New Facile Synthesis of 2-Alkylthiopyrimidin-4(3H)-ones by Tandem Aza-Wittig Reaction Starting from the Baylis–Hillman Adducts

Abstract

Iminophosphoranes reacted with CS₂ at –5 °C to produce the isothiocyanates, which were treated with primary amine to give thioureas in 73–91% yields. The subsequent reaction of thioureas with alkyl bromides in the presence of solid K₂CO₃ produced 2-alkylthiopyrimidin-4(3H)-ones in 68–88% yield via tandem intramolecular cyclization–isomerization–S-alkylation.

Key words

pyrimidin-4(3H)-one - Baylis–Hillman reaction - aza-Wittig reaction - isothiocyanate - isomerization

• References and Notes

• 1a Saladino R, Crestini C, Palamara AT, Danti MC, Manetti F, Corelli F, Garaci E, Botta M. J. Med. Chem. 2001; 44: 4554-4554
• 1b Singh K, Singh K, Balzarini J. Singh K, Singh K, Balzarini J. Eur. J. Med. Chem. 2013; 67: 428-428
• 2 Rashad AE, Shamroukh AH, Yousif NM, Salama MA, Ali HS, Ali MM, Mahmoud AE, El-Shahat M. Arch. Pharm. Chem. Life Sci. 2012; 345: 729-729
• 3 Malothu N, Bhandaru JS, Kulandaivelu U, Jojula M, Adidala RR, Umadevi KR, Dusthackeer AV. N, Kaki VR, Akkinepally RR. Bioorg. Med. Chem. Lett. 2016; 26: 836-836
• 4 Taylor EC, Zhou P, Tice CM, Lidert Z, Roemmele RC. Tetrahedron Lett. 1997; 38: 4339-4339
• 5 Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, Lee B, Aertgeerts K, Jennings A, Xu R, Kassel DB, Kaldor SW, Navre M, Webb DR, Gwaltney SL. II. J. Med. Chem. 2011; 54: 510-510
• 6 Artico M, Massa S, Mai A, Marongiu ME, Piras G, Tramontano E, La Colla P. Antivir. Chem. Chemother. 1993; 4: 361-361
• 7 Rotili D, Tarantino D, Nawrozkij MB, Babushkin AS, Botta G, Marrocco B, Cirilli R, Menta S, Badia R, Crespan E, Ballante F, Ragno R, Esté JA, Maga G, Mai A. J. Med. Chem. 2014; 57: 5212-5212
• 8 Ramajayam R, Mahera NB, Neamati N, Yadav MR, Giridhar R. Arch. Pharm. Chem. Life Sci. 2009; 342: 710-710
• 9 Zhang Y, Sun X, Fan N, Zhao J, Tu J, Chen X, Liu J, Wang X. Med. Chem. Commun. 2015; 6: 1438-1438
• 10 Mai A, Artico M, Sbardella G, Massa S, Novellino E, Greco G, Loi AG, Tramontano E, Marongiu ME, La Colla P. J. Med. Chem. 1999; 42: 619-619
• 11 Mugnaini C, Alongi M, Togninelli A, Gevarija H, Brizzi A, Manetti F, Bernardini C, Angeli L, Tafi A, Bellucci L, Corelli F, Massa S, Maga G, Samuele A, Facchini M, Clotet-Codina I, Armand-Ugón M, Esté JA, Botta M. J. Med. Chem. 2007; 50: 6580-6580
• 12 Nawrozkij MB, Rotili D, Tarantino D, Botta G, Eremiychuk AS, Musmuca I, Ragno R, Samuele A, Zanoli S, Armand-Ugón M, Clotet-Codina I, Novakov IA, Orlinson BS, Maga G, Esté JA, Artico M, Mai A. J. Med. Chem. 2008; 51: 4641-4641
• 13a Basavaiah D, Reddy BS, Badsara SS. Chem. Rev. 2010; 110: 5447-5447
• 13b Declerck V, Martinez J, Lamaty F. Chem. Rev. 2009; 109: 1-1
• 13c Singh V, Batra S. Tetrahedron 2008; 64: 4511-4511
• 14 Reddy RS, Lagishetti C, Kiran IN. C, You H, He Y. Org. Lett. 2016; 18: 3818-3818
• 15 Yang Y, Ma C, Thumar NJ, Hu W. J. Org. Chem. 2016; 81: 8537-8537
• 16 Basavaiah D, Pal S, Veeraraghavaiah G, Bharadwaj KC. Tetrahedron 2015; 71: 4659-4659
• 17 Bharadwaj KC, Tiwari DK. Tetrahedron 2016; 72: 312-312
• 18a Wei H, Li Y, Xiao K, Cheng B, Wang H, Hu L, Zhai H. Org. Lett. 2015; 17: 5974-5974
• 18b Hu Y, Li X, Wan B. Tetrahedron 2015; 71: 6935-6935
• 18c Welsch SJ, Umkehrer M, Kalinski C, Ross G, Burdack C, Kolb J, Wild M, Ehrlich A, Wessjohann LA. Tetrahedron Lett. 2015; 56: 1025-1025
• 18d Ramachary DB, Shruthi KS. J. Org. Chem. 2016; 81: 2405-2405
• 18e Qu F, Hu R.-F, Gao L, Wu J, Cheng X.-H, Wang S, He P. Synthesis 2015; 47: 3701-3701
• 18f Nishimura Y, Cho H. Synlett 2015; 26: 233-233
• 19 Palacios F, Alonso C, Aparicio D, Rubiales G, Santos JM. Tetrahedron 2007; 63: 523-523
• 20a Ding MW, Fu BQ, Cheng L. Synthesis 2004; 1067-1067
• 20b Xie H, Liu JC, Wu L, Ding MW. Tetrahedron 2012; 68: 7984-7984
• 21a Yan YM, Rao Y, Ding MW. J. Org. Chem. 2016; 81: 1263-1263
• 21b Yuan D, Kong HH, Ding MW. Tetrahedron 2015; 71: 419-419
• 21c Wang L, Ren ZL, Chen M, Ding MW. Synlett 2014; 25: 721-721
• 21d Wang Y, Chen M, Ding MW. Tetrahedron 2013; 69: 9056-9056
• 21e Zhong Y, Wu L, Ding MW. Synthesis 2012; 44: 3085-3085
• 22a Yadav JS, Gupta MK, Pandey SK, Reddy BV. S, Sarma AV. S. Tetrahedron Lett. 2005; 46: 2761-2761
• 22b Sá MM. J. Braz. Chem. Soc. 2003; 14: 1005-1005
• 23 General Procedure for the Preparation of Thioureas 8 To the azides 4 (2 mmol) in dry CH₂Cl₂ (10 mL) was added dropwise Ph₃P (0.52 g, 2 mmol) in CH₂Cl₂ (5 mL) under N₂. The mixture was stirred at r.t. for 1–2 h to form iminophosphorane (TLC monitoring). The CS₂ (1.52 g, 20 mmol) was then added at –5 °C, and the mixture was continuing stirred at –5 °C for 4–6 h. After the reaction was completed, the solvent and excess CS₂ were removed in reduced pressure. Primary amine (2 mmol) was added to the residue in CH₂Cl₂ (10 mL), and the mixture was stirred overnight at r.t. The solvent was removed, and the residue was purified by column chromatography (PE–EtOAc, 4:1) to give thioureas 8. Compound 8a: light yellow solid (yield 0.53 g, 87%), mp 72–74 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.85 (s, 1 H, =CH), 7.42–7.38 (m, 5 H, Ar–H), 6.59 (br, 2 H, 2NH), 4.49 (br, 2 H, NCH₂), 3.82 (s, 3 H, OCH₃), 3.38 (br, 2 H, NCH₂), 1.49–1.29 (m, 4 H, 2CH₂), 0.89 (t, J = 7.2 Hz, 3 H, CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 181.1, 168.4, 143.5, 133.8, 129.5, 129.4, 128.8, 127.2, 52.5, 44.6, 41.2, 30.8, 19.9, 13.7. HRMS: m/z calcd for [C₁₆H₂₂N₂O₂S + H]⁺: 307.1475; found: 307.1479.
• 24 General Procedure for the Preparation of 2-Alkylthiopyrimidin-4(3H)-ones 11 To the thioureas 8 (2 mmol) in MeCN (10 mL) was added solid K₂CO₃ (0.28 g, 2 mmol). The mixture was stirred at 50 °C for 5–6 h to form 2-thioxopyrimidin-4(1H)-ones 10 (TLC monitoring). The alkyl bromide (2 mmol) was then added with continuing stir. After the reaction was completed, the solid was filtered. The filtrate was removed, and the residue was purified by column chromatography (PE–EtOAc, 20:1) to give 2-alkylthiopyrimidin-4(3H)-ones 11. Compound 11m: white solid (yield 0.502 g, 75%), mp 102–104 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.61 (s, 1 H, Ar–H), 7.51–7.21 (m, 10 H, Ar–H), 3.77 (s, 2 H, CH₂), 2.97 (t, J = 7.8 Hz, 2 H, SCH₂), 1.66–1.60 (m, 2 H, CH₂), 0.94 (t, J = 7.2 Hz, 3 H, CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 162.4, 161.4, 149.7, 138.8, 135.9, 129.8, 129.7, 129.1, 128.5, 128.4, 126.3, 123.4, 34.2, 33.6, 21.9, 13.4. HRMS: m/z calcd for [C₂₀H₂₀N₂OS + H]⁺: 337.1369; found: 337.1373.
• 25 General Procedure for the Preparation of 2-Alkylthiopyrimidin-4(3H)-ones 11 (R¹ = alkyl) at Room Temperature To the thioureas 8 (2 mmol) and alkyl bromides (2 mmol) in MeCN (10 mL) was added solid K₂CO₃ (0.28 g, 2 mmol). The mixture was stirred at r.t. for 24–48 h. After the reaction was completed, the solid was filtered. The filtrate was removed, and the residue was purified by column chromatography (PE–EtOAc, 20:1) to give 2-alkylthiopyrimidin-4(3H)-ones 11. Compound 11a: colorless oil (yield 0.53 g, 84%). ¹H NMR (600 MHz, CDCl₃): δ = 7.50 (s, 1 H, Ar–H), 7.29–7.19 (m, 5 H, Ar–H), 4.01 (t, J = 7.8 Hz, 2 H, NCH₂), 3.73 (s, 2 H, CH₂), 3.10 (t, J =7.2 Hz, 2 H, SCH₂), 1.73–1.71 (m, 4 H, 2CH₂), 1.43–1.39 (m, 2 H, CH₂), 1.03–0.95 (m, 6 H, 2 CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 162.1, 160.0, 149.2, 138.9, 129.0, 128.4, 126.2, 122.4, 44.7, 33.8, 33.7, 29.3, 22.1, 20.2, 13.7, 13.4. HRMS: m/z calcd for [C₁₈H₂₄N₂OS + H]⁺: 317.1682; found: 317.1683.