An efficient synthesis of isoquinolines via rhodium-catalyzed direct C-H functionalization of arylhydrazines

Article abstract of DOI:10.1039/c5ob01171j

A highly efficient rhodium-catalyzed C-H activation of arylhydrazines and coupling with internal alkynes has been realized under mild conditions. The isoquinolines have been prepared in moderate to excellent yields in high efficiency. This methodology features the use of readily available starting materials, and a simple hydrazine moiety as a directing group, in the absence of an external metal co-oxidant under an air atmosphere. The C-H bond activation and the N-N bond cleavage have been successively realized under mild conditions.

Full text of DOI:10.1039/c5ob01171j

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DOI: 10.1039/C5OB01171J
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An Efficient Synthesis of Isoquinolines via Rhodium-
Catalyzed Direct C-H Functionalization of
Arylhydrazines
Cite this: DOI: 10.1039/x0xx00000x
Sai Zhang,a,b Dairui Huang,a Guangyang Xu,a Shengyu Cao,a Rong Wang,a Shiyong
Penga and Jiangtao Sun*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient rhodium-catalyzed C-H activation of activation under mild conditions in 2012. Recently, Huang reported
arylhydrazines and coupling with internal alkynes has been an efficient Cp*Rh(H2O)3(OTf)2-catalyzed conversion of azines to
realized under mild conditions. The isoquinolines have been
prepared in moderate to excellent yields in high efficiency.
This methodology features the use of readily available
starting materials, simple hydrazine moiety as directing
group, in the absence of an external metal co-oxidant under
an air atmosphere. The C-H bond activation, N-N bond
cleavage have been successively realized under mild
conditions.
Isoquinolines are key motifs found in numerous natural products and
pharmaceuticals with diverse biological activities.1 Thus, various
methods have been developed to construct the isoquinoline skeleton
over the past decades.2 Recently, the transition-metal-catalyzed
direct C-H bond functionalization of arenes bearing a pre-installment
directing groups followed by coupling with internal alkynes, has
represented as a powerful tool to rapidly construct the diverse and
functional group flexible isoquinolines.3
In 2009, Fagnou reported the rhodium-catalyzed oxidative
isoquinoline synthesis using N-t-Bu aryl aldimines as directing
groups and internal nitrogen source.4 Satoh and Miura developed the
use of benzophenone imines in this reaction.5 However, the use of
stoichiometric amount of Cu(OAc)2 as an external oxidant was
crucial to complete the catalytic cycle. In 2010, Chiba described a
rhodium-catalyzed synthesis of isoquinolines from ketone O-
acyloximes and internal alkynes with the use of NaOAc as an
effective additive and an external co-oxidant was not needed.7 Later,
Li reported the use of oxime as directing group and CsOAc as the
additive also leading to the rapid formation of isoquniolines.7 The
oximes have been thought as oxidizing-directing groups during the
rhodium-catalyzed procedures. By replacing the rhodium catalysts
with ruthenium complexes, Jeganmohan8 and Ackermann9
independently realized the synthesis of isoquinolines via C-H bond
Scheme 1 Synthesis of isoquinolines via transition-metal-catalyzed C-H
functionalization.
synthesize isoquinolines.10 Notably, this reaction was performed
under an air atmosphere under room temperature in the presence of
25 mol% of benzoic acid. In 2013, Cheng reported the introduction
of hydrazone as oxidizing directing group in isoquinoline synthesis
using stoichiometric of acetic acid.11 Li and co-workers described
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d
at room temperature. 1 mol% of [Cp*RhCl2]2 was used and the reaction
time was 8 hours.
the use of aziridinylimines as practical substrates in the presence of
AgNO3 and Cu(OAc)2.12 They also found that the use of free
hydrazines resulted in the formation of indenes. Just recently, our
group realized the first C-H functionalization of diazo compounds
through rhodium relay catalysis to produce isoquinolines in high
efficiency.13 Consistent with our former report, we reported here a
highly efficient rhodium-catalyzed isoquinolines synthesis from aryl
hydrazines and internal alkynes under mild conditions. This
approach has several advantages: the readily available substrates
which can be prepared by simple condensation of ketones with cheap
hydrazine. An external co-oxidant is not indispensable and benzoic
acid is an effective additive to promote the catalytic cycle under air.
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DOI: 10.1039/C5OB01171J
Under the optimal reaction condition, the substrate scope of
hydrazines and alkynes were investigated (Table 2). Generally, all of
the reactions proceeded smoothly to afford isoquinolines 3 in
moderate to excellent yields. The reaction of 1a with various alkynes
was firstly carried out to examine the reactivity of alkynes in this
reaction. For the symmetric diaryl alkynes, the phenyl moiety
bearing electron-donating substituents displayed better reactivity and
gave the corresponding products in higher yield than the electron-
withdrawing substituents (3b to 3e). The alkyl alkyne and alkyl
phenyl were also tolerated in this reaction and the desired products
were obtained in high yields (3f and 3g). The hydroxyl substituted
alkyne gave the isoquinoline 3h in 87% yield. However, when un-
symmetric diaryl alkyne was used, two regio-isomers were detected
in almost 1:1 ratio (3i/3i').
Initially, hydrazine (1a) and alkyne (2a) were employed as model
substrates to screen the reaction parameters (Table 1). First, using
2.5 mol% of rhodium complexes in methanol at 80 oC in the
presence of 0.25 eq. of benzoic acid revealed that [Cp*RhCl2]2 gave
the best result and afforded 3a in 88% isolated yield in 2 hours
(entry 2), whereas Rh2(OAc)4, Rh2(esp)2 and [RhCl(cod)]2 were
totally inert in this reaction (entries 3 to 5). Also, in the absence of
benzoic acid, no 3a was detected (entry 1). This phenomenon
indicated that to accomplish the catalytic cycle, the acid is
indispensable to facilitate the molecular oxygen to oxidize RhI to
regenerate the active RhIII species.10,14 When p-toluenesulfonic acid
and pivalic acid were used as additive, 3a was isolated in low to
moderate yield (entries 6 and 7). Next, several solvents were also
examined. The use of DMF and toluene led to quite low yields
(entries 8 and 9). Other alcohols such as n-butanol and ethanol gave
lower yields (entries 10 and 11). Moreover, both increasing and
reducing the amount of benzoic acid were detrimental to the reaction
(entries 12 and 13). Furthermore, the reaction was sluggish at room
temperature (entry 14). Lower catalyst loading (1 mol%) gave a
slightly lower yield with longer reaction time (entry 15).
Table 2 Substrate scopea,b
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Additive (equiv.)
Solvent
Yield (%)b
[Cp*RhCl2]2
[Cp*RhCl2]2
Rh2(OAc)4
-
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
<5
88
0
1
2
3
4
5
6
PhCO2H (0.25)
PhCO2H (0.25)
PhCO2H (0.25)
PhCO2H (0.25)
TsOH (0.25)
Rh2(esp)2
0
[RhCl(cod)]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
0
36
55
12
<5
24
52
76
63
PivOH (0.25)
PhCO2H (0.25)
PhCO2H (0.25)
PhCO2H (0.25)
PhCO2H (0.25)
PhCO2H (0.5)
PhCO2H (0.1)
7
8
toluene
n-BuOH
EtOH
9
10
11
12
MeOH
MeOH
aAll reactions were carried out with 1 (1 mmol), 2 (1.2 mmol), [Cp*RhCl2]2
(2.5 mol%), PhCO2H (0.25 mmol), in MeOH (3 mL) under air at 80 oC for 2
hours. bIsolated yields.
13
14c
15d
[Cp*RhCl2]2
[Cp*RhCl2]2
PhCO2H (0.25)
PhCO2H (0.25)
MeOH
MeOH
31
82
Reaction conditions: aAll reactions were carried out with 1a (1 mmol), 2a
o
Next, the reaction of different hydrazines with alkynes was further
examined (Table 2). The symmetric para-fluoro substituted
(1.2 mmol), catalyst (0.025 mmol), solvent (3 mL) under air at 80 C for 2
hours unless otherwise noted. Isolated yields. The reaction was performed
b
c
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diphenylmethylene hydrazine afforded the corresponding for their financial supports. S. Zhang thanks for an internship
isoquinolines in lower yields than none-substituted and para-methyl from Changzhou University.
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substituted hydrazines (3j to 3m compared with 3a to 3e and 3n to
3q). The un-symmetric aryl hydrazine gave two regio isomers in 1:1
ratio (3r vs 3r'). The phenylalkylidene hydrazines were also
evaluated as ideal substrates in this reaction and led to the
corresponding isoquinolines in high yields (3s to 3u). The use of
thiophene substituted hydrazine also produced the isoquinoline in 77%
yield (3v). Moreover, the meta-methyl substituted phenyl hydrazine
delivered 3w as single isomer in 87% yield. Notably, the use of
propiolates in this reaction only provided 3x as the final product and
the corresponding isoquinoline was not detected. Moreover, the
terminal alkyne was totally inert in this reation.
Based on the above experiments, a possible reaction mechanism
was proposed in Scheme 2. In the presence of [Cp*RhCl2]2, the
ortho-C-H activation of 1a occurs under the assistance of the
nitrogen atom of the hydrazine, which generates the active
intermediate A. Then A undergoes insertion to alkyne 2a to give
formation of seven-membered intermediate B. Then reductive
elimination of this iminium cation would lead to the formation of
isoquinolinium cation C and [RhI] species, which would provide
isoquinoline 3a and regeneration of the [RhIII] species under a redox
process in the presence of air and benzoic acid.
DOI: 10.1039/C5OB01171J
Notes and references
a
School of Pharmaceutical Engineering & Life Science, Changzhou
University, Changzhou 213164, P. R. China. E-mail: jtsun08@gmail.com;
Fax: +86 519 86334598; Tel: +86 519 86334597.
b
Department of Chemistry, St. Francis Xavier University, Antigonish,
Nova Scotia B2G 2W5, Canada.
Electronic Supplementary Information (ESI) available: [details of
experiment procedures, and spectra datas]. See DOI: 10.1039/c000000x/
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Scheme 2 Proposed reaction mechanism
In summary, we have demonstrated here a highly efficient
rhodium-catalyzed approach to prepare isoquinolines. This
methodology featured the use of readily available hydrazine as the
directing group, in the presence of simple benzoic acid and in the
absence of an external metal co-oxidant under mild reaction
conditions. Moreover, the C-H bond activation and N-N bond
cleavage have been realized under an air atmosphere.
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (No. 21172023), A Project Funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD) and Jiangsu Key Laboratory
of Advanced Catalytic Materials and Technology (BM2012110)
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