The Journal of Organic Chemistry
NOTE
Scheme 3. Synthesis of Bis-Oxazole 29
the product was extracted with EtOAc (2 ꢁ 7 mL). The combined organics
were washed with a saturated solution of brine (4 mL), dried (Na2SO4),
filtered, and purified by flash chromatography or preparative TLC.
Ethyl 2-(4-bromophenyl)oxazole-4-carboxylate (4): colorless
solid, 100%; mp 97ꢀ99 °C; Rf 0.31 (4:1, petrolꢀEtOAc); νmax/cmꢀ1
3171, 3011, 1736; 1H NMR (400 MHz, CDCl3) δ8.30 (s, 1 H), 8.01 (d, J=
8.5 Hz, 2 H), 7.65 (d, J = 8.5 Hz, 2 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.44 (t, J =
7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.6, 161.2, 143.8, 134.8,
132.1, 128.3, 125.8, 125.3, 61.4, 14.3; HRMS (ESI) calcd for C12H10
BrNNaO3 [M þ Na]þ 317.9742, found 317.9726.
Ethyl 2-(4-nitrophenyl)oxazole-4-carboxylate (18): pale yel-
low solid, 80%; mp 120ꢀ122 °C; Rf 0.18(4:1, petrolꢀEtOAc); νmax/cmꢀ1
2927, 2855, 1738, 1526; 1H NMR (400 MHz, CDCl3) δ 8.35 (m, 5 H),
4.47 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 160.9, 160.3, 149.2, 144.7, 135.5, 131.8, 127.8, 124.2, 61.6, 14.3;
HRMS (ESI) calcd for C12H10N2NaO5 [M þ Na]þ 285.0487, found
285.0469.
Scheme 4. Possible Mechanism for Silver-Mediated Oxazole
Formation
Ethyl 2-(3-nitrophenyl)oxazole-4-carboxylate (19). colorless
solid, 81%; mp 124ꢀ126 °C; Rf 0.15 (4:1, petrolꢀEtOAc); νmax/cmꢀ1
2959, 1738, 1521; 1H NMR (400 MHz, CDCl3) δ 8.97 (app t, J = 1.8 Hz,
1 H), 8.49(m, 1 H), 8.38 (ddd, J = 8.4, 2.3, 1.1Hz, 1 H), 8.37 (s, 1 H), 7.72
(t, J = 8.2 Hz, 1 H), 4.47 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 160.9, 160.1, 148.6, 144.4, 135.1, 132.4,
130.2, 128.0, 125.6, 121.7, 61.6, 14.1; HRMS (ESI) calcd for
C12H10N2NaO5 [M þ Na]þ 285.0487, found 285.0469.
Ethyl 2-(furan-2-yl)oxazole-4-carboxylate (21): colorless solid,
81%; mp 46ꢀ48 °C; Rf 0.20 (4:1, petrolꢀEtOAc); νmax/cmꢀ1 3172,
3010, 1737; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1 H), 7.61 (dd, J =
1.7, 0.7 Hz, 1 H), 7.19 (dd, J = 3.5, 0.6 Hz, 1 H), 6.58 (dd, J = 3.5, 1.8 Hz, 1
H), 4.44 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 161.0, 154.9, 145.1, 143.1, 141.9, 134.6, 113.2, 112.0,
61.4, 14.3; HRMS (ESI) calcd for C10H9NNaO4 [M þ Na]þ 230.0429,
found 230.0423.
2-Bromo-1-[2-(4-methoxyphenyl)oxazol-4-yl]ethanone
(31): white solid, 47%; mp 147ꢀ148 °C; νmax/cmꢀ1 (neat) 3124, 3072,
2956, 1697, 1462; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1 H),
8.01ꢀ8.03 (m, 2 H), 6.99ꢀ7.01 (m, 2 H), 4.53 (s, 2 H), 3.89 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 186.3, 162.3, 162.1, 142.5, 139.2, 128.6,
118.9, 114.3, 55.4, 32.1; HRMS (ESI) calcd for C12H10BrNNaO3 [M þ
Na]þ 317.9736, found 317.9728.
Bis- and polyoxazoles are common motifs in many natural
products, for example diazonamide A19 and telomestatin,20 and
we were keen to establish if our methodology could be extended
to the synthesis of simple bis-oxazoles. In a test experiment, when
1,4-dibromo-2,3-butanedione (30) was reacted with 4-methoxy-
benzamide (7), a separable mixture of mono-oxazole 31 and bis-
oxazole 29 were recovered in 47% and 37% isolated yield,
respectively (Scheme 3). This preliminary result was encourag-
ing for more detailed studies.
Mechanistically, we suppose that the silver salt activates the
R-bromo-group in 2 to nucleophilic attack by the amide 1, driven
by the formation of a strong silver bromide bond.
Dehydration of the oxazoline intermediate 3 may be assisted by
protonation of the tertiary alcohol by the conjugate acid HSbF6, or
perhaps by coordination to silver (Scheme 4). Detailed investiga-
tions are underway and will be reported in due course.
In conclusion, we have developed a silver-mediated one-step
synthesis of di- and trisubstituted oxazoles from primary amides
and activated β-bromo-R-ketones. The method is simple to
perform under mild conditions. The silver salt (AgBr) can be
readily recovered at the end of the reaction by simple filtration.
The yields obtained are superior compared to many other
methods.3ꢀ5 We believe that our method complements related
technologies, providing an alternative to known syntheses of
oxazoles, especially those pertaining to the synthesis of oxazole-
4-carboxylates.3b,c,8,9,13
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details and
b
analytical data (NMR, HRMS, IR) for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: john.moses@nottingham.ac.uk.
’ ACKNOWLEDGMENT
’ EXPERIMENTAL SECTION
The authors would like to thank the EPSRC, AICR, GSK, and
the University of Nottingham for support. We also would like to
thank Dr. Pallavi Sharma for fruitful discussion.
General Microwave Procedure for Optimized Conditions.
To a dry tube under Ar atmosphere were added the amide (0.30 mmol), β-
bromo-R-oxoester (0.30 mmol), anhydrous 1,2-dichloroethane (0.45 mL),
and AgSbF6 (0.30 mmol, 103 mg). The mixture was stirred for 1 min then
heated to 90 °C in a sealed tube in a microwave reactor for 2 h (3 h in the
case of 27) with stirring. After this time the reaction was cooled to room
temperature and a saturated solution of NaHCO3 (5 mL) was added and
’ REFERENCES
(1) Palmer, D. C.; Taylor, E. C. The Chemistry of Heterocyclic
Compounds. Oxazoles: Synthesis, Reactions and Spectroscopy, Parts A & B;
Wiley: Hoboken, NJ, 2004; Vol. 60.
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dx.doi.org/10.1021/jo1025332 |J. Org. Chem. 2011, 76, 3519–3522