Synthesis of bromohydrins using NBS in presence of iodine as catalyst

Indian Journal of Chemistry
Vol. 53B, November 2014, pp 1425-1429
Synthesis of bromohydrins using NBS in presence of iodine as catalyst
Raj Sekhar Lodh, Arun Jyoti Borah & Prodeep Phukan*
Department of Chemistry, Gauhati University, Guwahati 781 014, India
E-mail: pphukan@ yahoo.com
Received 3 December 2013; accepted (revised) 4 September 2014
Iodine has been found to catalyze bromohydrin formation reaction using NBS as a brominating agent. The procedure is
efficient and produces high yield of the product at 0°C within a short time. Cinnamic esters can easily be transformed to
corresponding bromohydrins in high yield.
Keywords: Bromohydrin, NBS, catalyst, iodine
Vicinal halohydrins have been drawing interest to
organic chemists because of their wide applications in
the
synthesis
of
pharmaceuticals,
active
1
2
intermediates , dyes, flame retardants , additives and
plasticizers, agrochemicals, etc3. Various reagents
have been developed by researchers for the
halohydrin formation reaction over the years. A
common method for the synthesis of vic-halohydrins
is the regioselective ring opening of epoxides with
hydrogen halides4. Several research groups have
reported different methods for the synthesis of vichalohydrins from oxiranes using a variety of reagents
such as elemental halogen5, metal halides6,
chlorosilanes7, haloboranes8, etc. Sharghi and his coworkers reported the ring opening halogenations of
epoxides by elemental halogens (I2 or Br2) in the
presence of thiourea or isonocotinic hydrazide under
mild reaction condition to yield halohydrin9. In the
presence of magnesium nitrate catalyst, Suh et al.
reported a highly regioselective conversion of epoxide
to bromohydrins using tetrabutyl ammonium
bromide10. Various oxidative halogenation methods
were also reported where residual HX is regenerated
by various oxidants such as metals, persulfates, and
hypervalent iodine oxidants11. In the oxidative
halogenation methods11, the halogen source requires a
metal salt, an oxidizing agent and a catalyst to perform
the transformations. In addition, different metal
complexes in presence of haloperoxidases12 have been
introduced in the biosynthesis of many halogenated
marine natural products like terpenes, indoles,
phenols, etc. Biotransformations of alkenes by
haloperoxidases for regiospecific bromohydrin
formation from cinnamyl substrates in neutral aprotic
media have also been reported13.
Generally
bromohydrin
synthesis
using
N-bromosuccinimide (NBS) require a catalyst14.
N-Bromosuccinimide generally acts as brominating
agent for the synthesis of bromohydrins in moist
dimethylsulfoxide
as
reaction
medium15.
Hydrobromination of olefins using NBS in ionic liquid
has also been reported16. Use of molecular halogens in
place of N-halosuccinimide has several disadvantages
such as hazardous nature of molecular halogens, low
yield and longer reaction time17 and inability to
transform electron deficient alkenes18. N,N-Dibromo-ptoluene-sulfonamide has also been found to be an
effective reagent for bromohydrin formation19.
However, due to commercial availability, NBS has
been most widely utilized for the synthesis of
bromohydrins. In continuation of the ongoing work
on iodine catalyzed reactions20, herein is reported a
new methodology for the synthesis of bromohydrin
using NBS in presence of iodine as catalyst (Scheme I).
The emphasis is on the extension of the procedure for
relatively inactive substrates such as cinnamic esters.
Since we are more interested in studying the
process for substrates like cinnamate, initial
experiments were performed using ethyl cinnamate as
the model substrate (Table I). In a typical reaction,
ethylcinnamate (1 mmol) was added to a mixture of
NBS (1.2 mmol) and iodine (10 mol %) in a mixture
(4:1 ratio) of acetonitrile and water (5 mL) at RT.
Further improvement of yield was observed, when the
reaction was performed at 0°C. The reaction without
catalyst produced poor yield under these particular
reaction conditions.
After optimizing the reaction conditions we
extended the procedure using different olefins. The
results are summarized in Table II. From Table II it
INDIAN J. CHEM., SEC B, NOVEMBER 2014
1426
R
OH
NBS (1.2 eq)
R/
I2 (10 mol %)
CH3CN : H2O (4:1)
R
R
/
Br
R = Ar
R/= Ar, COOEt, COOMe, H, etc.
Scheme I — Bromohydrin synthesis using NBS in presence iodine as catalyst
Table I — Synthesis of bromohydrin from ethylcinnamate under various conditionsa
Entry
Catalyst (mmol)
NBS (mmol)
Temp.
Time (h)
Yieldb (%)
1
0.1
1.2
RT
2
68
2
0.1
1.2
0°C
1
79
3
0.1
1.1
0°C
1
70
4
_
1.2
RT
10
55
a
Reaction condition: ethylcinnamate (1 mmol); MeCN-H2O (4:1, 5 mL); bIsolated yield.
can be concluded that the bromohydrins could be
synthesized from different olefins such as ethyl
cinnamate, methyl cinnamate, trans-stibene, styrene,
indene and 1,2-dihydro naphthalene in excellent yield.
In all cases, the rate of reaction is fast. However, in
case of chalcone (Entry 7), the reaction produced
lower yield. In all cases, the reaction displays high
regioselectivity.
Mechanistically, the reaction may proceed through
the iodine catalyzed formation of bromonium ion
intermediate. Iodine is known to behave as a soft acid
(electron acceptor) due to the presence of vacant dorbital. Similar to other Lewis acids, iodine activates
NBS by coordinating with one of the carbonyl oxygen
atom of NBS. This results in weakening of N-Br
bond, which finally facilitate the transfer of Br+
species to alkenes (Scheme II). This is followed by
the nucleophilic attack by water in an anti-selective
fashion. Final step of the reaction is the deprotonation
of the resulting complex to form the bromohydrin.
In conclusion, a general catalytic method has been
developed for the bromohydrin reaction of various
olefinic substrates in the presence of iodine using
NBS as brominating agent with high yield. The
important features of this methodology are mild
reaction condition, cleaner reaction profile,
operational simplicity and cheap, non-toxic and
readily available catalyst. This procedure is very
effective for relatively inactive cinnamic esters.
Experimental Section
All the chemicals used were that of analytical
grade. IR spectra were recorded by using PerkinElmer Spectrum RX I FT-IR spectrometer. 1H and 13C
% of anti product
>99
>99
-
NMR spectra were measured in CDCl3 at 300 and
75 MHz respectively, using Bruker Avance 300 MHz
spectrometer using TMS as internal standard.
Synthetic procedures
To a solution of olefin (1 mmol) and NBS
(1.2 mmol), in acetonitrile-water (4:1) (5 mL) in a
25 mL round-bottom flask was added iodine
(0.1 mmol) at 0°C. The mixture was stirred at 0°C
using a magnetic stirrer for the appropriate time as
found by monitoring the progress of the reaction by
TLC from time to time till completion. After
completion of the reaction, the reaction mixture was
washed with 10% aqueous Na2S2O3 (10 mL). Ethyl
acetate was added to the reaction mixture and the
organic layer was separated. The aqueous layer was
extracted with ethyl acetate (2×20mL) and combined
organic extract was washed with brine solution. The
organic layer thus obtained was dried over anhydrous
Na2SO4 and the solvent evaporated to give crude
product. The crude product was purified by column
chromatography over silica gel (230-400 mesh) with
petroleum ether-EtOAC as eluent which gave the pure
bromohydrin.
Spectroscopic Data
Ethyl 2-bromo-3-hydroxy-3-phenyl propanoate,
1b: White solid m.p. 76-78°C [ Lit.9f 76-77°C]; IR
(KBr): 3450, 2979, 2930, 1719, 1599, 1430, 1285,
1020 cm-1; 1H NMR (CDCl3, 300 MHz): δ 1.28 (t, J =
6 Hz, 3H), 4.22 – 4.29 (q, J = 2 HZ, 2H), 4.36 – 4.38
(d, J = 9.6Hz, 1H), 5.03 – 5.08 (m, 1H), 7.31 (m, 5H);
13
C NMR (CDCl3, 75 MHz): δ 13.7, 47.6, 62.2, 74.9,
126.8, 128.5, 138.9, 169.3.
LODH et al.: SYNTHESIS OF BROMOHYDRINS
1427
Table II — Synthesis of bromohydrin from various olefinsa
Entry
Olefin/ Styrene
(a)
Product
(b)
O
1
O
OH
Time (h)
Yieldb (%)
1
79
1.5
72
3
72
2.5
67
1.3
83
1.5
75
2
67
2
78
1.5
76
1
85
1
81
OEt
OEt
Br
O
2
OH
O
OMe
OMe
MeO
Br
MeO
Cl
Cl
O
3
OH
O
OMe
OMe
Br
O
OH
O
4
OMe
OMe
Br
OMe
CH3O
O
5
OH
O
OMe
MeO
OMe
Br
MeO
OH
6
Ph
Ph
Ph
Ph
Br
O
7
O
OH
Br
Cl
Cl
OH
8
Br
OH
9
Cl
Br
Cl
OH
10
Br
OH
11
Br
a
Reaction condition: olefin (1 mmol); NBS (1.2 mmol), I2 (0.1 mmol), MeCN-H2O (4:1, 5 mL); bIsolated yield.
INDIAN J. CHEM., SEC B, NOVEMBER 2014
1428
I2
O
R1
N
Br
OH
H2O:
R1
+
2
R2
R
R2
R1
Br
+
Br
O
Scheme II — Plausible mechanism of iodine catalyzed bromohydrin formation
Methyl 2-bromo-3-chloro-4-methoxy phenyl-3hydroxy propanoate, 2b: Yellow Oil; IR (KBr): 3460,
2960, 1701, 1601, 1435, 1268, 1198, 1062, 987, 537
cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.70 (s, 3H), 3.73
(s, 3H) 4.23 (d, J = 9 Hz, 1H), 4.9 (d, J = 8.7 Hz, 1H),
6.84 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.4Hz, 1H), 7.34
(s, 1H); 13C NMR (CDCl3, 75 MHz): δ 14.1,
21.0, 47.7, 53.3, 56.1, 74.0, 111.7, 122.2, 128.8, 132.4,
154.9.
Methyl 2-bromo-3-hydroxy-3-phenyl propanoate,
3b: White solid; m.p. 64-65°C [Lit.9f 63°C]; IR (KBr):
3466, 2954, 2916, 1732, 1595, 1442, 1280, 1022 cm-1;
1
H NMR (CDCl3, 300 MHz): δ 3.76 (s, 3H), 4.35 (d,
J = 8.7 Hz, 1H), 5.01-5.1 (m, 1H), 7.33-7.42 (m, 5H);
13
C NMR (CDCl3, 75 MHz): δ 47.4, 53.0, 74.9, 126.9,
128.3, 128.6, 138.9, 169.8.
Methyl 2-bromo-3-hydroxy-3-(3-methoxy phenyl)propanoate, 4b: White solid; m.p. 75-77°C; IR (KBr):
3450, 2970, 1708, 1602, 1440, 1260, 1195, 1055, 534
cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.82 (s, 6H), 6.36
(d, J = 15.9 Hz, 1H), 6.7–6.89 (m, 1H), 7.09–7.10 (m, 1H),
7.47 (d, 9 HZ, 1H), 7.9 (d, 15.9 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): δ 51.7, 55.3, 112.3, 117.4, 120.5,
133.8, 143.0, 158.8, 166.6.
Methyl 2-bromo-3-hydroxy-3-(4-methoxyphenyl)
propanoate, 5b: White solid; m.p. 59°C [Lit.9f 5960°C]; IR (KBr): 3440, 2950, 1715, 1600, 1430,
1265, 1195, 1065, 535 cm-1; 1H NMR (CDCl3, 300
MHz): δ 3.55-3.82 (m, 6H), 4.21-4.35 (m, 1H), 4.825.0 (m, 1H), 6.86 (d, J = 6Hz, 2H), 7.26 (d, J = 6Hz,
2H); 13C NMR (CDCl3, 75 MHz): δ 47.7, 53.0, 55.0,
74.5, 113.7, 128.1, 131.1, 159.5, 169.8.
2-Bromo-1, 2-diphenylethanol, 6b: White solid;
m.p. 83-84°C [Lit.11a 83-84°C]; IR (KBr): 3440, 2950,
1597, 1430, 535 cm-1; 1H NMR (CDCl3, 300 MHz): δ
2.47 (br, s, 1H), 5.1 (d, J = 6 Hz, 1H), 5.21 (d, J = 6H13
C NMR (CDCl3, 75
Z, 1H), 7.26-7.62 (m, 10H);
MHz): δ 56.8, 78.0, 127.8, 128.1, 128.4, 128.7, 128.8,
128.9, 139.6, 139.9.
2-Bromo-3-(4-chloro-phenyl)-3-hydroxy-1-phenylpropan-1-one, 7b: White solid; m.p. 95°C [Lit.11b
96°C ]; IR (KBr): 3440, 2950, 1715, 1597, 1430,
1065, 987, 535 cm-1; 1H NMR (CDCl3, 300 MHz): δ
3.5 (bs, 1H), 5.14 (d, J = 8.5Hz, 1H), 5.32 (d, J =
8.1 Hz, 1H), 7.21-7.69 (m, 7H), 8.02 (d, J = 7.2 HZ,
2H); 13C NMR (CDCl3, 75 MHz): δ 47.7, 74.0, 128.7,
128.8, 129.04, 134.3, 134.4, 137.9, 194.4.
2-Bromo-1-phenylethanol, 8b: Thick oil; IR
(neat): 3408, 2935, 2952, 1600, 1460, 1062, 708 cm-1;
1
H NMR (CDCl3, 300 MHz): δ 3.1 (bs, 1H), 3.513.67 (m, 2H), 4.90-4.95 (m, 1H), 7.26-7.39 (m, 5H);
13
C NMR (CDCl3, 75 MHz): δ 40.7, 73.8, 125.9,
128.5, 128.7, 140.1.
2-Bromo-1-(4-chlorophenyl)ethanol, 9b: White
solid, m.p. 61-63°C. (lit.9g 61-62°C). IR (neat): 3430,
2945, 1594, 1445, 1068, 743 cm-1; 1H NMR
(300 MHz, CDCl3): δ 2.84 (bs, 1 H), 3.47-3.62 (m, 2
H), 4.83-4.91 (m, 1 H), 7.25-7.37 (m, 4 H); 13C NMR
(75 MHz, CDCl3): δ 40.5, 73.5, 126.8, 129.1, 134.0,
139.1.
2-Bromo-2,3-dihydro-1H-inden-1-ol, 10b: White
solid; m.p. 124-125°C; IR (KBr): 3440, 2947, 1448,
565 cm-1; 1H NMR (CDCl3, 300 MHz): δ 3.15-3.2 (m,
1H), 3.5-3.62 (m, 1H), 4.2-4.30 (m, 1H), 5.27-5.32
(m, 1H), 7.15-7.5 (m, 4H); 13C NMR (CDCl3,
75 MHz): δ 40.5, 54.5, 83.4, 124.1, 124.6, 127.6,
129.0, 139.8, 141.7.
Bromo-1,2,3,4-tetrahydron phthalen-1-ol, 11b:
White solid; IR (KBr): 3440, 2947, 2924, 1587, 555
cm-1; 1H NMR (CDCl3, 300 MHz): δ 2.41-2.7 (m,
2H), 2.85-3.1 (m, 2H), 4.21-4.5 (m, 1H), 4.85-5.1 (m,
1H), 7.12-7.25 (m, 2H), 7.47-7.53 (m, 2H); 13C NMR
(CDCl3, 75 MHz): δ 28.1, 29.8, 56.3, 74.1, 126.8,
128.2, 128.6, 135, 135.5.
LODH et al.: SYNTHESIS OF BROMOHYDRINS
Acknowledgement
Financial Support from UGC, India (Grant No. 41206/2012-SR) is gratefully acknowledged. AJB
thanks CSIR for research fellowship.
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