Organic Letters
Letter
8. Surprisingly, terminal alkynes were not considered in this
work. In this context, we knew from our own previous work
that, contrary to what occurs with internal alkynes, the use of
terminal alkynes (such as 1) favored the cyclization through an
endo-mechanism and, thus, under appropriate conditions
cycloalkanones 6 could be obtained, instead of cycloalkyl
ketones 8.3,5 Herein, we present the successful development of
the proposed cationic cyclization reaction for the synthesis of
cyclohexanone derivatives.
(triflate) of the acid promoter (TfOH).3b Again, it seems that
trapping of cation 3 by the water formed in the first step of the
process is not favored under these conditions. Formation of the
undesired alkenyl triflate 4b was also observed when other
typical solvents were used. Thus, to avoid the formation of
triflate 4b, we decided to change the acid promoter from triflic
acid to tetrafluoroboric acid (HBF4·OEt2). First, we attempted
the reaction with this acid by using 1,2-dichloroethane (DCE)
as solvent (Table 1, entry 4). Unfortunately, the desired ketone
6a was not formed, and the only product we could isolate in
high yield (92%) was the chloride 4a. Next, we utilized a
chlorine-free solvent, such as hexane (Table 1, entry 5). Under
these conditions, a new product, the alkenyl fluoride 4c, was
formed in high yield (92%). This compound is formed when
the alkenyl cation 3 is trapped by a fluoride coming from the
tetrafluoroborate anion. All these experiments demonstrate that
the synthesis of the desired cyclic ketones 6 was not as easy as
initially thought because trapping of alkenyl cation 3 by
different nucleophilic partners present in the reaction media
seemed to be favored over the desired trapping with water.
However, after further experimentation, we found that the use
of tetrafluoroboric acid as a promoter in combination with
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as solvent was the
key to achieving the synthesis of ketones 6.6 In fact, when
alkynol 1a was treated with 1 equiv of tetrafluoroboric acid in
HFIP as solvent we were able to isolate the ketone 6a in 85%
yield (Table 1, entry 6). Interestingly, the amount of the acid
could be reduced to just 0.05 equiv without erosion in the
chemical yield (90%; Table 1, entry 7). It is important to
remark that the cyclization occurred exclusively through a 6-
endo mode, and formation of alternative products coming from
a 5-exo mode was not observed.
In our initial experiments, alkynol 1a, comprising a terminal
alkyne, was used as a model substrate to explore the viability of
the proposed strategy (Table 1). As a starting point, we took
Table 1. Initial Experiments
entry
acid (equiv)
TfOH (0.1)
solvent
product
yield (%)
ab
,
1
2
3
4
5
6
7
DCE
11a
87
72
98
92
92
85
90
c
TfOH (1)
DCE
4a
TfOH (1)
hexane
DCE
4b
b
HBF4·OEt2 (1)
HBF4·OEt2 (1)
HBF4·OEt2 (1)
HBF4·OEt2 (0.05)
4a
d
hexane
HFIP
HFIP
4c
6a
6a
a
b
Formation of 4a (<10%) was also detected. Reaction extended for
c
d
16 h. Formation of 4b (10%) was also detected. Reaction extended
for 8 h.
Encouraged by the initial result mentioned above, we
explored the scope of the reaction. For this purpose, a
representative set of alkynols 1 were subjected to the optimized
reaction conditions (Scheme 2). To our delight, we observed
that most of the cyclohexanones 6 were isolated in high yields.
As shown, not only tertiary but also secondary benzylic alcohols
1 could be used (see products 6d,f,k,r). In this context, it
should be noted that secondary alcohols were not considered in
the previous work from Jin and Yamamoto on the synthesis of
cycloalkyl ketones with internal alkynes.4 However, in our case,
the use of this type of alcohols does not seem to be a problem.
Interestingly, this methodology could be applied to the
synthesis of naphthalenone derivatives (6g,k). Substitution at
different positions of the alkyl chain connecting the alcohol and
alkyne functionalities in 1 is also allowed (see products
6g,k,m,n,o,r). Particularly remarkable are those products
containing functional groups that allow further functionaliza-
tion. For example, ester-derived compounds 6o,r could be
easily transformed through this functionality. We were also able
to obtain the alkyne-substituted cyclohexanone derivative 6q
from diyne 1q. It should be noted that, in this case, we
observed an exclusive reaction through one of the alkyne
moieties. In other words, we observed the exclusive formation
of a six-membered cyclic ketone in a process where the second
alkyne of 1q remained untouched. Interestingly, the pendant
alkyne of 6q could be used for additional functionalization. The
spirocyclic functionalized ketone derivative 6m was also
available in high yield. Furthermore, the new cyclization
reaction herein presented does not seem to be limited to the
synthesis of carbocyclic ketones. Thus, the piperidin-3-one
derivative 6p could also be accessed using in this case triflic acid
the experimental conditions reported by Jin, Yamamoto and co-
workers in their synthesis of cycloalkyl ketones 8 from alkynols
7 containing internal alkynes.4 Thus, alkynol 1a was treated
with 10 mol % of triflic acid (TfOH) in 1,2-dichloroethane
(DCE) as solvent at room temperature for 16 h (Table 1, entry
1). Under these conditions, instead of the expected ketone 6a,
we observed the exclusive formation of the enyne derivative
11a, along with a small amount (<10%) of the cyclic alkenyl
chloride 4a. Interestingly, when 1 equiv of triflic acid was used,
we could isolate the cyclic alkenyl chloride 4a in 72% yield, but
formation of the desired ketone 6a was not observed (Table 1,
entry 2). These initial experiments showed differential reactivity
of alkynol derivatives, such as 1a comprising a terminal alkyne
when compared with alkynols 7 containing internal alkynes.
Thus, it seems that, under similar conditions, the endocyclic
alkenyl cation 3 preferentially reacts with a chloride coming
from the solvent (DCE), while the exocyclic cation 10 tends to
react with the water formed in the initial step of the reaction.
Formation of alkenyl chlorides similar to 4a, instead of ketone
derivatives, could be the reason why terminal alkynes were not
considered in that previous work. Thus, after verifying that the
conditions reported by Jin, Yamamoto and co-workers were not
appropriate to obtain our desired cyclic ketone 6a, we started to
screen different reaction conditions. At this point, it seemed
clear that the obvious option to avoid the formation of the
undesired alkenyl chloride 4a was the replacement of 1,2-
dichloroethane (source of the chlorine atom of 4a) with some
other chlorine-free solvent. However, when the reaction was
performed in hexane, we observed the exclusive formation of
the alkenyl triflate 4b (98%; Table 1, entry 3). This product is
formed when the alkenyl cation 3 is trapped by the counterion
B
Org. Lett. XXXX, XXX, XXX−XXX