N-bromosuccinimide reactions of some heterocycles in the presence or absence of water: An overview of ring versus side chain bromination for the synthesis of important brominated heterocyclic synthons

Article abstract of DOI:10.1002/jhet.5570380125

Reactions of various heterocycles 1-6 with N-bromosuccinimide in the presence or absence of water have been studied for side chain versus ring bromination to afford some new and important heterocyclic synthons. Interestingly, the N-bromosuccinimide reaction in the presence of perchloric acid, a new condition, affords exclusively the new dibromo aminopicoline 1f, which is not obtained by other presently studied methods.

Full text of DOI:10.1002/jhet.5570380125

Jan-Feb 2001 N-Bromosuccinimide Reactions of Some Heterocycles in the Presence or
AbsenceofWater:AnOverviewofRingVersusSideChainBromination
for the Synthesis of Important Brominated Heterocyclic Synthons
173
Shyamaprosad Goswami*, Kumaresh Ghosh, Reshmi Mukherjee,
Avijit Kumar Adak and Ajit Kumar Mahapatra
Department of Chemistry, Bengal Engineering College (Deemed University), Howrah-711103, India
Received December 23, 1998
Dedicated to the Late Dr. Raymond N. Castle
Reactions of various heterocycles 1-6 with N-bromosuccinimide in the presence or absence of water have
been studied for side chain versus ring bromination to afford some new and important heterocyclic synthons.
Interestingly, the N-bromosuccinimide reaction in the presence of perchloric acid, a new condition, affords
exclusively the new dibromo aminopicoline 1f, which is not obtained by other presently studied methods.
J. Heterocyclic Chem., 38, 173 (2001).
Specific functionalised heterocycles are highly desirable
because of their many uses in heterocyclic chemistry,
industrial chemistry and as ligands for neutral organic
molecules [1]. Specifically, pyridine derivatives are
important as precursors for pharmacologically active
compounds [2], and for the synthesis of liquid crystals [3]
and polymers etc.
Bromination using N-bromosuccinimide, in the presence
or absence of water, as well as with molecular bromine are
undertaken on the pyridine and naphthyridine derivatives
enroute to the synthesis of functionalised bromomethyl-
pyridine or naphthyridine for our molecular recognition
research [4a-d]. They are also prepared for the synthesis of
heterocyclic benzylic bromides to study our newly
discovered cobalt (I) oxidation reaction [4e].
2-amino-6-methylpyridine is reported [10] to afford ring
bromo compounds. Treatment of 2-amino-4,6-lutidine
with bromine in acetic acid or with N-bromosuccinimide
in chloroform yields [11] only the 3,5-dibromo derivative
resulting from ring bromination. The results of our investi-
gation on the bromination of acetyl protected 1 and
p-nitrobenzoyl protected (more electron withdrawing)
2-amino-6-methylpyridine 2 under different conditions are
shown in Scheme 1.
The reaction of compound 1 with N-bromosuccinimide
in dry carbon tetrachloride with a catalytic amount of
benzoyl peroxide (3 mol%) gives the ring bromo deriva-
tive 1a in 75% yield, the side chain monobromo derivative
1b in 10-15% yield and also the dibromo derivative 1c in
5-10% yield. Use of a large amount of carbon tetrachloride
solvent slightly increases the yield of 1b. Compound 1a
N-bromosuccinimide reactions under different
conditions [5] (N-bromosuccinimide in sodium hydroxide,
in aqueous sulphuric acid or catalytic amount of concen-
trated sulphuric acid, p-toluenesulphonic acid, silica
gel etc.) continue to be an area of active interest. From the
known brominating agents for aromatic rings [6],
N-bromosuccinimide is widely used in free radical, allylic
or benzylic brominations [7] and also for the electrophilic
substitution of aromatic rings [8]. Very recently, bromine
in water [9] has been used for the free radical bromination
of some selected nonheterocyclic compounds. We report
here our results on acyl group protected 2-amino-6-
methylpyridine, 2,6-dimethylpyridine and 2,7-dimethyl-
pyridine under different conditions that generated some
new, as well as known important ring or side chain bromi-
nated heterocyclic synthons. These were successfully
characterised after, in some cases, a difficult separation
(Schemes 1 and 2). By this method, a new convenient
synthesis of 2-amino-6-pyridinemethanol has been
developed from 2-phthalimido-6-bromomethylpyridine
(Scheme 3).
and 1b have indentical R values and are therefore
f
inseparable. As a result, compounds 1a and 1b were
treated with sodium acetate and the resulting
2-N-acetamido-6-acetoxymethylpyridine (1d) was sepa-
rated and characterised as the acetate derivative of 1b.
Presence of water droplets (about 10-15 equivalents) in
this reaction condition accelerates the rate of N-bromo-
succinimide reactions. Interestingly in the presence of
water and benzoyl peroxide (3 mol%), 1a is produced in
62% yield along with 1e, a new bromo derivative in 37%
yield. Under the same reaction conditions without the
addition of benzoyl peroxide (i.e, N-bromosuccinimide in
carbon tetrachloride, water, hv) only 1a is produced within
1.5 hours in 85% yield. In the presence of benzoyl
peroxide (3%) in pure water (as solvent) instead of carbon
tetrachloride, 1a is produced in 90% yield within 1 hour.
Interestingly, there is no bromination reaction of 2,6-luti-
dine with N-bromosuccinimide in acetonitrile in the
presence of light, without the presence of benzoyl peroxide
or water at room temperature, however with refluxing the
6-bromomethyl-2-methylpyridine is obtained as the major
product (50%) along with starting material. The effect of
water in bromination reactions on heterocyclic compounds
was further examined by starting with other heterocycles
The free radical side chain bromination of acetyl
protected 2-amino-6-methylpyridine 1 with N-bromo-
succinimide competes with the reaction leading to ring
bromination. Bromination using molecular bromine on

174
S. Goswami, K. Ghosh, R. Mukherjee, A. K. Adak and A. K. Mahapatra
Vol.38
such as compounds 3, 4 and 5 (Scheme 2). Bromination of
3 (N-bromosuccinimide in benzene) is reported to produce
3a only in 20% yield [5], however using our procedure
(N-bromosuccinimide along with benzoyl peroxide in dry
carbon tetrachloride containing 15 equivalents of water),
the yield of 3a is enhanced to 45%.
Compound 4 [12], in the presence of water, gives 4a in
30% yield along with some of the dibromo product 4b. The
presence of water in this reaction marginally changes the
yield of 4a but makes the reaction faster. Under the same reac-
tion condition, compound 5 gives 5a in 40% yield while the
previous reported condition of N-bromosuccinimide in chlo-
roform gives 26% yield [12]. The bromination reaction of 4
with N-bromosuccinimide in acetonitrile in the presence of
light without the addition of benzoyl peroxide or water
afforded 4a (25%) and the 2,6-dibromomethylnaphthyridine
(4c) (20%) but 4b was not obtained. Under the same reaction
conditions, compound 5 affords compounds 5a and 5b in
50% and 30% respectively (Scheme 2). Interestingly, by treat-
ing 2,6-dipivaloylaminopyridine (6) with N-bromo-
succinimide in acetonitrile in the presence of light without the
presence of benzoyl peroxide or water products 6a and 6b are
obtained in 60% and 40% respectively.
Thus, in most cases, the presence of water droplets in the
bromination reaction accelerates the rate of bromination of
heterocyclic compounds. The presence of water droplets

Jan-Feb 2001
175
N-Bromosuccinimide Reactions of Some Heterocycles
may increase the polarity of the solvent mixture and also
the co-product hydrobromic acid, generated in the reaction
medium, is scavenged and thus maintaining a more
uniform distribution of free radicals thereby increasing the
extent of side chain bromination relative to that of ring
bromination. However, this effect varies depending on the
substrate. Use of AIBN rather than benzoyl peroxide as
radical initiator in the reaction medium also produces a
similar effect.
In order to reduce the electron density in the pyridine ring,
a factor responsible for ring bromination, the acetyl group in
1 is replaced by the more electron withdrawing 4-nitroben-
zoyl group (Scheme 1). By changing to the more electro-
negative 4-nitrobenzoyl protecting group (compound 2)
from that of the acetyl group (compound 1), the yield of side
chain brominated product is found to increase to some extent
(2a; 25%). This shows that by changing the protecting
groups one can change the ratio of side chain (benzylic
position) versus ring bromination. Use of perchloric acid to
make a salt of 1 was then exploited to decrease the ring elec-
tron density, and it was hoped that it would reduce the ring
brominated product. However, compound 1 in the presence
of perchloric acid in carbon tetrachloride produces another
interesting new product (1f, 90%) where the protecting
acetyl group is simultaneously deprotected. The new
dibromo product 1f, which is potentially useful for the
synthesis of polyaza heterocycles, cannot be obtained by
other combinations that we have used here. The presence of
perchloric acid in bromination of 2 gives 2a (without depro-
tecting the 4-nitrobenzoyl group) instead of 1f without sig-
nificant improvement of the yield. The absence of 1f from 2,
under this condition of the N-bromosuccinimide reaction,
likely results because the 4-nitrobenzoyl group remains
intact in this case. All these perchloric acid mediated bromi-
nation reactions in the absence of benzoylperoxide show the
same effect, although the mechanistic role of
benzoylperoxide is still not clear to us.
N-bromosuccinimide in acetonitrile, a mild and
regiospecific nuclear brominating agent [8], gives 1a as
the sole product from 1 (Scheme 1). This combination of

176
S. Goswami, K. Ghosh, R. Mukherjee, A. K. Adak and A. K. Mahapatra
Vol.38
Table 1
o
1
Starting
material
Product
Yield
(%)
mp ( C)
H NMR (deuteriochloroform)
+
and mass (M ) of major compounds
1
1a
75 [a]
62 [b]
155
7.91 (d, 1H, J = 8 Hz), 7.88 (s, 1H), 7.75 (d, 1H,
J = 8 Hz), 2.53 (s, 3H), 2.19 (s, 3H); M : 228, 230
+
90 [c]
85 [d]
90 [e]
1
1
1b [f]
1c [f,g]
1e
10-15 [a]
-
8.13 (d, 1H, J = 8 Hz), 7.92 (s, -NH-), 7.70 (t, 1H, J = 8 Hz),
7.14 (d, 1H, J = 8 Hz), 4.41 (s, 2H), 2.21 (s, 3H);
8.15 (d, 1H, J = 8 Hz), 7.96 (s, NH), 7.75 (t, 1H, J = 8 Hz),
7.36 (d, 1H, J = 8 Hz), 6.50 (s, 1H), 2.20 (s, 3H);
5-10 [a]
37 [b]
-
198-200
8.05 (d, 1H, J = 8 Hz), 7.84 (s, -NH-), 7.82 (d, 1H, J = 8 Hz),
+
4.55 (s, 2H), 2.21 (s, 3H). M : 308, 310.
1
2
1f
2a
90
25 [a]
134
107-109
7.72 (s, 1H), 4.84 (bs, NH ), 2.44 (s, 3H).
2
8.62 (s, NH), 8.38 (d, 2H, J = 10 Hz), 8.31 (d, 1H, J = 8Hz),
8.13 (d, 2H, J = 10 Hz), 7.80 (t, 1H, J = 8 Hz), 7.23 (d, 1H, J =
+
8 Hz), 4.44 (s, 2H). M : 336, 338.
2
3
4
2b
68 [a]
45 [b]
192-194
8.45 (s, NH), 8.36 (d, 2H, J = 8 Hz), 8.09 (d, 3H, J = 8Hz), 7.85
(d, 1H J = 8 Hz), 2.58 (s, 3H).
7.70 (t, 1H, J = 8 Hz), 7.35 (d, 2H, J = 8 Hz), 4.53 (s, 4H).
3a [g]
3b
4a
82
-
26 [a]
30 [b]
128-130[h]
8.20 (d, 1H, J = 8 Hz), 8.06 (d, 1H, J = 8 Hz), 7.63 (d, 1H,
J = 8 Hz), 7.43 (d, 1H, J = 8 Hz), 4.74 (s, 2H), 2.89 (s, 3H).
+
M : 236, 238.
4
5
4b [f]
-
8.29 (d, 1H, J = 8 Hz), 8.23 (d, 1H, J = 8 Hz), 7.70 (d, 1H,
J = 8 Hz), 7.45 (d, 1H, J = 8 Hz), 4.74 (s, 2H), 6.85 (s, 1H).
8.22 (d, 2H, J = 8.26), 7.72 (d, 2H, J = 8.2), 4.76 (s, 4H).
4c
5a [g]
5b
20
40 [b]
239 (dec.)
-
169
8.57 (1H, d, J = 8.82), 8.38 (bs, 1H), 8.27 (1H, d, J = 8.40),
8.22 (1H, d, J = 8.82), 8.05(1H, d, J = 7.84), 6.77 (1H, s), 2.3
(3H, s).
6
6a
60 [c]
80
8.73 (s, 1H), 8.15 (s, 1H), 7.49 (d, 1H, J = 8Hz), 7.80 (d, 1H,
J = 8 Hz), 1.35 (s, 9H), 1.25 (s, 9H).
6
7
6b
7a
40 [c]
62 [b]
228
125-130
8.15 (s, 2H), 8.04 (s, 1H), 1.34 (s, 18H).
8.16 (m, 3H), 7.81 (m, 2H), 7.54 (d, 1H, J = 8Hz), 7.35
(d, 1H, J = 8 Hz), 4.59 (s, 2H).
7
7c
46-50
93
7.27 (t, 1H, J = 8 Hz), 6.42 (d, 1H, J = 8 Hz), 6.30 (d, 1H,
J = 8Hz), 5.5 (brs, 1H, -OH), 4.44 (s, 2H), 3.5 (brs, 2H, -NH ).
2
[a] N-bromosuccinimide in the absence of water in carbon tetrachloride; [b] N-bromosuccinimide in the presence of water in carbon tetrachloride; [c] N-
bromosuccinimide in acetonitrile; [d] N-bromosuccinimide in the absence of benzoyl peroxide in carbon tetrachloride containing water; [e]
N-bromosuccinimide in pure water; [f] characterised from the mixture due to difficulty in purification; [g] characterised by comparison of NMR and mp
data with literature; [h] decomposition temperature.
N-bromosuccinimide/acetonitrile affords the ring bromi-
nated products (6a and 6b) from 2,6-dipivaloylaminopy-
ridine 6 in better yields compared to the method of
bromine in acetic acid (Scheme 2). Therefore, side-chain
bromination over ring bromination of 2-amino-6-
methylpyridine was really an interesting problem for
2-amino-6-methylpyridine until the phthalimido
protected amino picoline 7 [13] was chosen, where the
resonating lone pair of amino nitrogen towards pyridine
ring is locked, that affords a good yield of benzylic
bromination without any ring bromination product. In
this case, the presence of water did not significantly
change the yield of the side chain monobromination
product 7a from 2-N-phthalimido-6-methylpyridine.
This phthalimido monobromo product 7a is important as
it was conveniently converted to 7c via the intermediacy
of the uncharacterised 7b (Scheme 3). To our know-
ledge, the single step deprotection of both phthalimido
as well as acetate groups of 7b represents a new route for
the synthesis of 2-amino-6-methylpyridine 7c [14]. The
physical constants and spectral details of new
compounds are given in Table 1.
In summary, we have studied the N-bromosuccinimide
reactions of various heterocycles in the presence and in the
absence of water, in some cases giving an overview of
side-chain versus ring bromination. The cases where side-
chain bromination is favoured over ring bromination may
be the result of a change in the polarity of the solvent
mixture due to the addition of water. This is the first report
of N-bromosuccinimide reactions of heterocycles in water.
Interestingly, the N-bromosuccinimide reaction, in the
presence of perchloric acid, afford exclusively the new

Jan-Feb 2001
177
N-Bromosuccinimide Reactions of Some Heterocycles
organic solvent was evaporated in vacuo and was purified by
column chromatography using benzene/ethylacetate (6:1) as the
mobile phase to give 1a.
dibromo aminopicoline 1f, which is not obtained by other
presently studied methods. The details of the mechanism
and the applications of this reaction in different conditions
with heterocycles are however not completed and further
work is in progress. This will be reported in due course.
Anal. Calcd. for C H N Br : C, 27.07; H, 2.27; N, 10.50.
6
6
2
2
Found: C, 27.33; H, 2.89; N, 10.61.
2-N-Acetylamino-6-acetoxymethylpyridine (1d).
EXPERIMENTAL
A mixture of compounds 1a and 1b (50 mg) was refluxed in
dry dimethylformamide under a nitrogen atmosphere for
12 hours at 80-90 °C. The mixture was then poured into water
and thoroughly extracted with dichloromethanne. The solution
was dried with anhydrous sodium sulphate and was evapo-
rated in vacuo. Purification by column chromatography using
benzene:ethylacetate (6:1) gave compound 1d in 75% yield
(6 mg) and 41 mg compound 1a. Hence the presence of
All reactions are carried out under nitrogen. Compounds were
purified by repeated silica gel (60-120 mesh) chromatography as
well as preparative tlc. For bromination, a 250 W ordinary bulb
was used as a light source.
General Procedure for N-Bromosuccinimide Reaction.
compound 1b in the mixture estimated was 9 mg and the
In the Absence of Water.
1
overall yield of 1b varied from 10-15%. H-NMR (CDCl ,
3
A stirred mixture of 2-acetamido-6-methylpyridine
(1g, 6.6 mmol), N-bromosuccinimide (1.42 g, 8.0 mmol) in dry
carbon tetrachloride (80 ml) was refluxed in the presence of
benzoylperoxide (50 mg, 0.2 mmol, 3 mol %) and light for 12-
16 hours. The reaction mixture was then cooled to room
temperature, succinimide was removed by filtration and the
solvent was evaporated on a rotary evaporator. The crude product
was chromatographed [benzene:ethylacetate (6:1)] to give the
pure bromo product, 1a.
200 MHz): δ 8.45 (s, -NH-), 8.17 (d, 1H, J = 8 Hz), 7.75 (t,
1H, J = 8 Hz), 7.10 (d, 1H, J = 8 Hz), 5.11 (s, 2H), 2.23 (s,
3H), 2.17 (s, 3H).
2-Amino-6-hydroxymethylpyridine (7c).
To a stirred solution of 2-N-phthalimido-6-bromomethyl-
pyridine 7a (100 mg, 0.32 mmol) in dry ethanol, sodium
acetate was added along with a catalytic amount of sodium
iodide. The mixture was refluxed under a nitrogen atmos-
phere. Conversion of the starting material to the product was
monitored by tlc. After stirring 15 hours the solvent was evap-
orated to dryness and ethylacetate was added. The solution
was then passed through a silica gel bed to remove inorganic
materials. Ethylacetate was evaporated in vacuo and to a
warm ethanolic suspension of the crude acetate product 7b
(without characterising) hydrazine hydrate (0.68 mmol) was
added. The solution was stirred in an oil bath and conversion
was monitored by tlc. The mixture was poured into water and
was extracted with chloroform. After evaporation of the
solvent the crude product was purified by column
chromatography using 10% methanol in chloroform as eluent
to give the pure product 7c in 46-50% yield (18-19 mg).
Anal. Calcd. for C H ON Br: C, 41.95; H, 3.96; N, 12.23.
8
9
2
Found : C, 42.21; H, 3.87; N, 12.51.
Compound (2) Compound 2-methyl-6-(4-nitrobenzoylamino)-
pyridine was also brominated by this procedure yielding 2a in
25% yield and 2b in 68% yield.
In the Presence of Water.
To a stirred solution of 2-acetamido-6-methylpyridine
(1g, 6.6 mmol) in carbon tetrachloride containing water (0.17 ml,
9.9 mmol, 15 equivalents), was added N-bromosuccinimide
(crystallised) (1.42 g, 8.0 mmol) and benzoyl peroxide (50 mg,
0.20 mmol, 3 mol %). The mixture was refluxed in the presence
of light and the reaction was completed within 1.5 hour. The
solvent was evaporated in vacuo and the reaction mixture was
purified chromatographically using benzene/ethylacetate 96:1).
2,6-Dimethylpyridine and 2,7-dimethylnapthyridine were
brominated by this method.
Acknowledgement.
We thank Department of Science and Technology and
CSIR, Government of India for previous financial support. We
also thank IIT, Kharagpur, IICB, Calcutta for NMR (Bruker
AM 200 and 300 respectively) and IACS, Calcutta for
elemental analysis.
In Acetonitrile.
To a solution of 2-acetamido-6-methylpyridine (0.1 g,
0.66 mmol) in 5 ml of acetonitrile was added N-bromo-
succinimide (0.14 g, 0.8 mmol). The reaction was stirred at room
temperature in presence of light for 2-3 hours. The solvent was
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