Gold(III)-catalyzed synthesis of isoxazoles by cycloisomerization of α,β-acetylenic oximes

Article abstract of DOI:10.1055/s-0029-1219342

Cycloisomerization of,-acetylenic oximes leading to substituted isoxazoles was achieved using AuCl₃ as catalyst, under moderate reaction conditions. The reaction can be applied to various acetylenic oximes and gives good to excellent yields. Th

Full text of DOI:10.1055/s-0029-1219342

LETTER
777
Gold(III)-Catalyzed Synthesis of Isoxazoles by Cycloisomerization of
a,b-Acetylenic Oximes
G
old(III)-Catalyz
.
edSynthesis
P
of Isoxazolesraveen, A. Kalyanasundaram, P. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 30 November 2009
cycle-forming reactions.12 Recently, Larock and
coworkers reported a novel method for the synthesis of
isoxazoles through electrophilic cyclization of 2-alkyn-1-
one-O-methyl oximes,7c,d although this approach was lim-
Abstract: Cycloisomerization of a,b-acetylenic oximes leading to
substituted isoxazoles was achieved using AuCl3 as catalyst, under
moderate reaction conditions. The reaction can be applied to vari-
ous acetylenic oximes and gives good to excellent yields. The meth-
odology is amenable for the selective synthesis of 3-substituted, 5- ited by the use of hazardous halogenating reagents. Short
substituted or 3,5-disubstituted isoxazoles by simply altering the
et al. reported the K2CO3-mediated cyclization of propar-
gyl oximes leading to isoxazoles,13 although this method
substituents on the acetylenic oximes.
Key words: a,b-acetylenic oximes, gold(III) chloride, cyclo-
isomerization, isoxazoles
suffers from the use of stoichiometric amounts of reagent
and long reaction times. To circumvent such limitations in
reagent scope, and to establish a mild catalytic protocol,
we envisioned the synthesis of a,b-acetylenic oximes (2)
Isoxazoles are an important class of heteroaromatic mole- followed by gold-catalyzed cyclization leading to isox-
cules that are components in a variety of natural products azoles (3; Scheme 1).
and medicinally useful compounds.1 Typical biological
R2
R2
uses of such compounds include analgesic, antiinflamma-
tory, ulcerogenic, antimicrobial, antifungal, COX-2 inhib-
itory, antinociceptive and applications as anticancer
agents.2 They also find application in organic synthesis as
synthetic intermediates3 and as chiral ligands.4 The liquid
crystalline properties of isoxazole derivatives, and thus
their potential application in optoeletric devices, has also
made them attractive synthetic targets.5 Thus, the devel-
opment of new methods for the synthesis of the isoxazole
skeleton is an area of considerable ongoing interest.6 In
general, the synthetic methods most used to generate isox-
azoles involes either the [3+2] cycloaddition of alkenes/
alkynes with nitrile oxides, or the reaction of hydroxyl-
amine with a three-carbon component. However, due to
their importance as substructures in a broad range of nat-
ural and designed products, significant effort continues to
be directed toward the development of new isoxazole-
based structures and new methods for their construction.7
However, most of these protocols suffer from the use of
strong acids/bases, high reaction temperatures, prolonged
reaction time, low yields, tedious workup procedures, stoi-
chiometric reagents or provide poor regioselectivity.
R1
R1
cat. [Au]
R1
H2NOH
N
O
R2
N
O
OH
1
2
3
Scheme 1 Synthetic approach to isoxazoles
The requisite oximes were easily prepared in good to ex-
cellent yields by stirring a mixture of a-acetylenic ke-
tones/aldehydes14 with hydroxylammonium chloride and
10% NaHCO3 solution in methanol. For substrates where
R = H or Me, a 1:1 mixture of E/Z oximes was formed;
when R = Ph, the Z-isomer was obtained predominantly.
This observation was in complete agreement with results
obtained using Larock’s procedure.7c,d Having established
a satisfactory procedure for the preparation of the required
oximes, we next set out to investigate the reaction condi-
tions necessary for the synthesis of isoxazoles. Initial
studies were conducted using oxime 2a as a prototype
reaction in dichloromethane at 30 °C for 30 minutes
(Scheme 2).
In recent years, gold salts and their complexes have re-
ceived increasing attention as catalysts for organic trans-
formations.8 The use of AuCl3 as a homogeneous
cycloisomerization catalyst was first reported by Hashmi
et al.9 Recently, few gold-catalyzed protocols for the syn-
thesis of dihydroisoxazoles10 and the isomeric oxazoles11
have emerged in the literature. We have studied the appli-
cation and catalytic effect of gold salts in various hetero-
Ph
Me
[Au]
Me
CH2Cl2, 30 °C, 30 min, N2
N
O
Ph
N
OH
2a
3a
Scheme 2 Effect of different gold catalysts on the cyclization of
acetylinic oxime 2a
We first tested the reaction of oxime 2a in the presence of
1 mol% AuBr3 in dichloromethane at room temperature
(Table 1). To our delight, the reaction proceeded well and
SYNLETT 2010, No. 5, pp 0777–0781
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219342; Art ID: G36809ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
3
.2
0
1
0

778
C. Praveen et al.
LETTER
SiMe3
SiMe3
+
SiMe3
AuCl3 (1 mol%)
Me
HO
Me
N
Me
HO
N
O
+
N
N
CH2Cl2, reflux,
30 min, N2
Me
SiMe3
OH
2n
2n'
3n
2n'
Scheme 3 Reaction of a mixture of oxime-isomers (2n and 2n¢) under gold catalysis
the product 3a was obtained in 72% yield (entry 1). To op- electron-withdrawing groups (entries 6 and 7). The reac-
timize the reaction conditions, other gold catalysts were tion conditions were also amenable to substituents pos-
explored. Treatment of oxime 2a with 1 mol% of a range sessing hydroxy and polyaromatic functionalities,
of cationic gold complexes led to product formation in although in these cases the products were formed in more
good yields (entries 2, 3 and 4). Gratifyingly, when 1 moderate yields (entries 8 and 10). Substrates possessing
mol% AuCl3 was used, an excellent yield (93%) of the a silyl group (2k and 2n) underwent cyclization only after
product was obtained (entry 5). The use of AuCl also led heating to reflux for 30 minutes. This may be due to the
to good yield of the product (entry 6). A control reaction presence of the electron-withdrawing silyl group, which
without any catalyst did not led to any product formation, renders the triple bond more electron-deficient, thus mak-
even when the reaction was carried out at reflux tempera- ing attack on the triple bond by the nucleophile (=NOH)
ture. Because the use of 1 mol% AuCl3 at room tempera- more difficult. The cycloisomerization of silyl oximes (2k
ture gave a better yield than with other catalysts for the and 2n) by our methodology seems to be superior, since
parent system, the scope of the reaction with this catalyst the silyl group was left intact, whereas using the related
was tested with a wide range of acetylenic oximes.15
K2CO3 method, desilylated products were obtained.11 One
of the noteworthy advantages of this methodology is the
cycloisomerization of oximes possessing a terminal
alkyne (2l), leading to 3-substituted isoxazole 3l. A simi-
lar type of cyclization has been reported that uses only in-
ternal alkynes to lead to the formation of 3,5-disubstituted
isoxazoles only.7c,d To test the efficacy of the cyclo-
isomerization, when a mixture of Z and E oximes (2n and
2n¢) were tested under the gold-catalyzed cyclization con-
ditions, we found that only the Z-isomer underwent the
cyclization and the E-isomer remained unreacted
(Scheme 3).
Table 1 Screening of Gold Catalysts for the Synthesis of Isoxazole 3a
Entry Catalyst
Yield (%)a
1
2
3
4
5
6
7
1 mol% AuBr3
72
65
68
60
93
80
1 mol% Me3PAuCl, 2 mol% AgBF4
1 mol% Ph3PAuCl, 2 mol% AgBF4
1 mol% Et3PAuCl, 2 mol% AgSbF6
1 mol% AuCl3
Formation of the isoxazole-products were characterized
by the appearance of a sharp singlet in the 1H NMR spec-
trum at dH = 6.2–6.8 ppm, which is characteristic of the
isoxazolinyl proton. Moreover, all the products exhibited
a 13C peak at dC = 170.0–170.9 ppm, which is characteris-
tic of the C5 carbon of the isoxazole ring.
1 mol% AuCl
b
no catalyst
–
a Isolated yield.
b The reaction was carried out at r.t. and at reflux temperature.
A mechanistic proposal for the formation of isoxazole is
given in Scheme 4. Thus, p-activation of carbophilic
AuCl3 with the triple bond of the oxime 1 leads to p-com-
plex 4. The latter species undergoes 5-endo-dig cycliza-
tion to afford the cyclized intermediate 5, which, upon
subsequent protodeauration, results in the formation of
isoxazole 3.
Under these optimized conditions, all the substrates tested
underwent the reaction completely and resulted in good
yields of the product (Table 2). However, the rate of the
reaction seems to be dependent on the substituents on the
substrates. Oximes having an electron-releasing group on
the alkyne residue (entries 1–5, 9, 13 and 15–18) more
readily underwent the cyclization than those possessing
[Au]
R2
R2
R1
R1
[Au]–
R2
R1
R1
[Au]
– [Au]
N
N
•
N
N
•
O
R2
O
H+
OH
OH
2
4
3
5
Scheme 4 Proposed mechanism for the gold(III)-catalyzed cycloisomerization of acetylenic oximes
Synlett 2010, No. 5, 777–781 © Thieme Stuttgart · New York

LETTER
Gold(III)-Catalyzed Synthesis of Isoxazoles
779
Table 2 Gold-Catalyzed Synthesis of Isoxazoles by Cycloisomerization of a,b-Acetylenic Oximesa
Entry
Acetylenic oxime 2
Isoxazole 3b
Time (min)
Yield (%)c
R1
R2
Ph
N
O
O
1
2
2a
2b
Me
Ph
3a
3b
10
10
92
94
Me
Ph
Ph
N
4-MeOC6H4
OMe
N
N
O
O
OMe
3
4
2c
2d
Ph
Ph
3-MeOC6H4
4-MeC6H4
3c
3d
Ph
Ph
10
10
91
95
Me
Me
N
N
N
O
O
O
5
6
7
2e
2f
Ph
Ph
3-MeC6H4
2-NCC6H4
4-FC6H4
3e
3f
10
20
20
93
82
83
Ph
Ph
Ph
CN
2g
Ph
Ph
3g
F
N
O
8
2h
6-methoxy-2-naphthyl
3h
15
81
Ph
OMe
N
O
9
2i
2j
4-MeC6H4
Me
3i
3j
10
25
90
78
Me
Me
Ph
N
N
O
10
Ph
2-hydroxybutyl
OH
Me
O
Et
11
12
13
14
2k
2l
Ph
SiPhMe2
H
3k
3l
30
25
10
30
75d
80
Me
SiMe2Ph
N
N
N
O
O
O
Ph
Ph
Ph
2m
2n
Me
Me
Ph
3m
3n
93
Ph
SiMe3
79d
Me
N
SiMe3
O
OMe
15
2o
H
3-MeOC6H4
3o
10
92
Synlett 2010, No. 5, 777–781 © Thieme Stuttgart · New York

780
C. Praveen et al.
LETTER
Yield (%)c
95
Table 2 Gold-Catalyzed Synthesis of Isoxazoles by Cycloisomerization of a,b-Acetylenic Oximesa (continued)
Entry
16
Acetylenic oxime 2
Isoxazole 3b
Time (min)
10
R1
R2
N
O
2p
H
4-MeC6H4
3p
Me
N
O
O
17
18
2q
2r
H
H
n-Pr
3q
10
10
89
88
N
n-Pent
3r
a All reactions were carried out at 30 °C in CH2Cl2 using 1 mol% AuCl3 under a nitrogen atmosphere.
b All products were characterized by IR, 1H NMR, 13C NMR and MS.
c Isolated yield.
d Reaction was carried out at reflux.
(4) (a) Takenaka, K.; Nakatsuka, S.; Tsujihara, T.; Koranne,
P. S.; Sasai, H. Tetrahedron: Asymmetry 2008, 19, 2492.
(b) Koranne, P. S.; Tsujihara, T.; Arai, M. A.; Bajracharya,
G. B. Suzuki T., Onitsuka K., Sasai H. Tetrahedron:
Asymmetry 2007, 18, 919.
(5) (a) Tanaka, M.; Haino, T.; Ideta, K.; Kubo, K.; Mori, A.;
Fukazawa, Y. Tetrahedron 2007, 63, 652. (b) Tanaka, M.;
Haino, T.; Ideta, K.; Kubo, K.; Mori, A.; Fukazawa, Y.
Tetrahedron Lett. 2004, 45, 2277. (c) Vieira, A. A.; Bryk,
F. R.; Conte, G.; Bortoluzzi, A. J.; Gallardo, H. Tetrahedron
Lett. 2009, 50, 905.
(6) (a) Wakefield, B. J. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations, Vol. 11; Shaumann,
E., Ed.; Georg Thieme Verlag: Stuttgart, 2001, 229–288.
(b) Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2005, 9,
925. (c) Jager, V.; Colinas, P. A. In Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products, Vol. 59; Padwa, A., Ed.; Wiley:
Hoboken, 2002, 361–472.
(7) (a) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. Org. Lett. 2009,
11, 3982. (b) Bourbeau, M. P.; Rider, J. T. Org. Lett. 2006,
8, 3679. (c) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7,
5203. (d) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72,
9643. (e) Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem.
2005, 70, 7761. (f) Girardin, M.; Alsabeh, P. G.; Lauzon, S.;
Dolman, S. J.; Ouellet, S. G.; Hughes, G. Org. Lett. 2009, 11,
1159. (g) Lautens, M.; Roy, A. Org. Lett. 2000, 2, 555.
(h) Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org.
Lett. 2008, 10, 1691. (i) Himo, F.; Lovell, T.; Hilgraf, R.;
Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin,
V. V. J. Am. Chem. Soc. 2005, 127, 210. (j) Grecian, S.;
Fokin, V. V. Angew. Chem. Int. Ed. 2008, 47, 8285. (k) Xu,
J. P.; Hamme, A. T. III Synlett 2008, 0919.
In summary, we have shown that gold(III) chloride effi-
ciently catalyzes the cycloisomerization of various a,b-
acetylenic oximes, leading to the formation of isoxazoles
in excellent yields. Further studies to extend the scope,
synthetic utility and application of the method to natural
product synthesis are in progress.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research,
New Delhi, India for the research fellowship.
References and Notes
(1) (a) Carlsen, L.; Dopp, D.; Dopp, H.; Duus, F.; Hartman, H.;
Lang-Fugmann, S.; Schulze, B.; Smalley, R. K.; Wakefield,
B. J. In Houben-Weyl Methods of Organic Chemistry, Vol.
E8a; Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart,
Germany, 1992, 45–204. (b) Sperry, J.; Wright, D. Curr.
Opin. Drug Discovery Dev. 2005, 8, 723.
(2) (a) Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli,
V. M. C.; Mangano, N. G.; Caruso, A. Arch. Pharm. Pharm.
Med. Chem. 1999, 332, 50. (b) Tomita, K.; Takahi, Y.;
Ishizuka, R.; Kamamura, S.; Nakagawa, M.; Ando, M.;
Nakanishi, T.; Nakamura, T.; Udaira, H. Ann. Sankyo Res.
Lab. 1973, 1, 25; Chem. Abstr. 1974, 80, 120808.
(c) Talley, J. J. Prog. Med. Chem. 1999, 13, 201. (d)Talley,
J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C.
M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer,
A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med.
Chem. 2000, 43, 775. (e) Giovannoni, M. P.; Vergelli, C.;
Ghelardini, C.; Galeotti, N.; Bartolini, A.; Kal Piaz, V.
J. Med. Chem. 2003, 46, 1055. (f) Li, W.-T.; Hwang, D.-R.;
Chen, C.-P.; Shen, C.-W.; Huang, C.-L.; Chen, T.-W.; Lin,
C.-H.; Chang, Y.-L.; Chang, Y.-Y.; Lo, Y.-K.; Tseng, H.-Y.;
Lin, C.-C.; Song, J.-S.; Chen, H.-C.; Chen, S.-J.; Wu, S.-H.;
Chen, C.-T. J. Med. Chem. 2003, 46, 1706.
(8) For reviews of gold-catalyzed organic reactions, see:
(a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed.
2006, 45, 7896. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180. (c) Amijs, C. H. M.; Ferrer, C.; Echavarren, A. M.
Chem. Commun. 2007, 698. (d) Fürstner, A.; Davies, P. W.
Angew. Chem. Int. Ed. 2006, 46, 3410. (e) Hoffmann-
Roder, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387.
(f) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2005, 44, 6990;
Angew. Chem. 2005, 117, 7150. (g) Núñez, E. J.;
(3) (a) Roy, A. K.; Rajaraman, B.; Batra, S. Tetrahedron 2004,
60, 2301. (b) Wankhede, K. S.; Vaidya, V. V.; Sarang, P. S.;
Salunkhe, M. M.; Trivedi, G. K. Tetrahedron Lett. 2008, 49,
2069.
Synlett 2010, No. 5, 777–781 © Thieme Stuttgart · New York

LETTER
Echavarren, A. M. Chem. Commun. 2007, 333.
Gold(III)-Catalyzed Synthesis of Isoxazoles
781
(12) (a) Praveen, C.; Sagayaraj, Y. W.; Perumal, P. T.
(h) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006,
4555. (i) Shen, H. C. Tetrahedron 2008, 64, 7847. (j) Shen,
H. C. Tetrahedron 2008, 64, 3885. (k) Li, Z.; Brouwer, C.;
He, C. Chem. Rev. 2008, 108, 3289. (l) Wang, M.-Z.;
Wong, M.-K.; Che, C.-M. Chem. Eur. J. 2008, 14, 8353.
(m) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.
Eur. J. 2008, 14, 8353. (n) Gorin, D. J.; Toste, D. Nature
2007, 446, 395. (o) Asao, N. Synlett 2006, 1645. (p) Ma, S.;
Yu, S.; Gu, Z. Angew. Chem. Int. Ed. 2006, 45, 200.
(q) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev. 2004,
33, 431. (r) Dyker, G. Angew. Chem. Int. Ed. 2000, 39,
4237. (s) Hashmi, A. S. K. Gold Bull. 2004, 37, 51.
(t) Ishida, T.; Haruta, M. Angew. Chem. Int. Ed. 2007, 46,
7154. (u) Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917.
(9) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem. Int. Ed. 2000, 39, 2285; Angew. Chem. 2000,
112, 2382.
(10) (a) Debleds, O.; Zotto, C. D.; Vrancken, E.; Campagne,
J.-M.; Retaileau, E. Adv. Synth. Catal. 2009, 351, 1991.
(b) Winter, C.; Krause, N. Angew. Chem. Int. Ed. 2009, 48,
6339. (c) Yeom, H.-S.; Lee, E.-S.; Shin, S. Synlett 2007,
2292.
(11) (a) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst,
T.; Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.;
Visus, J.; Rominger, F.; Frey, W.; Bats, J. W. Chem. Eur. J.
2009, DOI, 10.1002/chem.200902472. (b) Hashmi, A. S.
K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey, W. Eur. J.
Org. Chem. 2006, 4905. (c) Hashmi, A. S. K.; Salathé, R.;
Frey, W. Synlett 2007, 1763. (d) Hashmi, A. S. K.;
Weyruch, J. P.; Schymura, W.; Bats, J. W. Org. Lett. 2004,
6, 4391.
Tetrahedron Lett. 2009, 50, 644. (b) Praveen, C.; Kiruthiga,
P.; Perumal, P. T. Synlett 2009, 1990. (c) Praveen, C.;
Jegatheesan, S.; Perumal, P. T. Synlett 2009, 2795.
(d) Praveen, C.; Karthikeyan, K.; Perumal, P. T.
Tetrahedron 2009, 65, 9244.
(13) Short, K. M.; Ziegler, C. B. J. r. Tetrahedron Lett. 1993, 34,
75.
(14) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977,
1977. (b) Lin, C.-F.; Lu, W.-D.; Wang, I.-W.; Wu, M.-J.
Synlett 2003, 2057. (c) Kobayashi, T.; Tanaka, M. J. Chem.
Soc., Chem. Commun. 1981, 333. (d) Mohamed Ahmed,
M. S.; Mori, A. Org. Lett. 2003, 5, 3057. (e) Birkofer, L.;
Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96, 3280.
(15) Synthesis of 3-Methyl-5-trimethylsilylisoxazole (3);
Typical Procedure: To a solution of oxime 2n (500 mg,
3.22 mmol) in anhydrous CH2Cl2, was added AuCl3 (9.76
mg, 0.0321 mmol) under an N2 atmosphere and the solution
was stirred for the specified time (Table 2) at 30 °C. After
completion of the reaction (as indicated by TLC), the
reaction mixture was concentrated under reduced pressure
and purified by column chromatography over silica gel
(100–200 mesh) to afford pure product, 3-methyl-5-
trimethylsilylisoxazole (3n) as a yellow oil; IR (neat): 3302,
2912, 1604, 1419, 1338, 1085, 885, 757 cm–1. 1H NMR (500
MHz, CDCl3): d = 0.29 [s, 9 H, Si(CH3)3], 2.29 (s, 3 H,
CH3), 6.24 (s, 1 H, isoxazolinyl-H). 13C NMR (125 MHz,
CDCl3): d = –1.8, 10.8, 113.5, 157.7, 177.8. MS (EI): m/z =
172 [M]+. Anal. Calcd for C7H13NOSi: C, 54.15; H, 8.44; N,
9.02. Found: C, 53.95; H, 8.47; N, 9.15.
Synlett 2010, No. 5, 777–781 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.