Asymmetric Formal [3 + 2]-Cycloaddition of Azomethine Imines with Azlactones to Synthesize Bicyclic Pyrazolidinones

Article abstract of DOI:10.1021/acs.orglett.7b02772

An efficient enantioselective formal [3 + 2]-cycloaddition of azomethine imines with azlactones has been realized by using a chiral bifunctional bisguanidinium hemisalt as the catalyst. Optically active bicyclic pyrazolidinone compounds were generated under mild reaction conditions in high yields (up to 99%) with good dr (up to 88:12) and excellent ee values (up to 99%). This simple and efficient strategy provides a method to construct biologically important chiral tetrahydropyrazolo[1,2-a]pyrazole-1,7-dione derivatives bearing vicinal aza-quaternary and tertiary carbon centers.

Full text of DOI:10.1021/acs.orglett.7b02772

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Asymmetric Formal [3 + 2]-Cycloaddition of Azomethine Imines with
Azlactones To Synthesize Bicyclic Pyrazolidinones
Qian Zhang, Songsong Guo, Jian Yang, Kunru Yu, Xiaoming Feng, Lili Lin, and Xiaohua Liu*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: An efficient enantioselective formal [3 + 2]-
cycloaddition of azomethine imines with azlactones has been
realized by using a chiral bifunctional bisguanidinium hemisalt
as the catalyst. Optically active bicyclic pyrazolidinone
compounds were generated under mild reaction conditions
in high yields (up to 99%) with good dr (up to 88:12) and
excellent ee values (up to 99%). This simple and efficient
strategy provides a method to construct biologically important
chiral tetrahydropyrazolo[1,2-a]pyrazole-1,7-dione derivatives
bearing vicinal aza-quaternary and tertiary carbon centers.
yrazolidinones and their analogues represent a group of
heterocyclic compounds which exhibit rich biological
organocatalyzed Knoevenagel−aza-Michael cyclocondensation
of Meldrum’s acid.8b Very recently, Kerrigan’s group demon-
strated the formation of chiral tetrahydropyrazolo[1,2-a]-
pyrazole-1,7-diones bearing 2,3-disubstituents from 1,3-dipolar
cycloaddition of ketenes generated in situ.8c Using lithium
ynolates as the dipolarophiles allowed access to similar
structures but only in a diastereoselective fashion.9a Despite
these reports, the core framework (Figure 1) bearing
substituents at both C2 and C3 positions could be obtained
from a spontaneous cyclization between azomethine imines
with azlactones.10a This reaction occurred efficiently without a
catalyst, but it would be difficult to achieve an enantioselective
catalytic version. This is also one of the few applications of
azlactones acting as dipolarophiles in [3 + 2]-cycloaddition,12
rather than as masked azomethine ylides.13,14 Encouraged by
our studies on the asymmetric transformations of azlactones
promoted by bifunctional guanidine catalysts,15 we were
interested in the challenging asymmetric synthesis of
tetrahydropyrazolo[1,2-a]pyrazole-1,7-diones containing vicinal
aza-quaternary and tertiary carbon centers. We report a chiral
bisguanidinium hemisalt promoted diastereo- and enantiose-
lective formal 1,3-dipolar cycloaddition of azlactones with
azomethine imines. The reaction represents a unique approach
for the enantioselective construction of 2,2-disubstituted
derivatives of compound B.
P
activities.1 The N,N-bicyclic derivatives, especially tetrahydro-
pyrazolo[1,2-a]pyrazolones, have attracted considerable atten-
tion due to the fact that compounds A were investigated as
analogues of penicillin and cephalosporin antibiotics,2 and
compound B was developed as a potent drug for treatment of
cognitive dysfunctions such as Alzheimer’s disease3 (Figure 1).
Figure 1. Selected examples of biologically active tetrahydropyrazolo-
[1,2-a]pyrazolones.
Substituted tetrahydropyrazolo[1,2-a]pyrazolones are usually
chiral compounds; therefore, the development of efficient
approaches to construct such molecules in an enantioselective
manner is highly desirable for pharmaceutical assay and other
fields.
1,3-Dipolar cycloaddition of azomethine imines 1 with
various dipolarophiles, including olefins,4 alkynes,5 isocyanides,6
allenes,7 ketenes,8 ynolates,9 azlactones,10 and other types,11
provides a straightforward route for the synthesis of
pyrazolidinone-based bicyclic derivatives. However, there are
a few examples related to the enantioselective synthesis of the
N,N-fused bicyclic five-membered ring system. The Fu group
utilized a chiral Cu(I) complex to accelerate the reaction of
alkynes to generate 2,3-dihydropyrazolo[1,2-a]pyrazol-1-one-
Our initial investigations commenced with a model reaction
between azomethine imine 1a and azlactone 2a in Et2O at 25
°C for chiral guanidine catalyst optimization (Table 1). When
chiral guanidine-amides G-1 to G-3 were used as the catalyst,
the reaction performed smoothly and two diastereomers of the
product 3aa were generated almost equally without obvious
s.5a,b Later, Brier
synthesis of tetrahydropyrazolo[1,2-a]pyrazole-1,5-dione via
̀
e and co-workers reported the asymmetric
Received: September 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Information). Screening of the solvents revealed that other
reaction solvents including toluene, THF, and CH2Cl2 reduced
the yield and enantioselectivity sharply, along with reverse
diastereoselection (Table 1, entries 9−12). In addition, lower
temperatures restrained the reaction activity (Table 1, entry
13). Increasing the ratio of azlactone 2a to azomethine imine
1a and reducing the reaction concentration delivered a slight
improvement with a 96% yield, 82:18 dr, and 90% ee at 30 °C
(Table 1, entry 14).
Table 1. Optimization of the Reaction Conditions
Substrate generality was investigated by changing the aryl
group of azomethine imines (Table 2). These, with electron-
Table 2. Scope of Azomethine Imines 1 in Cycloaddition
a
with Azlactone 2a
b
c
c
entry
cat.
solvent
yield (%)
dr
ee (%)
b
c
c
1
G-1
G-2
G-3
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
toluene
THF
CH2Cl2
Et2O
Et2O
33
26
18
5
47:53
53:47
45:55
50:50
50:50
64:36
21:79
30:70
18:82
79:21
68:32
71:29
18:82
17:83
5/3
entry
1, R1
1a; C6H5
3, yield (%)
dr
ee (%)
2
0/3
1
3aa, 96
3ba, 96
3ca, 97
3da, 99
3ea, 96
3fa, 56
3ga, 69
3ha, 76
3ia, 77
3ja, 76
3ka, 73
3la, 86
3ma, 94
3na, 90
3oa, 89
84:16
85:15
85:15
79:21
70:30
84:16
64:36
79:21
75:25
85:15
88:12
84:16
81:19
77:23
81:19
90
98
95
97
95
95
95
81
81
81
86
83
84
86
87
3
0/17
2
1b; 2-FC6H4
1c; 2-ClC6H4
1d; 2-BrC6H4
1e; 2-MeC6H4
1f; 2-MeOC6H4
1g; 2-O2NC6H4
1h; 3-FC6H4
1i; 3-MeOC6H4
1j; 4-FC6H4
4
BG-1
20/30
19/14
14/18
51/57
10/11
66/83
25/28
18/69
30/59
−/85
−/90
3
5
BG-2
42
15
75
30
84
34
27
35
22
96
4
6
BG-3
5
7
BG-1·HBArF
BG-2·HBArF
BG-3·HBArF
BG-3·HBArF
BG-3·HBArF
BG-3·HBArF
BG-3·HBArF
BG-3·HBArF
4
4
4
4
4
4
4
4
6
8
7
9
8
10
11
12
9
10
11
12
13
14
15
1k; 4-MeOC6H4
1l; 4-iPrC6H4
1m; 2-furyl
d
13
e
14
a
Unless otherwise noted, the reactions were carried out with guanidine
(10 mol %), 1a (0.05 mmol), and 2a (1.0 equiv) in solvent (1.0 mL)
at 25 °C. Isolated yield. Determined by HPLC analysis. At 0 °C.
1n; 2-thienyl
1o; 1-naphthyl
b
c
d
a
Unless otherwise noted, the reactions were carried out with BG-3·
e
1a (0.10 mmol), and 2a (1.2 equiv) in Et2O (6.0 mL) at 30 °C.
HBArF (10 mol %), 1 (0.10 mmol), and 2 (1.2 equiv) in Et2O (6.0
4
HBArF = HB[3,5-(CF3)2C6H3]4.
b
4
mL) at 30 °C for 10 h. Isolated yield of the two diastereomers.
c
Determined by HPLC analysis.
enantioselection (Table 1, entries 1−3). In view of the fact that
the structure and counterion of guanidine catalysts are critical
for both the reactivity and enantioselectivity in our previous
study,15,16 we next examined the performance of several C2-
symmetric bisguanidine catalysts and the corresponding
hemisalts. It was disappointing that when BG-1−BG-3 were
used, no satisfactory results were obtained in terms of yield and
stereoselectivity (Table 1, entries 4−6). BG-1, which was useful
for a formal [4 + 2]-cycloaddition of azlactones with
chalcone,15a resulted in an extremely low yield (Table 1,
entry 4). (S)-Tetrahydroisoquinoline-3-carboxylic acid derived
bisguanidines BG-2 and BG-3 containing benzene-1,3-diamine
and benzene-1,2-diamine linkage showed a difference in
reactivity, resulting in 42% and 15% yields, respectively
(Table 1, entry 6 vs 5). This indicates that the linkage changes
the catalytic environment remarkably. Furthermore, the use of
bisguanidinium hemisalts instead changed both the reactivity
and stereoselectivity significantly, especially for the related salts
of BG-1 and BG-3 (Table 1, entries 7−9). Catalyst BG-3·
rich and -deficient substituents on the aromatic ring, reacted
smoothly with azlactone 2a, generating the desired tetrahydro-
pyrazolo[1,2-a]pyrazole-1,7-diones 3aa−3oa in moderate to
good yields (56−99%) with good to excellent enantioselectiv-
ities (ee = 81−98%) and good diastereoselectivities (Table 2,
entries 1−12). Higher enantioselectivities were achieved with
substituents at the ortho-position of the aryl group than at the
meta- and para-positions (Table 2, entries 1−7 vs 8−12).
Heteroaromatic and 1-naphthyl substituted azomethine imines
were also tolerable in the current system. The products 3ma−
3oa were given in high yields (89−94%) with satisfactory
stereoselectivity (ee = 84−87%, dr = 81:19−78:22) (Table 2,
entries 13−15).
Next, the substrate scope was probed through azlactones
with varied substituents at the C2 and C4 positions (Table 3).
Azomethine imine 1b was selected as the dipole. Azlactones
2b−2d synthesized from alanine, 2-aminobutanoic acid, and
leucine were tolerated under optimized reaction conditions,
providing methyl, ethyl, or isobutyl substitution on to the core
scaffold in moderate to good yields with good enantioselectiv-
ities (ee = 88−89%) (3bb−3bd). High enantioselectivity (ee =
99%) was achieved for one diastereomer with an indolylmethyl
group albeit with a lower 45% yield and diastereoselectivity of
HBArF led to a striking result, and product 3aa could be
4
isolated in 84% yield with good diastereo- and enantioselectiv-
ities (dr = 82:18 and ee = 83% for the major diastereomer)
(Table 1, entry 9). Sterically hindered acid with stronger acidity
afforded a higher yield and ee value (see Supporting
B
DOI: 10.1021/acs.orglett.7b02772
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
intermediate. Subsequent lactonization leads to the formation
of the 2-alkyl-2-amino-3-aryl substituted tetrahydropyrazolo-
[1,2-a]pyrazo-le-1,7-dione product.
Table 3. Scope of Azlactones 2 in Cycloaddition with
Azomethine Imines 1b
a
In conclusion, an organocatalyzed asymmetric formal [3 +
2]-cycloaddition of N,N-cyclic azomethine imines with
azlactones has been developed. A new bisguanidinium hemisalt
was selected as a bifunctional catalyst to promote the reaction
in good to excellent yields and enantioselectivity. It provided
easy access to tetrahydropyrazolo[1,2-a]pyrazole-1,7-dione
derivatives with vicinal aza-quaternary and tertiary carbon
centers that represent scaffolds with potential bioactivity. We
anticipate that chiral guanidine and guanidinium may find
utility in other reactions for the synthesis of biologically
intriguing small molecules.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02772.
Crystallographic data for 3da (CIF)
Experimental details, analytic data (NMR, HPLC, ESI-
HRMS, and X-ray) (PDF)
AUTHOR INFORMATION
■
a
Same as in Table 2.
Corresponding Author
*E-mail: liuxh@scu.edu.cn.
ORCID
3be. Further investigation suggested that the position and its
electronic property of the substituent at the C2-aryl group of
azlactones had a significant impact on yields and diastereo- and
enantioselectivities. 4-Halo-substituted ones gave higher yields
than the electron-donating substituted ones, and the corre-
sponding cyclization products of 3bf−3bj were afforded in
good to excellent yields (68−99%) and stereoselectivities (ee =
77−90%, dr = 71:29−80:20).
Xiaoming Feng: 0000-0003-4507-0478
Xiaohua Liu: 0000-0001-9555-0555
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
To demonstrate the scalability and the practicality of this
protocol, we conducted a gram-scale reaction with 1d (2.30
mmol) and 2a (2.76 mmol) in the presence of 10 mol % of
■
We thank the National Natural Science Foundation of China
(Nos. 21625205, 21332003, 21290182), and National Program
for Support of Top-notch Young Professionals for financial
support.
BG-3·HBArF in Et2O at 30 °C (Scheme 1). Gratifyingly, the
4
Scheme 1. Scale-up Version of the Reaction and X-ray
Crystal Structure of the Product 3da
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Organic Letters
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DOI: 10.1021/acs.orglett.7b02772
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