.
Angewandte
Communications
Initial efforts were made to systematically investigate
various catalytic reaction conditions for the cyclization of 2-
alkylbenzaldehyde and styrene. Silver salts were chosen as the
catalysts because they were typically regarded as good
aminopyridine (DMAP), and 2,6-dimethylpyridine, to assist
the enolization process proved to be unhelpful (see entries 6–
9 in Table S1 in the Supporting Information). These results
could be attributed to the strong coordinating capability of
the nitrogen atoms of these bases, thus poisoning the silver
catalysts. However, the more weakly coordinating base, 2,6-
dibromopyridine (DBP), furnished the desired product in
62% yield (entry 6). This positive result is consistent with the
aforementioned hypothesis of poisoning, so we targeted those
bases that are weakly coordinating. Recently, Zhang and co-
workers reported that pyridine N-oxide derivatives served as
weak bases in the gold-catalyzed cycloisomerization of (2-
ethynylphenyl)alkynes.[14] Inspired by this work, we turned to
pyridine N-oxide derivatives, but a negative effect was
observed when pyridine N-oxide (PNO) was added as
additive (entry 7). The even more weakly coordinating 4-
nitropyridine N-oxide (NPO) was then used, and to our
surprise the yield of 6a increased to 83% (entry 8). The yield
fell to 58% when the amount of NPO was lowered to
0.5 equivalents (entry 9). Higher temperature (458C) fur-
nished the product in better yield (90%; entry 10), and
dehydration was observed when the temperature was
increased to 808C. The 3,4-dihydronaphthalene 6a’ was
obtained in 92% yield with a d.r. of 8:1 (entry 11). When
1.0 equivalents of NPO were added to the systems using
AgNTf2 and AgOTf, the same trends were observed, albeit
with lower yields than those obtained with AgSbF6 (entries 12
and 13). All the results clearly illustrated that NPO had
a remarkably positive effect on the transformations. The
control reactions revealed that a silver salt is essential for the
reaction (see entries 22 and 23 in Table S1). It was noted that
only two diastereoisomers were obtained (d.r. 9:1). The
structure of the major isomer was determined by single-
crystal X-ray analysis (see Table S5 in the Supporting
Information), which showed that the hydroxy and carbonyl
groups are syn relative to each other, and the phenyl group is
anti relative to the hydroxy and carbonyl groups.
=
catalysts for the activation of carbonyl groups and C C
bonds. 2-Methylbenzaldehyde (3a) was initially tested for the
cyclization by reacting it with 5.0 equivalents of styrene.
When the reaction was conducted in DCE at room temper-
ature with 5 mol% of AgNTf2 as the catalyst, the desired
product 5a was not detected (Table 1, entry 1). It is supposed
Table 1: Optimization of the reaction conditions.[a]
Entry
R (3)
Cat.
Additive
Yield [%][b]
d.r.
1
2
3
4
5
6
7
H (3a)
Ph (3b)
AgNTf2
AgNTf2
AgNTf2
AgOTf
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgOTf
–
–
–
–
n.d. (5a)
n.d. (5b)
trace (6a)
23 (6a)
34 (6a)
62 (6a)
trace (6a)
83 (6a)
58 (6a)
90 (6a)[f]
92 (6a’)
12 (6a)
50 (6a)
–
–
–
–
–
9:1
–
9:1
9:1
9:1
8:1
–
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
COPh (3c)
–
DBP[c]
PNO
NPO
NPO[e]
NPO
NPO
NPO
NPO
8[d]
9[d]
10[d]
11[g]
12
13
–
[a] Unless otherwise noted, the reaction was performed in DCE at RT for
12 h using 5 mol% catalyst and 1.0 equiv additive under N2. The molar
ratio of 3/4=1:5. [3]=0.25m. [b] Yield determined by 1H NMR spec-
troscopy. [c] 2,6-Dibromopyridine (DBP) [d] Yield of isolated product.
[e] 0.5 equiv NPO. [f] 458C. [g] 808C, 3,4-dihydronaphthalene 6a’
obtained. DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl.
With the optimized reaction conditions (Table 1, entries 8
and 10) in hand, the substrate scope was examined. As
summarized in Table 2, the catalytic process could be
successfully applied to different kinds of alkene substrates
and a variety of 2-ethanone benzaldehydes 3. For example, in
addition to styrene, various styrene derivatives could be
effectively reacted with 2-(2-formyl-phenyl)ethanone (3c;
Table 2, 6b–m’) as well. The yields were generally higher than
70%, and the d.r. values of the products derived from styrenes
substituted with electron-donating groups are higher than
those obtained from styrenes substituted with electron-with-
drawing groups. Higher temperatures gave lower diastereo-
selectivities and bulky substrates gave worse diasteroselectiv-
ities. For example, the d.r. values for 4-CF3- and 4-NO2-
substitued styrenes were 76:24 and 78:22, respectively (6k
and 6l), and 2,4,6-trimethylstyrene gave a diastereoselectivity
of 71:29 for 6e. Notably, the reaction could proceed smoothly
by simply enhancing the temperature to 808C, even for the
extremely electron-deficient pentafluorostyrene. However, in
this case the elimination alkene product 6m’ was obtained
instead in good yield; presumably the higher temperature
promoted the elimination of the hydroxy group. The
that the low acidity of the methyl group in 3a makes this
substrate difficult to enolize. To enhance the acidity of the
substrates, a phenyl group (3b) and carbonyl group (3c) were
introduced. When 2-benzylbenzaldehyde (3b) was used
under the same reaction conditions, the desired product 5b
was not detected (entry 2). However, trace amounts of the
desired product 6a were detected when utilizing 3c as the
substrate (entry 3). Encouraged by this observation, we then
conducted the systematic screening of the reaction conditions
by using 3c as the substrate. The anions of the silver salts play
an essential role in the catalytic activities (entries 3–5). In
contrast to the weakly coordinating NTf2, more ionic silver
salts gave better yields of 6a. For example, the yields were
23% and 34% for AgOTf and AgSbF6, respectively (entries 4
and 5). This trend could be explained by the fact that the more
ionic silver salts coordinated the carbonyl oxygen atom more
strongly than the less ionic silver salts, thus the former
catalyzed the enolization more efficiently. Trying to increase
the reaction yields by increasing the reaction temperature
resulted in a complex reaction mixture. The use of an organic
base such as triethylamine (TEA), pyridine, N,N-dimethyl-
2
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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