Chiral bis(imidazolidine)pyridine-Cu complex-catalyzed enantioselective [3+2]-cycloaddition of azomethine imines with propiolates

Article abstract of DOI:10.3390/molecules17056170

[3+2] Cycloaddition of azomethine imines with electron-deficient terminal alkynes was smoothly catalyzed by a chiral bis(imidazolidine)pyridine-CuOAc complex to give bicyclic pyrazolo[1,2-a]pyrazolone derivatives with up to 74% ee.

Full text of DOI:10.3390/molecules17056170

Molecules 2012, 17, 6170-6178; doi:10.3390/molecules17056170
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Chiral Bis(Imidazolidine)Pyridine-Cu Complex-Catalyzed
Enantioselective [3+2]-Cycloaddition of Azomethine Imines
with Propiolates
Takayoshi Arai * and Yuta Ogino
Department of Chemistry, Graduate School of Science, Chiba University, 1-33, Yayoi, Inage,
Chiba 263-8522, Japan
* Author to whom correspondence should be addressed; E-Mail: tarai@faculty.chiba-u.jp;
Tel./Fax: +81-43-290-2889.
Received: 27 April 2012; in revised form: 18 May 2012 / Accepted: 21 May 2012 /
Published: 24 May 2012
Abstract: [3+2] Cycloaddition of azomethine imines with electron-deficient terminal
alkynes was smoothly catalyzed by a chiral bis(imidazolidine)pyridine-CuOAc complex to
give bicyclic pyrazolo[1,2-a]pyrazolone derivatives with up to 74% ee.
Keywords: pyrazolone; [3+2] cycloaddition; asymmetric synthesis; catalyst; chiral ligand
1. Introduction
Highly functionalized complex molecules are key tools for promoting biochemical research and
developing pharmaceuticals, because the network of chiralities, the positions of heteroatoms, and the
direction of lone-pairs in the molecules correlate strictly with their biological activities. The unique
pyrazolone heterocycles, five-membered-ring lactams containing N-N conjunction, are examples of
highly functionalized complex molecules, which have been used for the development of fine
chemicals (e.g., dyes, textile, photography, and cosmetics) and the pharmaceuticals (Figure 1) [1–3].
Anti-inflammatory activity has been studied on phenylbutazones [4–6]. BW357U shows anorectic
activity [7]. Inhibitory activities of lipoxygenase and cyclooxygenase are also reported on phenidone
and BW755C [8,9]. More complex bicyclic pyrazolo[1,2-a]pyrazolone derivatives exhibit diverse
bioactivities, and utilized as antibacterial agents, herbicides, pesticides, antitumor agents, calcitonin
agonists, and potent drugs to relieve Alzheimer’s disease. LY173013 and LY186826 are the

Molecules 2012, 17
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representative examples of antibacterial agents, which have been developed as the analogues of
penicillin and cephalosporin antibiotics [10–14].
Figure 1. Representative examples of biologically active pyrazolone heterocycles.
For accessing the fascinating bicyclic pyrazolo[1,2-a]pyrazolone skeleton, the [3+2] cycloaddition
of azomethine imines has apparent advantage for the straightforward construction of the core structure
(Scheme 1) [15–29]. Due to the importance of these molecules on the biological study, the synthesis of
these molecules in chiral form is highly demanded. In 2003, Fu et al. succeeded in the first catalytic
asymmetric cyclization of azomethine imines and terminal alkynes using phosphaferrocene-oxazoline-
CuI catalyst [30]. After the pioneering work of Fu’s group [30,31], several remarkable catalytic
asymmetric [3+2] cyclizations using azomethine imines were reported by Sibi [32], Maruoka [33],
Suga [34], and Chen [35,36].
Scheme 1. General scheme of [3+2] cycloaddition of azomethine imines.
In 2010 we succeeded in the development of bis(imidazolidine)pyridine, abbreviated as PyBidine,
for the catalytic asymmetric [3+2] cycloaddition of iminoesters with nitroalkene (Scheme 2) [37]. We
envisioned that the new chiral PyBidine ligand would have wide potential to promote various
asymmetric reactions, and the [3+2] cycloaddition using azomethine imines was set to study for
constructing the fascinating bicyclic pyrazolo[1,2-a]pyrazolones in this report.

Molecules 2012, 17
Scheme 2. Asymmetric [3+2] cycloaddition catalyzed by PyBidine-Cu(OTf)2 complex.
6172
2. Results and Discussion
The study started with an exploration of the most appropriate metal salts for the [3+2] cycloaddition
of azomethine imines with ethyl propiolate (Table 1).
Table 1. Catalyst activity of PyBidine-metal salt complex for [3+2] cycloaddition of
azomethine imine with ethyl propiolate.
Entry Metal salt
Time (h)
Yield (%)
99
ee (%)
1
2
3
4
5
6
7
8
CuI
3
5
44
60
60
46
21
-
CuBr
80
CuOAc
Cu(OAc)2
Cu(OTf)2
Co(OAc)2
Ni(OAc)2
Zn(OAc)2
2
99
3
99
24
31
32
50
69
trace
trace
trace
-
-
As reported in the former papers [30,31], Cu(I) salt showed good catalytic activity, and the
PyBidine-CuI gave the product in 99% yield with 44% ee (rt, 3h). The PyBidine-CuOAc complex
improved catalyst activity to give the product in 99% yield with 60% ee (entry 3). It was noteworthy
that the Cu(II) salts also had catalyst activity, although the stereoselectivities of the product were
reduced [27]. Because the other PyBidine-metal complex derived from the divalent acetate salts of the
first row transition metals (Ni(OAc)2, Co(OAc)2, and Zn(OAc)2) gives traces of product, the copper
element has unique and essential role for the [3+2] cycloaddition using azomethine imines. In all cases
we examined, (S, S, S, S)-PyBidine-Cu catalyst gave the (R)-enriched product.
Next, the reaction conditions were optimized for the PyBidine-CuOAc catalyzed reaction (Table 2).
The solvent effects were examined in the reaction using methyl propiolate. Various solvents (CHCl3,

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CH2Cl2, PhMe, THF, dioxane, EtOH) can be utilized to give the compound with good chemical yield,
though the use of MeCN resulted in low yield. Among the solvents we examined, the reaction in
CH2Cl2 gave the product with the best stereoselectivity (entry 2). 3,3-Dimethylpyrazolidinone
also transformed to the bicyclic pyrazolo[1,2-a]pyrazolone in CH2Cl2 with 53% ee (entry 8). The
azomethine imines prepared from substituted 4-iodo- or 3-chlorobenzaldehyde were examined in
entries 11–14. A lower reaction temperature is helpful for improving the enantiomeric excesses in
some cases (entries 9–10, and 13–14), though the reaction time was prolonged. To accelerate the
reaction at low temperature, the addition of bases was also examined. The addition of DIPEA
significantly accelerated the reaction to give the product with slightly improved enantioselectivity
(entries 9 and 15), although the addition of pyridine or K2CO3 resulted in low stereoselectivity. For the
ethyl propiolate, when the reaction was performed at −20 °C with DIPEA, the PyBidine-CuOAc gave
the product with 74% ee (entry 19).
Table 2. PyBidine-CuOAc catalyzed [3+2] cycloaddition of azomethine imine with methyl
propiolate a.
Entry Ar
R1
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
R2
Me
Me
Me
Me
Me
Me
Me
Me
Et
Base b
Solvent Temp (°C) Time (h) Yield (%) ee (%)
1
Ph
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CHCl3
rt
24
4
66
95
99
39
96
95
88
67
99
97
99
58
88
62
99
99
90
78
68
55
67
56
52
61
35
44
53
60
65
59
54
47
62
70
40
32
72
74
2
Ph
CH2Cl2 rt
3
Ph
PhMe
MeCN
THF
rt
rt
rt
2.5
27
24
24
28
24
2
4
Ph
5
Ph
6
Ph
dioxane rt
EtOH rt
7
Ph
8
Ph
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 −10
CH2Cl2 rt
CH2Cl2 −10
CH2Cl2 rt
CH2Cl2 −10
9
Ph
10
11
12
13
14
15
16
17
18
19
Ph
Et
45
2
4-IC6H4-
4-IC6H4-
3-ClC6H4-
3-ClC6H4-
Ph
Et
Et
23
3
Et
Et
23
1
Et
DIPEA CH2Cl2 rt
Pyridine CH2Cl2 rt
Ph
Et
1
Ph
Et
K2CO3
DIPEA CH2Cl2
DIPEA CH2Cl2 −20
CH2Cl2 rt
16
25
58
Ph
Et
0
Ph
Et
a The absolute configurations of the products are provided by analogy with the products reported in
ref. [30]; b 0.5 eq. of base were used to azomethine imine.

Molecules 2012, 17
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Although the enantiomeric excesses of the products are moderate, the reaction mechanism is
assumed to be as summarized in Scheme 3. As proposed in former reports, the formation of copper
acetylide would be a key for promoting the catalyst, though the Cu(II) salts also showed significant
catalyst activity in our study. When the copper acetylide is generated on the (S,S,S,S)-PyBidine-Cu
catalyst, the approach of (Z)-azomethine imine from an upper-side is considered on the reaction sphere.
The approach of (Z)-azomethine imine to the Cu-acetylide would be assisted using the Lewis acidic
apical cite of the Cu center. In a model A, a phenyl-ring of the PyBidine (emphasized by purple color)
would have a steric repulsion with the aromatic ring of the (Z)-azomethine imine. To avoid the
repulsion, the reaction would proceed via a model B to give the (R)-bicyclic pyrazolo[1,2-a]pyrazolone.
Scheme 3. Plausible mechanism of asymmetric [3+2] cycloaddition catalyzed by
PyBidine-CuOAc complex.
3. Experimental
3.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on a JEOL JNM-ECA500 or JEOL JNM-ECA400
1
spectrometer, operating at 500 MHz or 400 MHz for H-NMR and 125 MHz or 100 MHz for
1
13C-NMR. Chemical shifts in CDCl3 were reported downfield from TMS (=0 ppm) for H-NMR. For
13C-NMR, chemical shifts were reported downfield from TMS (=0 ppm) or in the scale relative to
CHCl3 (77.00 ppm for 13C-NMR) as an internal reference. Optical rotations were measured on a
JASCO P-1020 Polarimeter. The enantiomeric excess (ee) was determined by HPLC analysis. Column,
DAICEL CHIRALPAK AD-H; mobile phase, hexane-i-PrOH; flow rate, 1.0 mL/min. General
experimental details for synthesis of PyBidine ligand see reference in the manuscript [37]. Azomethine
imine were synthesized according to known procedure [30].
3.2. General Procedure
PyBidine (0.0075 mmol) and CuOAc (0.00825 mmol) were added to a round flask containing a
stir bar under Ar. Next CH2Cl2 (1 mL) was added to the flask and the mixture was stirred over 12 h. To
the resulting solution, azomethine imine (0.15 mmol) were added, followed by ethyl propiolate
(0.18 mmol) that was added dropwise at rt. After being stirred for an appropriate time, the reaction
mixture was purified by silica gel column chromatography (Et2O/hexane = 2/1 to Et2O) to afford
the corresponding cycloadduct. The enantiomeric excess of the products was determined by

Molecules 2012, 17
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chiral stationary-phase HPLC analysis (Daicel CHIRALPAK AD-H, i-PrOH/hexane 20/80, flow rate
1.0 mL/min).
(R)-Ethyl 5-oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carboxylate. Yellow oil; FTIR
(neat) 3,403, 3,087, 3,063, 3,031, 2,980, 2,928, 2,853, 1,699, 1,602, 1,551, 1,499, 1,455, 1,433, 1,414,
1,388, 1,364, 1,321, 1,300, 1,251, 1,206, 1,173, 1,104, 1,077, 1,039, 1,027, 986, 914, 874, 842, 819,
1
765, 752, 725, 700, 663 cm−1; H-NMR (CDCl3) δ 7.54 (d, J = 0.5 Hz, 1H), 7.44–7.25 (m, 5H), 5.15
(d, J = 1.7 Hz, 1H), 4.15–3.95 (m, 2H) 3.41–3.36 (m, 1H) 3.08–3.00 (m, 1H) 2.95–2.83 (m, 1H),
13
2.79–2.70 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H); C-NMR (CDCl3) δ 164.7, 163.4, 138.2, 128.5, 128.4,
128.3, 128.2, 118.5, 73.3, 60.4, 51.6, 35.7, 14.0; HRMS [ESI] Calcd. for C15H16N2O3Na+ [M+Na]+:
295.1053, found 295.1048; HPLC analysis: tR 10.7 min (major, 87%) and 13.1 min (minor, 13%),
detection at 330 nm]; []D24 −207 (c 1.01, CHCl3).
(R)-Ethyl 1-(3-chlorophenyl)-5-oxo-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carboxylate. Yellow
oil; FTIR (neat) 3,403, 3,086, 2,981, 2,927, 2,851, 1,697, 1,599, 1,474, 1,433, 1,387, 1,363, 1,319,
1,248, 1,198, 1,171, 1,105, 1,055, 1,024, 986, 934, 883, 842, 820, 785, 763, 735, 718, 693, 663 cm−1;
1H-NMR (CDCl3) δ 7.53 (s, 1H), 7.42 (s, 1H), 7.30 (d, J = 1.4 Hz, 3H), 5.12 (d, J = 1.8 Hz, 1H),
4.15–3.95 (m, 2H), 3.50–3.45 (m, 1H), 3.09–3.02 (m, 1H), 2.98–2.89 (m, 1H), 2.78–2.72 (m, 1H), 1.16
(t, J =7.2 Hz, 3H); 13C-NMR (CDCl3) δ 164.7, 163.2, 140.9, 134.4, 129.6, 128.7, 128.5, 128.3, 126.5,
73.0, 60.5, 52.1, 35.5, 14.0; HRMS [ESI] calcd for C15H16N2O3Cl+ [M+H]+: 307.0844, found
307.0839; HPLC analysis: tR 9.1 min (major, 81%) and 11.1 min (minor, 19%), detection at 330 nm];
[]D24 −362 (c 1.00, CHCl3).
(R)-Ethyl 1-(4-iodophenyl)-5-oxo-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carboxylate. Yellow
oil; FTIR (neat) 3,403, 3,084, 2,981, 2,925, 2,851, 2,309, 1,696, 1,604, 1,509, 1,434, 1,388, 1,364,
1
1,319, 1,250, 1,171, 1,105, 1,026, 986, 921, 849, 796, 758, 732, 664 cm−1; H-NMR (CDCl3) δ
7.53–7.52 (m, 1H), 7.40–7.36 (m, 2H), 7.09–7.03 (m, 2H), 5.14 (d, J = 1.6 Hz, 1H), 4.13–4.01 (m, 2H)
3.46–3.41 (m, 1H), 3.08–3.01 (m, 1H), 2.97–2.90 (m, 1H), 2.79–2.72 (m, 1H), 1.15 (t, J = 7.2, 3H);
13C-NMR (CDCl3) δ 164.6, 163.3, 134.4, 129.86, 129.79, 128.5, 118.1, 115.5, 115.3, 72.8, 60.4, 51.8,
35.6, 14.0; HPLC analysis: tR 9.4 min (major, 77%) and 13.2 min (minor, 23%), detection at 330 nm];
[]D24 −290 (c 1.00, CHCl3).
(R)-Methyl 5-oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carboxylate. Yellow solid;
FTIR (neat) 3,373, 3,083, 2,921, 2,862, 1,995, 1,714, 1,604, 1,496, 1,456, 1,407, 1,305, 1,246, 1,210,
1
1,167, 1,105, 958, 910, 836, 808, 771, 753, 735, 700 cm−1; H-NMR (CDCl3) δ 7.53 (brs, 1H),
7.38–7.31 (m, 5H), 5.17 (d, J = 1.6 Hz, 1H), 3.62 (s, 3H), 3.41–3.36 (m, 1H), 3.08–3.01 (m, 1H),
2.94–2.85 (m, 1H), 2.79–2.72 (m, 1H);13C-NMR (CDCl3) δ 164.7, 163.8, 138.1, 128.6, 128.5, 128.2,
+
117.9, 73.1, 51.5, 35.7; HRMS [ESI] Calcd for C14H15N2O3 [M+H]+: 259.1077, Found 259.1073;
24
HPLC analysis: tR 11.3 min (major, 84%) and 12.7 min (minor, 16%), detection at 330 nm]; []D
−296 (c 1.00, CHCl3).
(R)-Methyl 7,7-dimethyl-5-oxo-1-phenyl-1,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-2-carboxylate. Yellow
solid; FTIR (neat) 3,414, 3,076, 3,030, 2,950, 1,695, 1,600, 1,495, 1,455, 1,385, 1,322, 1,256, 1,227,

Molecules 2012, 17
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1
1,120, 1,102, 1,042, 1,028, 1,006, 962, 913, 888, 847, 803, 755, 715, 698 cm−1; H-NMR (CDCl3) δ
7.52 (d, J = 1.6 Hz, 1H), 7.46–7.26 (m, 5H), 5.46 (brs, 1H), 3.62 (s, 3H), 2.87 (d, J = 15.6 Hz, 1H),
2.40 (d, J = 15.9 Hz, 1H), 1.24 (s, 3H), 1.15 (s, 1H); 13C-NMR (CDCl3) δ 166.6, 164.1, 142.0, 129.4,
128.4, 127.9, 127.8, 116.8, 64.51, 64.46, 51.4, 49.3, 24.9, 18.9; HPLC analysis (i-PrOH/hexane 10/90,
flow rate 1.1 mL/min: tR 9.0 min (minor, 24%) and 9.8 min (major, 76%), detection at 330 nm.
4. Conclusions
In conclusion, we have examined the application of PyBidine-Cu(OAc) complex for the [3+2]
cycloaddition of azomethine ylide and propiolate for the construction the bicyclic pyrazolo[1,2-
a]pyrazolone skeletons with 74% ee. This shows the broad utility of the PyBidine ligand for various
metal-catalyzed reactions. In addition to a detailed study on the reaction mechanism, the extensive
application to other catalytic reactions based on the unique functions of PyBidine is in progress.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and the Takeda Science Foundation.
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