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longer detectable by TLC. After quenching of the reaction
with saturated aqueous NaHCO3, 1,3-cyclohexadiene 4a was
isolated unexpectedly in 48% yield along with alkoxyamines
5 and 6, which were obtained in 13% combined yield.[12]
We were interested in the potential of this unexpected
reaction and began to study it (Table 1). By TLC of the
azaadamantane-type oxoammonium salts would also show
high reactivity. Gratifyingly, we found that 4-Cl-AZA-
DO+ BF4 (9) exhibited modestly improved reactivity as
À
compared with 5-F-AZADO+ BF4À (2; Table 1, entry 7).[14–16]
Having optimized the reaction conditions, we evaluated
the scope of the reaction in terms of possible substrates
(Scheme 3). The O-protected cyclohexenemethanols 3a–c
were efficiently dehydrogenated to give their corresponding
1,3-cyclohexadienes 4a–c. In contrast, it was confirmed that
a mixture of regioisomers 4c and 4c’ was obtained in low yield
by the conventional dibromination–dehydrobromination
Table 1: Optimization of the reaction conditions.
sequence (Scheme 4).[17] The 4-Cl-AZADO+ BF4 -promoted
À
dehydrogenation tolerated azide (product 4d), phthalimide
(product 4e), carbamate (product 4 f), and sulfonamide
(product 4g) functional groups. This reaction proceeded
well with both trans- and cis-4,5-disubstituted cyclohexenes
3h–j, even on a gram scale (see 4h). Notably, these cis-4,5-
disubstituted cyclohexenes were converted into 5,6-disubsti-
tuted 1,3-cyclohexadienes as single regioisomers; however,
Entry Oxoammonium salt
Base (equiv)
t [h] Yield [%][a]
1
2
3
4
5
6
7
5-F-AZADO+ BF4À (2)[b]
5-F-AZADO+ BF4À (2)
5-F-AZADO+ BF4À (2)À
sat. aq. NaHCO3
DBU (3)
none
6
6
48
60
6
18
4-NHAc-TEMPO+ BF4 (1) DBU (3)
48
48
48
2
<2[c]
1-Me-AZADO+ BF4À (7)
DBU (3)
DBU (3)
DBU (3)
8[c]
58
65
the
conventional
dibromination–dehydrobromination
AZADO+ BF4 (8)À
À
sequence converts these substrates into a mixture of 1,6-
disubstituted (major) and 5,6-disubstituted (minor) 1,3-cyclo-
hexadiene regioisomers.[7d] The bicyclic substrates 3k and 3l
were also dehydrogenated by 4-Cl-AZADO+ BF4À in moder-
ate yield. Whereas cyclohexene 3m, which bears a methyl
group at its allylic position, gave the 1,3-cyclohexadiene
product 4m in modest yield, cyclohexene 3n, which instead
bears a phenyl group, gave the product 4n in good yield.
Unfortunately, 1-substituted and 1,2-disubstituted cyclohex-
enes 3o and 3p were not converted into the desired cyclo-
hexadienes, but rather into the corresponding alkoxyamines,
which are generated by the O-preferential addition of
oxoammonium species to alkenes (Scheme 1a).[17] The 4,4-
disubstituted cyclopentenes 3q and 3r were smoothly con-
verted into the corresponding 5,5-disubstituted cyclopenta-
dienes 4q and 4r in good yield. O-Benzoyl cyclopentenol 3s
gave a complex mixture, and the desired cyclopentadiene 4s
was not isolated. Cycloheptenes 3t and 3u were dehydro-
4-Cl-AZADO+ BF4 (9)
[a] Yield of the isolated product. [b] The reaction was carried out with
1.1 equivalents of 2. [c] The yield was determined by 1H NMR spectros-
copy.
reaction mixture, we found that cyclohexene 3a reacted with
oxoammonium salt 2 to form a highly polar intermediate. This
intermediate was partially converted into 1,3-cyclohexadiene
4a after treatment with aqueous NaHCO3. We hypothesized
that the basicity of NaHCO3 causes the conversion of the
highly polar intermediate into 1,3-cyclohexadiene 4a and that
a different base would improve the conversion of the highly
polar intermediate into 4a. Indeed, the screening of bases
identified DBU as the ideal base, with the yield increasing
from 48 to 60% (Table 1, entry 2). When no base was used to
quench the reaction, a marked decrease in yield was observed
(Table 1, entry 3). Next, we compared the reactivity of various
oxoammonium salts (Table 1, entries 4–7). Almost no reac-
tion was observed with the TEMPO-derived oxoammonium
salt 4-NHAc-TEMPO+ BF4À (1), which oxidizes trisubstituted
À
genated in moderate yield. The 4-Cl-AZADO+ BF4 -pro-
moted dehydrogenation of cyclooctene 3v was also possible,
but only in a low yield of 16%.[18]
The synthetic use of the cycloalkadienes is exemplified by
the synthesis of carbasugar derivatives.[19] Thus, upon expo-
1
sure to O2, 4h was converted into endoperoxide 10, and the
À
O O bond was cleaved with thiourea to give diol 11
(Scheme 5a). After dibenzoylation of the diol 11, the result-
ing tetrabenzoate was subjected to OsO4-catalyzed dihydrox-
ylation, followed by acetonization to give 12 as a single
diastereoisomer. On the other hand, when 4i was subjected to
a hetero-Diels–Alder reaction with tert-butyl nitrosoformate,
generated in situ from tert-butyl N-hydroxycarbamate,
adducts 13 and 13’ were formed in a 9:1 mixture (Scheme 5b).
This mixture was subjected to dihydroxylation, benzoylation,
alkenes (entry 4).[9] 1-Me-AZADO+ BF4 (7), which bears
À
a methyl group adjacent to the oxoammonium moiety, also
showed very low reactivity (entry 5). Unsubstituted AZA-
À
DO+BF4 (8) afforded the desired diene in good yield but
required a longer reaction time (entry 6). These results
indicate that the steric accessibility of the oxoammonium
moiety is essential to induce dehydrogenation and that
electron-withdrawing groups at a remote position from the
oxoammonium moiety enhance the reactivity of oxoammo-
nium salts. However, we thought that the ideal oxoammo-
À
and N O bond cleavage to give the aminocarbasugar
derivative 14 and an isomer as an inseparable 9:1 mixture.
To gain insight into the mechanism of this novel dehy-
drogenation reaction, we identified the reaction intermedi-
ates. First, the treatment of O-bound alkoxyamines 5 and 6
with DBU did not afford 1,3-diene 4a, which suggests that
À
nium salt 5-F-AZADO+BF4 (2) would be unsuitable for
widespread use owing to its low availability.[13] Instead, we
envisioned that more readily available 4-halo-substituted
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!
Nagasawa, Shota
