Facile access to pyrazolines via domino reaction of the Huisgen zwitterions with aziridines

Article abstract of DOI:10.1021/ol7022888

A novel, efficient, and general domino reaction of 2-acylaziridines with the Huisgen zwitterions to furnish 2-pyrazoline rings is described. A possible mechanism for the domino sequence is proposed.

Full text of DOI:10.1021/ol7022888

ORGANIC
LETTERS
2008
Vol. 10, No. 1
13-16
Facile Access to Pyrazolines via
Domino Reaction of the Huisgen
Zwitterions with Aziridines
Sun-Liang Cui, Jing Wang, and Yan-Guang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027,
People’s Republic of China
orgwyg@zju.edu.cn
Received September 24, 2007
ABSTRACT
A novel, efficient, and general domino reaction of 2-acylaziridines with the Huisgen zwitterions to furnish 2-pyrazoline rings is described. A
possible mechanism for the domino sequence is proposed.
2-Pyrazolines are a medicinally important class of hetero-
cyclic small molecules that have shown potential bioactivity
in numerous screening tests.1 A number of compounds con-
taining the pyrazoline core have been examined for antide-
pressant activity through screening against monoamine
oxidases,2 treatment of obesity as cannabinoid-1 antagonists,3
antiviral activity against the West Nile virus,4 and multidrug
resistance modulators in tumor cells.5 Pyrazolines are also
synthetically useful scaffolds in organic chemistry.6 The 1,3-
dipolar cycloaddition reaction is a classical and widely used
method for the construction of 2-pyrazolines.7
zwitterion,8 which plays an important role in the Mitsunobu
reaction.9 Recently, it was reported that the Huisgen zwit-
terion reacted with carbonyl compounds to afford various
products.10 Very recently, Nair and co-workers used this
zwitterion to synthesize N,N-dicarboethoxy monohydrazones,
(4) Goodell, J. R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.;
Ferguson, D. M. J. Med. Chem. 2006, 49, 2127-2137.
(5) Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.;
Chimenti, P.; Ferlini, C.; Scambia, G. Bioorg. Med. Chem. Lett. 2005, 15,
4632-4635.
(6) (a) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2,
4265-4267. (b) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 3955-3957. (c) Ruano, J. L. G.; de Diego, S. A. A.; Mart´ın, M. R.;
Torrente, E.; Castro, A. M. M. Org. Lett. 2004, 6, 4945-4948.
(7) (a) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 2174-2175. (b) Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 11279-11282. (c) Chen, Y.; Lam, Y. L.; Lai, Y. H. Org. Lett. 2003,
5, 1067-1069. (d) Simovic, D.; Di, M.; Marks, V.; Chatfield, D. C.; Rein,
K. S. J. Org. Chem. 2007, 72, 650-653. (e) Mish, M.; Guerra-Martinez,
F.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379-8380. (f) Mu¨ller,
T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed. 2000, 39, 1253-
1256.
(8) (a) Huisgen, R. In The AdVenture Playground of Mechanisms and
NoVel Reactions: Profiles, Pathways and Dreams; Seeman, J. I., Ed.;
American Chemical Society: Washington, DC, 1994; p 62. (b) Huisgen,
R.; Blaschke, H.; Brunn, E. Tetrahedron Lett. 1966, 7, 405. (c) Brunn, E.;
Huisgen, R. Angew. Chem., Int. Ed. 1969, 8, 513- 515.
Triphenylphosphine and dialkyl azodicarboxylates were
utilized as the redox couple for the formation of Huisgen
(1) (a) Manyem, S.; Sibi, M. P.; Lushington, G. H.; Neuenswander, B.;
Schoenen, F.; Aube, J. J. Comb. Chem. 2007, 9, 20-28. (b) Schreiber, S.
L. Nat. Chem. Biol. 2005, 1, 64-66. (c) Spring, D. R. Chem. Soc. Rev.
2005, 34, 472-482. (d) Camacho, M. E.; Leon, J.; Entrena, A.; Velasco,
G.; Carrion, M. D.; Escames, G.; Vivo, A.; Acuna-Castroviejo, D.; Gallo,
M. A.; Espinosa, A. J. Med. Chem. 2004, 47, 5641-5650. (e) Camacho,
E.; Leon, J.; Carrion, A.; Entrena, A.; Escames, G.; Khaldy, H.; Acuna-
Castroviejo, D.; Gallo, M. A.; Espinosa, A. J. Med. Chem. 2002, 45, 263-
274.
(2) (a) Chimenti, F.; Bolasco, A.; Manna, F.; Secci, D.; Chimenti, P.;
Befani, O.; Turini, P.; Giovannini, V.; Mondovi, B.; Cirilli, R.; La Torre,
F. J. Med. Chem. 2004, 47, 2071-2074. (b) Rajendra Prasad, Y.; Lakshmana
Rao, A.; Prasoona, L.; Murali, K.; Ravi Kumar, P. Bioorg. Med. Chem.
Lett. 2005, 15, 5030-5034.
(3) Lange, J. H. M.; van Stuivenberg, H. H.; Veerman, W.; Wals, H. C.;
Stork, B.; Coolen, H. K. A. C.; McCreary, A. C.; Adolfs, T. J. P.; Kruse,
C. G. Bioorg. Med. Chem. Lett. 2005, 15, 4794-4798.
(9) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughs, D. L. Org. Prep.
Proced. Int. 1996, 28, 127-164. (c) Prakash, G. K. S.; Chacko, S.; Alconcel,
S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46,
4933-4936.
(10) Otte, R. D.; Sakata, T.; Guzei, I. A.; Lee, D. Org. Lett. 2005, 7,
495-498.
10.1021/ol7022888 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/07/2007

dihydro-1,2,3-benzoxadiazoles, and functionalized pyrazole,
pyrazoline, as well as pyrazolopyridazine derivatives.11
Inspired by these works and as a part of our continuing
program on development of domino reactions,12 we are
interested in the domino reaction of Huisgen zwitterion with
2-acylaziridines. We anticipated that the in situ generated
Huisgen zwitterion could be intercepted by the carbonyl
group of 2-acylaziridine, followed by an intramolecular
domino process to construct a class of 2-pyrazolines.
In our initial investigations, we found that diethyl azodi-
carboxylate (1a) reacted with triphenylphosphine and 2-acyl-
aziridine 2a to yield quantitatively pyrazoline 3aa when the
reaction was performed in toluene and refluxed for 2 h (Table
1, entry 1). Benzene also worked effectively as the solvent,
affording 3aa in 95% yield (see the Supporting Information).
synthesized from the corresponding chalcones according to
a previous report by Shi.13 In all of our cases, both the elec-
tron-donating and electron-withdrawing group substituted
aziridines 2 reacted with the zwitterions to give the corre-
sponding pyrazolines 3 in excellent yields, exhibiting a
remarkable efficiency.
The two hydrogen atoms at the CH2 group of the pyrazo-
1
line ring determined by H NMR spectrum resonate as two
1
doublets displaying H resonance signals at about 3.39 and
4.49 ppm, respectively, and their coupling constants exceed
17 Hz.14 The structure of 3ha was firmly established by X-ray
analysis (Figure 1).
Table 1. Synthesis of Pyrazolines via Domino Reaction of
Huisgen Zwitterions with Aziridinesa
entry
R1
R2
C6H5
R
product yield (%)b
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
Et
3aa
3ab
3ac
3ba
3bb
3ca
3cb
3da
3ea
3eb
3ec
3fa
99
98
98
98
96
95
94
92
98
98
97
95c
98
98
99
98
98
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4 Et
4-MeOC6H4 i-Pr
4-MeOC6H4 t-Bu
i-Pr
t-Bu
Et
i-Pr
Et
Figure 1. Crystal structure of 3ha.
3,4-Me2C6H3
3,4-Me2C6H3
4-ClC6H4
It is interesting that the reaction of 1a with aziridine 2g
or 2i afforded pyrazoline 3gc or 3ia along with hydrazone
4a or 4b, respectively (Table 2). We also found that products
4-ClC6H4
i-Pr
Et
2-furyl
4-O2NC6H4
10 4-O2NC6H4
11 4-O2NC6H4
12 3,4-(OCH2O)C6H3 2-ClC6H4
13 2-naphthyl
14 2-naphthyl
15 C6H5
Table 2. Synthesis of Pyrazolines 3 and Hydrazones 4a
i-Pr
i-Pr
t-Bu
2-ClC6H4
2-ClC6H4
3-O2NC6H4 Et
3-O2NC6H4 i-Pr
3-O2NC6H4 t-Bu
3ga
3gb
3ha
3hb
3hc
16 C6H5
17 C6H5
a Reaction conditions: dialkyl azodicarboxylate 1 (1.3 mmol), aziridine
2 (1 mmol), PPh3 (1.3 mmol), toluene, reflux, 2 h. b Isolated yields refer to
aziridines. c Reaction was performed at rt for 8 h.
entry
R1/R2
product/yield (%)b
1
2
2-naphthyl/2-ClPh (2g)
4-PhC6H4/2-MePh (2i)
3gc/35 + 4a/60
3ia/31 + 4b/65
With suitable reaction conditions in hand, we next focused
our attention on exploring the scope using a variety of
aziridines 2 (Table 1, entries 2-17), which were easily
a Reaction conditions: aziridine (1 mmol), dialkyl azodicarboxylate (1.3
mmol), PPh3 (1.3 mmol), toluene, reflux, 2 h. b Isolated yields refer to
aziridines.
(11) (a) Nair, V.; Biju, A. T.; Abhilash, K. G.; Menon, R. S.; Suresh, E.
Org. Lett. 2005, 7, 2121-2123. (b) Nair, V.; Biju, A. T.; Vinod, A. U.;
Suresh, E. Org. Lett. 2005, 7, 5139-5142. (c) Nair, V.; Biju, A. T.;
Mohanan, K.; Suresh, E. Org. Lett. 2006, 8, 2213-2216. (d) Nair, V.;
Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem., Int. Ed. 2007, 46,
2070-2073.
(12) (a) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517-
4520. (b) Wang, Y. G.; Cui, S. L.; Lin, X. F. Org. Lett. 2006, 8, 1241-
1244. (c) Cui, S. L.; Lin. X. F.; Wang, Y. G. J. Org. Chem. 2005, 70,
2866-2869. (d) Cui, S. L.; Wang, J.; Lin, X. F.; Wang, Y. G. J. Org.
Chem. 2007, 72, 7779-7782.
3 and 4 were stable in toluene and could not transform each
other even in the presence of PPh3 and 1a under reflux
conditions. The structure 4a was unambiguously confirmed
by crystal X-ray analysis (see the Supporting Information).
(13) Shen, Y. M.; Zhao, M. X.; Xu, J. X.; Shi, Y. Angew. Chem., Int.
Ed. 2006, 45, 8005-8008.
14
Org. Lett., Vol. 10, No. 1, 2008

To view insight into the reaction mechanism, we conducted
two deuterium-labeling experiments, i.e., the reaction of
deuterated aziridine D-2a (>95% D) with 1b (Scheme 1)
On the basis of these results we depicted our current
working hypothesis in Scheme 3. The formation of a strained
five-membered ring can be rationalized as being initiated
by the combination of PPh3 and diethyl azodicarboxylate 1
to Huisgen zwitterion A. A undergoes addition to the
carbonyl group of 2-acylaziridine 2 to form B, which
subsequently cyclizes to C. Then the resulting C decomposes
to triphenylphosphine oxide and the oxadiazoline D,16
followed by an intramolecular addition reaction to E and a
subsequent proton migration to F. The high strained fusion
ring F expands to G and then opens to H. Two possibilities
for the next steps remain. One possibility is that H undergoes
an intramolecular Michael-type addition to afford pyrazoline
3 (path a). The other possibility is the formation of 4 via a
proton migration (path b).
Scheme 1. The Deuterium-Labeling Experiment A
and the reaction of deuterated aziridine D′-2a (>95% D)
with 1a (Scheme 2). In the first case, we isolated the
The utility of the domino reaction of Huisgen zwitterions
with aziridines for facile access to pyrazolines was imme-
diately realized in an ideal transformation to pyrazoles. As
shown in Table 3, the pyrazolines 3 underwent elimination
to afford pyrazoles 5 or 6 in excellent yields.
Scheme 2. The Deuterium-Labeling Experiment B
In conclusion, we have developed a novel and general
domino reaction of 2-acylaziridines with the Huisgen zwit-
terions to furnish pyrazoline rings in excellent yields. A
possible mechanism for the domino sequence is proposed,
and the evidence has been established by isolation of some
byproducts and the deuterium-labeling experiments. Fur-
thermore, the resulting pyrazolines could be easily converted
to pyrazoles. Therefore, the present methodology extends
promise for a convenient synthetic protocol for the prepara-
tion of pyrazoline and pyrazole compounds.
deuterated product D-3ab (>95% D) in 98% yield. In the
second case, we obtained the deuterated product D-3aa
(>95% D) in quantitative conversion.15
Scheme 3. Proposed Mechanism for the Formation of Pyrazolines 3 and Hydrazones 4
Org. Lett., Vol. 10, No. 1, 2008
15

Project of Ministry of Science and Technology (No. 2002CB
713808).
Table 3. Synthesis of Pyrazoles from Pyrazolines 3a
Supporting Information Available: Detailed experi-
1
mental procedures, characterizaton data, copies of H and
13C NMR spectra for all products, and crystallographic
information files (CIF) for compounds 3ha and 4a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
product/yield (%)b
entry
R1
4-ClC6H4
3,4-(OCH2O)C6H3 2-ClC6H4
R2
R
5
6
1
2
3
4
Ph
Et
i-Pr
i-Pr
5a/91
5b/85
5c/83
2-naphthyl
Ph
2-ClC6H4
3-O2NC6H4 t-Bu
OL7022888
6a/90
a Reaction conditions: 3 (0.5 mmol), 2 M H2SO4 (1.5 mmol), MeOH (5
mL), reflux, 8 h. b Yields refer to 3.
(14) For similar details of the 1H NMR spectrum of the methylene group
of the strained pyrazoline ring scaffold, see ref 7.
(15) The reaction was performed in benzene-d6. After the reaction was
completed, the resulting solution containing D-3aa was directly subjected
1
to H NMR analysis.
(16) We have isolated the resulting triphenylphosphine oxide as a
byproduct. For similar domino processes, see ref 11.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20672093) and the 973
16
Org. Lett., Vol. 10, No. 1, 2008