Phosphine-Catalyzed Cascade Annulation of MBH Carbonates and Diazenes: Synthesis of Hexahydrocyclopenta[c]pyrazole Derivatives

Article abstract of DOI:10.1021/acs.orglett.1c01975

A phosphine-catalyzed cascade annulation of Morita-Baylis-Hillman (MBH) carbonates and diazenes was achieved, giving tetrahydropyrazole-fused heterocycles bearing two five-membered rings in moderate to excellent yields. The reaction underwent an unprecedented reaction mode of MBH carbonates, in which two molecules of MBH carbonates were fully merged into the ring system.

Full text of DOI:10.1021/acs.orglett.1c01975

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Letter
Phosphine-Catalyzed Cascade Annulation of MBH Carbonates and
Diazenes: Synthesis of Hexahydrocyclopenta[c]pyrazole Derivatives
Hongxiang Li,# Wangyu Shi,# Chang Wang, Hao Liu, Wei Wang, Yongjun Wu, and Hongchao Guo*
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ABSTRACT: A phosphine-catalyzed cascade annulation of
Morita−Baylis−Hillman (MBH) carbonates and diazenes was
achieved, giving tetrahydropyrazole-fused heterocycles bearing two
five-membered rings in moderate to excellent yields. The reaction
underwent an unprecedented reaction mode of MBH carbonates,
in which two molecules of MBH carbonates were fully merged into
the ring system.
Scheme 1. Lewis Base-Catalyzed Annulation Reactions of
Diazenes
yrazole, dihydropyrazole, and tetrahydropyrazole are
among the most widespread motifs in agrochemicals and
P
drugs.1 The related heterocycles are privileged structures in
agrochemical and medicinal chemistry.2 Therefore, their
synthesis is highly desirable and has attracted much attention.
In the past two decades, phosphine-catalyzed annulation
reactions have been developed as a powerful tool for synthesis
of carbo- and heterocycles.3 Among them, the annulation
reactions with Morita−Baylis−Hillman (MBH) carbonates as
phosphine acceptor have been extensively investigated.3h,j,4−11
MBH carbonates often worked as a three-membered synthon
to achieve [3 + 2],5 [3 + 3],6 [3 + 4],7 and [3 + 6]8 annulation
reactions and sometimes functioned as a C1 synthon to furnish
[1 + 4] annulation reactions.9 In these reactions, electron-
deficient carbon−carbon,5a−g carbon−nitrogen,5h,i carbon−
oxygen,5j and nitrogen−nitrogen11 double bonds are widely
used as electrophiles to accomplish numerous annulation
reactions. Obviously, the annualtion reactions of nitrogen−
nitrogen double bond with MBH carbonates are a concise
synthetic tool for pyrazole, dihydropyrazole, and tetrahydro-
pyrazole compounds (Scheme 1).11 At an early stage, in the
presence of an equivalent of phosphine, azodicarboxylates were
used as phosphine acceptor for synthesis of dinitrogen-fused
compounds.12 In 2015, Meng and Wang developed a Bu3P-
catalyzed desulfonylative [3 + 2] cycloaddition of MBH
carbonates with arylazosulfones for synthesis of pyrazole
derivatives in good to excellent yields (Scheme 1a).11a With
the use of 4-dimethylaminopyridine (DMAP) as the catalyst,
Meng and Wang also achieved a similar [3 + 2] cycloaddition
of isatin-derived MBH carbonates with diazenes for the
construction of 3-spiropyrazole-2-oxindoles in good to
excellent yields.11c The same research group also reported a
DMAP-catalyzed [2 + 4] cycloaddition of allenoates and N-
acyldiazenes to generate 1,3,4-oxadiazine derivatives in
moderate to good yields (Scheme 1b).11b In 2019, we
accomplished a phosphine-catalyzed asymmetric [3 + 2]
cycloaddition of diazenes with MBH carbonates to give chiral
Received: June 14, 2021
Published: July 7, 2021
https://doi.org/10.1021/acs.orglett.1c01975
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5571−5575
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dihydropyrazoles in high yields with excellent enantioselectiv-
ities (Scheme 1c).11d On the basis of our previous work,11d,13
we herein disclose an unprecedented phosphine-catalyzed
cascade annulation of MBH carbonates and diazenes for
synthesis of hexahydrocyclopenta[c]pyrazole derivatives
(Scheme 1d). Different from previous annulation reactions
involving MBH carbonates, two molecules of MBH carbonates
were merged into two five-membered rings in the current
reaction.
2a to diazene 1a did not help enhance the yield (entry 15).
The effect of temperature was also explored. Increasing
reaction temperature to 40 °C reduced the yield (entry 16),
while decreasing reaction temperature to 0 °C had no negative
effect on the yield but required longer reaction time (entry 17).
On the basis of the above screening, the optimal reaction
conditions were determined as follows: 0.1 mmol of diazenes
and 0.3 mmol of MBH carbonates with 20 mol % CyPh2P in 2
mL of MeCN at 25 °C.
Initially, we began our investigation of cascade annulation
between diazene 1a and MBH carbonate 2a in dichloro-
methane at room temperature (Table 1). A variety of
Under the optimized reaction conditions, we examined
reactions between various diazenes 1 with MBH carbonate 2a
(Table 2, entries 1−16). Diazenes with both electron-donating
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of Diazenes
b
b
entry
R3P
Ph3P
MePh2P
BnPh2P
CyPh2P
Bn3P
solvent
T (°C)
yield (%)
entry
R/Ar in 1
t (h)
3
yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
THF
toluene
MeCN
1,4-dioxane
MeOH
MeCN
MeCN
MeCN
MeCN
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
0
trace
48
42
64
62
58
44
67
42
37
82
trace
trace
84
82
68
82
1
2
3
4
5
6
7
8
Me/2-MeC6H4 (1b)
Me/3-MeC6H4 (1c)
Me/4-MeC6H4 (1d)
Me/2,4-Me2C6H3 (1e)
Me/3-MeOC6H4 (1f)
Me/4-MeOC6H4 (1g)
Me/4-EtC6H4 (1h)
Me/4-i-PrC6H4 (1i)
Me/3-FC6H4 (1j)
Me/4-FC6H4 (1k)
Me/3,4-F2C6H3 (1l)
Me/4-ClC6H4 (1m)
Me/2-BrC6H4 (1n)
Me/4-BrC6H4 (1o)
Me/2-naphthyl (1p)
Me/6-Br-2-naphthyl (1q)
t-Bu/C6H5 (1r)
2
2
5
2
2
3
2
5
3
1
2
2
2
3
3
6
2
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
45
84
61
65
82
59
89
88
48
63
61
55
46
70
77
63
68
Cy3P
Bu3P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
CyPh2P
9
9
10
11
12
13
10
11
12
13
14
15
16
17
c
14
d
15
16
17
e
a
a
Unless otherwise indicated, reactions of 1a (0.10 mmol) and 2a
(0.24 mmol) were carried out in the presence of phosphine (0.02
Unless otherwise indicated, all reactions were carried out with 1 (0.1
mmol), 2a (0.3 mmol), and CyPh2P (0.02 mmol) in 2 mL of MeCN
at 25 °C. Isolated yield, >20:1 dr.
b
c
b
mmol) in 2 mL of the solvent for 3 h. Isolated yield, >20:1 dr. 0.3
mmol of 2a was used in the reaction. 0.4 mmol of 2a was used in the
reaction. The reaction time was 13 h.
d
e
and -withdrawing groups on the phenyl ring were well
tolerated to produce the corresponding annulation products
in moderate to good yields. Various diazenes bearing
functional groups such as methoxy (1f and 1g), fluorine
(1j−1l), chlorine (1m) and bromine (1n and 1o) behaved
properly in this catalytic system. The substrates having an
ortho-substituted phenyl (1b and 1n) gave relatively low yields
of the corresponding products, indicating that steric hindrance
has a remarkable influence on the reactivity of the substrates
(entries 1 and 13). Diazenes with disubstituted phenyl such as
1e and 1l were proven to be suitable substrates for the cascade
cycloaddition, giving the hexahydrocyclopenta[c]pyrazole
derivatives in good yields (entries 4 and 11). To our delight,
2-naphthyl and substituted naphthyl group (1p and 1q) were
also carried out, and the corresponding products (3pa and
3qa) were obtained in high yields (entries 15 and 16). The
relative configuration of the annulation products has been
confirmed by X-ray crystallography of the product 3aa.
phosphine catalysts were explored (entries 1−7). The Ph3P
with a low nucleophilicity did not efficiently catalyze the
reaction, leading to only a trace of the desired product (entry
1). Other phosphines having at least one alkyl group displayed
certain catalytic activity, leading to the desired product in
moderate to high yields (entries 2−7). Among these
phosphines, CyPh2P demonstrated relatively good catalytic
ability, resulting in the product in 64% yield (entry 4). With
the use of CyPh2P as the catalyst, a concise solvent screening
was performed (entries 8−13). The chlorinated solvent 1,2-
dichloroethane was compatible with the reaction and provided
a 67% yield close to that obtained in the solvent CH2Cl2 (entry
8 vs entry 4). Toluene and THF gave inferior results (entries 9
and 10). Polar solvent acetonitrile was efficient, offering a high
82% yield (entry 11). Another two polar solvents, 1,4-dioxane
and methanol, were incompatible, affording only a trace of
products (entries 12 and 13). Increasing the ratio of MBH
carbonate to diazene resulted in a slightly higher 84% yield
(entry 14), but further increasing the ratio of MBH carbonate
As shown in Table 3, the scope of MBH carbonates was also
evaluated (entries 1−7). The reactions of several MBH
carbonates with different alkyl groups in the ester moiety
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Letter
a
Boc group in the product 3ra was easily removed to give the
derivative 5ra in high yield with good dr.
Table 3. Scope of MBH Carbonates
On the basis of phosphine catalysis principles, a plausible
mechanism was proposed for this cascade annulation reaction
(Scheme 3). Initially, the phosphine catalyst attacks the MBH
Scheme 3. A Plausible Mechanism
b
entry
R
t (h)
3
yield (%)
1
2
3
4
5
6
7
Et (2b)
2
2
2
2
2
3ab
3ac
3ad
3ae
3af
71
59
95
57
60
53
trace
n-Pr (2c)
Cy (2d)
Bn (2e)
i-Pr (2f)
Ad (2g)
t-Bu (2h)
2
24
3ag
3ah
a
Unless otherwise indicated, all reactions were carried out with 1a
(0.1 mmol), 2 (0.3 mmol), and CyPh2P (0.02 mmol) in 2 mL of
b
MeCN at 25 °C. Ad: 1-adamantyl. Isolated yield, >20:1 dr.
(2b−2g) proceeded smoothly to give the desired products
(3ab−3ag) in moderate to high yields (entries 1−6).
Particularly, when the cyclohexyl-bearing MBH carbonate 2d
was used, 95% yield of the annulation product 3ad was
obtained (entry 3). The tert-butyl substituted MBH carbonate
2h was not reactive, leading to only a trace of product 3ah
(entry 7), probably because of its steric hindrance. It should be
noted that those MBH carbonates derived from other
aldehydes, such as benzaldehyde, did not work in this reaction.
To our delight, the scale-up reaction still worked well under
standard reaction conditions. As indicated in Scheme 2, 2
Scheme 2. Scale-up Reaction and Further Transformations
of the Products
carbonate 2a to form zwitterionic intermediate A. Its
tautomeric isomer B then attacks the diazene 1a to give the
ylide C, which reacts with another molecule of MBH carbonate
2a to generate the intermediate D. Subsequent deprotonation
of the intermediate D through tert-butoxy anion from
decarboxylation of the substrate 2a leads to the ylide E,
which performs an isomerization to afford the intermediate F.
Consequent intramolecular nucleophilic addition triggers
highly diastereoselective cascade annulation to furnish the
intermediate G having two five-membered rings. Subsequent
formation of the carbon−carbon double bond with simulta-
neous regeneration of phosphine catalyst produces the final
product 3aa.
In summary, we achieved the cascade annulation of MBH
carbonates with diazenes under mild reaction conditions. A
variety of tetrahydropyrazole-fused heterocycles were obtained
in moderate to excellent yields. The reaction undergoes a very
interesting reaction pathway and demonstrates an unprece-
dented reaction mode of MBH carbonates under phosphine
catalysis conditions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
mmol of the diazene 1a (0.33 g) reacted with MBH carbonate
2a (6 mmol, 1.30 g) in acetonitrile at room temperature for 3
h, leading to the cycloaddition product 3aa in 85% yield (0.61
g). No loss of yield was observed in the scale-up reaction,
compared with the reaction at 0.1 mmol scale. Further
transformations of the product 3 also were investigated
(Scheme 2). Treatment of 3aa with N-bromosuccinimide
(NBS) gave the brominated product 4aa in excellent yield with
>20:1 dr. In the presence of trifluoroacetic acid (TFA), the
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01975.
Experimental procedure, characterization data, NMR
spectra, and X-ray crystallographic data (PDF)
Accession Codes
CCDC 2055670 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
5573
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
Hongchao Guo − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China; orcid.org/0000-0002-7356-
4283; Email: hchguo@cau.edu.cn
Authors
Hongxiang Li − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China
Wangyu Shi − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China
Chang Wang − Department of Chemistry and Innovation
Center of Pesticide Research, China Agricultural University,
Beijing 100193, P.R. China; orcid.org/0000-0003-2870-
6518
Hao Liu − Department of Chemistry and Innovation Center of
Pesticide Research, China Agricultural University, Beijing
100193, P.R. China
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Wei Wang − College of Public Health, Zhengzhou University,
Zhengzhou 450001, P.R. China
Yongjun Wu − College of Public Health, Zhengzhou
University, Zhengzhou 450001, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01975
Author Contributions
#H.L. and W.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the Natural Science Foundation of
China (Nos. 21871293 and 22071264).
■
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