Microwave promoted oxazole synthesis: Cyclocondensation cascade of oximes and acyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2005.06.063

Microwave irradiation promotes the rapid O,N-acylation-cyclodehydration cascade reaction of oximes and acid chlorides to give oxazoles.

Full text of DOI:10.1016/j.tetlet.2005.06.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5463–5466
Microwave promoted oxazole synthesis: cyclocondensation
cascade of oximes and acyl chlorides
Peter Wipf,* Joan M. Fletcher and Laura Scarone
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 18 May 2005; revised 10 June 2005; accepted 14 June 2005
Available online 1 July 2005
Abstract—Microwave irradiation promotes the rapid O,N-acylation–cyclodehydration cascade reaction of oximes and acid chlo-
rides to give oxazoles.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Oxazoles are key building blocks of natural products,
pharmaceuticals, and synthetic intermediates.1 They
are most commonly obtained by the Hantzsch reaction2
or the cyclodehydration of b-ketoamides.3 The dehydro-
genation of oxazolines4 and other processes such as aza-
Wittig reactions,5 Schmidt rearrangements,6 the use of
isocyanides,7 TosMIC,8 and intramolecular alkyne addi-
tions9 have also been employed. An interesting conver-
sion of ketoximes to oximes via N,N-diacylated
enamides was reported in 1980 by Bhat and Reddy
(Scheme 1).10 While, quite likely due to the harsh ther-
mal and acidic conditions and long reaction times this
reaction was rarely applied,11 we were intrigued by the
possibility to optimize this procedure and generate con-
ditions for a streamlined process in the microwave
reactor.
with various ketones in a household microwave to form
a-[(2,4-dinitrobenzene)sulfonyl]oxy ketones, which are
converted to oxazoles through treatment with amides.13a
Similarly, reacting ketones with benzonitrile and mer-
cury(II) p-toluenesulfonate yielded substituted oxazoles
in the microwave.13b Our first attempts of employing
Malamas et al.Õs conditions11 for converting oxime 1
to oxazole 3 with acid chloride 2 under microwave irra-
diation at various temperatures in pyridine/toluene
(5.6:1) did not lead to oxazole formation (Scheme 2,
Table 1). We switched to 1,2-dichlorobenzene, a more
polar solvent that was better suited for microwave
irradiation, and catalytic DMAP was added in an
attempt to facilitate acyl transfer processes. Several
temperatures and various reaction times were explored
until we obtained moderate isolated yields of oxazole.
Both thermal and microwave reactions failed with anhy-
drides or acyl imidazoles, but under optimized micro-
wave conditions, a range of oximes and acyl chlorides
were converted to the desired heterocycles (Scheme 3,
Table 2).14 While the yields were variable, the scope of
oxime substituents was quite broad, and both cyclic
Microwave chemistry is becoming increasingly popu-
lar;12 however, there are few examples of oxazole forma-
tions using microwave irradiation. Lee et al. developed a
solvent free method in which [hydroxy-(2,4-di-
nitrobenzenesulfonyloxy)iodo]benzene (HDNIB) reacts
O
O
NOH
R2
Pyridine, Ac2O
AcCl, 100 °C
HCl (g), 100 °C
N
O
N
R1
OAc
R1
R1
R2
50-80%
R2
Scheme 1. Oxazole synthesis from ketoximes and acetyl chloride under conventional conditions.10
Keywords: Microwave; Oximes; Oxazoles; Cascade reaction; Rearrangement.
*
Corresponding author. Tel.: +1 412 6248606; fax: +1 412 6240787; e-mail: pwipf@pitt.edu
0040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.063

5464
P. Wipf et al. / Tetrahedron Letters 46 (2005) 5463–5466
OH
Br
O
N
solvent
N
Cl
conditions
F3C
F3C
O
Br
1
2
3
Scheme 2. Cyclocondensation of oxime 1 and acyl chloride 2 leading to oxazole 3.
Table 1. Reaction optimization for microwave promoted oxazole formation
Entry
Solvent (v/v)
Conditions
Additive
3 (Yield/%)b
1
Pyridine/toluene (5.6:1)
Pyridine/toluene (5.6:1)
1,2-Dichlorobenzene
1,2-Dichlorobenzene
100 ꢁC, 24 h
—
—
—
2
lW, 180 ꢁC, 10 min
lW, 115 ꢁC, 30 min
lW, 160 ꢁC, 45min
lW, 180 ꢁC, 10 min
lW, 220 ꢁC, 5min
—
3
DMAPa
DMAP a
DMAPa
DMAP a
—
16
4
51,2-Dichlorobenzene
6
34
Trace
1,2-Dichlorobenzene
a 6.3 mol % of DMAP was used.
b Isolated yields after chromatography on SiO2.Yields are based on oximes.
R1
oxazole formation also failed for reasons that are not yet
clear.
HO
R1
N
O
O
1,2-dichlorobenzene
6.3 mol% DMAP
N
+
R3
R2
R3
Cl
R2
µW irradiation
In addition to a much faster conversion, the major
advantage of microwave irradiation was a considerably
increased yield. Control reactions with oxime 13 and
acid chloride 2 under a range of thermal and optimized
microwave conditions shown in Table 3 illustrate the
improvement in the reaction process using microwave
technology.
10 min, 180 ˚C
Scheme 3. Oxazole formation under microwave irradiation (lW)
conditions.
and acyclic, aromatic and aliphatic ketoximes work
well. Some of the starting material was recovered, but
most of the remaining mass balance was converted into
intractable polar side products. Interestingly, we found
that the yield was higher for the more readily enolizable
oximes. This is particularly well illustrated in entries 7
and 8 in Table 2. In addition, we found that methyl
aryl ketone derived oximes did not provide oxazoles
under either thermal or microwave conditions. In the
presence of carboxyl groups with enolizable a-positions,
In conclusion, we have investigated the scope of the
preparation of substituted oxazoles from oximes and
acid chlorides and improved this methodology by using
a monomode microwave generator. The microwave irra-
diation allowed considerable acceleration of the rate of
oxazole formation and increased the yield of this syn-
thetically attractive heterocycle formation process. The
starting oximes were readily obtained from commer-
Table 2. Oxazole preparations under optimized microwave irradiation conditions15
Entry
R1
R2
Oxime
R3
Oxazole
Yield (%)a
1
p-BrC6H4
p-BrC6H4
p-BrC6H4
Et
Me
Me
Me
Me
1
1
p-CF3C6H4
Ph
t-Butyl
3
4
34
26
26
53
38
53
23
62
2
3
1
5
4
6
p-CF3C6H4
p-CH3OC6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
7
5Et
6
Me
6
8
i-Propyl
Ph
Me
Me
Me
Ph
9
10
12
14
7
11
13
8
9
15
15
15
p-CF3C6H4
16
17
18
38
28
25
10
11
BnOCH2
C6H5CH@CH
12
19
p-CF3C6H4
20
40
a Isolated yields after chromatography on SiO2. Yields are based on oximes.

P. Wipf et al. / Tetrahedron Letters 46 (2005) 5463–5466
5465
Table 3. Comparison of thermal and microwave conditions for the conversion of oxime 13 and acid chloride 2 to oxazole 14
Entry
Solvents
Time
Temperature
14 (Yield/%)a
1
2
3
4
Toluene/pyridine, 5.6:1 (v/v)
Toluene/pyridine, 5.6:1 (v/v)
1,2-Dichlorobenzene
24 h
12 h
100 ꢁC
30
34
43
62
120 ꢁC
10 min
10 min
180 ꢁCb
1,2-Dichlorobenzene
180 ꢁC (lW)
Entries 1–3 are under standard thermal conditions.
a Isolated yields after chromatography on SiO2. Yields are based on oximes.
b A sand bath was preheated to 180 ꢁC.
2501–2504; (d) Wipf, P.; Aoyama, Y.; Benedum, T. E.
Org. Lett. 2004, 6, 3593; (e) Wipf, P.; Graham, T. H. Org.
Biomol. Chem. 2005, 3, 31; (f) Milton, M. D.; Inada, Y.;
Nishibayashi, Y.; Uemura, S. Chem. Comm. 2004,
2712.
cially available ketones in yields exceeding 90%, and the
yields of isolated oxazoles ranged from 23% to 62%.
Acknowledgments
10. Bhatt, M. V.; Reddy, G. S. Tetrahedron Lett. 1980, 21,
2359.
11. Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu,
W.; McDevitt, R.; Adebayo, F. O.; Sawicki, D. R.;
Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med. Chem.
2000, 43, 1293.
This work was supported by the National Institutes of
Health (GM-55433).
References and notes
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in a solution of hydroxylamine hydrochloride and ethanol/
water at reflux according to literature protocols: (a)
Harada, T.; Ohno, T.; Kobayashi, S.; Mukaiyama, T.
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Reactions, and Spectroscopy; J. Wiley & Sons: Hoboken,
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J.; Liu, J.; Petrillo, D. E.; Leone, J. F.; Laquidara, J.;
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Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61, 6496.
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15. In a typical procedure, oxime (1.0 equiv) and acid chloride
(2.5equiv) were added to 1,2-dichlorobenzene to give a
2.5M solution. After addition of 6.3 mol % of DMAP, the
reaction mixture was heated in the microwave for 10 min
at 180 ꢁC (150 W), poured into water, extracted with ethyl
acetate, dried (MgSO4), and concentrated. The residue
was purified using chromatography on SiO2 to afford the
pure oxazole. 4-Ethyl-5-methyl-2-(4-trifluoromethylphen-
yl)-oxazole (7). To a solution of 3-pentanone oxime 6 (37.4
mg, 0.370 mmol) and DMAP (2.40 mg, 0.0196 mmol) in
1,2-dichlorobenzene (0.140 mL) at 0 ꢁC was added drop-
wise 4-trifluoromethylbenzoyl chloride (140.0 lL, 0.915
mmol). The reaction mixture was heated in the microwave
for 10 min at 180 ꢁC (150 W) and poured into water
(5mL). The aqueous layer was extracted with ethyl acetate
(3 · 10 mL) and the combined organic layers were dried
(MgSO4) and concentrated. The crude residue was purified
by chromatography on SiO2 (hexanes/EtOAc, 20:1) to give
(50.0 mg, 53%) of 7 as a colorless solid: mp 57.0–58.8 ꢁC
(hexanes/EtOAc); IR (neat) 2965, 2931, 1617, 1414, 1329,
1
1322, 1298 cmÀ1; H NMR 8.10 (d, 2H, J = 8.2 Hz), 7.68
(d, 2H, J = 8.3 Hz), 2.54 (q, 2H, J = 7.6 Hz), 2.36 (s, 3H),
1.26 (t, 3H, J = 7.5Hz); 13C NMR 157.8, 143.8, 138.3,
131.1 (q, J = 32.3 Hz), 131.0, 126.0, 125.7, 124.0 (q,
J = 270.7 Hz), 19.2, 13.7, 10.2; MS (EI) m/z (rel intensity)
255 (M+, 100), 240 (96), 173 (21), 172 (42), 145(17);
HRMS (EI) m/z calcd for C13H12F3NO 255.0871, found
255.0874. 2-Styryl-4,5,6,7-tetrahydrobenzoxazole (18). To
a solution of cyclohexanone oxime 15 (28.0 mg, 0.250
mmol) and DMAP (2.00 mg, 0.0163 mmol) in 1,2-dichloro-
benzene (0.100 mL) at 0 ꢁC was added cinnamoyl chloride
(105.0 mg, 0.630 mmol). The reaction mixture was heated
in the microwave for 10 min at 180 ꢁC (150 W) and poured
8. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen,
A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516.
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1989, 26, 269; (b) Wipf, P.; Rahman, L. T.; Rector, S. R. J.
Org. Chem. 1998, 63, 7132; (c) Arcadi, A.; Cacchi, S.;
Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3,

5466
P. Wipf et al. / Tetrahedron Letters 46 (2005) 5463–5466
into water (5mL). The aqueous layer was extracted with
3H), 7.42–7.28 (m, 3H), 6.89 (d, 1 H, J = 16.4 Hz), 2.73–
2.63 (m, 2H), 2.62–2.52 (m, 2H), 1.98–1.79 (m, 4H); 13C
NMR d 159.8, 146.8, 136.1, 135.5, 134.4, 128.9, 128.8,
127.1, 114.5, 23.2, 23.1, 23.0, 22.1; MS (EI) m/z (rel
intensity) 225(M +, 62), 224 ([MÀH]+, 100), 196 (25), 168
(9), 115(61); HRMS (EI) m/z calcd for C15H14NO
224.1075(M ÀH), found 224.1075.
ethyl acetate (3 · 10 mL) and the combined organic layers
were dried (MgSO4) and concentrated. The crude residue
was purified by chromatography on SiO2 (hexanes/EtOAc,
4:1) to give (14.0 mg, 25%) of 18 as a yellow solid: mp 113–
115 ꢁC (hexanes/EtOAc); IR (neat) 2927, 2846, 1701, 1639,
1546, 1525, 1493, 1444 cmÀ1 1H NMR d 7.55–7.47 (m,
;