by EtOH giving 18;14,19 presumably the formation of 19
occurs via a similar N-oxidation pathway.
Scheme 3
Figure 3. X-ray crystal structure of (1S,2S,7R,RR)-13 (selected
H-atoms are omitted for clarity).
Following our optimized procedure for transannular
iodoamination,5 treatment of 14 with I2 in CH2Cl2
(EtOH stabilized)14 produced a complex mixture of prod-
ucts containing R-methyl-p-methoxybenzyl ethyl ether
185 and p-acetanisole 19. Upon basification of the crude
reaction mixture with K2CO3 in THF, and subsequent
chromatographic purification, C(4)-iodo substituted
8-azabicyclo[3.2.1]octane 17 was isolated in 11% yield
and >99:1 dr (Scheme 3).15 Recrystallization of this mix-
ture from CH2Cl2/Et2O enabled the relative configuration
within 17 to be unambiguously assigned via single crystal
X-ray diffraction analysis13 (Figure 4), and the determina-
tion of a Flack x parameter16 of ꢀ0.04(3) for the crystal
structure of 17 allowed the absolute (1R,2S,3S,4R,5S)-
configuration within 17 (and therefore the absolute con-
figurations within 10 and 14) to be unambiguously as-
signed. This stereochemical outcome is entirely consistent
with our previous observations concerning this class of
ring-closing iodoamination reaction5 and a mechanism in
which reversible formation of iodonium ion 15 is followed
by cyclization of the amino group onto the C(4) carbon
atom [i.e., distal to the C(2)-hydroxyl group]17,18 to give
ammonium ion 16. Subsequent loss of the R-methyl-p-
methoxybenzyl cation then gives 8-azabicyclo[3.2.1]octane
17, and the R-methyl-p-methoxybenzyl cation is trapped
Figure 4. X-ray crystal structure of (1R,2S,3S,4R,5S)-17
(selected H-atoms are omitted for clarity).
Treatment of 13, however, with I2 in CH2Cl2 (EtOH
stabilized)14 proceeded very cleanly to give a mixture
of only 185 and C(4)-iodo substituted 8-azabicyclo-
[3.2.1]octane 20 as the corresponding hydroiodide salt.
Recrystallization of this mixture from CH2Cl2/Et2O gave
(14) The presence of EtOH is not required, but it does make the
procedure more practical as the p-methoxybenzyl residues are efficiently
scavenged by the EtOH enabling their separation from the desired
reaction product.
(15) Attempted optimization did not improve the yield of 17, which
was also found to be susceptible to decomposition.
(16) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(17) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737. (b)
Addy, J. K.; Parker, R. E. J. Chem. Soc. 1963, 915.
(18) We have also observed this phenomenon during our investiga-
tions into the chemo- and diastereoselective oxidation of allylic and
homoallylic amines; see: (a) Aciro, C.; Claridge, T. D. W; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008,
6, 3751. (b) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762. (c)
Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa,
W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson,
J. E. J. Org. Chem. 2009, 74, 6735. (d) Davies, S. G.; Fletcher, A. M.;
Kurosawa, W.; Lee, J. A.; Poce, G.; Roberts, P. M.; Thomson, J. E.;
Williamson, D. M. J. Org. Chem. 2010, 75, 7745.
20 HI in 72% yield and >99:1 dr and also enabled the
relative configuration within 20 HI to be unambiguously
3
3
assigned via single crystal X-ray diffraction analysis
(Figure 5).13 Furthermore, the determination of a Flack
x parameter16 of ꢀ0.01(7) for thecrystal structureof20 HI
3
allowed the absolute (1R,2S,3R,4R,5S)-configuration within
20 to be assigned unambiguously. In an effort to isolate 20
as the free base, a mixture of 18 and 20 HI was partitioned
3
between 1.0 M aq KOH and CHCl3 which gave 20 in 46%
yield after chromatographic purification. However, it was
found that the yield of 20 could be improved further upon
stirring the crude reaction mixture from the ring-closing
iodoamination reaction with K2CO3 in THF, prior to
chromatographic purification, which gave 20 in 92%
isolated yield. Reduction of the CꢀI bond within 20 with
(19) See also: Srihari, P.; Bhunia, D. C.; Sreedhar, P; Yadav, J. S.
Synlett 2008, 1045.
Org. Lett., Vol. XX, No. XX, XXXX
C