CC BY-ND-NC 4.0 · SynOpen 2018; 02(04): 0263-0267
DOI: 10.1055/s-0037-1610370
letter
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.


#

The thiourea motif is ubiquitous in organic chemistry. In particular, S-alkyl- and S-aryl isothioureas are widely employed as precursors to sulfur-containing heterocycles[1] such as thiazoles[2] and thiouracils.[3] They are also useful in the preparation of sulfonyl chlorides,[4] thiols,[5] sulfides,[6] disulfides[7] and guanidines.[8] The sulfur transfer reagent 3-mercaptopropionitrile is typically accessed from the corresponding isothiourea derivative.[9] More recently, S- and N-substituted thioureas have been incorporated into various organocatalysts to facilitate asymmetric induction through hydrogen bonding.[10] Interestingly, isobenzofuran-substituted isothioureas undergo unusual base-mediated thermal rearrangement reactions to form isoindoles[11] while isothiourea-substituted indolones rearrange under similar conditions to form thiazoles.[12] The corresponding benzofuran-2-one analogues likewise rearrange to furnish 1,3-isothiazolidin-4-ones.[13]

S-Alkyl and S-aryl thioureas are notable molecules in their own right. They are known to inhibit a number of enzyme systems including nitric oxide synthase (NOS)[14], monoamine oxidase (MAO)[15] and H3 histamine receptors.[16] Their inhibitory effect on multidrug resistant bacterial strains has also been described.[17] Isothioureas have been found to disrupt biofilm formation in P. aeruginosa.[18] Indolamine 2,3-dioxygenase (IDO), an enzyme that is overexpressed in several disease states including cancer, is inhibited by a range of simple S-alkyl isothioureas.[19] Allylic isothioureas have displayed potent antileukemia activity.[20]

While the formation of S-alkyl isothioureas is well-studied,[1a] [1c] [5f] [20] [21] there remains few systematic studies on the synthesis of S-acyl derivatives. It has previously been shown that thiourea reacts quantitatively with acetyl or benzoyl chloride to form the corresponding acylated thiourea adducts.[22] However, it was not clear whether substitution had occurred on the sulfur or nitrogen atoms and these compounds were not characterised by modern techniques.

Herein, we report an efficient method for the selective S-acylation of thiourea, and we confirm that acylation occurs exclusively on the sulfur atom. Our method can be applied to a broad range of substrates, including the non-steroidal anti-inflammatory drugs (NSAIDs) Indomethacin, Aspirin, Diclofenac and Ibuprofen.

In the course of our studies on sulfur transfer reagents, we observed the formation of S-benzoyl isothiourea hydrochloride (2) on addition of benzoyl chloride (1) to a warm solution of thiourea in acetonitrile (Scheme [1]).

Zoom Image
Scheme 1 Synthesis of S-benzoyl isothiourea hydrochloride (2)

The reaction proceeded rapidly with instantaneous precipitation of the product, which was isolated in quantitative yield without need for further purification. It was subsequently found that treatment of thiourea with a range of aryl-substituted acid chlorides furnished the corresponding S-acyl isothioureas 29 quantitatively (Scheme [2]). The reaction tolerates aromatic acid chlorides with either electron-donating or electron-withdrawing substituents. This route also provides access to more sterically hindered ortho-substituted products, such as 4. Evidence that acylation had occurred exclusively on the sulfur atom, rather than on either of the nitrogen atoms, was provided by the apparent equivalence of the chemical shift values for the isothiouronium protons in the 1H NMR spectrum of 29. No evidence for the formation of the N-acylated regioisomers was present in the spectra of the crude reaction mixtures. Additionally, recrystallisation of 5 and subsequent single-crystal X-ray diffraction confirmed that acylation had indeed occurred at the sulfur atom (see the Supporting Information for details) (Figure [1]). The equivalent C–N bond lengths in S-acyl isothiourea 5 confirm the delocalization of the cation across the amidine portion of the molecule (Figure [2]). These bond lengths are similar to those of previously described alkyl isothiourea 10.[23] The S-C-N bond angle is smaller in 5 than in 10, perhaps reflecting the influence of the adjacent carbonyl group. The hydrogen bond network in 5 is constructed through bridging chloride ions via N–H···Cl hydrogen bonding. Although the quaternary carbon signal of the isothiouronium group was not always apparent by 13C NMR analysis, extending the relaxation delay from 1.00 second to 4.00 seconds allowed for the detection of the isothiouronium carbon in 2 (see the Supporting Information).

Zoom Image
Figure 1 Crystal structure of 5, demonstrating that acylation has occurred at the sulfur atom
Zoom Image
Figure 2 Comparison of bond lengths (in red) and S-C-N bond angles (in blue) between 5 and 10 [23]

Alkyl- and alkyl-aryl-substituted acid chlorides were subjected to the same conditions, affording 1118 in quantitative yields (Scheme [3]). As part of an ongoing effort in our laboratory to develop novel anti-inflammatory agents, we wondered whether this methodology could also be applied to some common NSAIDs. Diclofenac, Aspirin, Ibuprofen and Indomethacin were converted into their corresponding acid chlorides with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide.[24] Addition of the resultant acid chlorides to a solution of thiourea in acetonitrile furnished NSAID derivatives 1922, again in quantitative yields, with no apparent difference in reactivity (Scheme [4]).

Zoom Image
Scheme 2 Preparation of aryl-substituted S-acyl isothioureas 29 [25]

In conclusion, a method for the facile synthesis of S-acyl isothioureas has been described. The reactions proceed quantitatively, and the resulting solids are isolated without the need for further purification. We have shown that acylation occurs exclusively on the sulfur atom through crystallographic analysis. Several common NSAIDs were converted into their S-acyl isothiourea derivatives using this approach.

Zoom Image
Scheme 3 Preparation of alkyl and aryl-alkyl derivatives 1118 [25]
Zoom Image
Scheme 4 Preparation of NSAID derivatives 1922 [25]

#

Acknowledgment

Dr Lorraine Bateman and Dr Denis Lynch are acknowledged for assistance with NMR spectroscopy.

Supporting Information

  • References and Notes

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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

  • References and Notes

    • 1a Krishnamurthy M, Basavaprabhu, Sharanabai KM, Sureshbabu VV. Tetrahedron Lett. 2014; 55: 5609
    • 1b Kim H.-Y, Kwak SH, Lee G.-H, Gong Y.-D. Tetrahedron 2014; 70: 8737
    • 1c Alcolea V, Garnica P, Palop J, Sanmartín C, González-Peñas E, Durán A, Lizarraga E. Molecules 2017; 22: 1314
    • 1d Friebe M, Mahmood A, Spies H, Berger R, Johannsen B, Mohammed A, Eisenhut M, Bolzati C, Davison A, Jones AG. J. Med. Chem. 2000; 43: 2745
    • 1e Wu Y.-J, Guernon J, Park H, Thompson LA. J. Org. Chem. 2016; 81: 3386
    • 2a Hickey SM, White JM, Pfeffer FM, Ashton TD. Synlett 2015; 26: 1759
    • 2b Takaya J, Mio K, Shiraishi T, Kurokawa T, Otsuka S, Mori Y, Uesugi M. J. Am. Chem. Soc. 2015; 137: 15859
    • 2c Xu Z, Guo J, Yang Y, Zhang M, Ba M, Li Z, Cao Y, He R, Yu M, Zhou H, Li X, Huang X, Guo Y, Guo C. Eur. J. Med. Chem. 2016; 123: 309
    • 3a Palanki MS. S, Erdman PE, Manning AM, Ow A, Ransone LJ, Spooner C, Suto C, Suto M. Bioorg. Med. Chem. Lett. 2000; 10: 1645
    • 3b Zanatta N, Fortes AS, Bencke CE, Marangoni MA, Camargo AF, Fantinel CA, Bonacorso HG, Martins MA. P. Synthesis 2015; 47: 827
    • 3c Kaur H, Balzarini J, de Kock C, Smith PJ, Chibale K, Singh K. Eur. J. Med. Chem. 2015; 101: 52
    • 3d Murai K, Miyazaki S, Fujioka H. Tetrahedron Lett. 2012; 53: 3746
    • 4a Liu C, Guo W, Shi X, Kaium MA, Gu X, Zhu YZ. Eur. J. Med. Chem. 2011; 46: 3996
    • 4b Qiu K, Wang R. Synthesis 2015; 47: 3186
    • 4c Yang Z, Zheng Y, Xu J. Synlett 2013; 24: 2165
    • 5a Fujisaki S, Fujiwara I, Norisue Y, Kajigaeshi S. Bull. Chem. Soc. Jpn. 1985; 58: 2429
    • 5b Murphy Kessabi F, Beaudegnies R, Quaranta L, Lamberth C. Tetrahedron Lett. 2016; 57: 5511
    • 5c Floyd N, Vijayakrishnan B, Koeppe JR, Davis BG. Angew. Chem. Int. Ed. 2009; 48: 7798
    • 5d Brown TJ, Chapman RF, Cook DC, Hart TW, McLay IM, Jordan R, Mason JS, Palfreyman MN, Walsh RJ. A. J. Med. Chem. 1992; 35: 3613
    • 5e Minard TA, Oswin CT, Waldie FD. C, Howell JK, Scott BM. T, Mondo DD, Sullivan RJ, Stein B, Jennings M, Schlaf M. J. Mol. Catal. A: Chem. 2016; 422: 175
    • 5f Zong J, Mague JT, Pascal JrR. A. Tetrahedron 2017; 73: 455
    • 5g Rotili D, De Luca A, Tarantino D, Pezzola S, Forgione M, Morozzo della Rocca B, Falconi M, Mai A, Caccuri AM. Eur. J. Med. Chem. 2015; 89: 156
    • 6a Su X, Pradaux-Caggiano F, Vicker N, Thomas MP, Halem H, Culler MD, Potter BV. L. ChemMedChem 2011; 6: 1616
    • 6b Marciniec K, Pawełczak B, Latocha M, Skrzypek L, Maciążek-Jurczyk M, Boryczka S. Molecules 2017; 22: 300
    • 6c Lee YS, Kim HY, Kim Y, Seo JH, Roh EJ, Han H, Shin KJ. Bioorg. Med. Chem. 2012; 20: 4921
    • 7a Emerson DW, Bennett BL, Steinberg SM. Synth. Commun. 2005; 35: 631
    • 7b Chukicheva IY, Sukrusheva OV, Shumova OA, Mazaletskaya LI, Shevchenko OG, Kuchin AV. Russ. J. Gen. Chem. 2016; 86: 2052
    • 7c Younai A, Fettinger JC, Shaw JT. Tetrahedron 2012; 68: 4320
  • 8 Aoyagi N, Furusho Y, Endo T. Synlett 2014; 25: 983
    • 9a Jones DJ, O’Leary EM, O’Sullivan TP. Tetrahedron Lett. 2017; 58: 4212
    • 9b Raz R, Rademann J. Org. Lett. 2011; 13: 1606
    • 10a Najda-Mocarska E, Zakaszewska A, Janikowska K, Makowiec S. Synth. Commun. 2018; 48: 14
    • 10b Supady A, Hecht S, Baldauf C. Org. Lett. 2017; 19: 4199
    • 10c Serdyuk OV, Heckel CM, Tsogoeva SB. Org. Biomol. Chem. 2013; 11: 7051
    • 10d Fang X, Wang C.-J. Chem. Commun. 2015; 1185
    • 10e Lippert KM, Hof K, Gerbig D, Ley D, Hausmann H, Guenther S, Schreiner PR. Eur. J. Org. Chem. 2012; 5919
  • 11 Váňa J, Sedlák M, Padělková Z, Hanusek J. Tetrahedron 2012; 68: 9808
  • 12 Kammel R, Tarabová D, Brož B, Hladíková V, Hanusek J. Tetrahedron 2017; 73: 1861
  • 13 Kammel R, Hanusek J. Heterocycles 2014; 89: 1183
    • 14a Southan GJ, Szabo C. Biochem. Pharmacol. 1996; 51: 383
    • 14b Southan GJ, Zingarelli B, O’Connor M, Salzman AL, Szabo C. Br. J. Pharmacol. 1996; 117: 619
    • 14c Southan GJ, Szabo C, Thiemermann C. Br. J. Pharmacol. 1995; 114: 510
    • 14d Jang D, Szabo C, Murrell GA. Eur. J. Pharmacol. 1996; 312: 341
    • 15a Mostert S, Mentz W, Petzer A, Bergh JJ, Petzer JP. Bioorg. Med. Chem. 2012; 20: 7040
    • 15b Booysen HP, Moraal C, Terre’Blanche G, Petzer A, Bergh JJ, Petzer JP. Bioorg. Med. Chem. 2011; 19: 7507
  • 16 Ganellin CR, Hosseini SK, Khalaf YS, Tertiuk W, Arrang JM, Garbarg M, Ligneau X, Schwartz JC. J. Med. Chem. 1995; 38: 3342
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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

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Scheme 1 Synthesis of S-benzoyl isothiourea hydrochloride (2)
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Figure 1 Crystal structure of 5, demonstrating that acylation has occurred at the sulfur atom
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Figure 2 Comparison of bond lengths (in red) and S-C-N bond angles (in blue) between 5 and 10 [23]
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Scheme 2 Preparation of aryl-substituted S-acyl isothioureas 29 [25]
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Scheme 3 Preparation of alkyl and aryl-alkyl derivatives 1118 [25]
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Scheme 4 Preparation of NSAID derivatives 1922 [25]