Copper(I) acetate-catalyzed cycloaddition between azomethine imines and propiolates under additive-free conditions

Article abstract of DOI:10.1002/ejoc.201300753

Because propiolates easily undergo base-catalyzed self-Michael addition, most popular catalytic systems in CuAAC cannot be used in the cycloaddition between azomethine imines and propiolates, because such reactions usually require the use of tertiary amin

Full text of DOI:10.1002/ejoc.201300753

FULL PAPER
DOI: 10.1002/ejoc.201300753
Copper(I) Acetate-Catalyzed Cycloaddition between Azomethine Imines and
Propiolates under Additive-Free Conditions
Changwei Shao,[a] Qun Zhang,[a] Guolin Cheng,[a] Chuanjie Cheng,[a] Xinyan Wang,*[a] and
Yuefei Hu*[a]
Keywords: Alkynes / Copper / Cycloaddition / Click chemistry
Because propiolates easily undergo base-catalyzed self-
Michael addition, most popular catalytic systems in CuAAC
cannot be used in the cycloaddition between azomethine
serves as a ligand and is converted into acetic acid during
the reaction. Thus, copper(I) acetate catalyzed cycloaddition
actually proceeds under additive-free conditions (without
imines and propiolates, because such reactions usually re- exogenous ligand) to efficiently give 6,7-dihydropyr-
quire the use of tertiary amines as additives (as base and/or
ligand). We found that this problem can be resolved simply
by using copper(I) acetate as catalyst, in which the acetate
azolo[1,2-a]pyrazolone derivatives, in which the side-reac-
tions and byproducts caused by basic additives are com-
pletely avoided.
Introduction
Many bicyclic polyhydropyrazolo[1,2-a]pyrazolone de-
rivatives have important medicinal properties.[1] As shown
in Figure 1, compounds LY173013 and LY186826 are anti-
bacterial agents that are analogues of penicillin and cepha-
losporin.
Scheme 1.
In the past decade, copper-catalyzed azide–alkyne cyclo-
addition (CuAAC)[6] has been developed as a prime exam-
ple of “click chemistry”, in which high regioselectivity was
achieved for many types of terminal alkynes.[7] The combi-
nations of CuSO4·5H2O/NaAsc/aq. tBuOH and CuI/NR3
(NR3, as an additive, served as base and/or ligand, such as
CuI/DIPEA and CuI/TEA) are two popular and efficient
catalytic systems. However, neither approaches were used
directly in the cycloaddition between 1 and 2, because the
inner salt 1 decomposes in aqueous media and propiolate 2
easily undergoes self-Michael addition in the presence of
common tertiary amines (Scheme 2).[8]
Figure 1. The structures of LY173013 and LY186826.
In the early preparation of LY173013 and LY186826, cy-
cloaddition[2] between azomethine imines 1 and propiolates
2 was employed to construct their molecular skeletons and
introduce the ester groups in a single step. However, this
thermal cycloaddition[3] was usually performed at high tem-
perature to produce regioisomers (for example 3a and 4 in
Scheme 1) when unsubstituted propiolate (as terminal
alkyne) was used as dipolarophile.[4] Recently, an improved
regioselective method was reported that involved Fisher
carbene complexes of propiolate as dipolarophiles under
thermal conditions.[5]
Scheme 2. Self-Michael addition of propiolate.
[a] Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China
Indeed, to the best of our knowledge, only five copper-
catalyzed protocols have been reported for the cycload-
dition between 1 and 2 to date. In two CuI-catalyzed proto-
cols,[9] an uncommon, highly hindered N-methyldicyclohex-
ylamine was used as an additive. In the other three proto-
cols,[4,10] pre-made heterogeneous catalysts were used.
E-mail: yfh@mail.tsinghua.edu.cn
E-mail: wangxinyan@mail.tsinghua.edu.cn
Homepage: http://www.chem.tsinghua.edu.cn/publish/chemen/
2141/2011/20110331184801309598874/
20110331184801309598874_.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300753.
Eur. J. Org. Chem. 2013, 6443–6448
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C. Shao, Q. Zhang, G. Cheng, C. Cheng, X. Wang, Y. Hu
FULL PAPER
Therefore, there remains a need to develop a highly efficient tivity may be improved significantly by simply using cop-
homogeneous catalytic system for this cycloaddition under per(I) acetate as catalyst.
tertiary-amine-free conditions.
Thus, screening experiments were made by using 1a and
2a as model substrates. As shown in Table 1, the desired
product 3a could be obtained in 88% yield by using a large
amount of CuI/Cy2NMe (Entry 1),[9b] but the same product
was isolated in 46% yield from a mixture when a small
amount of CuI/Cy2NMe was used (Entry 2). Not surpris-
ingly, use of the combination of CuI/Et3N gave a mixture
from which 3a was isolated in 38% yield (Entry 3). Interest-
ingly, use of the CuSO4·5H2O/NaOAc combination showed
moderate catalytic activity in this cycloaddition. As shown
in Table 1, Entry 4, when a clear solution of 1a, 2a, and
CuSO4·5H2O/NaOAc in aq. tBuOH was stirred for 2 h, 3a
crystallized from the solution in 56% yield. The low yield
may be caused by decomposition of the inner salt 1a in
water (benzaldehyde was detected in the reaction mixture).
As expected, 3a was obtained in high yield (93%) by stirring
a suspension of 1a, 2a, and [(MeCO2Cu)2]n in CH2Cl2 for
50 min (Entry 5). Other copper(I) sources, such as CuI,
CuBr, CuCl, Cu2O or CuCN (Entries 6–10), showed low
efficiency, possibly because they normally need to be acti-
vated by additives.[7] As shown in Table 1, Entries 11 and
12, copper(II) acetate and copper(II) benzoate also showed
strong catalytic activity, because the CuI species could be
generated in situ by CuII-catalyzed oxidative coupling of 2a.
The effect of solvent on the reaction was then tested with
[(MeCO2Cu)2]n as catalyst. As shown in Table 2, cyclohex-
ane and toluene (Entries 1 and 2) showed low efficiency,
because both substrate 1a and product 3a had poor solubil-
ity in these solvents, and it was clearly difficult to directly
convert solid 1a into solid 3a. When EtOH was used as
solvent, the reaction stopped within 1 h (Entry 3). To our
delight, the use of MeCN, tetrahydrofuran (THF) and
CH2Cl2 all gave excellent yields of 3a in short reaction times
(Entries 4–6). From a practical point of view, CH2Cl2 was
Results and Discussion
In the CuAAC reaction, tertiary amines are typically
used as additives (base and/or ligand) for three reasons:
(a) they can promote the formation of the acetylide anion;
(b) they can coordinate with copper(I) acetylide to prevent
the formation of inactive polymeric structures such as
[(RCϵCCu)2]n, and (c) they can dissociate the inactive poly-
meric (CuI)n into active CuI, when commercial copper(I)
iodide is used as CuI source. However, we recently reported
a novel copper(I) acetate {as a complex [(MeCO2Cu)2]n}
catalyzed CuAAC under tertiary-amine-free conditions.[11]
As shown in Scheme 3, copper(I) acetate is a conjugate base
of acetic acid that is strong enough to form copper(I) acet-
ylide. Furthermore, the acetic acid that is released in situ
not only activates the polymer [(RCϵCCu)2]n, but also ac-
celerates the protonation of the intermediate 5-cuprous
1,2,3-trizoles.[12] Because cycloaddition between 1 and 2 was
proposed to proceed through a similar mechanism and in-
volve similar intermediates to those of the CuAAC reac-
tion,[4,9,10] we envisioned that its efficiency and regioselec-
Scheme 3.
Table 1. Effects of the copper(I) sources on the cycloaddition.[a]
Entry
Cu catalyst (0.01 equiv.)
Time [min]
Yield of 3a [%][b]
1[c]
2
CuI (0.05 equiv.)/Cy2NMe (0.5 equiv.)
20 h
180
180
120
50
88
46
38
56
93
10
48
40
20
15
82
84
CuI/Cy2NMe (0.02 equiv.)
CuI/Et3N (0.02 equiv.)
CuSO4·H2O/NaOAc (0.02 equiv.)
3
4[d]
5
[(MeCO2Cu)2]n
CuI
6[e]
7[e]
8[e]
9[e]
10[e]
11
12
60
CuBr
CuCl
Cu2O
CuCN
60
60
60
60
80
90
(MeCO2)2Cu
(PhCO2)2Cu
[a] Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), Cu catalyst (0.01 mmol, 0.01 equiv.), CH2Cl2 (2 mL), r.t. [b] Isolated yield. [c] Data
from ref.[9b] [d] tBuOH/H2O (1:2 v/v) was used as a solvent for the solubility of CuSO4·5H2O and NaOAc. [e] The reaction was not
complete.
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Cycloaddition of Azomethine Imines and Propiolates
the best solvent, because it was clear when the reaction end-
point was reached; CH2Cl2 is a poor solvent for the inner
salt 1a but good solvent for the product 3a, thus the reac-
tion endpoint was clearly indicated by the conversion of a
suspension into a transparent solution. When the ratio of
[(MeCO2Cu)2]n was increased, the reaction time was short-
ened sharply, and higher yields were obtained (Entries 7
and 8). Finally, standard conditions were established to be
those detailed in Table 2, Entry 7.
Table 2. Effect of solvent on the cycloaddition.[a]
Entry
Solvent
CuOAc [equiv.] Time [min] Yield of 3a
[%][b]
Scheme 5.
1
2
3
4
5
6
7
8
cyclohexane
toluene
EtOH
MeCN
THF
CH2Cl2
CH2Cl2
CH2Cl2
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.04
120
120
120
80
60
50
32
45
51
89
91
93
96
97
Table 3. Copper(I) acetate catalyzed cycloaddition.
22
10
[a] Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), [(MeCO2-
Cu)2]n (0.01 mmol, 0.01 equiv.), solvent (2 mL), r.t. [b] Isolated
yield.
It was interesting to observe that an identical, bright-
yellow solid was a common intermediate for reactions per-
formed in a number of solvents (Table 2, Entries 4–8); it
had very poor solubility in all solvents and was assigned as
CuCϵCCO2Et (5a, without exogenous ligands) on the basis
of IR spectra and elemental analysis data.[13] In a stoichio-
metric reaction of [(MeCO2Cu)2]n and HCϵCCO2Et (2a)
in MeCN, 5a was obtained in 91% yield at room tempera-
ture after 1 h (Scheme 4). This efficient procedure is there-
fore a valuable new addition to the methods available for
the preparation of copper propiolates.[14]
Scheme 4.
Further experiments showed that no reaction occurred
between 1a and 5a by using H2O, tBuOH or aqueous solu-
tion of NaOAc as a proton source (Scheme 5). However,
when DOAc was used as a source of deuterium, the ex-
pected product 3a-d1 was obtained in 94% yield and 87%
deuterium incorporation within 15 min. Thus, two conclu-
sions can be reached: (a) intermediate 6a exists in this cyclo- phenyl, pyridyl or alkyl groups. There was no negative effect
addition; (b) HOAc is an excellent promoter for both cyclo- on the preparation of 3m and 3o when C-7 bears one sub-
addition of 5a and protonation of 6a. These conclusions stituent. However, the use of substrates with two substitu-
are in full agreement with the hypothesis proposed in earlier ents on C-7 (3n) required longer reaction times and gave
studies.[4,9,10]
lower yields. Although but-3-yn-2-one (2b) proved to be an
Finally, the scope of this method was tested with a range excellent dipolarophile in the preparation of 3p, phenyl-, (4-
of substrates. As shown in (Table 3), all tested samples gave fluorophenyl)- and (2-pyridyl)ethynes (i.e., which are not
excellent yields in short reaction times under the standard α,β-unsaturated carbonyl compounds) proved to be unsatis-
conditions. No significant difference was observed in the factory dipolarophiles for this cycloaddition. These findings
preparation of products 3a–l when C-1 was substituted by are in full agreement with previously reported results.[4,10]
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FULL PAPER
Ethyl 1-(3-Methoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3c):[10b] Isolated as a yellowish solid; m.p.
88–89 °C (PE/Et2O). H NMR: δ = 7.54 (s, 1 H), 7.30–7.24 (m, 1
H), 6.97–6.92 (m, 2 H), 6.89–6.84 (m, 1 H), 5.13 (d, J = 1.4 Hz, 1
H), 4.15–4.01 (m, 2 H), 3.80 (s, 3 H), 3.43–3.38 (m, 1 H), 3.08–2.96
(m, 1 H), 2.92–2.81 (m, 1 H), 2.79–2.69 (m, 1 H), 1.43 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.8, 163.5, 159.9, 140.0, 129.6,
128.6, 120.7, 118.3, 113.9, 113.8, 73.3, 60.5, 55.3, 51.7, 35.8,
14.2 ppm.
Conclusions
1
A novel copper(I) acetate catalyzed cycloaddition be-
tween azomethine imines 1 and propiolates 2 was devel-
oped, in which the highly efficient preparation of 5-oxo-6,7-
dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate de-
rivatives 3 was achieved under extremely convenient and
mild conditions. The method benefited significantly from
the formation of CuCϵCCO2Et under additive-free condi-
tions, which meant that self-Michael addition of propiolates Ethyl 1-(4-Methylphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3d): Isolated as a white solid; m.p. 86–
was avoided completely. By using DOAc in an isotopic ex-
periment, the other promotion activities of copper(I) acet-
ate were also described and proved.
88 °C (PE/Et O). IR ν = 1717, 1695, 1604, 1437, 1407, 1362 cm–1.
˜
2
1H NMR: δ = 7.53–7.52 (m, 1 H), 7.27–7.24 (m, 2 H), 7.21–7.16
(m, 2 H), 5.13 (d, J = 1.4 Hz, 1 H), 4.13–3.98 (m, 2 H), 3.39–3.32
(m, 1 H), 3.08–2.96 (m, 1 H), 2.92–2.71 (m, 2 H), 2.34 (s, 3 H),
1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.3, 163.1, 137.9,
135.0, 129.0 (2 C), 128.1, 127.8 (2 C), 118.1, 72.6, 60.0, 51.1, 35.4,
20.9, 13.8 ppm. MS: m/z (%) = 286 (51.2) [M+], 195 (100), 129
(13.2), 55 (86.3). C16H18N2O3 (286.33): calcd. C 67.12, H 6.34, N
9.78; found C 67.43, H 6.50, N 9.64.
Experimental Section
General: All melting points were determined on a Yanaco melting
point apparatus and were uncorrected. IR spectra were recorded
on a Nicolet FT-IR 5DX spectrometer with KBr. The 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
JEOL JNM-ECA 300 spectrometer in CDCl3. TMS was used as
an internal reference and J values were given in Hz. HRMS were
obtained on a Bruker micrOTOF-Q II spectrometer. PE is petro-
Ethyl
1-[4-(dimethylamino)phenyl]-5-oxo-6,7-dihydro-1H,5H-pyr-
azolo[1,2-a]pyrazole-2-carboxylate (3e): Isolated as a yellow solid;
m.p. 102–103 °C (PE/Et O). IR ν = 1709, 1691, 1604, 1522, 1440,
˜
2
1406, 1362 cm–1. H NMR: δ = 7.51 (s, 1 H), 7.19 (d, J = 8.3 Hz,
1
o
leum ether (boiling range 60–90 C).
2 H), 6.70 (d, J = 8.3 Hz, 2 H), 5.12 (s, 1 H), 4.13–3.98 (m, 2 H),
3.32–3.24 (m, 1 H), 3.04–2.96 (m, 1 H), 2.95 (s, 6 H), 2.83–2.76 (m,
2 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.1, 163.3,
150.3, 128.7 (2 C), 127.7, 124.7 (2 C), 118.7, 112.0 (2 C), 71.9, 60.0,
50.3, 40.2, 35.6, 13.9 ppm. MS: m/z (%) = 315 (100) [M+], 259
(34.8), 195 (58.3), 158 (34.9). C17H21N3O3 (315.37): calcd. C 64.74,
H 6.71, N 13.32; found C 64.97, H 6.82, N 13.41.
Typical Procedure for 1a: A stirred solution of NH2NH2·H2O
(1.0 g, 20 mmol) and H2C=CHCO2Me (1.9 g, 22 mmol) in EtOH
(20 mL) was heated at 70–80 °C for 4 h. EtOH was then removed in
vacuo, and the residue was diluted with MeOH (5 mL) and PhCHO
(3.2 g, 30 mmol). The resultant mixture was stirred for 12 h, then
MeOH was removed in vacuo. The residue was purified by
chromatography (silica gel; MeOH/EtOAc, 20%) to give 1a (2.2 g,
63%) as a white solid.
Ethyl
1-(2-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3f): Isolated as a white solid; m.p. 112–
The same procedure was used for the preparation of 1b–o, which
were used directly in the next step without further purification or
characterization.
1
114 °C (PE/Et O). IR ν = 1728, 1694, 1603, 1363 cm–1. H NMR:
˜
2
δ = 7.62–7.56 (m, 2 H), 7.40–7.31 (m, 2 H), 7.21–7.13 (m, 1 H),
5.81 (s, 1 H), 4.13–3.97 (m, 2 H), 3.47–3.38 (m, 1 H), 3.28–3.21 (m,
2 H), 2.91–2.70 (m, 1 H), 1.12 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR:
δ = 164.7, 162.9, 137.3, 132.8, 129.6 (2 C), 129.3, 127.7, 124.3,
Typical Procedure for 3a: To a stirred suspension of [(CuOAc)2]n
(calculated based on CuOAc, 2.5 mg, 0.02 mmol, 0.02 equiv.) and
1a (174 mg, 1.0 mmol) in CH2Cl2 (2 mL), was added HCϵCCO2Et 117.3, 71.1, 60.3, 51.9, 35.5, 13.9 ppm. MS: m/z (%) = 352 (11.9)
(2a; 108 mg, 1.1 mmol) at room temperature until the suspension
was converted into a transparent solution (22 min, monitored by
TLC). The solvent was removed in vacuo, and the residue was puri-
fied by fast chromatography (silica gel; Et2O/PE, 50%) to give the
desired product 3a (261 mg, 96%) as a yellow solid.
[M + 2], 350 (12.0) [M+], 195 (96.2), 55 (100). C15H15BrN2O3
(351.20): calcd. C 51.30, H 4.31, N 7.98; found C 51.46, H 4.38, N
7.92.
Ethyl
1-(3-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3g): Isolated as a yellow solid; m.p. 124–
1
125 °C (PE/Et O). IR ν = 1728, 1694, 1603, 1363 cm–1. H NMR:
The same procedure was used for the preparation of products 3b–
p.
˜
2
δ = 7.58–7.53 (m, 2 H), 7.50–7.43 (m, 1 H), 7.40–7.31 (m, 1 H),
7.28–7.23 (m, 1 H), 5.11 (s, 1 H), 4.11–3.97 (m, 2 H), 3.49–3.44 (m,
1 H), 3.12–2.89 (m, 2 H), 2.81–2.70 (m, 1 H), 1.15 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR: δ = 164.6, 163.0, 141.1, 131.2, 131.1, 129.8,
128.6, 126.9, 122.4, 117.4, 72.9, 60.3, 52.0, 35.4, 13.9 ppm. MS:
m/z (%) = 352 (7.6) [M + 2], 350 (7.7) [M+], 195 (86.6), 55 (100).
C15H15BrN2O3 (351.20): calcd. C 51.30, H 4.31, N 7.98; found C
51.57, H 4.51, N 7.83.
Ethyl 5-Oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-
carboxylate (3a):[4] Isolated as a yellow solid; m.p. 96–98 °C (PE/
1
Et2O). H NMR: δ = 7.54 (s, 1 H), 7.38–7.28 (m, 5 H), 5.15 (s, 1
H), 4.13–3.97 (m, 2 H), 3.42–3.36 (m, 1 H), 3.05–3.01 (m, 1 H),
2.96–2.84 (m, 1 H), 2.80–2.71 (m, 1 H), 1.13 (m, J = 8.6 Hz, 3 H)
ppm. 13C NMR: δ = 164.4, 163.0, 138.2, 128.2, 128.12 (2 C), 128.0,
127.9 (2 C), 117.9, 73.0, 60.0, 51.4, 35.3, 13.7 ppm.
Ethyl 1-(4-Methoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3b):[4] Isolated as a yellowish solid; m.p.
87–88 °C (PE/Et2O). 1H NMR: δ = 7.52 (s, 1 H), 7.28 (d, J =
Ethyl
1-(4-Bromophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3h): Isolated as a yellowish solid; m.p.
92–93 °C (PE/Et O). IR ν = 1725, 1692, 1592, 1431, 1364 cm–1. 1H
˜
2
8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 5.13 (d, J = 1.1 Hz, 1 H), NMR: δ = 7.53–7.48 (m, 3 H), 7.31–7.26 (m, 2 H), 5.11 (d, J =
4.13–4.04 (m, 2 H), 3.80 (s, 3 H), 3.36–3.33 (m, 1 H), 3.10–2.98 (m, 1.7 Hz, 1 H), 4.13–4.04 (m, 2 H), 3.47–3.43 (m, 1 H), 3.10–2.89 (m,
1 H), 2.96–2.71 (m, 2 H), 1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: 2 H), 2.80–2.71 (m, 1 H), 1.16 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR:
δ = 164.2, 163.1, 159.3, 129.9, 129.0 (2 C), 127.9, 118.1, 113.5 (2
C), 72.2, 60.0, 54.9, 50.9, 35.4, 13.8 ppm.
δ = 164.5, 163.0, 137.7, 131.4 (2 C), 129.8 (2 C), 128.5, 122.1, 117.5,
72.8, 60.3, 51.8, 35.4, 13.9 ppm. MS: m/z (%) = 352 (12.6) [M + 2],
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Cycloaddition of Azomethine Imines and Propiolates
350 (12.9) [M+], 195 (92.3), 55 (100). C15H15BrN2O3 (351.20):
calcd. C 51.30, H 4.31, N 7.98; found C 51.54, H 4.47, N 7.90.
(m, 2 H), 1.12 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 166.0,
163.2, 140.1, 135.7, 129.4, 128.2 (3 C), 127.7 (2 C), 127.5 (2 C),
127.4, 127.2 (2 C), 116.9, 72.8, 71.4, 60.1, 44.1, 13.8 ppm. MS: m/z
(%) = 348 (28.0) [M+], 271 (68.0), 131 (100). C21H20N2O3 (348.40):
calcd. C 72.40, H 5.79, N 8.04; found C 72.28, H 5.64, N 8.19.
Ethyl
1-(2-Fluorophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3i):[10b] Isolated as a yellow solid; m.p.
1
98–99 °C (PE/Et2O). H NMR: δ = 7.59 (s, 1 H), 7.36–7.26 (m, 2
H), 7.18–7.03 (m, 2 H), 5.56 (d, J = 1.0 Hz, 1 H), 4.16–4.02 (m, 2
H), 3.46–3.41 (m, 1 H), 3.20–3.10 (m, 1 H), 2.96–2.73 (m, 2 H),
1.15 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR: δ = 164.4, 162.6, 160.5
(d, J = 245.9 Hz), 129.4 (d, J = 7.9 Hz), 129.0 (d, J = 3.6 Hz), 125.4
(J = 14.4 Hz), 123.8 (d, J = 2.9 Hz), 116.0, 114.9 (d, J = 21.8 Hz),
73.0, 65.5, 59.9, 51.3, 35.0, 13.5 ppm.
2-Acetyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole
(3p):[4] Isolated as a yellow solid; m.p. 116–118 °C (PE/Et2O). 1H
NMR: δ = 7.53 (s, 1 H), 7.40–7.29 (m, 5 H), 5.21 (s, 1 H), 3.43–
3.36 (m, 1 H), 3.09–3.01 (m, 1 H), 2.97–2.85 (m, 1 H), 2.81–2.72
(m, 1 H), 2.22–2.21 (m, 3 H) ppm. 13C NMR: δ = 192.5, 165.4,
138.1, 128.4 (3 C), 128.1, 127.9 (2 C), 126.9, 72.8, 51.3, 35.4,
26.6 ppm.
Ethyl
1-(4-Fluorophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3j): Isolated as a yellowish solid; m.p.
Supporting Information (see footnote on the first page of this arti-
103–105 °C (PE/Et O). IR ν = 1697, 1604, 1510, 1429, 1389,
˜
2
1
cle): H and 13C NMR spectra.
1365 cm–1. H NMR: δ = 7.53 (s, 1 H), 7.40–7.35 (m, 2 H), 7.08–
1
7.01 (m, 2 H), 5.14 (s, 1 H), 4.11–4.04 (m, 2 H), 3.44–3.40 (m, 1
H), 3.05–2.95 (m, 1 H), 2.95–2.86 (m, 1 H), 2.83–2.71 (m, 1 H),
1.15 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.4, 163.1, 162.4
(d, J = 244.5 Hz), 134.3, 129.7 (d, J = 8.6 Hz, 2 C), 128.3, 117.8,
115.1 (d, J = 21.5 Hz, 2 C), 72.5, 60.2, 51.6, 35.4, 13.8 ppm. MS:
m/z (%) = 290 (39.7) [M+], 195 (93.4), 133 (31.2), 56 (100).
C15H15FN2O3 (290.29): calcd. C 62.06, H 5.21, N 9.65; found C
62.23, H 5.36, N 9.60.
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (21072112 and 21221062).
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˜
1601, 1433, 1387, 1364 cm–1. 1H NMR: δ = 8.62–8.59 (m, 1 H),
7.75–7.68 (m, 1 H), 7.58 (s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.28–
7.23 (m, 1 H), 5.29–5.28 (m, 1 H), 4.13–3.97 (m, 2 H), 3.58–3.51
(m, 1 H), 3.21–3.12 (m, 1 H), 2.98–2.87 (m, 1 H), 2.78–2.67 (m, 1
H), 1.11 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 164.7, 163.1,
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(PE/Et2O). H NMR: δ = 7.39 (s, 1 H), 4.29–4.14 (m, 2 H), 4.09–
4.05 (m, 1 H), 3.63–3.54 (m, 1 H), 3.03–2.90 (m, 2 H), 2.69–2.58
(m, 1 H), 2.08–1.92 (m, 1 H), 1.85–1.10 (m, 13 H) ppm. 13C NMR:
δ = 166.4, 164.0, 129.6, 115.7, 75.6, 60.2, 56.1, 39.2, 35.0, 30.1,
26.7, 26.5, 26.2, 25.9, 14.2 ppm.
1
Ethyl
7-Methyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-2-carboxylate (3m):[4] Isolated as a yellow solid; m.p. 95–
97 °C (PE/Et2O). 1H NMR: δ = 7.48–7.41 (m, 3 H), 7.410–7.23 (m,
3 H), 5.16 (d, J = 1.7 Hz, 1 H), 4.09–4.00 (m, 2 H), 3.46–3.42 (m,
1 H), 2.69–2.60 (m, 2 H), 1.13–1.07 (m, 6 H) ppm. 13C NMR: δ =
166.0, 163.3, 140.8, 128.7, 128.2 (2 C), 128.0 (2 C), 127.9, 117.6,
73.4, 63.5, 60.2, 42.8, 17.3, 13.9 ppm.
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110–111 °C (PE/Et2O). 1H NMR: δ = 7.52–7.51 (m, 1 H), 7.47–
7.41 (m, 2 H), 7.38–7.25 (m, 3 H), 5.46 (s, 1 H), 4.13–3.98 (m, 2
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128.9, 127.9 (2 C), 127.5 (2 C), 127.4, 116.7, 64.1, 64.0, 59.9, 48.9,
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Ethyl 5-Oxo-1,7-diphenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyraz-
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˜
2
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Eur. J. Org. Chem. 2013, 6443–6448
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6447

C. Shao, Q. Zhang, G. Cheng, C. Cheng, X. Wang, Y. Hu
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Received: May 23, 2013
Published Online: August 22, 2013
6448
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6443–6448