Facile Guanidine Formation under Mild Acidic Conditions

Abstract

An efficient method for converting isothioureas into guanidines was developed. The use of amine salts of bis(trifluoromethanesulfonyl)imide as a nitrogen source was found to induce an efficient conversion under weak acidic conditions at 50 °C. The conversion was applicable to the various amines and carbamate-protected thioureas, and various carbamate-protected cyclic guanidines were obtained in high yields. In particular, ammonium bis(trifluoromethanesulfonyl)imide salt is a useful N1 source with which to construct monoprotected cyclic guanidines.

Key words

guanidinylation - cyclic guanidine - isothiourea - bis(trifluoromethansulfonyl)imide - ammonium bis(trifluoromethansulfonyl)imidate

• References and Notes

• 1a Tahara Y. J. Pharm. Soc. Jpn. 1909; 29: 587
• 1b Tahara Y. Biochem. Z. 1911; 30: 255
• 1c Goto T, Kishi Y, Takahashi S, Hirata Y. Tetrahedron 1965; 21: 2059
• 1d Tsuda K, Ikuma S, Kawamura M, Tachikawa R, Sakai K, Tamura C, Amakasu O. Chem. Pharm. Bull. 1964; 12: 1357
• 1e Woodward RB. Pure. Appl. Chem. 1964; 9: 49
• 1f Furusaki A, Tomie Y, Nitta I. Bull. Chem. Soc. Jpn. 1970; 43: 3332
• 2 Patil AD, Kumar NV, Kokke WC, Bean MF, Freyer AJ, Brosse CD, Mai S, Truneh A, Carte B. J. Org. Chem. 1995; 60: 1182
• 3 Iwatsuki M, Uchida R, Yoshijima H, Ui H, Shiomi K, Matsumoto A, Takahashi Y, Abe A, Tomoda H, Omura S. J. Antibiot. 2008; 61: 222
• 4 Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin T.-H, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA. J. Med. Chem. 2000; 43: 3482
• 5a Blondeau P, Segura M, de Mendoza J, Pérez-Fernández R. Chem. Soc. Rev. 2007; 36: 198
• 5b Sullivan JD, Giles RL, Looper RE. Curr. Bioact. Compd. 2009; 5: 39
• 6a Corey EJ, Grogan MJ. Org. Lett. 1999; 1: 157
• 6b Terada M, Ube H, Yaguchi Y. J. Am. Chem. Soc. 2006; 128: 1454
• 6c Kiesewetter MK, Scholten MD, Kirn N, Weber RL, Hedrick JL, Waymouth RM. J. Org. Chem. 2009; 74: 9490
• 6d Misaki T, Takimoto G, Sugimura T. J. Am. Chem. Soc. 2010; 132: 6286
• 6e Alsarraf J, Ammar YA, Robert F, Cloutet E, Cramail H, Landais Y. Macromolecules 2012; 45: 2249
• 6f Huang Li, Li J, Zhao Y, Ye X, Liu Y, Yan L, Tan C.-H, Liu H, Jiang Z. J. Org. Chem. 2015; 80: 8933

For recent reviews, see:
• 7a Berlinck RG. S, Burtoloso AC. B, Kossuga MH. Nat. Prod. Rep. 2008; 25: 919
• 7b Zhang W.-X, Xu L, Xi Z. Chem. Commun. 2015; 51: 254
• 7c Alonso-Moreno C, Antiñolo A, Carrillo-Hermosilla F, Otero A. Chem. Soc. Rev. 2014; 43: 3406
• 7d Tahir S, Badshah A, Hussain RA. Bioorg. Chem. 2015; 59: 39
• 8a Kyoung S, Qian L. Tetrahedron Lett. 1993; 34: 7677
• 8b Kent DR, Cody WL, Doherty AM. Tetrahedron Lett. 1996; 37: 8711
• 8c Levallet C, Lerpiniere J, Ko SY. Tetrahedron 1997; 53: 5291
• 8d Gers T, Kunce D, Markowski P, Izdebski J. Synthesis 2004; 37
• 8e Bergeron RJ, McManis JS. J. Org. Chem. 1987; 52: 1700
• 8f Porcheddu A, De Lua L, Giacomelli G. Synlett 2009; 3368
• 9a Boukouvalas J, Golding BT. Angew. Chem. Suppl. 1983; 22: 860
• 9b Bernatowicz MS, Wu YL, Matsueda GR. J. Org. Chem. 1992; 57: 2497
• 9c Bernatowicz MS, Wu YL, Matsueda GR. Tetrahedron Lett. 1993; 34: 3389
• 9d Drake B, Patek M, Lebel M. Synthesis 1994; 579
• 9e Robinson S, Roskamp EJ. Tetrahedron 1997; 53: 6697
• 9f Yong YF, Kowalski JA, Lipton MA. J. Org. Chem. 1997; 62: 1540
• 9g Golding BT, Mitchinson A, Clegg W, Elsegood MR. J, Griffin RJ. J. Chem. Soc., Perkin Trans. 1 1999; 349
• 9h Dräger G, Solodenko W, Messinger J, Schön U, Kirschning A. Tetrahedron Lett. 2002; 43: 1401
• 9i Castillo-Melendez JA, Golding BT. Synthesis 2004; 1655
• 9j Solodenko W, Bröker P, Messinger J, Schön U, Kirschning A. Synthesis 2006; 461
• 10a Feichtinger K, Zapf C, Sings HL, Goodman M. J. Org. Chem. 1998; 63: 3804
• 10b Feichtinger K, Sings HL, Baker TJ, Matthews K, Goodman M. J. Org. Chem. 1998; 63: 8432
• 10c Kim H, Mathew F, Ogbu C. Synlett 1999; 193
• 10d Linton BR, Carr AJ, Orner BP, Hamilton AD. J. Org. Chem. 2000; 65: 1566
• 11a Maryanoff CA, Stanzione RC, Plampin JN, Mills JE. J. Org. Chem. 1986; 51: 1882
• 11b Noël R, Song X, Jiang R, Chalmers MJ, Griffin PR, Kamenecka TM. J. Org. Chem. 2009; 74: 7595
• 12a Katritzky AR, Rogovoy BV, Chassaing C, Vvedensky V. J. Org. Chem. 2000; 65: 8080
• 12b Wu Y.-Q, Hamilton SK, Wilkinson DE, Hamilton GS. J. Org. Chem. 2002; 67: 7553
• 12c Musiol H.-J, Moroder L. Org. Lett. 2001; 3: 3859
• 13a Ref. 8d.
• 13b Shinada T, Umezawa T, Ando T, Kozuma H, Ohfune Y. Tetrahedron Lett. 2006; 47: 1945
• 13c Li Q, Wang S, Zhou S, Yang G, Zhu X, Liu Y. J. Org. Chem. 2007; 72: 6763
• 13d Zhu X, Du Z, Xu F, Shen Q. J. Org. Chem. 2009; 74: 6347
• 13e Looper RE, Haussener TJ, Mack JB. C. J. Org. Chem. 2011; 76: 6967
• 13f Li J, Neuville L. Org. Lett. 2013; 15: 6124
• 13g Tsubokura K, Iwata T, Taichi M, Kurbangalieva A, Fukasec K, Nakao Y, Tanaka K. Synlett 2014; 25: 1302
• 13h Zeng C.-J, Chen C.-J, Chang C.-W, Chen H.-T, Chien T.-C. Aust. J. Chem. 2014; 67: 1134
• 13i Li P, Cheng G, Zhang H, Xu X, Gao J, Cui X. J. Org. Chem. 2014; 79: 8156
• 13j Tran LQ, Li J, Neuville L. J. Org. Chem. 2015; 80: 6102
• 14a Dukat M, Abdel-Rahman A, Ismaiel A, Ingher S, Teitler M, Gyermek L, Glennon R. J. Med. Chem. 1996; 39: 4017
• 14b Filosa R, Buonerba M, Loddo R. J. Pham. Pharmacol. 2006; 58: 1415
• 14c Ube H, Uraguchi D, Terada M. J. Organomet. Chem. 2007; 692: 545
• 14d Genc M, Servi S. Synth. Commun. 2009; 39: 3263
• 14e Wahab KM, Uddin MK, Ali M, Rahman MS, Rashid MA, Chowdhury R. J. Heterocycl. Chem. 2014; 51: 216
• 14f Kitamura M, Yuasa R, Vranken DL. V. Tetrahedron Lett. 2015; 56: 3027

For patents, see:
• 15a Shum P, Gross A, Ma L, McGarry DG, Merriman GH, Rampe D, Ringheim G.h, Sabol JS, Volz Francis AA. US 20050026916, 2005
• 15b Askew BC, Breslin MJ, Duggan ME, Hutchinson JH, Meissner RS, Perkins JJ, Steele TG, Patane MA. A. WO 2001053262, 2001
• 16a Daboun HA, Ibrahim YA. J. Heterocycl. Chem. 1982; 19: 41
• 16b Wiskur SL, Lavigne JJ, Metzger A, Tobey SL, Lynch V, Anslyn EV. Chem. Eur. J. 2004; 10: 3792
• 16c Lanman BA, Overman LE. Heterocycles 2006; 70: 557
• 16d Subtel’na I, Atamanyuk D, Szymańska E, Kieć-Kononowicz K, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Bioorg. Med. Chem. 2010; 18: 5090
• 16e Lewellyn K, Bialonska D, Chaurasiya ND, Tekwani B, Zjawiony JK. Bioorg. Med. Chem. Lett. 2012; 22: 4926
• 17 Namba K, Takeuchi K, Kaihara Y, Oda M, Nakayama A, Nakayama A, Yoshida M, Tanino K. Nat. Commun. 2015; 6: 8731

In the case of unprotected acyclic isothioureas, there have been several examples of guanidinylation reaction under mild acidic conditions. For selected recent examples, see:
• 18a Chai B, Wang S, Yu W, Li H, Song C, Xu Y, Liu C, Chang J. Bioorg. Med. Chem. Lett. 2013; 23: 3505
• 18b Aoyagi N, Furusho Y, Endo T. Synlett 2014; 25: 983
• 18c Vazdar K, Kunetskiy R, Saame J, Kaupmees K, Leito I, Jahn U. Angew. Chem. Int. Ed. 2014; 53: 1435
• 19 General Procedure for the Transformation of Isothiourea 1 into Guanidine 3a To a solution of isothiourea 1 (100 mg, 0.359 mmol) in DCE (1.8 mL) were added BnNH₂ (39.2 μL, 0.718 mmol) and 1 M DCE solution of Tf₂NH (718 μL, 0.718 mmol) at 0 °C. After being stirred at 50 °C for 5 h, the reaction was quenched with 1 M NaOH. The mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were washed with sat. aq NaHCO₃ solution, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane–EtOAc, 1:2 to 0:1) to afford guanidine 3a (116 mg, 0.345 mmol, 96%) as yellow oil. Analytical Data Compound 3a: ¹H NMR (500 MHz, CDCl₃): δ = 7.45–7.25 (m, 10 H), 7.05 (br s, 1 H), 5.17 (s, 2 H), 4.48 (s, 2 H), 3.58 (s, 2 H), 1.30 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.16, 151.12, 138.01, 135.21, 128.65, 128.58, 128.55, 128.13, 127.60, 127.37, 67.73, 60.93, 58.63, 46.76, 29.70. IR (KBr): 3378, 3032, 2962, 2926, 2360, 2341, 1710, 1648, 1532, 1460, 1402, 1353, 1324, 1183, 1127, 1005, 913, 801, 742, 697, 610, 442, 418 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₀H₂₄N₃O₂: 338.1869; found: 338.1863. Compound 3b: ¹H NMR (500 MHz, CDCl₃): δ = 7.43–7.33 (m, 5 H), 6.58–6.45 (br s, 1 H), 5.16 (s, 2 H), 3.85 (oct, J = 6.5 Hz, 1 H), 3.50 (s, 2 H), 1.25 (s, 6 H), 1.20 (d, J = 6.5 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.16, 149.85, 135.43, 128.58, 128.45, 128.40, 67.34, 60.98, 58.24, 43.93, 29.82, 22.73. IR (KBr): 3374, 2967, 2928, 2360, 1712, 1646, 1529, 1457, 1402, 1358, 1322, 1280, 1190, 1165, 1131, 1059, 988, 913, 765, 743, 698, 597, 576, 419 cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₄N₃O₂: 290.1862; found: 290.1863.
• 20a Zehavi U, Amit B, Patchornik A. J. Org. Chem. 1972; 37: 2281
• 20b Zehavi U, Patchornik A. J. Org. Chem. 1972; 37: 2285
• 20c Ohtsuka E, Tanaka S, Ikehara M. J. Am. Chem. Soc. 1978; 100: 8210
• 20d Chow YL In The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives. Patai S. Wiley; New York: 1982. Suppl. F, Part 1 181
• 20e Klán P, Šolomek T, Bochet CG, Blanc A, Givens R, Rubina M, Popik V, Kostikov A, Wirz J. Chem. Rev. 2013; 113: 119

For recent application of nitrobenzyl group to total synthesis, see:
• 21a Groneberg RD, Miyazaki T, Stylianides NA, Schulze TJ, Stahl W, Schreiner EP, Suzuki T, Iwabuchi Y, Smith AL, Nicolaou KC. J. Am. Chem. Soc. 1993; 115: 7593
• 21b Smith AL, Pitsinos EN, Hwang CK, Mizuno Y, Saimoto H, Scarlato GR, Suzuki T, Nicolaou KC. J. Am. Chem. Soc. 1993; 115: 7612
• 21c Nicolaou KC, Hummel CW, Nakada M, Shibayama K, Pitsinos EN, Saimoto H, Mizuno Y, Baldenius KU, Smith AL. J. Am. Chem. Soc. 1993; 115: 7625
• 21d Nicolaou KC, Lu Z, Li R, Woods JR, Sohn T. J. Am. Chem. Soc. 2015; 137: 8716
• 22a Forsyth CM, MacFarlane DR, Golding JJ, Huang J, Sun J, Forsyth M. Chem. Mater. 2002; 14: 2103
• 22b Davidson MG, Raithby PR, Johnson AL, Bolton PD. Eur. J. Inorg. Chem. 2003; 3445
• 22c Aidoui A, Bendahou S, Demonceau A, Delaude L. J. Comb. Chem. 2008; 10: 886