Palladium-catalyzed amidation by chemoselective C(sp3)-H activation: Concise route to oxindoles using a carbamoyl chloride precursor

Article abstract of DOI:10.1002/anie.201108889

Quite select: A new strategy was developed for the synthesis of various oxindoles from carbamoyl chlorides. Under the optimum reaction conditions, with Ad₂PBu as a ligand, tBuCONHOH as an additive, and a CO atmosphere, selective C(sp³

Full text of DOI:10.1002/anie.201108889

Angewandte
Chemie
DOI: 10.1002/anie.201108889
Synthetic Methods
3
À
Palladium-Catalyzed Amidation by Chemoselective C(sp ) H
Activation: Concise Route to Oxindoles Using a Carbamoyl Chloride
Precursor**
Chihiro Tsukano, Masataka Okuno, and Yoshiji Takemoto*
As oxindole forms the core of many complex natural products
and is an important pharmacophore, its structure has
attracted attention for over a century.[1] The oxindole
structure has been constructed by the formation of a lactam
from aniline,[1a] Wolff–Kishner-like reduction of isatin,[1b]
oxidation of indole,[1c] transition metal catalyzed intramolec-
ular amidation,[1d–f] and the Heck reaction.[1g,h] However,
a concise method is still required for ready access to the
various oxindoles.
À
Scheme 1. Synthetic strategies for oxindole based on C H activation.
À
Recent research has focused on C H bond activation
À
after C C bond formation because the syntheses are straight-
2
3
À
À
forward and atom-economical. While catalytic C(sp ) H
presumably because of the difficulty of C(sp ) H activation
2
[13]
À
À
activation and subsequent C C bond formation have been
compared to C(sp ) H activation.
In the course of our
3
À
studied by many groups, the corresponding C(sp ) H fuction-
research, we have used carbamoyl chloride in palladium-
catalyzed reactions.[14] It is a useful intermediate for preparing
lactam moieties, and earlier reports suggest that it could be
applied to C H activation chemistry. Herein we describe
a new strategy for the preparation of various oxindoles from
a carbamoyl chloride precursor using C H activation chemis-
try. Selective C(sp ) H activation in the presence of a C(sp )
H bond is discussed.
alization is less developed.[2] With palladium(0)-catalyzed
3
À
C(sp ) H activation of a methyl group, Baudoin and co-
workers reported the synthesis of cyclobutenes,[3a–d] and
several groups[3e–6] described intramolecular cyclization of
a five-membered ring. Yu and co-workers also achieved Pd0/
À
À
3
[7]
3
2
À
À
À
PR3-catalyzed intermolecular arylation of C(sp ) H bonds.
3
À
C(sp ) H bond activation of methyl and methylene groups
[8,9]
À
and subsequent C C bond formation is challenging.
As
On the basis of an earlier report, we first examined the
reaction of (2,6-dimethylphenyl)(methyl)carbamoyl chloride
1a, which was prepared from the corresponding aniline 2a in
84% yield, with Pd(OAc)2 (3 mol%), PCy3·HBF4 (6 mol%),
and Cs2CO3 (1.1 equiv) in mesitylene at 1358C under
argon.[4a] 1,7-Dimethylindolin-2-one (3a) was obtained in an
approximately 10% yield along with a large amount of 2a
(Table 1, entry 1). As Fagnou et al. reported, addition of
pivalic acid (PivOH) gave a better yield,[4a] but 2a was still
obtained as a major product (entry 2). Interestingly, the
reaction without PivOH under a CO atmosphere gave
a comparable yield (entry 3). It is noteworthy that addition
of PivOH was compatible with the CO atmosphere, and the
reaction under these reaction conditions proceeded smoothly
to give 3a in good yield (entry 4). Next, the reaction
temperature, and several additives and ligands were exam-
ined. The reaction at 1208C had a comparable yield (entry 5)
to that obtained at 1358C. Although the Ac2NH and PivNH2
additives had little or no effect on the yield, N-hydroxypival-
amide (PivNHOH)[15] was a good additive and the cyclized
product 3a was obtained in 84% yield (entries 6–8). Addition
of a bulky alkyl ligand, such as tBu3P·HBF4[16] or tBu2PPh, was
not effective (entries 9 and 10). The ligand Ad2PBu[17]
(entry 11; optimum reaction conditions) gave better results
than PCy3·HBF4. We also tried to reduce the amount of the
palladium catalyst and the reaction with 1 mol% of Pd(OAc)2
and 2 mol% of Ad2PBu gave 3a in 80% yield, but additional
discussed by Fagnou and co-workers[4a] and Glorius and co-
workers,[9b] C(sp ) H activation proceeds selectively in the
2
À
3
À
presence of the competitive C(sp ) H bond. Thus, the
selectivity for C(sp ) H activation also needs to be addressed
for its application to constructing complex molecules.
Oxindole could be readily synthesized using C H activa-
tion chemistry. As shown in Scheme 1, there are three
possible synthetic routes: a) palladium(0)-catalyzed C(sp )
H bond activation after C C bond formation at the ortho
3
À
À
2
À
À
2
À
position of aniline, b) palladium(II)-catalyzed C(sp ) H bond
amidation, and c) C(sp ) H bond activation after insertion of
3
À
3
À
carbon monoxide (CO) or C(sp ) H bond amidation. Routes
a) and b) have been developed by the groups of Buchwald,[10]
Yu,[11] and Murakami[12] independently. Although route c)
would be a complementary method, it has not been reported,
[*] Dr. C. Tsukano, M. Okuno, Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto, 606-8501 (Japan)
E-mail: takemoto@pharm.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovation Area “Molecular Activation Directed toward Straight-
forward Synthesis” from The Ministry of Education, Culture, Sports,
Science and Technology (Japan) (C.T.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108889.
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Table 1: Investigation of the reaction conditions.[a]
To investigate the scope of the reaction we applied the
optimum reaction conditions to several carbamoyl chlorides,
1b–p, having various substituents on the aromatic ring and the
nitrogen atom. The substrates 1b–p were obtained from the
corresponding anilines 2b–p in moderate to excellent yield by
treatment with triphosgene and pyridine; the exceptions
being 1i and 1n. These low yields were presumably a result of
the instability of the products. Treatment of 1b, which has no
substituent on the aromatic ring (R = H), with Pd(OAc)2
(3 mol%), Ad2PBu (6 mol%), and Cs2CO3 (1.1 equiv) in
mesitylene at 1208C gave the cyclized product 3b in 62%
yield (Table 2, entry 1). The reactions of 1c and 1d, having
methyl groups at the C4- and C5-positions gave oxindoles 3c
and 3d, respectively (entries 2 and 3). These results indicate
that the substituent at the C6-position is not essential, and
starting materials with substituents at other positions can be
used. The reactions of 1e and 1 f gave oxindoles 3e and 3 f,
respectively, with excellent chemoselectivity (entries 4 and 5).
The desired product 3g was not obtained and degradation to
aniline 2g (81%) was observed in the case of (2,6-
diethylphenyl)(methyl)carbamoyl chloride 1g (entry 6).
Entry
Ligand
Additive and atmosphere
Yield [%][b]
3a
2a
1[c]
2[c]
3[c]
4[c]
5
6
7
8
9
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
Cy3P·HBF4
tBu3P·HBF4
tBu2PPh
none, Ar
PivOH, Ar
none, CO
ca.10
32
35
67
72
52
28
84
7
10
48
1
9
1
PivOH, CO
PivOH, CO
Ac2NH, CO
PivNH2, CO
PivNHOH, CO
PivNHOH, CO
PivNHOH, CO
PivNHOH, CO
3
11
10
6
35
6
10
11
27
88
Ad2PBu
[a] The mixture of 1a was treated with the palladium catalyst (3 mol%),
ligand (6 mol%), base (1.1 equiv), and additives in mesitylene at 1208C.
[b] Yield of isolated product. [c] The reaction was performed at 1358C.
Ad=adamantyl, Piv=pivaloyl.
À
Under these reaction conditions, C H activation of the
methyl group only occurred to form a five-membered ring.
The reaction of substrate 1h with an ethyl group on the
nitrogen atom proceeded smoothly to give oxindole 3h in
79% yield (entry 7). Several functional groups, such as
reduction in the amount of catalyst and ligand decreased the
yield. For example, with 0.3 mol% of Pd(OAc)2 the yield was
60% (data not shown).
Table 2: Reaction scope and limitations.[a,b]
Entry
1
Carbamoyl
chloride (1)
Oxindole (3)
Entry
6
Carbamoyl
chloride (1)
Oxindole (3)
Entry
11
Carbamoyl
chloride (1)
Oxindole (3)
2
7
12
3
4
5
8
13
14
15
9
10
[a] A solution of 1 in mesitylene was treated with Pd(OAc)2 (3 mol%), Ad2PBu (6 mol%), Cs2CO3 (1.1 equiv), and PivNHOH (0.3 equiv) under CO at
1208C. [b] Yield of isolated product indicated within parentheses. [c] Pd(OAc)2 (5 mol%), and Ad2PBu (10 mol%) were used.
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methoxy, chlorine, fluorine, ester, and trifluoromethyl, were
tolerated under these reaction conditions. The reactions of
1i–n gave the corresponding oxindoles 3i–n in moderate to
good yield (entries 8–13). In some cases, the corresponding
aniline 2 was observed as a by-product. The reaction of
carbamoyl chloride 1o with a nitro group gave the desired
oxindoles 3o along with a large amount of aniline 2o in
approximately 20% yield (entry 14). Surprisingly, the reac-
tion of 1p gave the oxindole 3p as the major product and
2
À
a small amount of by-product (15%) derived from C(sp ) H
3
À
Scheme 3. Possible reaction mechanism.
activation, which is a more favorable process than C(sp ) H
activation.[4a,6] Our conditions could be applied to substrates
with various functional groups to prepare oxindoles.
3
Because selective C(sp ) H activation was observed, we
along with the production of Pd0. The effect of PivNHOH is
À
3
À
investigated to see whether or not the selectivity could be
controlled by changing the electron density of the aromatic
ring. Compounds 4a–c and 5 were designed and treated under
the same reaction conditions (Scheme 2). The reactions of 4a
not clear, but we assume that it assists in benzylic C(sp ) H
activation from A.
3
À
In summary, a new strategy using C(sp ) H activation was
investigated for rapid access to various oxindoles using
carbamoyl chloride precursors. The reaction with Ad2PBu
as a ligand and PivNHOH as an additive under CO was
effective. Under the developed reaction conditions, selective
3
À
C(sp ) H activation occurred in the presence of the com-
2
À
petitive C(sp ) H bond. These results will be helpful in
synthesis of complex molecules using C(sp ) H activation.
Further mechanistic studies and synthetic application are in
progress.
3
À
Received: December 16, 2011
Revised: January 6, 2012
Published online: February 2, 2012
À
Keywords: C H activation · chemoselectivity · heterocycles ·
palladium · synthetic methods
.
Scheme 2. Investigation of the reaction conditions.
and 4b (R = Me and CF3) gave oxindoles 6a and 6b,
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À
respectively, each derived from C(sp ) H activation, and
a small amount of the isomers 7a and 7b (11–15%), which
were derived from C(sp ) H activation. Interestingly, with
the methoxy group as a substituent, the reaction of 4c
2
À
2
À
proceeded smoothly and the competitive C(sp ) H activation
was mostly suppressed. The reaction of 5, having a naphtha-
lene moiety, gave only oxindole 8. Additionally, when
carbamoyl chloride 1p was treated under the previously
reported reaction conditions (Pd(OAc)2 (3 mol%),
Cy3P·HBF4 (6 mol%) and Cs2CO3 (1.1 equiv) in mesitylene
at 1358C),[4a] no selectivity was observed and 3p (24%), 10
(23%), and the corresponding aniline (36%) were obtained
3
À
(data not shown). These results indicate that C(sp ) H
2
À
activation is more favorable than C(sp ) H activation under
these reaction conditions. To the best of our knowledge, this is
a first example of a chemoselective palladium(0)-catalyzed
3
À
C(sp ) H activation.
The proposed mechanism is shown in Scheme 3. The
reaction commences with oxidative addition of Pd0 to give the
intermediate A. Under the optimum reaction conditions, CO
elimination from A was suppressed by performing the
reaction under a CO atmosphere. The formation of a six-
3
membered transition state[3b,c,4] led to C(sp ) H activation to
À
give the intermediate B, which was converted into oxindole
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