Phosphine-Catalyzed Asymmetric Cycloaddition Reaction of Diazenes: Enantioselective Synthesis of Chiral Dihydropyrazoles

Article abstract of DOI:10.1021/acs.orglett.9b02800

Although carbon-carbon, carbon-nitrogen, and carbon-oxygen double bonds or their combinations have extensively been applied in phosphine-catalyzed asymmetric cycloaddition, a nitrogen-nitrogen double bond has never been investigated in chiral phosphine ca

Full text of DOI:10.1021/acs.orglett.9b02800

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphine-Catalyzed Asymmetric Cycloaddition Reaction of
Diazenes: Enantioselective Synthesis of Chiral Dihydropyrazoles
Chang Wang, Yuehua Chen, Jingyu Li, Leijie Zhou, Bo Wang, Yumei Xiao, and Hongchao Guo*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
S
* Supporting Information
ABSTRACT: Although carbon−carbon, carbon−nitrogen, and carbon−oxygen double bonds or their combinations have
extensively been applied in phosphine-catalyzed asymmetric cycloaddition, a nitrogen−nitrogen double bond has never been
investigated in chiral phosphine catalysis. In this paper, we present phosphine-catalyzed asymmetric [3+2] cycloaddition of
diazenes with Morita−Baylis−Hillman (MBH) carbonates to give chiral dihydropyrazoles in high yields with excellent
enantioselectivities. Various MBH carbonates and diazenes worked well under the mild reaction conditions.
he pyrazole1 and pyrazoline2 system are privileged
structures in numerous pharmaceuticals and agrochem-
runs through the addition of the chiral phosphine catalyst to
the electrophilic phosphine acceptors such as alkenes, alkynes,
and allenes to form zwitterionic intermediates, which then
react with electrophilic coupling partners to complete various
transformations.8 To date, hundreds of reports of asymmetric
phosphine catalysis have been focused on the discovery of
electrophilic coupling partners incorporating electron-deficient
carbon−carbon,10,12a,b,13c,e,g,j carbon−nitrogen,11a,c,d,12c,d,13b,f,j
and carbon−oxygen11b,e,13a double bonds or their combina-
tions,13k,n,q and the fantastic success has been attained in
developing asymmetric reactions.8 However, phosphine-
catalyzed asymmetric transformations involving a nitrogen−
nitrogen double bond have never been reported. Actually,
diazenes such as diethyl azodicarboxylate (DEAD) and its
analogues had often been used as achiral phosphine acceptor
for the synthesis of dinitrogen-fused compounds, albeit with
the use of equivalents of phosphines (Scheme 1a).14 Recently,
T
icals. Among them, many compounds exhibit bioactivities.3
Some of them serve as medicines (Figure 1). For example,
Figure 1. Several bioactive pyrazole and pyrazoline derivatives.
phenazone is a medicine for relieving pain and fever.4
Edaravone is an intravenous medication used to help with
recovery following a stroke and was approved by the U.S. Food
and Drug Administration in 2017 to treat amyotrophic lateral
sclerosis (ALS).5 Phenylbutazone displayed anti-inflammatory
activity.6 Dipyrone was used as an analgesic and an
antipyretic.7 Therefore, developing novel synthetic methods
for pyrazole and pyrazoline systems, especially chiral
molecules, is highly desirable.
Scheme 1. Nitrogen−Nitrogen Double Bond in Phosphine-
Promoted Reactions
Over the past two decades, asymmetric phosphine catalysis
has emerged as a practical and reliable tool for the construction
of chiral molecular frameworks and synthesis of natural
products.8 Numerous asymmetric organic transformations
such as kinetic resolution of secondary alcohols,9 Rauhut−
Currier reactions,10 Morita−Baylis−Hillman (MBH) reac-
tions,11 addition reactions,12 and multifarious annulations13
have innovatively been developed through chiral phosphine
catalysis, providing plentiful access to chiral molecules. In the
asymmetric phosphine catalysis, the catalysis cycle normally
Received: August 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02800
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Bu3P-catalyzed [3+2] cycloaddition/aromatization reaction of
MBH carbonates with diazenes was described for the synthesis
of pyrazole derivatives.15 On the basis of these works and our
continuous efforts on phosphine catalysis,16 we envisioned that
a nitrogen−nitrogen double bond having electron-deficient
properties may work in chiral phosphine-catalyzed asymmetric
reactions and thus intensely studied its application in
asymmetric phosphine catalysis. Herein, we present our initial
results on the first phosphine-catalyzed asymmetric [3+2]
cycloaddition reaction of MBH carbonates with diazenes to
give pharmaceutically interesting functionalized chiral dihy-
dropyrazoles (Scheme 1b).
applicable, affording a trace of the product (entry 7). Toluene
behaved like CH2Cl2 and 1,2-dichloroethane (DCE), providing
similar results (entry 8 vs entries 5 and 6). In particular, in the
polar solvent acetonitrile, the [3+2] cycloaddition reaction was
completed in 40 min, providing product 3aa in 99% yield with
87% ee (entry 8). Further improvement of enantioselectivity
was accomplished with a decrease in reaction temperature
(entries 6−9). When the reaction was performed at −20 °C,
both the yield and the enantioselectivity were excellent (99%
yield and 97% ee) (entry 10). On the basis of the screening
results mentioned above, the optimal reaction conditions were
determined as follows: in acetonitrile at −20 °C with 20 mol %
phosphine P5 as the chiral catalyst.
Initially, MBH carbonate 1a and methyl 2-phenyldiazene-1-
carboxylate 2a were employed as model substrates to examine
the optimized catalytic system for the expected [3+2]
cycloaddition. Several easily accessible chiral phosphines P1−
P5 were screened with CH2Cl2 as the solvent at room
temperature (Table 1, entries 1−5, respectively). Unexpect-
edly, all of these phosphines promoted the reaction to give the
desired product. Among them, spirocyclic chiral phosphine P5
gave the best results (95% yield with 86% ee) (entry 5).
Subsequently, with the use of P5 as the catalyst, the solvent
effect was explored (entries 6−9). The THF solvent was not
With the optimized reaction conditions in hand, we then
performed the cycloaddition of various MBH carbonates 1
with methyl 2-phenyldiazene-1-carbonate 2a (Table 2). In
a
Table 2. Scope of MBH Carbonates
b
c
entry
R in 1
C6H5 (1a)
t (h)
3/yield (%)
ee (%)
a
Table 1. Optimization of Reaction Conditions
1
2
3
4
5
6
7
8
5
10
3
4.5
4
9
12
2
5
3
2
4
12
3
4
12
6
11
48
48
3aa/99
3ba/97
3ca/95
3da/96
3ea/95
3fa/98
3ga/99
3ha/99
3ia/95
3ja/93
3ka/96
3la/95
3ma/93
3na/96
3oa/99
3pa/98
3qa/98
3ra/83
3sa/97
3ta/91
97
96
95
96
98
97
96
98
98
>99
98
98
94
98
96
99
99
95
77
80
2-FC6H4 (1b)
3-FC6H4 (1c)
4-FC6H4 (1d)
3-ClC6H4 (1e)
4-ClC6H4 (1f)
2-BrC6H4 (1g)
3-BrC6H4 (1h)
4-BrC6H4 (1i)
4-NO2C6H4 (1j)
3-MeC6H4 (1k)
4-MeC6H4 (1l)
2-OMeC6H4 (1m)
3-OMeC6H4 (1n)
4-OMeC6H4 (1o)
3,4-OMe2C6H3 (1p)
2-naphthyl (1q)
2-thienyl (1r)
Et (1s)
9
10
11
12
13
14
15
16
17
18
19
20
i-Pr (1t)
a
b
c
Unless otherwise stated, all reactions were performed with 2a (0.1
mmol), 1 (0.15 mmol), and P5 (0.02 mmol) in 1 mL of MeCN at
−20 °C. Isolated yield. Determined by HPLC analysis using a chiral
stationary phase.
entry
Px
solvent
T (°C)
t
yield (%)
ee (%)
b
c
1
2
3
4
5
6
7
8
P1
P2
P3
P4
P5
P5
P5
P5
P5
P5
P5
P5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
THF
toluene
MeCN
MeCN
MeCN
MeCN
25
25
25
25
25
25
25
25
25
3 h
48
46
72
19
95
98
trace
94
99
99
−37
−33
51
40
86
84
−
86
87
95
97
97
2 days
40 min
2 days
1.5 h
1 h
3 days
4 h
40 min
1.5 h
5 h
general, the reaction worked pretty well, tolerating MBH
carbonates 1 with various substituents (Table 2, entries 1−20).
The desired transformations were extremely efficient when R
was aryl or heteroaryl, furnishing the corresponding [3+2]
cycloadducts 3 in 93−99% yields with 94−99% ees (entries 1−
18). For substituted phenyl groups, the substituent on the
phenyl (regardless of electronic properties, substituted
position, or its number) has no virtually obvious effect on
yield and ee value (entries 2−16). Both 2-naphthyl- and 2-
thienyl-substituted MBH carbonates (1q and 1r, respectively)
displayed good performance, giving products 3qa and 3ra in
98% yield and 99% ee and 83% yield and 95% ee, respectively
(entries 17 and 18, respectively). Gratifyingly, the alkyl-
9
10
11
12
−10
−20
−30
99
95
16 h
a
Unless otherwise indicated, reactions of 1a (0.10 mmol) and 2a
(0.15 mmol) were carried out in the presence of chiral phosphine
b
c
(0.02 mmol) in 1 mL of the solvent. Isolated yield. Determined by
chiral HPLC analysis.
B
DOI: 10.1021/acs.orglett.9b02800
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted MBH carbonates (1s and 1t) were suitable
substrates for the [3+2] cycloaddition, providing pyrazoline
3 in excellent yield with good ee (entries 19 and 20). The
absolute configuration of the product has been verified through
single-crystal X-ray analysis of product 3ha.17
Scheme 2. Scale-Up Synthesis and Synthetic
Transformations
As indicated in Table 3, a range of diazenes were found to be
compatible substrates for the cycloaddition reaction. Generally,
a
Table 3. Scope of Diazenes
b
c
entry
R in 2
t (h)
3/yield (%)
ee (%)
1
2
3
4
5
6
7
8
2-FC6H4 (2b)
3-FC6H4 (2c)
4-FC6H4 (2d)
3,4-F2C6H3 (2e)
3-ClC6H4 (2f)
4-ClC6H4 (2g)
2-BrC6H4 (2h)
3-BrC6H4 (2i)
4
3.5
6
3
12
2
5
5
3
48
10
4
6
24
6
3ab/ 97
3ac/99
3ad/96
3ae/95
3af/87
3ag/94
3ah/91
3ai/96
3aj/99
3ak/35
3al/99
3am/96
3an/99
3ao/92
3ap/99
3aq/97
3ar/98
3as/99
3at/99
90
97
91
92
98
95
97
91
95
92
95
98
96
96
97
98
96
99
96
9
4-BrC6H4 (2j)
10
11
12
13
14
15
16
17
18
19
4-CF3C6H4 (2k)
2-MeC6H4 (2l)
3-MeC6H4 (2m)
4-MeC6H4 (2n)
2,4-Me2C6H3 (2o)
4-EtC6H4 (2p)
3-OMeC6H4 (2q)
4-OMeC6H4 (2r)
2-naphthyl (2s)
6-Br-2-naphthyl (2t)
4
0.1 mmol. Cycloadduct 3ah was further converted into
biphenyl heterocyclic product 4 through the coupling reaction
in the presence of Pd(Ph3P)4. Treatment of 3ah with SmI2 led
to hydrogenation/transesterification, giving tetrahydropyrazole
derivative 5 in 67% yield with 96% ee. Reduction of 3ah with
aluminum diisobutyl hydride (DIBAL-H) in THF furnished
tetrahydropyrazole derivative 6 in 37% yield with 96% ee.
In summary, we have disclosed that the nitrogen−nitrogen
double bond could conduct chiral phosphine-catalyzed
asymmetric cycloaddition reaction, resulting in enantioselec-
tive synthesis of chiral dihydropyrazoles. The mild reaction
conditions and commercially available chiral catalyst make this
reaction a feasible way toward chiral dihydropyrazoles. This
example demonstrates that nitrogen−nitrogen double bonds
may function like carbon−carbon and carbon−nitrogen double
bonds for various asymmetric transformations and thus will
potentially have a large application in organocatalyst and
metal-catalyzed asymmetric catalysis. Further investigations on
the application of a nitrogen−nitrogen double bond in the
asymmetric reactions are in progress in our laboratory.
12
2.5
3
a
Unless otherwise indicated, all reactions were carried out with 2 (0.1
mmol), 1a (0.15 mmol), and P5 (0.02 mmol) in 1 mL of MeCN at
b
c
−20 °C. Isolated yield. Determined by HPLC analysis using a chiral
stationary phase.
with respect to variations on the phenyl group of the diazenes,
the [3+2] cycloaddition reactions proceed efficiently with
excellent enantioselectivity (90−99% ee) for a series of
substitution patterns (Table 3, entries 1−19). By employing
phenyldiazenes 2 bearing a halogen (2b−2j), alkyl (2l−2p), or
alkoxyl (2q and 2r) group on the phenyl group to this
cycloaddition, dihydropyrazole derivatives 3 were obtained in
great yields (87−99%) and with excellent ee values (90−98%,
entries 1−9, 11−15, and 16 and 17, respectively). In addition,
p-trifluoromethyl-substituted phenyldiazene 2k produced
cycloadduct 3ak with 92% ee, albeit in 35% yield (entry 10).
To our delight, the cycloaddition of 2-naphthyl- and
bromonaphthyl-substituted diazenes (2s and 2t, respectively)
occurred under the optimized conditions with excellent yields
and enantioselectivities (entries 18 and 19, respectively).
Having determined the scope of phosphine-catalyzed
asymmetric [3+2] cycloaddition of diazenes, we then carried
out an experiment to further showcase the application of this
methodology in organic synthesis. As shown in Scheme 2, the
cycloaddition reaction on the 1 mmol scale worked smoothly,
affording pyrazoline derivative 3ah without a remarkable loss
of yield and enantioselectivity, compared with the reaction at
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02800.
Experimental procedure, characterization data, HPLC
analysis dada, NMR spectra, and X-ray crystallographic
data (PDF)
C
DOI: 10.1021/acs.orglett.9b02800
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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CCDC 1940604 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hchguo@cau.edu.cn.
ORCID
Chang Wang: 0000-0003-2870-6518
Hongchao Guo: 0000-0002-7356-4283
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the Natural Science Foundation of
China (21572264 and 21871293) and the Chinese Universities
Scientific Fund (2018TC052, 2018TC055, and 2019TC085).
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DOI: 10.1021/acs.orglett.9b02800
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