Communication
nishing positively charged dimeric species I-B, from which loss
of a proton leads to the observed product II. This proposal is
supported by the fact that HBF4·Et2O (0.5 equiv) catalyzes the
dimerization of 1a to 2a under the same conditions (CH2Cl2,
508C, 8 h) and in a similar yield (92%). The extreme strength
of this acid may account for its success in promoting this reac-
tion in contrast to the other Lewis or protic acids tested. Alter-
natively, (but unlikely), the reaction may be directly catalyzed
by BF3·Et2O (see Scheme S28b, Supporting Information).[8] In
order to distinguish between the possibilities of protic and
Lewis acid catalysis we carried out the reactions in the pres-
ence of 2,6-di-tert-butylpyridine, a base known to react with
H+ but not BF3.[9] As it turned out, inclusion of 0.2 equiv of 2,6-
di-tert-butylpyridine in the otherwise identical conditions
(0.5 equiv BF3·Et2O, CH2Cl2, 508C, 12 h) led to a significant de-
crease in substrate conversion (6% yield of dimer 2a). The di-
merization reaction was completely inhibited in the presence
of 2.0 equiv of this base. The mechanism proposed in
Scheme 2 was supported by further studies on the role of H2O
on the reaction and deuterium exchange experiments (see
Supporting Information for details).
Scheme 3. Cascade reaction leading from 2-oxazolone 1g to pentacycle 3a
via intermediate 2g, and mechanistic rationale.
nishes cationic species 2g-B. Aromatization of the latter
through loss of a proton then affords the observed product
3a.
The generality and scope of this reaction was demonstrated
with several substrates as shown in Table 2. Thus, substrates
1g, 1k, 1m–o furnished diastereoselectively pentacyclic prod-
ucts 3a–e in good to excellent yields when exposed to
BF3·Et2O at 508C for 16 h (entries 1–5, Table 2). In contrast, 2-
oxazolones bearing electron-withdrawing groups on the aryl
moiety and a methyl substituent at C4 (e.g., 1i and 1j, en-
tries 9 and 10, Table 1) failed to undergo the cyclization step
even after 36 h at 508C, with the cascade stopping instead at
the dimerization stage (see entries 9 and 10, Table 1), under-
scoring the importance of electron density on the N-aryl sub-
stituent. On the other hand, substrates 4a–g, lacking the
methyl substituent on the olefinic bond of the oxazolone
moiety (prepared by literature procedures[10]), were found to
undergo both the dimerization and cyclization steps at 258C
and in good to excellent yields regardless of the nature of the
substituents on the aryl moiety (entries 6–12, Table 2). The ste-
reochemical arrangements of all pentacyclic compounds
shown in Table 2 were assigned based on NMR spectroscopic
analysis (NOE correlations) carried out on products 3e and 3j
(see Supporting Information). Interestingly, all products ob-
tained by the dimerization/cyclization reaction were single dia-
stereoisomers of the all-syn configuration as shown in Table 2
(see Supporting Information for more details).
Scheme 2. Plausible mechanism for the dimerization of 2-oxazolones (I).
Aiming to shine more light on the mechanism of this dimeri-
zation reaction, we applied Density Functional Theory (DFT) to
study its course via the above proposed mechanisms. Thus,
the overall activation free energy for the BF3-catalyzed path-
way was found to be 14.5 kcalmolÀ1 higher than that for the
H+-catalyzed pathway (see Figure S1, Supporting Information
for further details), suggesting the latter as the most favored
mode of the oxazolone dimerization and thereby providing
further support for the experimentally-derived conclusion dis-
cussed above.
An interesting observation made during these studies led to
another cascade sequence of reactions furnishing further mo-
lecular complexity (see Scheme 3). Thus, from the reaction of
2-oxazolone 1g with BF3·Et2O in CH2Cl2 at 258C was isolated
(in addition to dimer 2g) a small amount of pentacycle 3a
(single disastereoisomer).[2] Conditions were optimized
(BF3·Et2O, CH2Cl2, 508C, 16 h) under which compound 3a was
formed exclusively as a single diastereoisomer and in 86%
yield. Scheme 3 depicts a mechanistic rationale for this reac-
tion, a hypothesis supported by the direct conversion of dimer
2g to 3a (93% yield) under the same optimized conditions.
Thus, facilitated by electron flow from the N-aryl moiety, inter-
mediate 2g undergoes protonation leading to iminium species
2g-A, whose intramolecular Friedel–Crafts-type reaction fur-
To examine the scalability of these transformations, the reac-
tion of 1a was conducted on a 1 g (8.0 mmol, 16 h) scale,
yielding 2a in 93% isolated yield. For comparisons, the reac-
tions of selected substrates (entries 1, 7, 8 and 10, Table 2) with
the addition of 0.5 equiv of H2O were conducted. These experi-
ments demonstrated that the addition of 0.5 equiv of water
had little effect on the yields of these reactions, although they
proceeded at somewhat lower rates.
The ubiquitous nature and importance of iminosugar (also
termed azasugar) derivatives[11] prompted us to exploit the
Chem. Eur. J. 2016, 22, 7696 – 7701
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