Aryl alkyl ketones in a one-pot Gewald synthesis of 2-aminothiophenes

Synlett

Volumn , Issue 16, 2006, Pages 2559-2564

  Tormyshev, Victor M ^a   Trukhin, Dmitry V ^a   Rogozhnikova, Olga Yu ^a   Mikhalina, Tatiana V ^a   Troitskaya, Tatiana I ^a   Flinn, Anthony ^b  

^a N N VOROZHTSOV NOVOSIBIRSK INSTITUTE OF ORGANIC CHEMISTRY   (Russian Federation)

^b Onyx Scientific Limited   (United Kingdom)

Author keywords

4 aryl 2 aminothiophene 3 carboxylates; Aryl alkyl ketones; Gewald reaction

Indexed keywords

ACETIC ACID DERIVATIVE; ALKYL ARYL KETONE; MORPHOLINE; SULFUR ACID DERIVATIVE; THIOPHENE DERIVATIVE;

ARTICLE; CHEMICAL REACTION; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; SYNTHESIS;

EID: 33750081476     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2006-951484     Document Type: Article

References (28)

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16. Microwave irradiation was reported to be an efficient tool for the one-pot microscale synthesis of N-acylated thiophenes 2 from acetophenones (ref. 5a). However, earlier attempts to use the microwave technique showed that acetophenone was unreactive in the one-pot Gewald reaction: Hoener, A. P. F.; Henkel, B.; Gauvin, J.-C. Synlett 2003, 63.
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18. Similar yields of 9-43% were reported for a series of 4-aryl-substituted thiophenes 2 resulted from the two-step Gewald reaction: Shvedov, V. I.; Ryzhkova, V. K.; Grinev, A. N. Khim. Geterotsikl. Soedin. 1967, 3, 239;
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23. To dissolve crystalline ammonium salts a small amount of 95% ethanol was added (0.5 mL per 1 mmol of acetophenone). DMF was also shown to be a good choice.
24. Replacement of morpholine with alternative amines or acetic acid with TFA caused a substantial drop in the conversion of acetophenone. Thus, changing the amine from morpholine to diethylamine produced a heavily contaminated reaction mixture with only 18% conversion. At the same time employing half the amount of morpholine (1.5 equiv) and acetic acid (0.5 equiv) with acetophenone cyanoacetate (1 equiv) and sulfur (1 equiv) resulted in only a small decrease in ketone conversion (57%).
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27. We were also interested in investigating if the combination of organic base and acid were essential for the formation of 3a and if we could reach a similar equilibrium in the absence of acetic acid, that is, under conditions generally used in classical one-pot Gewald reaction (see ref. 1). In contrast to the former experiment, even heating for 12 hours was insufficient for the mixture of acetophenone, ethyl cyanoacetate, and morpholine (1:1:3) to give any condensation products at detectable concentrations. The same result was obtained for the reaction of acetophenone, ethyl cyanoacetate, and acetic acid in the absence of morpholine. Kinetic measurements and further experiments made it possible to consider that the acid-base 'catalyst', morpholinium acetate, was required in high concentrations to enhance the rate of the process leading to nitriles 3a, which in turn was a key intermediate for the latter steps of thiolation and ring closure.
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