Although the involvement of aziridinium intermediates in
numerous substitution reactions is well recognized,5 the
participation of nitrogen lone pairs of hydrazines in similar
transformations has been less described.6 We therefore
decided to first establish the formation of such a reactive
intermediate before studying epoxide rearrangements.
The racemization observed during the solvolysis of opti-
cally active exo-brosylate 7 is now a textbook experiment
for the characterization of a transient σ-delocalized sym-
metrical carbonium ion in the norbornane series (Figure 1).7
retention of relative configuration as a single diastereomer.10
Alcohol 9 was then obtained after hydrolysis, however, in a
partially racemized form. Not surprisingly, alcohol 9 was
recovered without any racemization after a classical esteri-
fication-hydrolysis sequence, showing that racemization
occurred during the substitution reaction.
A similar behavior was observed with p-nitrophenol as a
nucleophile, leading to the largely racemized substituted
bicycle 11 (Scheme 3).
Scheme 3. Stereochemical Studies of the Nucleophilic
Substitution of 9 under Mitsunobu Conditions with
p-Nitrophenol
Figure 1. Racemizing solvolysis of brosylate 7.
We therefore investigated similar transformations starting
from enantiomerically enriched hydrazino-alcohol 9 (Scheme
2).8
Scheme 2. Stereochemical Studies of the Nucleophilic
Substitution of 9 under Mitsunobu Conditions with
p-Nitrobenzoic Acida
In both cases, partial epimerization of the three stereogenic
centers and the overall retention of relative configuration
under Mitsunobu conditions clearly indicate that the substitu-
tion occurred via a transient meso-aziridinium intermediate.11
Having established that the nitrogen lone pairs of bicyclic
hydrazines could be involved in the stabilization of bridged
cationic species, we then turned our attention to the acid-
catalyzed rearrangement of epoxide 4. This reaction has been
reported on norbornene oxide 12 to involve a skeletal
rearrangement leading to 2,7-syn disubstituted norbornane
13 (Figure 2).12
a Determined by chiral HPLC.
According to our preliminary studies with nucleophilic
substitutions, assisted ring opening should be followed by
the formation of a transient aziridinium, leading to a
rearranged skeleton after regioselective nucleophilic attack.
The use of Mitsunobu reaction conditions9 with p-
nitrobenzoic acid led to substituted compound 10 with
(5) Reviews: (a) Cossy, J.; Gomez Pardo, D. Targets Heterocycl. Syst.
2002, 6, 1. (b) Dahanukar, V. H.; Zavialov, L. A. Curr. Opin. Drug.
DiscoVery DeV. 2002, 5, 918.
(6) For a NMR description of aziridinium imide, see: Poon, T. H. W.;
Park, S. H.; Elemes, Y.; Foote, C. S. J. Am. Chem. Soc. 1995, 117, 10468.
The bromination of diazanorbornenes has been described to occur with
nitrogen participation and rearrangement in a seminal study: Raasch, M.
S. J. Org. Chem. 1975, 40, 161.
(7) (a) Winstein, S.; Trifan, D. S. J. Am. Chem. Soc. 1949, 71, 2953. (b)
Winstein, S.; Trifan, D. S. J. Am. Chem. Soc. 1952, 74, 1147. (c) Winstein,
S.; Trifan, D. S. J. Am. Chem. Soc. 1952, 74, 1154. (d) For a general
discussion on norbornyl cations, see: Olah, G. A. Acc. Chem. Res. 1976,
9, 41.
(8) Enantiomerically enriched 9 was prepared by a reported procedure:
see ref 3a.
(10) Nucleophilic substitutions with retention of configuration under
Mitsunobu conditions involving aziridinium species are precedented. See
for example: Freedman, J.; Vall, M. J.; Huber, E. W. J. Org. Chem. 1991,
56, 670. For a rearrangement triggered by a Mitsunobu reaction, see:
Dondoni, A.; Richichi, B.; Marra, A.; Perrone, D. Synlett 2004, 1711.
(11) The solvolysis of brosylate 7 has been described to occur with
complete racemization, whereas only partial epimerization was observed
in our experiments. The partial retention of configuration could tentatively
be explained by the formation of a meso, but not fully symmetrical, distorted
aziridinium intermediate having unequal bond lengths and leading to the
preferential attack of the nucleophile on the carbon that bared the leaving
group. We observed that the enantiomeric ratio of the substituted hydrazine
11 was not solvent (THF, toluene) nor temperature (rt to 110 °C) dependent.
(12) Walborsky, H. M.; Loncrini, D. F. J. Org. Chem. 1957, 22, 1117.
(9) Mitsunobu, O. Synthesis 1981, 1.
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Org. Lett., Vol. 8, No. 14, 2006