The synthesis and activity of oxazole and thiazole analogues of urocanic acid

Article abstract of DOI:10.1016/S0040-4020(00)00019-3

Direct exposure of human skin to sunlight leads to suppression of the immune system, believed to be mediated by urocanic acid. The synthesis of oxazole and thiazole analogues of urocanic acid is reported, as is their effect on biological markers of the hu

Full text of DOI:10.1016/S0040-4020(00)00019-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 811–816
The Synthesis and Activity of Oxazole and Thiazole Analogues of
Urocanic Acid
b
b
David S. Millan,a Rolf H. Prager,a, Catherine Brand and Prue H. Hart
*
aSchool of Chemistry, Physics and Earth Sciences, Flinders University of South Australia, G.P.O. Box 2100, Adelaide 5001, Australia
bDepartment of Microbiology and Infectious Diseases, School of Medicine, Flinders University of South Australia, G.P.O. Box 2100,
Adelaide 5001, Australia
Received 18 October 1999; revised 6 December 1999; accepted 23 December 1999
Abstract—Direct exposure of human skin to sunlight leads to suppression of the immune system, believed to be mediated by urocanic acid.
The synthesis of oxazole and thiazole analogues of urocanic acid is reported, as is their effect on biological markers of the human immune
system. ᭧ 2000 Published by Elsevier Science Ltd. All rights reserved.
Introduction
evaluate them as potential agonists or antagonists of the
(Z)-UCA receptor site.
UV-A (320–400 nm) and UV-B (290–320 nm) light has
been shown to suppress the immune system.1 Subsequent
research has identified (Z)-urocanic acid (UCA) 1 as a
chemical mediator responsible for inducing immuno-
suppression.2
Results and Discussion
Recent work in our group has led to the development of a
novel route to oxazoles8 and thiazoles9 from isoxazol-
5(2H)-ones, and we envisaged that the oxazoles and
thiazoles required in this project could be derived in this
way. Due to its ease of formation8 (Scheme 1), ethyl
2-phenyloxazole-5-carboxylate 4 was chosen as the model
starting compound for the synthesis of the analogues of
UCA.
(E)-UCA arises from the deamination of the amino acid
histidine, and is generally present to the extent of about
0.7% in human skin;3 the immunosuppressive (Z)-UCA is
formed upon UV irradiation of the (E)-isomer. In an attempt
to discover the molecular structure necessary for immuno-
suppressive activity, Norval and co-workers4 tested several
analogues of 1 for their ability to suppress the immune
system. They concluded that the heteroaromatic ring,
together with the side chain, is necessary to induce immuno-
suppression. However, even when the side chain was
reduced or the carboxyl group replaced by amino, the
compound retained its activity. Since then further analogues
have been synthesised and tested, with somewhat ambigu-
ous results.5–7 This paper aims to probe further the structure
necessary for immunosuppressive activity by synthesising
oxazole and thiazole analogues 2 and 3 of UCA and to
Transformations on the oxazole ester 4, as depicted in
Scheme 2, gave the desired compounds 8 and 9. Direct
reduction of the ester 4 to aldehyde 5 with diisobutyl-
aluminium hydride proceeded poorly. Hence the aldehyde
was obtained by reduction of 4 with lithium aluminium
hydride to afford 6, followed by Swern oxidation of 6 to
give the aldehyde in 83% overall yield. Reaction of 5 with
malonic acid in refluxing pyridine delivered 7, which gave
essentially a 1:1 mixture of (Z)-9 and (E)-7 isomers upon
exposure to UV light; further irradiation of this mixture did
not improve the yield of the (Z)-isomer. The dicarboxylate
compound 8 was prepared by adapting the procedure of
Keywords: oxazoles; thiazoles; anti-inflammatory compounds.
* Corresponding author. Tel.: ϩ61-8201-2357; fax: ϩ61-8201-3035;
e-mail: rolf.prager@flinders.edu.au
Scheme 1.
0040–4020/00/$ - see front matter ᭧ 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00019-3

812
D. S. Millan et al. / Tetrahedron 56 (2000) 811–816
the work carried out by Hart and co-workers,11 in which
(Z)-UCA induced PGE2 synthesis and suppressed TNF-a
levels in human monocytes. It was concluded that the reduc-
tion of TNF-a, by a PGE2-dependent mechanism, may be
implicated in the suppression of the immune system by
(Z)-UCA.
The biological data are summarised in Table 1, and all
trends (average of three determinations) have been repli-
cated at least twice. It is apparent that the (E)-isomer of
each UCA analogue 7, 11, 14 and 20, except 17, induced
PGE2 synthesis and reduced LPS induced TNF-a levels
suggesting that they may be acting as anti-inflammatory
agents. Analogue 20 increased PGE2 levels and dramati-
cally reduced TNF-a levels, relative to 17, and so it was
concluded that the necessary functionality at C-2 of the five
membered ring was a phenyl group, suggesting that hydro-
phobicity plays a role in the activity of each respective
compound. Compound 20 decreased the production of
TNF-a to 34% of the control, being more active than
(Z)-UCA (62% of control), and the suppression was additive
(23% of control when 1:1). However, this suppression
appears to occur by a mechanism less dependent on PGE2
production than that of (Z)-UCA, as it was only partially
restored by the addition of indomethacin, a cyclooxygenase
inhibitor. In addition, production of PGE2 was only mildly
stimulated (24% of that by (Z)-UCA).
Scheme 2.
Lehnert10 followed by base hydrolysis to give 10. The
analogues 10–20 were synthesised by similar procedures.
Biological Experimentation
The UCA analogues 7, 9, 10–20 were tested in vitro for
their ability to stimulate human peripheral blood monocyte
prostaglandin E2 (PGE2) production and their ability to
suppress lipopolysaccharide (LPS) induced tumour necrosis
factor-a (TNF-a) levels. The procedure was adapted from
Table 1. Effect on LPS-induced production of TNF-a and PGE 2
Compounda
TNF-a (%) Controlb
PGE 2 (%) Controlb
(E)-UCA
(Z)-UCA
7
7ϩ9 (1:1)
10
11
11ϩ12 (3:2)
13
14
14ϩ15 (1:2)
16
17
102
62c
39d
196
101
83e
137
138
82
64
1105
782
281
93
691
376
57
410
119
152
163
133
97
207
129
84
17ϩ18 (2:3)
19
20
99
138
34f
23
265
774
20ϩ(Z)-UCA
a All concentrations 0.1 mg mLϪ1, ca: 5 × 10Ϫ4 M:
b Production induced by lipopolysaccharide (LPS) alone.
c Returned to 138% in the presence of indomethacin (10Ϫ5 M).
d Returned to 110% in the presence of indomethacin.
e Returned to 94% in the presence of indomethacin.
f Returned to 72% in the presence of indomethacin.

D. S. Millan et al. / Tetrahedron 56 (2000) 811–816
813
1
The mixture of (E)- and (Z)-isomers 7/9, 11/12, 14/15 and
17/18 obtained from the UV isomerisation of each
(E)-isomer could not be separated by reverse phase HPLC
or ion exchange chromatography, except on an analytical
scale, and so each was tested as a mixture (see Table 1).
Although the isomer ratio of the mixtures 7/9, 11/12, 14/15
and 17/18 appeared to be stable under ordinary laboratory
conditions, assay samples were protected from light. While
the (E)-isomers 7, 11, 14 and 20 significantly reduced
TNF-a (production, the corresponding (E)/(Z) mixtures
actually increased TNF-a levels. Similarly, the level of
induced PGE2 synthesis due to the (E)-isomers was reduced
in the presence of the (Z) isomer. The dicarboxylate
compounds 10, 13, 16 and 19 affected PGE2 or TNF-a
levels in a way suggesting that they were acting as both
(E)- and (Z)-isomers, supporting the supposition that the
(E)- and (Z)-isomers were antagonistic.
68.6; H, 5.2; N, 8.0%; found C, 68.7; H, 5.3; N, 8.1%. H
NMR d: 4.43 (bs, 1H); 4.68 (s, 2H); 7.00 (s, 1H); 7.36–7.44
(m, 3H); 7.92–8.00 (m, 2H). 13C NMR d: 54.7, 125.4,
126.3, 127.0, 128.8, 130.6, 151.5, 162.1. IR nmax: 3192,
1549, 1452, 1361, 1026 cmϪ1. Mass spectrum m/z: 175
(M, 100%), 158 (16), 144 (94), 116 (97), 105 (40), 89
(47). HRMS calcd for C10H9NO2 175.0633, found 175.0634.
2-Phenyloxazole-5-carboxaldehyde 5. To a solution of
oxalyl chloride (1.16 g; 0.80 mL; 9.14 mmol) in dichloro-
methane (20 mL) at Ϫ78ЊC was added a solution of
dimethyl sulphoxide (1.26 g; 1.14 mL; 0.016 mol) in
dichloromethane (10 mL). The mixture was maintained at
Ϫ78ЊC for 10 min and then a solution of the alcohol 6
(0.40 g; 2.28 mmol) in dichloromethane (10 mL) was
added dropwise over 5 min and then stirring was continued
for 30 min at Ϫ78ЊC. Triethylamine (3.00 g; 4.14 mL;
0.03 mol) was added dropwise over 5 min. The solution
was allowed to warm to 0ЊC and was then quenched with
saturated ammonium chloride solution. The solvent was
evaporated and the residue diluted with ether (50 mL)
and washed twice with 2 M HCl (20 mL) and the
solvent removed to give a pale yellow solid. The solid
was recrystallised from ether–light petroleum affording
the title compound12 5 as white needles (0.36 g; 91%), mp
66–68ЊC. Anal for C10H7NO2, calcd C, 69.4; H, 4.1; N,
Conclusions
In contrast to what we initially envisaged, the (E)-isomers 7,
11, 14, and 20 act in the same way as (Z)-UCA and appear to
be synergistic with it. While (E)-UCA has little effect on
the production of TNF-a, the (Z)-isomers of the above
analogues are clearly antagonistic to the effect of their
(E)-isomers and to (Z)-UCA. The (E)-isomers 7, 11, 14,
and 20 may act as anti-inflammatory agents.
1
8.1%; found C, 69.3; H, 4.4; N, 8.3%. H NMR d: 7.48–
7.60 (m, 3H); 7.96 (s, 1H); 8.14–8.21 (m, 2H); 9.83 (s, 1H).
13C NMR d: 126.0, 127.8, 129.2, 132.4, 139.2, 149.8, 165.7,
176.5. IR nmax: 1683, 1531, 1454, 1378, 1148 cmϪ1. Mass
spectrum m/z: 173 (M, 94%), 144 (100), 116 (96), 89 (43).
HRMS calcd for C10H7NO2 173.0477, found 173.0478.
Experimental
Proton (1H) and carbon (13C) nuclear magnetic resonance
(NMR) spectra were recorded with a Varian Gemini spec-
trometer at 300 and 75.5 MHz, respectively. Spectra were
measured in deteuriochloroform (CDCl3) unless otherwise
indicated and coupling constants were recorded in Hertz.
Infrared spectra were recorded on a Perkin–Elmer 1600
Fourier-transform IR spectrometer, with samples measured
as a nujol mull (solid) or as a neat film (oil). Mass spectra
and high-resolution mass spectra were recorded on a Kratos
MS25RF spectrometer operating at an electron ionising
energy of 70 eV. Melting points were determined on a
Reichert hot-stage apparatus and remain uncorrected.
Analytical thin-layer chromatography was carried out with
Merck silica gel 60 F254 aluminium backed sheets. Radial
chromatography was performed with silica gel PF254
coated glass rotors using a Chromatotron 7924T. All organic
extracts were dried with anhydrous sodium sulphate. Micro-
analyses were performed by the Microanalytical Service,
University of Otago.
(E)-3-(2-Phenyloxazol-5-yl)propenoic acid 7. Malonic
acid (0.09 g; 0.87 mmol) was added to a solution of the
aldehyde 5 (0.15 g; 0.87 mmol) in pyridine (10 mL) and
piperidine (2 drops) and the solution refluxed for 2 h. The
solvent was evaporated and the residue acidified with 10 M
HCl and extracted twice with ethyl acetate (40 mL) and the
extract dried and evaporated to give a pale yellow solid,
which was recrystallised from ethyl acetate–light petro-
leum, affording pale brown needles of the title compound
7 (0.18 g; 97%), mp 188–190ЊC. Anal for C12H9NO3, calcd
C, 66.9; H, 4.0; N, 6.5%; found C, 67.0; H, 4.2; N, 6.5%. 1H
NMR (CDCl3/(CD3)2SO) d: 6.46 (d, Jˆ15.9 Hz, 1H); 7.39
(s, 1H); 7.46–7.54 (m, 4H); 8.06–8.12 (m, 2H). 13C NMR
(CDCl3/(CD3)2SO) d: 118.7, 126.4, 126.5, 127.5, 128.7,
131.0, 131.3, 148.0, 162.8, 168.1. IR nmax: 1699, 1685,
1646, 1465, 1303 cmϪ1 Mass spectrum m/z: 215 (M, 6%),
84 (25), 79 (100). HRMS calcd for C12H9NO3 215.0582,
found 215.0581.
(Z)-3-(2-Phenyloxazol-5-yl)propenoic acid 9. The pro-
penoic acid 7 (0.10 g; 0.47 mmol) was dissolved in
methanol (200 mL) and irradiated through pyrex (300 nm)
for 1 h. The solvent was evaporated affording a yellow solid
(0.10 g), which was shown to be a mixture (55:45) of the
(Z)-9 and (E)-propenoic acid 7 by NMR analysis. Further
irradiation did not change the (Z) to (E) ratio. Attempts to
separate the mixture by silica gel column chromatography
(ethyl acetate–methanol, 1:4), anion exchange (acetate form)
column chromatography (water–0.2 M acetic acid gradient
elution), and reverse phase HPLC (methanol–water, 4:96)
5-Hydroxymethyl-2-phenyloxazole 6. To a stirred solution
of lithium aluminium hydride (0.19 g; 5 mmol) in ether
(100 mL) was added a solution of ethyl 2-phenyloxazole-
5-carboxylate8 4 (1.00 g; 4.61 mmol) in ether (20 mL)
dropwise. The mixture was stirred for 16 h at 20ЊC and
then excess lithium aluminium hydride was quenched by
dropwise addition of saturated ammonium chloride
solution. The mixture was filtered and the solvent dried
and evaporated affording a pale yellow solid, which was
recrystallised from ether–light petroleum as white needles
(0.73 g; 91%), mp 72–74ЊC. Anal for C10H9NO2, calcd C,

814
D. S. Millan et al. / Tetrahedron 56 (2000) 811–816
were unsuccessful. (Z)-propenoic acid 9: 1H NMR (CDCl3/
(CD3)2SO) d: 5.96 (d, Jˆ12.9 Hz, 1H); 6.88 (d, Jˆ12.9 Hz,
1H); 7.44–7.56 (m, 3H); 8.04–8.14 (m, 2H); 8.37 (s, 1H).
13C NMR (CDCl3/(CD3)2SO) d: 117.9, 126.6, 126.7, 127.8,
128.8, 131.5, 134.2, 161.9, 168.5.
129.8, 130.3, 130.9, 134.7, 135.2, 135.6, 147.1, 171.4,
172.8. IR nmax: 1690, 1616, 1465, 1377, 1315, 1259 cmϪ1
Mass spectrum m/z: 263 (M, 100%), 262 (84), 140 (13), 128
(10), 110 (16), 100 (16). HRMS calcd for C12H9NO2S2
263.0075, found 263.0071.
.
Diethyl 2-(2-phenyloxazol-5-yl)methylenemalonate 8. A
solution of titanium tetrachloride (0.44 g; 0.25 mL;
2.31 mmol) in carbon tetrachloride (10 mL) was added to
THF (20 mL), and then a mixture of the aldehyde 5 (0.20 g;
1.16 mmol) and diethyl malonate (0.19 g; 1.16 mmol) in
THF (10 mL) was added. A solution of pyridine (0.37 g;
0.37 mL; 4.67 mmol) in THF (20 mL) was then added drop-
wise over 1 h. The reaction mixture was stirred at 20ЊC for
16 h and then water (20 mL) was added and the reaction
mixture extracted twice with ether (40 mL) and the extract
dried and evaporated to give a colourless oil. The oil was
chromatographed on silica by radial chromatography
(ether–dichloromethane–light petroleum, 1:2:7) affording
a colourless oil, which solidified on standing. The solid
was recrystallised from ether–light petroleum as white
cubes (0.24 g; 67%), mp 56–57ЊC. Anal for C17H17NO5,
calcd C, 64.8; H, 5.4; N, 4.4%; found C, 64.6; H, 5.3; N,
4.4%. 1H NMR d: 1.34 (t, Jˆ7.0 Hz, 3H); 1.36 (t, Jˆ7.0 Hz,
3H); 4.32 (q, Jˆ7.0 Hz, 2H); 4.47 (q, Jˆ7.0 Hz, 2H); 7.44–
7.52 (m, 3H); 7.55 (s, 2H); 8.00–8.06 (m, 2H). 13C NMR d:
13.7, 13.8, 61.6, 61.7, 123.9, 124.4, 126.3, 126.8, 128.8,
131.4, 134.8, 146.1, 163.6, 164.0, 165.7. IR nmax: 1728,
1711, 1459, 1278, 1225, 1207 cmϪ1. Mass spectrum m/z:
315 (M, 95%), 270 (21), 184 (28), 156 (18), 138 (31), 105
(100). HRMS calcd for C17H17NO5 315.1107, found
315.1107.
(Z)-3-(2-Phenylsulphanylthiazol-5-yl)propenoic acid 12.
Photolysis of 11 as above for 1 h gave a yellow-brown oil
(0.10 g), which later solidified and was identified as a
mixture (2:3) of the (Z)-12 and (E)-propenoic acid 11.
1
(Z)-propenoic acid 12: H NMR d: 5.77 (d, Jˆ12.1 Hz,
1H); 7.04 (d, Jˆ12.1 Hz, 1H); 7.36–7.58 (m, 3H); 7.62–
7.80 (m, 2H); 7.89 (s, 1H). 13C NMR d: 114.2, 129.9, 130.1,
132.7, 134.3, 134.6, 150.7, 170.4, 175.0.
Diethyl 2-(2-phenylsulphanylthiazol-5-yl)methylene-
malonate. 2-Phenylsulphanylthiazole-5-carboxaldehyde was
reacted with diethyl malonate as above. After 16 h, water
(20 mL) was added and the mixture extracted twice with
ether (40 mL) and the extract dried and evaporated to give
a colourless oil (0.40 g). The oil was then purified on silica by
radial chromatography (ether–dichloromethane–light petro-
leum, 1:2:7) as a pale yellow oil, which solidified on standing
and was recrystallised from ether–light petroleum as white
cubes (0.22 g; 61%), mp 77–79ЊC. Anal for C17H17NO4S2,
calcd C, 56.2; H, 4.7; N, 3.9%; found C, 56.0; H, 4.7; N,
3.8%. 1H NMR d: 1.19 (t, Jˆ7.2 Hz, 3H); 1.30 (t,
Jˆ7.2 Hz, 3H); 4.16 (q, Jˆ7.2 Hz, 2H); 4.26 (q, Jˆ7.2 Hz,
2H); 7.40–7.52 (m, 3H); 7.64–7.71 (m, 2H); 7.73 (s, 1H);
7.86 (s, 1H). 13C NMR d: 13.6, 13.9, 61.6, 61.7, 123.3, 129.6,
130.2, 130.7, 131.4, 132.1, 135.1, 150.6, 164.1, 165.6, 175.2.
IR nmax: 1729, 1716, 1614, 1465, 1379, 1283 cmϪ1. Mass
spectrum m/z: 363 (M, 48%), 180 (16), 155 (17), 133 (54),
115 (96), 93 (24), 91 (87), 71 (100). HRMS calcd for
C17H17NO4S2 363.0599, found 363.0598.
5-Hydroxymethyl-2-phenylsulphanylthiazole. The title
compound was prepared from ethyl 2-phenylsulphanyl-
thiazole-5-carboxylate9 as was 6. The product was purified
by radial chromatography (ether–dichloromethane, 1:1) on
silica as a pale orange oil (0.73 g; 67%). 1H NMR d: 4.63 (s,
2H); 4.80 (bs, 1H); 7.31–7.40 (m, 4H); 7.50–7.56 (m, 2H).
13C NMR d: 56.5, 129.5, 129.6, 131.2, 133.5, 139.9, 140.9,
4-Hydroxymethyl-2-phenylthiazole. The starting thiazole
was prepared by the procedure of Badr and co-workers.13
The crude material was purified by radial chromatography
on silica (ether–dichloromethane, 1:4) as a pale yellow oil,
which solidified on standing (0.65 g; 56%), mp 53–54ЊC
166.6. IR nmax: 3296, 1475, 1441, 1398, 1041, 1024 cmϪ1
.
1
Mass spectrum m/z: 223 (M, 50%), 222 (65), 49 (100).
(lit.14 mp 67–68ЊC). H NMR d: 4.20 (bs, 1H); 4.78 (s,
HRMS calcd for C10H9NOS2 223.0126, found 223.0122.
2H); 7.13 (s, 1H); 7.35–7.45 (m, 3H); 7.80–7.90 (m, 2H).
13C NMR d: 60.4, 114.6, 126.4, 128.8, 130.0, 133.2, 157.5,
168.8. IR nmax: 3297, 3084, 1464, 1033, 1003 cmϪ1. Mass
spectrum m/z: 191 (M, 100%), 190 (58), 162 (38), 121 (13),
104 (31). HRMS calcd for C10H9NOS, 191.0405, found
191.0410.
2-Phenylsulphanylthiazole-5-carboxaldehyde. Oxidation
of the above-mentioned product, as for 5, gave a pale yellow
oil which was purified by radial chromatography on silica
(ether–dichloromethane, 1:4) as a pale yellow oil (0.64 g;
99%). 1H NMR d: 7.47–7.59 (m, 3H); 7.66–7.72 (m, 2H);
8.20 (s, 1H); 9.81 (s, 1H). 13C NMR d: 128.9, 130.3, 131.1,
135.2, 138.7, 152.14 180.1, 180.9. IR nmax: 1657, 1508,
1388, 1345, 1271, 1233, 1165, 1050 cmϪ1. Mass spectrum
m/z: 221 (M, 100%), 220 (96), 192 (14), 109 (25), 89 (18),
86 (11). HRMS calcd for C10H7NOS2 220.9969, found
220.9973.
2-Phenylthiazole-4-carboxaldehyde. Swern oxidation as
above gave a yellow oil which was purified by radial chro-
matography on silica (dichloromethane) as a pale yellow oil
that solidified on standing and was not further purified
1
(0.59 g; 99%) (lit.15 mp 52ЊC). H NMR d: 7.43–7.50 (m,
3H); 7.96–8.04 (m, 2H); 8.17 (s, 1H); 10.08 (s, 1H). 13C
NMR d: 126.8, 127.3, 129.1, 130.9, 132.5, 155.6, 169.6,
184.9. IR nmax:1683, 1469, 1440, 1133, 1006 cmϪ1. Mass
spectrum m/z: 189 (M, 72%), 150 (89), 128 (28), 104 (21),
86 (24). HRMS calcd for C10H7NOS 189.0248, found
189.0252.
(E)-3-(2-Phenylsulphanylthiazol-5-yl)propenoic acid 11.
Acid 11 was obtained following the above procedure, and
was recrystallised from ethyl acetate–light petroleum as
pale yellow needles (116 mg; 97%), mp 142–144ЊC. Anal
for C12H9NO2S2, calcd C, 54.8; H, 3.4; N, 5.3%; found C,
54.5; H, 3.1; N, 5.3%. 1H NMR d: 5.92 (d, Jˆ15.6 Hz, 1H);
7.45–7.57 (m, 3H); 7.66–7.79 (m, 4H). 13C NMR d: 118.5,
(E)-3-(2-Phenylthiazol-4-yl)propenoic acid 14. The crude
product, obtained as above with 7, was recrystallised from

D. S. Millan et al. / Tetrahedron 56 (2000) 811–816
815
ethyl acetate–light petroleum as a pale brown powder
(0.30 g; 98%), mp 188–190ЊC (lit.16 mp 192–194ЊC).
Anal for C12H9NO2S, calcd C, 62.3; H, 3.9; N, 6.1%;
found C, 61.8; H, 3.9; N, 6.4%. 1H NMR (CDCl3/
(CD3)2SO) d: 6.87 (d, Jˆ15.5 Hz, 1H); 7.42–7.54 (m,
4H); 7.67 (d, Jˆ15.5 Hz, 1H); 7.94–8.04 (m, 2H). 13C
NMR (CDCl3/(CD3)2SO) d: 120.7, 121.7, 126.8, 129.1,
130.7, 133.0, 137.3, 152.44 169.1, 169.9. IR nmax: 3097,
1667, 1435, 1321 cmϪ1. Mass spectrum m/z: 231 (M,
10%), 187 (100). HRMS calcd for C12H9NO2S 231.0354,
found 231.0357.
134.1, 150.4, 161.0, 172.1. IR nmax: 3570, 1699, 1654,
1590, 1458, 1309, 1275, 1186 cmϪ1. Mass spectrum m/z:
167 (M, 48%), 149 (55), 123 (52), 111 (29), 80 (34), 43
(100). HRMS calcd for C8H9NO3 167.0582, found
167.0587.
(Z)-3-(2,5-Dimethyloxazol-4-yl)propenoic acid 18. Photoly-
sis for 1 h gave a cream solid that contained a 3:2 mixture of
(Z)-18 and (E)-propenoic acid 17. (Z)-propenoic acid 18: 1H
NMR d: 2.43 (s, 3H); 2.53 (s, 3H); 5.92 (d, Jˆ13.1 Hz, 1H);
6.60 (d, Jˆ13.1 Hz, 1H). 13C NMR d: 9.8, 13.3, 121.1,
125.3, 129.8, 151.2, 159.6, 166.8.
(Z)-3-(2-Phenylthiazol-4-yl)propenoic acid 15. Photolysis
for 1 h gave a yellow-brown solid, which was identified as
a mixture (2:1) of the (Z)-15 and (E)-propenoic acid 14.
(Z)-propenoic acid 15: 1H NMR (CDCl3/(CD3)2SO) d:
6.11 (d, Jˆ13.1 Hz, 1H); 6.86 (d, Jˆ13.1 Hz, 1H);
7.42–7.60 (m, 3H); 7.62 (s, 1H); 7.86–7.94 (m, 2H). 13C
NMR (CDCl3/(CD3)2SO) d: 123.3, 124.1, 126.8, 129.0,
129.5, 130.7, 131.9, 149.5, 166.4, 169.9.
Diethyl 2-(2,5-dimethyloxazol-4-yl)methylenemalonate.
2,5-Dimethyloxazole-4-carboxaldehyde and diethyl malo-
nate were reacted as above. After 16 h at 20ЊC water
(20 mL) was added and the mixture extracted twice with
ether (40 mL). The resulting pale yellow oil was diluted
with light petroleum (10 mL) and cooled to Ϫ5ЊC for 16 h
to give a solid, which was washed twice with light petro-
leum (20 mL) and recrystallised from ether–light petroleum
as white cubes (0.47 g; 63%), mp 50–51ЊC. Anal for
C13H17NO5, calcd C, 58.4; H, 6.4; N, 5.2%; found C, 58.5;
H, 6.2; N, 5.3%. 1H NMR d: 1.32 (t, Jˆ7.2 Hz, 3H); 1.37 (t,
Jˆ7.2 Hz, 3H); 2.37 (s, 3H); 2.39 (s, 3H); 4.28 (q,
Jˆ7.2 Hz, 2H); 4.40 (q, Jˆ7.2 Hz, 2H); 7.40 (s, 1H). 13C
NMR d: 10.3, 13.7, 13.8, 14.0, 61.3, 124.3, 128.8, 130.7,
152.14 160.1, 164.5, 166.7. IR nmax: 1729, 1708, 1463,
1286, 1247, 1199 cmϪ1. Mass spectrum m/z: 267 (M,
14%), 221 (100), 149 (15), 123 (15). HRMS calcd for
C13H17NO5 267.1107, found 267.1104.
Dimethyl 2-(2-phenylthiazol-4-yl)methylenemalonate. The
crude product was purified by radial chromatography on
silica (ether–dichloromethane–light petroleum, 1:2:7) as a
pale yellow oil that solidified on standing, and was
recrystallised from ether–dichloromethane–light petroleum
as a white powder (0.26 g; 81%), mp 88–89ЊC. Anal for
C15H13NO4S, calcd C, 59.4; H, 4.3; N, 4.6%; found C,
1
59.4; H, 4.3; N, 4.6%. H NMR d: 3.86 (s, 3H); 3.95 (s,
3H); 7.42–7.49 (m, 3H); 7.58 (s, 1H); 7.66 (s, 1H); 7.88–
7.95 (m, 2H). 13C NMR d: 52.6, 52.7, 125.0, 126.0, 126.9,
129.1, 130.8, 133.1, 133.1, 150.2, 164.8, 167.0, 169.0. IR
nmax: 3123, 1729, 1629, 1459, 1255, 1232, 1213 cmϪ1. Mass
spectrum m/z: 303 (M, 100%), 272 (65), 244 (54), 215 (11),
204 (13), 189 (14). HRMS calcd for C15H13NO4S 303.0565,
found 303.0575.
5-Methyl-2-phenyl-4-hydroxymethyloxazole. The oxazole
was prepared by the procedure of Smith19 as white needles
(1.43 g; 82%), mp 111–112ЊC (lit.20 118–119ЊC). 1H NMR
d: 2.17 (s, 3H); 3.20 (bs, 1H); 4.66 (s, 2H); 7.37–7.45
(m, 3H); 7.93–9.02 (m, 2H). 13C NMR d: 11.2, 53.9,
2,5-Dimethyl-4-hydroxymethyloxazole. The starting
oxazole was prepared by the procedure of Treibs and
Sutter17 as a pale yellow solid that was recrystallised from
ether–light petroleum as pale orange cubes (1.86 g; 57%),
mp 76–78ЊC (lit.18 82–84ЊC). 1H NMR d: 2.28 (s, 3H); 2.39
(s, 3H); 4.46 (s, 2H); 4.72 (bs, 1H). 13C NMR d: 9.7, 13.4,
55.1, 130.0, 144.7, 160.0. IR nmax: 3253, 1585, 1456, 1378,
1284, 1025, 816 cmϪ1. Mass spectrum m/z: 127 (M, 48%),
110 (22), 98 (11), 86 (21), 43 (100). HRMS calcd for
C6H9NO2 127.0633, found 127.0633.
126.2, 127.1, 128.7, 130.34 134.8, 145.6, 160.5. IR nmax:
3203, 1461, 1551, 1446, 1017, 783 cmϪ1. Mass spectrum
m/z: 189 (M, 100%), 172 (79), 130 (71), 105 (90), 77
(66). HRMS calcd for C11H11NO2 189.0790, found
189.0788.
5-Methyl-2-phenyloxazole-4-carboxaldehyde. Swern oxida-
tion as above gave pale green needles of the title compound
1
(0.37 g; 53%), mp 103–104ЊC (lit.21 mp 90.5–91.5ЊC). H
NMR d: 2.56 (s, 3H); 7.43–7.62 (m, 3H); 8.08–8.22 (m,
2H). 13C NMR d: 12.6, 125.8, 127.5, 128.9, 132.0, 145.0,
150.1, 163.8, 176.3. IR nmax: 1673, 826 cmϪ1. Mass spec-
trum m/z: 187 (M, 100%), 158 (53), 130 (82), 104 (35).
HRMS calcd for C11H9NO2 187.0633, found 187.0633.
2,5-Dimethyloxazole-4-carboxaldehyde.
The
crude
product was purified by radial chromatography on silica
(dichloromethane–light petroleum, 1:1) as a pale yellow
oil18 (0.71 g; 80%). H NMR d: 2.48 (s, 3H); 2.60 (s, 3H);
1
9.90 (s, 1H). 13C NMR d: 11.0, 13.2, 134.7, 156.4, 160.2,
184.8. IR nmax: 1699, 1614 cmϪ1. Mass spectrum m/z: 125
(M, 95%), 110 (55), 84 (48), 82 (44), 43 (100). HRMS calcd
for C6H7NO2 125.0477, found 125.0480.
(E)-3-(5-Methyl-2-phenyloxazol-4-yl)propenoic acid 20.
Reaction of the above aldehyde with malonic acid gave a
solid that was recrystallised from ethyl acetate–light
petroleum as a pale brown powder (235 mg; 96%), mp
1
150–152ЊC. H NMR d: 2.38 (s, 3H); 6.36 (d, Jˆ15.4 Hz,
(E)-3-(2,5-Dimethyloxazol-4-yl)propenoic acid 17. The
usual procedure gave the title compound 17 (0.26 g;
64%), mp 150–152ЊC. Anal for C8H9NO3, calcd C, 57.5;
H, 5.4; N, 8.4%; found C, 57.6; H, 5.5; N, 8.2%. 1H NMR d:
2.40 (s, 3H); 2.46 (s, 3H); 6.52 (d, Jˆ15.6 Hz, 1H); 7.52 (d,
Jˆ15.6 Hz, 1H). 13C NMR d: 10.2, 13.5, 117.4, 131.8,
1H); 7.38–7.60 (m, 3H); 7.59 (d, Jˆ15.4 Hz, 1H); 8.00–
8.20 (m, 2H). 13C NMR d: 12.0, 115.0, 126.4, 126.9, 128.9,
131.3, 143.0, 143.4, 162.3, 171.8. IR nmax: 3063, 1716,
1704, 1638, 1457, 1258, 1174 cmϪ1. Mass spectrum m/z:
229 (M, 100%), 126 (63), 105 (70). HRMS calcd for
C13H11NO3 229.0739, found 229.0738.

816
D. S. Millan et al. / Tetrahedron 56 (2000) 811–816
7. Sirieix, J.; de Viguerie, N.; Riviere, M.; Lattes, A. New J. Chem.
1999, 103–109.
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C. M. Tetrahedron Lett. 1996, 37, 675–678; Prager, R. H.; Smith,
J. A.; Weber, B.; Williams, C. M. J. Chem. Soc., Perkin Trans. 1
1997, 2665–2672.
Potassium dicarboxylate compounds 10, 13, 16 and 19.
The dicarboxylate compounds 10, 13, 16 and 19 were
prepared from the diester compounds by stirring each with
two molar equivalents of potassium hydroxide in ethanol
for 1 h at 20ЊC. The solvent was evaporated to give a
white solid confirmed to be the potassium salt by NMR
spectroscopy.
9. Prager, R. H.; Taylor, M. R.; Williams, C. M. J. Chem. Soc.,
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10. Lehnert, W. Tetrahedron Lett. 1970, 54, 4723–4724.
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Acknowledgements
The authors are grateful to the Australian Research Council
for support of this work. D.S.M. acknowledges the
Australian Post-graduate Award.
13. Badr, M. Z. A.; Aly, M. M.; Fahmy, A. M.; Mansor, M. E. Y.
Bull Chem. Soc. Jpn. 1981, 54, 1844–1847.
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