A Novel, One-Pot, Three-Component Synthesis of 1,2,4-Oxadiazoles under Microwave Irradiation and Solvent-Free Conditions

Abstract

A novel synthesis of 3,5-disubstituted 1,2,4-oxadiazoles is described from a one-pot, three-component reaction between ­nitriles, hydroxylamine, and Meldrum’s acids under microwave ­irradiation and solvent-free conditions in good to excellent yields.

Meldrum’s acids - nitriles - 1,2,4-oxadiazoles - three-component reaction - solvent-free synthesis

References and Notes

1 Jochims JC. In Comprehensive Heterocyclic Chemistry II   Vol. 4:  Katritzky AR. Rees CW. Scriven EVF. Pergamon Press; London: 1996.  Chap. 4. p.179-228  ; and references therein

2 Clapp LB. Adv. Heterocycl. Chem.  1976,  20:  65 

3 Vu CB. Corpuz EG. Merry TJ. Pradeepan SG. Bartlett C. Bohacek RS. Botfield MC. Lynch BA. MacNeil IA. Ram MK. van Schravendijk MR. Violette S. Sawyer TK. J. Med. Chem.  1999,  42:  4088 

4a Bezerra NMM. De Oliveira SP. Srivastava RM. Da Silva JR. Il Farmaco  2005,  60:  955 

4b Diana GD. Volkots DL. Hitz TJ. Bailey TR. Long MA. Vescio N. Aldous S. Pevear DC. Dutko FJ. J. Med. Chem.  1994,  37:  2421 

4c Swain CJ. Baker R. Kneen C. Moseley J. Saunders J. Seward EM. Stevenson G. Beer M. Stanton J. Watling KJ. J. Med. Chem.  1991,  34:  140 

4d Orlek BS. Blaney FE. Brown F. Clark MSG. Hadley MS. Hatcher J. Riley GJ. Rosenberg HE. Wadsworth HJ. Wyman PJ. J. Med. Chem.  1991,  34:  2726 

4e Watjen F. Baker R. Engelstoff M. Herbert R. Macleod A. Knight A. Merchant K. Moseley J. Saunder J. Swain CJ. Wong E. Springer JP. J. Med. Chem.  1989,  32:  2282 

4f Ankersen M. Peschke B. Hansen BS. Hansen TK. Bioorg. Med. Chem. Lett.  1997,  7:  1293 

5 Hagen H, and Becke F. inventors; Ger. Offen. DE  2,060,082.  ; Chem. Abstr. 1972, 77, 88511

6 Torgova SI. Karamysheva LA. Geivandova TA. Strigazzi A. Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A  2001,  365:  99 

7a Wang Y. Miller RL. Sauer DR. Djuric SW. Org. Lett.  2005,  7:  925 

7b Evans MD. Ring J. Schoen A. Bell A. Edwards P. Berthelot D. Nicewonger R. Baldino CM. Tetrahedron Lett.  2003,  44:  9337 

7c Kaboudin B. Navaee K. Heterocycles  2003,  60:  2287 

8 Microwaves in Organic Synthesis   2nd reprint:  Loupy A. Wiley-VCH; Weinheim: 2004. 

9

The experiments were performed using a microwave oven (ETHOS 1600, Milestone) with a power of 600 W specially designed for organic synthesis.

10a Clarke K. J. Chem. Soc.  1954,  4251 

10b Srivastava RM. Mendes e Silva LM. J. Chem. Eng. Data  1984,  29:  221 

10c Young TE. Beidler WT. J. Org. Chem.  1985,  50:  1182 

10d Chiou S. Shine HJ. J. Heterocycl. Chem.  1989,  26:  125 

11

Preparation of 5-Methyl-3-phenyl-1,2,4-oxadiazole ( 5a); General Procedure.
A mixture of benzonitrile (0.21 g, 2 mmol), NH₂OH 50% (0.13 g, 2 mmol), and a catalytic amount of AcOH was irradiated with microwaves at 100 °C for 1 min. After nearly complete conversion to the corresponding amidoxime as was indicated by TLC, Meldrum’s acid (0.29 g, 2 mmol) was added to the reaction mixture and it was irradiated at 150 °C for a further 2 min. After cooling to r.t., the solid residue was sublimated and 5a obtained as colorless crystals. In the case of the products 5d-h, the obtained crude solid were purified by recrystallization from 95% EtOH, and the products 5b,c,i-n were purified by column chromatography (4:1 n-hexane-EtOAc as eluent, Merck silica gel 60 mesh).
Selected Data.
Compound 5a: colorless crystals. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.60 (3 H, s, CH₃), 7.45 (3 H, m, 3 × CH), 8.04 (2 H, dd, J = 7.8 Hz and J = 1.7 Hz, 2 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 12.30 (CH₃), 124.01 (C), 127.32, 128.80, and 131.05 (3 × CH), 168.38 (NCN), 176.29 (NCO).
Compound 5d: colorless crystals. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.36 (3 H, s, PhCH₃), 2.58 (3 H, s, CH₃), 7.23 (2 H, d, J = 7.8 Hz, 2 × CH), 7.92 (2 H, d, J = 7.8 Hz, 2 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 12.25 (CH₃), 21.44 (PhCH₃), 124.00 (C), 127.21 and 129.48 (2 × CH), 141.31 (C), 168.32 (NCN), 176.27 (NCO).
Compound 5e: colorless crystals. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.62 (3 H, s, CH₃), 7.37 (1 H, t, J = 7.9 Hz, CH), 7.43 (1 H, dd, J = 8.1 Hz and J = 1.1 Hz, CH), 7.91 (1 H, d, J = 7.7 Hz, CH), 8.03 (1 H, s, CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 12.30 (CH₃), 125.36 and 127.45 (2 × CH), 128.58 (C), 130.11 and 131.09 (2 × CH), 134.92 (C), 167.41 (NCN), 176.78 (NCO).
Compound 5j: colorless oil. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.40 (3 H, t, J = 7.6 Hz, CH₂CH ₃), 2.35 (3 H, s, CH₃), 2.91 (2 H, q, J = 7.6 Hz, CH₂), 7.22 (2 H, d, J = 8.0 Hz, 2 × CH), 7.92 (2 H, d, J = 8.0 Hz, 2 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 10.78 (CH₂ CH₃), 20.27 (CH₂), 21.45 (PhCH₃), 124.21 (C), 127.29 and 129.48 (2 × CH), 141.26 (C), 168.22 (NCN), 180.51 (NCO).
Compound 5l: colorless crystals. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.42 (3 H, t, J = 7.6 Hz, CH₃), 2.94 (2 H, q, J = 7.6 Hz, CH₂), 7.42 (2 H, d, J = 8.5 Hz, 2 × CH), 7.98 (2 H, d, J = 8.5 Hz, 2 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 10.78 (CH₃), 20.30 (CH₂), 125.51 (C), 128.69 and 129.11 (2 × CH), 137.15 (C), 167.46 (NCN), 180.91 (NCO).
Compound 5n: colorless crystals. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.44 (3 H, t, J = 7.6 Hz, CH₃), 2.97 (2 H, q, J = 7.6 Hz, CH₂), 7.60 (2 H, d, J = 8.5 Hz, 2 × CH), 7.94 (2 H, d, J = 8.5 Hz, 2 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 10.81 (CH₃), 20.33 (CH₂), 125.59 and 125.98 (2 × C), 128.91 and 132.11 (2 × CH), 167.59 (NCN), 180.98 (NCO).