Thiazole formation through a modified Gewald reaction

Summary The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. 1,4-Dithiane-2,5-diol was used as the aldehyde precursor to give either 2-substituted thiazoles or 2-substituted aminothiophenes depending on the substitution of the α-carbon to the cyano group.


Synthesis and spectroscopic data of starting materials.
Scheme S1: Synthesis of starting materials.

Ethyl 2-cyano-2-(4-methoxyphenyl)acetate (22):
General procedure: 2 4-Methoxyphenylacetonitrile (0.7 g, 4.76 mmol, 1.00 equiv) was dissolved in dry THF (4.7 mL) and cooled to −78 °C. At this temperature n-butyllithium (3.0 mL, 4.76 mmol, 1.00 equiv) was added dropwise and the colour of the solution changed immediately to yellow. After further stirring for 20 min at −78 °C, a solution of ethyl chloroformate (SI-2) (0.52 g, 4.76 mmol, 1.00 equiv) in THF (1 mL) was added slowly to the stirring solution. The reaction mixture stirred for 30 min at this temperature and was then allowed to warm to room temperature and stirred for another 1 h. The reaction was quenched with water and EtOAc was added. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layer was washed twice with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude material was further purified on a silica column 1:9-4:6 EtOAc/hexane gradient to give the product. Isolated yield: 0.54 g (52%, 4.76 mmol scale), colourless oil; R f : 0.32 (2/8, EtOAc/hexane). 1

Methyl 2-cyano-2-(4-nitrophenyl)acetate (26):
Potassium hydroxide (0.40 g, 7.09 mmol, 1.00 equiv) was stirred in DMSO (5 mL) to form a homogeneous solution in a sealed microwave vial. After 10 min of stirring in a water bath at 85 °C methyl 2-cyanoacetate SI-6 (1.51 mL, 7.09 mmol, 1.00 equiv) was added by means of a syringe and the solution was stirred for a further 30 min. Then a solution of 1-fluoro-4-nitrobenzene SI-5 (2.00 g, 7.09 mmol, 1.00 equiv) in DMSO (2 mL) was added dropwise at 85 °C. After 4 h the reaction mixture was poured in a beaker filled with ice and 1 M HCl (5 mL). The vial was washed with EtOAc (20 mL) and the resulting solution was allowed to stir for 2 h. The two layers were separated and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed twice with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude material was further purified on a silica column with pure hexanes as eluent to remove SI-5. Methyl 2-cyanoacetate was removed on high vacuum. Isolated yield: 0.834 g (53%, 7.09 mmol scale), red solid; R f : 0.

Ethyl 2-cyano-2-(4-nitrophenyl)acetate (28)
Potassium hydroxide (0.80 g, 14.18 mmol, 1.00 equiv) was stirred in DMSO (10 mL) to a homogeneous solution in a sealed microwave vial. After 10 min of stirring in a water bath at 85 °C ethyl 2-cyanoacetate SI-7 (1.51 mL, 14.18 mmol, 1.00 equiv) was added by means of a syringe and the solution was stirred for further 30 min. Then a solution of 1-fluoro-4-nitrobenzene SI-5 (2.00 g, 14.18 mmol, 1.00 equiv) in DMSO (4 mL) was added dropwise at 85 °C. After 4 h a TLC showed complete conversion and the mixture was transferred in a beaker prepared with ice and 1 M HCl (10 mL). The vial was washed with EtOAc (40 mL) and the resulting solution was allowed to stir for 2 h. The two layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed twice with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. For the final purification a silica column with pure hexane as eluent was used to remove SI-5. Ethyl 2-cyanoacetate was removed on high vacuum.  163.8,148.6,136.6,129.3,124.6,114.6,64.2,43.5,14.0;IR (neat)

Ethyl 2-cyano-2-(4-nitrophenyl)acetate (30)
General procedure: 4 Malonitrile SI-9 (1.06 g, 16.00 mmol, 2.00 equiv) and iodobenzene SI-8 (1.63 g, 8.00 mmol, 1.00 equiv) were stirred in DMSO (20 mL) with copper iodide (0.152 g, 0.8 mmol, 0.1 equiv) and potassium carbonate (4.40 g, 32.00 mmol, 4 equiv). The reaction mixture was heated to 120 °C. After 20 h the reaction mixture was poured in a beaker with 1 M HCl (15 mL). The resulting mixture was filtered through silica and extracted with EtOAc (50 mL). The two layers were separated and the organic layer was washed five times with brine (5 × 250 mL). The combined organic layers were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was then purified using a silica column with EtOAc/hexane as eluent to give the product as a white solid.