Palladium-catalyzed one-pot diarylamine formation from nitroarenes and cyclohexanones

Article abstract of DOI:10.1021/ol3002442

The first palladium-catalyzed diarylamine formation from nitroarenes and cyclohexanone derivatives using borrowed hydrogen is described. Various diarylamines were selectively obtained in good to excellent yields. The reaction tolerated a wide range of functionalities. The nitro reduction, cyclohexanone dehydrogenation, and imine formation and reduction were realized in a cascade without an external reducing reagent and oxidant.

Full text of DOI:10.1021/ol3002442

ORGANIC
LETTERS
2
012
Vol. 14, No. 7
692–1695
Palladium-Catalyzed One-Pot Diarylamine
Formation from Nitroarenes and
Cyclohexanones
1
Yanjun Xie, Saiwen Liu, Yong Liu, Yuqing Wen, and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China
gjdeng@xtu.edu.cn
Received January 30, 2012
ABSTRACT
The first palladium-catalyzed diarylamine formation from nitroarenes and cyclohexanone derivatives using borrowed hydrogen is described. Various
diarylamines were selectively obtained in good to excellent yields. The reaction tolerated a wide range of functionalities. The nitro reduction,
cyclohexanone dehydrogenation, and imine formation and reduction were realized in a cascade without an external reducing reagent and oxidant.
The prevalence of diarylamines in pharmaceuticals, agro-
chemicals, dyes, and electronic industries has prompted the
development of novel and efficient methodologies for the
made in the field of Pd-catalyzed aromatic CꢀN bond-
5
forming reactions. In particular, contributions from the
research groups of Buchwald and Hartwig have established
the powerful nature of this method by reacting aryl halides
with anilines in the presence of a suitable ligand and base
1
construction of aromatic CꢀN bonds. While many chem-
ical methods exist for the preparation of diarylamines, the
search for new strategies that offer concise and regiospecific
6
(
the BuchwaldꢀHartwig coupling). Electrophilic partners
2
access remains a topic of considerable interest. Conven-
other than aryl halides for catalytic aniline arylations have
7
also been exploited. In recent years, the direct amination of
tional methods toward diarylamine bond construction
mainly rely on the Cu-mediated Ullmann coupling between
an aryl halide and an aniline under rather high reaction
CꢀH bonds presents a powerful alternative synthetic route
for arylamines under oxidative conditions and great
progress has been made in the intra- and intermolecular
3
temperatures. These approaches can sometimes be proble-
matic due to harsh conditions, therefore restricting their use
in complex molecule synthesis. Since Migita et al. developed
a Pd-catalyzed aromatic amination of aryl bromides with N,
8
amination of CꢀH bonds (Scheme 1A).
4
N-diethylaminotributyltin, tremendous progress has been
(
6) For reviews, see: (a) Jiang, L.; Buchwald, S. L. Metal-Catalyzed
Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004. (b) Hartwig, J. F.
In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002. (c) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (d) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534. For selected reports on diarylamine
formation, see: (e) Guram, S.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
(
1) (a) Lawrence, S. A. Amines: Synthesis Properties and Applications;
Cambridge University Press: Cambridge, 2004. (b) Ricci, A. Amino Group
Chemistry: From Synthesis to the Life Sciences; Wiley-VCH: Weinheim,
008.
(2) (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001,
7, 7785. (b) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (c) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27.
(
K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (c) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2004, 43, 1043.
(
2
1
16, 7901. (f) Paul, F.; Patt., J.; Hartwig, J. F. J. Am. Chem. Soc. 1994,
116, 5969. (g) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
996, 118, 7215. (h) Hamann, B.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
5
1
120, 7369. (i) Strieter, E.; Blackmond, D.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 13978. (j) Gajare, A. S.; Toyota, K.; Yoshifuji, M.;
Ozawa, F. J. Org. Chem. 2004, 69, 6504. (k) Biscoe, M. R.; Fors, B. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686. (l) Fors, B. P.; Davis,
N. R.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 5766. (m) Naber,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 9469. (n) Fors,
B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 15914.
3) (a) Ullmann, F. Ber. 1903, 36, 2382. For reviews, see: (b) Kunz,
4) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
5) Ricci, A. Modern Amination Methods; Wiley-VCH: Weinheim,
(
2
000.
1
0.1021/ol3002442 r 2012 American Chemical Society
Published on Web 03/12/2012

a
Scheme 1. Different Pathways for the Arylamine Formation
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
solvent
NMP
yield (%)
1
Pd(OAc)
2
2
2
2
2
2
2
2
2
trace
trace
29
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
DPEPhos
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
3
PPh
3
4
dppe
33
5
dppp
40
6
dppm
72
The catalytic oxidative dehydrogenation reactions are
very useful tools for the construction of CdC, CdO, and
9
C;N bonds. Very recently, the research groups of Stahl
7
dppb
60
8
Xantphos
bipyridine
93
9
14
0
and Huang developed various Pd-catalyzed mild aerobic de-
hydrogenation reactions of cyclohexanones and ketones/
aldehydes using oxygen as the sole oxidant, and various
phenols and R,β-unsaturated ketones/aldehydes were syn-
10
11
Pd(OAc)2
PdO
2,2 -biquinoline NMP
74
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
NMP
NMP
NMP
NMP
NMP
DMF
DMSO
DMA
trace
trace
62
12
13
14
15
PdCl
Pd(OH)
Pd(acac)
Pd(CF CO
Pd(OAc)2
2
2
84
1
0
2
thesized selectively. Milstein et al. successfully developed a
Ru-catalyzed amide synthesis from alcohols and amines
3
2
)
2
61
16
17
30
11
with the liberation of H2 without any oxidant.
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
trace
75
1
1
2
2
8
9
0
1
1,4-dioxane
xylene
24
(
7) (a) Anderson, K. W.; Mendez-Perez, M.; Priego, J.; Buchwald,
43
S. L. J. Org. Chem. 2003, 68, 9563. (b) Roy, A. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 8704. (c) Huang, X.; Anderson, K. W.; Zim, D.;
Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
c
NMP
84
a
6653. (d) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198. (e)
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol %),
ligand (10 mol %), solvent (0.3 mL), 24 h under argon unless otherwise
noted. GC yield based on 1a. 0.3 mmol of 2a was used.
Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 13848. (f) Fors,
B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc.
b
c
2008, 130, 13552. (g) So, C. M.; Zhou, Z.; Lau, C.; Kwong, F. Angew.
Chem., Int. Ed. 2008, 47, 6402. (h) Shimasaki, T.; Tobisu, M.; Chatani,
N. Angew. Chem., Int. Ed. 2010, 49, 2929. (i) Ramgren, S. D.; Silberstein,
A. L.; Yang, Y.; Grag, N. K. Angew. Chem., Int. Ed. 2011, 50, 2171. (j)
Ackermann, L.; Sandmann, R.; Song, W. F. Org. Lett. 2011, 13, 1784.
Furthermore, Williams et al. developed various catalytic
systems for direct amine formation from alcohols and
amines using a borrowing hydrogen strategy (or hydrogen
(
7
k) Xie, X.; Ni, G.; Ma, F.; Ding, L.; Xu, S.; Zhang, Z. Synlett 2011,
, 955.
8) For reviews: (a) Collet, F.; Dodd, R.; Dauban, P. Chem. Com-
mun. 2009, 5061. (b) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed.
010, 49, 2282. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068.
9) For reviews on dehydrogenations: (a) Dobereiner, G. E.;
12,13
(
transfer).
We and others further extended this strategy
for aromatic CꢀN bond formation from alcohols and
2
1
4
nitroarenes. This method affords a short synthetic route
for CꢀN bond formation. However, the borrowing hydro-
gen methodology is limited for the alkylation of amines and
not suitable for diarylamine preparation. We envisioned
that it might be possible using nitroarenes and cyclohex-
anones instead of alcohols as starting materials for diaryla-
mine formation using a sequent dehydrogenation and
borrowing hydrogen strategy. First, nitroarene could be
reduced to amine using hydrogen generated from a cyclo-
hexanone oxidation step. The condensation of cyclohexa-
none (or cyclic enone) with amine will generate an imine
intermediate. Second, the imine intermediate could be
reduced to diarylamine using the borrowing hydrogen
methodology. This method can afford a shortcut for diary-
lamine synthesis using cheap and stable starting materials
without any external reducing reagent and oxidant. Herein,
we report a Pd-catalyzed one-pot diarylamine formation from
nitroarenes and cyclohexanones using the dehydrogenation and
borrowing hydrogen strategy (Scheme 1B).
(
Crabtree, R. H. Chem. Rev. 2010, 110, 681. (b) Muzart, J. Eur. J. Org.
Chem. 2010, 3779. (c) Scheuermann, C. J. Chem.;Asian J. 2010, 5, 436.
(
(
d) Gunanathan, C.; Milstein, D. Acc. Chem. Res. 2011, 44, 588.
e) Choi, J.; MacArthur, A.; Brookhart, M.; Goldman, A. S. Chem.
Rev. 2011, 111, 1761.
10) (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209. (b)
(
Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (c) Gao, W. M.;
He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012, 3, 883. (d) Diao,
T.; Wadzinski, T. T.; Stahl, S. S. Chem. Sci. 2012, 3, 887.
(11) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007,
3
1
17, 790. (b) Gnanprakasam, B.; Milstein, D. J. Am. Chem. Soc. 2011,
33, 1682.
(12) For excellent recent reviews, see: (a) Nixon, T. D.; Whittlesey,
M. K.; Williams, J. M. J. Dalton Trans. 2009, 5, 753. (b) Guillena, G.;
Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611. (c) Watson, A.;
Williams, J. M. J. Science 2010, 329, 635.
(13) For reaction mechanism study: Hamide, M.; Liana Allen, C.;
Lamb, G.; Maxwell, A.; Maytum, H.; Watson, A.; Williams, J. M. J.
J. Am. Chem. Soc. 2009, 131, 1766.
(14) (a) Feng, C.; Liu, Y.; Peng, S. M.; Shuai, Q.; Deng, G. J.; Li, C.-J.
Org. Lett. 2010, 12, 4888. (b) Liu, Y.; Chen, W.; Feng, C.; Deng, G. J.
Chem.;Asian J. 2011, 6, 1142. (c) Cui, X. J.; Zhang, Y.; Shi, F.; Deng,
Y. Q. Chem.;Eur. J. 2011, 17, 2587. (d) Zanardi, A.; Mata, J. A.; Peris,
E. Chem.;Eur. J. 2010, 16, 10502. (e) Cano, R.; Ram oꢀ n, D. J.; Yus, M.
J. Org. Chem. 2011, 76, 5574. (f) Tang, C. H.; He, L.; Liu, Y. M.; Cao, Y.;
He, H. Y.; Fan, K. N. Chem.;Eur. J. 2011, 17, 7172. (g) Xiao, F. H.;
Liu, Y.; Tang, C. L.; Deng, G. J. Org. Lett. 2012, 13, 984.
Our initial investigations were focused on the arylation
of commercially available and inexpensive nitrobenzene
Org. Lett., Vol. 14, No. 7, 2012
1693

a
a
Table 2. Reaction of 2a with Various Nitroarenes
Table 3. Reaction of 1a with Cyclohexanones
a
2
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc) (5 mol %),
Xantphos (10 mol %), NMP (0.3 mL), 150 °C, 24 h under argon unless
otherwise noted. Isolated yields based on 1.
b
a
2
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc) (5 mol %),
Xantphos (10 mol %), NMP (0.3 mL), 150 °C, 24 h under argon unless
b
c
(1a) with cyclohexanone (2a), and the results are summar-
ized in Table 1. When Pd(OAc) catalyzed the reaction of
otherwise noted. Isolated yields based on 1a. XPhos (10 mol %) was
d e
used. 4 equiv of 2k were used. 3 equiv of 2l were used.
2
nitrobenzene with 2 equiv of cyclohexanone in the absence
of ligand in NMP at 150 °C, no desired diphenylamine
and PdCl were inefficient in this reaction (entries 11 and
2
1
3aa) was formed as determined by GC-MS and H NMR
(
12). Other palladium salts such as Pd(OH) , Pd(acac) ,
2
2
methods (Table 1, entry 1). Subsequently, various ligands
were tested for this reaction under an atmosphere of argon
using Pd(OAc) as the catalyst. No desired product was
observed when DPEPhos was used as the ligand (entry 2).
The desired product was obtained in 29% yield when
and Pd(CF CO ) were effective and gave the desired
3 2 2
product in good yields (entries 13ꢀ15). The effect of
solvents on this reaction was also investigated (entries
16ꢀ20). The reaction was efficient in DMA (entry 18).
Other solvents were not proper reaction media for this
transformation. Notably, a good yield was obtained when
the amount of 2a was reduced to 1.5 equiv, and the desired
product was obtained in 84% yield (entry 21).
With the optimized reaction conditions established, the
scope of the reaction with respect to cyclohexanone and
various nitroarenes was investigated (Table 2). The reac-
tions with nitroarenes bearing electron-donating groups
(entries 2 and 3) and electron-withdrawing substituents
para to the nitro group (entry 4) proceeded smoothly to
2
10 mol % of PPh was employed (entry 3). The use of dppe,
3
dppp, dppm, dppb all effectively catalyzed the reactions
entries 4ꢀ7). The best yield was obtained when Xantphos
was used, and the desired product was obtained in 93% yield
entry 8). Nitrogen-containing ligand bipyridine was
(
(
not effective for this transformation (entry 9). However,
0
a good yield was achieved when 2,2 -biquinoline was used
as the ligand (entry 10). Subsequently, various palladium
salts were investigated using Xantphos as the ligand. PdO
1
694
Org. Lett., Vol. 14, No. 7, 2012

give the desired products in good yields. A slightly lower
yield was obtained when p-nitroacetophenone (1e) was
used (entry 5). Ester functional groups were well tolerated
under the optimized conditions, and the reactions of methyl
Scheme 2. Proposed Reaction Mechanism
4-nitrobenzoate (1f) and ethyl 4-nitrobenzoate (1g) with 2a
resulted in the desired products in 83% and 81% yields,
respectively. The position of the substituents on the phe-
nyl ring of nitroarenes did not affect the reaction yield
significantly. Good to excellent yields were obtained
when 2-nitrotoluene (1h), 3-nitrotoluene (1i), and 2,
4
-dimethylnitrobenzene(1j) wereused asstarting materials
(
entries 8ꢀ10). More steric substrates such as 1-nitro-
naphthalene (1k) also efficiently coupled with 2a and gave
the desired product in 92% yield (entry 11). Unfortunately,
aliphatic nitro compounds were not effective substrates for
this kind of transformation.
To further explore the scope of the reaction, a number of
substituted cyclohexanone derivatives were employed to
react with nitrobenzene. Ingeneral, good to excellent yields
were obtained under the standard optimized or modified
reaction conditions (Table 3). Varying the position of the
methyl substituent on the cyclohexanone had little effect
onthe outcomeof the reaction;thecorresponding3ab, 3ac,
and 3ad were each obtained in good yields (entries 1ꢀ3).
However, the position of the phenyl group affected the
reaction yields significantly (entries 4 and 5). Other func-
tional groups including ethyl, tert-pentyl, acetyl-amino,
and ester were well tolerated, and all afforded the cor-
responding products in good yields. Notably, 3,4-dihydro-
and reduction of this intermediate afford the final dipheny-
lamine 3aa.
In summary, we have developed a novel Pd-catalyzed
direct arylation of nitroarenes with cyclohexanone deriva-
tives using the dehydrogenation and borrowing hydrogen
methodology. Cyclohexanone derivatives acted as both
hydrogen donors and aryl sources, and no external reduc-
ing reagent was required. Various diarylamines were for-
med in good to excellent yields. The reaction showed very
good selectivity, and secondary arylamines were formed as
the sole products in all cases. Functional groups such as
methyl, ethyl, methoxy, ester, and acetyl were well tolerated
under the optimized conditions. The nitro reduction, cyclo-
hexanone dehydrogenation, and imine formation and re-
duction were realized in a cascade. Further investigation,
including the scope and mechanism of this reaction, is in
progress in our laboratory.
2
-napthol (2k) and 3-methyl-2-cyclohexen-1-one (2l) both
successfully reacted with 1a and gave the desired products
in 94% and 88% yields, respectively (entries 10 and 11).
However, 4 and 3 equiv of 2k and 2l were required to
obtain high yields because less hydrogen was generated for
these substrates. In general, the direct arylation of nitroar-
enes showed very good selectivity and diarylamines were
formed as the sole products.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (20902076,
21172185), the Hunan Provincial Natural Science Founda-
Based on observations by Stahl et al. and ourselves, a
tentative mechanism to rationalize this transformation
is illustrated in Scheme 2. The reaction of cyclohexanone
with a Pd catalyst generates a complex A, which subse-
quently affords cyclohex-2-enone B through β-H elimina-
tion and transfers dihydrogen to the palladium catalyst.
In the meantime, nitrobenzene 1a can be reduced into
aniline C by the hydride borrowed from the dehydro-
genation reaction of cyclohexanone. The condensation of
cyclohexanone (including cyclohex-2-enone) with aniline
generates an imine intermediate D. Finally, dehydrogenation
tion of China (11JJ1003), the New Century Excellent
Talents in University from Ministry of Education of China
(NCET-11-0974), and the Undergraduate Investigated-
Study and Innovated Experiment Plan of Hunan Province.
Supporting Information Available. General experimental
procedure and characterization data of the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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