Pd-catalyzed intermolecular ortho-C-H amidation of anilides by N-nosyloxycarbamate

Article abstract of DOI:10.1021/ja106364r

A palladium-catalyzed ortho-C-H amidation of anilides by N-nosyloxycarbamates was developed for the synthesis of 2-aminoanilines. This reaction can be carried out under relatively mild conditions and exhibits excellent regioselectivity and functional group tolerance. The amidation reaction is probably initiated by rate-limiting C-H cyclopalladation (k _H/k_D = 3.7) to form an arylpalladium complex, followed by nitrene functionalization.

Full text of DOI:10.1021/ja106364r

Published on Web 08/25/2010
Pd-Catalyzed Intermolecular ortho-C-H Amidation of Anilides by
N-Nosyloxycarbamate
Ka-Ho Ng, Albert S. C. Chan, and Wing-Yiu Yu*
State Key Laboratory for Chirosciences and The Institute of Molecular Technology for Drug DiscoVery and
Synthesis, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity,
Hung Hom, Kowloon, Hong Kong
Received July 18, 2010; E-mail: bcwyyu@inet.polyu.edu.hk
AcOH (20 equiv) as additive at 100 °C (entry 1). Previously, Lebel
Abstract: A palladium-catalyzed ortho-C-H amidation of anilides
and co-workers reported that N-tosyloxycarbamates are effective
by N-nosyloxycarbamates was developed for the synthesis of
2-aminoanilines. This reaction can be carried out under relatively
mild conditions and exhibits excellent regioselectivity and func-
tional group tolerance. The amidation reaction is probably initiated
reagents for the Rh-catalyzed intermolecular nitrene insertion of
aliphatic C-H bonds.12a As shown in Table 1, the N-pivalate (OPiv)
and N-pentafluorobenzoate (OPFB) derivatives are ineffective
reagents for the amidation reaction (entries 2 and 3); the best result
by rate-limiting C-H cyclopalladation (kH/kD ) 3.7) to form an
(70% yield) was achieved with ethyl N-nosyloxycarbamate 2a (entry
arylpalladium complex, followed by nitrene functionalization.
4). Without Pd(OAc)2, no 3aa was formed under the same
experimental conditions (entry 5).
Table 1. Reaction Optimizationa
2-Aminoanilines are essential precursors for benzimidazoles, 1,5-
benzodiazepines, quinoxalines, and benzotriazoles, which are
common scaffolds of many pharmaceutical products.1 Notable
examples include omaprazoles (Nexium), olanzapine (Zyprexa), and
bromonidine (Alphagan P) with a combined global sales value of
over $6.5 billion in 2008.2 Conventionally, 2-aminoanilines are
prepared from 2-fluoronitrobenzenes via a nucleophilic substitu-
additive
(20 equiv)
temp
(°C)
yieldb
(%)
entry
Pd
Y
solvent
tion-nitro group reduction sequence;1c,3 methods for direct ami-
nation of substituted aromatics are rare. Recently, Pd-catalyzed
aromatic C-H bond functionalizations proved to be an effective
strategy for C-C bond formation.4 With the assistance of a donor
group (e.g., pyridyl, imino, amido, carboxylato), highly ortho-
selective direct arylation and vinylation have been achieved.5,10b
To devise a straightforward synthesis of 2-aminoanilines, a protocol
for catalytic ortho-C-H amidation of anilides should be highly
desirable because of the improved synthetic efficiency.
Catalytic aromatic C-H amidation has been a subject of
extensive investigation.6 Since the pioneering work by Buchwald
and co-workers,7g Pd-catalyzed oxidative intramolecular amidation
has achieved significant advances.7 A majority of these transforma-
tions may proceed by initial arene C-H palladation, followed by
C-N bond formation probably via the PdII/PdIV manifold. Recently,
Hartwig and co-workers showed that the Pd0/PdII catalysis can also
effect the intramolecular aromatic C-H amination with oxime
esters.8 Yet, the analogous intermolecular amidation/amination
remains a challenge.9 Motivated by our earlier findings that
intermolecular coupling of organopalladium with nitrene would lead
to C-N bond formation,10e herein we describe a Pd-catalyzed
protocol for intermolecular C-H amidation of anilides by N-
nosyloxycarbamate.
1
2
3
4
5
6
7
8
Pd(OAc)2
OTs
OPFB
OPiv
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
ONs
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
--
dioxane 100
dioxane 100
dioxane 100
dioxane 100
dioxane 100
57
<5
0
70
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
--
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2(MeCN)2
Pd(OPiv)2
dioxane
DCE
toluene
THF
DMA
DMF
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
80
80
80
80
80
80
80
80
80
80
80
80
80
84
67
58
34
12
28
0
76
78
56
86
86
90c
9
10
11
12
13
14
15
16
17
--
--
--
--
Pd(OTs)2(MeCN)2 ONs
18d Pd(OTs)2(MeCN)2 ONs
--
a Conditions: 2′,4′-dimethylpivalanilide (0.2 mmol), N-oxycarbamate
(1 equiv), Pd (10 mol %), solvent (2 mL), 6 h. b Yields determined by
1H NMR. c Isolated yield
N-nosyloxycarbamate was used.
)
84%. d 1.2 equiv of ethyl
Employing Pd(OAc)2 (10 mol %) and 2a (1 equiv), changing
the solvent systems (e.g., DCE, toluene, THF, DMA, MeCN) did
not lead to more favorable outcomes (entries 7-12). Yet, the
amidation reaction was mostly suppressed in the MeCN/AcOH
system (entry 12). Interestingly, the Pd(OAc)2-catalyzed amidation
was found to be equally effective at 80 °C in dioxane without
AcOH, and 3aa was obtained in 76% yield (entry 13). Inspired by
the recent works of Yu11a and Llyod-Jones11c on the C-H
carbonylation of anilides and N-phenylureas, we found that treating
1a with Pd(OTs)2(MeCN)2 (10 mol %) and 2a (1.2 equiv) in
dioxane at 80 °C for 6 h would furnish 90% of 3aa (entry 18).
Initially, we found that N-pivalanilide 1a failed to undergo
amidation reaction upon treatment with Pd(OAc)2 (10 mol %), ethyl
carbamate, and K2S2O8 (5 equiv) in DCE at 100 °C, and the starting
anilide was completely recovered. While there are many successful
examples of ortho-C-H cleavage of the anilides by Pd(II) cataly-
sis,11 we sought to overcome the amidation problem by searching
for more effective reagents. After screening several reagents,
gratifyingly 3aa was obtained in 57% yield with ethyl N-
tosyloxycarbamate and Pd(OAc)2 (10 mol %) in dioxane with
9
12862 J. AM. CHEM. SOC. 2010, 132, 12862–12864
10.1021/ja106364r  2010 American Chemical Society

C O M M U N I C A T I O N S
With the optimized conditions in hand, we turned to examine
the scope and generality of the Pd-catalyzed amidation reaction
(Table 2). Acetanilides and benzamides can be converted to their
respective amides 3ba (52%) and 3ca (57%); however, pivalanilides
apparently produced better product yields (3aa: 84% yield) presum-
ably due to its favorable conformational properties. Parallel with
this finding, substrates with a tertiary amide group would undergo
facile ortho-C-H amidation in 68-85% yields for 3da-3fa. We
considered that this C-H amidation reaction would become
synthetically useful if amide groups of orthogonal reactivity can
be introduced to the anilides. Thus, further transformations of the
anilide scaffolds can be pursued by selective manipulation of the
nitrogen protecting groups.13 In this work, we studied the C-H
amidation reaction with 2,2,2-trichloroethyl (Troc) N-nosyloxycar-
bamate 2b and benzyl N-nosyloxycarbamate 2c as reagents. When
1a was treated with 2b/2c (1.2 equiv) and Pd(OTs)2(MeCN)2 (10
mol %) in dioxane at 80 °C for 6 h, the corresponding amides 3ab
and 3ac were obtained in 87% and 75% yield, respectively.
According to the literature, the N-Troc and N-benzyl groups can
be selectively removed by Zn reduction and hydrogenolysis without
affecting the N-pivaloyl group.13
than the ester group. In all cases, only monoamidation products
were obtained exclusively under our experimental conditions.15
It is plausible that the amidation reaction would be initiated by
cyclopalladation of 1a (Scheme 1). By means of competitive
experiments with acetanilide and acetanilide-d5 as substrates, a
primary kinetic isotope effect (kH/kD) ) 3.7 was obtained; this value
is compatible with the rate-determining C-H activation step.16
Consistent with this notion, the cyclopalladated complex 1a-Pd17
is an effective catalyst for the amidation reaction. It is noteworthy
that the stoichiometric reaction of 1a-Pd with 2a alone would afford
3aa in only 45% yield. However, when 1a-Pd was treated with 2a
(2 equiv) in the presence of free 1a (2 equiv), 3aa was formed in
70% yield.18 While the role of the free 1a is unclear, however, the
added anilide may be needed to stabilize some reactive Pd species
after the C-N bond forming step.
Scheme 1. Proposed Mechanism
Table 2. Substrate Scope Studiesa b
,
To probe the nature of the reactive nitrogen species,19 we
performed the stoichiometric reaction in the presence of inorganic
bases (e.g., K2CO3). It is known that treatment of arylsulfonyloxy-
carbamates with inorganic bases would spontaneously produce
reactive nitrene species.20 As expected, treatment of 1a-Pd (1 equiv)
and 1a (2 equiv) with 2a (2 equiv) in the presence of K2CO3 (2
equiv) in dioxane at 80 °C, furnished 3aa in 74% yield. Based on
this finding, it is possible that the N-nosyloxycarbamate produced
nitrene, which would then undergo formal nitrene insertion to the
cyclopalladated complex via a metal-nitrene pathway.21 Alterna-
tively, the C-N bond formation may involve the formation of a
Pd(IV)22b,c or a dimeric Pd(III) complex,18a,22a and its subsequent
reductive elimination would afford the product amide. A detailed
mechanistic investigation is underway.
In summary, we developed an intermolecular ortho-C-H ami-
dation of anilides using N-nosyloxycarbamate and have demon-
strated its high functional group tolerance, regioselectivity, and
scope under relatively mild conditions. In view of the synthetic
utility of 2-aminoanilines, this reaction would be of broad interest
to synthetic chemistry.
Acknowledgment. We thank the financial support from the
Hong Kong Research Grants Council (PolyU5017-07P; SEG_01
PolyU) and The Area of Excellence Scheme (AoE/P-10-01)
administered by the Hong Kong University Grants Committee.
K.H.N. thanks the Hong Kong Polytechnic University for the award
of a Postgraduate Studentship.
a Conditions: anilide (0.2 mmol), N-nosyloxycarbamate (1.2 equiv),
[Pd(OTs)2(MeCN)2] (10 mol %), 1,4-dioxane (2 mL), 80 °C, 6 h.
b Isolated yields. c Batchwise addition of 2a (2 × 1.2 equiv/6 h),12 h;
40% starting anilide was recovered. d Reaction run for 12 h.
As shown in Table 2, electron-donating (Me, benzyl, OMe) and
-withdrawing (F, Cl, Br) groups are tolerated under the amidation
conditions. Interestingly, anilides bearing a vinyl substituent can
be transformed to the expected amide 3ra in 50% yield. Note that
40% of the starting anilide was recovered after the reaction; this
reaction exhibits a mass balance of ca. 85%. Liu and Xu reported
earlier that O-pivaloyl esters would undergo Pd-catalyzed ortho-
C-H arylations.14 In this work, treating the pivalanilide containing
a pivaloyl ester moiety with 2a afforded 3sa exclusively in 67%
yield, suggesting that the amide group is a stronger directing group
Supporting Information Available: Experimental procedures,
characterization data, and experimental data for reaction optimization.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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