Organic Letters
Letter
At the outset, we investigated efficient reaction conditions for
the F/Cl and F/Br exchange reactions of the simple alkyl
fluoride, 1-fluorooctane 1a (Table 1). Halomethanes were
Table 2. Fluorine/Iodine Exchange Reaction of 1-
Fluorooctane
Table 1. Fluorine/Chlorine and Fluorine/Bromine Exchange
Reaction of 1-Fluorooctane
a
entry
halogen source
trialkyl aluminum
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
CH2I2
CH2I2
CH2I2
CH2I2
Me Al
rt
(99)
(99)
94
3
Me Al
−40 to rt
rt
3
Et Al
3
Et Al
−40 to rt
rt
(99)
99
3
iBu
Al
3
a
CH
2
I
2
entry
halogen source
trialkyl aluminum
metallocene
Cp TiCl
yield (%)
i
CH2I2
CHI3
CH3I
Bu Al
−40 to rt
−40 to rt
−40 to rt
99
3
1
2
3
4
5
6
7
8
9
CH Cl2
Me Al
29
2
3
2
2
2
2
Et Al
3
99
CH Cl2
Et Al
Cp TiCl
2
70
2
3
Et Al
3
4
i
CH Cl2
Bu Al
Cp TiCl
2
(99)
77
2
3
a
i
NMR yields. The yields of isolated products are given in parentheses.
CH Cl2
Bu Al
3
Cp TiF
2
2
2
i
CH Cl2
Bu Al
3
Cp ZrCl
2
17
2
2
i
fluorides, secondary and tertiary fluorides were more reactive.
The reaction of these fluorides finished within 30 min. The
reaction of secondary alkyl fluorides 2a, diiodomethane, and
CHCl3
CCl4
Bu Al
3
Cp TiCl
87
2
2
2
2
2
2
i
Bu Al
3
Cp TiCl
2
99
CH Br2
Me Al
Cp TiBr
2
69
2
3
Et Al gave minor products (entry 5). Cyclic compound 4a
3
CH Br2
Et Al
Cp TiBr
2
(99)
99
2
3
afforded a mixture of halocyclohexane and an elimination side
product (cyclohexene) (entries 6 and 7). In the case of the F/
Br substitution of tertiary alkyl fluoride, a competing alkylation
reaction decreased the yields of halogenated products (entries
and 10). Notably, substrate 6a, which possesses a fluorine and
i
1
1
1
1
0
1
2
3
CH Br2
Bu Al
3
Cp TiBr
2
2
CH Br2
Et Al
3
Cp TiF
2
92
2
2
CH Br2
Et Al
3
Cp ZrBr
2
60
7
2
2
CHBr3
Et Al
3
Cp TiBr
2
99
2
8
a
NMR yields. The yields of isolated products are given in parentheses.
chlorine atom, did not undergo chlorine/halogen exchange and
substitution of a fluorine atom occurred selectively (entries 12
and 13). The strong Lewis acidity and high fluoride affinity of
an aluminum reagent enabled selective activation of the C−F
bond. As a further demonstration of selectivity for alkyl
fluorides, we carried out the reaction of three kinds of alkyl
halides containing alkyl fluorides with an organic bromine or
iodine source (Scheme 2). 100% conversion of 1-fluorooctane
into the corresponding alkyl halides was observed, whereas less
than 0.5% of the other halides were consumed.
To obtain mechanistic insight into the F/Cl and F/Br
exchange, we carried out reactions without using the titanocene
catalyst, trialkyl aluminum, or organic halide. The results were
summarized in Scheme 3. First, we performed the reaction
without using the titanocene catalyst. Only an alkylated product
was obtained in 99% yield, and no brominated compound 7c
employed as halogen sources due to their availability and ease
of isolation of the product. A survey of different solvents
that Bu Al was the most effective for the F/Cl exchange
i
3
(
entries 1−3). The starting compound was consumed, and 1-
chlorooctane 1b was obtained in 99% yield (entry 3). In
contrast, a full conversion was not achieved and substitution of
the fluorine atom with an alkyl group on the aluminum center
7
occurred as a side reaction when Me Al or Et Al was used
entries 1 and 2). For the F/Br substitution, Et Al and Bu Al
3
3
i
(
3 3
gave 1-bromooctane 1b in 99% yield (entries 9−11). According
to the titanocene-catalyzed C−F bond activation developed by
5
b,c,e
Lentz et al.,
we investigated the activity of [Cp TiF ] as a
2 2
7
catalyst for the reaction. However, a small amount of the
starting material remained (entries 4 and 11). Compared with
titanocene catalysts, zirconocene catalysts gave lower yields
was observed. This result shows that the halogen atom of the
organic halogen source is not activated by a trialkyl aluminum
and the titanocene catalyst is essential for transferring the
halogen atom of an organic halide to the substrate. This is in
sharp contrast to the F/I exchange reaction, where an organic
halide such as CH I is activated. Notably, activation of the C−
F bond was observed due to the strong Lewis acidity of the
aluminum reagent. Second, no reaction occurred under the
conditions without a trialkyl aluminum. Third, the reaction
without an organic halogen source gave a mixture of a
hydrodefluorinated compound, an alkylated compound, and
brominated compound 7c. Clearly, the bromine atom of
compound 7c is derived from [Cp TiBr ]. This result suggests
that the halogen atom of organic halides is transferred to
titanocene first, and then a substitution reaction of an alkyl
fluoride with a halogen atom on titanocene affords the product.
To reveal how the halogen atom on organic halides is
transferred to the substrate, we conducted the reaction of 1-
fluorododecane with CH Br (organic bromine source) and
(
entries 5 and 12). The reaction using trihalomethane and
tetrahalomethane gave good results (entries 6, 7, and 13).
The F/I exchange was also examined (Table 2). Reactions
with trialky aluminum reagents gave 1-iodooctane 1d in good
yields (entries 1−7). However, formation of an alkylated
compound (n-decane) was observed when Et Al was used
entry 3). A lower temperature at the beginning of the reaction
suppressed the side reaction and afforded 1-iodooctane 1d in
9% yield (entry 4). The reaction with Bu Al and CH I gave
isobutyl iodide as an undesired byproduct even at low
temperatute (entries 5 and 6). Triiodomethane was effective
2
2
3
7
(
i
9
3 2 2
2
2
8
as a halogen source (entry 7), while the use of iodomethane
gave only 4% of product (entry 8).
With the optimized conditions, the substrate scope for
halogen exchange reaction of primary, secondary, and tertiary
fluorides was investigated (Table 3). A variety of alkyl fluorides
were effectively converted into the corresponding alkyl halides
in good to excellent yields. Compared with primary alkyl
2
2
titanocene dichloride (chlorine source) in the presence of Et Al
(Scheme 4). A mixture of 1-chlorododecane 7b and 1-
3
B
Org. Lett. XXXX, XXX, XXX−XXX