Synthesis of 3,4-disubsituted isoxazoles via enamine [3+2] cycloaddition

Article abstract of DOI:10.1055/s-0032-1317923

Enamine-triggered [3+2]-cycloaddition reactions of aldehydes and N-hydroximidoyl chlorides in the presence of triethylamine give rise to 3,4-disubstituted isoxazoles upon oxidation of the cycloadduct 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihydroisoxazoles. This offers a high yielding, regiospecific and metal-free synthetic route for the synthesis of 3,4-disubstituted isoxazoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317923

LETTER
▌79
lSetyternthesis of 3,4-Disubsituted Isoxazoles via Enamine [3+2] Cycloaddition
Synthesis of 3,4-Disubstituted Isoxazoles
Qian-fa Jia,a Pooi Ming Shurn Benjamin,b Jiayao Huang,b Zhiyun Du,*a Xi Zheng,a Kun Zhang,a Allan H. Conney,a
Jian Wang*a,b
a
Allan H. Conney Laboratory for Anticancer Research, Guang Dong University of Technology, Guang Dong, 510006, P. R. of China
b
Department of Chemistry, National University of Singapore, Block S15, Level 5, 3 Science Drive 3, 117543, Singapore
Fax +65(677)91691; E-mail: chmwangj@nus.edu.sg
Received: 05.11.2012; Accepted after revision: 23.11.2012
O
O
Abstract: Enamine-triggered [3+2]-cycloaddition reactions of
aldehydes and N-hydroximidoyl chlorides in the presence of tri-
ethylamine give rise to 3,4-disubstituted isoxazoles upon oxidation
of the cycloadduct 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihy-
droisoxazoles. This offers a high yielding, regiospecific and metal-
free synthetic route for the synthesis of 3,4-disubstituted isoxazoles.
N
N
O
N
HN
Cl
O
NH
S
O
R
O
II
R
I
Key words: isoxazole, enamines, 1,3-dipoles, [3+2] cycloaddition
drug candidate for
liver fibrosis
antianaphylactic agent
R
F3C
Since Quilico and Claisen reported their methods,1,2 syn-
thetic methodologies that manipulate the synthesis of
isoxazoles have progressively gained awareness in organ-
ic synthesis. As one of the prominent medicinal scaffolds,
the isoxazole group is featured in a large number of phar-
maceutically important compounds and natural products.3
As exemplified in Figure 1, isoxazole compounds I–VI
exhibit some biologically and pharmacologically impor-
tant properties, such as anticancer, antianaphylactic, and
antitumor activity.3,4
O
N
O
N
HN
O
N
N
O
III
IV
cognitive enhancer
leflunomide
OH
HO
O
O
N
O
O
Although various synthetic methods for isoxazoles syn-
thesis have been developed,5 regioselective control of
isoxazole functionalization is still the main concern.
Moreover, synthetic methods that are available for 3,4-di-
substituted isoxazoles are currently rather scarce. Known
methods either require multiple steps,6 metal catalyst,7 or
give low yields.8 Therefore, there is an urgent need to de-
velop an efficient method for the synthesis of 3,4-disubsti-
tuted isoxazoles under mild conditions.9
N
NH
Cl
O
N
NH
H
O
HO
S
O
N
VI
V
NVP-AUY922,
anticancer drug
cloxacillin
Figure 1 Selected examples of bioactive isoxazole compounds
Our group has recently reported the use of enamines as di-
polarophiles to react with azide compounds to afford sub-
stituted 1,2,3-triazole compounds with high levels of
regioselectivities.10 Given that enamines formed in situ
from aldehydes are regiospecific, we envisioned that cy-
cloaddition of nitrile oxides with enamines may give rise
to the corresponding 3,4-disubstituted isoxazoles upon
oxidation of the cycloadduct 3,4,5-trisubstituted 5-(pyrro-
lidinyl)-4,5-dihydroisoxazoles generated in the first step
(Scheme 1). Herein, we wish to report a new metal-free
strategy for the facile synthesis of 3,4-disubstituted isoxa-
zoles that is based on this approach.
OH
Cl
O
N
N
O
Et3N
H
+
+
0 °C to r.t.
N
H
N
1a
2a
3a
4aa
Scheme 1 Enamine-promoted [3+2] cycloaddition reaction
Initial experiments were conducted to examine various re-
action parameters (Table 1). Reactions carried out in polar
solvents gave low yields, whereas high yields were
achieved in less polar solvent (Table 1, entries 1–4 vs. en-
tries 5–7). The substrate ratio 1a/2a/3a indicated that an
excess of 2a and 3a facilitated a higher yield (Table 1, en-
tries 12–15), probably due to a competitive self-aldol side
reaction. Lowering the concentration of 1a to 0.1 mol/L
allowed higher conversion and gave the desired product in
SYNLETT 2013, 24, 0079–0084
Advanced online publication: 10.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317923; Art ID: ST-2012-W0942-L
© Georg Thieme Verlag Stuttgart · New York

80
Q.-f. Jia et al.
LETTER
99% yield (Table 1, entry 11). Surprisingly, only one 99%; Scheme 2, 4aa–af and 4ai–ak).12,13 Examination of
trans-3,4-disubstituted diastereomer was generated.11 The a range of N-hydroxyimidoyl chlorides revealed that the
1H NMR spectrum of the crude product revealed that the reaction also tolerated a wide range of substituents
diastereomeric ratio (d.r.) was more than 19:1.
(Scheme 2, 1a–j), including phenyl, heterocyclic, and ali-
phatic groups, to give the corresponding 3,4,5-trisubstitut-
ed dihydroisoxazoles (77–98%; Scheme 2, 4bi–ii and
4ia).
We then investigated the use of secondary amines as cat-
alysts (Table 2). Six other secondary amines were
screened and it was found that pyrrolidine 3a gave the best
yield (99%; Table 2, entry 1). Reactions with 3c, 3e and Importantly, 3,4,5-trisubstituted 4,5-dihydroisoxazoles
3g did not afford the desired product.
can undergo Cope elimination by addition of m-chloro-
peroxybenzoic acid (MCPBA) to afford 3,4-disubstituted
isoxazoles in high yields [95 and 93%, respectively;
Scheme 3, eq. (1) and (2)]. We then examined the feasibil-
ity of using a direct one-pot process for the synthesis of
isoxazoles from 1a, 2a and 3a [Scheme 3, eq. (3)] and
found that 4aa could be obtained in a yield of 83%. How-
ever, five equivalents of MCPBA were required to allow
the reaction to reach completion. To this end, the develop-
Having the optimized conditions in hand, we examined
the substrate scope of the reaction (Scheme 2). Reactions
between a range of acetaldehydes and N-hydroxyimidoyl
chlorides gave good to high yields (77–99%; Scheme 2).
The reaction tolerated a broad range of functional groups
on both the acetaldehyde and N-hydroxyimidoyl chloride.
Acetaldehydes bearing aliphatic and aromatic groups
(Scheme 2, 2a–f and 2i–k) both gave high yields (82–
Table 1 Optimization of Reaction Conditionsa
OH
Cl
O
N
N
O
Et3N
H
+
+
N
H
0 °C to r.t.
N
1a
4aa
2a
3a
Entry
Solvent
Concn (mol/L)
Ratio
Yield (%)b,f
1a
2a
3a
1
2
Toluene
Et2O
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.1
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
1.0
4.0
2.0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.0
1.2
2.2
98
97
93
98
72
58
39
64
80
95
99
90
82
92
93
3
THF
4
CH2Cl2
MeCN
MeOH
Brine
5
6
7
c
8
CH2Cl2
d
9
CH2Cl2
10
11
12e
13
14
15
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.8 mmol, 4.0 equiv), 3a (0.44 mmol, 2.2 equiv), Et3N (0.2 mmol, 1.0 equiv), 0 °C (0.5 h),
r.t. (1.5 h).
b Yield of isolated product after column chromatography and diastereoisomeric ratio (all d.r. > 19:1) were determined by 1H NMR analysis of
the crude mixture.
c N-Hydroxybenzimidoyl chloride added in one portion.
d Reaction carried out at 40 °C for 1.5 h instead of room temperature.
e Without Et3N.
f The relative configuration of 4aa (trans-structure) was determined by X-ray crystal analysis.11
Synlett 2013, 24, 79–84
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3,4-Disubstituted Isoxazoles
81
ment of a more efficient and concise one-pot synthetic stituted isoxazoles that were previously accessed through
method is in progress in our laboratory.
either low-yielding methods or required transition-metal
catalysis can now be made through a metal-free, high-
yielding reaction under mild conditions.
To illustrate the broad synthetic utility of our developed
methodology, we undertook the formal synthesis of her-
pes virus replication inhibitor 7.14 Intermediate 4bi was Mechanistically, we propose that nitrile oxide D will be
easily transformed into 5bi through a Cope elimination generated from N-hydroxyimidoyl chloride A upon treat-
step (93%; Scheme 4). Compound 5bi was efficiently re- ment with base (Scheme 5). Enamine E is rapidly gener-
duced to 6bi in the presence of tin(II) chloride (98%; ated in situ when acetaldehyde B reacts with secondary
Scheme 4), and 6bi could be converted into the reported amine C. Subsequently, D will undergo an inverse-elec-
herpes virus replication inhibitor 7 following known tron-demand [3+2]-cycloaddition reaction with E, which
methods.10 Consequently, the presented method provides behaves as a dipolarophile, to form the cycloadduct F.
a convenient and high-yielding process for the synthesis The latter undergoes oxidation to form amine oxide G. Fi-
of 3,4-disubstituted isoxazoles, which are useful interme- nally, intermediate G will convert into target isoxazole H
diates for drug design and synthesis. Notably, 3,4-disub- through subsequent elimination (Scheme 5).
R1
N
O
O
OH
Cl
Et3N
N
+
+
N
H
R2
H
0 °C to r.t.
CH2Cl2
N
R1
R2
4
3a
1
2
O
O
O
OH
OH
Cl
OH
Cl
OH
Cl
N
N
N
Cl
N
C2H5
i-Pr
H
H
H
Cl
2c
2b
2a
O
O
O2N
Cl
O
1a
1b
1c
1d
n-C4H9
n-C3H7
n-C5H11
H
H
H
OH
OH
Cl
OH
Cl
OH
N
N
2d
O
2e
2f
OMe
N
N
N
O
S
O
H
Cl
Cl
H
H
1g
1h
1e
1f
2g
2h
2i
OH
Cl
N
O
O
O
H
H
H
1i
2j
2k
N
N
N
N
N
N
O
O
O
O
O
O
n-C5H11
N
n-C3H7
4ad, 82%
N
H
C2H5
n-C4H9
N
N
N
N
4af, 87%
4ae, 84%
4ab, 89%
4ac, 84%
4aa, 99%
O2N
Cl
Cl
N
N
N
N
O
N
N
O
O
O
O
O
N
N
N
N
N
N
N
N
O
4aj, 96%
4ai, 98%
4di, 81%
4bi, 83%
4ci, 80%
4ak, 95%
OMe
N
N
N
N
O
N
O
N
N
O
S
O
O
O
N
N
N
N
N
N
4ia, 97%
4ei, 86%
4gi, 81%
4ii, 98%
4fi, 83%
4hi, 77%
Scheme 2 Substrate scope. a Unless specified, see the experimental section for reaction conditions. b All d.r. > 19:1.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 79–84

82
Q.-f. Jia et al.
LETTER
Table 2 Effect of the Secondary Aminea
OH
Cl
O
N
N
R3
HN
O
Et3N
H
+
+
R4
0 °C to r.t.
CH2Cl2
N
R3
R4
1a
3a–g
4
2a
Ph
Ph
HN
Ph
COOH
CO2Et
N
H
N
H
N
H
N
N
N
H
Ph
H
H
OTMS
3a
3b
3d
3e
3g
3c
3f
Entry
Amine
Yield (%)b
Entry
Amine
Yield (%)b
[c]
1
2
3
4
3a
3b
3c
3d
99
76
5
6
7
3e
3f
–
37
[c]
[c]
–
3g
–
75
a Unless specified, see the experimental section for reaction conditions.
b Yield of isolated product after column chromatography; diastereoisomeric ratio > 19:1.
c No reaction.
N
N
O
O
MCPBA (1.5 equiv)
(1)
CH2Cl2 (0.5 M)
r.t., 4 h
N
5aa; 95%
4aa
O2N
O2N
N
N
MCPBA (1.5 equiv)
O
O
(2)
CH2Cl2 (0.5 M)
r.t., 4 h
N
4bi
5bi; 93%
OH
Cl
O
N
N
MCPBA
(5.0 equiv)
standard
conditions
O
H
(3)
+
+
N
H
1a
2a
3a
5aa; 83%
one-pot synthesis
Scheme 3
Notably, this methodology provides a regioselective route elimination step. Further investigations into the applica-
to 3,4-disubstituted isoxazoles. Due to the regiospecific tions of this enamine-promoted [3+2] strategy for the syn-
formation of the enamine from acetaldehyde, only one re- thesis of other important biological scaffolds are
gioisomer is finally formed in the 1,3-dipolar cycloaddi- underway.
tion process.
In conclusion, we have described a new synthetic route to
3,4,5-trisubstituted dihydroisoxazole through an en-
amine-promoted [3+2]-cycloaddition reaction under mild
conditions and high regioselectivities. These 3,4,5-trisub-
stituted dihydroisoxazoles can be rapidly converted into
3,4-disubstituted isoxazoles through a high-yielding Cope
Acknowledgment
The authors acknowledge financial support from the Ministry of
Education and National Research Foundation (Singapore) (MOE
R143000443112, R143000480112 and NRF-CRP7-2010-03).
Synlett 2013, 24, 79–84
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3,4-Disubstituted Isoxazoles
83
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H2N
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N
N
1. SnCl2, HCl
EtOH, reflux
O
O
MCPBA (1.5 equiv)
4bi
CH2Cl2 (0.5 M)
r.t., 4 h
2. H2O, r.t.
5bi; 93%
6bi; 98%
ref. 10
(5) For selected examples of 3,5-disubstituted isoxazole
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O
N
R2
S
N
N
H
H
R1
7
herpes virus replication inhibitor
Scheme 4 Synthesis of herpes virus replication inhibitor 7
R1
O
N
OH
Cl
O
N
+
H
R1
R2
R2
B
A
H
R3
HN
Et3N
C
R4
(8) Schmitt, D. C.; Lam, L.; Johnson, J. S. Org. Lett. 2011, 13,
5136.
– HONR3R4
+
(9) For other synthetic methods of isoxazolines and isoxazoles,
see: (a) Perez, C.; Janin, Y. L.; Adams, D. R.; Monneret, C.;
Grierson, D. S. J. Chem. Soc., Perkin Trans. 1 1997, 901.
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Pocar, D.; Trimarco, P. Chem. Ber. 1987, 120, 1797.
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Filapek, M.; Danikiewicz, W.; Kania, M.; Gębarowska, K.;
Grudzka, I. Tetrahedron 2010, 66, 5972. (e) de Almeida, V.
M.; dos Santos, R. J.; da Silva Góes, A. J.; de Lima, J. G.;
Correia, C. R. D.; de Faria, A. R. Tetrahedron Lett. 2009, 50,
684. (f) Krompiec, S.; Bujak, P.; Szczepankiewicz, W.
Tetrahedron Lett. 2008, 49, 6071. (g) Brooking, P.;
Crawshaw, M.; Hird, N. W.; Jones, C.; MacLachlan, W. S.;
Readshaw, S. A.; Wilding, S. W. Synthesis 1999, 1986.
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Corsico, A.; Corsaro, A.; Del Monte, D.; Marinone Albini,
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(10) (a) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J.
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(11) CCDC-876696 (4aa) contains the supplementary
crystallographic data for this paper. These data can be
ontained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(12) Synthesis of 4aa–ia; General Procedure: Pyrrolidine 3a
(74.5 μL, 0.88 mmol) and Et3N (53.9 μL, 0.4 mmol) was
dissolved in CH2Cl2 (4 mL), the mixture was cooled to 0 °C
Et3NHCl–
H2O
R3
O
R4
N
O
N
O
R4
N
R4
N
N
+
R1
R2
N
R3
R1
C
R1
H
R3
R2
O
H
R2
D
E
F
G
Scheme 5 Proposed mechanism
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 79–84

84
Q.-f. Jia et al.
LETTER
and isovaleraldehyde 2a–i (173.9 μL, 1.6 mmol) was added.
Immediately afterwards, N-hydroxybenzimidoyl chloride 1a
(62.2 mg, 0.4 mmol) in CH2Cl2 (0.2 mL) was added in five
portions in five-minute intervals. After complete addition of
N-hydroxybenzimidoyl chloride, the reaction mixture was
stirred for a further 10 min at 0 °C, after which, it was
allowed to warm to r.t. slowly and stirred for another 1.5 h.
The reaction was then stopped and the product was purified
by flash column chromatography with silica gel (EtOAc–
hexane, 10%) to afford 4aa–ia.
MHz, CDCl3): δ = 7.75–7.69 (m, 2 H), 7.48–7.41 (m, 3 H),
5.41 (d, J = 2.7 Hz, 1 H), 3.40 (dd, J = 3.5, 2.8 Hz, 1 H),
2.91–2.68 (m, 4 H), 2.22–2.13 (m, 1 H), 1.83–1.78 (m, 4 H),
1.10 (d, J = 6.9 Hz, 3 H), 0.83 (d, J = 6.9 Hz, 3 H); 13C NMR
(75 MHz, CDCl3): δ = 157.2, 129.6, 128.8, 126.8, 95.3, 56.2,
46.9, 28.1, 23.8, 20.6, 17.1; HRMS (ESI): m/z [M + H]+
calcd for C16H23N2O: 259.1805; found: 259.1812.
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