Synthesis of 5,6-Dihydropyrazolo[5,1-a]isoquinolines through Indium(III)-Promoted Halocyclizations of N-Propargylic Sulfonylhydrazones

Article abstract of DOI:10.1021/acs.orglett.6b00534

A novel method for the preparation of 5,6-dihydropyrazolo[5,1-a]isoquinoline via indium(III)-promoted halocyclizations of N-propargylic sulfonylhydrazones has been developed. The pyrazole and 3,4-dihydroisoquinoline moieties were synchronously formed via

Full text of DOI:10.1021/acs.orglett.6b00534

Letter
pubs.acs.org/OrgLett
Synthesis of 5,6-Dihydropyrazolo[5,1‑a]isoquinolines through
Indium(III)-Promoted Halocyclizations of N‑Propargylic
Sulfonylhydrazones
Ren-Hao Li, Cheng-Ke Ding, Ya-Nan Jiang, Zong-Cang Ding, Xiao-Ming An, Hai-Tao Tang, Qi-Wei Jing,
and Zhuang-Ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, People’s
Republic of China
S
* Supporting Information
ABSTRACT: A novel method for the preparation of 5,6-
dihydropyrazolo[5,1-a]isoquinoline via indium(III)-promoted
halocyclizations of N-propargylic sulfonylhydrazones has been
developed. The pyrazole and 3,4-dihydroisoquinoline moieties
were synchronously formed via a cascade cyclization reaction
using easily assembled open-chain compounds. The pyrazole
and 3,4-dihydroisoquinoline moieties were formed via a
cascade cyclization reaction using easily assembled open-
chain compounds.
he pyrazole core is present in many pharmaceuticals,1
agrochemicals,2 biologically active compounds,3 and other
(iodo(phenyl)methylene)-5,6-dihydropyrazolo[5,1-a]-
isoquinoline (2a) in 50% isolated yield (Table 1, entry 1). The
structure of 2a was confirmed by single-crystal X-ray structure
analysis.18 When we carried out the reaction in the presence of
InI3 (1.0 equiv), the yield was improved to 93% (Table 1, entry
2). Other reagents with halogen such as CuI, CuI2, ZnI2, SmI3,
FeBr3, AuCl3, AgBr, elemental iodine, elemental bromine, and
ICl were not effective (Table 1, entries 3−12). A screen of
In(III) salts revealed In(III) bromide and chloride were suitable
catalysts. Under these conditions, the vinyl bromide 3a and
chloride 4a were isolated in 80% and 64% yields (Table 1,
entries 13 and 14). The reaction time required increased from
InI3 to InBr3 to InCl3. With the chloride salt, the reaction
required heating at 70 °C in 1,2-dichloroethane (DCE) for 12 h
to consume the starting material. InF3 and In(OAc)3 exhibited
no activity in this reaction (Table 1, entries 15 and 16), which
may be due to the weak nucleophilicity of F− and AcO−
compared to other halide anions. Attempts to enhance the
efficiency of product formation further by screening different
amounts of InI3 were unsuccessful (Table 1, entries 17 and 18).
Some halide sources such as TMSI and KI were screened
hoping to reduce the amount of In(III) salt used but without
success (Table 1, entries 19 and 20). The formation of 2a was
suppressed by changing the solvents of DCM, acetonitrile, 1,4-
dioxane, toluene, DMF, and DMSO.19 Hence, the optimum
conditions involved conducting the reaction in DCE at 70 °C
with the use of stoichiometric In(III) halides as the promoter
and halide source.
T
useful chemicals.4 Among those pyrazole derivatives, com-
pounds based on the pyrazolo[1,5-a]pyridine framework have
attracted increasing attention due to their promising biological
activities. Typical examples of bioactive pyrazolo[1,5-a]-
pyridines include the well-known antiallergic and cerebroactive
agent ibudilast,5 the novel adenosine A1 receptor antagonist
FK838,6 the adenosine antagonist FK453,7 and a series of
highly selective D4 receptors ligands.8 Although several
strategies have been developed for the synthesis of 5,6-
dihydropyrazolo[5,1-a] isoquinoline, they usually rely on the
functionalization of substrates with the preinstalled pyrazole9 or
3,4-dihydroisoquinoline10 ring. As far as we know, methods that
form both rings of the 5,6-dihydropyrazolo[5,1-a]isoquinoline
via a domino reaction have not been reported.
Recently, Lewis acid promoted cyclization of diynes have
been actively studied for synthesis of 2,2-disubstituted
tetrahydrofurans,11 indeno[1,2-c]chromenes,12 and indene
derivatives.13 In this context, Snyder and co-workers14 have
recently shown that cyclization of 1,6-diynes promoted by
stoichiometric Ga(III) halides produces iodotetrahydropyr-
idines. Indium is widely used in the fields of organic synthesis.15
We have reported the selective transformations of N-
propargylic sulfonylhydrazones to (1E,3E)-2-sulfonyl-1,3-di-
enes16 and pyrazoles.17 As part of our ongoing research, we
discovered the synthesis of 5,6-dihydropyrazolo[5,1-a]-
isoquinoline from N-propargylhydrazones bearing diynes via
an indium(III)-promoted halocyclization method.
In our initial studies, the reaction of N-propargylic
sulfonylhydrazone 1a was investigated (Table 1). Under a
nitrogen atmosphere, compound 1a was reacted with GaI3 (1.0
equiv) in DCE at 70 °C to give (Z)-5-(4-bromophenyl)-6-
Received: February 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00534
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Letter
a
,b
a,b
Table 1. Optimization of the Reaction Conditions
Table 2. Halocyclization Substrate Scope
entry
MXn
GaI3
time (h)
yield (%)
1
0.5
0.5
6
50
93
2
InI3
c
3
CuI
NR
4
CuI2
ZnI2
SmI3
FeBr3
AuCl3
AgBr
I2
6
NR
5
6
NR
6
6
NR
7
6
NR
8
0.5
0.5
0.5
0.5
0.5
6
complex
NR
9
10
11
12
13
14
15
16
17
18
19
20
complex
complex
complex
80
Br2
ICl
InBr3
InCl3
InF3
In(OAc)3
InI3
12
6
64
NR
6
NR
d
12
0.5
0.5
0.5
41
e
InI3
91
f
InI3
complex
g
InI3
14
a
Reaction conditions: 1a (0.5 mmol), MXn (0.5 mmol), DCE (5 mL),
b
c
d
N2 atmosphere, 70 °C. Isolated yield. NR = no reaction. Run with
0.25 mmol of InI3 Run with 1.0 mmol of InI3. Run with 0.1 mmol of
InI3 and 0.5 mmol of TMSI. Run with 0.1 mmol of InI3 and 0.5 mmol
e
f
g
a
Reaction conditions: 1 (0.5 mmol) and InX3 (0.5 mmol) in DCE (5
of KI.
b
c
mL), N2 atmosphere, 70 °C, 0.5−12 h. Isolated yields. Determined
by H NMR.
1
The range of N-propargylhydrazones amenable to this
chemistry was then explored using InI3 (Table 2). Hydrazones
derived from a number of aldehydes including aryl aldehydes
and alkyl aldehydes were all suitable substrates (Table 2,
products 2a−h, 54−93% yields). However, the reaction was
somewhat sensitive to the electron-donating group and ortho-
substitution of the aryl aldehydes. The low yields of 2b and 2c
were probably caused by the steric hindrance of the o-bromo
substituent for the former and the electron-donating effect of
the −OMe group for the latter. A hydrazone synthesized from
ketone was also cyclized (Table 2, product 2i, 44% yield). n-
Pentyl-terminated alkyne 1j also reacted smoothly (Table 2,
product 2j, 40% yield). When R5 = H, the reaction led to a
complex product mixture. Branching at the propargylic position
(1k) or substitution at the linking aryl ring with a methyl group
(1l) was tolerated (Table 2, products 2k,l, 60−88% yields).
The trifluoromethyl (CF3) group is present in many
pharmaceuticals and agrochemicals.20 As a result, the synthesis
of CF3-substituted heterocycles has attracted considerable
attention in recent years. The reaction of hydrazone derived
from trifluoroacetaldehyde formed the desired product 2n in
excellent yield (Table 2, product 2n, 92% yield, isomer ratio of
the mixture = 4.0:1.0).
Scheme 1. Tetracyclic Scaffold Products
Scheme 2. Reaction Carried out on Gram Scale
Conversion of hydrazones 1 to the vinyl bromide 3 and vinyl
chloride 4 also proceeded smoothly using InBr3 and InCl3 but
in diminished efficiency (Table 2). Hydrazones derived from
aryl aldehydes were all suitable substrates (Table 2, product 3a,
80% yield; product 3c, 52% yield; product 4a, 64% yield;
product 4c, 40% yield). Additionally, substrates bearing methyl
at the propargylic, 4-BrPh group at the terminated alkyne all
B
DOI: 10.1021/acs.orglett.6b00534
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Letter
the reaction of 5,6-dihydropyrazolo[5,1-a]isoquinoline 2a with
AlCl3 under air afforded ketone 9 in 78% yield (Scheme 3, eq
1). In addition, Suzuki−Miyaura coupling of 2a with p-
methylphenylboronic acid produced the tetrasubstituted alkene
10 in good yield (Scheme 3, eq 2).
Scheme 3. Synthesis of Pyrazolo[5,1-a]isoquinoline 9 and
Suzuki−Miyaura Coupling Product 10
A plausible mechanism for the reaction is proposed and
depicted in Scheme 4. The coordination of the indium(III)
catalyst with the alkyne activates the triple bond for
nucleophilic attack by the imine nitrogen atom, leading to
the cyclized intermediate 11. Subsequently, intramolecular
nucleophilic attack of the alkyne unit of 11 produces tricyclic
vinyl cation 12. Trapping of this vinyl cation by a halide ion
leads to 13. Proto-demetalation and aromatization through
elimination of a molecule of TsH results in the generation of
the 5,6-dihydropyrazolo[5,1-a]isoquinoline products 2, 3, or 4.
When R1, R2 are cyclopentyl or cyclohexyl, this mechanism also
anticipates the formation of ring-expansion product 5 via an
intramolecular rearrangement and elimination reaction. When
R1 is hydrogen and R2 is styryl or propenyl, the vinyl cation 12
proceeds with an electrophilic addition reaction with styryl or
propenyl and produces tetracyclic scaffold products 6−8.
In conclusion, we have developed a highly efficient
indium(III)-promoted halocyclization method for the synthesis
of 5,6-dihydropyrazolo[5,1-a]isoquinolines, and the product
can be oxidized to afford pyrazolo[5,1-a]isoquinolines. In
addition, hydrazones derived from cyclic ketones or olefin
aldehydes gave the tetracyclic scaffold products followed by
ring-expansion or electrophilic addition. Application of the
bicyclization protocol for the synthesis of other heterocycles is
underway in our laboratory.
reacted smoothly to afford the desired products (Table 2,
product 3k, 54% yield; product 4k, 46% yield; product 3m,
35% yield). Notably, cyclization of hydrazones synthesized
from trifluoroacetaldehyde produced vinyl bromide and
chloride in good yield (Table 2, product 3n, 80% yield, isomer
ratio of the mixture = 1.6:1.0; product 4n, 71% yield, isomer
ratio of the mixture = 1.6:1.0). With the use of indium halides
as promoters, the yield increased from InCl3 to InBr3 to InI3.
However, hydrazones derived from cyclopentanone and
cyclohexanone gave the tetracyclic scaffold derivatives 5
followed by a ring-expansion reaction (Scheme 1, eq 1).
When the catalyst was reduced to 0.1 equiv, the desired
tetracyclic product 5a was obtained in similar yield (40% yield).
And hydrazones derived from cinnamaldehyde and butenal
gave the tetracyclic scaffold products 6−8 followed by
electrophilic addition (Scheme 1, eq 2).
ASSOCIATED CONTENT
* Supporting Information
■
The scalability of this novel 5,6-dihydropyrazolo[5,1-a]-
isoquinoline synthesis was evaluated by performing the
iodocyclization of 1a on a gram scale. The reaction furnished
the desired product 2a in 90% yield (Scheme 2), similar to that
obtained on a smaller scale.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00534.
Vinyl halides had been utilized broadly in drug development
and natural product synthesis.21 The vinyl iodide moiety of the
product can participate in further transformations. For example,
Experimental procedures and characterization of com-
pounds 2a−l,n, 3a,c,k,m,n, 4a,c,k,m, 5a,b, 6, 7a,b, 8−10,
and 1a−r (PDF)
Scheme 4. Proposed Mechanism
C
DOI: 10.1021/acs.orglett.6b00534
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Organic Letters
Crystallographic data for 2a (CIF)
Letter
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P.; Yu, Z. K. Chem. - Eur. J. 2011, 17, 10547.
(14) Strom, K. R.; Impastato, A. C.; Moy, K. J.; Landreth, A. J.;
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AUTHOR INFORMATION
■
(15) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 13002. (b) Tsuji, H.; Yamagata, K. i.; Itoh, Y.; Endo, K.;
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(c) Tsuji, H.; Tanaka, I.; Endo, K.; Yamagata, K.-i.; Nakamura, M.;
Nakamura, E. Org. Lett. 2009, 11, 1845. (d) Gibeau, A. L.; Snyder, J. K.
Org. Lett. 2011, 13, 4280.
Corresponding Author
*E-mail: zpzhan@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
(16) Zhu, Y.; Tang, H. T.; Zhan, Z. P. Adv. Synth. Catal. 2013, 355,
1291.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (No. 21272190), NFFTBS (No.
J1310024), and PCSIRT in University is gratefully acknowl-
edged.
(17) Wen, J. J.; Tang, H. T.; Xiong, K.; Ding, Z. C.; Zhan, Z. P. Org.
Lett. 2014, 16, 5940.
(18) See the Supporting Information (Figure S1).
(19) See the Supporting Information (Table S1).
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Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (c) Muller, K.; Faeh,
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DOI: 10.1021/acs.orglett.6b00534
Org. Lett. XXXX, XXX, XXX−XXX