Palladium-catalyzed oxidative aminocarbonylation: A new entry to amides via C-H activation

Article abstract of DOI:10.1021/ol401419u

A novel palladium-catalyzed oxidative aminocarbonylation reaction via C(sp³)-H activation was established, which provides a convenient and general method for the construction of arylacetamides via the carbonylation reaction of alkyl aromatics and amines. By using this protocol, the marketed drug ibuprofen could be easily obtained.

Full text of DOI:10.1021/ol401419u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Oxidative
Aminocarbonylation: A New Entry
to Amides via CÀH Activation
Pan Xie, Chungu Xia, and Hanmin Huang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
hmhuang@licp.cas.cn
Received May 19, 2013
ABSTRACT
A novel palladium-catalyzed oxidative aminocarbonylation reaction via C(sp3)ÀH activation was established, which provides a convenient and
general method for the construction of arylacetamides via the carbonylation reaction of alkyl aromatics and amines. By using this protocol, the
marketed drug ibuprofen could be easily obtained.
Transition-metal-catalyzed direct and selective function-
alization of CÀH bonds has become one of the most
promising synthetic strategies in organic synthesis.1 As
an attractive strategy for constructing a diversity of carbonyl
compounds without the need for a prefunctionalized site,
transition-metal-catalyzed CÀH carbonylation reactions
have attracted broad interest from both academia and
industry.2 Since the pioneer studies of Fujiwara in 1980,3 a
growing number of CÀH carbonylation catalyses that
allow for carbonyl group formation have been developed
by Chatani, Orito, Yu, and others.4,5 However, most of
the current CÀH carbonylation reactions for forming
carbonyl group are typically limited to substrates with
directing groups. To the best of our knowledge, only a few
examples have been demonstrated on the transition-metal-
catalyzed nondirected C(sp3)ÀH bonds carbonylation
with CO,6 which indicated that the direct carbonylation
of simple C(sp3)ÀH is still a great challenge.
Amides are important chemicals that exist in pharma-
ceuticals, natural products, and many functional mate-
rials.7 As a type of important amides, arylacetamides have
gained considerable attention because of their pharmaco-
logical and biological activities.8 Drivenby this prevalence,
various methods have been developed for the synthesis of
these compounds.9 Among methods documented, direct
amidation of carboxylic acids10 or their derivatives11 pro-
vides the most straightforward procedure for the synthesis
of arylacetamides (Scheme 1, paths A and B). However, these
reactions generally require harsh conditions (>150 °C) or
multistep operations. Alternatively, transition-metal-
catalyzed aminocarbonylation has emerged as an efficient
strategy toward such types of compounds. Although
some interesting examples of palladium-catalyzed amino-
carbonylation of benzyl halides with ammonia and
primary amines have recently been described (Scheme 1,
path C),12 the aminocarbonylation of benzyl halides with
secondary amines and aliphatic primary amines was
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r
10.1021/ol401419u
XXXX American Chemical Society

via C(sp3)ÀH bond functionalization reactions.13 Re-
cently, we showed that Pd(Xantphos)Cl2 is capable of
catalyzing the carbonylation of alkyl aromatics to afford
the arylacetic acid esters via nondirected CÀH activa-
tion.6c Herein, we wish to report a novel methodology for
the synthesis of arylacetamides via a palladium-catalyzed
aminocarbonylation of alkyl aromatics with different
amines.
Scheme 1. Synthetic Methods of Phenylacetamides
On the basis of our experience with palladium-catalyzed
carbonylation reactions, toluene (1a) and dibenzylamine
(2a) were chosen as model substrates, and the reaction was
performed under 10 atm of CO at 120 °C for 16 h. With
Pd(Xantphos)Cl2 as the catalyst precursor and TBP as the
oxidant, N,N-dibenzyl-2-phenylacetamide 3aa was ob-
tained in 41% yield, while other oxidants gave lower yields
(Table 1, entries 1À5). Furthermore, when the ratio of
TBP/2a was increased from 1.2/1 to 1.8/1, the yield of
product 3aa dramatically increased to 71% (Table 1, entry 6).
With 1.8 equiv of TBP as the oxidant, other reaction
expected to be a very challenging endeavor because these
amines tend to react with benzyl halides directly to form
benzyl amines due to their high nucleophilicity. As a
result, further development of new and versatile strategies
for establishing an efficient aminocarbonylation reaction
toward such arylacetamides is highly desired. One of the
goals in our laboratory is the development of some
strategies to synthesize the valuable organic compounds
Table 1. Optimization of the Reaction Conditionsa
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entry
[M]
PdCl2
ligand
oxidant
TBP
yield [%]b
1b
2b
3b
4b
5b
6
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
41
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
TBHP
DCP
NR
40
NFSI
PhI(OAc)2
TBP
NR
NR
71
ꢀ
J. G.; Tyler, S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-
7
Pd(CF3COO)2 Xantphos
TBP
39
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Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312. (n) Lu, Y.; Leow, D.;
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8
Pd2(dba)3
Xantphos
Xantphos
Xantphos
Xantphos
BINAP
TBP
53
9
RhCl3 XH2O
TBP
38
3
10
11
12
13
14
15c
16d
17e
18f
19
NiBr2
TBP
NR
NR
NR
21
RuCl3 XH2O
TBP
3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
TBP
MeO-BIPHIEP TBP
DPPE
TBP
TBP
TBP
TBP
TBP
TBP
NR
58
Xantphos
Xantphos
Xantphos
Xantphos
61
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bond carbonylation, see: (a) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 17378. (b) Hasegawa, N.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
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Watanabe, J.; Uchida, Y.; Taniguchi, H. Chem. Lett. 1989, 1687. (b)
Ryu, I.; Tani, A.; Fukuyama, T.; Ravelli, D.; Fagnoni, M.; Albini, A.
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0
a General conditions: 1a (20 mmol), 2a (0.2 mmol), [M] (5 mol %),
ligand (5 mol %), oxidant (0.36 mmol), CO (10 atm), at 120 °C for 16 h,
isolated yield. b Oxidant (0.24 mmol). c CO (5 atm). d CO (20 atm).
e 100 °C instead of 120 °C. f 140 °C instead of 120 °C.
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parameters were investigated. Screening of metal salts
revealed that PdCl2 was the most effective palladium
source (Table 1, entries 7À11). To achieve better results,
various commercially available phosphine ligands were
screened, and the results proved that Xantphos was the
best choice (Table 1, entries 12À14). After these optimized
conditions were developed, the effects of pressure of CO
and temperature were also examined. With either an
increase or decrease of the pressure of CO, inferior results
were observed. The best yield of3aa was obtained whenthe
reaction was conducted at 120 °C. Finally, control reac-
tions revealed that the desired product was not detected at
all in the absence of palladium catalyst (Table 1, entry 19).
Taken together, we can conclude that the carbonylation
was carried out by stirring a solution of toluene, dibenzyl-
amine, 5 mol % of Pd(Xantphos)Cl2, and 1.8 equiv of TBP
at 120 °C under 10atm ofCOfor 16h togivethe product in
the best yield.
aliphatic benzylamines were used as substrates. For exam-
ple, N-benzylpropan-1-amine smoothly furnished the de-
sired amide 3ah in 71% yield, but the sterically hindered
N-benzyl-2-methylpropan-2-amine gave the product 3ai in
58% yield. Besides benzylamines, the reactions of other
secondary amines also proceeded smoothly and gave the
amide products in moderate yields(Scheme 2, 3aj, 3ak, and
3al). Not surprisingly, the aminocarbonylation reaction of
the primary amines proceeded smoothly. Although the
reaction of aniline yielded the corresponding product in
lower yield, the reactions of aliphatic primary amines
proceededsmoothly. Bothcyclohexanamine and n-propyl-
amine could be utilized as amine sources, and the corre-
sponding products were obtained in 70 and 65% yields,
respectively. Notably, when the catalyst loading was de-
creased from 5 to 0.125 mol %, product 3ad was obtained
in 39% yield with a turnover number (TON) of 312 (see
Supporting Information), which could increase the practi-
cality of our reaction process dramatically.
With the optimized reaction conditions in hand, we next
investigated the substrate scope of amines. First, a series of
substituted dibenzylamines were subjected to the present
reaction, and the corresponding carbonylation products
3aaÀ3ae were obtained in moderate to good yields.
Among them, N-benzyl-1-(naphthalen-1-yl)methanamine
was transformed into the corresponding amide in 82%
Table 2. Substrate Scope of Alkyl Aromaticsa
Scheme 2. Substrate Scope of Aminesa
entry
R
product
yield (%)
1
H
3ad
3bd
3cd
3dd
3ed
3fd
82
82
83
85
85
74
52
52
67
70
67
2
2-Me
3
3-Me
4
4-Me
5
4-MeO
4-F
6
7
2-Cl
3gd
3hd
3id
8
3-Cl
9
4-Cl
10
11b
1-naphthyl
2-naphthyl
3jd
3kd
a General conditions: 1 (20 mmol), 2d (0.2 mmol), Pd(Xantphos)Cl2
(5 mol %), TBP (0.36 mmol), CO (10 atm), at 120 °C for 16 h, isolated
yield. b 1k (10 mmol) in 1 mL of benzene.
To further explore the synthetic potential of this process,
a series of alkyl aromatics were subjected to this reaction
under the optimized reaction conditions. As summarized
in Table 2, various alkyl aromatics were found to be
tolerated in this carbonylation process. For example, sub-
strates bearing electron-rich substituents (Table 2, entries
2À5) on the aryl ring underwent this reaction to furnish the
corresponding products in high yields (82À85%). How-
ever, substrates containing an electron-withdrawing group
encountered some difficulties in our procedure, affording
the desired amides in relatively lower yields under the same
conditions (Table 2, entries 6À9). It is worth noting that
the tolerance of halogens on the aromatic ring in this
transformation offers an opportunity for subsequent
cross-coupling, which facilitates expedient synthesis of com-
plex arylacetamides. An obvious steric hindrance effect on
a Reaction conditions: 1a (20 mmol), 2 (0.2 mmol), Pd(Xantphos)Cl2
(5mol%), TBP(0.36mmol), CO(10atm), at120°C for 16 h, isolated yield.
yield. N-Benzyl aromatic amines were also suitable sub-
strates, and moderate yields were obtained. However,
an obvious steric hindrance effect was observed when
Org. Lett., Vol. XX, No. XX, XXXX
C

the reactivity was also observed: 4-chlorotoluene could
give the amide product in 67% yield, but 2-chlorotoluene
gave the corresponding product in 52% yield (Table 2,
entry 7 vs entry 9). Besides, 1-methylnaphthalene also
worked well in our reaction system, furnishing the corre-
sponding amide in 70% yield (Table 2, entry 10). With
benzene as solvent, the solid substrate 2-methylnaphtha-
lene was smoothly converted to the corresponding product
in 67% yield (Table 2, entry 11).
Through further optimization of the reaction conditions
(see Supporting Information), we were delighted to find
that the challenging ethylbenzene was successfully em-
ployed in the aminocarbonylation reaction, and the corre-
sponding amide 3ld was obtained in 75% yield when the
pressure of CO was increased to 40 atm and an additional
2.5 mol % of Xantphos was introduced into the catalytic
system. The carbonylation reaction with other secondary
amines proceeded smoothly and gave rise to the corre-
sponding amides in moderate to good yields (Scheme 3).
Furthermore, 1-ethyl-4-isobutylbenzene 1m was success-
fully converted to the corresponding amide 3md in good
yield under the above conditions. Through simple hydro-
lysis, this amide 3md could be transformed into ibuprofen,
which has been widely used for pain relief, fever reduction,
and to reduce swelling.
product was not formed via the aminolysis of tert-butyl-2-
phenylacetate.6c The tribenzylamine could be generated
from the reaction of toluene and dibenzylamine in the
presence of TBP (Scheme 4, eq 2), indicating that the
aminyl radical might be involved in the present reaction.
However, amide 3aa could not be generated from the
carbonylation of tribenzylamine under the standard con-
ditions (Scheme 4, eq 3), which revealed that triben-
zylamine was not invovled in the present carbonylation
process.
Scheme 4. Controlling Experiments
Although the detailed reaction mechanism remains to be
elucidated, we believe that the aminocarbonylation reac-
tion proceeds via a benzylpalladium intermediate which
could be formed via direct oxidative addition of radicals to
Pd(0).6c CO insertion and subsequent reductive elimina-
tion would afford the amide product, and the Pd(0) species
could be regenerated to complete the catalytic cycle.
Insummary, we have successfullydevelopeda novel syn-
thetic method toward arylacetamides through palladium-
catalyzed oxidative CÀH aminocarbonylation of simple
alkyl aromatics. The catalysis accommodates a diverse
set of functional groups including fluoride, chloride, as
well as alkoxy groups. Moreover, this reaction can also be
employed to synthesize the 2-arylpropanamides via CÀH
activation, which are precursors for many important mar-
keted drugs. Further investigations to gain a detailed
mechanistic understanding of this reaction and developing
more synthetically useful and mechanistically novel trans-
formation by exploration of this powerful CÀH activation
strategy are currently in progress.
Scheme 3. Aminocarbonylation of Ethylbenzene Derivativesa
a Reaction conditions: 1 (20 mmol), 2 (0.2 mmol), Pd(Xantphos)Cl2
(5 mol %), Xantphos (2.5 mol %), TBP (1 mmol), CO (40 atm), at 120 °C
for 16 h, isolated yield. b 1m (30 mmol), 2d (0.3 mmol), TBP (1.5 mmol).
Acknowledgment. This work was supported financially
by the Chinese Academy of Sciences and National Natural
Science Foundation of China (21222203, 21172226, and
21133011).
To gain insight into the mechanism, the following experi-
ments were carried out. When radical scavengers, such as
TEMPO or 1,1-diphenylethylene, were introduced into the
standard reaction, the desired aminocarbonylation was
stopped, which suggested that a free radical process
was involved with aminocarbonylation (see Supporting
Information). Subsequently, when tert-butyl-2-phenylace-
tate served as a substrate to react with dibenzylamine
under other identical conditions (Scheme 4, eq 1), no
desired product was detected, indicating that the amide
Supporting Information Available. Experimental de-
tails and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX