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Synlett 2009(13): 2093-2096  
DOI: 10.1055/s-0029-1217700
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Domino Alkylation-Cyclization Reaction of Propargyl Bromides with Thioureas/Thiopyrimidinones: A New Facile Synthesis of 2-Aminothiazoles and 5H-Thiazolo[3,2-a]pyrimidin-5-ones

Daniele Castagnoloa, Mafalda Paganoa, Martina Bernardinia, Maurizio Botta*a,b
a Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. de Gasperi 2, 53100 Siena, Italy
b Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA
Fax: +39(0577)234333; e-Mail: botta@unisi.it;
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Publikationsverlauf

Received 15 April 2009
Publikationsdatum:
15. Juli 2009 (online)

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Abstract

A new synthesis of 2-aminothiazoles and 5H-thiazolo[3,2-a]pyrimidin-5-ones was developed as a domino alkylation-cyclization reaction of propargyl bromides with thioureas and thio­pyrimidinones, respectively. Domino reactions were performed under microwave irradiation leading to desired compounds in a few minutes and high yields.

Key words

domino reaction - 2-aminothiazole - thiazolopyrimidinone - microwave synthesis - antiviral agents

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7

Reaction of alkyne 7 with thiourea 8a was also carried out under the same reaction conditions but in the absence of K2CO3. No traces of aminothiazole 9g were detected in this case and only complex side products, whose characterization was difficult, were isolated.

10

Synthesis of 2-Aminothiazoles 9a-i; General Procedure: Alkyne 3, 6 or 7 (1.0 mmol) and the appropriate thiourea 8a-c (1.0 mmol) were suspended in anhyd DMF (1.0 mL) in a 10 mL glass vial equipped with a small magnetic stirring bar. K2CO3 (1.0 mmol) was then added to this solution and the mixture was irradiated under microwave conditions at 130 ˚C (2 × 5 min), using an irradiation power of 300 W. Microwave irradiations were conducted using a CEM Discover Synthesis Unit (CEM Corp., Matthews, NC). The mixture was then poured into H2O (10 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified by flash column chromatography (SiO2; hexanes-EtOAc, 1:1), to yield the 2-aminothiazoles 9a-i as tan-colored oils.

11

Characterization of 13a: ¹H NMR (CDCl3): δ = 7.54 (s, 1 H, SCHCHCH3), 7.08-7.06 (m, 1 H, Ph), 6.75-6.71 (m, 2 H, Ph), 4.56-4.54 (m, 1 H, CH3CHPh), 2.34 (s, 3 H, NCCH 3), 1.94 (s, 3 H, CH 3), 1.58 (d, 3 H, CHCH 3). ¹³C NMR (CDCl3): δ = 162.61, 160.13, 159.36, 151.22, 128.20, 128.00, 124.85, 119.38, 117.84, 111.64, 34.27, 17.88, 13.47, 10.35. MS (ESI): m/z = 321 [M + H]+, 343 [M + Na]+. Characterization of 13b: ¹H NMR (CDCl3): δ = 7.08-7.04 (m, 1 H, Ph), 6.76-6.72 (m, 2 H, Ph), 6.27 (s, 1 H, SCHCHCH3), 4.54-4.49 (m, 1 H, CH3CHPh), 2.70 (s, 3 H, NCCH 3), 1.89 (s, 3 H, CH 3), 1.58 (d, 3 H, CHCH 3). ¹³C NMR (CDCl3): δ = 162.63, 162.24, 160.14, 146.41, 135.98, 128.09, 119.37, 112.86, 111.38, 105.68, 34.07, 18.56, 17.77, 10.23. MS (ESI): m/z = 321 [M + H]+, 343 [M + Na]+.

12

Characterization of 14: ¹H NMR (CDCl3): δ = 7.11-7.04
(m, 3 H, Ph), 6.81-6.72 (m, 4 H, Ph), 5.97 (s, 1 H, SCH), 4.53 (m, 1 H, CH3CHPh), 4.50 (s, 2 H, CH 2PhOMe), 3.71
(s, 3 H, OCH 3), 1.91 (s, 3 H, CH 3), 1.59 (d, J = 8.0 Hz,
3 H, CHCH 3). ¹³C NMR (CDCl3): δ = 162.60, 161.85, 160.35, 158.61, 140.31, 130.62, 130.38, 129.99, 119.34, 114.38, 113.84, 111.77, 111.30, 106.19, 55.40, 37.06, 33.96, 17.80, 10.77. MS (ESI): m/z = 427 [M + H]+, 449 [M + Na]+.