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CC BY-ND-NC 4.0 · SynOpen 2018; 02(04): 0263-0267
DOI: 10.1055/s-0037-1610370
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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
,
Uday B. Rao Khandavilli 
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
,
Simon E. Lawrence 
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
,
Timothy P. O’Sullivan  *
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)

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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.

Key words

isothiourea - thiourea - organosulfur - sulfur transfer

Supporting Information

    Details of the crystallographic analysis of compound 5 and full characterisation for all novel compounds with associated 1H and 13C NMR spectra can be found in the Supporting Information. The crystallographic data associated with this article have been deposited with the Cambridge Crystallographic Data Centre, CCDC 1586073. Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610370.
  • 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