Rh(III)-catalyzed C-H activation/cyclization of oximes with alkenes for regioselective synthesis of isoquinolines

Article abstract of DOI:10.1039/c6ob00942e

A Rh(iii)-catalyzed C-H activation/cyclization of oximes and alkenes for facile and regioselective access to isoquinolines has been developed. This protocol features mild reaction conditions and easily accessible starting materials, and has been applied to the concise synthesis of moxaverine. A kinetic isotope effect study was conducted and a plausible mechanism was proposed.

Full text of DOI:10.1039/c6ob00942e

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Rh(III)-catalyzed C−H activation/cyclization of oximes with alkenes
for regioselective synthesis of isoquinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Renjie Chen, Jifeng Qi, Zhenjun Mao, and Sunliang Cui*
DOI: 10.1039/x0xx00000x
www.rsc.org/
(a)
A
Rh(III)-catalyzed C−H activation/cyclization of oximes and
alkenes for facile and regioselective access to isoquinolines has
been developed. This protocol is featured with mild reaction
conditions and easy accessible starting materials, and has been
applied to concise synthesis of Moxaverine. Kinetic isotope effect
study was conducted and a plausible mechanism was proposed.
X
Rh, Ru
N
N
+
R
R
R
(X = OH, H)
R
(b)
Isoquinoline represents an important class of structural motifs
existing in numerous pharmaceuticals, natural products and
ligands.1 Therefore, various methods have been developed for
accessing those compounds.2 In recent years, the transition-
metal-catalyzed C−H activation/cyclization of aryl oximes,
imines, azides with internal alkynes has been explored for the
achievement of isoquinolines (Fig 1a).3 However, these
protocols suffer from difficult regiocontrol. Recently, Glorius
(Fig 1b) and Cheng (Fig 1c) have independently found that 1,3-
dienes and geminal-substituted vinyl acetate could serve as
cyclization partners in Rh(III)-catalysis for regioselective
synthesis of isoquinolines.4 Despite these advances, the
development of general and efficient method for the
construction of these compounds, especially with good
regioselectivity and broad functional group tolerance, still
remains important and interesting, since various privileged
biologically interesting isoquinolines bear functional groups
like ketone.
OPiv
+
N
N
Rh
Rh
N
R
R
(c)
OPiv
+
OAc
N
R
R
N
(d) This work
R1
R3
R1
Rh(III)
R3
N
+
OH
R2
R2
- simple starting materials
- mild reaction conditions
- good functional group tolerance
R2 = alkyl, aryl, ketone, ester
R3 = CO(X)
- total synthesis application
Recently,
Rovis
reported
Rh(III)-catalyzed
C−H
Represented privileged isoquinolines
activation/cyclization of oxime esters and alkenes for accessing
pyridines,5 indicating that alkenes act as a coupling component
in the cyclization process and could probably be applied to
isoquinoline synthesis. In continuation of our interests in
Rh(III)-catalyzed C−H functionalization for biologically
interesting small molecule synthesis.6 Herein, we would like to
report a Rh(III)-catalyzed C−H activation/cyclization of oximes
with alkenes for regioselective synthesis of isoquinolines,
MeO
MeO
Et MeO
Me
O
N
N
N
O
MeO
MeO
O
EtO
EtO
Pulcheotine
Moxaverine
Dimoxyline
Fig. 1 Rh(III)-catalyzed regioselective isoquinoline synthesis.
and its application in total synthesis of Moxaverine (Fig. 1d).
We commenced our study by investigating oxime 1a and
acrolein 2a, with [Cp*RhCl2]2 as catalyst and the addition of
PivOH at room temperature in the solvent of CH3CN. With the
addition of 2 equivalent amount of CsOAc, we were pleased to
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, 310058, P. R. China.
Email: slcui@zju.edu.cn
† Electronic Supplementary Information (ESI) available: Detailed synthetic
procedure and characterization of new compounds. See DOI: 10.1039/x0xx00000x
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find that the isoquinoline product 3a was formed and isolated
in 43% yield (Table 1, entry 1). The formation of 3a indicated a
C−H activation/cyclization occurring in the process. This
encouraged us to further screen the additives, and Cu(OAc)2
was found inferior to shut down the reactivity (entry 2). We
next turn to screen the silver salts and found that AgOAc was
optimal to increase the yield to 57% (entry 3). The use of AgBF4
and Ag2O were found to further improve the yield (entries 4
and 5). Gratifyingly, the addition of Ag2CO3 as additive was
superior, leading to a dramatic improvement of the yield to 84%
(entry 6).7 Control reaction showed that the removement of
PivOH would completely shut down the reactivity,
demonstrating the importance of PivOH (entry 7). The solvent
screening showed that DCE, MeOH and THF were not effective,
resulting trace product formation (entries 8-10). Other oximes
good yields (3n and 3o). It should be noted that 3j and 3n are
the core structures of Moxaverine and Pulcheotine to
demonstrate the synthetic utility. Moreover, the bicyclic oxime
1p could also proceed well to deliver tricyclic product in
moderate yield (3p, 55%). Next, we test the substrate scope of
alkenes. The acrylates and acryl amides could proceed well in
this process to generate the products in moderate to excellent
yields (3q
Furthermore, a variety of vinyl ketones were also tested and
found tolerable in this process to furnish the isoquinolines (3u
-3t) under a slightly modified reaction condition.
-
3x), with the valuable substitution like furan and thiophene.
Considering the wealth of isoquinoline in natural products and
Scheme 1. Variation of Oximes.a
such as O-methyl oxime
4 and O-pivaloyl oxime 5 were also
tested and found not applicable in this protocol (Fig. 2).
Table 1. Optimization of reaction conditions.a
entry
additive
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
yield (%)b
43
1
CsOAc (2 equiv)
Cu(OAc)2 (2 equiv)
AgOAc (2 equiv)
AgBF4 (2 equiv)
Ag2O (2 equiv)
Ag2CO3 (2 equiv)
Ag2CO3 (2 equiv)
Ag2CO3 (2 equiv)
Ag2CO3 (2 equiv)
Ag2CO3 (2 equiv)
2
trace
57
3
4
60
5
69
6
84
7c
8
trace
trace
trace
trace
9
MeOH
THF
10
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol),
[Cp*RhCl2]2 (2 mol %), PivOH (0.4 mmol), solvent (1 mL), RT, 18
h. bYields of isolated product. cWithout PivOH.
Fig. 2 Other screened oximes without reactivity.
With the optimized reaction condition in hand, we next
investigated the generality of the reaction (Scheme 1). Various
aromatic oximes with valuable functional groups on the
aromatic ring, such as methyl, benzyloxy, chloro, bromo, nitro,
amino, could react smoothly with acrolein 2a to afford the
corresponding products (3b-3g) in moderate to excellent yields
(56%-95%), thus offering ample opportunity for further
derivation. Additionally, when a meta substituted oxime 1h
was used, the reaction afforded a separatable mixture of
isoquinoline products 3ha and 3hb. When the substitution is
varied on the methyl group, a variety of functional groups
were tolerated in this process. For example, the groups like
ethyl, benzyl, sulfone, phenyl, were well applicable in this
aReaction conditions:
1 (0.2 mmol), 2a (0.6 mmol), (Cp*RhCl2)2
cyclization to furnish the structural different isoquinolines (3i
-
(2 mol %), PivOH (0.4 mmol), CH3CN (1 mL), RT, 18 h, yields of
isolated products. bPMP = para-methoxyphenyl. cRun at 76 oC.
3m). Interestingly, the ketone and ester substituted oximes
were also applicable in this process to furnish the products in
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Based on the experiments and literature precedents,9
a
pharmaceuticals, this method provides a direct approach
toward the achievement of these heterocycles from readily
available starting materials under mild reaction conditions.
Next, the synthetic utility of this protocol was further
demonstrated by concise synthesis of Moxaverine, a drug used
to treat functional gastrointestinal disorders (Fig. 3). 8 Initially,
the simple phenylacetic acid was converted to phenylacetyl
chloride, which underwent a Friedel-Crafts reaction with 1,2-
plausible mechanism is proposed in Fig. 4. The initial [Cp*RhIII]
was generated from [Cp*RhCl2]2 and Ag2CO3, and reacted with
oxime
intermediate
complex . The sequential regioselective insertion of alkene
from led to intermediate , and a redox-neutral cyclization
furnished and Rh(I). The reduction of by Rh(I) regenerates
[Cp*RhIII] catalyst to enable the catalytic cycle and also delivers
dihydroisoquinoline species . Finally, the oxidation of by
, thus
1
with a C−H activation/cyclorhodation step to afford
A
, which is coordinated with alkenes to form
2
B
B
C
D
D
dimethoxybenzene to afford
and subject to the standard reaction condition with methyl
vinyl ketone to deliver isoquinoline . The next transformation
6. 6 was then converted to oxime
E
E
7
Ag2CO3 delivered the aromatic isoquinoline products
the amount of Ag2CO3 should be equivalent.
3
8
of ketone to tosyl hydrazone and a following DIBAL-reduction
finally furnished Moxaverine in 65% yield.
To gain insight to the reaction mechanism, kinetic isotope
In summary, a Rh(III)-catalyzed C−H activation/cyclization of
oximes and alkenes has been developed for regioselective
effect (KIE) study was conducted (Fig. 4), and a large primary synthesis of isoquinolines. The protocol is featured with broad
KIE value (2.8) was obtained, suggesting that C−H bond
cleavage occurs during the rate-determing step.
substrate scope and mild reaction conditions, and also applied
to concise synthesis of Moxaverine. Furthermore, kinetic effect
study was conducted and
proposed.
a plausible mechanism was
This work was financially supported by National Natural Science
Foundation of China (grant no 21472163).
Notes and references
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Fig. 5 Proposed reaction mechanism.
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