ACS Catalysis
Letter
a
the reaction was first performed under standard conditions.
After which, the insoluble succinimide was filtered and washed
with small amount of diethyl ether/hexane mixture. The filtrate
was concentrated to give lactone 6a in 97% yield and the purity
is >99% based on the 1H NMR study. Pure succinimide
Table 3. Indole-Catalyzed Bromocyclization
1
(confirmed by H NMR) was recovered in 95% yield.
To explore the substrate scope for indole 1a catalyzed phase
transfer reaction, a series of alkenoic acids 5 were investigated
using hexane or heptane as the solvent, and the results are
summarized in Table 2. In general, the reactions proceeded
Table 2. Indole-Catalyzed Bromolactonization of 5 in
a
Hexane and Heptane
yield in hexane yield in heptane
entry
product, R
6a, C6H5
time (h)
(%)
(%)
1
2
5
6
97
94
75
77
81
91
77
90
95
89
97
95
70
71
79
90
71
90
96
85
6b, 4-Cl-C6H4
6c, 4-CH3-C6H4
6d, 4-CF3O-C6H4
6e, 4-NC-C6H4
6f, 2-Cl-C6H4
6g, 3-CH3O-C6H4
6h, 2-naphthyl
6i, CH3
b
3
9
b
4
b
9
5
9
6
6
b
7
c
9
8
9
9
9
b
10
6j, H
24
a
Reactions were conducted with olefinic acid 5 (0.5 mmol), catalyst 1a
(1 mol %), and NBS (0.6 mmol) in hexane or heptane (5 mL) at 25
b
c
°C. 10 mol % of 1a was used. 20 mol % of 1a was used.
a
Reactions were conducted with olefinic substrate 5 (0.5 mmol),
catalyst 1a (10 mol %), and NBS (0.6 mmol) in heptane (5 mL) at 25
°C. 20 mol % of 1a was used.
smoothly, and the desired lactone products 6 were obtained in
good to excellent yields. The catalytic protocol was compatible
with both electron-rich and electron-poor olefinic substrates.
For sterically hindered ortho-chloro substrate 5f, the corre-
sponding lactone 6f could be obtained in 91% yield. The
methyl and unsubstituted substrates 5i and 5j, the desired
products could still be furnished in high yielding. Other
substrates were also examined as shown in Table 3. Although
the cyclization of 5k was relatively sluggish (Table 3, entry 1),
the indole-catalyzed bromolactonization of 5l−5m and
bromoetherification of 5n−5o proceeded smoothly with good
yields and diastereoselectivities (Table 3, entries 2−5).
b
On the basis of the experimental results, it appears that
indole 1a might first react with the poorly soluble NBS to give
the hexane-soluble brominating species 2 (Scheme 6). The
generation of 2 could be facilitated by the formation of the
insoluble succinimide byproduct. Subsequent electrophilic
bromolactonization of 5 by 2 could furnish lactone 6 together
with the regeneration of indole 1a. It is noteworthy that
typically α-carbonyl halide is not an active electrophilic halogen
source, and a strong Lewis acid is required to activate the α-
carbonyl halide for electrophilic halogenation reactions.16 For
example, a stoichiometric amount of ZrCl4 has been used to
activate 2,2-dichloro-1,3-diketone 9 for the electrophilic
chlorination.16c We speculated that the sole origin of reactivity
of 2 could be attributed to the driving force from the
rearomatization of the indole (i.e., 2 → 1a) in the electrophilic
bromination process. Although no desired chlorolactone
product was obtained when using NCS as the halogen source
(Table 1, entry 10), it was found that significant amount of
chlorinated indole 11 was isolated when reacting 1a with NCS
(1:1), potentially going through the reactive species 10.17
In summary, we have developed a novel indole-catalyzed
bromolactonization using NBS as the stoichiometric brominat-
ing agent. The reaction can be conducted in green lipophilic
media such as heptane and cyclohexane. The workup process
can be facilitated, and the bromine carrier succinimide can be
Besides the reactions that are catalyzed by indole 1a, as
shown above, we also applied this type of catalysis in the
synthesis of base-sensitive compound. Previously, our group
reported a bromolactonization reaction of olefinic acid 5p
amino-thiocarbamate 8 as the catalyst (Scheme 5).15 However,
a mixture of 6p and 6p′ with similar polarity was obtained in
which 6p could readily undergo vicinal dehydrobromination to
give 6p′ in the presence of base. Indeed, when sodium
carbonate, a base commonly used to promote bromolactoniza-
tion, was employed, a 5:1 mixture of 6p:6p′ was obtained.
Nonetheless, when the indole catalyst was applied, 6p was
furnished in 90% yield when using heptane as the solvent, and
1
no 6p′ was detected on the basis of the H NMR experiment
on the crude mixture.
Other substrates (5q−5s) also worked well under this
catalytic protocol to yield the corresponding lactones 6q−6s in
excellent yields.
4753
ACS Catal. 2015, 5, 4751−4755