On a Simple Hydrogen Cyanide-Based Access to Piperazin-2-ones

Abstract

This report describes a scope exploration of a rarely used access to piperazin-2-ones from carbonyls, hydrogen cyanide (generated in situ from acetic acid and potassium cyanide), and ethylenediamine as well as N- or C-substituted alkyl 1,2-diamines. Our findings show that this synthesis plausibly proceeds via imines and/or imidazoline intermediates and, upon addition of hydrogen cyanide, to α,δ-diaminonitriles. Their ensuing cyclization leads to piperazin-2-imines, which then require a hydrolysis stage at high temperature, using a microwave oven, to generate the corresponding piperazin-2-ones. Although the reaction proceeds sometimes in very modest yields (ranging from 4% to 84%), its rather large scope (illustrated by 73 original examples) are described here, as well as the many commercially available starting materials offering at least a one-pot alternative to prepare original libraries of chemicals featuring a piperazin-2-one component.

Keywords

Heterocycles - Lactams - Ring closure - Piperazinone - α,δ-Diaminonitriles

Publication History

Received: 25 July 2025

Accepted after revision: 29 August 2025

Accepted Manuscript online:
19 September 2025

Article published online:
24 October 2025

• References

• 1a Darko L, Karliner J. J Org Chem 1971; 36: 3810
• 1b Dunmore GC, Taylor KC, Kolthammer BWS. Patent US 4767860
• 1c Chassonnery D, Chastrette F, Chastrette M, Blanc A, Mattioda G. Bull Soc Chim Fr 1994; 131: 188
• 1d Alexakis A, Tranchier J-P, Lensen N, Mangeney P. J Am Chem Soc 1995; 117: 10767
• 1e Tripier R, Chuburu F, Le Baccon M, Handel H. Tetrahedron 2003; 59: 4573
• 1f Kinoyama I, Taniguchi N, Kawaminami E. et al. Chem Pharm Bull 2005; 53: 402
• 1g Abreu A, Ochoa MA, Farfán N, Santillan R. Magn Reson Chem 2006; 44: 25
• 2a Petasis NA, Patel ZD. Tetrahedron Lett 2000; 41: 9607
• 2b Wojaczynska E, Baikowicz J, Dorsz M, Skarziewski J. J Org Chem 2013; 78: 2808
• 3 Xie RG, Zhou H, Lu H, Mu Y, Xu G, Chang M. Org Lett 2022; 24: 9033
• 4a Snowden TS. ARKIVOC 2012; ii: 20
• 4b Serafini M, Murgia I, Giustiniano M, Pirali T, Tron GC. Molecules 2021; 26: 558
• 5 Gukasyan AO, Galstyan LK, Avetisyan AA. Russ Chem Rev 1991; 60: 1318
• 6 Willgerodt C, Genieser A. J Prakt Chem 1888; 37: 361
• 7 Jocić ZZ. Russ Fiz Khim Ova 1897; 29: 97
• 8 Bargellini G. Gazz Chim Ital 1906; 36: 329
• 9a Lai JT. J Org Chem 1980; 45: 754
• 9b Lai JT. Synthesis 1981; 40
• 9c Rychnovsky SD, Beauchamp T, Vaidyanathan R, Kwan T. J Org Chem 1998; 63: 6363
• 9d Moeller M, Hentschel C, Chi L, Studer A. Org Biomol Chem 2011; 9: 2403
• 10a Alanine TA, Stokes S, Scott JS. Synlett 2017; 28: 357
• 10b Smalley AP, Cuthbertson JD, Gaunt M. J Am Chem Soc 2017; 139: 1412
• 10c Nappi M, He C, Whitehurst WG, Chappell BNG, Matthew J. Angew Chem Int Ed 2018; 130: 3232
• 11a Castro Pineiro JL, Dinnell K, Elliot JM, Hollingworth GJ, Shaw DE, Swain CJ. Patent US 20030236250
• 11b Francavilla C, Turtle ED, Kim B. et al. Bioorg Med Chem Lett 2011; 21: 3029
• 11c Dreyer A, Doods H, Gerlach K. et al. Patent US 20120196872
• 11d Ostermeier M, Sieger P. Patent WO 2014012859
• 12a Perryman MS, Harris ME, Foster JL, Joshi A, Clarkson GJ, Fox DJ. Chem Commun 2013; 49: 10022
• 12b Perryman MS, Earl WME, Cgreatorex S, Clarkson GJ, Fox DJ. Org Biomol Chem 2015; 13: 2360
• 13 Krischuns T, Paisant S, Chen KY. et al. Synthesis 2025; 57: 1627
• 14a Strong JS, Graig WE, Elkind VT. Patent US 2700668
• 14b Ito N, Sasaki H, Tai K, Shinohara T. Patent WO 2012036253
• 14c Masuzawa K, Masaki M, Ohta M. Bull Chem Soc Jpn 1968; 41: 702
• 14d Sut A, Podesta M, Lattes MA. Chim Ther 1969; 4: 167
• 15 Janin YL. Beilstein J Org Chem 2022; 18: 1355
• 16 Siegl WO. J Org Chem 1872; 1977: 42
• 17 Forsberg JH, Spaziano VT, Balasubramanian TM. et al. J Org Chem 1987; 52: 1017
• 18 Kobayashi S, Ishitani H, Ueno M. Synlett 1997; 115
• 19 Boulos Z, Abbott SD, Baigent CB, Doyle C, Yalaga RS. Eur J Org Chem 2018; 6486
• 20 Perrin CL, Nunez O. J Am Chem Soc 1986; 108: 5997
• 21a Padwa A, Gasdaska JR, Haffmanns G, Rebello H. J Org Chem 1987; 52: 1027
• 21b Abdulla ZM, Iyer RP, Akamanchi KG, Degani MS, Coutinho ECJ. Heterocycl Chem 2011; 48: 38
• 22a Erickson JG. J Org Chem 1955; 20: 1569
• 22b De Benneville PL, Strong JS, Elkind VT. J Org Chem 1956; 21: 772
• 23 Ruby P, DeBeneville PL. J Am Chem Soc 1953; 75: 3027
• 24 Liu J, Kozlowski J, Kim R. et al. Patent WO 2016164284
• 25 Qingpan L, Qiang Z, Wenwu R. et al. Patent CN 109485648A
• 26 Bergman J, Vallberg H. Acta Chem Scand 1997; 51: 742
• 27a Wollweber H, Kurz J, Nägele W. Arch Pharm 1971; 304: 774
• 27b Ye F, Li GY, Fu Y, Xing ZY. Heterocycl Commun 2013; 19: 75
• 28 Coutant EP, Goyard S, Hervin VO. et al. Org Biomol Chem 2019; 17: 3709
• 29 Coutant EP, Gagnot G, Hervin VO. et al. Chem Eur J 2020; 26: 948
• 30 Gnichtel H, Schmitt B, Schunk G. Chem Ber 1981; 114: 2536
• 31 Bhatt U, Mohamed N, Just G, Roberts E. Tetrahedron Lett 1997; 38: 3679
• 32 Knoll AG. Patent FR 2340317
• 33 Horwell DC, Lewthwaite RA, Pritchard MC, Ratcliffe GS, Rubin JR. Tetrahedron 1998; 54: 4591
• 34 Pohlmann A, Schanen V, Guillaume D, Quirion JC, Husson HP. J Org Chem 1997; 62: 1016
• 35a Suwal S, Kodadek T. Org Biomol Chem 2013; 11: 2088
• 35b Lao BB, Drew K, Guarracino DA. et al. J Am Chem Soc 2014; 136: 7877
• 36 Peng H, Carrico D, Thai V. et al. Org Biomol Chem 2006; 4: 1768
• 37 Karasic TB, Chiorean EG, Sebti SM, O’Dwyer PJ. Target Oncol 2019; 14: 613
• 38 Cattori V, Kessler U, Kessler BDP. Patent WO 2021144302
• 39a Kessler U, Cattori V, Cook C, Vakiti RR, Johnson KRD. Patent WO 2009118973
• 39b Vacher-Comet I, Cloos PAC, Hentsch B, Stoier JF. Patent WO 2024245974
• 40 Matsumoto S, Ishii M, Kimura K, Ogura K. Bull Chem Soc Jpn 1897; 2004: 77
• 41 Meninno S, Lattanzi A. J Org Chem 2023; 88: 7888
• 42 Kitano T, Shirai N, Motoi M, Sato YJ. Chem Soc Perkin Trans 1992; 1: 2851
• 43 Jang JI, Kang SY, Kang KH, Park YS. Tetrahedron 2011; 67: 6221
• 44 Kumar D, Unnikrishnan U, Kuram MR. Chem Commun 2024; 60: 5691