the selective synthesis of the chroman framework is yet to
be developed.
although the yield decreased with a decrease in the catalyst
loading (entry 4). Further, we found that the use of
2-methylbut-3-en-2-ol or isoprene instead of 2a brought
about a decrease in the yield (entries 5 and 6). These results
indicated that 2a is an optimal substrate for the present
cyclocoupling.
The biosynthesis of natural chromans was assumed to
occur through the assembly of a chroman skeleton via the
Friedel-Crafts-type allylation of a phenolic core with an
allylic pyrophosphate and the subsequent cyclization of the
resulting o-allylated intermediate. On the basis of this
biosynthetic mechanism, one can assume that the cyclocou-
pling of phenols with allylic alcohols or congeners is an
alternative viable method of synthesizing chromans. Indeed,
the very first syntheses of R-tocopherol were accomplished
by the cyclocoupling of TMHQ with phytyl bromide or
phytol,5 and since then, this method has been widely used
for the syntheses of R-tocopherol and its analogues.6 Ko-
cˆovsky´ and co-workers also reported a few examples of the
[3 + 3] cyclocoupling of phenol and p-cresol with some
allylic compounds catalyzed by molybdenum Lewis acids
under mild reaction conditions; however, the generality of
this novel Mo-catalyzed method is yet to be established.7
We have previously reported that the combination of a
molybdenum(II) complex, CpMoCl(CO)3, with an organic
oxidant, o-chloranil, efficiently catalyzes the Friedel-Crafts-
type reactions of benzenes with alkenes or alcohols to yield
alkylation products with ortho/para and Markovnikov selec-
tivities.8 As a continuation of our previous study, we herein
report the application of our catalytic protocol to the
cyclocoupling of phenols with allylic alcohols for the
selective synthesis of various chromans.
Table 1. Synthesis of Chroman 3aa from p-Cresol (1a)a
entry substrates
conditions
3aa (%)b
1
2
3
4
5
6
A
A
A
A
B
C
5 mol % cat., 60 °C, 4 h
5 mol % cat., 80 °C, 4 h
5 mol % cat., MW 150 °C, 1 h
2 mol % cat., MW 150 °C, 1 h
5 mol % cat., MW 150 °C, 1 h
5 mol % cat., MW 150 °C, 1 h
69
68
84
68
65
72
a Substrates (1 mmol; A, prenyl alcohol; B, 2-methylbut-3-en-2-ol; C,
isoprene), 1a (3 mL), CpMoCl(CO)3/o-chloranil (1:2). b Isolated yields based
on the olefinic substrates.
We examined the cyclocoupling of various phenol deriva-
tives with 2a under the optimal reaction conditions (Table
2). Both p-chlorophenol 1b and p-methoxyphenol 1c were
converted into the corresponding chromans 3ba and 3ca in
74% and 61% yields, respectively (entries 1 and 2). Chro-
mans 3da and 3ea were selectively obtained in moderate
yields from 2,4-dimethylphenol 1d and 3,5-dimethylphenol
1e, respectively (entries 3 and 4), although a small amount
of p-prenylated side product was detected in the reaction
involving 1e. We also studied the cyclocouplings of naph-
thols 1f-h with 2a. The reaction of 2-naphthol 1f afforded
the desired tricyclic product 3fa along with a known bis(2-
naphthyl) ether.9 This side reaction was suppressed when
we carried out the coupling in chlorobenzene under conven-
tional heating conditions at 60 °C to obtain 3fa in 70% yield
(entry 5). In contrast, the reaction of 1-naphthol 1g afforded
only a modest yield of 3ga (entry 6). The more electron-
rich 4-methoxy analogue 1h underwent cyclocoupling more
effectively to afford dihydrolapachenole 3ha in a higher yield
(entry 7).
The generality of this catalytic method with respect to the
allylic alcohol components was explored (Table 3). Phytol
2b was allowed to react with 1a under optimal conditions
to afford the corresponding chroman 3ab in 85% yield (entry
1). The use of isophytol instead of phytol diminished the
yield of 3ab to 75%. 2-Cyclohexylideneethanol 2c and 3,5,5-
trimethylcyclohex-2-en-1-ol 2d also underwent cyclocoupling
uneventfully to afford spirotricyclic 3ac and bridged tricyclic
3ad in 73% and 66% yields, respectively (entries 2 and 3).
At the outset, we examined the model reaction for the
conversion of p-cresol (1a) to chroman 3aa to identify the
optimal reaction conditions (Table 1). Prenyl alcohol (2a, 1
mmol) and excess 1a (3 mL) were stirred at 60 °C in the
presence of 5 mol % CpMoCl(CO)3 and 10 mol % o-
chloranil for 3 h. Purification of the crude by silica gel
chromatography afforded the desired product 3aa in 69%
isolated yield (based on 2a, entry 1). A similar yield was
obtained at a higher reaction temperature of 80 °C (entry
2). Subsequently, we carried out the abovementioned reac-
tions under microwave (MW) irradiation conditions in a
closed vessel. We found that the yield obtained with MW
heating at 150 °C for 1 h was the highest (84%, entry 3),
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