A Simple and Efficient Synthesis of N-Substituted Cyclohex-3-enamines

Abstract

A straightforward preparation of N-substituted cyclohex-3-enamines starting from the commercially available trans-4-aminocyclohexanol hydrochloride is described. Cyclohex-3-enamino-functionalized compounds have proven to be interesting intermediates in medicinal chemistry. The method here described is cheaper, more scalable and tolerant of a broader variety of functional groups than those found in the literature for this type of compound.

Key words

eliminations - olefinations - medicinal chemistry - amines - nitrogenated cyclohexenes

References

• 2a Gómez-Sánchez E. Soriano E. Marco-Contelles J. J. Org. Chem.  2008,  73:  6784 
• 2b Gómez-Sánchez E. Soriano E. Marco-Contelles J. J. Org. Chem.  2007,  72:  8656 
• 2c Gómez-Sánchez E. Marco-Contelles J. Lett. Org. Chem.  2006,  3:  827 
• 3 Kapferer P. Vasella A. Helv. Chim. Acta  2004,  87:  2764 ; and references therein
• 4 Quirante J. Vila X. Escolano C. Bonjoch J. J. Org. Chem.  2002,  67:  2323 ; and references therein
• For a review including recent syntheses of epibatidine, see:
• 5a Olivo H. Hemenway MS. Org. Prep. Proc. Int.  2002,  34:  1 
• For other reviews focused on biological properties, see:
• 5b Daly JW. J. Med. Chem.  2003,  46:  445 
• 5c Romanelli MN. Gualteri F. Med. Res. Rev.  2003,  23:  393 
• 5d Broka CA. Med. Chem. Res.  1994,  4:  449 
• 6 Triggle DJ. Kwon YW. Abraham P. Pitner JB. Mascarella SW. Carroll F. J. Med. Chem.  1991,  34:  3164 
• 7 Kwak Y.-S. Winkler JD. J. Am. Chem. Soc.  2001,  123:  7429 
• 8a Jehanno E. Vaultier M. Tetrahedron Lett.  1995,  36:  4439 
• 8b Singleton DA. Redman AM. Tetrahedron Lett.  1994,  35:  509 
• 8c Noiret N. Youssofi A. Carboni B. Vaultier M. J. Chem. Soc., Chem. Commun.  1992,  1105 
• 9a Corey EJ. Loh T.-P. AchyuthaRao S. Daley DC. Sarshar S. J. Org. Chem.  1993,  58:  5600 
• 9b Pfister JR. Wymann WE. Synthesis  1983,  38 
• 10 Maier ME. Lapeva T. Synlett  1998,  891 
• 11a Gómez-Sánchez E. Marco-Contelles J. J. Heterocycl. Chem.  2006,  43:  1455 
• 11b Gómez-Sánchez E. Marco-Contelles J. Tetrahedron  2005,  61:  1207 
• In fact, compound 1a˙HCl has been previously used for the preparation of 7-azabicyclo[2.2.1]heptanes which did not require a cyclohexene-type precursor. Thus, under certain conditions and derivatizations, intramolecular cyclization is favored. See:
• 12a Trudell ML. Cheng J. Org. Lett.  2001,  3:  1371 
• 12b Olivo HF. Hemenway MS. J. Org. Chem.  1999,  64:  8968 
• 12c Hassner A. Belostotskii AM. Tetrahedron Lett.  1995,  36:  1709 
• 12d

  In this paper we are presenting a straightforward and general strategy, which affords N-substituted cyclohex-3-enamines, in themselves interesting synthetic units, which could be used as precursors of certain 7-azabicyclo[2.2.1]heptanes and 7-azabicyclo[2.2.1]hept-2-enes through subsequent cyclization.

• 13a Zhu Z. Espenson JH. J. Org. Chem.  1996,  61:  324 ; and references therein
• 13b Laali K. Gerzina RJ. Flajnik CM. Geric CM. Dombroski AM. Helv. Chim. Acta  1987,  70:  607 ; and references therein
• 14 Xu F. Simmons B. Reamer RA. Corley E. Murry J. Tschaen D. J. Org. Chem.  2008,  73:  312 
• 16 Noguchi H. Aoyama T. Shioiri T. Heterocycles  2002,  58:  471 
• 17 Marinko P. Obreza A. Peterlin-Mašič L. Krbavčič A. Kikelj D. J. Heterocycl. Chem.  2000,  37:  405 
• 18 Lange GL. Gottardo C. Synth. Commun.  1990,  1473 
• 22 Boger DL. Yohannes D. J. Org. Chem.  1989,  54:  2498 
• 23 Plettenburg O, Hofmeister A, Kadereit D, Brendel J, and Loehn M. inventors; PCT Int. Appl.  WO2007012422.  ; Chem. Abstr. 2007, 146, 206217
• 24 Bayer A. Hansen LK. Gautun OR. Tetrahedron: Asymmetry  2002,  13:  2407 

1

New address: Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040-Madrid, Spain.

15

See experimental section.

19

A preliminary attempt to perform both steps in one pot gave rise to 20% of 2c and 32% of 3c, which is quite promising but requires further optimization.

20

Starting from 7 g of 1c, 5.6 g of 2c was obtained after purification.

21

The moderate yield obtained starting from compound 1f might be due to its low solubility in CH₂Cl₂ and/or the ease of hydrolysis of the trifluoroacetamide group.