D. Liang et al. / Tetrahedron Letters 57 (2016) 5390–5394
5393
Table 2 (continued)
Entry
15c
Anilides
Products
t (min)
Yield (%)b
1440
Nr
NHBz
Br
1o
16c
1440
1440
56
Bn
N
Br
Bn
N
Bz
Bz
2o
1p
4
17c
Nr
NHAc
a
Reaction conditions: 1 (0.5 mmol), HBr (0.55 mmol), Selectfluor (0.6 mmol), H2O (3.0 mL), room temperature.
Isolated yields.
KBr was used instead of HBr, and the reaction was run at 100 °C.
b
c
oxidation of a bromide ion with a wide range of oxidants [18],
and in this protocol Selectfluor was unique and essential (entries
1–10), Selectfluor might be more than an oxidant here.
(a)
(b)
NHAc
NHAc
HBr (3.3 equiv), Selectfluor (3.6 equiv), H2O, rt, 12 h
or KBr (3.3 equiv), Selectfluor (3.6 equiv), H2O, reflux, 12 h
Br
Br
2e, 92%
Attempts to achieve chlorination, iodination and fluorination
reactions of 1a by using chlorine, iodine and fluorine sources met
with no success. While no reaction occurred by using HCl (37%
aqueous) or HI (47% aqueous, entry 21) at room temperature, or
by using KI or KF (entry 23) in refluxing water, the use of HCl or
HI at 100 °C resulted in complex mixture (note f, entry 21), proba-
bly due to the hydrolysis of amides. Interestingly, the use of NaCl
as the ‘‘halogen source” at refluxing temperature gave N-(2-flu-
oro-4-methylphenyl)acetamide 3 in 13% yield after 24 h (entry
22). To document the practicality of our protocol, a multigram-
scale experiment was carried out, and the yield of 2a was not com-
promised (entry 24).
1g
KBr (2.2 equiv)
Selectfluor (2.4 equiv)
NHAc
NHAc
Cl
NHAc
or
or
H2O, reflux, 12 h
1a
1i
1l
NHAc
NHAc
Cl
NHAc
or
or
Br
Br
Br
2a, 91%
2i, 93%
2l, 91%
Scheme 2. Attempts of multibromination of acetanilides.
Under the optimized reaction conditions (entry 15, Table 1), the
substrate scope was then explored (Table 2). It proved that sub-
strates 1a-c with different electron-withdrawing N-protecting
groups, including acetyl (entry 1), benzoyl (entry 2), and phenyl-
sulfonyl (entry 3), all worked well to furnish the ortho-brominated
products 2a-c in excellent yields [19]. Acetanilides 1d,e bearing a
chloro or bromo group at the para-position could also be bromi-
nated, providing expected 2-bromoacetanilides 2d,e in excellent
yields (entries 4 and 5). Surprisingly, the reaction of anilide 1f hav-
ing a methoxy group para to the amide group gave meta-selective
product 2f exclusively, as evidenced by the 1H NMR spectroscopic
analysis of the crude reaction mixture, in 91% yield within 15 min
(entry 6). This reversed regioselectivity reflected the fact that the
methoxy is a stronger orienting group than the amide. In all of
the above cases, no di-brominated products were observed.
It is worthy of notice that generally when there was no para-
substituent on the benzene ring, para-mono-bromination occurred
exclusively. For example, 4-bromoanilides 2g,h were efficiently
synthesized in excellent yields from acetanilide 1g and benzanilide
1h, respectively (entries 7 and 8), and no regioisomeric ortho- or
meta-brominated product, or di- or tri-brominated anilide was
detected by 1H NMR spectroscopic analyses of the crude reaction
mixtures. Anilides 1i-l with a methyl or chloro group at either
the ortho- (entries 9–11) or meta-position (entry 12) were also
competent substrates in this transformation, and 4-brominated
products 2i-l were afforded in 90–94% yields. The para-bromina-
tion still proceeded smoothly when N-(2-bromo-5-chlorophenyl)
acetamide 1n with two electron-withdrawing groups (EWGs) on
the benzene ring was used, affording polyhalogenated anilide 2n
in 90% yield (entry 14). This reaction was rather sensitive to steric
hindrance, since incredible meta-selectivity was observed by
Br
OH
OH
HBr (1.1 equiv), Selectfluor (1.2 equiv)
1)
2)
H2O, rt, 10 min
5
6, 94%
CN
CN
S
S
HBr (1.5 equiv), Selectfluor (1.5 equiv)
H2O, rt, 6 h
S
S
Br
7
8
, 97%
Scheme 3. Bromination of naphthalen-2-ol and 2-(1,3-dithiolan-2-ylidene)
acetonitrile.
as the solvent, the bromination took a much longer time to com-
plete (entry 20). Water was chosen as the solvent for further stud-
ies for reasons of efficiency, cost, safety, and environmental
concerns. Though there is no unifying theory that explains the rate
acceleration observed under heterogeneous aqueous conditions to
date, the increase in interfacial area, trans-phase hydrogen-bond-
ing between the water surface and the transition states, and the
cohesive energy density of the solvent might be key factors respon-
sible for the on-water effect [17].
When the model reaction under optimized conditions was
doped with
2 equiv of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), the results were unaffected (note f, entry 15), while
when the reaction was heated under otherwise optimal conditions,
reddish-brown vapors were observed in the condenser, suggesting
that a radical pathway could be ruled out, and that there might be
Br2 generated in situ, which might be the actual brominating
reagent. However, as Br2 is known to be readily produced via
Liang, Deqiang
