative conditions
because of fast decomposition of the organometallic species
(1) Lawrence, S. A. Amines: Synthesis, Properties and Applications;
Cambridge University Press: Cambridge, U.K., 2004.
(2) Catalyzed Carbon-Heteroatom Bond Formation; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2011.
(3) For example: (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–
1544. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338–6361. (c) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
(4) (a) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739–2740.
(b) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 7838–7842. (c) Kienle, M.; Dubbaka, S. R.; del Amo, V.;
Knochel, P. Synthesis 2007,8, 1272–1278. (d) Kienle, M.; Dunst, C.; Knochel,
P. Org. Lett. 2009, 11, 5158–5161. (e) Alberti, A.; Cane, F.; Dembech, P.;
Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61, 1677–1681.
(5) For example: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400–5449 and references therein. (b) Chan, D. M. T.; Monaca,
K. L.; Wanag, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936.
(c) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979–7982. (d)
Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.;
Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601. (f) Lam, P. Y. S.;
Clark, C. G.; Subern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs,
A. Synlett 2000, 5, 674–676. (g) Elliott, G. I.; Konopelski, J. P. Org. Lett.
2000, 20, 3055–3057. (h) Sorenson, R. J. J. Org. Chem. 2000, 65, 7747–7749.
(6) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236.
(b) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem.
2001, 66, 1528–1531. (c) Lam, Y. S. P.; Vincent, G.; Clark, C. G.;
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(d) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079.
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r
10.1021/ol302688u
Published on Web 10/25/2012
2012 American Chemical Society

to give undesired homocoupling products (path a). The
decomposition of organoiron species is especially fast,11 and
this pathway was dominant in our previous studies. We
hypothesized that a nickel catalyst could be more efficient,
because organonickel species are more stable,12 and the oxi-
dation of organonickel amides to generate a CÀN bond
is known to proceed smoothly.8 Indeed, we found that the
reaction of a zinc amide generated in situ from p-toluidine
(1, 1 g) with PhMgBr (2.5 equiv) in the presence of Ni(acac)2
(5 mol %), 1,2-dichloroisobutane (DCIB) as an oxidant,11
and DMPU as an additive13 in THF at rt gives N-phenyl-
p-toluidine (2) in 100% yield (eq 1). Only a small amount
of the homocoupling product (i.e., biphenyl, 21% based
on PhMgBr) was observed. Notably, the reaction also
proceeded with a nearly stoichiometric (1.2 equiv) amount
of PhMgBr, when the amount of biphenyl was reduced to
6%, but the reaction became much slower and the yield de-
creased to 77% isolated yield (from 0.5 mmol of 1, recovery
of 1 in 23%). No overarylated product (N,N-diphenyl-
p-toluidine) was observed.
conditions using an iron catalyst that we previously
reported7 resulted in exclusive CÀC bond formation and
recovery of the starting amine 1 (entry 2). In the absence of
a catalyst, neither CÀN nor CÀC bond formation pro-
ceeded (entry 3). Under the standard reaction conditions,
other metal catalysts such as Co(acac)3, CuCl2, and PdCl2-
(PPh3)2 (entry 4) did not give any of the CÀN product 2,
and CÀC bond formation and recovery of substrate 1 was
observed, with the exception of the Cu catalyst, where
homocoupling also hardly proceeded (3%). Without oxi-
dant, 2 was not obtained at all, and homocoupling pro-
ceeded stoichiometrically (entry 5), suggesting that the
oxidant promotes the reductive elimination step, rather
than just reoxidizing the nickel species (see also eq 3). A
polar additive such as DMPU had a beneficial effect
and retarded homocoupling (entries 1 and 6); however,
the reason is unclear.13 A lithium amide prepared from 1
and BuLi did not react at all, and 1 was mostly recovered,
together with the formation of biphenyl (entry 7).
Table 1. Effect of Several Key Parameters on the Ni-Catalyzed
Oxidative Reaction of p-Tolylamidozinc Chloride with PhMgBr
entry
conditions
2 (%)b 1 (%)b PhÀPh (%)c
1
2
3
4
5
6
7
Cat. Ni(acac)2, DCIB, DMPUa
Fe(acac)3
100
0
0
21
96
44
No Ni(acac)2
0
89
trace
3À66
9
Co(acac)3, CuCl2, PdCl2(PPh3)2
without DCIB
0
84À94
96
0
without DMPU
68
0
27
53
without ZnCl2 TMEDA
100
42
3
Scheme 1. Competition between CÀN and CÀC Bond Formation
under Oxidative Catalysis
a The zinc amide was generated from 1 (0.50 mmol), n-BuLi in hexane
(1.0 equiv), and ZnCl2 TMEDA (1.0 equiv), and then it was reacted with
PhMgBr (2.5 equiv) in the presence of Ni(acac)2 (10 mol %) and DCIB
(2.0 equiv) in THF at rt for 3 h. b Yield determined by 1H NMR. c Based
on PhMgBr.
3
With the optimized conditions in hand, we next investi-
gated the scope ofthis reaction(Tables2 and 3). Compared
with the previously reported reaction using iron catalysis,7
the reaction scope was expanded to include sterically
hindered anilines, hydroxyl-, ester-, and ketone-possessing
substrates, diamine, indolylamine, benzamide, and pro-
tectedaminoarylmagnesiumreagents.AsshowninTable2,
various anilines, including electron-rich (entries 2, 10,
and 11) and electron-deficient (entries 3À5 and 7) anilines
reacted well. Sterically demanding amines (entries 11
and 12), which gave poor results under iron catalysis,7
reacted smoothly under the present conditions. We did not
observe any overarylatedproduct(i.e., triarylamine) inany
cases; however, the reaction of diarylamine 2 (entry 9) gave
a small amount of triarylamine. A diamine (m-phenylene-
diamine, entry 10) was monoarylated at both amine sites
We examined a variety of catalysts and reaction condi-
tions; the results are summarized in Table 1. The reaction
(8) Stoichiometric reactions: (a) Koo, K.; Hillhouse, G. L. Organo-
metallics 1995, 14, 4421–4423. (b) Koo, K.; Hillhouse, G. L. Organome-
tallics 1996, 15, 2669–2671. (c) Mindiola, D. J.; Hillhouse, G. L. J. Am.
Chem. Soc. 2001, 123, 4623–4624. (d)Lin, B. L.; Clough,C. R.; Hillhouse,
G. L. J. Am. Chem. Soc. 2002, 124, 2890–2891.
~
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ꢀ~
(9) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
Chem., Int. Ed. 2007, 46, 7125–7127.
(10) While this manuscript was in preparation, a reaction of boronic
acids with amines catalyzed by 20 mol % of nickel, presumably under
oxidative conditions, was reported: Raghuvanshi, D. S.; Gupta, A. K.;
Singh, K. N. Org. Lett. 2012, 14, 4326–4329.
(11) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 5858–5859. (b) Yoshikai, N.; Matsumoto,
A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925–
2928. (c) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 6557–6559. (d) Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 7672–7675. (e) Yoshikai, N.; Asako, S.; Yamakawa, T.;
Ilies, L.; Nakamura, E. Chem.;Asian J. 2011, 6, 3059–3065. (f) Ilies, L.;
Kobayashi, M.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. Adv. Synth.
Catal. 2012, 354, 593–596.
(12) Modern Organonickel Chemistry; Tamaru, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2005.
(13) (a) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 428–429. (b) Ilies, L.; Chen, Q.; Zeng, S.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 5221–5223. (c) Chen, Q.; Ilies, L.; Yoshikai, N.;
Nakamura, E. Org. Lett. 2011, 13, 3232–3234.
Org. Lett., Vol. 14, No. 21, 2012
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Table 2. Nickel-Catalyzed Oxidative Monoarylation of Various
Amines with PhMgBra
Table 3. Nickel-Catalyzed Oxidative Monoarylation of
p-Toluidine with Various Grignard Reagentsa
a Reaction conditions: the zinc amide was generated from 1(0.50 mmol),
n-BuLi in hexane (1.0 equiv), and ZnCl2 TMEDA (1.0 equiv), and then
3
it was reacted with ArMgBr (3.0 equiv) in the presence of Ni(acac)2
(10 mol %) and DCIB (2.0 equiv) in THF at rt. See the Supporting
Information for details. b Isolated yield. The homocoupling product
was observed in 5À20% yield (based on the starting ArMgBr); a larger
amount was observed when electron-rich ArMgBr was used. c The
SiMe3 groups were removed under acidic conditions.
chemoselectively over the phenol. Unprotected 5-aminoin-
dole (entry 13) reacted with selectivity at the primary amine
but with low yield; protection of the heteroaromatic nitrogen
greatly improved the yield (entry 14), suggesting unproduc-
tive coordination of the indole’s nitrogen to the active nickel
species. Other heteroaromatic amines did not react under
the present conditions. Benzamide could also be used as
a substrate (entry 15) to produce benzanilide. An aliphatic
amine could also be used (entry 16), albeit with low yield.
The scope of the Grignard reagent is summarized in
Table 3. Both electron-deficient (entries 1 and 7) and
electron-rich (entries 2À6) reagents gave the desired di-
arylamines in good yields. A dimethylamino group was
tolerated (entry 4), and a Grignard reagent possessing
a bis(trimethylsilyl)amino group (entry 5) gave a mono-
N-substituted phenylenediamine in quantitative yield
after removing the trimethylsilyl group under acidic condi-
tions. Although para- (entries 1À4) and meta-substituted
(entries 5À7) arylmagnesium reagents reacted well, ortho-
substitution (entry 8) completely shut off the reaction.
a Reaction conditions: the zinc amide was generated from the
corresponding amine (0.50 mmol), n-BuLi in hexane (1.0 equiv), and
ZnCl2 TMEDA (1.0 equiv), and then it was reacted with PhMgBr (3.0
equiv) in the presence of Ni(acac)2 (10 mol %) and DCIB (2.0 equiv) in
THF at rt. See the Supporting Information for details. b Isolated yield.
The homocoupling product was observed in 5À20% yield (based on the
starting PhMgBr), except when the yield was low. c Reaction performed
with 2.5 equiv of PhMgBr and 5 mol % of Ni(acac)2. d Reaction per-
formed with 1 g of substrate. e Yield determined by GC in the presence
of tridecane as an internal standard. f 5 equiv of PhMgBr, 12 equiv of
DMPU, and 4 equiv of DCIB were used.
3
with complete selectivity. The mild reaction conditions
allowed the tolerance of chloride (entry 4 and Table 3,
entry 7), bromide (entry 5), ester (entry 7), and ketone
(entry 8). p-Hydroxyaniline (entry 6) could be reacted
without the need to protect the hydroxyl group, and
despite using only 1 equiv of BuLi/ZnCl2, the aniline reacted
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Org. Lett., Vol. 14, No. 21, 2012

2-Naphthylmagnesium bromide (entry 9) and a heterocyc-
lic Grignard (entry 10) reacted with moderate to good yield.
Alkylmagnesium compounds did not react under these
conditions.
radical species, possibly generated from DCIB by single-
electron transfer11 from Ni(II).
The chemoselectivity of the amination reaction under
oxidative conditions could be exploited for sequential oxi-
dative phenylation of bromoaniline 3, followed by one-
pot KumadaÀTamaoÀCorriu coupling with PhMgBr or
protected aminophenyl Grignard to give 4 and 5, res-
pectively (eq 2). The cross-coupling reaction proceeded
upon simply adding a phosphine ligand and heating
at 60 °C.
In conclusion, we have developed a nickel-catalyzed
oxidative coupling of zinc amides with organomagnesium
compounds under mild reaction conditions and without
the need for an external ligand, to produce diarylamines
selectively and with tolerance of chloride, bromide, hydroxyl,
ester, and ketone groups. We have shown here that a new
catalysis design can control the hetero ligand coupling
over homocoupling that is often so problematic in oxida-
tive coupling reactions. The new catalysis design resulted
in higher yields, milder reaction conditions, and expanded
scope and functional group tolerance as compared with
previous iron catalysis.7 This work suggests the potential of
nickel catalysis for oxidatively induced carbonÀheteroatom
formation, a strategy that has often been exploited recently in
palladium and copper catalysis.15
On the basis of reports from Hillhouse that Ni(III)À
amide complexes undergo facile reductive elimination to
form a CÀN bond,8 we speculate that a nickel arylamide
species is oxidized by DCIB to a higher valent species that
readily undergoes reductive elimination to give the diaryl-
amine product. This conjuncture is supported by the
complete shutoff of the CÀN bond-forming reaction in
the absence of an oxidant, even when a stoichiometric
amount of nickel salt is used, while the homocoupling
reaction proceeds regardless of the oxidant (eq 3). Heat-
induced reductive elimination of the putative Ni(II) species
did not produce the CÀN bond,14 and only homocoupling
proceeded (eq 3), demonstrating the unique chemoselec-
tivity of the oxidatively induced process. When a radical-
trapping reagent such as TEMPO was added, the CÀN
bond-forming reaction was largely shut off, whereas the
homocoupling reaction was unaffected (eq 4). This may
suggest that the CÀN bond-forming process involves
Acknowledgment. We thank MEXT for financial support
(KAKENHI Specially Promoted Research No. 22000008
to E.N. and Grant-in-Aid for Young Scientists (B) No.
23750100 to L.I.).
Supporting Information Available. Experimental pro-
cedures and physical properties of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Ni-catalyzed, thermally induced CÀN bond formation:
(a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054–
6058. (b) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39, 5359–5362.
(c) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008,
73, 1429–1434. (d) Gao, C.-Y.; Yang, L.-M. J. Org. Chem. 2008, 73,
1624–1627.
(15) (a) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177–185
and references therein. (b) Muniz, K. Angew. Chem., Int. Ed. 2009, 48,
9412–9423.
~
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5573