Facile Synthesis of Isoindolinones via Rh(III)-Catalyzed One-Pot Reaction of Benzamides, Ketones, and Hydrazines

Article abstract of DOI:10.1021/acs.orglett.5b01016

A Rh(III)-catalyzed one-pot reaction of benzamides, ketones, and hydrazines for facile access to isoindolinones is reported. In this method, various ketones are transformed into donor-donor diazo compounds, which sequentially engage in insertion with benzamides under Rh(III) catalysis to generate N-substituted quaternary isoindolinones. (Chemical Presented).

Full text of DOI:10.1021/acs.orglett.5b01016

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Isoindolinones via Rh(III)-Catalyzed One-Pot
Reaction of Benzamides, Ketones, and Hydrazines
Yan Zhang, Dahai Wang, and Sunliang Cui*
Institute of Materia Medica and College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058,
P. R. China
*
S Supporting Information
ABSTRACT: A Rh(III)-catalyzed one-pot reaction of benza-
mides, ketones, and hydrazines for facile access to
isoindolinones is reported. In this method, various ketones
are transformed into donor−donor diazo compounds, which
sequentially engage in insertion with benzamides under
Rh(III) catalysis to generate N-substituted quaternary
isoindolinones.
soindolinones represent an important class of nitrogen-
formation and subsequent [4 + 2], [4 + 1], and [4 + 3]
cyclization.
I
containing heterocycles, which widely exist in natural
1
products and biologically active compounds. Representative
examples are depicted in Figure 1. Pestalachloride A was
Diazo compounds are reactive carbon components in
rhodium catalysis, the donor group of diazo compounds
stabilizing the electron-deficient metal carbenes and attenuating
8
their reactivity. Recently, Rovis reported a Rh(III)-catalyzed
C−H activation/cyclization of benzamides with donor/accept-
or diazo compounds as a method for accessing to
9
isoindolinones (eq 1), and more recently, Yu also
Figure 1. Representative structures involving isoindolinone.
identified as an antifungal metabolite from the plant endophytic
2
fungus Pestalotiopsis adusta by Che and co-workers, lennox-
amine is also an isoindolinone alkaloid isolated from the
3
Chilean barberries species, and chlortalidoneis a diuretic drug
4
used to treat hypertension. Functionalized isoindolinones have
also been investigated as HIV-1 reverse transcriptase inhibitors5,
aldolase reductive inhibitors, and also chemical sensors.
Therefore, the ability to access these types of heterocycles
from simple materials is important.
Rh(III)-catalyzed direct functionalization of C−H bonds has
become a powerful tool for C−C, C−O, and C−N bond
formation, offering a straightforward entry into the synthesis of
independently reported the same reaction using acceptor/
10
acceptor diazo compounds (eq 2). Meanwhile, Zhu and co-
workers developed an alternative synthesis of isoindolinones via
Rh(III)-catalyzed C−H activation/cyclization of benzamides
6
various valuable heterocycles. In particular, Rh(III)-catalyzed
C−H activation/cycloaddition of a benzamide with an alkyne,
alkene, allene, and diazo compound have been well developed
by Miura, Fagnou, Glorius, Li, Rovis, etc. over the past five
Received: April 9, 2015
7
years. Mechanistically, these reactions involve rhodacycle
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01016
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Organic Letters
Letter
11
with electron-defficient olefins (eq 3). Despite this, the
development of Rh(III)-catalyzed C−H activation of benza-
mides and the coupling with donor−donor diazo compounds
remains a challenge and of importance.
Continuing our interest in Rh(III)-catalyzed C−H activa-
12
tion/cyclization for heterocycles synthesis, herein we report a
facile synthesis of isoindolinones with an N-substituted
quaternary center via a Rh(III)-catalyzed one-pot reaction of
Figure 2. ORTEP representation of the X-ray crystal structure of 4a.
benzamides and ketones using MnO as oxidant. The main
a
2
Table 2. Substrate Scope of Benzamides
advantage of the method is that it features simple starting
materials, mild reaction conditions, and easy operation (eq 4).
We initially commenced our study by investigating the one-
pot reaction of acetophenone 1a, hydrazine 2, and N-
(
pivaloyloxy)benzamide 3a with a catalytic amount of
[
Cp*RhCl ] in CH CN at room temperature. To our delight,
2 2 3
we found that formation of the isoindolinone product 4a
occurred in 45% yield (Table 1, entry 1). Our survey of
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive
CsOAc (1 equiv)
solvent
yield (%)
1
2
3
4
5
6
CH CN
45
20
50
36
53
3
CsOAc (1 equiv)
MeOH
DCM
toluene
THF
CsOAc (1 equiv)
CsOAc (1 equiv)
CsOAc (1 equiv)
a
c
Isolated yields are given. Reaction conditions: 1 (0.34 mmol), 2 (0.4
HOAc (0.2 equiv)/CsOAc (1 equiv)
HOAc (0.2 equiv)/CsOAc (1 equiv)
HOAc (0.2 equiv)/CsOAc (1 equiv)
HOAc (0.2 equiv)/CsOAc (1 equiv)
HOAc (0.2 equiv)/CsOAc (1 equiv)
THF
72 (75)
d
mmol), HOAc (0.04 mmol), THF (2 mL), 2−3 h, 60 °C; then 3 (0.2
7
THF
41
38
0
e
mmol), MnO (14 equiv), CsOAc (0.2 mmol), [Cp*RhCl ] (2.5 mol
2
2 2
8
THF
f
%), rt, 8−10 h.
9
THF
g
1
0
THF
75
a
moderate to good yields (40%−72%), thus offering ample
opportunity for further derivatization. Additionally, when meta-
substituted benzamides were applied, good regioselectivity
favoring activation of the less hindered C−H bond was
observed, and a single product (4j) was obtained. Moreover,
polysubstituted acetophenones were also tolerated in this
process affording isoindolinones, and interestingly, when
piperonyloyl amide was used, the reaction favored activation
of the more hindered C−H bond to deliver the product 4k in
excellent yield. Heterocyclic amides such as thiophene-3-
carboxamide were also applicable in this transformation to
afford the corresponding fused lactam analogue 4l. Additionally,
N-(pivaloyloxy)-1H-pyrrole-1-carboxamide and N-(pivaloy-
loxy)-1H-indole-1-carboxamides reacted smoothly to deliver
the privileged imidazolidinones 4m−p.
Next, a variety of aryl ketones were utilized to construct
diverse isoindolinones (Table 3). Differential substitution on
the aromatic ring of acetophenones gave the desired products
in good yields (5a,b). Heterocyclic ketones were tolerated and
proceeded well in this process to deliver the products in good
yields (5c,d). Moreover, functionalized ketones were applicable
regardless of aryl substitution or alkyl substitution to produce
the isoindolinones in good yields (5e−i). It should be noted
that cyclic ketones such as 9-fluorenone and N-methylisatin
proceeded well in this one-pot transformation to deliver the
fused isoindolinones (5j−l). Therefore, this process represents
a general and distinct approach toward privileged isoindoli-
nones from simple starting materials.
Reaction conditions: 1a (0.34 mmol), 2 (0.4 mmol), solvent (2.0
b
mL), 3a (0.2 mmol), [Cp*RhCl ] (2.5 mol %), and additive. Yields
2
2
c
of isolated products. The value in parenthese refers to 1 mmol scale.
d
e
f
Conducted at 50 °C. 6.0 equiv of MnO . Pd(OAc) was used as
2
2
g
catalyst. Acetophenone and hydrazine were replaced with acetophe-
none hydrazone.
solvents (entries 2−5) showed that THF was optimal for
furnishing the product in 53% yield (entry 5). Interestingly, the
catalytic addition of acetic acid could facilitate this reaction to
improve the yield to 72% yield (entry 6), probably because
acetic acid could accelerate formation of the hydrazone
intermediate, and the yield of the 1 mmol scale could be up
to 75%. An attempt to lower MnO loading led to a decreased
2
13
yield of 41% (entry 7). Further optimization showed that
increasing the temperature to 50 °C also resulted in a lower
yield (entry 8). Replacing [Cp*RhCl2]2 with Pd(OAc)2
completely shut down the reactivity, demonstrating the
necessity of the Rh(III) catalyst (entry 9), while the direct
use of (1-phenylethylidene) hydrazine would deliver the
product in a slightly higher yield (entry 10). The structure of
isoindolinone 4a was unambiguously confirmed by single-
14
crystal X-ray analysis (Figure 2).
With the optimized conditions in hand, we evaluated the
generality of this reaction. As depicted in Table 2, various
benzamides with valuable functional groups like isopropyl,
methoxy, chloro, iodo, and nitro reacted smoothly in this one-
pot reaction to afford the corresponding isoindolinones 4a−i in
B
DOI: 10.1021/acs.orglett.5b01016
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Organic Letters
Letter
a
Table 3. Substrate Scope of Aromatic Ketones
acetophenone and hydrazine would also lead to the same
product.
In summary, we have developed a unique Rh(III)-catalyzed
one-pot reaction of benzamides, ketones, and hydrazines for
facile access to functionalized isoindolinones. Its main
advantage is that it features simple starting materials, mild
reaction conditions, and high efficiency.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Detailed experimental procedures and compound character-
ization. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01016.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: slcui@zju.edu.cn. Tel: (86) 571-8898 1456.
Notes
The authors declare no competing financial interest.
a
Isolated yields are given. Reaction conditions: 1 (0.34 mmol), 2 (0.4
mmol), HOAc (0.04 mmol), THF (2 mL), 2−3 h, 60 °C; then 3 (0.2
mmol), MnO (14 equiv), CsOAc (0.2 mmol), [Cp*RhCl ] (2.5 mol
ACKNOWLEDGMENTS
■
2
2 2
b
We are grateful for financial support from NSFC of China
%
), rt, 8−10 h. Corresponding hydrazones were used in this reaction.
c
(21202143, 21402163).
PMP = p-methoxyphenyl.
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DOI: 10.1021/acs.orglett.5b01016
Org. Lett. XXXX, XXX, XXX−XXX