CC BY ND NC 4.0 · SynOpen 2018; 02(04): 0263-0267
DOI: 10.1055/s-0037-1610370
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Copyright with the author

Efficient S-Acylation of Thiourea

David J. Jones
a  School of Chemistry, University College Cork, Cork, Ireland   Email: tim.osullivan@ucc.ie
b  Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
e  Synthesis and Solid-State Pharmaceutical Centre, University College Cork, Cork, Ireland
,
a  School of Chemistry, University College Cork, Cork, Ireland   Email: tim.osullivan@ucc.ie
b  Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
,
Eileen M. O’Leary
c  Department of Physical Sciences, Cork Institute of Technology, Cork, Ireland
,
a  School of Chemistry, University College Cork, Cork, Ireland   Email: tim.osullivan@ucc.ie
b  Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
e  Synthesis and Solid-State Pharmaceutical Centre, University College Cork, Cork, Ireland
,
a  School of Chemistry, University College Cork, Cork, Ireland   Email: tim.osullivan@ucc.ie
b  Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
d  School of Pharmacy, University College Cork, Cork, Ireland
› Author Affiliations

This research received financial support from Science Foundation Ireland­ under Grant Numbers 12/RC/2275, 05/PICA/B802/EC07, 14/US/E2915 (UBRK) and the UCC Strategic Research Fund (UBRK and DJJ).
Further Information

Publication History

Received: 16 August 2018

Accepted after revision: 12 September 2018

Publication Date:
17 October 2018 (online)

Abstract

Efficient S-acylation of thiourea using a variety of acid chlorides is reported. Structurally diverse aryl and alkyl substrates are compatible with this methodology. Confirmation that acylation occurs exclusively­ on the sulfur atom of thiourea is provided by single-crystal X-ray crystallographic analysis.

Supporting Information

 
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  • 25 General Procedure: To a stirred solution of thiourea (78 mg, 1.00 mmol, 1.00 equiv) in acetonitrile (10 mL) at 50 °C was added a solution of the required acid chloride (1.00 mmol, 1.00 equiv) in acetonitrile (10 mL) dropwise. The resulting thick suspension was allowed to stir at this temperature for a further one hour to ensure complete reaction. After one hour, the reaction mixture was cooled on ice and then vacuum filtered. The cake was washed with ethyl acetate (2 × 10 mL) to afford the products. The products were obtained quantitatively unless otherwise stated.Representative Examples: S-(3-Methoxybenzoyl)isothiouronium Chloride (5)Mp 166–168 °C (MeCN). 1H NMR (400 MHz, DMSO-d 6): δ = 3.80 (s, 3 H, OCH3 ), 7.19 (dd, J = 8.15, 1.83 Hz, 1 H, ArC(2)H), 7.39–7.44 (m, 2 H, overlapping ArC(6)H and ArC(3)H), 7.53 (d, J = 8.15 Hz, 1 H, ArC(4)H), 9.62 (bs, 4 H, NH 2=C-NH 2). 13C NMR (100 MHz, DMSO-d 6): δ = 55.2, 113.8, 118.9, 121.5, 129.7, 132.1, 159.2, 167.1. IR (KBr): 3329, 3281, 3163, 3085, 2954, 2836, 1697, 1609, 1583, 1526, 1470, 1420, 1311, 1293, 1267, 1051, 755 cm–1. HRMS (ESI+): m/z calcd. for C9H11N2O2S+: 211.0536; found: 211.0528. Anal. Calcd. for C9H11N2O2ClS: C, 44.00; H, 4.10; N, 11.40; Found: C, 44.31; H, 4.18; N, 11.71. S-(Decanoyl)isothiouronium Chloride (14)Mp 115–117 °C (MeCN).1H NMR (400 MHz, DMSO-d 6): δ = 0.86 (t, J = 7.51 Hz, 3 H, CH 3(10)), 1.24 (m, 12 H, CH 2(9-4)), 1.46–1.50 (m, 2 H, CH 2(3)), 2.18 (t, J = 7.88 Hz, 2 H, CH 2(2)), 9.18 (bs, 4 H, NH 2=C-NH 2). 13C NMR (100 MHz, DMSO-d 6): δ = 13.9, 22.1, 24.5, 28.5, 28.6, 28.7, 31.2, 33.6, 174.5. IR (KBr): 3385, 3261, 3175, 3031, 2822, 2859, 1748, 1676, 1427, 732 cm–1. HRMS (ESI+): m/z calcd for C11H23N2OS: 231.1531; Found: 231.1536. Anal. Calcd for C11H23N2OClS: C, 49.52; H, 8.69; N, 10.50; Found: C, 49.18; H, 8.75; N, 10.71.Indomethacin Analogue 21Mp 168–171 °C (MeCN).1H NMR (400 MHz, DMSO-d 6): δ = 2.22 (s, 3 H, ArCH 3), 3.67 (s, 2 H, CH 2), 3.76 (s, 3 H, OCH 3), 6.72 (dd, J = 8.18, 1.33 Hz, 1 H, C(6)H), 6.92 (d, J = 8.18 Hz, 1 H, C(7)H), 7.05 (d, J = 1.33 Hz, 1 H, C(4)H). 7.64–7.70 (m, 4 H, Ar(2′, 3′, 5′ and 6′)H). 13C NMR (100 MHz, DMSO-d 6): δ = 13.2, 29.5, 55.4, 101.7, 111.3, 113.4, 114.6, 116.5, 129.0, 130.2, 130.71, 131.1, 134.1, 135.1, 137.6, 155.5, 167.8, 172.0. IR (KBr): 3332, 3312, 2952, 1727, 1687, 1657, 1482, 1308, 1227, 1047, 792 cm–1. HRMS (ESI+): m/z calcd for C20H19ClN3O3S+: 416.0830; Found: 416.0851. Anal. Calcd for C20H19Cl2N3O3S: C, 53.10; H, 4.23; N, 9.29; Found: C, 53.33; H 4.29; N, 9.45