Rhodium(III)-catalyzed oxidative ciH coupling of N-methoxybenzamides with aryl boronic acids: One-pot synthesis of phenanthridinones

Article abstract of DOI:10.1002/anie.201206890

General solution: An efficient rhodium-catalyzed dual CiH bond activation and cyclization of N-methoxybenzamides 1 with aryl boronic acids 2 (see scheme; Cp=Me₅C₅) provides a straightforward and general approach to the phenanthridinone structure, which occurs widely in natural products and drugs. Highly regioselective CiC and CiN bond formation under mild conditions afforded a wide range of substituted phenanthridinones 3. Copyright

Full text of DOI:10.1002/anie.201206890

Angewandte
Chemie
DOI: 10.1002/anie.201206890
À
C H Activation
À
Rhodium(III)-Catalyzed Oxidative C H Coupling of
N-Methoxybenzamides with Aryl Boronic Acids: One-Pot Synthesis of
Phenanthridinones**
Jaganathan Karthikeyan, Radhakrishnan Haridharan, and Chien-Hong Cheng*
À
À
In recent years, transition-metal-catalyzed directing-group-
boronic acids through one-pot C C/C N bond formation
under mild conditions. To the best of our knowledge, this is
À
assisted C H activation has emerged as a sustainable and
À
À
À
À
intriguing protocol for the construction of C C, C N, C O,
the first rhodium-catalyzed dual oxidative C H bond cou-
[1]
À
À
À
and C X bonds. In particular, one-pot C C/C N bond-
forming reactions have been used as key steps for the
synthesis of nitrogen-containing natural products and hetero-
cycles in drug discovery.[2] In this context, rhodium catalysts
have proven valuable for applications in the step-economical
synthesis of complex molecular scaffolds.[3] Although a vast
pling of two aromatic[4h,15] compounds to give a formal [4+2]
cyclization product (Scheme 1).
number of rhodium(III)-catalyzed directing-group-assisted
[4]
C H activation reactions of alkenes and alkynes[5] and
À
nucleophilic addition reactions[6] have been reported,
À
rhodium(III)-catalyzed oxidative C H coupling reactions
between arenes or between an arene and an organometallic
reagent remain relatively unexplored.[7,8]
Organoboron reagents are stable and powerful reagents
for versatile transformations, including the well-known
Suzuki–Miyaura coupling. However, very few examples of
the use of organoboron reagents as the coupling reagents in
Scheme 1. Synthesis of phenanthridinone derivatives.
The treatment of N-methoxybenzamide (1a) and phenyl-
boronic acid (2a) with [{RhCp*Cl2}2] (Cp* = Me5C5; 2 mol%)
and Ag2O (4 equiv) in methanol at 608C for 3 h afforded
phenanthridinone 3a in 94% yield (Table 1, entry 1). Control
experiments revealed that the reaction did not proceed in the
absence of rhodium. The presence of a silver salt is crucial to
the reaction. We examined various silver salts and found that
3a was formed in the highest yield with Ag2O. A combination
of Ag2O (2 equiv) and oxygen (1 atm) afforded 3a in 82%
yield. A series of solvents or solvent combinations and
oxidants were examined for the reaction of 1a with 2a. The
reaction in MeOH gave the best result (Table 1, entry 1).
Other solvents tested were less effective or totally ineffective
(see the Supporting Information).
We examined the reaction of various substituted N-
methoxybenzamides 1b–q with phenylboronic acid (2a)
under the optimized reaction conditions. Gratifyingly, excel-
lent yields and regioselectivity were generally observed for
these substrates with electron-donating or electron-withdraw-
ing groups (Table 1, entries 2–17).
À
palladium- and rhodium(I)-catalyzed C H activation reac-
tions are known.[9,10] In 2009, Miura and co-workers reported
a rhodium(III)-catalyzed oxidative coupling of aryl boronic
acids with alkynes to give naphthalenes and anthracenes.[11]
We have become interested in the use of N-methoxyben-
zamides as an important motif for rapid access to phenan-
thridinone derivatives, which are well-represented in natural
products and drugs.[12] Recently, Wang et al. and our research
group reported the palladium-catalyzed synthesis of phenan-
thridinone derivatives from N-methoxybenzamides with
iodoarenes[13a] and simple arenes,[13b] respectively. Although
a variety of methods have been documented, a more straight-
forward alternative method with wide scope under mild
conditions is desired for the synthesis of phenanthridinones.
À
Our continuing efforts in metal-catalyzed C H bond activa-
tion and cyclization reactions[13b,14] prompted us to explore the
reaction of N-methoxybenzamides with aryl boronic acids.
Herein we report the RhIII-catalyzed regioselective synthesis
of phenanthridinones from N-methoxybenzamides and aryl
À
C H bond activation at C2 in 1 is less likely than
activation at C6 if a meta substituent is present owing to the
stronger steric repulsion between the substituent and the
complex (see Table 1, entries 3, 4, 6, 11, and 16). In contrast,
in the case of 3,4-methylenedioxy-N-methoxybenzamide
[*] J. Karthikeyan, R. Haridharan, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
À
(1g), C H bond activation occurred at C2 instead of C6 to
À
afford 3g in 82% yield (Table 1, entry 7). In the C H bond
[**] We thank the National Science Council of the Republic of China
(NSC 98-2119-M-007-002-MY3) for support of this research.
activation of 1g, coordination of both the 3-oxy and the N-
methoxycarboxamide group probably occurs to cause activa-
tion at the C2 site.[14f]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206890.
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[a]
À
Table 1: Rhodium-catalyzed dual C H activation of N-methoxybenzamides with aryl boronic acids.
Entry
1
1
2
Product 3
Yield [%][b]
1a
1b
1c
1d
1e
1 f
1g
1h
1i
2a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
94
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
91
84
82
87
85
82
86
83
10
11
12
1j
1k
1l
2a
2a
2a
3j
3k
3l
86
81
89
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Table 1: (Continued)
Entry
1
2
Product 3
Yield [%][b]
13
14
15
16
17
18
1m
1n
1o
1p
1q
1a
2a
3m
3n
3o
3p
3q
3r
91
2a
2a
2a
2a
2b
84
87
76
79
90
19
20
1a
1a
2c
2d
3s
3t
84
77
21
22
1a
1a
2e
2 f
3u
3v
84
72
23
24
1a
1a
2g
2h
3w
3x
85
83
[a] Reactions conditions: 1 (0.60 mmol), 2 (1.20 mmol), [{RhCp*Cl2}2] (2.0 mol%), Ag2O (2.40 mmol), MeOH (3 mL), 608C, 3 h. [b] Yield of the
isolated product.
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To further explore the scope of the reaction, we inves-
tigated the reaction of various aryl boronic acids 2b–h with 1a
under the optimized conditions. Thus, the treatment of 1a
with 4-methylphenyl-, 4-bromophenyl-, and 4-biphenylbor-
onic acid (2b–d) provided phenanthridinones 3q–s in 77–
90% yield (Table 1, entries 18–20). The reactions of 3-
methoxyphenyl-, 3-chlorophenyl-, and 3-methyl-4-fluorophe-
nylboronic acid also proceeded with high regioselectivity to
give the less-hindered regioisomeric products 3u–w in good
yields (Table 1, entries 21–23). Notably, products 3u–w could
not be made by the previously reported palladium-catalyzed
reaction (Scheme 1) from 1 and an arene coupling partner
owing to the para reactivity of the arenes.[13b] Finally, 2-
naphthylboronic acid reacted with 1a to give the sterically
more hindered product 3x in 83% yield (Table 1, entry 24).
A plausible mechanism to account for the present reaction
of 1a with 2a to give 3a is proposed in Scheme 2. The catalytic
Scheme 3. Kinetic isotope effects for the rhodium-catalyzed oxidative
coupling of 1a with 2a.
results are in agreement with the proposed mechanism
(Scheme 2), according to which the binding of substrate 1a
(probably through the amide nitrogen atom) to rhodium
À
occurs prior to an irreversible C H bond cleavage to form
4.[16] The substrate-binding step would not show selectivity for
1a or [D5]1a, but different rates would be observed for the
À
following C H bond-cleavage step. As a result, a small KIE of
1.40 was observed for the intermolecular competition experi-
ment. In contrast, for the intramolecular H/D competition
À
experiment, the irreversible C H bond cleavage would be the
product-determining step, and a primary KIE was observed.
Finally, we conducted an intramolecular competition experi-
ment with the aryl boronic acid [D1]2a and 1a as substrates
for the formation of product [D1]3a. The KIE value kH/kD was
À
only 1.28. This observation indicates that the C H bond
cleavage of [D1]2a is not the product-determining step to
form intermediate 8; binding of the phenyl ring to the
À
rhodium center, which would not show selectivity for a C H
À
À
or C D bond of [D1]2a, probably occurs before the C H
bond cleavage.
In conclusion, we have successfully demonstrated a rho-
À
dium-catalyzed dual C H activation of N-methoxybenza-
mides with aryl boronic acids under mild conditions. The
catalytic reaction proceeds with high regioselectivity and
Scheme 2. A proposed mechanism for the catalytic reaction.
À
provides various substituted phenanthridinones through C C
À
cycle is probably initiated by the removal of a chloride ligand
from [{RhCp*Cl2}2] by Ag+, followed by N-metalation and
and C N bond formation in very good yields. This method is
complementary to previously reported methods based on the
use of palladium catalysts.[13] Further application of this
methodology in natural product synthesis is in progress.
À
a turnover-limiting C H activation to form a five-membered
rhodacycle 4. Transmetalation with 2a then leads to inter-
mediate 5, which undergoes reductive elimination to give the
ortho-arylated product 6 and a RhI species. RhI is reoxidized
to RhIII by Ag2O. Subsequent deprotonative coordination of
the nitrogen atom in 6 to RhIII forms intermediate 7. Further
Experimental Section
General procedure: A sealed tube (20 mL) containing [{RhCp*Cl2}2]
(8.5 mg, 0.012 mmol, 2.0 mol%), 1 (0.60 mmol), 2 (1.20 mmol), and
Ag2O (556 mg, 2.40 mmol) was evacuated and purged with nitrogen
gas three times. Methanol (3.00 mL) was then added with a syringe.
The reaction mixture was stirred at 608C for 3 h, then diluted with
dichloromethane (30 mL) and stirred in air for 10 min. The mixture
was filtered through a Celite and silica-gel pad and washed with
dichloromethane. Concentration of the filtrate and purification of the
residue on a silica-gel column with hexane/ethyl acetate as the eluent
afforded the desired product 3.
À
C H activation to give the seven-membered rhodacycle 8 is
followed by reductive elimination to afford 3a and RhI, which
is oxidized by Ag2O to regenerate the active RhIII species for
the next cycle. Strong evidence in support of 6 as a catalytic
intermediate was provided by the observation that when
compound 6 was heated under the catalytic conditions,
product 3a was formed in 94% yield (see the Supporting
Information for details).
To gain further understanding of the mechanistic details of
this catalytic reaction, we measured the kinetic isotopic
effects (KIEs) of the reaction by carrying out inter- and
intramolecular competition reactions (Scheme 3). An inter-
molecular KIE of kH/kD = 1.40 was observed for the compet-
itive reaction of 1a and deuterium-labeled [D5]1a with 2a to
give 3a. On the other hand, an intramolecular competition
experiment with [D1]1a and 2a showed kH/kD = 3.6. These
Received: August 25, 2012
Published online: October 26, 2012
À
Keywords: C H activation · cross-coupling ·
homogeneous catalysis · phenanthridinones · rhodium
.
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