Catalyst-free synthesis of N -(1,7-dioxotetrahydropyrazolo[1,2-a]pyrazol-2- yl)benzamide derivatives by 1,3-dipolar cycloaddition and rearrangement

Article abstract of DOI:10.1055/s-0033-1341056

N-(1,7-Dioxotetrahydropyrazolo[1,2-a]pyrazol-2-yl)-benzamide derivatives, a novel class of compounds, were synthesized by 1,3-dipolar cycloaddition of azomethine imines with azlactones and subsequent rearrangement. The reaction can be completed rapidly under mild conditions without a catalyst. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341056

LETTER
▌1093
lCettaertalyst-Free Synthesis of N-(1,7-Dioxotetrahydropyrazolo[1,2-a]pyrazol-2-
yl)benzamide Derivatives by 1,3-Dipolar Cycloaddition and Rearrangement
N-(1,7-Dioxotetrahydropyrazolo[1,2-a]pyrazol-2-yl)benzamides
Wenjing Liu, Yu Xu,* Xingxia Sun, Dapeng Lu, Lijuan Guo
Department of Chemistry and Anhui Key Lab for Biomass Clean Energy, University of Science and Technology of China, Hefei 230026,
P. R. of China
Fax +86(551)63606689; E-mail: xyu@ustc.edu.cn
Received: 17.01.2014; Accepted after revision: 02.03.2014
challenging task in organic chemistry. We discovered a
Abstract: N-(1,7-Dioxotetrahydropyrazolo[1,2-a]pyrazol-2-yl)-
novel approach to the synthesis of a N,N-bicyclic core
benzamide derivatives, a novel class of compounds, were synthe-
through 1,3-dipolar cycloaddition of azomethine imines
sized by 1,3-dipolar cycloaddition of azomethine imines with azlac-
with azlactones. Whereas there are many reports in the lit-
erature on 1,3-cycloaddition reactions in the presence of
various catalysts and ligands, we have developed a new
approach for the synthesis of N-(1,7-dioxotetrahydropyr-
azolo[1,2-a]pyrazol-2-yl)benzamide derivatives through
1,3-cycloaddition of azomethine imines at the C-4 and
C-5 positions of azlactones in the absence of a catalyst
(Scheme 1).
tones and subsequent rearrangement. The reaction can be completed
rapidly under mild conditions without a catalyst.
Key words: cycloadditions, azomethine imines, azlactones, hetero-
cycles, bicyclic compounds
Five-membered nitrogen-containing heterocycles are core
structural elements in organic synthesis, usually appear-
ing in biologically active molecules. Recently, N,N-bicy-
clic derivatives, which have some important and useful
bioactivities, have been investigated as potent drugs for
the treatment of cognitive dysfunctions, such as Alzheim-
er’s disease.1,2
O
O
O
O
5
R2
N
N
R2
N–
N+
CH2Cl2
25 °C
O
4
+
2
NHCOPh
N
R1
H
Ph
R1
R1 = aryl, heteroaryl, Cy
R2 = Ar, Me, H
Because of the pharmaceutical properties of N,N-bicyclic
derivatives, their synthesis has attracted the interest of
chemists. The 1,3-dipolar cycloaddition reaction of azo-
methine imines with various olefins is a powerful ap-
proach for the synthesis of N,N-bicyclic heterocyclic
compounds.3 In recent decades, catalytic asymmetric 1,3-
dipolar cycloaddition reactions have been developed for
several 1,3-dipoles, including nitrones,4,5 nitrile imines,6
and azomethine imines.7 Recently, Fu and co-workers re-
ported [3+2] cycloaddition reactions of azomethine im-
ines with copper acetylides containing a phosphaferrocene–
oxazoline ligand.7b,7c Sommer and co-workers reported a
[3+2] cycloaddition of azomethine imines with ethyl pro-
piolate in the presence of copper(I) zeolites as catalysts.7f
Yu and co-workers reported a [3+2] cycloaddition of azo-
methine imines with 1-alkynyl Fischer carbene complex-
es to give functionalized N,N-bicyclic pyrazolidin-3-
ones.7g
cis
Scheme 1 Cycloaddition additions of azomethine imines with azlac-
tones
Initially, we optimized the reaction conditions for the cy-
cloaddition of 2-benzylidene-5-oxopyrazolidin-2-ium-1-
ide (1a) with 2,4-diphenyl-1,3-oxazol-5(4H)-one (2a)
(Table 1). Initially, the reaction was carried out at 25 °C
in dichloromethane for two hours. The [3+2] cycloaddi-
tion product 3a was obtained in 91% yield (Table 1, entry
1). In an attempt to identify a more suitable solvent, we
performed the reaction without a catalyst in several polar
solvents, including various aprotic solvents (chloroform,
dimethyl sulfoxide, acetonitrile, and diethyl ether) and a
protic solvent (ethanol); however, the yields (76–85%)
were lower than those obtained in dichloromethane (en-
tries 2–6). Nonpolar solvents were not used because the
substrates were insoluble in such solvents.
Azlactones possess three reactive sites at C-2, C-4, and
C-5, of which C-2 and C-5 are electrophilic and C-4 is nu-
cleophilic. Azlactones are therefore extremely versatile
reactants in synthetic organic chemistry8 and can undergo
a range of useful cycloaddition reactions. For instance, cy-
cloaddition reactions of the C-4 and C-5 positions of
azlactones with various olefins have been developed.
However, the synthesis of N,N-bicyclic cores remains a
Reports in the literature suggest that copper salts can be
used as catalysts to improve product yields.7b,c,9 We tried
several copper salts, but none gave an increase in the yield
(entries 8–13). Adding 4 Å molecular sieves also failed to
increase the yield, suggesting that the presence of water in
the solvent has no effect on the yield (entry 7).
To accelerate the 1,3-cycloaddition, we increased the tem-
perature to 40 °C, but this did not increase the yield sig-
nificantly (entry 15). Lowering the temperature to 0 °C
also failed to increase the yield (entry 14). Overall, the na-
ture of the solvent, the presence or absence of a copper
SYNLETT 2014, 25, 1093–1096
Advanced online publication: 03.04.2014
DOI: 10.1055/s-0033-1341056; Art ID: ST-2014-W0050-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1094
W. Liu et al.
LETTER
salt, and the temperature have little effect on the yield. Fi- moderate yield (entries 11 and 12). Unfortunately, linear
nally, we chose dichloromethane at 25 °C in the absence aliphatic-substituted azomethine imines failed to give the
of a catalyst as the optimal reaction conditions.
desired products. However, we were able to synthesize a
cyclohexyl-substituted azomethine imine, the reaction of
which with an azlactone gave only a 43% yield under the
optimized conditions (entry 13).
Table 1 Optimization of the Reaction Conditions
O
O
O
O
N
N
Ph
Ph
N–
N+
+
O
Table 2 Cycloaddition Reactions of Azomethine Imines 1a–m with
Azlactones 2a–d
NHCOPh
2 h
N
H
Ph
Ph
Ph
O
O
O
O
1a
2a
3a
N
N
R2
CH2Cl2
R2
N–
N+
O
Entrya
Solvent
Additive (mol%)
Temp (°C) Yieldb (%)
+
NHCOPh
25 °C, 6 h
N
R1
R1
H
Ph
1
2
CH2Cl2
CHCl3
DMSO
MeCN
Et2O
–
25
25
25
25
25
25
25
25
25
25
25
91
85
76
80
81
80
82
87
81
54
77
75
65
76
86
1a–m
2a–d
3a–p
–
Entrya R1
R2
Time (h) Product Yieldb (%)
3
–
1
2
3
4
5
6
7
8
Ph
Ph
2
5
6
3
3
3
4
4
4
5
4
4
5
5
4
6
3a
3b
3c
3d
3e
3f
91
70
30
85
70
72
59
67
62
55
62
69
43
68
72
35
4
–
4-MeOC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-F3CC6H4
3-ClC6H4
2-ClC6H4
2-thienyl
2-furyl
Ph
5
–
Ph
6
EtOH
–
Ph
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4 Å MS
CuBr (10)
CuI (10)
Cu(OTf)2 (10)
CuBr2 (10)
Ph
8
Ph
9
Ph
3g
3h
3i
10
11
12
13
14
15
Ph
9
Ph
Cu(OAc)2·H2O (10) 25
10
11
12
13
14
15
16
Ph
3j
CuCl2·H2O (10)
25
0
Ph
3k
3l
–
–
Ph
40
Cy
Ph
3m
3n
3o
3p
a Reaction conditions: sealed tube, 1a (1.2 equiv), 2a (0.2 mmol), sol-
vent (0.5 mL).
Ph
Me
H
b Isolated yield.
Ph
Ph
4-ClC6H4
Having established the optimal conditions, we examined
the reactions between various substituted azomethine im-
ines and azlactones10 (Table 2). The protocol was shown
to tolerate a wide range of substituted aromatic imines.
When the phenyl group of the azomethine imine 1 was
substituted with electron-donating or electron-withdraw-
ing groups, yields were reduced (Table 2, entries 2–8). A
4-methyl substituent on the aryl group reduced the yield to
only 30% (entry 3). We therefore attempted to increase
the yield by adding a catalyst, raising the reaction temper-
ature, and prolonging the reaction time, but no increase
was achieved. Steric hindrance might be responsible for
the reduced yield of the cycloaddition product. When a
chloro substituent was moved from the para- through the
meta- to the ortho-position, the yield fell from 70% to
55% (entries 5, 9, and 10). This might be explained by ste-
ric hindrance preventing the double bond of the azlactone
from approaching the azomethine imine. When we used
hetaryl-substituted azomethine imines, the reaction gave a
a Reaction conditions: 1b–m (1.2 equiv), 2b–d (0.2 mmol), CH2Cl2
(0.5 mL), 25 °C.
b Isolated yield.
We then examined the reactions of substituted azlactones.
An electron-withdrawing substituent on the azlactone had
an obvious effect on the synthesis, and the yield in this
case was only 35% (entry 16). Whereas the reaction of the
phenyl-substituted azomethine imine 1a with the phenyl-
substituted azlactone 2a gave a 91% yield (entry 1), meth-
yl-substituted and unsubstituted azlactones gave yields of
68% and 72%, respectively (entries 14 and 15). A possible
reason is that unsubstituted azlactones and methyl-substi-
tuted azlactones have relatively lower contents of the cor-
responding enol isomers.
The structure of product 3a was confirmed by X-ray crys-
tal structure analysis (Figure 1).
Synlett 2014, 25, 1093–1096
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-(1,7-Dioxotetrahydropyrazolo[1,2-a]pyrazol-2-yl)benzamides
1095
In conclusion, we have developed a new and simple meth-
od for the synthesis of N-(1,7-dioxotetrahydropyrazo-
lo[1,2-a]pyrazol-2-yl)benzamide derivatives directly
from azomethine imines and azlactones in the absence of
a catalyst. This reaction conditions were mild, and yields
were moderate to high. Substituents on the rings of azo-
methine imines and azlactones had obvious effects on the
yields. A possible mechanism is described. This method
can be used to synthesize N,N-bicyclic derivatives with
important bioactivities. Further studies aimed at preparing
optically active compounds are ongoing in our laboratory.
Acknowledgment
Figure 1 X-ray crystal structure of pure N-(3,5-dioxo-1,2-diphenyl-
tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl)benzamide (3a)
We are grateful to the Chinese Universities Scientific Fund, the An-
hui Provincial Natural Science Foundation of China
(No.11040606M47), and the University of Science and Technology
of China.
On the basis of the configuration of 3a, we propose a pos-
sible mechanism for the 1,3-dipolar cycloaddition reac-
tion of azomethine imines with azlactones (Scheme 2).
Regioselectivity is determined by electronic effects. Ini-
tially, the structure of the azomethine imines can be repre-
sented in terms of two resonance forms 1 and 1′.
Resonance structure 1′ contains C+ and N– centers. Azlac-
tones isomerize to their enol forms 2′,8h,i,11,12 which can
form Cδ+ and Cδ– centers. Then, the enols 2′ undergo
[3+2]-cycloaddition reaction with the azomethine imines
1′ to give intermediates 3′, which are unstable and readily
rearrange to form the products 3. The 1,3-cycloaddition
reaction is a syn-addition with respect to both the azlac-
tone and the azomethine imine. The azlactone adds to one
face of the azomethine imine, and the azomethine imine
adds to one face of the azlactone. There is no opportunity
for any of the substituents to change their stereochemical
positions during the course of reaction. Substituents that
are on the same side of the azlactone and the azomethine
imine will be in a cis orientation on the newly formed ring,
so that the products of 1,3-cycloaddition reaction are a
pair of enantiomers with two chiral carbon centers. The
diastereoselectivity of the reactions was high. (dr > 20:1;
determined by 1H NMR spectroscopy).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SunpIofoiprmntgirStanouIifpog
r
t
iornat
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O
Ph
O
OH
HO
O
R2
δ+
δ–
N–
1,3-cycloaddition
N
N
N
R2
+
O
N
N
+
R1
R1
Ph
H
1'
2'
3'
rearrangement
O
O
O
R2
O
N–
N+
O
NHCOPh
R2
R1
N
N
N
R1
Ph
2
H
1
3
Scheme 2 Possible mechanism for the formation of products 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1093–1096

1096
W. Liu et al.
LETTER
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C25H21NaN3O3: 434.1475; found: 434.1468.
N-[1-(4-Methoxyphenyl)-3,5-dioxo-2-phenyltetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazol-2-yl]benzamide (3b)
White solid; yield: 61.5 mg (70%); mp 159–160 °C; IR
(KBr): 3413, 3061, 2932, 1783, 1713, 1597, 1503, 1267,
1173, 1045, 916, 835, 716 cm–1; 1H NMR (400 MHz,
CDCl3): δ = 7.54 (d, J = 8.4 Hz, 2 H), 7.45 (t, J = 6.9 Hz, 3
H), 7.38–7.33 (m, 5 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.87 (d, J
= 8.8 Hz, 2 H), 6.75 (s, 1 H), 4.68 (s, 1 H), 3.78 (s, 3 H), 3.39
(s, 1 H), 2.99–2.84 (m, 3 H); 13C NMR (101 MHz, CDCl3):
δ = 190.77, 165.57, 165.10, 160.22, 135.65, 133.49, 131.91,
131.82, 128.68, 128.59, 128.52, 126.90, 126.56, 122.56,
114.28, 114.24, 70.86, 55.52, 55.02, 35.69; HRMS (ESI):
m/z [M + Na]+ calcd for C26H23NaN3O4: 464.1581; found:
464.1573.
N-[1-(4-Fluorophenyl)-3,5-dioxo-2-phenyltetrahydro-
1H,5H-pyrazolo[1,2-a]pyrazol-2-yl]benzamide (3d)
White solid; yield: 72.6 mg (85%); mp 195–196 °C; IR
(KBr): 3414, 3074, 2922, 2851, 1796, 1714, 1644, 1515,
1292, 1222, 1034, 918, 706 cm–1; 1H NMR (400 MHz,
CDCl3): δ = 7.48 (dd, J = 18.5, 7.5 Hz, 5 H), 7.44–7.33 (m,
6 H), 7.25 (d, J = 3.1 Hz, 1 H), 7.05 (t, J = 8.5 Hz, 2 H), 6.67
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(s, 1 H), 4.82 (s, 1 H), 3.35 (s, 1 H), 3.01–2.88 (m, 3 H); 13
NMR (101 MHz, CDCl3): δ = 166.67, 165.88, 164.86,
164.39, 136.09, 133.29, 132.03, 129.33, 128.98, 128.93,
128.64, 128.53, 127.84, 127.25, 126.86, 126.41, 71.10,
35.71, 29.67; HRMS (ESI): m/z [M + Na]+ calcd for
C25H20FN3NaO3: 452.1381; found: 452.1377.
N-[1-(2-Furyl)-3,5-dioxo-2-phenyltetrahydro-1H,5H-
pyrazolo[1,2-a]pyrazol-2-yl]benzamide (3l)
White solid; yield: 55.2 mg (69%); mp 166–168 °C; IR
(KBr): 3424, 2932, 1783, 1713, 1666, 1502, 1314, 904, 730
cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.1 Hz,
2 H), 7.48–7.31 (m, 10 H), 6.52 (dd, J = 3.2, 0.5 Hz, 1 H),
6.29 (dd, J = 3.3, 1.9 Hz, 1 H), 5.90 (s, 1 H), 3.39–3.34 (m,
1 H), 2.94 (ddd, J = 16.1, 10.9, 9.0 Hz, 1 H), 2.80–2.65 (m,
2 H); 13C NMR (101 MHz, CDCl3): δ = 166.05, 165.50,
163.88, 147.86, 143.87, 135.51, 133.24, 131.71, 128.93,
128.74, 128.39, 126.79, 126.56, 113.92, 110.33, 69.23,
46.41, 35.05; HRMS (ESI): m/z [M + Na]+ calcd for
C23H19NaN3O4: 424.1268; found: 424.1261.
C
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N-(1-Cyclohexyl-3,5-dioxo-2-phenyltetrahydro-1H,5H-
pyrazolo[1,2-a]pyrazol-2-yl)benzamide (3m)
White solid; yield: 35.5 mg (91%); mp 141–143 °C; IR
(KBr): 3424, 2920, 1713, 1561, 1444, 1279, 1045, 815, 730
cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.1 Hz,
2 H), 7.65 (d, J = 7.3 Hz, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.44
(d, J = 12.3 Hz, 4 H), 7.37 (t, J = 6.7 Hz, 1 H), 6.70 (s, 1 H),
3.79 (t, J = 8.1 Hz, 1 H), 3.49 (d, J = 7.5 Hz, 1 H), 3.09 (dd,
J = 14.8, 6.9 Hz, 1 H), 2.99–2.91 (m, 1 H), 2.71 (dd, J = 16.4,
6.3 Hz, 1 H), 1.99 (d, J = 11.9 Hz, 1 H), 1.79 (d, J = 16.9 Hz,
2 H), 1.66–1.54 (m, 3 H), 1.20–1.06 (m, 5 H); 13C NMR (101
MHz, CDCl3): δ = 166.70, 165.12, 162.50, 138.27, 132.95,
132.24, 129.03, 128.88, 128.80, 127.11, 126.39, 76.06,
69.93, 56.20, 38.88, 35.96, 31.89, 29.89, 25.56; HRMS
(ESI): m/z [M + Na]+ calcd for C25H27NaN3O3: 440.1945;
found: 440.1950.
(9) (a) Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7,
1105. (b) Sansano, L. M.; Sibi, M. P. Chem. Rev. 2008, 108,
2887.
(10) N-(1,7-Dioxotetrahydro-1H,5H-pyrazolo[1,2-a]pyrazol-
2-yl)benzamides 3a–p; General Procedure
Azomethine imine 1 (1.2 equiv, 0.24 mmol), azlactone 2 (0.2
mmol), and CH2Cl2 (0.5 mL) were added to a small tube
containing a magnetic stirrer, and the mixture were stirred at
r.t. for 2–6 h. The crude product was purified by column
chromatography [silica gel, EtOAc–PE (1:1)].
N-(3,5-Dioxo-1,2-diphenyltetrahydro-1H,5H-
pyrazolo[1,2-a]pyrazol-2-yl)benzamide (3a)
(11) For recent reviews, see: (a) Enders, D.; Grondal, C.; Hüttl,
M. R. M. Angew. Chem. 2007, 119, 1590. (b) Grondal, C.;
Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(12) For recent examples of Michael additions of the enolate
forms of azlactones, see: (a) Alemán, J.; Milelli, A.; Cabrera,
S.; Reyes, E.; Jørgensen, K. A. Chem. Eur. J. 2008, 14,
10958. (b) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.;
Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008,
130, 12031. (c) Jiang, H.; Paixão, M. W.; Monge, D.;
Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 2775.
White solid; yield: 74.8 mg (91%); mp 191–192 °C; IR
(KBr): 3418, 3059, 2929, 2850, 1785, 1676, 1575, 1298,
918, 711 cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.48 (dd, J
= 15.3, 7.2 Hz, 5 H), 7.41–7.34 (m, 8 H), 7.24–7.19 (m, 2 H),
6.71 (s, 1 H), 4.77 (s, 1 H), 3.41 (s, 1 H), 3.00–2.81 (m, 3 H);
13C NMR (101 MHz, CDCl3): δ = 165.73, 165.00, 161.93,
135.68, 133.48, 131.83, 131.57, 131.03, 129.47, 128.90,
128.76, 128.71, 128.52, 127.38, 126.86, 126.57, 71.04,
50.17, 35.99; HRMS (ESI): m/z [M + Na]+ calcd for
Synlett 2014, 25, 1093–1096
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