A new approach to the synthesis of 2-aryl-4-halomethyl-5-methyl-1,3- oxazoles by highly regioselective direct halogenation with NBS or NCS/MeCN

Article abstract of DOI:10.1055/s-2004-834862

A simple and efficient method for the synthesis of 2-aryl-4-bromomethyl-5- methyl-1,3-oxazoles 2 and 2-aryl-4-chloromethyl-5-methyl-1,3-oxazoles 3 is described. The reaction of 2-aryl-4,5-dimethyl-1,3-oxazoles 1 with N-bromosuccinimide and N-chlorosuccini

Full text of DOI:10.1055/s-2004-834862

PAPER
2825
A New Approach to the Synthesis of 2-Aryl-4-halomethyl-5-methyl-1,3-oxa-
zoles by Highly Regioselective Direct Halogenation with NBS or NCS/MeCN
S
ynthesis of 2-A
a
ryl-4-halo
i
methyl
h
-5-methyl-1,3
e
-oxazole
s
i Yamane,* Hiroyuki Mitsudera, Takatsugu Shundoh
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited, Osaka, 532-8686,
Japan
Fax +81(6)63006251; E-mail: Yamane_Taihei@takeda.co.jp
Received 29 June 2004; revised 30 July 2004
O
Abstract: A simple and efficient method for the synthesis of 2-aryl-
N
4-bromomethyl-5-methyl-1,3-oxazoles 2 and 2-aryl-4-chlorometh-
POCl3 / CHCl3
Ar
yl-5-methyl-1,3-oxazoles 3 is described. The reaction of 2-aryl-4,5-
dimethyl-1,3-oxazoles 1 with N-bromosuccinimide and N-chloro-
O
succinimide in acetonitrile under mild conditions provides 4-ha-
lomethyl isomers with exceptionally high regioselectivity in
moderate to good yields.
X
4
N
Br2 / CCl4
N
Ar
5
O
Ar
Ar
Key words: oxazoles, halogenation, regioselectivity, heterocycles,
drugs
O
2 (X = Br)
3 (X = Cl)
?
N
Because of the important pharmacological activity of 1,3-
oxazoles (also known simply as oxazoles), general and ef-
ficient methods for their preparation are continually being
developed and new methods are required to meet the de-
mands to synthesize a wide variety of substituted ox-
O
1
Scheme 1 Selected synthetic routes to 2-aryl-4-halomethyl-5-me-
thyloxazoles 2 and 3
azoles.1
Among
them,
2-aryl-4-halomethyl-5-
methyloxazoles 2 and 3 appear as key intermediates in the
synthesis of biologically and pharmaceutically useful
molecules such as agonists of peroxisome proliferator-ac-
tivated receptors (PPARs),2 dipeptidyl peptidase IV
(DPP-IV) inhibitors,3 protein tyrosine phosphatase 1B
(PTP1B) inhibitors4 and 5-lipoxygenase (5-LO) inhibi-
tors.5
azoles with bromine in benzene, but it required several
steps to afford 2 (33% yield) from 2-aryl-4,5-dimethylox-
azoles, the regiochemical outcome of this reaction has not
been detailed and it has been reported that the chlorination
does not proceed.8
In our pursuit of an efficient method of synthesizing 2 and
3, we were intrigued with the possibility of the direct ha-
logenation of 2-aryl-4,5-dimethyloxazoles 1. Previously
we have reported the highly C4-methyl regioselective ha-
logenation of 2-aryl-4,5-dimethyl-1,3-thiazoles with NBS
or NCS in acetonitrile under mild conditions. The proto-
col works well with a variety of 2-aryl-4,5-dimethyl-1,3-
thiazoles.9
Despite the versatility of these compounds, only a few
methods for the synthesis of 2 and 3 are known
(Scheme 1). The most common approach disclosed by
Goto et al. involves the use of 2-aryl-4,5-dimethyloxazole
N-oxides, which upon treatment with POCl3 affords 2-
aryl-4-chloromethyl-5-methyloxazoles 3 (77–84% yield).
The synthesis of 2-aryl-4,5-dimethyloxazole N-oxides
was accomplished by the reaction of butane-2,3-dione
monoxime with benzaldehyde by bubbling HCl gas in an
acetic acid solution (84–90% yield).6 On the other hand,
Overman et al. reported that the bromination of 2-aryl-4-
methylene-4,5-dihydrooxazoles, which were synthesized
by a two-step sequence from but-3-yn-2-ol (60–90%
yield), with bromine furnished 2 (88% yield).7
As a continuation of our work in this field, we present a
general and practical method, which allows a highly C4-
methyl regioselective halogenation of readily accessible
2-aryl-4,5-dimethyloxazoles 1.
The compounds for our studies were a range of 2-aryl-4,5-
dimethyloxazoles 1a–l. These were conveniently pre-
pared in 31–63% yield by esterification of benzoic acids
with acetoin using 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride (EDAC-HCl) and a catalytic
amount of 4-(dimethylamino)pyridine (DMAP) in DMF
followed by cyclization with NH4OAc in refluxing acetic
acid (Scheme 2).10,11
Another technique involves the direct halogenation of 2-
aryl-4,5-dimethyloxazoles 1, however, relatively little at-
tention has been paid to this method. Gompper and Rühle
have reported the bromination of 2-aryl-4,5-dimethylox-
A brief analysis of the reaction conditions for the bromi-
nation of 1a revealed that the reactions with NBS (1.0
equiv) in acetonitrile at 25 °C gave 2a in a highly regiose-
SYNTHESIS 2004, No. 17, pp 2825–2832
Advanced online publication: 07.10.2004
DOI: 10.1055/s-2004-834862; Art ID: F09604SS
x
x.
x
x
.
2
0
0
4
© Georg Thieme Verlag Stuttgart · New York

2826
T. Yamane et al.
PAPER
O
Attention was next turned to the chlorination with NCS.
Once again, a successful C4-methyl-selective halogena-
tion of 2-aryl-4,5-dimethyloxazole 1a was achieved using
NCS (1 equiv) in acetonitrile at 60 °C and the compound
was isolated directly as a crystalline solid of 3a in 64%
yield by just adding water to the reaction mixture
(Table 2, entry 1). Similarly, the regioselectivity of the
crude reaction mixture as well as the isolated product was
also considerably high. As expected, the synthesis worked
well for a variety of aryl groups. The chlorides 3b–l were
also isolated with high regioselectivity and moderate to
good yield (Table 2, entry 2–12). The reactions were usu-
ally complete within 4–8 hours.
OH
O
O
O
CH3COONH4
EDAC–HCl
N
Ar
DMAP
DMF
CH3COOH
reflux, 8 h
Ar
OH
O
Ar
O
r.t., overnight
1
Scheme 2 Preparation of 1
lective manner12,13 in 73% yield (Table 1, entry 1). The
scope of the reaction was assessed using a structurally di-
verse set of 2-aryl-4,5-dimethyloxazoles 1b–k. In all cas-
es, isolation of the product was achieved in a
straightforward fashion by adding water to the crude reac-
tion mixture affording precipitates of 2-aryl-4-bromo-
methyl-5-methyloxazoles 2b–k in moderate to good
yields (Table 1, entry 2–11). The reactions were usually
complete within 1–2 hours.
Table 2 Chlorination of 2-Aryl-4,5-dimethyloxazoles
Cl
N
N
N
Cl
NCS (1 equiv)
+
Ar
Ar
O
O
Ar
MeCN
60 °C
O
3
regioisomer of 3
1
(minor)
(major)
Table 1 Bromination of 2-Aryl-4,5-dimethyloxazoles
Entry Substrate (Ar =)
Yield (%)a Regioselectivity (%)b,c
Br
N
N
NBS (1 equiv)
N
1
2
Ph (1a)
64 (3a)
68 (3b)
47 (3c)
71 (3d)
76 (3e)
63 (3f)
52 (3g)
57 (3h)
45 (3i)
70 (3j)
54 (3k)
48 (3l)
>99 (>99)
>99 (>99)
>99 (97)
98 (98)
Br
+
Ar
Ar
Ar
MeCN
25 °C
p-tBuC6H4 (1b)
p-PhC6H4 (1c)
2-naphthyl (1d)
p-BrC6H4 (1e)
p-ClC6H4 (1f)
m-BrC6H4 (1g)
m-ClC6H4 (1h)
3,4-Cl2C6H3 (1i)
2,4-Cl2C6H3 (1j)
p-CF3C6H4 (1k)
O
O
O
2
regioisomer of 2
1
3
(major)
(minor)
Yield (%)a Regioselectivity (%)b,c
4
Entry Substrate (Ar =)
5
97 (97)
1
2
Ph (1a)
73 (2a)
68 (2b)
70 (2c)
71 (2d)
70 (2e)
75 (2f)
78 (2g)
78 (2h)
80 (2i)
65 (2j)
64 (2k)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
98 (98)
p-tBuC6H4 (1b)
p-PhC6H4 (1c)
2-naphthyl (1d)
p-BrC6H4 (1e)
p-ClC6H4 (1f)
m-BrC6H4 (1g)
m-ClC6H4 (1h)
3,4-Cl2C6H3 (1i)
2,4-Cl2C6H3 (1j)
p-CF3C6H4 (1k)
6
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
7
3
8
4
9
5
10
11
12
6
7
3,4,5-(MeO)3C6H2
(1l)
8
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
9
a Yields refer to single runs and are given for isolated products expect
for entry 8 (recrystallized from MeCN–H2O).
10
11
b Regioselectivity was determined for isolated products by a HPLC
analysis (YMC Pack-SIL A-002 column with 40:1 n-hexane/THF as
the mobile phase).
c Regioselectivity in crude reaction mixtures determined by a HPLC
analysis (the same conditions for isolated products) is shown in paren-
theses.
a Yields refer to single runs and are given for isolated products.
b Regioselectivity was determined for isolated products by a HPLC
analysis (YMC Pack-SIL A-002 column with 40:1 n-hexane/THF as
the mobile phase).
c Regioselectivity in crude reaction mixtures determined by a HPLC
analysis (the same conditions for isolated products) is shown in paren-
theses.
Although the reactions required a higher temperature
(60 °C) and longer reaction time (4–8 h) than the bromi-
nation (25 °C, 1–2 h), identical reactivity trends as for the
bromination were observed.
The regioselectivity of not only the isolated compounds
but also the crude reaction mixtures was uniformly high,
irrespective of the aryl substituents present in substrate 1.
A plausible explanation of the regioselective halogenation
is depicted in Scheme 3. One possibility is that the reac-
tion proceeds via the formation of an addition product 4 to
the 4,5-double bond of an oxazole ring.14
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aryl-4-halomethyl-5-methyl-1,3-oxazoles
2827
Path B (minor)
Path A (major)
O
O
O
O
N
N
N
N
O
H
4
4
O
4
O
N
N
N
O
N
O
N
X
X
X
H
Ar
Ar
5
+
N
X
5
Ar
O
X
Ar
Ar
5
O
O
O
O
1
O
4
4
X
X
X
X
N
N
N
N
N
N
X
+
Ar
X
Ar
Ar
Ar
Ar
O
X
O
Ar
O
O
O
O
2, 3
5
X
(X = Br, Cl)
Scheme 3 Plausible reaction mechanism for the formation of 2 and 3 and their regioisomers
solution of the residual brown liquid in AcOH (× 6.7 v/w of aryl car-
boxylic acid) was added NH4OAc (28.75 g, 0.373 mol) and the mix-
ture was refluxed for 8 h and evaporated in vacuo. H2O (× 10 v/w of
aryl carboxylic acid) was added dropwise at r.t. to give a white to
pale yellow precipitation (1c–l). The precipitate was filtered,
washed with H2O (× 3 v/w of aryl carboxylic acid) and dried to af-
ford the corresponding 4,5-dimethyl-2-phenyloxazoles 1. [In the
case of 1a and 1b, H2O and EtOAc were added to the evaporated
residue. The aqueous layer was extracted with EtOAc and the com-
bined organic layers were washed with brine, dried (Na2SO4) and
evaporated in vacuo to give brown oil. The residue was purified by
column chromatography on silica gel using EtOAc and n-hexane
(3:7) to give 1a or 1b as pale yellow oil.]
According to this hypothesis, the halogenation occurs at
the 4,5-double bond of compound 1 in the first step of the
reaction to generate a halonium intermediate 4, which is
much more likely to give a C5-halogenated derivative
(Path A) than a C4-halogenated derivative (Path B) via a
ring opening reaction of the halonium 3-membered ring.
Loss of a proton and a halogen anion and subsequent at-
tack of a halogen anion to a C4 exomethylene site of an
oxonium intermediate 5 might furnish the compound 2 or
3 predominantly. However, none of the foregoing inter-
1
mediates was detected by either a HPLC analysis or H
NMR spectroscopy.
Bromides 2; General Procedure
The facile preparation of 2 and 3 is of interest to synthetic
and medicinal chemists. In this paper, we have presented
a highly regioselective and efficient method that allows
for the synthesis of 2-aryl-4-bromomethyl-5-methylox-
azoles 2 and 2-aryl-4-chloromethyl-5-methyloxazoles 3
utilizing the 2-aryl-4,5-dimethyloxazoles 1 readily pre-
pared from aryl carboxylic acid and acetoin. Since this
process involves no complicated operation, it should fre-
quently be the method of choice for the preparation of 2-
aryl-4-halomethyl-5-methyloxazoles.
To a solution of 2-aryl-4,5-dimethyl-1,3-oxazole 1 (22.1 mmol) in
MeCN (× 10 v/w of 1) was added NBS (3.93 g, 22.1 mmol) and the
reaction mixture was stirred at 25 °C for 1–2 h. To the mixture was
added H2O (× 5–10 v/w of 1) dropwise at r.t. to give a white to pale
yellow precipitation. The mixture was stirred at 0–5 °C for 1 h. The
precipitate was filtered and washed with H2O (× 3 v/w of 1) to af-
ford the corresponding bromides 2.
Chlorides 3; General Procedure
To a solution of 2-aryl-4,5-dimethyl-1,3-oxazole 1 (22.1 mmol) in
MeCN (× 10 v/w of 1) was added NCS (2.95 g, 22.1 mmol) and the
reaction mixture was stirred at 60 °C for 4–8 h. To the mixture was
added H2O (× 5–10 v/w of 1) dropwise at r.t. to give a white to pale
yellow precipitation. The mixture was stirred at 0–5 °C for 1 h. The
precipitate was filtered and washed with H2O (× 3 v/w of 1) to af-
ford the corresponding chlorides 3.
Melting points were determined on a Büchi 530 melting point appa-
ratus in open capillaries, and are uncorrected. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded on a Bruker DPX–
300 300 MHz spectrometer at r.t. 1H NMR spectra are reported as
follows: chemical shifts in ppm (d) downfield from tetramethylsi-
lane as an internal standard, multiplicity, integration and coupling
constants spectra (Hz). 13C NMR spectra are reported in ppm (d) rel-
ative to the central line of the triplet for CDCl3 at 77 ppm. All com-
mercial chemicals and solvents used were of reagent grade and were
used without further purification.
4,5-Dimethyl-2-phenyl-1,3-oxazole (1a)
Yield: 61%; pale yellow oil.
1H NMR (CDCl3): d = 2.16 (d, 3 H, J = 0.6 Hz), 2.31 (d, 3 H, J = 0.6
Hz), 7.38–7.45 (m, 3 H), 7.96–7.99 (m, 2 H).
13C NMR (CDCl3): d = 9.97, 11.1, 125.8, 127.7, 128.6, 129.6,
131.8, 143.3, 159.0.
LRMS (EI): m/z = 173 (M+).
2-Aryl-4,5-dimethyloxazoles 1; General Procedure
To a solution of aryl carboxylic acid (74.6 mmol) and acetoin (7.23
g, 82.1 mmol) in DMF (× 6.7 v/w of aryl carboxylic acid) was added
EDAC-HCl (21.45 g, 111.9 mmol) and DMAP (0.916 g, 7.5 mmol)
at r.t. After stirring the reaction mixture overnight at 25 °C, H2O
was added to the mixture. The mixture was extracted with EtOAc,
the organic layer was dried (Na2SO4) and evaporated in vacuo. To a
HRMS (EI): m/z calcd for C11H11NO: 173.0841; found: 173.0838.
2-(4-tert-Butylphenyl)-4,5-dimethyl-1,3-oxazole (1b)
Yield: 63%; pale yellow oil.
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York

2828
T. Yamane et al.
PAPER
1H NMR (CDCl3): d = 1.34 (s, 9 H), 2.15 (d, 3 H, J = 0.7 Hz), 2.30
(d, 3 H, J = 0.7 Hz), 7.43 (dd, 2 H, J = 6.7 Hz, 1.9 Hz), 7.90 (dd, 2
H, J = 6.7 Hz, 1.9 Hz).
1H NMR (CDCl3): d = 2.15 (d, 3 H, J = 0.8 Hz), 2.32 (d, 3 H,
J = 0.8 Hz), 7.35–7.36 (m, 2 H), 7.84–7.87 (m, 1 H), 7.97–7.98 (m,
1 H).
13C NMR (CDCl3): d = 10.0, 11.2, 31.2, 34.8, 125.1, 125.5, 125.6,
131.6, 143.0, 152.9, 159.2.
13C NMR (CDCl3): d = 10.0, 11.2, 123.8, 125.8, 129.4, 129.5,
129.9, 132.2, 134.7, 143.9, 157.7.
LRMS (EI): m/z = 229 (M+).
Anal. Calcd for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C,
63.54; H, 4.79; N, 6.80.
HRMS (EI): m/z calcd for C15H19NO: 229.1467; found: 229.1471.
2-(3,4-Dichlorophenyl)-4,5-dimethyl-1,3-oxazole (1i)
Yield: 45%; white solid; mp 125–126 °C.
1H NMR (CDCl3): d = 2.15 (s, 3 H), 2.32 (s, 3 H), 7.49 (d, 1 H,
J = 8.5 Hz), 7.80 (dd, 1 H, J = 2.0, 8.5 Hz), 8.07 (d, 1 H, J = 2.0
Hz).
13C NMR (CDCl3): d = 10.0, 11.2, 124.8, 127.5, 127.6, 130.7,
132.5, 133.0, 133.6, 144.2, 156.9.
2-Biphenyl-4-yl-4,5-dimethyl-1,3-oxazole (1c)
Yield: 58%; white solid; mp 145–147 °C.
1H NMR (CDCl3): d = 2.18 (d, 3 H, J = 0.8 Hz), 2.33 (d, 3 H, J = 0.8
Hz), 7.37–7.48 (m, 3 H), 7.62–7.69 (m, 4 H), 8.05 (dd, 2 H, J = 6.7,
1.9 Hz).
13C NMR (CDCl3): d = 10.1, 11.3, 126.3, 126.7, 127.0, 127.3,
127.7, 128.8, 132.0, 140.3, 142.3, 143.5, 159.0.
Anal. Calcd for C11H9Cl2NO: C, 54.57; H, 3.75; N, 5.79. Found: C,
54.42; H, 3.71; N, 5.81.
Anal. Calcd for C17H15NO (+1/10 H2O): C, 81.31; H, 6.10; N, 5.58.
Found: C, 81.31; H, 6.05; N, 5.59.
2-(2,4-Dichlorophenyl)-4,5-dimethyl-1,3-oxazole (1j)
Yield: 41%; white solid; mp 108–109 °C.
1H NMR (CDCl3): d = 2.18 (d, 3 H, J = 0.7 Hz), 2.33 (d, 3 H,
J = 0.7 Hz), 7.30 (dd, 1 H, J = 8.5, 2.1 Hz), 7.49 (d, 1 H, J = 2.1
Hz), 7.89 (d, 1 H, J = 8.5 Hz).
13C NMR (CDCl3): d = 10.0, 11.2, 125.2, 127.1, 130.8, 131.2,
132.2, 132.6, 135.6, 144.2, 156.1.
4,5-Dimethyl-2-(2-naphthyl)-1,3-oxazole (1d)
Yield: 58%; pale yellow solid; mp 81–82 °C.
1H NMR (CDCl3): d = 2.18 (d, 3 H, J = 0.8 Hz), 2.32 (d, 3 H, J = 0.8
Hz), 7.46–7.51 (m, 2 H), 7.80–7.90 (m, 3 H), 8.07 (dd, 1 H, J = 8.6,
0.7 Hz), 8.46 (s, 1 H).
13C NMR (CDCl3): d = 10.1, 11.3, 123.1, 125.1, 125.3, 126.5,
126.8, 127.7, 128.4, 128.5, 132.1, 133.1, 133.8, 143.6, 159.2.
Anal. Calcd for C11H9Cl2NO: C, 54.57; H, 3.75; N, 5.79. Found: C,
54.35; H, 3.88; N, 6.23.
Anal. Calcd for C15H13NO (+1/10 H2O): C, 80.05; H, 5.91; N, 6.22.
Found: C, 80.07; H, 5.87; N, 6.20.
4,5-Dimethyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazole (1k)
Yield: 36%; white solid; mp 99–101 °C.
1H NMR (CDCl3): d = 2.17 (d, 3 H, J = 0.6 Hz), 2.33 (d, 3 H,
J = 0.6 Hz), 7.67 (d, 2 H, J = 8.2 Hz), 8.08 (d, 2 H, J = 8.2 Hz).
13C NMR (CDCl3): d = 10.0, 11.1, 122.1, 125.6 (q, J = 3.8 Hz),
125.7, 125.9, 131.2 (d, J = 33 Hz), 132.6, 144.4, 157.7.
2-(4-Bromophenyl)-4,5-dimethyl-1,3-oxazole (1e)
Yield: 43%; white solid; mp 132–134 °C.
1H NMR (CDCl3): d = 2.15 (d, 3 H, J = 0.8 Hz), 2.31 (d, 3 H, J = 0.8
Hz), 7.55 (dd, 2 H, J = 6.8, 1.8 Hz), 7.84 (dd, 2 H, J = 6.8, 1.8 Hz).
13C NMR (CDCl3): d = 10.0, 11.2, 123.9, 126.7, 127.2, 131.8,
132.1, 143.7, 158.2.
Anal. Calcd for C12H10F3NO: C, 59.75; H, 4.18; N, 5.81. Found: C,
59.64; H, 4.12; N, 5.85.
Anal. Calcd for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,
52.18; H, 4.00; N, 5.65.
4,5-Dimethyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazole (1l)
Yield: 53%; white solid; mp 91–93 °C.
1H NMR (CDCl3): d = 2.15 (d, 3 H, J = 0.9 Hz), 2.31 (d, 3 H,
J = 0.9 Hz), 3.89 (s, 3 H), 3.93 (s, 6 H), 7.22 (s, 2 H).
13C NMR (CDCl3): d = 10.0, 11.1, 56.2, 60.9, 103.1, 123.1, 131.7,
139.6, 143.3, 153.4, 159.0.
2-(4-Chlorophenyl)-4,5-dimethyl-1,3-oxazole (1f)
Yield: 38%; pale yellow solid; mp 122–124 °C.
1H NMR (CDCl3): d = 2.15 (s, 3 H), 2.31 (s, 3 H), 7.39 (d, 2 H,
J = 8.6 Hz), 7.91 (d, 2 H, J = 8.6 Hz).
13C NMR (CDCl3): d = 10.0, 11.2, 126.3, 127.0, 128.8, 132.1,
135.5, 143.6, 158.1.
Anal. Calcd for C14H17NO4 (+4/3 H2O): C, 58.53; H, 6.90; N, 4.88.
Found: C, 58.64; H, 6.81; N, 4.73.
Anal. Calcd for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C,
63.55; H, 4.81; N, 6.81.
4-(Bromomethyl)-5-methyl-2-phenyl-1,3-oxazole (2a)
Pale yellow solid; mp 101–103 °C.
1H NMR (CDCl3): d = 2.39 (s, 3 H), 4.44 (s, 2 H), 7.40–7.45 (m, 3
H), 7.97–8.01 (m, 2 H).
13C NMR (CDCl3): d = 10.4, 23.9, 126.2, 127.2, 128.7, 130.2,
133.1, 146.4, 159.9.
2-(3-Bromophenyl)-4,5-dimethyl-1,3-oxazole (1g)
Yield: 38%; white solid; mp 71–73 °C.
1H NMR (CDCl3): d = 2.15 (s, 3 H), 2.31 (s, 3 H), 7.28 (t, 1 H,
J = 8.0 Hz), 7.49–7.53 (m, 1 H), 7.88–7.91 (m, 1 H), 8.13–8.14 (m,
1 H).
13C NMR (CDCl3): d = 10.0, 11.2, 122.7, 124.2, 128.7, 129.6,
130.1, 132.3, 132.4, 144.0, 157.6.
Anal. Calcd for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,
52.40; H, 3.95; N, 5.61.
Anal. Calcd for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,
52.35; H, 3.96; N, 5.59.
4-(Bromomethyl)-2-(4-tert-butylphenyl)-5-methyl-1,3-oxazole
(2b)
2-(3-Chlorophenyl)-4,5-dimethyl-1,3-oxazole (1h)
Yield: 31%; pale yellow solid; mp 63–65 °C.
White solid; mp 121–123 °C.
1H NMR (CDCl3): d = 1.34 (s, 9 H), 2.39 (s, 3 H), 4.44 (s, 2 H), 7.45
(dd, 2 H, J = 6.7, 1.9 Hz), 7.92 (dd, 2 H, J = 6.7, 1.9 Hz).
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York

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Synthesis of 2-Aryl-4-halomethyl-5-methyl-1,3-oxazoles
2829
13C NMR (CDCl3): d = 10.4, 23.9, 31.2, 34.9, 124.4, 125.6, 126.0,
132.9, 146.1, 153.7, 160.1.
Anal. Calcd for C11H9BrClNO: C, 46.11; H, 3.17; N, 4.89. Found:
C, 46.11; H, 3.04; N, 4.97.
Anal. Calcd for C15H18BrNO: C, 58.45; H, 5.89; N, 4.54. Found: C,
58.34; H, 5.90; N, 4.59.
4-(Bromomethyl)-2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazole
(2i)
White solid; mp 103–105 °C.
1H NMR (CDCl3): d = 2.41 (s, 3 H), 4.42 (s, 2 H), 7.51 (d, 1 H,
J = 8.4 Hz), 7.82 (dd, 1 H, J = 2.0, 8.4 Hz), 8.09 (d, 1 H, J = 2.0 Hz).
13C NMR (CDCl3): d = 10.5, 23.2, 125.2, 127.0, 127.9, 130.8,
133.2, 133.6, 134.5, 147.1, 157.8.
2-Biphenyl-4-yl-4-(bromomethyl)-5-methyl-1,3-oxazole (2c)
White solid; mp 125–127 °C.
1H NMR (CDCl3): d = 2.41 (s, 3 H), 4.45 (s, 2 H), 7.34–7.39 (m, 1
H), 7.43–7.48 (m, 2 H), 7.62–7.68 (m, 4 H), 8.06 (d, 2 H, J = 8.4
Hz).
13C NMR (CDCl3): d = 10.9, 24.2, 126.4, 127.1, 127.5, 127.8,
128.2, 129.3, 133.6, 140.6, 143.4, 146.9, 160.2.
Anal. Calcd for C11H8BrCl2NO (+1/5 H2O): C, 40.70; H, 2.61; N,
4.32. Found: C, 40.69; H, 2.48; N, 4.40.
Anal. Calcd for C17H14BrNO: C, 62.21; H, 4.30; N, 4.27. Found: C,
62.18; H, 4.43; N, 4.08.
4-(Bromomethyl)-2-(2,4-dichlorophenyl)-5-methyl-1,3-oxazole
(2j)
White solid; mp 94–96 °C.
1H NMR (CDCl3): d = 2.42 (s, 3 H), 4.45 (s, 2 H), 7.32 (dd, 1 H,
J = 8.5, 2.0 Hz), 7.50 (d, 1 H, J = 2.0 Hz), 7.92 (d, 1 H, J = 8.5 Hz).
13C NMR (CDCl3): d = 10.9, 23.7, 125.1, 127.6, 131.4, 132.0,
133.5, 133.7, 136.8, 147.6, 157.4.
4-(Bromomethyl)-5-methyl-2-(2-naphthyl)-1,3-oxazole (2d)
Pale yellow solid; mp 118–120 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 4.47 (s, 2 H), 7.50–7.53 (m, 2
H), 7.83–7.92 (m, 3 H), 8.09 (dd, 1 H, J = 8.6, 1.7 Hz), 8.49 (s, 1 H).
13C NMR (CDCl3): d = 10.5, 23.8, 123.2, 124.5, 126.0, 126.7,
127.2, 127.8, 128.6, 128.6, 133.0, 133.3, 134.1, 146.6, 160.1.
Anal. Calcd for C11H8BrCl2NO: C, 41.16; H, 2.51; N, 4.36. Found:
C, 41.20; H, 2.63; N, 4.44.
Anal. Calcd for C15H12BrNO: C, 59.62; H, 4.00; N, 4.64. Found: C,
59.46; H, 4.06; N, 4.67.
4-(Bromomethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-
oxazole (2k)
White solid; mp 106–108 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 4.44 (s, 2 H), 7.69 (d, 2 H,
J = 8.1 Hz), 8.11 (d, 2 H, J = 8.1 Hz).
13C NMR (CDCl3): d = 10.5, 23.3, 122.0, 125.7 (q, J = 4 Hz), 126.4,
130.3, 131.8 (d, J = 33 Hz), 133.7, 147.3, 158.5.
4-(Bromomethyl)-2-(4-bromophenyl)-5-methyl-1,3-oxazole (2e)
White solid; mp 116–118 °C.
1H NMR (CDCl3): d = 2.39 (s, 3 H), 4.42 (s, 2 H), 7.55–7.58 (m, 2
H), 7.83–7.87 (m, 2 H).
13C NMR (CDCl3): d = 10.4, 23.5, 124.7, 126.1, 127.6, 131.9,
133.3, 146.7, 159.0.
Anal. Calcd for C12H9BrF3NO: C, 45.03; H, 2.83; N, 4.38. Found:
C, 45.11; H, 2.89; N, 4.51.
Anal. Calcd for C11H9Br2NO: C, 39.91; H, 2.74; N, 4.23. Found: C,
39.86; H, 2.90; N, 4.28.
4-(Chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (3a)
White solid; mp 81–83 °C.
1H NMR (CDCl3): d = 2.36 (s, 3 H), 4.52 (s, 2 H), 7.38–7.42 (m, 3
H), 7.95–8.00 (m, 2 H).
13C NMR (CDCl3): d = 10.1, 37.0, 125.9, 126.9, 128.5, 130.1,
132.6, 146.4, 159.8.
4-(Bromomethyl)-2-(4-chlorophenyl)-5-methyl-1,3-oxazole (2f)
White solid; mp 98–100 °C.
1H NMR (CDCl3): d = 2.40 (s, 3 H), 4.43 (s, 2 H), 7.41 (dd, 2 H,
J = 6.7, 2.0 Hz), 7.93 (dd, 2 H, J = 6.7, 2.0 Hz).
13C NMR (CDCl3): d = 10.4, 23.5, 125.7, 127.4, 129.0, 133.3,
136.3, 146.6, 158.9.
Anal. Calcd for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C,
63.20; H, 4.78; N, 6.77.
Anal. Calcd for C11H9BrClNO: C, 46.11; H, 3.17; N, 4.89. Found:
C, 46.14; H, 3.17; N, 4.95.
4-(Chloromethyl)-2-(4-tert-butylphenyl)-5-methyl-1,3-oxazole
(3b)
White solid; mp 99–101 °C.
1H NMR (CDCl3): d = 1.34 (s, 9 H), 2.41 (s, 3 H), 4.54 (s, 2 H), 7.45
(d, 2 H, J = 8.7 Hz), 7.92 (d, 2 H, J = 8.7 Hz).
13C NMR (CDCl3): d = 10.3, 31.3, 34.9, 37.3, 124.4, 125.6, 126.0,
132.7, 146.2, 153.6, 160.2.
4-(Bromomethyl)-2-(3-bromophenyl)-5-methyl-1,3-oxazole
(2g)
White solid; mp 102–104 °C.
1H NMR (CDCl3): d = 2.40 (s, 3 H), 4.42 (s, 2 H), 7.30 (t, 1 H,
J = 7.9 Hz), 7.53–7.57 (m, 1 H), 7.90–7.94 (m, 1 H), 8.15–8.16 (m,
1 H).
13C NMR (CDCl3): d = 10.4, 23.4, 122.8, 124.6, 129.0, 129.1,
130.3, 133.1, 133.4, 146.9, 158.4.
Anal. Calcd for C15H18ClNO: C, 68.30; H, 6.88; N, 5.31. Found: C,
67.91; H, 6.78; N, 5.26.
Anal. Calcd for C11H9Br2NO: C, 39.91; H, 2.74; N, 4.23. Found: C,
39.95; H, 2.75; N, 4.35.
2-Biphenyl-4-yl-4-(chloromethyl)-5-methyl-1,3-oxazole (3c)
Pale yellow solid; mp 108–111 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 4.56 (s, 2 H), 7.37–7.48 (m, 3
H), 7.62–7.68 (m, 4 H), 8.05–8.08 (m, 2 H).
13C NMR (CDCl3): d = 10.4, 37.3, 126.0, 126.6, 127.0, 127.3,
127.8, 128.9, 133.0, 140.1, 142.9, 146.6, 159.9.
4-(Bromomethyl)-2-(3-chlorophenyl)-5-methyl-1,3-oxazole (2h)
White solid; mp 90–92 °C.
1H NMR (CDCl3): d = 2.41 (s, 3 H), 4.43 (s, 2 H), 7.34–7.42 (m, 2
H), 7.86–7.89 (m, 1 H), 7.99–8.01 (m, 1 H).
13C NMR (CDCl3): d = 10.4, 23.4, 124.2, 126.2, 128.8, 130.0,
130.2, 133.4, 134.9, 146.9, 158.6.
Anal. Calcd for C17H14ClNO: C, 71.96; H, 4.97; N, 4.94. Found: C,
71.90; H, 4.88; N, 5.10.
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PAPER
4-(Chloromethyl)-5-methyl-2-(2-naphthyl)-1,3-oxazole (3d)
Pale yellow solid; mp 105–107 °C.
Anal. Calcd for C11H8Cl3NO: C, 47.77; H, 2.92; N, 5.06. Found: C,
47.54; H, 2.96; N, 5.25.
1H NMR (CDCl3): d = 2.46 (s, 3 H), 4.58 (s, 2 H), 7.50–7.53 (m, 2
H), 7.83–7.93 (m, 3 H), 8.09 (dd, 1 H, J = 8.6, 1.7 Hz), 8.50 (s, 1 H).
13C NMR (CDCl3): d = 10.4, 37.3, 123.2, 124.5, 126.0, 126.7,
127.2, 127.8, 128.5, 128.6, 133.0, 133.1, 134.1, 146.7, 160.2.
4-(Chloromethyl)-2-(2,4-dichlorophenyl)-5-methyl-1,3-oxazole
(3j)
White solid; mp 95–97 °C.
1H NMR (CDCl3): d = 2.44 (s, 3 H), 4.57 (s, 2 H), 7.32 (dd, 1 H,
J = 8.5, 2.1 Hz), 7.50 (d, 1 H, J = 2.1 Hz), 7.92 (d, 1 H, J = 8.5 Hz).
13C NMR (CDCl3): d = 10.4, 37.0, 124.7, 127.2, 130.9, 131.6,
133.1, 133.1, 136.4, 147.4, 157.1.
Anal. Calcd for C15H12ClNO: C, 69.91; H, 4.69; N, 5.43. Found: C,
69.53; H, 4.56; N, 5.55.
2-(4-Bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole
(3e)2e
Anal. Calcd for C11H8Cl3NO: C, 47.77; H, 2.92; N, 5.06. Found: C,
47.69; H, 2.84; N, 5.12.
White solid; mp 97–99 °C.
1H NMR (CDCl3): d = 2.42 (s, 3 H), 4.54 (s, 2 H), 7.55–7.58 (m, 2
4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-
oxazole (3k)
H), 7.85–7.87 (m, 2 H).
13C NMR (CDCl3): d = 10.3, 37.1, 124.7, 126.1, 127.6, 132.0,
133.2, 146.8, 159.1.
White solid; mp 90–92 °C (Lit.4 mp 84–85 °C).
1H NMR (CDCl3): d = 2.45 (s, 3 H), 4.56 (s, 2 H), 7.70 (d, 2 H,
J = 8.1 Hz), 8.12 (d, 2 H, J = 8.1 Hz).
13C NMR (CDCl3): d = 10.4, 37.0, 122.0, 125.7 (q, J = 4 Hz), 126.4,
130.3, 131.8 (d, J = 33 Hz), 133.5, 147.5, 158.6.
Anal. Calcd for C11H9BrClNO: C, 46.11; H, 3.17; N, 4.89. Found:
C, 46.13; H, 3.14; N, 5.03.
4-(Chloromethyl)-2-(4-chlorophenyl)-5-methyl-1,3-oxazole
(3f)5
Anal. Calcd for C12H9ClF3NO: C, 52.29; H, 3.29; N, 5.08. Found:
C, 52.03; H, 3.13; N, 5.03.
White solid; mp 90–92 °C.
1H NMR (CDCl3): d = 2.42 (s, 3 H), 4.54 (s, 2 H), 7.41 (dd, 2 H,
J = 6.8, 1.8 Hz), 7.93 (dd, 2 H, J = 6.8, 1.8 Hz).
13C NMR (CDCl3): d = 10.3, 37.1, 125.7, 127.4, 129.0, 133.1,
136.3, 146.8, 159.1.
4-(Chloromethyl)-5-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-ox-
azole (3l)
White solid; mp 110–112 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 3.90 (s, 3 H), 3.94 (s, 6 H), 4.55
(s, 2 H), 7.24 (s, 2 H).
13C NMR (CDCl3): d = 10.3, 37.2, 56.3, 60.9, 103.5, 122.6, 132.9,
140.1, 146.5, 153.5, 159.8.
Anal. Calcd for C11H9Cl2NO: C, 54.57; H, 3.75; N, 5.79. Found: C,
54.61; H, 3.78; N, 5.71.
4-(Chloromethyl)-2-(3-bromophenyl)-5-methyl-1,3-oxazole
(3g)
Anal. Calcd for C14H16ClNO4: C, 56.48; H, 5.42; N, 4.70. Found: C,
56.21; H, 5.38; N, 4.72.
White solid; mp 87–89 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 4.54 (s, 2 H), 7.31 (t, 1 H,
J = 7.9 Hz), 7.54–7.57 (m, 1 H), 7.93 (d, 1 H, J = 7.9 Hz), 8.16 (t, 1
H, J = 1.5 Hz).
Acknowledgment
We would like to thank Dr. Kiminori Tomimatsu, Kokichi Yoshida
and Mitsuhisa Yamano for their support and helpful discussions.
13C NMR (CDCl3): d = 10.4, 37.0, 122.8, 124.6, 129.0, 129.1,
130.3, 133.2, 133.2, 147.1, 158.5.
Anal. Calcd for C11H9BrClNO: C, 46.11; H, 3.17; N, 4.89. Found:
C, 45.93; H, 3.08; N, 5.09.
References
(1) (a) Hartner, F. W. Jr. In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V.; Shinkai, I., Eds.; Elsevier: Oxford, 1996, 261–318.
(b) Boyd, G. V. In Comprehensive Heterocyclic Chemistry,
Vol. 6; Katritzky, A. R.; Rees, C. W.; Potts, K. T., Eds.;
Pergamon: Oxford, 1984, 177–233. (c) Lakhan, R.; Ternai,
B. Adv. Heterocycl. Chem. 1974, 17, 99.
(2) (a) Imoto, H.; Sugiyama, Y.; Kimura, H.; Momose, Y. Chem
Pharm. Bull. 2003, 51, 138. (b) Imoto, H.; Imamiya, E.;
Momose, Y.; Sugiyama, Y.; Kimura, H.; Sohda, T. Chem.
Pharm. Bull. 2002, 50, 1349. (c) Momose, Y.; Maekawa,
T.; Yamano, T.; Kawada, M.; Odaka, H.; Ikeda, H.; Sohda,
T. J. Med. Chem. 2002, 45, 1518. (d) Momose, Y.;
4-(Chloromethyl)-2-(3-chlorophenyl)-5-methyl-1,3-oxazole
(3h)
White solid; mp 77–79 °C.
1H NMR (CDCl3): d = 2.42 (s, 3 H), 4.53 (s, 2 H), 7.33–7.40 (m, 2
H), 7.85–7.89 (m, 1 H), 7.98–8.00 (m, 1 H).
13C NMR (CDCl3): d = 10.3, 37.0, 124.2, 126.2, 128.8, 130.0,
130.2, 133.2, 134.8, 147.0, 158.7.
Anal. Calcd for C11H9Cl2NO (+1/5 H2O): C, 53.77; H, 3.86; N, 5.70.
Found: C, 53.91; H, 3.67; N, 5.92.
4-(Chloromethyl)-2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazole
(3i)
White solid; mp 85–87 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H), 4.53 (s, 2 H), 7.51 (d, 1 H,
J = 8.4 Hz), 7.82 (dd, 1 H, J = 1.9, 8.4 Hz), 8.10 (d, 1 H, J = 1.9 Hz).
13C NMR (CDCl3): d = 10.4, 36.9, 125.2, 127.0, 127.9, 130.8,
133.2, 133.4, 134.5, 147.3, 158.0.
Maekawa, T.; Odaka, H.; Ikeda, H.; Sohda, T. Chem Pharm.
Bull. 2002, 50, 100. (e) Brooks, D. A.; Etgen, G. J.; Rito, C.
J.; Shuker, A. J.; Dominianni, S. J.; Warshawsky, A. M.;
Ardecky, R.; Paterniti, J. R.; Tyhonas, J.; Karanewsky, D. S.;
Kauffman, R. F.; Broderick, C. L.; Oldham, B. A.;
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York

PAPER
Montrose-Rafizadeh, C.; Winneroski, L. L.; Faul, M. M.;
Synthesis of 2-Aryl-4-halomethyl-5-methyl-1,3-oxazoles
2831
(12) (a) The structures of 2 and 3 were confirmed by synthesizing
the 2-aryl-5-halomethyl-4-methyloxazoles (the regioiso-
mers of 2 and 3) according to a known procedure (Scheme 4)
and comparing them with the help of 1H/13C NMR
spectroscopy and HPLC analysis. Compounds 2 or 3 and
their regioisomers are distinguishable clearly by chemical
shifts on 1H/13C NMR and retention time on a HPLC
analysis. (b) See: Fink, C. A.; Firoozina, F. Patent WO
9955723, 1999; Chem. Abstr. 1999, 131, 322913. (c) See
also: Chao, E. Y.-H.; Haffner, C. D.; Lambert, M. H. III;
Maloney, P. R.; Sierra, M. L.; Sternbach, D. D.; Sznaidman,
M. L.; Willson, T. M.; Xu, H. E.; Gellibert, F. J. Patent WO
0100603, 2001; Chem. Abstr. 2001, 134, 86235; and
references cited therein.
(13) The regioselectivity was determined by HPLC analysis
(HPLC conditions; YMC Pack-SIL A-002 column with
40:1–10:1 n-hexane–THF as the mobile phase). To
investigate regioselectivity, we used HPLC with the normal
phase, while the 5-halomethyl-4-methyl regioisomers easily
decomposed during a HPLC analysis with the reverse phase.
(14) One referee kindly suggested other plausible mechanisms
(Schemes 5 and 6).
McCarthy, J. R. J. Med. Chem. 2001, 44, 2061.
(f) Malamas, M. S.; Sredy, J.; McCaleb, M.; Gunawan, I.;
Mihan, B.; Sullivan, D. Eur. J. Med. Chem. 2001, 36, 31.
(g) Hulin, B.; Clark, D. A.; Goldstein, S. W.; McDermott, R.
E.; Dambek, P. J.; Kappeler, W. H.; Lamphere, C. H.; Lewis,
D. M.; Rizzi, J. P. J. Med. Chem. 1992, 35, 1853.
(h) Devasthale, P.; Jeon, Y. T. Patent WO 03040114, 2003;
Chem. Abstr. 2003, 138, 385420. (i) Bach, A. T.; Kapa, P.
K.; Lee, G. T.; Loeser, E. M.; Sabio, M. L.; Stanton, J. L.;
Vedananda, T. R. Patent WO 03043985, 2003; Chem. Abstr.
2003, 139, 6767.
(3) Boehringer, M.; Hunziker, D.; Kuehne, H.; Loeffler, B. M.;
Sarabu, R.; Wessel, H. P. Patent WO 03037327, 2003;
Chem. Abstr. 2003, 138, 368754.
(4) Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan, B.; Sawicki,
D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R. J. Med. Chem.
2000, 43, 995.
(5) Malamas, M. S.; Carlson, R. P.; Grimes, D.; Howell, R.;
Glaser, K.; Gunawan, I.; Nelson, J. A.; Kanzelberger, M.;
Shah, U.; Hartman, D. A. J. Med. Chem. 1996, 39, 237.
(6) Goto, Y.; Yamazaki, M.; Hamana, M. Chem. Pharm. Bull.
1971, 19, 2050.
(7) Overman, L. E.; Tsuboi, S.; Steven, A. J. Org. Chem. 1979,
44, 2323.
(8) Gompper, R.; Rühle, H. Liebigs Ann. Chem. 1959, 626, 83.
(9) Yamane, T.; Mitsudera, H.; Shundoh, T. Tetrahedron Lett.
2004, 45, 69.
(10) Wasserman, H. H.; Lu, T.-J. Tetrahedron Lett. 1982, 23,
3831.
(11) Unoptimized results.
O
CO2Et
O
O
O
Cl
CH3COONH4
N
Ar
K2CO3
DMF
O
Ar
OH
CH3COOH
reflux, 24 h
Ar
CO2Et
CO2Et
O
50 °C, 2 h
N
NBS, Ph3P
CH2Cl2
Br
Cl
Ar
O
SMEAH
N
0 °C, 1 h
OH
THF
Ar
O
0 °C, 1 h
SOCl2
N
toluene
Ar
O
0 °C
overnight
Scheme 4 Synthesis of regioisomers of 2 and 3
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York

2832
T. Yamane et al.
PAPER
Path A (major)
Path B (minor)
O
O
N
N
O
4
4
4
O
O
N
N
N
X
X
Ar
O
Ar
Ar
5
+
N
5
X
5
O
O
1
O
O
O
N
N
H
O
N
N
X
X
H
O
Ar
O
Ar
O
O
HN
O
O
HN
X
O
X
X
X
N
N
X
N
N
+
Ar
Ar
O
O
Ar
O
Ar
O
2, 3
X
(X = Br, Cl)
Scheme 5 Another plausible mechanism for the formation of 2-aryl-4-halomethyl-5-methyl-1,3-oxazoles
O
O
N
N
H
O
4
4
HX
O
N
N
N
N
X
X
O
H
Ar
Ar
5
Ar
Ar
+
N
X
5
O
O
O
O
1
O
O
N
Path A (major)
X
X
O
N
N
O
N
Ar
Ar
Ar
H
N
O
O
O
2, 3
O
+
O
O
N
H
N
O
O
N
N
N
X
Ar
Path B (minor)
Ar
Ar
O
O
O
X
(X = Br, Cl)
Scheme 6 A new mechanism suggested for the formation of 2-aryl-4-halomethyl-5-methyl-1,3-oxazoles
Synthesis 2004, No. 17, 2825–2832 © Thieme Stuttgart · New York