Syntheses of Oxazoles and Thiazoles
FULL PAPER
(125 mL). The filtrate was concentrated under reduced pressure and puri-
fied by column chromatography on silica gel (2:3 to 1:1 gradient of ethyl
acetate in hexane) to afford 2-phenyl-4-(hydroxymethyl)-oxazole (10a)
[1] G. Wuitschik, E. M. Carreira, B. Wagner, H. Fischer, I. Parrilla, F.
as
a light brown solid (125 mg, 36%); Rf =0.25 (1:1 ethyl acetate/
hexane); m.p. 80–818C (lit. m.p. 82–838C);[32] 1H NMR (400 MHz,
CDCl3): d=8.08–8.05 (m, 2H; ArH), 7.68 (s, 1H; H5), 7.49–7.47 (m, 3H;
ArH), 4.71 (d, J=4.6 Hz, 2H; ArCH2OH); 2.26 ppm (brs, 1H; CH2OH);
13C NMR (100 MHz, CDCl3): d=161.7, 141.1, 134.5, 130.0, 128.3, 126.8,
126.0, 58.4 ppm; IR (film): n˜ =3221, 3116, 1740, 1552, 1351, 1231,
1023 cmÀ1; MS (CI): m/z (%): 216 (7) [M+C3H5]+, 204 (13) [M+C2H5]+,
176 (40) [M+H]+, 158 (100) [MÀOH]+), 130 (5); HRMS (ESI): m/z
calcd for C10H10NO2: 176.0706 [M+H]+; found: 176.0705; tR (GC)=
12.71 min. Crystal data for C10H9NO2: Formula weight: 175.18; Tempera-
ture: 123(2) K; l=0.71073 ꢂ; Monoclinic system; Crystal size: 0.24ꢃ
0.18ꢃ0.10 mm3; Unit cell dimensions: a=8.5610(5), b=14.5900(8), c=
7.0504(4) ꢂ, a=90, b=104.625(6), g=908; Z=4; Reflection collected:
3925; R indices (all data): R1=0.0647, wR2=0.1033.
[3] a) M. A. J. Duncton, M. A. Estiarte, D. Tan, C. Kaub, D. J. R.
OꢀMahony, R. J. Johnson, M. Cox, W. T. Edwards, M. Wan, J. Kin-
ton, M. A. Estiarte, R. J. Johnson, M. Cox, D. J. R. OꢀMahony, W. T.
[4] J. A. Burkhard, B. H. Tchitchanov, E. M. Carreira, Angew. Chem.
10, 2717–2720; c) S. A. Ohnmacht, P. Mamone, A. J. Culshaw, M. F.
e) C. M. Counceller, C. C. Eichman, N. Proust, J. P. Stambuli, Adv.
medi, R. Giovannini, M. Mari, L. Marsili, E. Marcantoni, Eur. J.
Typical procedure: Preparation of 7 f: 4-Methoxybenzamide (376 mg,
2.5 mmol) was added to a suspension of P2S5/alumina reagent (773 mg,
3.5 mmol) in anhydrous THF (5 mL) and the reaction mixture was
heated in a microwave reactor at 608C for 20 min until TLC showed
complete conversion. The reaction mixture was evaporated onto a pad of
silica gel (8.6 g), eluted with diethyl ether (50 mL), and the eluent was
concentrated under reduced pressure to afford crude thioamide 7 f as a
yellow solid (660 mg). The crude product was taken up in anhydrous
THF (4 mL) and evaporated onto silica gel (2.6 g). The solid was trans-
ferred onto a pad of silica (10.6 g) in a sinter funnel that had been condi-
tioned with 1:1 diethyl ether/hexane. Non-polar impurities were removed
using 1:1 diethyl ether/hexane and product was eluted with 4:1 diethyl
ether/hexane to afforded 4-(methoxy)thiobenzamide 7 f as a yellow solid
(280 mg, 67%); Rf =0.23 (4:1 diethyl ether/hexane); m.p. 141–1438C;
1H NMR (400 MHz, CDCl3): d=7.92–7.88 (m, 2H; one half of an
AA’BB’ system, ArH), 7.48 (brs, 1H; C(S)NHaHb), 7.09 (brs, 1H;
C(S)NHaHb), 6.92–6.88 (m, 2H; one half of an AA’BB’ system ArH),
3.86 ppm (s, 3H; ArOCH3); 13C NMR (100 MHz, CDCl3): d=201.4,
163.0, 131.3, 129.1, 113.6, 55.6 ppm; IR (film): n˜ =3367, 3278, 3157, 2363,
1626, 1597, 1510, 1427, 1389, 1330, 1285, 1258, 1184, 1138, 1020 cmÀ1; MS
(ESI): m/z (%): 168 (100) [M+H]+, 151 (30) [MÀNH2], 135 (15). The
spectroscopic data were in agreement with those reported in the litera-
[9] R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D.
[10] T. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley, J. S. Scott,
[11] M. L. P. Le, L. Cointeaux, P. Strobel, J. C. Lepretre, P. Judeinstein, F.
[12] a) C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halstead, D. M. P.
[13] a) H. Bilel, N. Hamdi, F. Zagrouba, C. Fischmeister, C. Bruneau,
d) W. P. Jencks, J. Regenstein in Handbook of Biochemistry and Mo-
lecular Biology (Ed.: G. D. Fasman), CRC, Boca Raton, 1976,
pp. 305–351.
[16] For syntheses of thioamides from nitriles, see: a) P. Y. Lin, W. S. Ku,
C. Panuschka, A. Barta, W. Schmid, Synthesis 2008, 4012–4018.
[17] H. R. Lagiakos, A. Walker, M. I. Aguilar, P. Perlmutter, Tetrahedron
Lett. 2011, 52, 5131–5132.
ACHTUNGTRENNUNG
ture.[16a]
Computational methods: Electronic structure calculations were carried
out on a Dell Precision T1500 (Intel 4 Core i7 CPU 870@ 2.93 GHz Pro-
cessor, 8 GB RAM) running Spartanꢀ08 V1.2.0, 64 Bit. Transition struc-
tures were located via initial guesses that were optimised using the PM3
semi-empirical method, then re-optimised initially at the RI-MP2/6-31G*
or B3LYP/6-31G* levels of theory. These structures were then used as
the starting points for MP2/6-31+G*or B3LYP/6-311+G** optimisa-
tions with full frequency calculation at 298 K. Free energies were evaluat-
ed (in au) using Spartanꢀs internal algorithm and transferred to Excel for
further manipulation. Optimised structures had no imaginary frequen-
cies; unique imaginary frequencies were found for transition structures
and these are listed fully with the Cartesian coordinates in the Support-
ing Information.
Acknowledgements
[18] a) P. Ratcliffe, J. M. Adam, J. Baker, R. Bursi, R. Campbell, J. K.
Clark, J. E. Cottney, M. Deehan, A. M. Easson, D. Ecker, D. Ed-
wards, O. Epemolu, L. Evans, R. Fields, S. Francis, P. Harradine, F.
Jeremiah, T. Kiyoi, D. McArthur, A. Morrison, P. Passier, J. Pick,
P. G. Schnabel, J. Schulz, H. Steinbrede, G. Walker, P. Westwood, G.
We thank EPSRC and GSK (Industrial CASE studentship to A.T.), GSK
and the University of Strathclyde (studentship to D. O.), GSK Refractory
Respiratory Inflammation DPU for consumables, the EPSRC National
Mass Spectrometry Service Centre, Swansea for accurate mass measure-
ments, Dr Alan Kennedy (Pure and Applied Chemistry, University of
Strathclyde) for the X-ray structural determination of 10a, Dr. Rob
Young (GSK Stevenage) for helpful discussions about work-up methods,
and David Black (University of Strathclyde) for preliminary syntheses of
oxazoles 10.
[19] a) Z. Y. Li, L. Ma, J. Y. Xu, L. Y. Kong, X. M. Wu, H. Q. Yao,
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
7
&
ÞÞ
These are not the final page numbers!