Abstract
Guanidine is one of the most versatile functional groups in chemistry; compounds containing this system have found application in a diversity of biological activities, and in this chapter, the advances in the field of the synthesis of guanidines are presented. First, the preparation of acyclic guanidines involving the reaction of an amine with an activated guanidine precursor followed by the deprotection to yield the corresponding free guanidine is discussed. Thiourea derivatives as guanidylating agents have been widely used as guanidine precursors using coupling reagents or metal-catalysed guanidylation. Alternatively, S-methylisothiourea has shown to be a very efficient guanidylating agent, and N,N′,N″-trisubstituted guanidines have also been used to install the guanidine functionality. Despite the similarity between urea and thiourea, the former has received much less attention; however, its application in guanidine synthesis has also been proved. Examples of the preparation of guanidines using cyanamides that react with derivatised amines as well as the use of copper-catalysed cross-coupling chemistry are also presented. Moreover, cyclic guanidines such as 2-aminoimidazolines (five-membered rings), 2-amino-1,4,5,6-tetrahydropyrimidines (six-membered rings) and 2-amino-4,5,6,7-tetrahydro-1H-1,3-diazepines (seven-membered rings) are present in many natural products and compounds of medicinal interest. Accordingly, an overview of the methods found in the literature for the preparation of these cyclic guanidines is presented. Finally, some biological applications of guanidines as DNA minor groove binders, kinase inhibitors and α2-noradrenaline receptors antagonists are discussed.
Keywords
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- α2-AR:
-
α2-Adrenoceptor
- Boc:
-
tert-Butyloxycarbonyl
- Cbz:
-
Carboxybenzyl
- CSA:
-
Camphor sulfonic acid
- Dba:
-
Dibenzylideneacetone
- DCC:
-
Dicyclohexylcarbodiimide
- DDQ:
-
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
- DEAD:
-
Diethylazodicarboxylate
- DIPEA:
-
Diisopropylethylamine
- DMAP:
-
4-Dimethylaminopyridine
- DME:
-
Dimethoxyethane
- DMF:
-
Dimethylformamide
- DMP:
-
Dess–Martin periodinane
- DMSO:
-
Dimethyl sulfoxide
- DNA:
-
Deoxyribonucleic acid
- DtBPF:
-
1,1′-Bis(di-tert-butylphosphino)ferrocene
- EDCI:
-
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
- Fmoc:
-
Fluorenylmethoxycarbonyl
- Gua:
-
Guanidine
- HB:
-
Hydrogen bond
- LDA:
-
Lithium diisopropylamine
- LiHMDS:
-
Lithium hexamethyldisilazide
- MBH:
-
Morita–Baylis–Hillman
- MGB:
-
Minor groove binder
- mIBG:
-
meta-Iodobenzylguanidine
- Mtr:
-
2,3,6-Trimethyl-4-methoxybenzenesulfonyl
- NBS:
-
N-Bromosuccinimide
- NIS:
-
N-Iodosuccinimide
- NMM:
-
N-Methylmorpholine
- PET:
-
Positron emission tomography
- Ph:
-
Phenyl
- PhNO:
-
Nitrosobenzene
- Piv:
-
Pivaloyl
- PMB:
-
p-Methoxybenzyl
- Pmc:
-
2,2,5,7,8-Pentamethylchroman-6-sulfonyl
- Py:
-
Pyridine
- PyHBr3:
-
Pyridinium tribromide
- RNA:
-
Ribonucleic acid
- RSM:
-
Recovered starting material
- TBAB:
-
tetra-Butylammonium bromide
- TBD:
-
1,5,7-Triazabicyclo[4.4.0]dec-5-ene
- Tces:
-
2,2,2-Trichloroethoxysulfonyl
- TCT:
-
2,4,6-Trichloro-1,3,5-triazine
- TFA:
-
Trifluoroacetic acid
- TFAA:
-
Trifluoroacetic anhydride
- THF:
-
Tetrahydrofuran
- TIPS:
-
Triisopropylsilyl
- TMEDA:
-
Tetramethylenediamine
- TMG:
-
1,1,3,3-Tetramethylguanidine
- TON:
-
Turnover number
- Tosyl:
-
4-Toluenesulfonyl
- Trifyl:
-
Trifluoromethylsulfonyl
- Troc:
-
2,2,2-Trichloroethoxycarbonyl
- TsCl:
-
4-Toluenesulfonyl chloride
- Xantphos:
-
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
References
Menor-Salvan C, Marin-Yaseli MR (2012) Chem Soc Rev 41:5404–5415
Haas DJ, Harris DR, Mills HH (1965) Acta Crystallogr 19:676–679
Yamada T, Liu X, Englert U, Yamane H, Dronskowski R (2009) Chem Eur J 15:5651–5655
Parker EJ, Pratt AJ (2010) In: Hughes AB (ed) Amino acids, peptides, proteins in organic chemistry. Wiley-VCH, Weinheim, pp 1–82
Sokalingam S, Raghunathan G, Soundrarajan N, Lee SG (2012) PLoS One 7:e40410
Dougherty DA (2013) Acc Chem Res 46:885–893
Crowley PB, Golovin A (2005) Proteins 59:231–239
Blanco F, Kelly B, Sanchez-Sanz G, Trujillo C, Alkorta I, Elguero J, Rozas I (2013) J Phys Chem B 11:11608–11616
Kelly B, Sanchez-Sanz G, Blanco F, Rozas I (2012) Comput Theor Chem 998:64–73
Gund P (1972) J Chem Ed 49:100–103
Blanco F, Kelly B, Alkorta I, Rozas I, Elguero J (2011) Chem Phys Lett 511:129–134
Rozas I, Sanchez-Sanz G, Alkorta I, Elguero J (2013) J Phys Org Chem 26:378–385
Sączewski F, Balewski Ł (2013) Expert Opin Ther Pat 23:965–995
Berlinck RG, Trindade-Silva AE, Santos MF (2012) Nat Prod Rep 29:1382–1406
Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiura S, Kakoi H (1972) J Am Chem Soc 94:9217–9219
Suhs T, Konig B (2006) Mini Rev Org Chem 3:315–331
Kim KS, Qian LG (1993) Tetrahedron Lett 34:7677–7680
Chen H-M, Li G, Cao L-H (2008) J Chin Chem Soc 55:474–478
Diez-Cecilia E, Kelly B, Perez C, Zisterer DM, Nevin DK, Lloyd DG, Rozas I (2014) Eur J Med Chem 81:427–441
Kelly B, McMullan M, Muguruza C, Ortega JE, Meana JJ, Callado LF, Rozas I (2015) J Med Chem 58:963–977
Cunha S, Rodrigues MT, da Silva CC, Napolitano HB, Vencato I, Lariucci C (2005) Tetrahedron 61:10536–10540
O’Donovan DH, Rozas I (2011) Tetrahedron Lett 52:4117–4119
Cunha S, Rodrigues MT (2006) Tetrahedron Lett 47:6955–6956
Kelly B, Rozas I (2013) Tetrahedron Lett 54:3982–3984
Ramadas K, Srinivasan N (1995) Tetrahedron Lett 36:2841–2844
Shibanuma T, Shiono M, Mukaiyama T (1977) Chem Lett 575–576
Ohara K, Vasseur JJ, Smietana M (2009) Tetrahedron Lett 50:1463–1465
Porcheddu A, De Luca L, Giacomelli G (2009) Synlett 3368–3372
Maryanoff CA, Stanzione RC, Plampin JN, Mills JE (1986) J Org Chem 51:1882–1884
Isidro-Llobet A, Alvarez M, Albericio F (2009) Chem Rev 109:2455–2504
Manimala JC, Anslyn EV (2002) Tetrahedron Lett 43:565–567
Madalengoitia J, Flemer S (2007) Synthesis 1848–1860
Alonso-Moreno C, Antinolo A, Carrillo-Hermosilla F, Otero A (2014) Chem Soc Rev 43:3406–3425
Kantam ML, Priyadarshini S, Joseph PJA, Srinivas P, Vinu A, Klabunde KJ, Nishina Y (2012) Tetrahedron 68:5730–5737
Pottabathula S, Royo B (2012) Tetrahedron Lett 53:5156–5158
Toy PH, Lam Y (eds) (2012) Solid-phase organic synthesis: concepts, strategies, applications. Wiley, Hoboken
Drewry DH, Gerritz SW, Linn JA (1997) Tetrahedron Lett 38:3377–3380
Josey JA, Tarlton CA, Payne CE (1998) Tetrahedron Lett 39:5899–5902
Ube H, Uraguchi D, Terada M (2007) J Organomet Chem 692:545–549
Powell DA, Ramsden PD, Batey RA (2003) J Org Chem 68:2300–2309
Ma D, Xia C, Jiang J, Zhang J, Tang W (2003) J Org Chem 68:442–451
Kim M, Mulcahy JV, Espino CG, Bois JD (2006) Org Lett 8:1073–1076
Roizen JL, Zalatan DN, Bois JD (2013) Angew Chem Int Ed Engl 52:11343–11346
Wang S, Romo D (2008) Angew Chem Int Ed Engl 47:1284–1286
Feichtinger K, Zapf C, Sings HL, Goodman M (1998) J Org Chem 63:3804–3805
Baker TJ, Rew Y, Goodman M (2000) Pure Appl Chem 72:347–354
Wu YQ, Hamilton SK, Wilkinson DE, Hamilton GS (2002) J Org Chem 67:7553–7556
Bernatowicz MS, Wu YL, Matsueda GR (1992) J Org Chem 57:2497–2502
Yong YF, Kowalski JA, Thoen JC, Lipton MA (1999) Tetrahedron Lett 40:53–56
Musiol HJ, Moroder L (2001) Org Lett 3:3859–3861
Gagnon PE, Boivin JL, Dickson JH (1959) Can J Chem 37:520–524
Rachlin S, Bramm E, Ahnfelt-Ronne I, Arrigoni-Martelli E (1980) J Med Chem 23:13–20
Wang Z (2010) Comprehensive organic name reactions, reagents. Wiley, Hoboken
Elliott AJ, Morris PE Jr, Petty SL, Williams CH (1997) J Org Chem 62:8071–8075
Atwal KS, Ferrara FN, Ahmed SZ (1994) Tetrahedron Lett 35:8085–8088
Mitsunobu O, Yamada Y (1967) Bull Chem Soc (Japan) 40:2380–2382
Dembinski R (2004) Eur J Org Chem 2004:2763–2772
Feichtinger K, Sings HL, Baker TJ, Matthews K, Goodman M (1998) J Org Chem 63:8432–8439
Fishlock D, Guillemette JG, Lajoie GA (2002) J Org Chem 67:2352–2354
Olivier KS, Van Nieuwenhze MS (2010) Org Lett 12:1680–1683
Jacobson GB, Westerberg G, Markides KE, Långström B (1996) J Am Chem Soc 118:6868–6872
Ha HH, Kim JS, Kim BM (2008) Bioorg Med Chem Lett 18:653–656
Looper RE, Haussener TJ, Mack JB (2011) J Org Chem 76:6967–6971
Beletskaya IP, Cheprakov AV (2004) Coord Chem Rev 248:2337–2364
Sambiagio C, Marsden SP, Blacker AJ, McGowan PC (2014) Chem Soc Rev 43:3525–3550
Zhang H, Cai Q, Ma D (2005) J Org Chem 70:5164–5173
Cohen T, Wood J, Dietz AG (1974) Tetrahedron Lett 15:3555–3558
Paine AJ (1987) J Am Chem Soc 109:1496–1502
Deng X, McAllister H, Mani NS (2009) J Org Chem 74:5742–5745
Cortes-Salva M, Nguyen BL, Cuevas J, Pennypacker KR, Antilla JC (2010) Org Lett 12:1316–1319
Hammoud H, Schmitt M, Bihel F, Antheaume C, Bourguignon JJ (2012) J Org Chem 77:417–423
Beletskaya IP, Cheprakov AV (2012) Organometallics 31:7753–7808
Xing H, Zhang Y, Lai Y, Jiang Y, Ma D (2012) J Org Chem 77:5449–5453
Li J, Neuville L (2013) Org Lett 15:6124–6127
Miyabe H, Yoshida K, Reddy VK, Takemoto Y (2009) J Org Chem 74:305–311
Dardonville C, Goya P, Rozas I, Alsasua A, Martin I, Borrego J (2000) Bioorg Med Chem 8:1567–1577
Rodriguez F, Rozas I, Ortega JE, Meana JJ, Callado LF (2007) J Med Chem 50:4516–4527
Kan WM, Lin SH, Chern CY (2005) Synth Commun 35:2633–2639
Hensler ME, Bernstein G, Nizet V, Nefzi A (2006) Bioorg Med Chem Lett 16:5073–5079
McKay AF, Kreling ME (1957) Can J Chem 35:1438–1445
European Patent, EP01986801990
Ye WP, Leow DS, Goh SLM, Tan CT, Chian CH, Tan CH (2006) Tetrahedron Lett 47:1007–1010
Corey EJ, Grogan MJ (1999) Org Lett 1:157–160
Yamamoto Y, Mizuno H, Tsuritani T, Mase T (2009) Tetrahedron Lett 50:5813–5815
Li J (2009) Name reactions. Springer, Berlin, pp 332–333
González-Rosende ME, Castillo E, Asíns B, Mamouni R, Sepúlveda-Arques J (2007) Tetrahedron 63:8709–8714
Schroif-Gregoire C, Travert N, Zaparucha A, Al-Mourabit A (2006) Org Lett 8:2961–2964
Zhou L, Chen J, Zhou J, Yeung YY (2011) Org Lett 13:5804–5807
Bera S, Wallimann T, Ray S, Ray M (2008) FEBS J 275:5899–5909
Guiheneuf S, Paquin L, Carreaux F, Durieu E, Meijer L, Bazureau JP (2012) Org Biomol Chem 10:978–987
Li CM, Danishefsky SJ (2006) Tetrahedron Lett 47:385–387
Olson DE, Roberts DA, Du Bois J (2012) Org Lett 14:6174–6177
Hinman A, Du Bois J (2003) J Am Chem Soc 125:11510–11511
Mulcahy JV, Du Bois J (2008) J Am Chem Soc 130:12630–12631
Zhao B, Du H, Shi Y (2008) Org Lett 10:1087–1090
Butler DCD, Inman GA, Alper H (2000) J Org Chem 65:5887–5890
Godleski SA (1991) In: Trost BM, Fleming I, Semmelhack MF (eds) Comprehensive organic synthesis, vol 4. Pergamon, Oxford, pp 585–662, Chapter 3.3
Craig RA 2nd, O’Connor NR, Goldberg AF, Stoltz BM (2014) Chem Eur J 20:4806–4813
Hovelmann CH, Streuff J, Brelot L, Muniz K (2008) Chem Commun 2334–2336
Gainer MJ, Bennett NR, Takahashi Y, Looper RE (2011) Angew Chem Int Ed Engl 50:684–687
Ritter S, Horino Y, Lex J, Schmalz HG (2006) Synlett 3309–3313
Bhonde VR, Looper RE (2011) J Am Chem Soc 133:20172–20174
Pereshivko OP, Peshkov VA, Ermolatev DS, van Hove S, Van Hecke K, Van Meervelt L, van der Eycken EV (2011) Synthesis 1587–1594
Ishikawa M, Tsushima M, Kubota D, Yanagisawa Y, Hiraiwa Y, Kojima Y, Ajito K, Anzai N (2008) Org Proc Res Dev 12:596–602
Baskaran S, Hanan E, Byun D, Shen W (2004) Tetrahedron Lett 45:2107–2111
Looper RE, Runnegar MTC, Williams RM (2006) Tetrahedron 62:4549–4562
Larraufie MH, Ollivier C, Fensterbank L, Malacria M, Lacote E (2010) Angew Chem Int Ed Engl 49:2178–2181
Nilsson BL, Overman LE (2006) J Org Chem 71:7706–7714
Nagasawa K, Georgieva A, Takahashi H, Nakata T (2001) Tetrahedron 57:8959–8964
Perl NR, Ide ND, Prajapati S, Perfect HH, Duron SG, Gin DY (2010) J Am Chem Soc 132:1802–1803
Nishikawa T, Asai M, Isobe M (2002) J Am Chem Soc 124:7847–7852
Aranha Potter R, Bowser AM, Yang Y, Madalengoitia JS, Ziller JW (2013) J Org Chem 78:11772–11782
Ding H, Roberts AG, Harran PG (2012) Angew Chem Int Ed Engl 51:4340–4343
Buchi G, Rodriguez AD, Yakushijin K (1989) J Org Chem 54:4494–4496
Yu M, Pochapsky SS, Snider BB (2008) J Org Chem 73:9065–9074
Sawayama Y, Nishikawa T (2011) Angew Chem Int Ed Engl 50:7176–7178
Shaw JW, Grayson DH, Rozas I (2014) Eur J Org Chem 161–174
Shaw JW, Grayson DH, Rozas I (2014) Arkivoc 3565–3569
Zaed AM, Sutherland A (2010) Org Biomol Chem 8:4394–4399
Zhou HB, Alper H (2004) Tetrahedron 60:73–79
Sączewski F, Balewski Ł (2009) Expert Opin Ther Pat 19:1417–1448
Dardonville C, Barrett MP, Brun R, Kaiser M, Tanious F, Wilson WD (2006) J Med Chem 49:3748–3752
Nagle PS, Rodriguez F, Kahvedzic A, Quinn SJ, Rozas I (2009) J Med Chem 52:7113–7121
McKeever C, Kaiser M, Rozas I (2013) J Med Chem 56:700–711
O’Sullivan P, Rozas I (2014) ChemMedChem 9:2063–2073
Goonan Á, Kahvedzic A, Rodriguez F, Nagle PS, McCabe T, Rozas I, Erdozain AM, Meana JJ, Callado LF (2008) Bioorg Med Chem 16:8210–8217
Kahvedzic A, Nathwani S-M, Zisterer D, Rozas I (2013) J Med Chem 56:451–459
Nagle PS, Rodriguez F, Quinn SJ, O’Donovan DH, Kelly JM, Nguyen B, Wilson WD, Rozas I (2010) Org Biomol Chem 8:5558–5567
Nagle PS, Rodriguez F, Nguyen B, Wilson WD, Rozas I (2012) J Med Chem 55:4397–4406
Kahvedzic A, Nathwani S-M, Zisterer D, Rozas I (2015)
Diez-Cecilia E, Carson R, Kelly B, van Schaybroeck S, Murray JT, Rozas I (2015)
Rodriguez F, Rozas I, Ortega JE, Erdozain AM, Meana JJ, Callado LF (2008) J Med Chem 51:3304–3312
Rodriguez F, Rozas I, Erdozain AM, Meana JJ, Callado LF (2009) J Med Chem 52:601–609
Nakamura S (2012) Antidepressants and morphological plasticity of monoamine neurons. In: Lu R-B (ed) Effects of antidepressants. InTech, Rijeka. ISBN 978-953-51-0663-0
Muguruza C, Rodriguez F, Rozas I, Meana JJ, Uriguen L, Callado LF (2013) Neuropharmacology 65:13–19
O’Donovan DH, Muguruza C, Callado LF, Rozas I (2014) Eur J Med Chem 82:242–254
McMullan M, Kelly B, Erdozain AM, Callado LF, Rozas I (2015)
Nagle PS, McKeever C, Rodriguez F, Nguyen B, Wilson WD, Rozas I (2014) J Med Chem 57:4397–4406
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Shaw, J.W., Grayson, D.H., Rozas, I. (2015). Synthesis of Guanidines and Some of Their Biological Applications. In: Selig, P. (eds) Guanidines as Reagents and Catalysts I. Topics in Heterocyclic Chemistry, vol 50. Springer, Cham. https://doi.org/10.1007/7081_2015_174
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DOI: https://doi.org/10.1007/7081_2015_174
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