Synthesis of 5,6-dihydropyrazolo[1,5- c ]quinazolines through gold-catalyzed chemoselective bicyclization of N -propargylic sulfonylhydrazones

Article abstract of DOI:10.1021/ol503437n

An efficient method for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines via gold(I)-catalyzed chemoselective bicyclization of N-propargylic sulfonylhydrazones has been developed. This process relies on the chemoselective cyclization of the hydrazone nitrogen instead of the usually favored aniline nitrogen onto the alkyne. The synthetic utility of the current strategy is demonstrated through the synthesis of a potential Eg5/Kinesin spindle protein inhibitor.

Full text of DOI:10.1021/ol503437n

Letter
pubs.acs.org/OrgLett
Synthesis of 5,6-Dihydropyrazolo[1,5‑c]quinazolines through Gold-
Catalyzed Chemoselective Bicyclization of N‑Propargylic
Sulfonylhydrazones
Hai-Tao Tang, Kai Xiong, Ren-Hao Li, Zong-Cang Ding, and Zhuang-Ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, People’s Republic of
China
S
* Supporting Information
ABSTRACT: An efficient method for the preparation of 5,6-
dihydropyrazolo[1,5-c]quinazolines via gold(I)-catalyzed che-
moselective bicyclization of N-propargylic sulfonylhydrazones
has been developed. This process relies on the chemoselective
cyclization of the hydrazone nitrogen instead of the usually
favored aniline nitrogen onto the alkyne. The synthetic utility
of the current strategy is demonstrated through the synthesis
of a potential Eg5/Kinesin spindle protein inhibitor.
Scheme 1. Possibilities for Forming Different Fused
Tricyclic Scaffolds
yrazoles are widely present in ligands for organic
synthesis,1 agrochemicals,2 and bioactive compounds.3
P
Among those pyrazole derivatives, 5,6-dihydropyrazolo[1,5-
c]quinazolines have been used as antagonists for a number of
biological targets such as Gly/NMDA receptor,4a,b excitatory
amino acid,4c AMPA and kainate receptor,4d and adenosine
receptor,4e as well as inhibitors for IKK4f and phosphodiester-
ase 10A.4g Although several strategies have been developed for
the synthesis of 5,6-dihydropyrazolo[1,5-c]quinazolines, they
usually rely on the functionalization of substrates with the
pyrazole ring preinstalled.5,4c,e−g To the best of our knowledge,
methods that form both rings of the 5,6-dihydropyrazolo[1,5-
c]quinazoline in a single operation have not been reported.6
We have been interested in employing N-propargylic
sulfonylhydrazones for organic synthesis and recently reported
the selective transformations of these structures to (1E,3E)-2-
sulfonyl-1,3-dienes7 and pyrazoles.8 Gold-catalyzed intramolec-
ular cyclization of 2-alkynyl anilines to prepare indoles has been
well-studied (Scheme 1, eq 1).9 Considering the fact that the
nucleophilicity of the amino group is stronger than that of the
imine group, we surmised that gold-promoted cyclization of 2-
alkynyl aniline 1 that contains a propargylic hydrazone moiety
may lead to the formation of a tricylic indole derivative
(Scheme 1, eq 2). However, when 1 was treated with a gold
catalyst, none of the indole product was observed. Instead, 5,6-
dihydropyrazolo[1,5-c]quinazolines 2 was obtained in moderate
to excellent yields (Scheme 1, eq 3). We report herein the
development of this gold(I)-catalyzed chemoselective bicycliza-
tion reaction for the synthesis of a wide variety of 5,6-
dihydropyrazolo[1,5-c]quinazolines, which outcompetes the
generation of indole scaffolds.
room temperature did not yield any of the cyclized product
(Table 1, entries 1−6). When we carried out the reaction in the
presence of 10 mol % of AuPPh3NTf2 for 30 min, the desired
5,6-dihydropyrazolo[1,5-c]quinazoline 2a was isolated in 66%
yield (Table 1, entry 7). The structure of 2a is further
confirmed by single crystal X-ray structure analysis (Figure 1).
Other gold species such as AuCl3 and AuPPh3Cl were not
effective (Table 1, entries 8 and 9). However, the latter did
catalyze the cyclization to form 2a in moderate yields in the
presence of silver salts such as AgOTf, AgSbF6, or AgBF4,
suggesting the importance of the Lewis acidity of the gold
The cyclization of N-propargylic sulfonylhydrazone 1a was
used to optimize the reaction conditions. Treating 1a with
different metal catalysts such as AgOTf, In(OTf)3, Cu(OTf)2,
Sm(OTf)3, and Pd(PPh3)2Cl2 or trifluoroacetic acid in DMF at
Received: November 27, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503437n
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Letter
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of 5,6-Dihydropyrazolo[1,5-
a
,b
c]quinazolines 2 from N-Propargylic Sulfonylhydrazones 1
entry
catalyst
AgOTf
solvent
time
2 h
yield (%)
c
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
NR
NR
NR
NR
NR
NR
2
In(OTf)3
2 h
3
Cu(OTf)2
2 h
4
Sm(OTf)3
2 h
5
CF3COOH
2 h
6
Pd(PPh3)2Cl2
AuPPh3NTf2
AuCl3
2 h
7
30 min
2 h
66%
trace
trace
61%
47%
62%
trace
trace
86%
60%
25%
30%
8
9
AuPPh3Cl
2 h
10
11
12
13
14
15
16
17
18
19
AuPPh3Cl/AgOTf
AuPPh3Cl/AgSbF6
AuPPh3Cl/AgBF4
AuPPh3NTf2
AuPPh3NTf2
AuPPh3NTf2
AuPPh3NTf2
AuPPh3NTf2
AuPPh3NTf2
AuPPh3NTf2
30 min
30 min
30 min
1 h
DCM
DMSO
DMA
CH3NO2
CH3CN
DMSO
1 h
30 min
30 min
1 h
1 h
d
30 min
85%
a
Reaction conditions: The reaction was carried out using 1a (0.5
mmol) and catalyst (10 mol %) in the solvent (5 mL) at room
b
c
d
temperature. Isolated yields. NR = no reaction. The amount of
catalyst was decreased to 2 mol %.
a
Reaction conditions: The reaction was carried out using 1 (0.5
mmol) and catalyst (2 mol %) in DMSO (5 mL) at room temperature.
b
c
Isolated yields. The reaction was run at 120 °C.
somewhat sensitive to ortho substitution of the aryl aldehydes.
Due to the steric effect, the yields of 2b and 2f were much
lower. Notably, hydrazones synthesized from ketones also
cyclized nicely (Scheme 2, products 2j−k, 79−88% yields).
Branching at the propargylic position were tolerated (Scheme
2, products 2l−m, 79−83% yields). Additionally, substrates
bearing a methyl group at the aniline nitrogen or a variety of
substituents with different electronic properties at the aniline
phenyl ring all reacted smoothly to afford the desired products
(Scheme 2, products 2n−s, 63−90% yields).
Figure 1. Single crystal X-ray structure for 2a.
The synthetic utility of the current method was illustrated
through the preparation of 2t, a potential Eg5/Kinesin spindle
protein inhibitor.10 Fan’s group recently reported the synthesis
of 2t by assembling the quinazoline ring from a pyrazole-
containing precursor.5b We were gratified to demonstrate that
2t could be obtained in 84% yield in a single step by using the
gold-catalyzed chemoselective bicyclization of N-propargylic
sulfonylhydrazone 1t (Scheme 3).
5,6-Dihydropyrazolo[1,5-c]quinazolines synthesized from
aldehyde-derived hydrazones can be oxidized to afford
pyrazolo[1,5-c]quinazolines.5a Hence, 1a was subjected to
gold-catalyzed bicyclization followed by copper-catalyzed
aerobic oxidation in situ to produce 3a in 77% yield (Scheme
4).
catalyst for the reaction (Table 1, entries 10−12). Given these
data, AuPPh3NTf2 was chosen as the catalyst for further
optimization. The screening of various solvents revealed that
DMSO was the optimal solvent for the cyclization and the yield
could be improved to 86% (Table 1, entry 15). Reducing the
catalyst loading to 2 mol % did not affect the yield (Table 1,
entry 19). Hence, the optimal reaction conditions were
determined to be carrying out the cyclization in the presence
of 2 mol % of AuPPh3NTf2 in DMSO at room temperature
(Table 1, entry 19).
The scope of the bicyclization reaction was investigated and
is summarized in Scheme 2. Hydrazones derived from
numerous aldehydes including aryl aldehydes, cinnamaldehyde,
and alkyl aldehydes were all suitable substrates (Scheme 2,
products 2a-i, 44−97% yields). However, the reaction was
To gain some insight into the reaction mechanism,
sulfonylhydrazone 4 without an amino group and 5 with an
amino group positioned away from the alkyne were prepared
B
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Letter
the 5,6-dihydropyrazolo[1,5-c]quinazoline product. Other
possible pathways cannot be ruled out, such as concerted
aminal formation and cyclization, as well as cyclization after
imine transfer.
Scheme 3. Synthesis of 5-(2-Fluorophenyl)-2,9-dimethyl-5,6-
dihydropyrazolo[1,5-c]quinazoline 2t
In summary, we have developed a highly efficient and
chemoselective gold(I)-catalyzed method for the synthesis of
5,6-dihydropyrazolo[1,5-c]quinazolines. This method offers
rapid access to a wide variety of dihydropyrazolo[1,5-
c]quinazolines from easily available N-propargylic sulfonyl-
hydrazones under mild reaction conditions. The reversed
reactivity in the highly selective formation of 5,6-dihydro-
pyrazolo[1,5-c]quinazolines instead of the formation of the
usually favored indole scaffolds is observed. Application of the
bicyclization protocol for the synthesis of other heterocycles is
underway in our laboratory.
Scheme 4. Synthesis of Pyrazolo[1,5-c]quinazoline 3a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of compounds
1a−t, 2a−t, 3a, and crystallographic data (CIF) of 2a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
and reacted under the standard conditions (Scheme 5). These
substrates either failed to react (Scheme 5, eq 4) or led to
AUTHOR INFORMATION
Corresponding Author
Scheme 5. Mechanistic Studies
■
*E-mail: zpzhan@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (No. 21272190), PCSIRT in University
is gratefully acknowledged.
REFERENCES
■
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