1767
J. I. Trujillo et al.
Letter
Synlett
Org. Chem. 1998, 63, 9606; Note: To our knowledge, no reac-
tions of oxazole triflate/halo to oxazole-SR have been described
in the literature.
Acknowledgment
The authors acknowledge Pfizer Research Laboratories for supporting
this research. We thank Brian Samas (MatSci, PGRD-Groton) for X-ray
structure determination of sulfonamide 15 and Justin Stroh (PGRD-
Groton) for acquisition of high-resolution mass spectrometry.
(10) For reactions of diazospecies with acyl isothiocyanates and iso-
thiocyanates, respectively, see: (a) Regitz, M.; Weber, B.; Heydt,
A. Liebigs Ann. Chem. 1980, 305. (b) Martin, D.; Mucke, W. Justus
Liebigs Ann. Chem. 1965, 682, 90.
(11) (a) Shiori, T.; Aoyama, T.; Snowden, T. In Handbook of Reagents
for Organic Synthesis: Reagents for Silicon-Mediated Organic Syn-
thesis; Fuchs, P. L., Ed.; Wiley: New York, 2011, 590–598.
(b) Heydt, H. Science of Synthesis; Vol. 27; Thieme: Stuttgart,
2014, 843.
Supporting Information
Supporting information for this article is available online at
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(12) (a) Alternatively, an aqueous workup followed by treatment of
crude material with 1 M TBAF in THF (1.0 equiv) facilitated
removal of TMS group at 5-position of the oxazole. (b) A portion
of the remaining mass balance is 5-silyl derivative (ca. 5%),
while the remainder is undetermined.
(13) Skinner, G. S.; Vogt, H. C. J. Am. Chem. Soc. 1955, 77, 5440.
(14) (a) Lowe, D. Med. Chem. Commun. 2015, 6, 12. (b) Reymond, J. L.;
Ruddigkeit, L.; Awale, M. Comput. Chemogenomics 2014, 39.
(15) For recent reports of Ar/HetAr-SO2NHR/SO2Cl, see: (a) Emmet,
E. J.; Hayter, B. R.; Willis, M. C. Angew. Chem. Int. Ed. 2014, 53,
10204. (b) Johnson, M. W.; Bagley, S. W.; Mankad, N. P.;
Bergman, R. G.; Mascitti, V.; Toste, F. D. Angew. Chem. Int. Ed.
2014, 53, 4404. (c) Shavnya, A.; Coffey, S. B.; Smith, A. C.;
Mascitti, V. Org. Lett. 2013, 15, 6226. (d) DeBergh, J. R.;
Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135,
10638.
References and Notes
(1) (a) Ortwine, D. F.; Aliagas, I. Mol. Pharmaceutics 2013, 10, 1153.
(b) Meanwell, N. Chem. Res. Toxicol. 2011, 24, 1420.
(c) Metabolism, Pharmacokinetics and Toxicity of Functional
Groups; Smith, D., Ed.; RSC Publishing: Cambridge, 2010.
(d) TPSA (Topical Polar Surface Area) PropCalc v2.41.
(e) cSFlogD (prediction of distribution coefficient (logD) in
octanol/buffer at pH 7.4) Pfizer Internal Model.
(2) (a) Azman, A. M.; Mullins, R. J. In Heterocyclic Chemistry in Drug
Discovery; Li, J. J., Ed.; Wiley: New York, 2013, 231–281.
(b) Khartulyari, A.; Maier, M. E. Knowledge Updates, In Science of
Synthesis Vol. 3; Thieme: Stuttgart, 2011, 57.
(3) For the preparation of 2,4-disubstituted oxazole carboxylate
derivatives, see: Graham, T. Org. Lett. 2010, 12, 3614; and refer-
ences cited therein.
(16) For a recent report of 2,4,5-trisubstituted oxazole sulfonyl chlo-
ride, see: Kornienko, A. N.; Pil’o, S. G.; Prokopenko, V. M.;
Brovarets, V. S. Russ. J. Gen. Chem. 2014, 84, 686.
(4) For previous reports of 2,4-disubstituted oxazole thio deriva-
tives [SO2Ar, SMe, and SAr (c,d), respectively], see:
(a) Mortensen, D. S.; Perrin-Ninkovic, S. M.; Harris, R.; Lee, B. G.
S.; Shevlin, G.; Hickman, M.; Khambatta, G.; Bisonette, R. R.;
Fultz, K. E.; Sankar, S. Bioorg. Med. Chem. Lett. 2011, 21, 6793.
(b) DeMartino, J. K.; Garfunkle, J.; Hochstatter, D. G.; Cravatt, B.
F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2008, 18, 5842.
(c) Schroeder, R.; Schoellkopf, U.; Blume, E.; Hoppe, I. Justus
Liebigs. Ann. Chem. 1975, 3, 533. (d) Schoellkopf, U.; Blume, E.
Tetrahedron Lett. 1973, 9, 629.
(5) Sheehan, J. C.; Izzo, P. T. J. Am. Chem. Soc. 1949, 71, 4059.
(6) For examples in the synthesis of oxazole-containing natural
products, see: (a) Smith, A. B. III; Verhoest, P. R.; Minbiole, K. P.;
Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 4834. (b) Smith, A. B.
III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem.
Soc. 2001, 123, 10942.
(7) For synthesis of 2,4-substituted oxazole derivatives using tri-
flate, see: (a) Hoffman, T. J.; Rigby, J. H.; Arseniyadis, S.; Cossy, J.
J. Org. Chem. 2008, 73, 2400. (b) Flegeau, E. F.; Popkin, M. E.;
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L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485. (d) Smith, A. B. III;
Minbiole, K. P.; Freeze, S. Synlett 2001, 1739. (e) Barrett, A. G.
M.; Kohrt, J. T. Synlett 1995, 415.
(8) For applications of triflate in the synthesis of druglike com-
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McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D. III; Volante, R. P. J.
(17) General Procedure for Preparation of SBn Derivatives
To a solution of benzoylisothiocyanate (500 mg, 3.06 mmol) in
CH2Cl2 (15.0 mL, 0.12 M) cooled to 0 °C (ice-water bath) for 15
min was added TMSCHN2 (2 M in hexanes, 2.30 mL, 4.60 mmol,
1.5 equiv) slowly. The mixture became orange upon addition.
After stirring for 1 h at 0 °C a yellow suspension was evident. To
the mixture was slowly added DBU (0.92 mL, 6.13 mmol, 2.0
equiv), followed by the addition of BnBr (0.36 mL, 3.06 mmol) at
which time the color dissipated. The reaction allowed to warm
to ambient temperature and stirred overnight. The reaction was
diluted with CH2Cl2 (10 mL) and then washed with brine, dried
(Na2SO4), and the solvent removed to give a residue. The residue
was diluted with CH2Cl2 (10 mL) and HCl in Et2O (2 M) was
added (5 mL). Note: This was done to ensure removal of TMS
group at the 5-position, which was approximately 20% by GC–
MS. Alternatively, use of TBAF (2 M in THF was also used). The
mixture was stirred for 3 h and then portioned between brine
and CH2Cl2. The layers were separated and organic phase
washed with brine, dried (Na2SO4), and the solvent removed to
give a residue, which was purified by chromatography (silica,
12 g RediSep Column Gold, EtOAc–heptane, 0–40%, 15 CVs) to
give the desired product 4-(benzylthio)-2-phenyloxazole (362
mg, 44%) as an oil and N-(1,2,3-thiadiazol-5-yl)benzamide (138
mg, 22%).
4-(Benzylthio)-2-phenyloxazole (12, Table 1 and 14a, Table 2,
entry 1)
1H NMR (400 MHz, CDCl3): δ = 8.02–8.09 (m, 2 H), 7.44–7.52 (m,
3 H), 7.43 (s, 1 H), 7.20–7.33 (m, 5 H), 4.12 (s, 2 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 162.2, 139.4, 137.7, 134.3, 130.7,
130.2, 129.1, 128.9, 128.8, 128.4, 127.2, 127.1, 126.5, 38.6 ppm.
ESI-HRMS: m/z calcd for C16H13NOS [M + H]+: 268.0791; found:
268.0791
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1764–1768