Efficient and divergent synthesis of fully substituted 1H-pyrazoles and isoxazoles from cyclopropyl oximes

Article abstract of DOI:10.1021/ol800178x

Efficient and divergent one-pot synthesis of fully substituted 1H-pyrazoles and isoxazoles from cyclopropyl oximes based on reaction conditions selection is reported. Under Vilsmeier conditions (POCl₃/DMF), substituted 1H-pyrazoles were synthes

Full text of DOI:10.1021/ol800178x

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1691-1694
Efficient and Divergent Synthesis of
Fully Substituted 1H-Pyrazoles and
Isoxazoles from Cyclopropyl Oximes
Kewei Wang,† Dexuan Xiang,† Jinying Liu,† Wei Pan,† and Dewen Dong*,†,‡
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, China,
and Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, China
dongdw663@nenu.edu.cn
Received January 25, 2008
ABSTRACT
Efficient and divergent one-pot synthesis of fully substituted 1H-pyrazoles and isoxazoles from cyclopropyl oximes based on reaction conditions
selection is reported. Under Vilsmeier conditions (POCl3/DMF), substituted 1H-pyrazoles were synthesized from 1-carbamoyl, 1-oximyl
cyclopropanes via sequential ring-opening, chlorovinylation, and intramolecular aza-cyclization. In the presence of POCl3/CH2Cl2, substituted
isoxazoles were obtained from the cyclopropyl oximes via ring-opening and intramolecular nucleophilic vinylic substitution (SNV) reactions.
Pyrazole motif makes up the core structure of numerous
biologically active compounds, including blockbuster drugs
such as Celebrex1 and Viagra,2 that find a wide range of
applications in pharmaceutical and agrochemical industry.3,4
Many synthetic methods for pyrazoles are available, among
which notable methods involve the reactions between 1,3-
difunctional compounds with hydrazines or their derivatives,5
and 1,3-dipolar cycloadditions of diazo compounds onto
triple bonds.6 Isoxazole derivatives represent another im-
portant class of nitrogen-containing heterocycles along with
diverse useful bioactivities and are widely used as key
intermediates in the preparation of natural products and
related structures.7,8 Intensive research has generated numer-
ous approaches for the synthesis of isoxazoles,9 including
reactions of hydroxylamine with 1,3-dicarbonyl com-
pounds,10 R,ꢀ-unsaturated nitriles/carbonyl compounds,11,12
† Northeast Normal University.
(6) (a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley &
Sons: New York, 1984; Vol. I. (b) Martin, R.; Rodriguez Rivero, M.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079–7082. (c) Aggarwal,
V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68, 5381–5383.
(7) (a) Talley, J. J. Prog. Med. Chem. 1999, 13, 201–234. (b) Jaeger,
V.; Colinas, P. A. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Chemistry of Heterocyclic Compounds; Wiley: Hoboken, NJ,
‡ Chinese Academy of Sciences.
(1) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,
P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro,
J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton,
E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.;
Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem.
1997, 40, 1347–1365.
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10.1021/ol800178x CCC: $40.75
Published on Web 04/02/2008
2008 American Chemical Society

and ynones,13 reaction of an oxime-derived dianion with an
ester/amide,14 and [3 + 2] cycloaddition reaction between
an alkyne and a nitrile oxide.15
as indicated by TLC and furnished one product after workup
and purification by column chromatography. From the
spectral and analytical data, the product was characterized
as 5-chloro-4-(2-chloroethyl)-3-methyl-1-phenyl-1H-pyrazole
2a (Scheme 1).
On the other hand, the utility of cyclopropane derivatives
in organic synthesis has been recognized for their ready
accessibility and good reactivity originating from the inherent
ring strain that can lead to a variety of ring-opening reactions
under the influence of a wide range of chemicals, for
example, electrophiles, nucleophiles, and radicals.16,17 In our
recent work, we achieved one-pot synthesis of halogenated
pyridin-2(1H)-ones from 1-acyl, 1-carbamoyl cyclopropanes
under Vilsmeier conditions.18 In connection with this study
and our continued interest regarding the synthesis of carbo-
and heterocycles from ꢀ-oxo amide derivatives,19 we syn-
thesized a series of cyclopropyl oximes 1 and exploited their
synthetic potential. As a result of these studies, we developed
an alternative one-pot divergent synthesis of fully substituted
1H-pyrazoles and isoxazoles from a single multifunctional
reagent, cyclopropyl oximes, in the presence of POCl3/DMF
(Vilsmeier reagent, VR) and POCl3/CH2Cl2, respectively.
Herein, we wish to report our experimental results and
present proposed mechanisms involved in the ring-opening/
recyclizations.
Scheme 1. Reaction of 1a with POCl3/DMF
The reaction conditions, including reaction temperature and
the ration of 1a to POCl3/DMF, were then investigated. A
series of experiments revealed that 2.0 equiv of POCl3/DMF
was sufficient for the synthesis of 2a, and the optimal results
were obtained when the reaction of 1a was performed with
3.0 equiv of POCl3/DMF at room temperature (∼20 °C) for
0.5 h, whereby the yield of 2a reached 38% (Table 1, entry
The substrates, 1-carbamyl, 1-oximyl cyclopropanes 1,
were prepared by the reaction of 1-acyl, 1-carbamyl cyclo-
propanes3 with hydroxylamine (NH2OH·HCl) in the presence
of NaOAc in methanol at room temperature in high yields
(up to 95%). We then selected 1-(1-(hydroxyimino)ethyl)-
N-phenyl cyclopropanecarboxamide 1a from a series of
substrates 1 as the model compound to examine its behavior
under Vilsmeier conditions.
Table 1. Reactions of Cyclopropyl Oximes 1 under Vilsmeier
Conditionsa
Upon treatment of 1a with 5.0 equiv of POCl3/DMF at
room temperature for 1.0 h, the reaction proceeded smoothly
entry
1
R
Ar
2
yieldc (%)
(12) Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero, R. Tetrahedron 2002,
58, 4975–4980.
1
2
3
4
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
C6H5
C6H5
2a
2b
2c
2d
2e
2f
38
41
44
39
45
47
56
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeOC6H4
2,4-Me2C6H3
C6H5
(13) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205.
(14) (a) He, Y.; Lin, N.-H. Synthesis 1994, 989–992. (b) Barber, G. N.;
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5
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2839–2842. (b) Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005,
6
7b
1g
2g
70, 7761–7764
.
a Reagents and conditions: 1 (1.0 mmol), POCl3/DMF (3.0 mmol), rt,
(16) For reviews, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12,
66–72. (b) Brackman, F.; de Meijere, A. Chem. ReV. 2007, 107, 4493–
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1050. (h) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. (i)
0.5–1.5 h. b Reaction time, 6.0 h. c Isolated yield.
1). It should be mentioned that side products were obtained
from the reaction system as an inseparable mixture by
column chromatography over silica gel.
Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433–442
.
(17) For recent representative work, see: (a) Yadav, V. K.; Balamurugan,
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Secci, F.; Spiga, M. Org. Lett. 2005, 7, 4565–4568. (d) Ogoshi, S.; Nagata,
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J. J. Am. Chem. Soc. 2006, 128, 5348–5349. (g) Zhang, Z.; Zhang, Q.;
Having established the optimal conditions for the ring-
opening/recyclization process, we intended to determine its
scope with respect to the amide motif. Thus, a series of
cyclopropyl oximes 1b-g were subjected to POCl3/DMF
(3.0 equiv) at room temperature, and some of the results are
summarized in Table 1. The efficiency of the protocol proved
to be suitable for 1b-g bearing variable aryl amide groups
affording the corresponding 1H-pyrazoles 2b-g in moderate
yields (Table 1, entries 2–7).
Sun, S.; Xiong, T.; Liu, Q. Angew. Chem., Int. Ed. 2007, 46, 1726–1729
(18) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu,
Q. Org. Lett. 2007, 9, 2421–2423.
.
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Chem. Soc. 2005, 127, 4578–4579. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F.
Chem. Commun. 2005, 3580–3582. (c) Ouyang, Y.; Dong, D.; Yu, H.;
Liang, Y.; Liu, Q. AdV. Synth. Catal. 2006, 348, 206–210. (d) Xiang, D.;
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On the basis of the obtained results and our previously
reported work,18 a plausible mechanism for the synthesis of
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Org. Lett., Vol. 10, No. 9, 2008

Scheme 2. Plausible Mechanism for the Reaction of
Cyclopropyl Oximes 1 under Vilsmeier Conditions
Figure 1. ORTEP drawing of 3a.
Table 2. Reaction of Cyclopropyl Oximes 1 with POCl3 in
a
CH2Cl2
substituted 1H-pyrazoles 2 is presented in Scheme 2. The
transformation commences from the ring-opening reaction
of cyclopropyl oxime 1 mediated by Vilsmeier reagent to
generate iminium intermediate A followed by a halogenation
reaction to give iminium intermediate B,20 which undergoes
an intramolecular aza-cyclization to 2.
Encouraged by the results that cyclopropyl oximes can
undergo a ring-cleavage reaction under Vilsmeier conditions,
we subsequently examined the reaction behavior of cyclo-
propyl oximes 1 toward POCl3 in absence of DMF. Thus,
the reaction of 1a was performed with POCl3 (3.0 equiv) in
CH2Cl2 at room temperature. The substrate was consumed
within 1.0 h as shown by TLC monitoring of the reaction.
After workup and purification by column chromatography,
the reaction furnished a white solid, which was characterized
as 4-(2-chloroethyl)-3-methyl-N-phenyl isoxazol-5-amine 3a
instead of a 1H-pyrazole on the basis of its spectral and
analytical data (Scheme 3). The structure of 3a was further
entry
1
R
Ar
3
yieldb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
C6H5
C6H5
3a
3b
3c
3d
3e
3f
90
88
93
87
81
78
75
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeOC6H4
2,4-Me2C6H3
C6H5
1g
3g
a Reagents and conditions: 1 (1.0 mmol), POCl3 (1.5 mmol), CH2Cl2,
rt, 0.5–1.5 h. b Isolated yield.
optimal results were obtained when 1a was treated with 1.5
equiv of POCl3 in CH2Cl2 at room temperature (∼20 °C)
for 1.0 h, whereby the yield of 3a reached 90% (Table 2,
entry 1) and 2a was not even detectable.
Under the optimal conditions as for 3a, a range of reactions
of 1b-g with POCl3 (1.5 equiv) were carried out in CH2Cl2
at room temperature, and some of the results are summarized
in Table 2. All the reactions proceeded smoothly to afford
the corresponding fully substituted isoxazoles 3b-g in good
to high yields (Table 2, entries 2–7). The results suggested
that POCl3, being a reagent,21 showed different reaction
behavior from Vilsmeier reagent, POCl3/DMF. It was as-
sumed that the formation of substituted isoxazoles 3 involved
the ring-opening reaction of cyclopropyl oximes 1 mediated
by POCl3 and subsequent intramolecular nucleophilic vinylic
substitution (SNV) reaction,22 as depicted in Scheme 4.
Scheme 3. Reaction of 1a with POCl3 in CH2Cl2
confirmed by the X-ray single-crystal analysis (Figure 1).
The optimization of reaction conditions, including reaction
temperature and the ration of 1a to POCl3 were then
investigated. A series of experiments revealed that 1.0 equiv
of POCl3 was sufficient for the synthesis of 3a, and the
(21) For POCl3-mediated heteroannulations, see: (a) Venkatesh, C.;
Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169–
2172. (b) Charles, I.; Latham, D. W. S.; Hartley, D.; Oxford, A. W.; Scopes,
D. I. C. J. Chem. Soc., Perkin Trans. 1980, 1, 1139–1146. (c) Gammon,
D. W.; Hunter, R.; Wilson, S A. Tetrahedron 2005, 61, 10683–10688.
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Bernasconi, C. F.; Schuck, D. F.; Ketner, R. J.; Eventova, I.; Rappoport,
Z. J. Am. Chem. Soc. 1995, 117, 2719–2725. (c) Bernasconi, C. F.; Ketner,
R. J.; Chen, X.; Rappoport, Z. J. Am. Chem. Soc. 1998, 120, 7461–7468.
(20) (a) Jutz, C. Iminium Salts in Organic Chemistry. In AdVances in
Organic Chemistry; Taylor, E. C.,. Ed.; John Wiley & Sons: New York,
1976; Vol. 9, Part I, pp 225–342. (b) Meth-Cohn, O.; Tarnowski, B. AdV.
Heterocycl. Chem. 1987, 31, 207–236. (c) Marson, C. M. Tetrahedron 1992,
48, 3659–3726. (d) Jones, G.; Stanforth, S. P. In Organic Reactions;
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Org. Lett., Vol. 10, No. 9, 2008
1693

lecular SNV reactions to yield the corresponding isoxazoles
in high yields. This protocol is associated with readily
available starting materials, mild conditions, dense and
flexible substitution patterns, important synthetic potential
of the final products, and easy control of the reaction
orientation by reaction conditions selection.
Scheme 4. Plausible Mechanism for the Reaction of
Cyclopropyl Oximes 1 with POCl3 in CH2Cl2
Acknowledgment. Financial support of this research by
the National Natural Science Foundation of China (Grants
20572013 and 20711130229) is greatly acknowledged.
Note Added after ASAP Publication. References 5c,d,
10b,c, and 16b were missing in the version published ASAP
April 2, 2008; the corrected version was published ASAP
April 10, 2008.
In summary, an efficient and divergent one-pot synthesis
of fully substituted 1H-pyrazoles 2 and isoxazoles 3 has been
developed from readily available 1-carbamoyl, 1-oximyl
cyclopropanes 1 based on approporiate reaction conditions.
Thus, a series of cyclopropyl oximes underwent sequential
ring-opening, chlorovinylation, and intramolecular aza-
cyclization under Vilsmeier conditions (POCl3/DMF), to
afford substituted 1H-pyrazoles. In the presence of POCl3/
CH2Cl2, they underwent tandem ring-opening and intramo-
Supporting Information Available: Experimental details
and spectral characterization data for 1–3. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800178X
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Org. Lett., Vol. 10, No. 9, 2008