Regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles from enaminones

Article abstract of DOI:10.1021/ol203282h

A highly regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles from enaminones based on reaction condition selection is reported. 3-Arylaminoisoxazoles were produced by treating enaminones with aqueous hydroxylamine in DMF at 100 °C, whereas

Full text of DOI:10.1021/ol203282h

ORGANIC
LETTERS
2012
Vol. 14, No. 2
644–647
Regioselective Synthesis of 3-Arylamino-
and 5-Arylaminoisoxazoles from
Enaminones
Dexuan Xiang, Xiaoqing Xin, Xu Liu, Rui Zhang,* Jiming Yang, and Dewen Dong*
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun,
130022, China
ariel@ciac.jl.cn; dwdong@ciac.jl.cn
Received December 8, 2011
ABSTRACT
A highly regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles from enaminones based on reaction condition selection is reported.
3-Arylaminoisoxazoles were produced by treating enaminones with aqueous hydroxylamine in DMF at 100 °C, whereas 5-arylaminoisoxazoles
were synthesized by subjecting enaminones to aqueous hydroxylamine in the presence of KOH and TBAB in water under reflux. A mechanism for
the regioselective synthesis of 3-arylamino- and 5-arylaminoisoxazoles is proposed.
The vast number of bioactive natural products and
pharmaceutical drugs based on the isoxazole ring system,1
such as valdecoxib, leflunomide, and cloxacillin, has be-
come very important areas of research in natural product
and pharmaceutical chemistry.2 In addition, isoxazoles are
widely used as key intermediates in the preparation of
natural products and related structures.3 So far, extensive
work has generated many approaches for the synthesis
of isoxazoles,4 based on either (i) intermolecular [2 þ 3]
cycloadditions of 1,3-dipoles to alkynes5 or (ii) condensa-
tions of hydroxylamine with β-diketone equivalent three
carbon 1,3-electrophilic units bearing sp or sp2 carbons,
such as propargylic ketones, enones, and R,β-unsaturated
nitriles.6 However, the appealing generality of these meth-
ods is somewhat vitiated because of the frequent formation
of a regioisomeric mixture of unsymmetrical isoxazoles in
these reactions. Therefore, several elegant methods for the
regioselectivesynthesis of isoxazoles have been reported by
altering the electrophilicity of the terminal carbons in the
C3 units,7 controlling the pH of the reaction medium and
the reaction conditions,8 or introducing bromo/benzotria-
zolyl moieties at the R-position of R,β-unsaturated ketones
as the leaving groups that allow for the direct transformation
(1) (a) Lang, S. A.; Lin, Y.-I. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R., Rees, C. M., Potts, K. T., Eds.; Pergamon Press: New
York, 1984; Vol. 6, p 61. (b) Sutharchanadevi, M.; Murugan, R.
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U. K., 1996; Vol. 3, p 221.
(c) Cicchi, S.; Cordero, F. M.; Giomi, D. Prog. Heterocycl. Chem. 2003,
15, 261.
(2) (a) Sperry, J.; Wright, D. Curr. Opin. Drug Discovery Dev. 2005, 8,
723. (b) Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.;
Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.;
Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45, 2454.
(c) Lee, Y.; Park, S.; Kim, B. Bioorg. Med. Chem. Lett. 2009, 19, 1126.
(3) (a) Manning, J.; Davies, H. J. Am. Chem. Soc. 2008, 130, 8602. (b)
Baraldi, P.; Barco, A.; Benetti, S.; Pollini, G.; Simoni, D. Synthesis 1987,
857.
(5) (a) Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70,
2839. (b) Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70,
7761.
€
(6) (a) Bandiera, T.; Grunanger, P.; Albini, F. M. J. Heterocycl.
Chem. 1992, 29, 1423. (b) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7,
5203. (c) Vicentini, C. B.; Verones, A. C.; Poli, T.; Guarneri, M.; Giori,
P.; Ferretti, V. J. Hetercycl. Chem. 1990, 27, 1481. (d) Cuadrado, P.;
Gonzalez-Nogal, A. M.; Valero, R. Tetrahedron 2002, 58, 4975. (e) He,
Y.; Lin, N.-H. Synthesis 1994, 989. (f) Barber, G. N.; Olofson, R. A.
J. Org. Chem. 1978, 43, 3015. (g) Nitz, T. J.; Volkots, D. L.; Aldous,
D. J.; Oglesby, R. C. J. Org. Chem. 1994, 59, 5828.
(7) (a) Rahman, A.; Vishwakarama, J. N.; Yadav, R. D.; Ila, H.;
Junjappa, H. Synthesis 1984, 247. (b) Rudorf, W. D.; Augustin, M.
J. Prakt. Chem. 1978, 320, 585. (c) Dornow, A.; Dehmer, K. Chem. Ber.
1967, 100, 2577. (d) Gompper, R.; Topfl, W. Chem. Ber. 1962, 95, 2881.
€
(4) For reviews, see: (a) Jager, V.; Colinas, P. A. In Synthetic Applica-
tions of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Ed.; Wiley: Hoboken, NJ, 2002; Vol. 59, p
361. (b) Wakefield, B. J. Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Shaumann, E., Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2001; Vol. 11, p 229. (c) Pinho e Melo, T. M. V. D.
Curr. Org. Chem. 2005, 9, 925.
r
10.1021/ol203282h
Published on Web 01/03/2012
2012 American Chemical Society

of the initially formed isoxazolines into the aromatic
isoxazoles.9 Neverthless, the development of new methods
forthehighlyregioselectivesynthesisofisoxazolesfrom the
same precursors is still a challenge for organic chemists.10
On the other hand, enaminones and related compounds
possessing the conjugated system N;CdC;CdO are
versatile synthetic intermediates that combine the ambi-
dent nucleophilicity of enamines with the ambident elec-
trophilicity of enones.11 During the course of our studies
on the chemistry of enaminones, we developed efficient
synthesis of pyrrolin-4-ones,12 2,3-dihydrofurans,13 pyri-
midin-4(3H)-ones,14pyridin-2(1H)-ones,15 cyclophospha-
mides,16 and pyranoquinolines17 from various enaminones.
In connection with these studies, we investigated the reac-
tions of cyclic enaminones, 2-arylamino-3-acetyl-5,6-dihy-
dro-4H-pyranes, with aqueous hydroxylamine under dif-
ferent conditions. As a result, we achieved regioselective
synthesis of 3-arylamino- and 5-arylaminoisoxazoles by
controlling the reaction conditions. Herein, we wish to
report our preliminary results and present the involved
mechanisms.
Scheme 1. Reaction of 1a with NH2OH in DMF
The optimization of the reaction conditions, including
reaction temperature, time and solvents, were then inves-
tigated. The reaction of 1a with hydroxylamine could pro-
ceed in other solvents, such as C2H5OH, CH3OH, and
water, but the conversion was very low. When 1a and
hydroxylamine were subjected to water in the presence of
TBAB under reflux, 2a was obtained in 52% yield along
with recovery of 1a (33%). After a series of experiments,
the optimal results could be obtained when the reaction of
1a and aqueous hydroxylamine (1.5 equiv) were con-
ducted in DMF at 100 °C for 12.0 h, whereby the yield
of 2a reached 83% (Table 1, entry 1).
The substrates, cyclic enaminones 1, were synthesized
from commercially available β-oxo amides and 1,3-dibro-
mopropane in excellent yields according to our published
procedure.15c With substrates 1 in hand, we selected 1a as
the model compound to examine its behavior under dif-
ferent conditions. Upon treatment of 1a with aqueous
hydroxylamine (1.5 equiv) in DMF at 80 °C for 14.0 h,
the reaction proceeded smoothly as indicated by TLC and
furnished a white solid after workup and purification
(column chromatography). The product was characterized
as 3-[5-methyl-3-(phenylamino)isoxazol-4-yl]propan-1-ol
2a (68% yield) on the basis of its spectral and analytical
data (Scheme 1).
Table 1. Reaction of Enaminones 1 with NH2OH in DMFa
entry
1
Ar
2
yieldb (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
C6H5
2a
2b
2c
2d
2e
2f
83
80
77
86
74
79
4-MeC6H4
4-MeOC6H4
4-ClC6H4
(8) (a) Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf,
T. I. J. Org. Chem. 1986, 51, 4037. (b) Jacobsen, N.; Kolind-Andersen,
H.; Christensen, J. Can. J. Chem. 1984, 62, 1940. (c) Purkayastha, M. L.;
Ila, H.; Junjappa, H. Synthesis 1989, 20.
4-CF3C6H4
2,4-Me2C6H3
a Reagents and conditions: 1 (1.0 mmol), NH2OH (aq, 1.5 mmol),
DMF (5 mL), 100 °C, 10.0ꢀ13.0 h. b Isolated yield.
(9) (a) Borkhade, K. T.; Marathey, M. G. Indian J. Chem. 1970, 8,
796. (b) Kashima, C.; Yoshihara, N.; Shirai, S. I. Heterocycles 1981, 16,
145. (c) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V.; Steel,
P. J. J. Org. Chem. 2001, 66, 6787. (d) Kashima, C.; Shirai, S.-I.;
Yoshiwara, N.; Omote, Y. J. Chem. Soc. Chem., Commun. 1980, 826.
(e) Kashima, C.; Yoshiwara, N.; Shirai, S.-I.; Omote, Y. J. Chem. Soc.,
Chem. Commun. 1982, 1455.
(10) (a) Sobenina, L. N.; Drichkov, V. N.; Mikhaleva, A. b. I.;
Petrova, O. V.; Ushakov, I. A.; Trofimov, B. A. Tetrahedron 2005, 61,
4841. (b) Pavlik, J. W.; Lowell, J. A.; Ervithayasuporn, V. J. Heterocycl.
Chem. 2005, 42, 1253.
(11) For reviews, see:(a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(b) Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463. (c)
Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
(12) Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong, D. Org. Lett.
2007, 9, 5345.
Having established the optimal conditions for the ring-
opening/recyclization process, we aimed to determine its
scope with respect to the amide motif of cyclic enaminones
1. Thus, a series of reactions of substrates 1bꢀf and aque-
ous hydroxylamine was carried out under identical condi-
tions as described for 2a (Table 1, entry 1), and some of the
results are summarized in Table 1. It was observed that all
the reactions proceeded smoothly to afford the corre-
sponding 3-arylaminoisoxazoles 2bꢀf in moderate to good
yields (Table 1, entries 2ꢀ6). In all these cases, the other
regioisomeric products were not even detected. Therefore,
we provided a facile regiospecific synthesis of 3-amino-
isoxazoles of type 2.
(13) Zhang, R.; Liang, Y.; Zhou, G.; Wang, K.; Dong, D. J. Org.
Chem. 2008, 73, 8089.
(14) Zhang, R.; Zhang, D.; Liang, Y.; Zhou, G.; Dong, D. J. Org.
Chem. 2011, 76, 2880.
(15) (a) Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong,
D. J. Org. Chem. 2008, 73, 9504. (b) Zhang, R.; Zhang, D.; Liang, Y.;
Dong, D. Synthesis 2009, 2497. (c) Xiang, D.; Yang, Y.; Zhang, R.;
Liang, Y.; Pan, W.; Huang, J.; Dong, D. J. Org. Chem. 2007, 72, 8593.
(16) Xiang, D.; Huang, P.; Wang, K.; Zhou, G.; Liang, Y.; Dong, D.
Chem. Commun. 2008, 6236.
To gain insight into the mechanism of the ring-opening/
recyclization reaction of 1, a separate experiment was
carried out. The reaction of 1d and hydroxylamine
(aq, 1.5 equiv) was performed at 70 °C for 1.5 h and then
(17) Xiang, D.; Xin, X.; Liu, X.; Santosh, K.; Dong, D. Synlett. 2011,
2187.
Org. Lett., Vol. 14, No. 2, 2012
645

in the presence of KOH (1.5 equiv) at 100 °C. The reac-
tion proceeded smoothly and furnished a product, after
workup and purification by column chromatography,
which was characterized as 3-[3-methyl-5-(phenylamino)
isoxazol-4-yl]propan-1-ol 4a (72% yield) on the basis of its
spectral and analytical data (Scheme 4).
Scheme 2. Reaction of 1d with NH2OH in DMF
Table 2. Reaction of 1a with NH2OH under Different Condi-
tionsa
quenched with brine. A main product was obtained,
which was characterized as 3-[(4-chlorophenyl)amino]-4-
(3-hydroxypropyl)-5-methyl-4,5-dihydroisoxazol-5-ol 3d in
65% yield; meanwhile, 3-aminoisoxazole 2d was obtain-
ed in 12% yield (Scheme 2). It is worth noting that 3d could
be converted into 2d in 94% yield upon treatment in DMF
at 100 °C.
yieldb (%)
entry solvent catalyst temp (°C) additive
2a
4a
Scheme 3. Plausible Mechanism for the Synthesis of Isoxazoles 2
from Enaminones 1 and NH2OH
1
2
3
4
5
6
7
8
DMF
EtOH
MeOH
H2O
none
100
80
KOH
KOH
KOH
KOH
KOH
K2CO3
Et3N
HCl
0
0
72
67
64
51
84
25
34
0
none
none
65
0
none
100
100
100
100
100
0
H2O
TBAB
TBAB
TBAB
TBAB
0
H2O
32
26
0
H2O
H2O
a Reagents: 1a (1.0 mmol), NH2OH (aq, 1.5 mmol), solvent (10 mL),
catalyst (0.1 mmol), additive (1.5 mmol). b Isolated yields.
The optimization of the 5-arylaminoisoxazole synthesis,
including reaction solvents, time, and base or acid as
additive, was then investigated. With KOH as base, the re-
action of 1a could proceed in other solvents, such as EtOH,
MeOH, or water (Table 2, entries 2ꢀ4). Interestingly,
when 1a was treated with hydroxylamine (aq, 1.5 equiv)
in water in the presence of KOH (1.5 equiv) and phase
transfer catalyst tetrabutylammonium bromide (TBAB,
0.1 equiv) at 100 °C, the reaction could furnish 4a in 84%
yield (Table 2, entry 5). However, in the presence of a weak
base, such as K2CO3 or Et3N, the reaction of 1a formed a
mixture, a pair of regioisomers 2a and 4a along with
recovery of some intact starting material 1a (Table 2,
entries 6 and 7). No reaction was observed when aqueous
HCl was employed instead of base (Table 2, entry 8).
Under the optimal conditions as for 4a in Table 2, entry
5, a range of reactions of selected cyclic enaminones 1 were
carried out, aiming to determine the scope of the 5-aryla-
minoisoxazole synthesis, and some of the results are sum-
marized in Table 3. It was found that the reactions of 1bꢀi
bearing variable aryl amine groups could proceed effi-
ciently to afford the corresponding 5-arylamino isoxazoles
2bꢀi in moderate to good yields (Table 3, entries 2ꢀ8). It is
worth mentioning that the structure of 4d was elucidated
by means of the X-ray single crystal analysis (Figure 1) and
confirmed by its spectral and analytical data. Therefore,
we provided a clean and convenient synthesis of 5-aryla-
minoisoxazoles based on the reaction of enaminones and
On the basis of the obtained results and our previously
reported work,12ꢀ16 a plausible mechanism for the synthe-
sis of 3-aminoisoxazoles 2 is presented in Scheme 3. The
ring-opening reaction of enaminone 1 is triggered by the
attack of N-nucleophile, hydroxylamine, to generate inter-
mediate A,10a followed by intramolecular cyclization to
formation of intermediates 30 and 3,8a,18 and subsequent
elimination of a water molecule to afford isoxazole 2.
Scheme 4. Reaction of 1a with NH2OH in DMF in the Presence
of KOH
The abovefindings encouraged us toenvisagethatunder
appropriate conditions, the regioselective synthesis of
5-arylaminoisoxazoles may be realized. Thus, enaminone
1a was treated with hydroxylamine (aq, 1.5 equiv) in DMF
(18) Martins, M. A. P.; Beck, P.; Cunico, W.; Pereira, C. M. P.;
Sinhorin, A. P.; Blanco, R. F.; Peres, R.; Bonacorso, H. G.; Zanatta, N.
Tetrahedron Lett. 2002, 43, 7005.
646
Org. Lett., Vol. 14, No. 2, 2012

synthesis of 5-arylaminoisoxazoles 4 is presented in
Scheme 5. In the presence of a strong base, aminohydroxy
anion isformed,19 which then, asan O-nucleophile, attacks
the β-position of enaminone 1 to generate intermediate
B via intermolecular nucleophilic vinylic substitution (SNV)
reaction,10a followed by an intramolecular cyclization to
give 5-arylamino isoxazole 4 with elimination of a water
molecule.20
Table 3. Reaction of Enaminones 1 with NH2OH in Water in the
Presence of KOHa
yieldb (%)
Scheme 5. Plausible Mechanism for the Synthesis of Isoxazoles 4
entry
1
Ar
4
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1f
C6H5
4a
4b
4c
4d
4f
84
81
77
89
80
72
83
78
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2,4-Me2C6H3
2-MeC6H4
2-ClC6H4
1g
1h
1i
4g
4h
4i
In summary, we have developed a facile and efficient
synthesis of 3-arylamino- and 5-arylaminoisoxazoles from
readily available enaminones 1 in a highly regioselective
manner by variation of the reaction conditions. This pro-
tocol is associated with readily available starting materials,
mild conditions, good yields, high regioselectivity, flexible
substitution patterns, and a wide range of synthetic poten-
tial of products. Further work on reaction mechanism and
extension of the scope of the present protocol are currently
underway in our laboratory.
3-MeC6H4
a Reagents and conditions: 1 (1.0 mmol), NH2OH (aq, 1.5 mmol),
H2O (10 mL), TBAB (0.1 mol), KOH (1.5 mmol), 100 °C, 5.5ꢀ8.5 h.
b Isolated yield.
hydroxylamine catalyzed by TBAB in the presence of
KOH in water.
Acknowledgment. Financial support of this research
by the National Natural Science Foundation of China
(20872136, 51073150, and 21172211) is greatly acknowl-
edged.
Supporting Information Available. Experimental details
and analytical data for all new compounds, copies of 1H
and 13C NMR spectra of 2, 3, and 4, and CIF data for 4d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. ORTEP drawing of 4d.
On the basis of the above experimental results together
with some literature studies, a plausible mechanism for the
(20) (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017. (b) Pavlik, J.;
Lowell, J.; Ervithayasuporn, V. J. Hetercycl. Chem. 2005, 42, 1253. (c)
Bonacorso, H.; Vezzosi, R.; Rodrigues, I.; Drekener, R.; Porte, L.;
Flores, A.; Zanatta, N.; Martins, M. J. Braz. Chem. Soc. 2009, 20, 1370.
(19) Kashima, C.; Yoshiwara, N.; Omote, Y. Tetrahedron Lett. 1982,
23, 2955.
Org. Lett., Vol. 14, No. 2, 2012
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