Synthesis of Hydrazinylpyridines via Nucleophilic Aromatic Substitution and Further Transformation to Bicyclo[2.2.2]octenes Fused with Two N-Aminosuccinimide Moieties

Abstract

Efficient and reliable synthesis of substituted hydrazinylpyridines in thick-wall ACE tubes via nucleophilic substitution of a chlorine substituent in different chloropyridines is presented. Hydrazine hydrate and alkylhydrazines were used as nucleophiles and simple alcohols and diethyl ether were the only organic solvents necessary, making the process environmentally and user friendly, potentially reaching 100% atomic efficiency. In the next step, transformations of succinic anhydride moieties fused to the bicyclo[2.2.2]octene framework into succinimide moieties via nucleophilic substitution of oxygens were conducted. As nucleophiles two of the synthesized hydrazinylpyridines (2-hydrazinyl-3-nitropyridine and 2-hydrazinyl-5-nitropyridine) and also hydrazine hydrate, phenylhydrazine, and 4-nitrophenylhydrazine were used. Reactions were again carried out in ACE tubes and only simple alcohols, diethyl ether, and acetone were needed as solvents. One of the prepared bicyclo[2.2.2]octene adducts displayed water solubility thus being a promising candidate for future studies as a novel bidentate ligand for various metal cations in aqueous solutions or acting as an unprecedented halogen bond acceptor.

Key words

green chemistry - chloropyridine - bicyclo[2.2.2]octene - water-soluble ligand - succinimide - nucleophilic substitution

Publication History

Received: 21 July 2020

Accepted after revision: 04 September 2020

Article published online:
12 October 2020

• References

• 1 Currently at: ‘Jožef Stefan’ Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia.
• 2 Hren J, Polanc S, Kočevar M. ARKIVOC 2008; (i): 209
• 3 Hren J, Kranjc K, Polanc S, Kočevar M. Heterocycles 2007; 72: 399
• 4 Martelanc M, Kranjc K, Polanc S, Kočevar M. Green Chem. 2005; 7: 737
• 5 Kobrakov KI, Ruchkina AG, Rybina II. Chem. Heterocycl. Compd. 2003; 39: 283
• 6 Mokrushina GA, Azev YA, Postovskii IY. Chem. Heterocycl. Compd. 1975; 11: 880
• 7 Jiang G, Lin Y, Cai M, Zhao H. Synthesis 2019; 51: 4487
• 8 Channapur MB, Hall RG, Kessabi J, Montgomery M, Shyadligeri AS. Synlett 2019; 30: 1057
• 9 Wang H, Sun X, Zhang S, Liu G, Wang C, Zhu L, Zhang H. Synlett 2018; 29: 2689
• 10 Rey M, Beaumont S. Synthesis 2019; 51: 3796
• 11 Schmitt DC, Taylor AP, Flick AC, Kyne RE. Org. Lett. 2015; 17: 1405
• 12 Ding Y, Zhang T, Chen QY, Zhu C. Org. Lett. 2016; 18: 4206
• 13 Anacona JR, Rincones M. Spectrochim. Acta, Part A 2015; 141: 169
• 14 Norafizan D, Chee A, Rodis ML, Saat N, Ngaini Z, Nadiah A, Halim A. Malaysian J. Anal. Sci. 2017; 21: 1143
• 15 Nayak TK, Hathaway HJ, Ramesh C, Arterburn JB, Dai D, Sklar LA, Norenberg JP, Prossnitz ER. J. Nucl. Med. 2008; 49: 978
• 16 Guan AY, Liu CL, Sun XF, Xie Y, Wang MA. Bioorg. Med. Chem. 2016; 24: 342
• 17 Wentland MP. Patent US 5334595 A, 1992
• 18 Twomey D. Proc. R. Ir. Acad. B 1974; 74: 37
• 19 Nagarajan K, David J, Shah RK. J. Med. Chem. 1976; 19: 508
• 20 Camargo AF, Marangoni MA, de Moraes PA, Nogara PA, Afolabi BA, Bencke CE, Rocha JB. T, Bonacorso HG, Martins MA. P, Zanatta N. Synthesis 2020; 52: 2347
• 21 Frahn JL, Illman RJ. Aust. J. Chem. 1974; 27: 1361
• 22 Baker R, Matassa VG, Street LJ. Patent US 5298520 A, 1994
• 23 Ray PC, Medikonduri S, Ramanjaneyulu GS. Patent EP 1981860 B1, 2007
• 24 Patel VR, Desai HT. J. Atoms Mol. 2013; 3: 520
• 25 Houghton PG. Patent US 5567819 A, 1996
• 26 Lanlan WL. Patent CN 102964270 B, 2012
• 27 Ray PC, Bandari M, Qadeeruddin M, Ramanjaneyulu GS. Patent WO 2007/054979 A1, 2007
• 28 Lewis A, Shepard RG. J. Heterocycl. Chem. 1971; 8: 41
• 29 Gawinecki R, Rasala DS. Heterocycles 1987; 26: 2727
• 30 Mann FG, Prior AF, Willcox TJ. J. Chem. Soc. 1959; 3830
• 31 Mengqi L. Patent CN 102249991 A, 2011
• 32 Jianli S. Patent CN 103588705 A, 2014
• 33 Brien KA, Garner CM, Pinney KG. Tetrahedron 2006; 62: 3663
• 34 Collins I, Roberts SM, Suschitzky H. J. Chem. Soc. C 1971; 167
• 35 Collins I, Suschitzky H. J. Chem. Soc. C 1970; 1523
• 36 Thimaradka V, Pangannaya S, Mohan M, Trivedi DR. Spectrochim. Acta, Part A 2018; 193: 330
• 37 Chou TC, Hwa CL, Lin JJ, Liao KC, Tseng JC. J. Org. Chem. 2005; 70: 9717
• 38 Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478
• 39 Mukherjee A, Tothadi S, Desiraju GR. Acc. Chem. Res. 2014; 47: 2514
• 40 Bálint E, Tajti Á, Tripolszky A, Keglevich G. Dalton Trans. 2018; 47: 4755
• 41 Kranjc K, Leban I, Polanc S, Kočevar M. Heterocycles 2002; 58: 183
• 42 Kranjc K, Kočevar M. ARKIVOC 2013; (i): 333
• 43 Hren J, Kranjc K, Polanc S, Kočevar M. Synthesis 2008; 452
• 44 Hoivik, A.; Kranjc, K. manuscript in preparation.
• 45 Kranjc K, Perdih F, Kočevar M. J. Org. Chem. 2009; 74: 6303