of the corresponding 7-azabicyclo[2.2.1]heptan-2-ols were
revealed.6-8 In an earlier report by Pfister et al.,5 it was
claimed that epoxide 4 was converted into the endo isomer
3. This procedure was also recently used to prepare 3 as an
intermediate in a synthesis of 1.7 However, in a recent report
using identical reaction conditions, Fletcher et al.6 described
the conversion of the N-benzyl derivative 5 into the exo
isomer 6. Although rare, the syn attack of the N-benzylamino
group on the epoxide was unequivocally established as the
net reaction pathway for the formation of 6. The difference
in the stereochemical outcome between the N-methyl and
N-benzyl systems was intriguing and prompted a further
investigation of this cyclization reaction.
NMR data originally reported for 3 by Pfister et al.,6 it was
apparent that the original stereochemical assignment was
incorrect and the actual product was the exo isomer 2.
With both stereoisomers in hand, attention focused on the
intramolecular cyclization reaction to unequivocally establish
the stereochemical outcome of the cyclization reaction of
the N-methyl analogue. A mixture of the epoxides 11 (3:1,
syn:anti) was prepared in fashion similar to that previously
described for N-trifluoroacetoamidocyclohex-3-ene (10)
(Scheme 2).7 Mixture 11 was then treated with potassium
Scheme 2
Initially, the 7-methyl-7-azabicyclo[2.2.1]heptan-2-ols 2
and 3 were prepared by an alternative method. As illustrated
in Scheme 1, the ketone 75 was hydrogenated over Adam’s
Scheme 1
carbonate to remove the trifluoroacetyl protecting group.
Although it was not noted in the original work,7 this afforded
syn-N-methylamino epoxide 12 as the sole product.
Subsequently, epoxide 12 was heated at 160 °C in
N-methylpyrrolidone/potassium carbonate for 72 h and then
allowed to cool to room temperature over 12 h. After workup,
a single product was obtained which corresponded to exo
isomer 27 (61% yield). This result also confirms the
stereochemistry of epoxide 12, since only syn isomer 11 can
afford exo isomer 2. The yield of 2 was diminished if the
heating period exceeded 72 h. After this time the formation
of side products became apparent by TLC and the yield of
2 decreased. It is believed that long exposure to high
temperatures results in thermal decomposition of the bicyclic
amine.
catalyst in anhydrous methanol to afford the 7-Boc-7-
azabicyclo[2.2.1]heptan-2-ols (8:9, 1:1) in 84% yield. The
isomeric mixture was separated by column chromatography,
and the isomers 88 and 98 were then independently converted
with LiAlH4 into the corresponding N-methyl analogues 2
and 3.9
1
The two stereoisomers were easily distinguished by H
and 13C NMR. Most notably, the chemical shift of the 2âH
(δ 4.34 ppm) of 3 was significantly shifted downfield due
the proximity of the lone pair of electrons on the nitrogen
atom, while the 2RH of 2 was more upfield (δ 3.62 ppm).
In addition, the stereochemistry of exo isomer 2 was
unequivocally established by X-ray crystallographic analysis
of the corresponding oxalate salt.10 Upon comparison of the
(6) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.; Hobbs,
S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J. Org. Chem.
1994, 59, 1771.
(7) Senokuchi, K.; Nakai, H.; Kawamura, M.; Katsube, N.; Nonaka, S.;
Sawaragi, H.; Hamanaka, N. Synlett 1994, 343.
(8) Pfister, J. R.; Wymann, W. E.; Weissberg, R. M.; Strosberg, A. M.
J. Pharm. Sci. 1985, 74, 208.
(9) (a) Data for 2: 1H NMR (300 MHz, CDCl3) δ 3.62 (dd, J ) 7.2, 2.1
Hz, 1H), 3.21 (br s, OH), 3.19 (d, J ) 2.7 Hz, 1H), 3.10 (d, J ) 3 Hz, 1H),
2.25 (s, 3H), 1.71 (m, 3H), 1.55 (m, 1H), 1.16 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 74.0, 68.3, 60.0, 43.4, 34.2, 24.3, 21.2. Anal. Calcd for
C7H13NO: C, 66.11; H, 10. 30; N, 11.01. Found: C, 66.00; H, 10. 20; N,
10.91. (b) Data for 3: 1H NMR (400 MHz, CDCl3) δ 4.34 (t, J ) 5.2 Hz,
1H), 3.25 (t, J ) 4.4 Hz, 1H), 3.19 (t, J ) 4.8 Hz, 1H), 2.99 (br s, OH),
2.28 (s, 3H), 2.13 (m, 2H), 1.88 (m, 1H), 1.67 (m, 1H), 1.47 (m, 1H), 0.95
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 70.3, 66.3, 62.7, 39.7, 34.6, 26.5,
17.5. Anal. Calcd for C7H13NO: C, 66.11; H, 10. 30; N, 11.01. Found: C,
66.31; H, 10. 50; N, 11.11.
It is noteworthy that a single diastereoisomer (12) was
obtained from the hydrolysis reaction of 11. It is believed
(10) X-ray data for 2‚1.5(CO2H)2 is available from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.: (C7H13NO)2‚(C2H2O4)3; P21/n; Z ) 4; a ) 13.361(4) Å; b )
6.819(9) Å; c ) 26.713(6) Å; â ) 94.46°.
1440
Org. Lett., Vol. 1, No. 9, 1999