Pd-catalyzed synthesis of aryl amines via oxidative aromatization of cyclic ketones and amines with molecular oxygen

Article abstract of DOI:10.1021/ol3027279

Pd-catalyzed intermolecular aerobic dehydrogenative aromatizations have been developed for the arylation of amines with nonaromatic ketones. Under optimized reaction conditions, primary and secondary amines are selectively arylated in good yields with cyclohexanones and 2-cyclohexen-1-ones in the presence of a Pd-catalyst under an atmosphere of molecular oxygen.

Full text of DOI:10.1021/ol3027279

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5606–5609
Pd-Catalyzed Synthesis of Aryl Amines via
Oxidative Aromatization of Cyclic Ketones
and Amines with Molecular Oxygen
Simon A. Girard,†,‡ Xiong Hu,‡,§ Thomas Knauber,†, Feng Zhou,†,
Marc-Olivier Simon,† Guo-Jun Deng,*,§ and Chao-Jun Li*,†
Department of Chemistry and FQRNT Center for Green Chemistry and Catalysis,
McGill University, Montreal, QC, H3A 2K6, Canada and Key Laboratory of
Environmentally Friendly Chemistry and Application of Ministry of Education,
College of Chemistry, Xiangtan University, Xiangtan 411105, China
cj.li@mcgill.ca; gjdeng@xtu.edu.cn
Received October 2, 2012
ABSTRACT
Pd-catalyzed intermolecular aerobic dehydrogenative aromatizations have been developed for the arylation of amines with nonaromatic ketones.
Under optimized reaction conditions, primary and secondary amines are selectively arylated in good yields with cyclohexanones and
2-cyclohexen-1-ones in the presence of a Pd-catalyst under an atmosphere of molecular oxygen.
Over the last few decades, an impressive number of
transition metal catalyzed tools for the selective synthesis
of aryl amines has been developed and found many
applications for the synthesis of pharmaceuticals, agro-
chemicals and functional materials.1 Arguably, the most
prominent reactions include Buchwald-Hartwig-couplings,2
Ullmann-type reactions3 and Chan-Lam-type aminations
(Scheme 1).4 In addition to the cross-coupling methodolo-
gies, several seminal dehydrogenative aromatization5 proce-
dures have been developed for the syntheses of aryl amines
from nonaromatic enamines and imines (Scheme 1). The
group of Semikolenov developed a gas-phase procedure
for the synthesis of 2,6-dimethylaniline that involves a
Pd-catalyzed cross-dehydrogenative aromatization step.6 In
2001, the group of Ishikawa and Saito demonstrated that
preformed enamines can be smoothly transferred into the
corresponding aryl amines in the presence of stoichiometric
quantities of a Pd(II) complex.7 The first Pd-catalyzed pro-
tocols have been developed independently by Cossy8 and
Beller9 using nitro benzene and benzyloxy carbonyl protec-
tive groups (Cbz) as hydrogen acceptors, respectively. Re-
cently, the group of Yoshikai encountered an oxidative
† McGill University.
‡ S.A.G. and X.H. contributed equally.
§ Xiangtan University.
T.K. and F.Z. contributed equally.
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r
10.1021/ol3027279
Published on Web 10/15/2012
2012 American Chemical Society

aromatization in the development of a Pd-catalyzed aerobic
indole synthesis.10
In addition to the Pd-catalyzed procedures, a few aroma-
tizations with stoichiometric quantities of SnCl4, Hg(OAc)2,
and TiCl4 have been reported.11
Scheme 2. Postulated Oxidative Arylamine Formation from
2-Cylohexenones and Cyclohexanones
Scheme 1. Strategies for the Synthesis of Aryl Amines
Inspired by pioneering work,12 the group of Stahl
succeeded in the utilization of molecular oxygen in cata-
lytic oxidative aromatization reactions. Cyclohexanone
derivatives have been transferred into the corresponding
phenols13 and cyclic enones14 in the presence of a Pd-
catalyst under O2 atmosphere.15 In regard of availability
and atom efficiency, molecular oxygen is the most attrac-
tive oxidant for Pd-catalyzed coupling reactions.16 This
year, our groups have independently developed the first
intermolecular arylation reactions of heteroatom nucleo-
philes with cyclic ketones. Aliphatic alcohols have been
arylated with 2-cyclohexen-1-ones in a Cu-catalyzed aero-
bic ether synthesis,17 and aryl amines have been accessed
from nitro arenes and cyclohexanones in a Pd-catalyzed
cross-dehydrogenative arylation.18
concept outlined in Scheme 2. The prospected reaction
starts with an enamine condensation19 followed by pallada-
tion of the enamine species III.20,7 Subsequent tautomeriza-
tion and β-hydride-elimination will liberate the aryl amine
IX or a cyclic diene intermediate VIII and a metal-hydride
species VII. The latter could be regenerated into the initial
catalyst IV in the presence of oxygen.21 The product IX will
be formed from the diene species VIII in a second catalytic
cycle.
To validate this hypothesis, we started with the simpler
arylation of amines with 2-cyclohexen-1-one, as only one
equivalent of molecular hydrogen and one molecule of
water have to be removed. Piperidine was chosen as test
substrate, and the results are outlined in Table 1.
The desired N-phenyl piperidine 3aa was detected in 8%
yield in the presence of the Cu-catalyst (Table 1, entry 1),
which mediates the aerobic synthesis of aryl ethers.17
Among the tested precatalysts,22 good yields of 61 and 66%
had been obtained with Pd(OAc)2 and [(PMePh2)2PdCl2],
respectively (Table 1, entries 2 and 3). However, the
reaction was accompanied by the formation of undefined
polymeric decomposition products.23 The addition of
P-, N- and O-ligands did not improve the reaction outcome.22
The reaction progress and the formation of intermediates
were thus monitored by 1H NMR experiments.22 The hemi-
aminal I was readily formed and accumulated in the reaction
mixture. The maximum concentration is reached after full
consumption of the piperidine (approximately 2ꢀ3 h).22
We envisaged that an aerobic aromatization of various
cyclohexanone derivatives with both primary and second-
ary amines would introduce a direct and atom-economic
access to various aryl amines. We reasoned that the trans-
formation might be possible by following the mechanistic
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Soc. 2004, 126, 9724–9734. (c) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S.
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(22) See Supporting Information for experimental details.
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Org. Lett., Vol. 14, No. 21, 2012
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Table 1. Optimization of the Pd-catalyst for the Aerobic
Amination of 2-Cyclohexen-1-one with Piperidine
Table 2. Scope of the Aerobic Amination of
2-Cyclohexen-1-onesa
catalyst (mol %)
additive
3aa (%)a
1
Cu(OTf)2 (10)
Pd(OAc)2 (10)
NHPI/H2O/KIb
8
2
-
61
3
[(PPh2Me)2PdCl2] (10)
-
66
00
4
AcOH
tBuCO2H
74
00
00
00
00
00
5
75
6
4-MeOC6H4CO2H
PhCO2H
78
78
7
˚
8
TsOH/MS 4 A
44
9
CF3CO2H
61
10
11c
[(PPh2Me)2PdCl2] (2)
00
PhCO2H
00
93
93(82)
a 1a (0.2 mmol), 2a (0.1 mmol), Pd-source, additive (20 mol %), O2
saturated toluene (0.2 mL), 100 °C, 18 h. Yields were determined by 1H
NMR analysis with 1,3,5-trimethoxy benzene as internal standard.
Isolated yields in brackets. b NHPI (20 mol %), H2O (1.0 equiv), KI
(1.0 equiv). c 2a (1.3 equiv).
The rate of the dehydration step releasing the enamine III
from I could be controlled by the addition of catalytic
quantities of moderately strong Brønsted acids (pKa ≈ 4)
(Table 1, entries 4ꢀ7). The best results were obtained with
anisic acid and benzoic acid which gave the desired product in
78% yield (Table 1, entries 6 and 7). In contrast, the addition
of strong acids (Table 1, entries 8 and 9) resulted in a too
rapid release of the enamine which was decomposed24 before
it could be converted efficiently by the catalyst. The yield was
further improved by lowering the catalyst loading (Table 1,
entry 10), and under optimized conditions (Table 1, entry 11),
3aa was detected in 93% yield.
a 1aꢀg (0.39 mmol, 1.3 equiv), 2aꢀk (0.3 mmol, 1.0 equiv),
[(PPh2Me)2PdCl2] (2 mol %), PhCO2H (20 mol %), O2 saturated toluene
(0.6 mL), 100 °C, 18 h. Isolated yields are based on 2. b Reaction on
2.00 mmol scale. c Yield determined by 1H NMR.
Table 3. Optimization of the Pd-catalyzed Aerobic
Aromatization of Cyclohexanone and Aniline
The scope of the procedure is illustrated in Table 2.
Under optimized reaction conditions various heterocyclic
and aliphatic secondary amines are arylated with 2-cyclo-
hexen-1-one in good yields. Amines containing β-hydro-
gen atoms such as 2i or 2j were arylated in high yields. The
reaction conditions are mild enough to be tolerated by
delicate amines, and the oxidatively sensitive compounds
2d or 2h and sensitive diallylamine 2k were smoothly
converted into the corresponding aryl amines. However,
weakly nucleophilic heterocyclic amines such as indole,
pyrrole or imidazole could not be arylated, and the sub-
strates were recovered after the reaction time. Various
moderately electron rich 2-cyclohexenones are converted
into the corresponding aryl amines in good yields. How-
ever, particular electron rich and less electrophilic 2-cyclo-
hexen-1-ones such as 1c resulted in low yields, and 78% of
unconverted 1c was detected even after 36 h reaction time.
ligand (mol %)
6aa (%)a
1
2
3
4
5
-
67
83
84
89
91
PhCOOH (5)
4-N,N-dimethylaminopyridine (5)
1,10-phenanthroline (5)
1,10-phenanthroline (10)
a 4a (0.24 mmol), 5a (0.2 mmol), Pd(OAc)2 (5 mol %), ligand, O2
saturated solvent (0.5 mL), 135 °C, 24 h. Yields were determined by
GC-analysis using mesitylene as internal standard.
Once the development of the simpler reaction was
successful, we decided to tackle the more challenging but
also more desirable arylation employing cheaper and more
readily available cyclohexanone. Unfortunately, low yields
(3%) were detected with piperidine under the optimized
conditions along with the decomposition of the substrates.22
Consequently, aniline (5a) was chosen as a robust test
(24) (a) Ebitani, K.; Nagashima, K.; Mizugaki, T.; Kaneda, K.
Chem. Commun. 2000, 869–870. (b) Blau, K.; Burgemeister, I.; Grasnick,
J.; Voerckel, V. J. Prak. Chem. 1991, 333, 455–466. (c) Blau, K.; Kapst,
€
U.; Voerckel, V. J. Prak. Chem. 1989, 331, 671–676. (d) Hoft, E.;
Schultze, H. Z. Chem. 1967, 7, 137–148.
5608
Org. Lett., Vol. 14, No. 21, 2012

entries 2ꢀ4). The best results were obtained with 10 mol %
of 1,10-phenanthroline (Table 3, entry 5).
Table 4. Scope of the Aerobic Amination of Cyclohexanones
Under optimized reaction conditions, 4a and 5a were
smoothly converted into the product 6aa in 91% yield.25
The scope of the new protocol is illustrated in Table 4.
Aniline (5a) was arylated with functionalized cyclohexanone
derivatives in good yields. Aromatic rings, linear or branched
alkyl chains, amides and esters were well tolerated on the
cyclohexanones. Electron rich (5g) and electron deficient
anilines (5j) were arylated in good yields. Halogen and tri-
fluoromethoxy groups were well tolerated. However, nitro-
and cyano-groups underwent undesired hydrogen transfer
reduction and only small quantities of the corresponding
diaryl amines were obtained. Good results were obtained
with 4-N,N-dimethylpyridine as ligand instead of 1,10-phe-
nanthrolineformeta-substitutedsubstrates (suchas4cor 5c).
However, heterocyclic anilines resulted in low yields, for
example, 2-amino pyridine was arylated in 15% yield.
In conclusion, two protocols have been developed for the
arylation of amines with nonaromatic ketones via a Pd-
catalyzed aerobic dehydrogenative aromatization. Second-
ary amines are arylated with 2-cyclohexen-1-ones in the
presence of a [(PMePh2)2PdCl2]/PhCO2H catalyst system,
whereas a Pd(OAc)2/1,10-phenanthroline catalyst mediates
the conversion of anilines into the corresponding diaryl
amines with cyclohexanones. Current investigations aim at
developing more reactive catalyst systems that allow broad-
ening the scope for the amines as well as extending the
aerobic dehydrogenative aromatization reaction on the
utilization of other heteroatom nucleophiles.
with Anilinesa
a 4aꢀj (0.24 mmol), 5aꢀl (0.2 mmol), Pd(OAc)2 (5 mol %), 1,10-
phenanthroline (10 mol %), O2 sat. toluene (0.5 mL), 135 °C, 36 h.
Isolated yields are based on 5. b 2.00 mmol scale. c 4-N,N-dimethyl-
aminopyridine (10 mol %) was used as ligand. d Yield was determined by
GC-analysis.
Acknowledgment. We thank the DAAD (postdoctoral
fellowship for T.K.), NSERC, FQRNT, the Canada Research
Chair (to C.-J.L.), the National Natural Science Foundation
of China (20902076, 21172185), and the Hunan Provincial
Natural Science Foundation of China (11JJ1003) for
financial support.
substrate (Table 3). N,N-Diphenylamine (6aa) was detected
in 67% yield in the presence of Pd(OAc)2 at 135 °C in
toluene (Table 3, entry 1). Premature catalyst deactivation
by precipitation of Pd-black was minimized by the addition
of oxidatively stable N- and O-containing ligands (Table 3,
Supporting Information Available. Full experimental
details and spectral data for all compounds are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(25) The reaction conditions do not apply for the arylation with
2-cyclohexen-1-one (16% of 6ab and 40% of 3aa have been detected with
5b and 2a, respectively).
The authors declare no competing financial interest.
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