One-Pot Van Leusen Synthesis of 4,5-Disubstituted Oxazoles in Ionic Liquids

Abstract

An efficient and mild protocol for the preparation of 4,5-disubstituted oxazoles through an improved one-pot van Leusen oxazole synthesis in ionic liquids is described. The oxazole products were prepared from tosylmethyl isocyanide (TosMIC), aliphatic halides and various aldehydes in high yields. The recovered ionic liquids could be reused as solvent for six runs without significant loss of yields.

ionic liquids - van Leusen oxazole synthesis - tosyl­methyl isocyanide - halides - aldehydes

References and Notes

1a Wipf P. Chem. Rev.  1995,  95:  2115 

1b Janvier P. Sun X. Bienayme H. Zhu J. J. Am Chem. Soc.  2002,  124:  2560 

1c Ikemoto N. Miller RA. Fleitz FJ. Liu J. Petrillo DE. Leone JF. Laquidara J. Marcune B. Karady S. Armstrong JD. Volante RP. Tetrahedron Lett.  2005,  46:  1867 

2a Turchi IJ. Dewar MJS. Chem. Rev.  1975,  75:  389 

2b Wasserman HH. McCarthy KE. Prowse KS. Chem. Rev.  1986,  86:  845 

2c Yeh VSC. Tetrahedron  2004,  60:  11995 

2d Martin R. Cuenca A. Buchwald SL. Org. Lett.  2007,  9:  5521 

2e Herrera A. Martinez-Alvarez R. Ramiro P. Molero D. Almy J. J. Org. Chem.  2006,  71:  3026 

2f Davies JR. Kane PD. Moody CJ. Tetrahedron  2004,  60:  3967 

3a Brahma S. Ray JK. J. Heterocycl. Chem.  2008,  45:  311 

3b Li B. Buzon RA. Zhang ZJ. Org. Process Res. Dev.  2007,  11:  951 

3c Baumann M. Baxendale IR. Ley SV. Smith CD. Tranmer GK. Org. Lett.  2006,  8:  5231 

3d Miller RA. Smith RM. Marcune B. J. Org. Chem.  2005,  70:  9074 

3e Davies JR. Kane PD. Moody CJ. Tetrahedron  2004,  60:  3967 

3f Xia Q. Ganem B. Synthesis  2002,  1969 

3g Ohba M. Kubo H. Seto S. Fujii T. Ishibashi H. Chem. Pharm. Bull.  1998,  46:  860 

3h Matsumoto K. Suzuki M. Yoneda N. Miyoshi M. Synthesis  1976,  805 

3i Possel O. Van Leusen A. Heterocycles  1977,  7:  77 

3j van Leusen AM. Hoogenboom BE. Siderius H. Tetrahedron Lett.  1972,  13:  2369 

For reviews, see:

4a Welton T. Chem. Rev.  1999,  99:  2071 

4b Wasserscheid P. Keim W. Angew. Chem. Int. Ed.  2000,  39:  3772 

4c Parvulescu VI. Hardacre C. Chem. Rev.  2007,  107:  2615 

4d van Rantwijk F. Sheldon RA. Chem. Rev.  2007,  107:  2757 

4e Martins MAP. Frizzo CP. Moreira DN. Zanatta N. Bonacorso HG. Chem. Rev.  2008,  108:  2015 

4f de Maria PD. Angew. Chem. Int. Ed.  2008,  47:  2 

5

Wu B., Zhang J., Zheng Z.-G., Yang M., Yu X.-Q.; Chin. J. Chem.; 2008, in press

6 van Leusen AM. Boerma GJM. Helmholdt RB. Siderius H. Strating J. Tetrahedron Lett.  1972,  2367 

7 Sisko J. Mellinger M. Sheldrake PW. Baine NH. Tetrahedron Lett.  1996,  37:  8113 

8 van Leusen AM. Bouma RJ. Possel O. Tetrahedron Lett.  1975,  3487 

9

Representative Preparation of Monosubstituted TosMIC: 1-Bromobutane (5a; 0.206 g, 1.5 mmol) was added to the mixture of TosMIC (4; 0.195 g, 1 mmol), K₂CO₃ (0.414 g, 3 mmol) and [bmim]Br (2.5 mL). After vigorous stirring for 12 h at r.t., the mixture was poured into H₂O (10 mL), and was extracted with Et₂O (3 × 10 mL). The combined organics were washed with H₂O and brine. The organic phase was dried over Na₂SO₄, and concentrated in vacuum. The crude product was purified by chromatography on silica gel (PE-EtOAc, 4:1) to provide pure compound 2a (95%).

10

Representative Preparation of 4,5-Disubstituted Oxazoles: 1-Bromobutane (5a; 0.206 g, 1.5 mmol) was added to the mixture of TosMIC (4; 0.195 g, 1 mmol), K₂CO₃ (0.414 g, 3 mmol) and [bmim]Br (2.5 mL). After vigorous stirring 12 h at r.t., 4 was consumed, and benzaldehyde (6a; 0.127 g, 1.2 mmol) was added. After about 10 h of stirring, the mixture was poured into H₂O (10 mL), and was extracted with Et₂O (3 × 10 mL). The combined organics were washed with H₂O and brine. The organic phase was dried over Na₂SO₄, and concentrated in vacuum. The crude product was purified by chromatography on silica gel (PE-EtOAc, 10:1) to provide pure compound 7a (85%).

11

Spectroscopic Data for Products:
Compound 2a: ^¹H NMR (400 MHz, CDCl₃): δ = 0.91-0.95 (t, J = 14.4 Hz, 3 H), 1.33-1.49 (m, 3 H), 1.56-1.65 (m, 1 H), 1.79-1.88 (m, 1 H), 2.15-2.21 (m, 1 H), 2.48 (s, 3 H), 4.43-4.46 (m, 1 H), 7.41-7.44 (d, J = 8.0 Hz, 2 H), 7.85-7.87 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.7, 21.8, 21.8, 27.4, 28.2, 73.0, 130.1, 130.2, 131.2, 146.6, 164.9.
Compound 2b: ^¹H NMR (400 MHz, CDCl₃): δ = 1.74-1.75 (d, J = 6.8 Hz, 3 H), 2.50 (s, 3 H), 4.60-4.65 (m, 1 H), 7.44-7.46 (d, J = 8.0 Hz, 2 H), 7.87-7.89 (d, J = 8.0 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 15.5, 21.8, 68.3, 130.2, 130.7, 146.7, 164.6.
Compound 2c: ^¹H NMR (400 MHz, CDCl₃): δ = 1.16-1.19 (t, J = 15.2 Hz, 3 H), 1.84-1.92 (m, 1 H), 2.23-2.29 (m, 1 H), 2.49 (s, 3 H), 4.38-4.42 (m, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 2 H), 7.86-7.88 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 9.9, 21.8, 22.5, 74.2, 130.0, 130.2, 131.3, 146.6, 164.9.
Compound 2d: ^¹H NMR (400 MHz, CDCl₃): δ = 0.86-0.90 (t, J = 13.6 Hz, 3 H), 1.27-1.37 (m, 10 H), 1.40-1.48 (m,
1 H), 1.58-1.65 (m, 1 H), 1.78-1.88 (m, 1 H), 2.14-2.22 (m, 1 H), 2.49 (s, 3 H), 4.43-4.47 (m, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 2 H), 7.86-7.88 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 22.0, 22.8, 25.6, 28.6, 28.8, 29.2, 29.3, 31.9, 73.2, 130.3, 130.3, 131.4, 146.7, 165.1.
Compound 2e: ^¹H NMR (400 MHz, CDCl₃): δ = 2.49 (s, 3 H), 2.96-3.02 (m, 1 H), 3.58-3.62 (m, 1 H), 4.58-4.61 (m, 1 H), 7.26-7.27 (m, 2 H), 7.29-7.37 (m, 3 H), 7.43-7.45 (d, J = 8.0 Hz, 2 H), 7.90-7.92 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.8, 34.8, 74.2, 128.1, 129.1, 129.3, 130.2, 130.2, 131.2, 133.3, 146.8, 166.0.
Compound 2f: ^¹H NMR (400 MHz, CDCl₃): δ = 2.49 (s,
3 H), 2.53-2.61 (m, 1 H), 2.95 (s, 1 H), 4.47-4.51 (m, 1 H), 5.28-5.33 (m, 2 H), 5.73-5.83 (m, 1 H), 7.43-7.45 (d, J = 8.0 Hz, 2 H), 7.87-7.89 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.8, 21.8, 29.7, 33.1, 72.3, 121.3, 121.4, 129.3, 130.2, 131.1, 146.7, 165.5.
Compound 2g: ^¹H NMR (400 MHz, CDCl₃): δ = 1.16-1.18 (d, J = 6.8 Hz, 3 H), 1.21-1.22 (d, J = 6.4 Hz, 3 H), 2.48 (s, 3 H), 2.70-2.77 (m, 1 H), 4.33-4.34 (d, J = 3.6 Hz, 1 H), 7.41-7.43 (d, J = 8.0 Hz, 2 H), 7.86-7.88 (d, J = 8.0 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 16.9, 20.8, 27.9, 30.9, 78.0, 129.6, 130.2, 133.0, 146.4, 165.5.
Compound 7a: ^¹H NMR (400 MHz, CDCl₃): δ = 0.93-0.97 (t, J = 14.8 Hz, 3 H), 1.38-1.48 (m, 2 H), 1.69-1.77 (m, 2 H), 2.75-2.79 (t, J = 15.6 Hz, 2 H), 7.31-7.35 (t, J = 14.8 Hz,
1 H), 7.42-7.46 (t, J = 15.2 Hz, 2 H), 7.59-7.61 (d, J = 8.8 Hz, 2 H), 7.83 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.5, 26.7, 30.8, 125.6, 127.8, 128.7, 129.0, 135.8, 145.3, 149.1. GC-MS (ES): m/z = 201 [M]⁺.
Compound 7b: ^¹H NMR (400 MHz, CDCl₃): δ = 0.92-0.96 (m, 3 H), 1.37-1.46 (m, 2 H), 1.68-1.75 (m, 2 H), 2.71-2.75 (t, J = 15.2 Hz, 2 H), 3.84 (s, 3 H), 6.96-6.98 (m, 2 H), 7.51-7.53 (m, 2 H), 7.80 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 13.9, 22.5, 26.6, 30.9, 55.3, 114.3, 121.7, 130.1, 130.1, 134.4, 145.4, 148.7, 159.3. GC-MS (ES): m/z = 231 [M]⁺.
Compound 7c: ^¹H NMR (400 MHz, CDCl₃): δ = 0.92-0.96 (t, J = 14.8 Hz, 3 H), 1.37-1.47 (m, 2 H), 1.68-1.76 (m, 2 H), 2.38 (s, 3 H), 2.73-2.77 (t, J = 15.2 Hz, 2 H), 7.23-7.25 (d, J = 8.0 Hz, 2 H), 7.48-7.50 (d, J = 8.0 Hz, 2 H), 7.81 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 21.2, 22.5, 26.7, 30.9, 125.7, 126.2, 129.5, 135.2, 137.8, 145.5, 148.9. GC-MS (ES): m/z = 215 [M]⁺.
Compound 7d: ^¹H NMR (400 MHz, CDCl₃): δ = 0.92-0.96 (t, J = 14.8 Hz, 3 H), 1.36-1.46 (m, 2 H), 1.67-1.75 (m, 2 H), 2.71-2.74 (t, J = 15.2 Hz, 2 H), 7.10-7.16 (m, 2 H), 7.53-7.58 (m, 2 H), 7.81 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 13.9, 22.5, 26.6, 30.8, 115.8, 116.0, 125.2, 125.2, 127.5, 135.5, 135.5, 144.6, 149.1, 161.0, 163.5. GC-MS (ES): m/z = 219 [M]⁺.
Compound 7e: ^¹H NMR (400 MHz, CDCl₃): δ = 0.93-0.96 (t, J = 14.8 Hz, 3 H), 1.39-1.44 (m, 2 H), 1.68-1.74 (m, 2 H), 2.72-2.76 (t, J = 5.6 Hz, 2 H), 7.45-7.47 (d, J = 8.8 Hz, 2 H), 7.56-7.58 (d, J = 8.4 Hz, 2 H), 7.84 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.5, 26.7, 30.7, 121.8, 127.1, 127.9, 128.1, 132.0, 136.4, 144.4, 149.3. GC-MS (ES):
m/z = 279 [M]⁺.
Compound 7f: ^¹H NMR (400 MHz, CDCl₃): δ = 0.85-0.89 (t, J = 14.4 Hz, 3 H), 1.29-1.35 (m, 2 H), 1.61-1.67 (m, 2 H), 2.51-2.55 (t, J = 15.2 Hz, 2 H), 7.33-7.39 (m, 3 H), 7.49-7.51 (m, 1 H), 7.91 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 13.8, 22.3, 25.7, 30.6, 126.7, 127.9, 130.2, 130.5, 131.8, 134.2, 137.9, 143.4, 150.2. GC-MS (ES): m/z = 235 [M]⁺.
Compound 7g: ^¹H NMR (400 MHz, CDCl₃): δ = 0.94-0.97 (t, J = 14.8 Hz, 3 H), 1.38-1.47 (m, 2 H), 1.69-1.77 (m, 2 H), 2.75-2.78 (t, J = 15.2 Hz, 2 H), 7.29-7.31 (m, 1 H), 7.35-7.39 (t, J = 15.6 Hz, 1 H), 7.46-7.49 (m, 1 H), 7.59-7.60 (t, J = 3.6 Hz, 1 H), 7.84 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.4, 22.5, 26.7, 30.7, 123.6, 125.6, 127.8, 130.0, 130.6, 134.8, 136.9, 144.1, 149.4. GC-MS (ES): m/z = 235 [M]⁺.
Compound 7h: ^¹H NMR (400 MHz, CDCl₃): δ = 0.93-0.96 (t, J = 14.8 Hz, 3 H), 1.39-1.45 (m, 2 H), 1.68-1.76 (m, 2 H), 2.72-2.76 (t, J = 15.2 Hz, 2 H), 7.39-7.42 (m, 2 H), 7.51-7.53 (m, 2 H), 7.83 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 13.9, 22.5, 26.7, 30.7, 126.8, 127.4, 129.0, 129.4, 129.4, 133.7, 136.3, 144.4, 149.2. GC-MS (ES): m/z = 235 [M]⁺.
Compound 7i: ^¹H NMR (400 MHz, CDCl₃): δ = 0.95-0.99 (t, J = 14.8 Hz, 3 H), 1.42-1.48 (m, 2 H), 1.72-1.78 (m, 2 H), 2.82-2.86 (t, J = 15.6 Hz, 2 H), 7.77-7.79 (m, 2 H), 7.93 (s, 1 H), 8.30-8.32 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.5, 27.1, 30.6, 124.3, 125.7, 128.1, 129.8, 134.9, 139.6, 143.5, 146.7, 150.3. GC-MS (ES): m/z = 246 [M]⁺.
Compound 7j: ^¹H NMR (400 MHz, CDCl₃): δ = 0.82-0.86 (t, J = 14.8 Hz, 3 H), 1.26-1.35 (m, 2 H), 1.63-1.71 (m, 2 H), 2.55-2.59 (t, J = 15.6 Hz, 2 H), 7.50-7.56 (m, 4 H), 7.83-7.85 (m, 1 H), 7.89-7.95 (m, 2 H), 8.00 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.8, 22.4, 25.9, 31.0, 125.1, 125.5, 126.0, 126.3, 126.7, 128.4, 128.5, 129.8, 131.9, 133.8, 137.8, 145.2, 150.2. GC-MS (ES): m/z = 251 [M]⁺.
Compound 7k: ^¹H NMR (400 MHz, CDCl₃): δ = 0.93-0.97 (t, J = 14.8 Hz, 3 H), 1.34-1.43 (m, 2 H), 1.63-1.71 (m, 2 H), 2.60-2.63 (t, J = 4.8 Hz, 2 H), 6.85-6.89 (d, J = 16.4 Hz,
1 H), 6.99-7.03 (d, J = 16.4 Hz, 1 H), 7.26-7.29 (t, J = 12.0 Hz, 1 H), 7.34-7.38 (t, J = 15.2 Hz, 2 H), 7.47-7.49 (d, J = 7.6 Hz, 2 H), 7.77 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 13.8, 13.9, 22.3, 31.0, 31.1, 112.5, 112.5, 126.4, 128.0, 128.0, 128.3, 128.4, 128.8, 128.8, 136.7, 136.7, 137.7, 145.1, 149.4, 149.4. GC-MS (ES): m/z = 227 [M]⁺.
Compound 7l: ^¹H NMR (400 MHz, CDCl₃): δ = 0.90-0.94 (t, J = 14.4 Hz, 3 H), 1.33-1.43 (m, 2 H), 1.64-1.71 (m, 2 H), 2.75-2.79 (t, J = 15.2 Hz, 2 H), 6.47-6.48 (m, 1 H), 6.54-6.54 (d, J = 3.2 Hz, 1 H), 7.47 (s, 1 H), 7.76 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.8, 22.3, 25.8, 30.8, 107.1, 111.3, 136.0, 138.6, 142.4, 149.0. GC-MS (ES): m/z = 191 [M]⁺.
Compound 7m: ^¹H NMR (400 MHz, CDCl₃): δ = 0.87-0.93 (m, 9 H), 1.28-1.34 (m, 2 H), 1.53-1.59 (m, 2 H), 1.88-1.95 (m, 1 H), 2.37-2.43 (m, 4 H), 7.65 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.3, 22.4, 25.3, 28.1, 31.2, 33.5, 135.0, 146.5, 148.9. GC-MS (ES): m/z = 181 [M]⁺.
Compound 7n: ^¹H NMR (400 MHz, CDCl₃): δ = 0.89-0.92 (t, J = 14.4 Hz, 3 H), 1.26-1.35 (m, 6 H), 1.50-1.59 (m, 4 H), 1.70-1.83 (m, 4 H), 2.42-2.49 (m, 2 H), 2.60-2.66 (m, 1 H), 7.64 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.3, 25.3, 25.8, 26.3, 31.5, 31.7, 34.8, 132.7, 148.5, 151.1. GC-MS (ES): m/z = 207 [M]⁺.
Compound 7o: ^¹H NMR (400 MHz, CDCl₃): δ = 1.31-1.35 (t, J = 15.2 Hz, 3 H), 2.78-2.84 (m, 2 H), 7.32-7.35 (t, J = 14.8 Hz, 1 H), 7.41-7.46 (m, 2 H), 7.59-7.61 (d, J = 7.6 Hz, 2 H), 7.84 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.1, 20.3, 125.7, 127.9, 128.8, 128.9, 136.9, 145.1, 149.2. GC-MS (ES): m/z = 173 [M]⁺.
Compound 7p: ^¹H NMR (400 MHz, CDCl₃): δ = 4.15 (s,
2 H), 7.19-7.28 (m, 4 H), 7.30-7.35 (m, 2 H), 7.40-7.43 (m, 2 H), 7.59-7.62 (m, 2 H), 7.87 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 32.9, 125.9, 126.5, 128.3, 125.5, 128.5, 128.6, 128.9, 133.9, 138.6, 146.6, 149.5. GC-MS (ES): m/z = 235 [M]⁺.
Compound 7q: ^¹H NMR (400 MHz, CDCl₃): δ = 0.89-0.92 (t, J = 14.8 Hz, 3 H), 1.58-1.67 (m, 2 H), 2.55-2.59 (t, J = 14.8 Hz, 2 H), 3.82 (s, 1 H), 7.11-7.22 (m, 4 H), 7.24-7.30 (m, 1 H), 7.70 (s, 2H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.6, 21.6, 26.5, 32.1, 126.3, 128.5, 128.6, 133.2, 139.3, 148.0, 149.1. GC-MS (ES): m/z = 235 [M]⁺.
Compound 7r: ^¹H NMR (400 MHz, CDCl₃): δ = 3.53-3.54 (d, J = 6.0 Hz, 2 H), 5.12-5.14 (m, 1 H), 5.17 (s, 1 H), 6.00-6.10 (m, 1 H), 7.30-7.34 (t, J = 14.4 Hz, 1 H), 7.40-7.44 (t, J = 15.2 Hz, 2 H), 7.58-7.60 (d, J = 8.0 Hz, 2 H), 7.84 (s,
1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 31.4, 116.6, 125.8, 128.2, 128.6, 128.8, 133.1, 134.4, 146.2, 149.4. GC-MS (ES): m/z = 185 [M]⁺.
Compound 7s: ^¹H NMR (400 MHz, CDCl₃): δ = 0.85-0.88 (t, J = 13.6 Hz, 3 H), 1.27 (s, 6 H), 1.55-1.60 (m, 2 H), 2.57-2.61 (t, J = 14.8 Hz, 2 H), 3.21-3.23 (d, J = 6.4 Hz, 2 H), 5.05-5.11 (m, 2 H), 5.87-5.96 (m, 1 H), 7.69 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 22.5, 24.4, 28.1, 28.7, 30.2, 31.4, 116.0, 131.9, 135.2, 147.9, 148.9. GC-MS (ES): m/z = 193 [M]⁺.
Compound 7t: ^¹H NMR (400 MHz, CDCl₃): δ = 1.32-1.34 (t, J = 6.8 Hz, 6 H), 3.23-3.30 (m, 1 H), 7.32-7.36 (t, J = 15.2 Hz, 1 H), 7.43-7.46 (t, J = 15.2 Hz, 2 H), 7.57-7.60 (t, J = 8.4 Hz, 2 H) 7.84 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 22.0, 25.7, 126.1, 128.0, 128.8, 129.0, 140.9, 144.2, 149.4. GC-MS (ES): m/z = 187 [M]⁺.
Compound 8a: ^¹H NMR (400 MHz, CDCl₃): δ = 0.90-0.94 (t, J = 14.8 Hz, 6 H), 1.29-1.36 (m, 4 H), 1.38-1.46 (m, 2 H), 1.49-1.55 (m, 2 H), 1.88-2.05 (m, 4 H), 2.48 (s, 3 H), 7.40-7.42 (d, J = 8.0 Hz, 2 H), 7.85-7.87 (d, J = 8.4 Hz, 2 H).