New Efficient Synthesis of 5-Ethoxyoxazoles and Oxazolo[3,2-c]quinazolines via Aza-Wittig Reaction

Abstract

5-Ethoxyoxazoles or 2-acylamino propanoates were synthesized by aza-Wittig reaction of iminophosphorane with acyl chloride in the presence of triethylamine. Reactions of 5-alkoxyoxazole with triphenyphosphine produced iminophosphoranes. A tandem aza-Wittig reaction of iminophosphorane with isocyanate or carbon disulfide generated oxazolo[3,2-c]quinazolines in satisfactory yields.

Key words

oxazole - oxazolo[3,2-c]quinazoline - aza Wittig reaction - carbodiimide - imidoyl chloride

References and Notes

• 1a Palmer DC. Venkatraman S. Oxazoles: Synthesis, Reactions, and Spectroscopy   Part A:  John Wiley; New York: 2003.  p.1-390  
• 1b Wasserman HH. McCarthy KE. Prowse KS. Chem. Rev.  1986,  86:  845 
• 1c Hartner FW. In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Shinkai I. Pergamon; Oxford UK: 1996.  p.262-318  
• 2 Jacobi PA. Lee K. J. Am. Chem. Soc.  1997,  119:  3409 
• 3a Doyle KJ. Moody CJ. Tetrahedron  1994,  50:  3761 
• 3b Moody CJ. Bagley MC. Synlett  1998,  361 
• 3c Ducept PC. Marsden SP. Synlett  2000,  692 
• 4a Huang W.-S. Zhang Y.-X. Yuan C.-Y. Synth. Commun.  1996,  26:  1149 
• 4b Bossio R. Marcaccini S. Pepino R. Heterocycles  1986,  24:  2003 
• 5a Jacobi PA. Kaczmarek CSR. Udodong UES. Tetrahedron  1987,  43:  5475 
• 5b Nahm S. Weinreb SM. Tetrahedron Lett.  1981,  22:  3815 
• 5c Collins DJ. Hughes TC. Johnson WM. Aust. J. Chem.  1996,  49:  463 
• 6a Chan J. Faul M. Tetrahedron Lett.  2006,  47:  3361 
• 6b Palacios F. Herran E. Alonso C. Rubiales G. Lecea B. Ayerbe M. Cossio FP. J. Org. Chem.  2006,  71:  6020 
• 6c Lertpibulpanya D. Marsden SP. Rodriguez-Garcia I. Kilner CA. Angew. Chem. Int. Ed.  2006,  45:  5000 
• 6d Palacios F. Alonso C. Aparicio D. Rubiales G. Santos JM. Tetrahedron  2007,  63:  523 
• 6e Zanatta N. Schneider JMFM. Schneider PH. Wouters AD. Bonacorso HG. Martins MAP. Wessjohann LA. J. Org. Chem.  2006,  71:  6996 
• 7 Takeuchi H. Yanagida S. Ozaki T. Hagiwara S. Eguchi S. J. Org. Chem.  1989,  54:  431 
• 8 Molina P. Fresneda PM. Almendros P. Heterocycles  1993,  36:  2255 
• 9 Zbiral E. Bauer E. Stroh J. Monatsh. Chem.  1971,  102:  168 
• 10a Ding MW. Xu SZ. Zhao JF. J. Org. Chem.  2004,  69:  8366 
• 10b Zhao JF. Xie C. Xu SZ. Ding MW. Xiao WJ. Org. Biomol. Chem.  2006,  4:  130 
• 10c Yuan JZ. Fu BQ. Ding MW. Yang GF. Eur. J. Org. Chem.  2006,  4170 
• 10d Ding MW. Fu BQ. Cheng L. Synthesis  2004,  1067 
• 10e Li HX. Xie C. Ding MW. Liu ZM. Yang GF. Synlett  2007,  2280 
• 10f Liu MG. Hu YG. Ding MW. Tetrahedron  2008,  64:  9052 

11

Oxazoles 4 and 2-Acylaminopropanoates 5
To a stirred solution of azide 1 (1.0 mmol) in CH₂Cl₂ (10 mL) was added a solution of Ph₃P (0.26 g, 1 mmol) in dry CH₂Cl₂ (5 mL) at r.t. After the reaction mixture was stirred for 2 h, acyl chloride (1.0 mmol) and Et₃N (0.30 g, 3.0 mmol) were added at r.t., and the color of the solution turned yellow. After stirring for 4 h, the mixture was filtered to remove the Et₃NHCl, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography (5:1, PE-Et₂O) to yield oxazoles 4 or
2-acylaminopropanoates 5.
Spectral Data for Some Unreported Compounds
Compound 4c: light yellow solid, mp 60-61 ˚C. IR (KBr): 1620, 1487, 1282, 1093, 1005 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.68-7.21 (m, 4 H, ArH), 6.05 (s, 1 H, ArH), 4.00 (q, J = 7.2 Hz, 2 H, OCH₂), 1.30 (t, J = 7.0 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.5, 150.9, 134.8, 128.5, 128.4, 126.2, 125.9, 125.7, 100.3, 100.1, 67.6, 14.2, 14.0. MS: m/z (%) = 223 (90) [M⁺], 195 (73), 167 (23), 139 (100), 111 (64). Anal. Calcd. for C₁₁H₁₀ClNO₂: C, 59.07; H, 4.51; N, 6.26. Found: C, 59.01; H, 4.61; N, 6.44.
Compound 4d: white solid, mp 52-54 ˚C. IR (KBr): 1613, 1503, 1282, 1222, 1046, 1008 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.91-7.07 (m, 4 H, ArH), 6.18 (s, 1 H, ArH), 4.20-4.13 (m, 2 H, OCH₂), 1.48-1.43 (m, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 164.1, 161.7, 159.4, 151.0, 126.9, 126.5, 123.6, 115.5, 115.3, 115.2, 114.9, 100.1, 99.7, 67.7, 67.4, 67.2, 13.9, 13.8. MS: m/z (%) = 207 (71) [M⁺], 178 (45), 151 (36), 134 (17), 123 (100), 107 (25). Anal. Calcd for C₁₁H₁₀FNO₂: C, 63.76; H, 4.86; N, 6.76. Found: C, 63.50; H, 4.98; N, 6.71.
Compound 4e: white solid, mp 46-47 ˚C. IR (KBr): 1613, 1503, 1279, 1099, 1046, 1008 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.81-7.21 (m, 4 H, ArH), 6.18 (s, 1 H, ArH), 4.16 (q, J = 7.2 Hz, 2 H, OCH₂), 2.37 (s, 3 H, CH₃), 1.45 (t, J = 7.2 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.4, 152.7, 139.5, 129.3, 129.2, 125.2, 125.0, 124.8, 100.4, 100.1, 67.9, 21.4, 21.2, 14.5, 14.3. MS: m/z (%) = 203 (14) [M⁺], 174 (5), 147 (13), 119 (100), 91 (20). Anal. Calcd for C₁₂H₁₃NO₂: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.60; N, 6.76.
Compound 4f: white solid, mp 51-52 ˚C. IR (KBr): 1616, 1506, 1254, 1024 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.8 Hz, 2 H, ArH), 6.91 (d, J = 8.8 Hz, 2 H, ArH), 6.15 (s, 1 H, ArH), 4.10 (q, J = 7.2 Hz, 2 H, OCH₂), 3.78 (s, 3 H, OCH₃), 1.41 (t, J = 7.2 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 160.3, 159.1, 152.2, 126.5, 120.1, 113.7, 99.9, 67.6, 54.8, 14.1. MS: m/z (%) = 219 (24) [M⁺], 190 (20), 163 (3), 135 (100), 118 (3), 107 (6). Anal. Calcd for C₁₂H₁₃NO₃: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.67; H, 6.05; N, 6.44.
Compound 4g: white solid, mp 50-51 ˚C. IR (KBr): 1601, 1556, 1481, 1282, 1043, 1005 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.86-7.28 (m, 4 H, ArH), 6.18 (s, 1 H, ArH), 4.13 (q, J = 7.0 Hz, 2 H, OCH₂), 1.42 (t, J = 7.0 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 150.6, 134.4, 129.7, 129.0, 124.9, 122.9, 100.6, 67.8, 14.2. MS: m/z (%) = 223 (19) [M⁺], 195 (22), 167 (16), 139 (100). Anal. Calcd for C₁₁H₁₀ClNO₂: C, 59.07; H, 4.51; N, 6.26. Found: C, 59.19; H, 4.70; N, 6.32.
Compound 4h: white solid, mp 45-46 ˚C. IR (KBr): 1610, 1497, 1478, 1282, 1229, 1043, 1027 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.91-7.11 (m, 4 H, ArH), 6.27 (s, 1 H, ArH), 4.16 (q, J = 7.0 Hz, 2 H, OCH₂), 1.43 (t, J = 7.0 Hz,
3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 160.4, 159.6, 157.9, 148.3, 130.7, 130.6, 128.1, 123.9, 116.4, 116.2, 115.5, 115.4, 100.4, 67.7, 14.1. MS: m/z (%) = 207 (16) [M⁺], 179 (13), 151 (6), 123 (100), 95 (22). Anal. Calcd for C₁₁H₁₀FNO₂: C, 63.76; H, 4.86; N, 6.76. Found: C, 63.70; H, 4.98; N, 6.83.
Compound 4i: light yellow solid, mp 52-54 ˚C. IR (KBr): 2130 (N₃), 1610 (C=O), 1594, 1493, 1304, 1285, 1033, 1005 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.88-7.17 (m, 4 H, ArH), 6.28 (s, 1 H, ArH), 4.19 (q, J = 7.0 Hz, 2 H, OCH₂), 1.47 (t, J = 7.0 Hz, 3 H, CH₃). MS: m/z (%) = 230 (50) [M⁺], 202 (39), 173 (55), 145 (57), 118 (29), 90 (100). Anal. Calcd for C₁₁H₁₀N₄O₂: C, 57.39; H, 4.38; N, 24.34. Found: C, 57.45; H, 4.50; N, 24.49.
Compound 4k: light yellow oil. ^¹H NMR (600 MHz, CDCl₃): δ = 7.80-7.21 (m, 4 H, ArH), 4.22 (q, J = 7.0 Hz,
2 H, OCH₂), 2.37 (s, 3 H, CH₃), 2.11 (s, 3 H, CH₃), 1.40 (t, J = 7.2 Hz, 3 H, CH₃). MS: m/z (%) = 217 (5) [M⁺], 136 (2), 119 (62), 91 (100).
Compound 4l: white solid, mp 83-85 ˚C. ^¹H NMR (600 MHz, CDCl₃): δ = 7.85-7.37 (m, 4 H, ArH), 4.23 (q, J = 7.2 Hz, 2 H, OCH₂), 2.11 (s, 3 H, CH₃), 1.40 (t, J = 7.2 Hz, 3 H, CH₃). MS: m/z (%) = 237 (75) [M⁺], 207 (13), 138 (100), 110 (43). Anal. Calcd for C₁₂H₁₂ClNO₂: C, 60.64; H, 5.09; N, 5.89. Found: C, 60.47; H, 5.24; N, 5.95.
Compound 5a: white solid, mp 76-77 ˚C. IR (KBr): 3347 (NH), 1749 (C=O), 1642, 1528, 1493, 1213, 1181 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.82-7.42 (m, 5 H, ArH), 6.84 (d, J = 6.4 Hz, 1 H, NH), 4.82-4.76 (m, 1 H, NCH), 4.24 (q, J = 7.0 Hz, 2 H, OCH₂), 1.52 (d, J = 6.8 Hz, 3 H, CH₃), 1.31 (t, J = 7.2 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.2, 166.7, 133.9, 131.6, 128.5, 127.0, 61.6, 48.5, 18.6, 14.1. MS: m/z (%) = 221 (4) [M⁺], 148 (66), 105 (100), 77 (24). Anal. Calcd for C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.33; H, 6.98; N, 6.43.
Compound 5b: white solid, mp 117-118 ˚C. IR (KBr): 3290 (NH), 1742 (C=O), 1635, 1556, 1203, 1162, 1024 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.72-7.23 (m, 4 H, ArH), 6.75 (d, J = 6.8 Hz, 1 H, NH), 4.82-4.74 (m, 1 H, NCH), 4.24 (q, J = 7.2 Hz, 2 H, OCH₂), 2.40 (s, 3 H, CH₃), 1.52 (d, J = 7.2 Hz, 3 H, CH₃), 1.31 (t, J = 7.2 Hz, 3 H, CH₃).
MS: m/z (%) = 235 (6) [M⁺], 162 (29), 119 (100), 91 (13). Anal. Calcd for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.44; H, 7.40; N, 5.99.
Compound 5c: white solid, mp 98-99 ˚C. IR (KBr): 3293 (NH), 1742, 1626, 1544, 1487, 1216, 1166, 1093, 1017
cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.4 Hz, 2 H, ArH), 7.40 (d, J = 8.4 Hz, 2 H, ArH), 6.84 (br, 1 H, NH), 4.80-4.72 (m, 1 H, NCH), 4.25 (q, J = 7.2 Hz, 2 H, OCH₂), 1.52 (d, J = 7.2 Hz, 3 H, CH₃), 1.32 (t, J = 7.2 Hz, 3 H, CH₃). MS: m/z (%) = 255 (4) [M⁺], 182 (68), 139 (100), 111 (14). Anal. Calcd for C₁₃H₁₇NO₃: C, 56.37; H, 5.52; N, 5.48. Found: C, 56.45; H, 5.78; N, 5.59.

12

Iminophosphorane 6 To a stirred solution of 4i (1.15 g, 5 mmol) in CH₂Cl₂ (15 mL) was added a solution of Ph₃P (1.31 g, 5 mmol) in dry CH₂Cl₂ (10 mL). After the reaction mixture was stirred for 2 h, the solvent was removed under reduced pressure, and the residue was recrystallized from Et₂O and EtOH (1:1; v/v) to give the iminophosphorane 6 (2.22 g, yield 96%); light yellow crystals; mp 175-177 ˚C. IR (KBr): 1606, 1468, 1435, 1353, 1271, 1118, 1035cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.86-6.53 (m, 19 H, ArH), 6.23 (s, 1 H, ArH), 4.14 (q, J = 7.0 Hz, 2 H, OCH₂), 1.45 (t, J = 7.0 Hz, 3 H, CH₃). MS: m/z (%) = 464 (100) [M⁺], 435 (65), 380 (92), 277 (18), 261 (10), 201 (11), 183 (16), 145 (16). Anal. Calcd for C₂₉H₂₅N₂O₂P: C, 74.99; H, 5.42; N, 6.03. Found: C, 74.77; H, 5.60; N, 6.12.

13

Oxazolo[3,2- c ]quinazolines 8 To a solution of iminophosphorane 6 (0.46 g, 1 mmol) in dry CH₂Cl₂ (10 mL) was added aryl isocyanate (1 mmol) under nitrogen at r.t. The solution turned red immediately. After stirred for 1 h, the solvent was evaporated under reduced pressure, and the residue was recrystallized from Et₂O and EtOH (1:1, v/v) to give oxazolo[3,2-c]quinazolines 8 as red crystals.
Compound 8a: red crystals, mp 151 ˚C (dec.). IR (KBr): 1764, 1690, 1640, 1560, 1474, 1440, 1307, 1251 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.68-6.94 (m, 10 H, ArH), 4.39 (q, J = 7.0 Hz, 2 H, OCH₂), 1.58 (t, J = 7.0 Hz, 3 H, CH₃). ^¹³C NMR (150 MHz, CDCl₃): δ = 157.5, 153.2, 150.8, 147.2, 143.4, 135.5, 129.1, 128.4, 125.6, 123.3, 121.7, 120.4, 102.7, 87.9, 70.5, 14.3. MS: m/z (%) = 305 (53) [M⁺], 248 (29), 231 (100), 205 (60), 166 (15), 104 (10), 90 (22). Anal. Calcd for C₁₈H₁₅N₃O₂: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.90; H, 4.99; N, 13.91.
Compound 8b: red crystals, mp 105-107 ˚C. IR (KBr): 1765, 1689, 1639, 1605, 1471, 1442, 1219, 1165 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.62-6.78 (m, 9 H, ArH), 4.34 (q, J = 7.0 Hz, 2 H, OCH₂), 2.35 (s, 3 H, CH₃), 1.56 (t, J = 7.0 Hz, 3 H, CH₃). ^¹³C NMR (150 MHz, CDCl₃): δ = 157.4, 153.6, 150.8, 148.2, 143.6, 137.8, 135.3, 128.1, 125.4, 124.0, 122.2, 121.6, 120.3, 119.8, 102.3, 87.7, 70.3, 21.6, 14.2. MS: m/z (%) = 319 (6) [M⁺], 291 (100), 262 (13), 248 (46), 235 (28), 91 (5). Anal. Calcd for C₁₉H₁₇N₃O₂: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.59; H, 5.50; N, 13.20.
Compound 8c: red crystals, mp 157 ˚C (dec.). IR (KBr): 1642, 1605, 1558, 1530, 1478, 1441, 1308, 1254, 1032
cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.64-6.92 (m, 9 H, ArH), 4.33 (q, J = 7.2 Hz, 2 H, OCH₂), 1.56 (t, J = 7.2 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 157.6, 152.8, 150.6, 135.7, 129.9, 128.2, 128.1, 126.1, 125.5, 124.4, 121.7, 121.0, 102.9, 88.0, 70.6, 14.3. MS: m/z (%) = 339 (100) [M⁺], 311 (68), 265 (88), 255 (81), 230 (53), 192 (10), 125 (24). Anal. Calcd for C₁₈H₁₄ClN₃O₂: C, 63.63; H, 4.15; N, 12.37. Found: C, 63.89; H, 4.22; N, 12.51.
Compound 8d: red crystals, mp 156 ˚C (dec.). IR (KBr): 1665, 1644, 1610, 1562, 1485, 1441, 1308, 1207, 1032
cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.65-6.89 (m, 9 H, ArH), 4.36 (q, J = 7.0 Hz, 2 H, OCH₂), 1.57 (t, J = 7.0 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 157.4, 156.7, 153.7, 144.7, 143.8, 135.4, 125.3, 124.5, 124.5, 121.7, 119.8, 114.8, 114.6, 102.3, 87.6, 70.3, 14.3. MS: m/z (%) = 323 (32) [M⁺], 295 (26), 266 (33), 250 (100), 239 (89), 223 (36), 125 (45). Anal. Calcd for C₁₈H₁₄FN₃O₂: C, 66.87; H, 4.36;N, 13.00. Found: C, 66.73; H, 4.54; N, 13.25.

14

Oxazolo[3,2- c ]quinazoline 10 To a solution of iminophosphorane 6 (0.46 g, 1 mmol) in MeCN (10 mL) was added CS₂ (1.50 g, 20 mmol). The mixture was heated to reflux for 10 h, the solvent was evaporated under reduced pressure, and the residue was recrystallized from EtOH to give oxazolo[3,2-c]quinazoline 10; yellow crystals, mp 138-139 ˚C. IR (KBr): 1654, 1635, 1484, 1434, 1321, 1298, 1176, 1054 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.94-7.38 (m, 5 H, ArH), 4.47 (q, J = 7.2 Hz, 2 H, OCH₂), 1.61 (t, J = 7.2 Hz, 3 H, CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 157.4, 148.4, 138.4, 135.7, 128.2, 126.8, 125.0, 121.5, 115.5, 91.3, 71.0, 14.2. MS: m/z (%) = 246 (37) [M⁺], 218 (25), 190 (28), 162 (100), 134 (34). Anal. Calcd for C₁₂H₁₀N₂O₂S: C, 58.52; H, 4.09; N, 11.37. Found: C, 58.59; H, 4.21; N, 11.41.