PAPER
Efficient Dehydration of N-Functionalized trans-Aminocyclohexanols
3653
3f
(4) Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org.
Chem. 2002, 67, 2323; and references therein.
Crystalline colorless solid; mp 64–66 °C.
(5) For a review including recent syntheses of epibatidine, see:
(a) Olivo, H.; Hemenway, M. S. Org. Prep. Proc. Int. 2002,
34, 1. For other reviews focused on biological properties,
see: (b) Daly, J. W. J. Med. Chem. 2003, 46, 445.
(c) Romanelli, M. N.; Gualteri, F. Med. Res. Rev. 2003, 23,
393. (d) Broka, C. A. Med. Chem. Res. 1994, 4, 449.
(6) Triggle, D. J.; Kwon, Y. W.; Abraham, P.; Pitner, J. B.;
Mascarella, S. W.; Carroll, F. J. Med. Chem. 1991, 34, 3164.
(7) Kwak, Y.-S.; Winkler, J. D. J. Am. Chem. Soc. 2001, 123,
7429.
(8) (a) Jehanno, E.; Vaultier, M. Tetrahedron Lett. 1995, 36,
4439. (b) Singleton, D. A.; Redman, A. M. Tetrahedron
Lett. 1994, 35, 509. (c) Noiret, N.; Youssofi, A.; Carboni,
B.; Vaultier, M. J. Chem. Soc., Chem. Commun. 1992, 1105.
(9) (a) Corey, E. J.; Loh, T.-P.; AchyuthaRao, S.; Daley, D. C.;
Sarshar, S. J. Org. Chem. 1993, 58, 5600. (b) Pfister, J. R.;
Wymann, W. E. Synthesis 1983, 38.
1H NMR (300 MHz, CDCl3): d = 6.41 (br s, 1 H, NH), 4.73 (s, 1 H,
HCI), 3.91 (m, 1 H, HCN), 2.28–1.60 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 156.6 (d, J = 37.2 Hz, C), 115.9 (d,
J = 288.1 Hz, C), 48.3 (CH), 35.2 (CH2), 32.1 (CH), 28.9 (CH2).
HRMS-ESI: m/z [M + H]+ calcd for C8H12F3INO: 321.9916; found:
321.9922.
N-Tosylated Compounds
Following the general procedure for dehydration, compound 1g12a
(2.69 g, 10 mmol) gave a 1.3:1 mixture (2.81 g, 92%) of N-(cyclo-
hex-3-ene)-p-toluenesulfonamide24 (2g) and N-(cis-4-iodocyclo-
hexyl)-p-toluenesulfonamide (3g) after flash chromatography
(EtOAc–hexane, 10 → 25%). Both compounds showed the same Rf
value. Reaction with DBU, starting from the 2g–3g mixture (2.81 g,
3.98 mmol of 3g, 9.15 mmol of 2g + 3g), gave olefin 2g (2.18 g,
95%); mp 65–67 °C (Lit.24 mp 65.8–67.0 °C).
(10) Maier, M. E.; Lapeva, T. Synlett 1998, 891.
(11) (a) Gómez-Sánchez, E.; Marco-Contelles, J. J. Heterocycl.
Chem. 2006, 43, 1455. (b) Gómez-Sánchez, E.; Marco-
Contelles, J. Tetrahedron 2005, 61, 1207.
2g–3g Mixture
Oil; Rf = 0.32 (EtOAc–hexane, 25%).
1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 8.2 Hz, 4.6 H, 2 × HC-
C-S in 2g, 2 × HC-C-S in 3g), 7.27 (d, J = 8.2 Hz, 4.6 H, 2 × HC-C-
Me in 2g, 2 × HC-C-Me in 3g), 5.61–5.53 (m, 1.3 H, CH=CH), 5.43
(dtd, J = 5.7, 4.5, 2.2 Hz, 1.3 H, CH=CH), 5.37 (d, J = 6.9 Hz, 1 H,
NH in 3g), 5.27 (d, J = 7.8 Hz, 1.3 H, NH in 2g), 4.48 (br s, 1 H,
HCI), 3.45–3.33 (m, 1.3 H, HCN in 2g), 3.21 (br s, 1 H, HCN in 3g),
2.39 (s, 6.9 H, Me in 2g, Me in 3g), 2.20–2.09 (m, 1.3 H, N-CH-
HHC-HC=CH), 2.07–1.92 (m, 4.6 H, HC=CH-CH2-CH2,
2 × CHH-CH-I), 1.84 (dqd, J = 16.0, 5.4, 2.7 Hz, 1.3 H, N-CH-
HHC-HC=CH), 1.76–1.67 (m, 1.3 H, HC=CH-CH2-CHH), 1.67–
1.56 (m, 6 H, 2 × CHH-CH-I, 2 × N-CH-CH2 in 3g), 1.55–1.43 (m,
1.3 H, HC=CH-CH2-CHH).
(12) 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: (a) Trudell, M. L.; Cheng, J. Org. Lett. 2001,
3, 1371. (b) Olivo, H. F.; Hemenway, M. S. J. Org. Chem.
1999, 64, 8968. (c) Hassner, A.; Belostotskii, A. M.
Tetrahedron Lett. 1995, 36, 1709. (d) 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.
(13) (a) Zhu, Z.; Espenson, J. H. J. Org. Chem. 1996, 61, 324; and
references therein. (b) Laali, K.; Gerzina, R. J.; Flajnik, C.
M.; Geric, C. M.; Dombroski, A. M. Helv. Chim. Acta 1987,
70, 607; and references therein.
13C NMR (75 MHz, CDCl3): d = 143.3, 143.2, 138.2, 138.1 (C),
129.7 (2 × CH), 126.9 (3 × CH), 124.0, 50.9, 49.0 (CH), 35.0, 32.3
(CH2), 31.6 (CH), 30.8, 28.8, 23.6 (CH2), 21.6 (2 × CH3).
Supporting Information for this article is available online at
(14) Xu, F.; Simmons, B.; Reamer, R. A.; Corley, E.; Murry, J.;
Tschaen, D. J. Org. Chem. 2008, 73, 312.
(15) See experimental section.
(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, G. L.; Gottardo, C. Synth. Commun. 1990, 1473.
(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.
Acknowledgment
J.M.C. thanks MEC (Spain) for a grant (SAF2006-08764-C02-01),
Comunidad de Madrid (S/SAL-0275-2006) and Instituto de Salud
Carlos III [RED RENEVAS (RD06/0026/1002)]. M.A.-P. thanks
Dr. Stephen M. Goldup and Dr. Bryan D. Koivisto for helpful
proofreading of the manuscript.
References
(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.
(22) Boger, D. L.; Yohannes, D. J. Org. Chem. 1989, 54, 2498.
(23) Plettenburg, O.; Hofmeister, A.; Kadereit, D.; Brendel, J.;
Loehn, M. PCT Int. Appl. WO2007012422, 2007; Chem.
Abstr. 2007, 146, 206217.
(24) Bayer, A.; Hansen, L. K.; Gautun, O. R. Tetrahedron:
Asymmetry 2002, 13, 2407.
(1) New address: Facultad de Ciencias Químicas, Universidad
Complutense de Madrid, Avda. Complutense s/n, 28040-
Madrid, Spain.
(2) (a) Gómez-Sánchez, E.; Soriano, E.; Marco-Contelles, J.
J. Org. Chem. 2008, 73, 6784. (b) Gómez-Sánchez, E.;
Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2007, 72,
8656. (c) 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.
Synthesis 2009, No. 21, 3649–3653 © Thieme Stuttgart · New York