Condensation of Amines with S-Methyl Thiouronium Salts: Another Entry for the Synthesis of Amidines

Dedicated to Professor H. Ila on the occasion of her 79^th birthday

Abstract

We present a condensation of primary aryl or alkyl amines with S-methyl thiouronium salts to obtain N,N,N′-trisubstituted amidines. High yields, short reaction times, and a fair substrate scope are the noteworthy features of this protocol. Surprisingly, the reaction of a thiouronium salt with 4-aminopyridine gave 1-(4-methoxybenzoyl)piperidine.

Key words

amidines - condensation - thiouronium salts - amides - amines

Publication History

Received: 09 September 2023

Accepted after revision: 02 January 2024

Accepted Manuscript online:
02 January 2024

Article published online:
24 January 2024

• References and Notes

• 1 Kumamoto T. In Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts, Chap. 10. Ishikawa T. Wiley; Chichester: 2009: 295
• 2 Greenhill JV, Lue P. Prog. Med. Chem. 1993; 30: 203
• 3 Maccallini C, Fantacuzzi M, Amoroso R. Mini-Rev. Med. Chem. 2013; 13: 1305
• 4 Arya S, Kumar N, Roy P, Sondhi SM. Eur. J. Med. Chem. 2013; 59: 7
• 5 Aly AA, Nour-El-Din AM. ARKIVOC 2008; (i): 153
• 6 Oxley P, Peak DA, Short WF. J. Chem. Soc. 1948; 1618
• 7 Charette AB, Grenon M. Tetrahedron Lett. 2000; 41: 1677
• 8 Katritzky AR, Huang T.-B, Voronkov MV. J. Org. Chem. 2001; 66: 1043
• 9 Katritzky AR, Cai C, Singh SK. J. Org. Chem. 2006; 71: 3375
• 10 Mandel HG, Hill AJ. J. Am. Chem. Soc. 1954; 76: 3978
• 11 Hill AJ, Johnston JV. J. Am. Chem. Soc. 1954; 76: 920
• 12 Kraft A. J. Chem. Soc., Perkin Trans. 1 1999; 705
• 13 Qian F, Liu K, Ma H. Dalton Trans. 2010; 39: 8071
• 14 Lin J.-P, Zhang F.-H, Long Y.-Q. Org. Lett. 2014; 16: 2822
• 15 Oszczapowicz J, Raczyńska E, Pawlik T. Pol. J. Chem. 1984; 58: 117
• 16 Hellal M, Bihel F, Mongeot A, Bourguignon J.-J. Org. Biomol. Chem. 2006; 4: 3142
• 17 Das VK, Thakur AJ. Tetrahedron Lett. 2013; 54: 4164
• 18 Phakhodee W, Wangngae S, Wiriya N, Pattarawarapan M. Tetrahedron Lett. 2016; 57: 5351
• 19 Flemer S, Madalengoitia JS. Synthesis 2011; 1638
• 20 Lee HK, Ten LN, Pak CS. Bull. Korean Chem. Soc. 1998; 19: 1148
• 21 Lange UE. W, Schäfer B, Baucke D, Buschmann E, Mack H. Tetrahedron Lett. 1999; 40: 7067
• 22 Baati R, Gouverneur V, Mioskowski C. Synthesis 1999; 927
• 23 Harada T, Tamaru Y, Yoshida Z. Tetrahedron Lett. 1979; 3525
• 24 Jones RC. F, Crockett AK. Tetrahedron Lett. 1993; 34: 7459
• 25 Gilbert I, Rees DC, Richardson RS. Tetrahedron Lett. 1991; 32: 2277
• 26 Harris RL. N. Aust. J. Chem. 1974; 27: 2635
• 27 Harada T, Tamaru Y, Yoshida Z.-i. Chem. Lett. 1979; 8: 1353
• 28 Santus M. Pol. J. Chem. 1980; 54: 1067
• 29 Matsuda K, Yonagisawa I, Isomura Y, Mase T, Shibanuma T. Synth. Commun. 1997; 27: 2393
• 30 Kiran KR, Swaroop TR, Sukrutha KP, Shruthi JB, Anil SM, Rangappa KS, Sadashiva MP. Synthesis 2019; 51: 4205
• 31 Kiran KR, Swaroop TR, Rajeev N, Anil SM, Rangappa KS, Sadashiva MP. Synthesis 2020; 52: 1444
• 32 Kiran KR, Swaroop TR, Santhosh C, Rangappa KS, Sadashiva MP. ChemistrySelect 2021; 6: 7262
• 33 Ravi Singh K, Santhosh C, Swaroop TR, Sadashiva MP. Org. Biomol. Chem. 2022; 20: 5771
• 34 Swaroop TR, Rangappa KS, Torun L. ChemistrySelect 2021; 6: 177
• 35 Sukrutha KP, Swaroop TR, Preetham R, Lokanath NK, Rangappa KS, Sadashiva MP. Synth. Commun. 2021; 51: 2316
• 36 Dukanya D, Swaroop TR, Shobith R, Rangappa KS, Basappa Basappa. SynOpen 2019; 3: 71
• 37 Dukanya D, Swaroop TR, Rangappa KS, Basappa Basappa. Curr. Org. Chem. 2020; 24: 2792
• 38 Amidines 2; General Procedure A solution of the appropriate S-methyl thiouronium salt 1 (2 mmol), amine (2 mmol), and K₂CO₃ (2 mmol) in DMF (2 mL) was stirred at r.t. for 2–3 h until the reaction was complete (TLC). Brine (25 mL) was added to the mixture, and the product was extracted with EtOAc (2 × 25 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to give a crude product that was purified by column chromatography [silica gel, EtOAc–hexane (1:9)]. (4-Methylphenyl)[phenyl(piperidin-1-yl)methylene]amine (2a) Viscous liquid; yield: 85%. IR (neat): 2933, 2852, 1588, 1275 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.62–1.69 (m, 6 H, (CH₂)₃), 2.16 (s, 3 H, Ar-CH₃), 3.25–3.5 (m, 4 H, (CH₂)₂), 6.47 (d, J = 8.0 Hz, 2 H, Ar-H), 6.80 (d, J = 8.0 Hz, 2 H, Ar-H), 7.12–7.14 (m, 2 H, Ar-H), 7.23–7.24 (m, 3 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.7, 25.0, 25.9, 47.1, 122.7, 128.1, 128.7, 129.0, 129.1, 129.8, 134.2, 148.6, 160.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₃N₂: 279.1861; found: 279.1860.
• 39 Khatri CK, Mali AS, Chaturbhuj GU. Monatsh. Chem. 2017; 148: 1463
• 40 Sundberg RJ, Powers Walters C, Bloom JD. J. Org. Chem. 1981; 46: 3730