Monatsh Chem (2010) 141:1093–1099
DOI 10.1007/s00706-010-0369-2
ORIGINAL PAPER
KHSO4: a highly efficient and reusable heterogeneous catalyst
for hydroarylation of styrenes
Rajendra D. Patil • Girdhar Joshi
Subbarayappa Adimurthy
•
Received: 15 December 2009 / Accepted: 3 August 2010 / Published online: 27 August 2010
Ó Springer-Verlag 2010
Abstract Hydroarylation of styrenes with arenes/heteroarenes using KHSO4 (10 mol%) as an efficient heterogeneous catalyst is described. High conversion and selectivity
([99%) were observed for hydroarylation of styrenes with
2-naphthol at reflux temperature of 1,2-dichloroethane.
Yields were quantitative with all styrenes. Moderate to
good conversions and selectivities were achieved with
other aromatics and heteroaromatics under the same conditions. Regeneration and reusability of KHSO4 were
demonstrated. Addition of a trace amount of water could
help to reactivate the KHSO4 through dispersion and to
facilitate the hydroarylation reaction.
Keywords KHSO4 Heterogeneous catalysis Hydroarylation Styrenes Aromatics
metal- and acid-catalyzed C–H transformations of arenes
and heteroarenes have been reported [1–6]. A number of
catalytic systems, including ruthenium [7–10], palladium
[11–17], platinum [18–20], nickel [21], and indium [22],
have been employed for functionalization of heterocycles
through carbon–carbon bond formation. Prominent systems, Bi(OTf)3 [23], BiCl3 [24], and FeCl3 [25] catalyzed
hydroarylation of styrenes were also reported for synthesis
of a variety of 1,1-diarylalkanes in good yields. Boronic
esters/acids with palladium complex [26], iodine [27], and
an ion-exchange resin [28] are recent developments in the
hydroarylation of alkenes. However, these methods require
use of stoichiometric or excess amounts of strong acids/
bases and air/moisture-sensitive organometallic reagents.
In most studies, the halide salts obtained as byproducts are
drawbacks of these reactions.
Introduction
Results and discussion
Functionalization of arenes and heteroarenes is of great
importance in synthesis of pharmaceuticals, and agro- and
fine chemicals; therefore, various procedures for their
acylation and alkylation have been reported. Transitionmetal-catalyzed hydroarylation of alkenes is of particular
importance due to its high selectivity, synthetic efficiency,
and environmental friendliness. Traditionally, these transformations are performed by Friedel–Crafts reactions with
acyl or alkyl halides in combination with at least equimolar
quantities of a Lewis acid. Recently, promising transition-
R. D. Patil G. Joshi S. Adimurthy (&)
Analytical Science Discipline, Central Salt and Marine
Chemicals Research Institute (CSIR), G. B. Marg,
Bhavnagar 364002, India
e-mail: [email protected]
In view of our ongoing quest for green and sustainable
processes for functionalization of alkenes [29–33] and
alkynes [34] for diverse applications, we envisioned a
metal-free catalyst system for hydroarylation of styrenes
with aromatic compounds in the presence of KHSO4
(10 mol%) as an efficient catalyst under mild conditions
(Scheme 1).
These reactions are particularly interesting from the
viewpoint of green chemistry because hydroarylation
exhibits perfect atom efficiency and relies on the use of
simple arene reactants and safe catalysts, no production of
toxic waste material, applicability of various substrates,
and heterogeneous catalysis, allowing facile catalyst/
product separation. Careful choice of inorganic acid, solvent, and reaction conditions enabled us to develop a
123
1094
R. D. Patil et al.
R
OH
+
R
Table 1 Screening of various catalysts and solvents for hydroarylation of styrene with b-naphthol
KHSO4 (10 mol%)
OH
DCE, Reflux
8h
OH
55-96%
1
Scheme 1
convenient protocol, which allows for efficient reaction of
various alkenes with various arene functionalities to give
the corresponding regioselectively alkylated product in a
number of cases.
Initially, to determine the optimum reaction conditions,
the reaction of b-naphthol (1) with styrene (2) using a
catalytic amount of KHSO4 and in different solvent media
was investigated, and the reaction progress and yield
were monitored by gas chromatography (GC) (Table 1).
The reaction of equimolar amount of 1 with 2 in 5 cm3
1,2-dichloroethane at reflux for 8 h in presence of 10 mol%
KHSO4 resulted in complete conversion to 3 (Table 1,
entry 1). GC and GC-mass spectrometry (GC–MS) analyses of the reaction mixture revealed 98% conversion of 1
to yield the arylated product 3 with more than 99%
selectivity. Use of excess amount of KHSO4 under the
same conditions resulted in less conversion and the formation of undesired products (Table 1, entries 2–4). When
neat reaction was carried out, it indeed gave [99% selective product 3, but led to less conversion (Table 1, entry 5).
Use of 10 mol% KHSO4 showed the highest catalytic
activity and selectivity for hydroarylation of styrene with
b-naphthol (Table 1, entry 1). Switching to other solvents
led to lower conversion and yields under these conditions
(Table 1, entries 6–10). Various other catalysts were also
applied to the hydroarylation reaction, but showed lower
catalytic activity and lower yield of the desired product
(Table 1, entries 11–17) than that of KHSO4.
The effect of temperature on the formation of 3 under
the conditions of Table 1 was also studied. This study
showed that, at room temperature and at 40 °C, there is no
conversion by GC analysis even when the reaction continued up to 15 h (Table 2, entries 1 and 2). However, at
60 °C, 9% conversion and 100% selectivity of the desired
product were observed (entry 3). At reflux temperature of
1,2-dichloroethane the best conversion and selectivity were
observed (entry 4). Therefore the rest of the experiments
were carried out under these optimized conditions.
The scope of the KHSO4-catalyzed hydroarylation
reactions of various styrenes with b-naphthol was examined under the optimized conditions, and results are
indicated in Table 3. The hydroarylation reaction of various styrenes having electron-donating substituents with
b-naphthol proceeded efficiently to give the corresponding
123
OH
Cat (mol%)
+
Solvent, Reflux
8h
2
3a
Entry Cat. (mol%)
Solvent
Conv. (%)a Yield (%)b Sel.c
1
KHSO4 (10)
DCE
98
100
[99:1
2
KHSO4 (12.5) DCE
93
100
[99:1
3
KHSO4 (50)
DCE
85
95
97:3
4
KHSO4 (100) DCE
84
100
93:7
5
KHSO4 (10)
Neat
63
100
100
6
KHSO4(10)
DCM
65
98
94:6
7
KHSO4 (10)
Cyclohexane 91
100
99:1
8
KHSO4 (10)
CH3CN
–
–
9
KHSO4 (10)
CH3OH
61
81
10
KHSO4 (10)
THF
–
–
11
NaHSO4 (10) DCE
88
99
98:2
12
13
HCl (10)
HCl (10)
DCE
Neat
77
91
95
100
98:2
89:11
14
H2SO4 (10)
DCE
56
97
11:89
15
HNO3 (10)
DCE
30
78
–
16
PTS
DCE
68
99
1:99
17
PTS
Neat
28
84
31:69
–
62:38
–
Reaction conditions: 3.5 mmol of 1, 3.5 mmol of 2, cat, 5 cm3 solvent/neat, reflux, 8 h
DCE 1,2-dichloroethane, DCM dichloromethane, PTS p-toluenesulfonic acid
a
GC conversions based on 1
b
GC yields of arylated products based on conversion
c
Selectivity determined by GC of 3a to others
arylated products in good to high yields with high
selectivity ([99:1) (Table 3, entries 1–3). However, hydroarylation reaction of b-naphthol with styrenes having electron-withdrawing substituents also offered high yields and
high selectivity (Table 3, entries 4 and 5), except with
4-acetoxystyrene (Table 3, entry 6) for which it gave product
3f with 93% selectivity, which may be due to the strong
electron-withdrawing property of the acetoxy group. All
products of Table 3 were formed with high selectivity
(except entry 6) of the desired product 3a–3f as determined
by 1H nuclear magnetic resonance (NMR) of the purified
products. Note that hydroarylation of various styrenes with
b-naphthol provided the desired product as major isomer with
all styrenes in excellent yields compared with the reported
procedures [33–35]. These facts indicate the efficiency,
selectivity, and catalytic activity of the present system.
KHSO4: a highly efficient and reusable heterogeneous catalyst
1095
Table 2 Effect of temperature on hydroarylation of styrene with
b-naphthol
100
98
85
83
82
1
2
3
OH
KHSO4 (10 mol%)
+
DCE, Reflux
1
2
3a
Conv. (%)
a
Temp. (°C)
Time (h)
1
RT
15
0
–
–
2
40
15
0
–
–
3
60
15
9
9
100
4
Reflux
8
98
98
[99:1
GC conversions based on 1
b
GC yields of arylated products
c
Selectivity determined by GC of 3a to others
Sel.
c
Entry
a
Yield (%)
b
OH
KHSO 4 (10 mol%)
DCE, Reflux
8h
R
1
2a-2f
Entry R
40
0
Fresh
No of Cycles
Fig. 1 KHSO4 recyclability chart
R
+
60
20
Table 3 Hydroarylation of different styrenes with b-naphthol
OH
Conversion / %
80
OH
3a-3f
Time Product Yield Selectivityb Referencec
(h)
(%)a
1
–H
8.0
3a
96
[99:1
2
–CH3
7.0
3b
93
99:1
3
–t-Bu
6.0
3c
88
99:1
4
–Br
5.0
3d
93
98:2
5
–Cl
8.0
3e
94
96:4
6
–OCOCH3 8.0
3f
73
93:7
[28]
Reaction conditions: 3.5 mmol of 1, 3.5 mmol of 2a–2f, 5 cm3 DCE
a
Isolated yields
b
Determined by 1H NMR of desired product to other isomer
c
Identity confirmed by comparison of spectroscopic data
To assess the reusability of KHSO4, after completion of
the reaction, the KHSO4 was retrieved from the reaction
mixture by simple filtration, dried, and recycled under
the same experimental conditions, but GC analysis showed
no formation of hydroarylated product. Furthermore, to
corroborate the reusability of the catalyst, another reaction
was carried out by the addition of a trace amount of water
(through a syringe) to the recovered catalyst under the
same conditions; GC analysis showed 85% conversion with
97% selectivity of the desired product (Fig. 1). This suggests that the hydrated form of the catalyst is active for this
transformation. Although a small amount of water was
beneficial for recycling the catalyst (KHSO4), when the
reaction was tested without KHSO4, on the addition of a
drop of water no product was detected by GC–MS analysis.
This fact helps to rule out the contribution of H2O alone
to promote the hydroarylation reactions. In another set of
recycling of KHSO4, when D2O was added instead of H2O,
no deuterated product was detected, however the desired
hydroarylated product was obtained. We reasoned that a
trace amount of water could help to disperse the KHSO4 to
facilitate the hydroarylation reaction [35].
As can be evidenced from the scanning electron
microscope (SEM) images (Fig. 2) of fresh and recovered
KHSO4, the fresh KHSO4 is surrounded by a number of
H2O molecules, which is not the case for the recovered
KHSO4. The surrounding water molecules help the dispersion of the catalyst, and thus activate the hydroarylation
reaction.
As evident from the recyclability chart of KHSO4
(Fig. 1), the catalyst could be easily recovered and reused
for up to three consecutive cycles with good conversions. Therefore a reaction mechanism for electrophilic
substitution of styrenes with 2-naphthol is proposed in
Scheme 2.
To explore the scope and limitations of the present catalytic procedure, representative examples of functionalized
aromatic and heteroaromatic compounds were treated with
styrene and substituted styrenes, and the results are summarized in Table 4.
As shown in Table 4, various substituted styrenes
reacted smoothly with a-naphthol to give corresponding
hydroarylated products in 48–72% isolated yields with
90–98% selectivity (Table 4, entries 1–3). The reaction of
phenol with t-butylstyrene (Table 4, entry 4) and styrene
(Table 4, entry 5) gave moderate yields (43% and 42%) of
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1096
R. D. Patil et al.
Fig. 2 Scanning electron
microscope (SEM) images
of KHSO4 catalyst
K2SO4 + HSO4- + H+
2 KHSO4
+
H+
R
O-H
R
OH
H
OH
Experimental
+
-H
R
R
Scheme 2
hydroarylated product with high selectivity ([99:1) in the
former case. The same trend is observed in the reaction of
p-cresol with methylstyrene and t-butylstyrene (Table 4,
entries 6 and 7), but with good yields. The relatively low
yield of thiophene with styrene is due its lower reactivity
compared with naphthols and phenols under the present
conditions (Table 4, entry 8). However, the reaction of 2methythiophene with t-butylstyrene gave the corresponding
hydroarylated product in good yield with high selectivity
(Table 4, entry 9).
Conclusions
Herein we describe a general, mild, and efficient method for
hydroarylation of styrenes with various aromatics and heteroaromatics using KHSO4 (10 mol%) as a highly efficient
and selective heterogeneous catalyst. Styrenes with electron-donating substituents showed higher selectivity for the
hydroarylation reaction than those with electron-withdrawing substituents. KHSO4 could be recovered and reused up
to a minimum of three consecutive cycles with good
123
conversion under the conditions studied. The present catalytic system has remarkable advantages such as: good
activity and selectivity in a number of cases, no need to
maintain dry or inert atmospheric conditions, ready availability, low cost, and recoverable and reusable catalyst, and
importantly, it does not generate any toxic waste. This
simple procedure offers a very attractive alternative for
synthesis of motifs that are found in various bioactive
molecules.
All products from Table 1 were analyzed by GC–MS using
a Shimadzu GCMS-QP2010. Gas chromatograms of compounds listed in Table 1 were recorded on a Thermo Trace
GC Ultra using HP-5 column. 1H and 13C NMR spectra
were recorded on a spectrometer operating at 500 and
125 MHz, respectively, in CDCl3 unless otherwise stated.
Chemical shifts are reported in ppm relative to the appropriate standard tetramethylsilane (TMS). Fourier-transform
infrared (FT-IR) spectra were recorded on a Perkin Elmer
GX-2000 spectrometer. Mass spectra were recorded on a
micromass Q-Tof microTM in ES? mode. Analytical thinlayer chromatography (TLC) was performed on Aluchrosep Silica Gel 60/UV254 plates. Purification of compounds
(Tables 3, 4) was carried out by column chromatography
using 100–200 mesh silica gel. All reactions were carried
out in air without any special precautions. Unless otherwise
stated, all reactions were carried out in an oil bath with
magnetic stirring, and yield refers to isolated yields in
Tables 3 and 4. Scanning electron microscope (SEM, LEO
1430 UP model) was used to observe the morphology of
KHSO4 before and after reaction.
General procedure for hydroarylation of styrenes
All reactions were carried out in air without any special
precautions. To a stirred solution of 1 or 4 (3.5 mmol) and
substituted styrene (3.5 mmol) in 5 cm3 1,2-dichloroethane
KHSO4: a highly efficient and reusable heterogeneous catalyst
1097
Table 4 Hydroarylation of styrenes with arenes and heteroarenes
R
KHSO4 (10 mol%)
Ar(Hetero)H +
R
4a-4e
4a = 1-Naphthol
4b = Phenol
4c = 4-Me-phenol
4d = Thiophene
4e = 2-Me-thiophene
Entry
4
DCE, Reflux
8-24 h
2a-2e
2
Ar(Hetero)
5a-5i
5a Ar = 1-HO-2-naphthyl, R = H
5b Ar = 1-HO-2-naphthyl, R = Cl
5c Ar = 1-HO-2-naphthyl, R = Br
5d Ar = 2-HO-phenyl, R = t-Bu
5e Ar = 2-HO-phenyl, R = H
2a R = H
2b R = CH3
2c R = t-Bu
2d R = Br
2e R = Cl
Time (h)
5
5f Ar = 2-HO-5-Me-phenyl, R = CH 3
5g Ar = 2-HO-5-Me-phenyl, R = t-Bu
5h Ar = 2-Thienyl, R = CH3
5i Ar = 5-Me-2-thienyl, R = t-Bu
Yield (%)a
Selectivityb
Referencec
[28]
1
4a
2a
8
5a
72
91:9
2
4a
2e
12
5b
67
90:10
3
4a
2d
24
5c
48
98:2
4
4b
2c
14
5d
43
[99:1
5
4b
2a
15
5e
42
77:23
6
4c
2b
10
5f
72
68:32
7
4c
2c
10
5g
73
70:30
8
4d
2b
15
5h
33
73:27
9
4e
2c
14
5i
53
[99:1
[27]
[27]
Reaction conditions: 3.5 mmol of 4a–4e, 3.5 mmol of 2a–2e, 10 mol% KHSO4, 5 cm3 DCE, 80 °C, 8 h
a
Isolated yield
b
Determined by 1H NMR of purified main product to other isomer
c
Identity confirmed by comparison of spectroscopic data
(DCE), 47.0 mg commercially available KHSO4 (10 mol%)
was added. The mixture was allowed to reflux at 80 °C for
8 h. The progress of the reaction was monitored by TLC.
The reaction mixture was cooled to room temperature
and filtered to remove KHSO4. The KHSO4 was washed
with 5 cm3 DCE, and the filtrate was concentrated in vacuo.
The residue was subjected to column chromatography on
silica gel (hexane–ethyl acetate) to obtain pure hydroarylated products.
1-(1-Phenylethyl)-2-naphthol (3a, C18H16O)
Brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.91 (s, 3H), 5.23 (s, 1H), 5.31 (q, J = 7.0 Hz, 1H),
7.1 (d, J = 9.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.44
(q, J = 8.0 Hz, 3H), 7.51 (d, J = 7.51 Hz, 2H), 7.56
(t, J = 8.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.91 (d,
J = 8.0 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H) ppm; 13C NMR
(125 MHz, CDCl3): d = 18.9, 36.5, 121.0, 124.6, 124.8,
125.6, 128.3, 128.4, 128.9, 130.4, 130.6, 130.7, 131.5,
134.6, 145.6, 153.2 ppm; IR (neat): m = 3,499, 3,059,
3,026, 2,969, 2,934, 2,876, 1,661, 1,623, 1,601, 1,512,
1,448, 1,374, 1,260, 1,210, 1,147, 1,075, 1,025, 933, 855,
813, 751, 701, 587, 529, 504, 450 cm-1; GC–MS:
m/z (%) = 248 (100) [M?], 233 (92), 215 (72), 203 (20),
189 (10), 115 (28), 77 (18), 63 (7); LRMS: calcd 248.12,
found 248.15.
1-[1-(4-tert-Butylphenyl)ethyl]-2-naphthol
(3c, C22H24O)
Reddish-brown viscous liquid. 1H NMR (500 MHz,
CDCl3): d = 1.21 (s, 9H), 1.67 (d, J = 7.0 Hz, 3H), 4.88
(s, 1H), 5.03 (q, J = 7.0 Hz, 1H), 6.90 (d, J = 8.5 Hz,
1H), 7.25 (m, 5H), 7.38 (t, J = 8.0 Hz, 1H), 7.57 (d,
J = 8.5 Hz, 1H), 7.70 (d, J = 8.0 Hz 1H), 7.98 (d,
J = 5.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 17.2, 31.3, 34.5, 119.5, 122.5, 123.1, 123.8, 126.1,
126.6, 126.9, 128.7, 128.9, 129.7, 132.9, 140.1, 149.9,
151.7 ppm; IR (neat): m = 3,452, 3,056, 2,959, 2,872,
1,664, 1,602, 1,511, 1,463, 1,393, 1,366, 1,261, 1,206,
1,148, 1,019, 932, 813, 749, 687, 559, 429 cm-1; GC–MS:
m/z (%) = 304 (100) [M?], 289 (95), 247 (40), 233 (30),
215 (25), 170 (60), 161 (15), 144 (27), 130 (15), 123 (38),
103 (18), 91 (12), 77 (8), 65 (3); LRMS: calcd 304.18,
found 304.28.
1-[1-(4-Bromophenyl)ethyl]-2-naphthol
(3d, C18H15BrO)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.68 (d, J = 7.0 Hz, 3H), 4.85 (s, 1H), 5.07 (q,
J = 7.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 7.13 (t, J = 7.0
Hz, 1H), 7.22 (q, J = 7.5 Hz, 3H), 7.27 (d, J = 7.5 Hz, 2H),
7.34 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.68 (d,
J = 8.0 Hz 1H), 7.92 (d, J = 8.5 Hz, 1H) ppm; 13C NMR
123
1098
(125 MHz, CDCl3): d = 17.2, 34.9, 119.4, 122.7, 123.1,
123.9, 126.6, 126.8, 127.2, 128.7, 128.9, 129.1, 129.7,
132.9, 143.8, 151.5 ppm; IR (neat): m = 3,397, 3,028, 2,998,
2,922, 2,837, 1,610, 1,510, 1,457, 1,369, 1,298, 1,246,
1,176, 1,109, 1,034, 827, 742, 688, 547, 419 cm-1; GC–MS:
m/z (%) = 326 (56) [M?], 311 (52), 293 (3), 231 (55), 215
(12.5), 202 (25), 170 (100), 141 (15), 128 (2.5), 116 (27),
101 (35), 89 (12.5), 77 (13); LRMS: calcd for C18H15BrO
[K?] 364.99, found 364.33.
1-[1-(4-Chlorophenyl)ethyl]-2-naphthol
(3e, C18H15ClO)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.69 (d, J = 7.0 Hz, 3H), 4.86 (s, 1H), 5.03 (q,
J = 7.5 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 7.17 (m, 4H),
7.23 (t, J = 7.5 Hz, 1H) 7.32 (t, J = 7.5 Hz, 1H), 7.57 (d,
J = 8.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.84 (d,
J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 17.4, 34.3, 119.0, 123.0, 123.2, 123.4, 126.6, 128.5,
128.82, 128.88, 128.9, 129.8, 132.1, 132.7, 142.8,
151.2 ppm; IR (neat): m = 3,487, 3,058, 2,962, 2,873,
1,622, 1,511, 1,462, 1,395, 1,365, 1,260, 1,205, 1,149,
1,018, 932, 812, 745, 689, 592, 468 cm-1; GC–MS:
m/z (%) = 282 (98) [M?], 267 (100), 249 (18), 231 (47),
215 (15), 170 (19), 139 (20), 116 (27), 101 (35), 88 (12), 77
(13), 63 (7); LRMS: calcd for C18H15ClO [Na?] 305.07,
found 305.20.
4-[1-(2-Hydroxy-1-naphthyl)ethyl]phenyl acetate
(3f, C20H18O3)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.77 (d, J = 7.0 Hz, 3H), 2.25 (s, 3H), 5.12 (q,
J = 7.5 Hz, 1H), 5.20 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H),
7.0 (d, J = 8.5 Hz, 2H), 7.31 (m, 3H), 7.40 (t, J = 7.0 Hz,
1H), 7.62 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H),
7.96 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 17.5, 21.1, 34.3, 119.1, 121.7, 123.0, 123.6,
126.5, 128.2, 128.7, 128.8, 129.7, 132.8, 141.9, 149.0,
151.4, 169.9 ppm; IR (neat): m = 3,434, 3,057, 2,966,
2,930, 1,739, 1,666, 1,625, 1,506, 1,436, 1,369, 1,199,
1,167, 1,017, 913, 848, 814, 744, 522, 463, 422 cm-1;
GC–MS: m/z (%) = 306 (5) [M?], 264 (100), 249 (89), 231
(52), 171 (85), 115 (48), 101 (29), 94 (13), 77 (18), 65 (12);
LRMS: calcd for C20H18O3 [Na?] 329.12, found 329.13.
2-[1-(4-Chlorophenyl)ethyl]-1-naphthol
(5b, C18H15ClO)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.6 (d, J = 7.0 Hz, 3H), 4.0 (q, J = 7.0 Hz, 1H), 5.1
(s, 1H), 7.1 (d, J = 8.5 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H),
7.3 (d, J = 8.0 Hz, 2H), 7.4 (t, J = 4.5 Hz, 2H), 7.7 (t,
J = 5.5 Hz, 2H), 8.0 (d, J = 8.5 Hz, 2H) ppm; 13C NMR
(125 MHz, CDCl3): d = 21.0, 38.2, 120.8, 121.0, 124.9,
123
R. D. Patil et al.
125.2, 125.6, 125.7, 125.9, 127.8, 128.9, 132.4, 133.5,
143.7, 148.1 ppm; IR (neat): m = 3,538, 3,059, 2,970,
2,932, 2,875, 1,659, 1,576, 1,490, 1,389, 1,262, 1,198,
1,090, 1,055, 1,016, 895, 820, 784, 749, 566, 542 cm-1;
GC–MS: m/z (%) = 282 (86) [M?], 267 (90), 249 (10),
231 (32), 215 (8), 202 (28), 170 (100), 141 (23), 115 (25),
101 (33), 89 (10), 77 (15); LRMS: calcd 282.08, found
282.85.
2-[1-(4-Bromophenyl)ethyl]-1-naphthol
(5c, C18H15BrO)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.6 (d, J = 7.5 Hz, 1H), 4.4 (q, J = 7 Hz, 1H), 5.1 (s,
1H), 7.1 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.5 Hz, 1H), 7.3
(d, J = 8.5 Hz, 2H), 7.4 (m, 2H), 7.7 (m, 1H), 8.0 (t,
J = 9.5 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d = 21.0, 38.4, 120.6, 120.9, 121.0, 124.9, 125.1, 125.71,
125.75, 126.0, 127.9, 129.4, 132.0, 133.5, 144.2,
148.1 ppm; IR (neat): m = 3,504, 3,059, 2,969, 2,871,
1,657, 1,573, 1,491, 1,352, 1,150, 1,016, 811, 786, 618,
450, 422 cm-1; GC–MS: m/z (%) = 326 (55) [M?], 311
(53), 293 (3), 231 (55), 215 (13), 202 (25), 170 (100), 141
(15), 128 (3), 116 (28), 101 (35), 89 (13), 77 (13); LRMS:
calcd 326.03, found 326.75.
2-[1-(4-tert-Butylphenyl)ethyl]phenol (5d, C18H22O)
Dark-brown viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.3 (s, 9H), 1.4 (d, J = 7 Hz, 2H), 3.6 (t, J = 6.5 Hz,
1H), 6.3 (m, 1H), 6.4 (d, J = 15.5 Hz, 2H), 7.2 (m, 2H),
7.3 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3): d = 22.8,
32.9, 43.6, 126.9, 127.0, 127.4, 128.5, 129.6, 136.3, 136.5,
144.3, 151.6 ppm; IR (neat): m = 3,413, 3,059, 3,019,
2,958, 2,869, 1,583, 1,511, 1,474, 1,447, 1,364, 1,270,
1,201, 1,098, 1,022, 820, 739, 693, 563, 479 cm-1;
GC–MS: m/z (%) = 254 (38) [M?], 239 (100), 223 (8),
197 (25), 181 (8), 165 (5), 121 (20), 98 (25), 91 (13), 77
(8); LRMS: calcd for C18H22O [–1] 253.17, found 252.83.
4-Methyl-2-[1-(4-methylphenyl)ethyl]phenol
(5f, C16H18O)
Colorless viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.58 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 2.29 (s, 3H),
4.27 (q, J = 7.0 Hz, 1H), 4.61 (s, 1H), 6.61 (d, J = 8.0 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.08 (d,
J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H) ppm; 13C NMR
(125 MHz, CDCl3): d = 20.9, 21.1, 21.2, 38.5, 116.0,
127.5, 127.9, 128.6, 129.5, 130.0, 131.9, 136.1, 142.4,
151.2 ppm; IR (neat): m = 3,502, 3,433, 3,021, 2,968,
2,926, 2,870, 1,611, 1,503, 1,457, 1,372, 1,328, 1,257,
1,190, 1,117, 1,047, 815, 781, 730, 511, 469, 419 cm-1;
GC–MS: m/z (%) = 226 (65) [M?], 211 (100), 196 (18),
134 (50), 105 (8), 91 (18), 77 (12), 65 (7); LRMS: calcd
226.14, found 226.24.
KHSO4: a highly efficient and reusable heterogeneous catalyst
2-[1-(4-tert-Butylphenyl)ethyl]-4-methylphenol
(5g, C19H24O)
Colorless viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.28 (s, 9H), 1.60 (d, J = 7.0 Hz, 3H), 2.28 (s, 3H),
4.28 (q, J = 6.5 Hz, 1H), 4.56 (s, 1H), 6.64 (d, J = 7.5 Hz,
1H), 6.90 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 7.17 (d,
J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H) ppm; 13C NMR
(125 MHz, CDCl3): d = 22.4, 22.6, 33.0, 36.0, 40.0,
127.2, 128.7, 129.4, 130.1, 131.5, 133.4, 143.6, 150.8,
152.7 ppm; IR (neat): m = 3,438, 2,963, 2,927, 1,632,
1,507, 1,383, 1,264, 1,114, 1,020, 669, 620, 421 cm-1;
GC–MS: m/z (%) = 268 (42) [M?], 253 (100), 211 (15),
197 (14), 134 (9), 105, 91 (15), 77 (11), 65 (8); LRMS:
calcd 268.18, found 268.24.
2-[1-(4-tert-Butylphenyl)ethyl]-5-methylthiophene
(5i, C17H22S)
Colorless viscous liquid. 1H NMR (500 MHz, CDCl3):
d = 1.2 (s, 9H), 1.5 (d, J = 7.0 Hz, 3H), 2.3 (s, 3H), 4.1
(q, J = 7 Hz, 1H), 6.5 (d, J = 3 Hz, 1H), 7.1 (d, J = 8 Hz,
2H), 7.2 (d, J = 8 Hz, 2H) ppm; 13C NMR (125 MHz,
CDCl3): d = 15.3, 23.2, 31.3, 31.4, 40.4, 42.0, 123.1,
124.4, 125.3, 125.8, 126.8, 126.9, 128.0, 134.7, 137.8,
143.1 ppm; IR (neat): m = 3,055, 3,024, 2,964, 2,870,
1,656, 1,511, 1,456, 1,405, 1,365, 1,266, 1,109, 1,018, 831,
800, 671, 572, 463, 419 cm-1; GC–MS: m/z (%) = 258
(48) [M?], 243 (100), 228 (18), 213 (13), 201 (8), 187 (3),
152 (3), 125 (8), 100 (25), 91 (5), 77 (3); LRMS: calcd for
C17H22S [-1] 257.14, found 256.91.
Acknowledgments We thank DST, New Delhi, India for the financial
support of this project under the Green Chemistry Task Force Scheme
(no. SR/S5/GC-02A/2006). We would like to acknowledge Mr. Hitesh,
Mr.V. K. Aggrawal, Mr. Harshad/Miss. Daksha, Mr. A. K. Das and Mr.
Jayesh of this institute for their help in analyzing NMR, IR, GC/GC-MS,
LC-MS and SEM, respectively. R. D. Patil and G. Joshi are thankful to
CSIR, New Delhi, India for the award of their Senior Research
Fellowships.
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123
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DOI: 10.1002/adsc.201100100
Copper-Catalyzed Aerobic Oxidation of Amines to Imines under
Neat Conditions with Low Catalyst Loading
Rajendra D. Patila and Subbarayappa Adimurthya,*
a
Analytical Science Division, Central Salt & Marine Chemicals Research Institute (CSIR), G.B. Marg, Bhavnagar –
364002, India
Fax: (+ 91)-278-256-7562; e-mail: [email protected]
Received: February 9, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100100.
Abstract: The copper (I)-catalyzed direct synthesis
of imines from amines under mild aerobic conditions is described. The method is applicable for the
synthesis of various imines from corresponding
amines such as benzylic, aliphatic, cyclic secondary,
heteroaromatic species and the oxidative condensation of benzylamines with anilines extends the
scope of the CuCl catalytic system. Noteworthy, solvent-free procedure, air as a benign oxidant, and
the cheap and easy availability of the catalyst are
the vital advantages of the method.
Keywords: copper; homogeneous catalysis; imines;
oxidation; synthetic methods
Imines are important intermediates in the synthesis of
various biologically active nitrogen-containing heterocyclic compounds and industrial synthetic processes.[1]
Significant progress has been made in recent years for
the synthesis of imines, including the direct synthesis
of imines from amines and alcohols in the presence of
catalyst,[2] self-condensation of primary amines with
oxidant[3] and oxidation of secondary amines.[4] Most
of these reactions were performed under solvent conditions. However, no attempts were made for the synthesis of imines by the direct oxidation of primary
amines to the corresponding imines under neat conditions, probably due to the rapid dehydrogenation of
imines to nitriles in solvent media.[5]
Notably, most of the applications are based on complexes of precious metals such as palladium, ruthenium, gold and vanadium. The limited availability of
these metals and their high price makes it highly desirable to search for more economical and environmental-friendly alternatives. Thus, the selective, catalytic synthesis of benzylimines directly from primary
Adv. Synth. Catal. 2011, 353, 1695 – 1700
benzylamines under relatively mild and neat conditions without producing waste is highly desirable economically and environmentally.
We recently reported a selective oxidation of various alcohols to the corresponding carbonyl compounds[6] with a mild and selective oxidizing agent
(BrOH) generated in-situ from the bromide/bromate
couple in aqueous acidic medium [Eq. (1)].[7]
When the same species (BrOH) is used for the oxidation of benzylamine to the imine, lower yields were
obtained under aqueous conditions.[8] Based on these
results we hypothesized that a related halogen species
under non-aqueous conditions may possibly provide
high selectivity for this transformation. To our delight,
we found that copper catalysts function well in this
context. Herein, we demonstrate a novel approach to
the direct synthesis of imines from readily available
benzylamines, under mild conditions using an inexpensive and commercially available copper catalyst
and air as an oxidant [Eq. (2)]. To the best of our
knowledge this is the first convenient catalytic process
ever reported for efficient syntheses of imines from
benzylamines using air as the oxidant under neat conditions with low catalyst loadings.
During our studies we examined the synthesis of
imine (2a) using the copper-catalyzed aerobic oxidative imination of benzylamine under mild and solvent-free conditions (Table 1). Employment of
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Rajendra D. Patil and Subbarayappa Adimurthy
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Table 1. Optimization of the conditions for the copper-catalyzed oxidation of 1.[a]
Entry Catalyst [mol%] Conversion
[%]
Yield
[%][b]
Selecivity
[%]
1
2
3
4
5
6
7
8
9
10
53
100
100
–
68
40
91
–
77
100
52
> 99
> 99
–
68
34
85
–
77
27
98
100
100
–
100
85
93
–
100
27
100
78
88
22
97
89
73
83
22
78
89
94
94
100
80
81
72
89
31
48
31
47
100
98
92
23
83
23
89
100
11
12
13
14
15
16
17
18
19[e]
20[f]
[a]
[b]
[c]
[d]
[e]
[f]
CuCl [0.2]
CuCl [0.5]
CuCl [1.0]
CuCl [0.5][c]
CuCl [0.5][c]
CuCl [0.5][d]
CuCl [0.5][d]
no catalyst
CuCl2 [0.5]
CuACHTUNGRE(ClO4)2·5 H2O
[0.5]
CuI [0.5]
CuBr [0.5]
CuBr2 [0.5]
CuF2 [0.5]
CuACHTUNGRE(OAc)2·H2O
[0.5]
CuACHTUNGRE(NO3)2·3 H2O
[0.5]
CuO [0.5]
CuSO4·5 H2O
[0.5]
CuCl [0.5]
CuCl [0.5]
Reaction conditions: benzylamine 1 (9.3 mmol), catalyst,
T = 100 8C, open air atmosphere; time = 18 h ( unless otherwise stated).
Yield based on GC area%.
Reaction carried out at room temperature (entry 4) and
at 60 8C (entry 5).
Reactions carried out in toluene (entry 6) and THF
(entry 7) as solvents.
Reaction performed under an oxygen atmosphere (balloon).
Reaction performed under an argon atmosphere.
0.5 mol% of copper(I) chloride as a catalyst under
neat conditions is the key step for the high efficiency
of this transformation (Table 1, entries 1 and 2). No
reduction of reaction time was observed when catalyst
loading was increased to 1 mol% (Table 1, entry 3).
Also no reaction occurred at room temperature, however at 60 8C, 68% conversion was observed (Table 1,
entries 4 and 5). Furthermore, no improvements were
observed when the reaction was carried out in toluene
and THF (Table 1, entries 6 and 7). The reaction does
not proceed without the catalyst (Table 1, entry 8).
Attempts were made to use copper halides and other
copper catalysts but they were not efficient to achieve
the required conversion and selectivity (Table 1, en1696
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tries 9–18). After extensive screening of various
copper catalysts, it was discovered that 0.5 mol% copper(I) chloride at 100 8C under air were the optimized
reaction conditions for the present investigation
(Table 1, entry 2).
Under these optimized conditions, various imines
were produced from their corresponding benzylamines. The results in Table 2 demonstrate that this reaction has a high degree of functional group tolerance. Both electron-rich (para, meta, and ortho substituted) and electron-deficient substrates were well tolerated and produced moderate to excellent yields. It
is noteworthy that halo-substituted benzylamines performed well, leading to halo-substituted imine compounds (Table 2, entries 5–10), which could be used
for further transformations along with the imine functionality. Furthermore, it should be noted that with
the use of a more than stoichiometric amount of gold
catalyst (2.5 equiv. referred to substrate) only a 7%
yield of 2h was reported.[9] However, under our conditions using copper(I) chloride as catalyst (0.005 equiv.
referred to substrate) the same product 2h could be
obtained in 90% yield (Table 2, entry 8). Furthermore, we admit that the isolated products of Table 2
indicate the presence of some aldehyde that could be
due to hydrolysis of the imine during work-up.[5e] This
is also evidenced from Table 1, when the crude mixture was analyzed by GC-MS, it showed only imine
with no evidence for the formation of aldehyde.
The successful transformation of benzylamines into
the corresponding imines under neat conditions with
such a low catalyst loading (0.5 mol%) prompted us
to investigate the generality of this method for the
synthesis of other imines with various amine substrates (Table 3). To our delight, we found this transformation to be very general for a wide range of
amines such as dibenzylamine (Table 3, entry 1),
cyclic secondary amines (Table 3, entries 2 and 3), a
heteroaromatic amine (Table 3, entry 4) and an aliphatic amine (Table 3, entry 5) as substrates and produced the corresponding imines in good yields. In the
case of pyridin-2-ylmethanamine, 60% of picolinamide also obtained in addition to the desired imine
(Table 3, entry 4) which is apparent according to the
literature.[3c] However, the conversion products of
cyclic amines[10] (Table 3, entries 2 and 3) and n-hexylamine (Table 3, entry 5) could be obtained in good
yields under the present reaction conditions but are
reported to be unaffected even with metal organic
framework solid catalytst.[3c]
By using the newly established protocol, we attempted the synthesis of unsymmetrically substituted
imines. Thus, syntheses of unsymmetrical imines 5
were carried out by reacting benzylamine 1a with different anilines 4a–e, 3-methyl-2-aminopyridine 4f and
the aliphatic amine 4g under neat conditions
(Table 4). Anilines bearing electron-releasing and
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1695 – 1700
Copper-Catalyzed Aerobic Oxidation of Amines to Imines under Neat Conditions
Table 2. Copper-catalyzed aerobic oxidation of benzylamines to imines.[a]
[a]
[b]
[c]
[d]
Reaction conditions: 1 (10 mmol), CuCl (0.05 mmol), T = 100 8C, open air atmosphere.
Isolated products.
Selectivity determined by 1H NMR.
Rest of starting benzylamine was recovered.
electron-withdrawing substituents provided good
yields of imines (Table 4, entries 1–4). The reaction of
benzylamine with the strong electron-withdrawing 3nitroaniline, however, produced only the symmetrical
imine 2a (Table 4, entry 5). A similar inclination was
observed with a heteroaromatic amine substrate
(Table 4, entry 6). This is due to the competitive nueleophilicity of amines. Thus, 3-nitroaniline and 3methyl-2-aminopyridine were recovered as such.
Although we have not isolated the intermediates
(A and B), we propose a reaction pathway as outlined
in Scheme 1. In the proposed mechanism the first step
Adv. Synth. Catal. 2011, 353, 1695 – 1700
is the formation of complex A with oxidative addtion
of copper to the amine.[11,12] Further oxidation of complex A, provided methanimine B. Reaction of methanimine B with another amine leads to the final imine
product with liberation of ammonia (path 1). On the
other hand the presence of water partly hydrolyses
the methanimine B to aldehyde (path 2). The final
step (path 2) is the condensation of the aldehyde with
the amine leading to the formation of the imine. Particularly, in unsymmetrical imine syntheses (Table 4),
the nucleophilicity of the amines plays a major role
and leads to a mixture of imines 5 and 2. However, n-
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Rajendra D. Patil and Subbarayappa Adimurthy
Table 3. Copper-catalyzed aerobic oxidation of other amines to imines.[a]
[a]
[b]
[c]
Reactions conditions: 1 (10 mmol), CuCl (0.05 mmol), T = 100 8C, open air atmosphere.
Yields based on 1H NMR of crude product unless otherwise stated.
Isolated yield.
Table 4. Synthesis of unsymmetrical imines. < W = 3
[a]
[b]
[c]
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Conversions based on benzylamine 1a (GC area%).
Isolated yield unless stated.
GC yields referred to 1a [4e and 4f remained unreacted].
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1695 – 1700
Copper-Catalyzed Aerobic Oxidation of Amines to Imines under Neat Conditions
References
Scheme 1. Possible mechanism for the copper-catalyzed
aerobic oxidation of primary amines to imines.
hexylamine as substrate produced the desired unsymmetrical imine in good yield (Table 4, entry 7).
In conclusion, we have developed a novel coppercatalyzed approach to obtain various imine compounds, which are highly valued chemicals and widely
used in industry. Both symmetrical, unsymmetrical
and cyclic imines can be conveniently prepared by
this method. Notably, the nominal catalyst loading
and air, the most environment friendly oxidant were
employed under mild reaction conditions. Studies are
underway in our laboratory to investigate further synthetic applications.
Experimental Section
Synthesis of Benzylimine (2a)
Copper(I) chloride (0.05 mmol, 0.005 equiv.) was added to a
two-necked, round-bottom flask containing the benzylamine
1a (9.3 mmol) at room temperature. The resulting reaction
mixture was heated at 100 8C for 18 h in an air atmosphere.
The progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was filtered
through a short bed of active neutral alumina, the residue
was washed with diethyl ether (3 5 mL). Stripping out the
solvent afforded pure benzylimine 2a; yield: 4.1 mmol
(88%).
Acknowledgements
We thank to Mr. Hitesh, Mr. A. K. Das and Ms. Daksha, Analytical Division of this institute, for supporting the NMR
and mass spectral analyses, respectively. R.D.P. is thankful to
Council of Scientific & Industrial Research (CSIR), New
Delhi, India for the award of Senior Research Fellowship and
S. A. is thankful to CSIR/CSMCRI for internal grants.
Adv. Synth. Catal. 2011, 353, 1695 – 1700
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2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Rajendra D. Patil and Subbarayappa Adimurthy
COMMUNICATIONS
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Ind. Eng. Chem. Res. 2010, 49, 8100–8105
HBr-H2O2: A Facile Protocol for Regioselective Synthesis of Bromohydrins and
r-Bromoketones and Oxidation of Benzylic/Secondary Alcohols to Carbonyl
Compounds under Mild Aqueous Conditions
Rajendra D. Patil, Girdhar Joshi, and Subbarayappa Adimurthy*
Analytical Science Discipline, Central Salt & Marine Chemicals Research Institute (CSIR), G. B. Marg,
BhaVnagar-364002 India
HBr-H2O2 is efficiently activated in water under mild conditions, allowing the bromohydroxylation of various
styrenes. HBr-H2O2 is more economic and easy to handle and offers sufficiently high regioselectivity (100%)
for bromohydrin synthesis. Further activation of bromohydrin with a catalytic amount of HBr (50 mol %)
and H2O2 in water affords R-bromoketones in moderate to good yields in a single step. Oxidation of benzylic/
secondary alcohols to the corresponding carbonyl compounds has been achieved with the HBr (10 mol %)
and H2O2 efficiently in aqueous dioxane under ambient conditions.
1. Introduction
2. Experimental Section
Bromohydrins and R-bromoketones are compounds of high
practical utility. These bromo intermediates are useful in the
synthesis of numerous functionalized compounds such as
antitumor and antibacterial agents and antioxidants1 as well as
specialty chemicals, agrochemicals, and pharmaceuticals.2 There
are many known methods for the synthesis of bromohydrins
either by the reaction of alkenes with NBS (N-bromosuccinimide)3 or by the ring-opening of an epoxide with the addition
of halo acids.4 The direct use of HBr for the selective synthesis
of bromohydrins from olefins has not been explored. However,
the HBr-H2O2 system has been reported for a number of elegant
bromination reactions by J. Iskra and co-workers5 including the
R-bromination of ketones. Our study on various vicinal functionalizations of olefins6 and the one-pot synthesis of R-bromoketones from olefins revealed that limited literature reports
are available for the access to R-bromoketones from olefins.7
On the other hand, the development of sustainable, efficient,
and selective catalysts for the oxidation of alcohols to aldehydes
is a fundamental goal in chemistry. During recent decades,
manifold transition metal-catalyzed reactions have been discovered which have significantly improved organic transformations. Notably, most of the applications are based on complexes
of precious metals such as palladium,8 platinum,9 gold,10
ruthenium,11 and other metal catalysts.12-16 TEMPO-imidazolium salts are efficient metal-free oxidants reported recently for
the oxidation of various alcohols.17 The limited availability of
these metals and their high price make it highly desirable to
search for more economical and environmentally friendly
alternatives. On the basis of our previous study, selective
oxidation of various organic substrates with bromate in combination with a catalytic amount of bromide could be achieved
under ambient conditions.18 Our present study shows that
HBr-H2O2 can regioselectively provide bromohydrins and
R-bromoketones from olefins (Scheme 1) and is effective for
the selective oxidation of benzylic/secondary alcohols to the
corresponding carbonyl compounds under mild conditions
(Scheme 2).
General Procedure for the Synthesis of Bromohydrins
from Olefins. Representative procedure for 2-bromo-1-phenylethanol (Table 1, entry 1): To a reaction mixture containing
styrene (0.52 g, 5.0 mmol), water (15 mL), and 46% aqueous
HBr (6.0 mmol, 1.2 equiv) was added 30% aqueous H2O2 (7.5
mmol, 1.5 equiv) during a period of 1 h at room temperature.
The above reaction mixture was then refluxed for 5 h (TLC).
After completion of the reaction, a sample was withdrawn and
analyzed by GC-MS, which showed 100% formation of the
desired bromohydrin (2-bromo-1-phenylethanol) based on GC
area %. To isolate the product, it was extracted with ethyl acetate
(15 mL × 3). The combined organic layers were washed with
dilute solutions of Na2S2O3. Finally it was dried over anhydrous
Na2SO4 and concentrated under reduced pressure to get a crude
product, which was purified by column chromatography on silica
gel (hexane-ethyl acetate 95:5) to afford the pure 2-bromo-1phenylethanol (1.81 g, 9.02 mmol) in 94% yield. The spectroscopic data (1H and 13C NMR) was in good agreement with
the reported data.6c A similar procedure was followed for the
syntheses of bromohydrins listed in Table 1.
General Procedure for the Synthesis of r-Bromoketones
from Olefins. Representative procedure for 2-bromo-1-phenylethanone (Table 3, entry 1): The first stage of obtaining
bromohydrin was followed as mentioned above (general procedure for the synthesis of bromohydins). The above reaction
Scheme 1
Scheme 2
* Corresponding author. Fax: +91-278-2567562. E-mail: sadimurthy@
yahoo.com.
10.1021/ie100492r  2010 American Chemical Society
Published on Web 07/21/2010
Ind. Eng. Chem. Res., Vol. 49, No. 17, 2010
mixture was allowed to attain room temperature, and another
0.5 equiv of 46% aqueous HBr (2.5 mmol) was added followed
by the gradual addition of 1.5 equiv of 30% aqueous H2O2 (7.5
mmol w.r.t. styrene) during 1 h. The stirring of the reaction
mixture was further continued at room temperature for 18 h.
The product was extracted with ethyl acetate (3 × 15 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, and the sample was analyzed by GC-MS. GC-MS
analysis showed 94% desired bromoketone (2-bromo-1-phenylethanone) formation based on GC area %. (Caution: All the
compounds are lachrymatic, and proper care should be taken
in handling).
The aqueous part remaining (containing 0.7 equiv of bromide)
after obtaining the bromoketone above was utilized further to
get bromohydrin. To the above aqueous layer was added a
further amount of the styrene (0.36 g, 3.5 mmol) followed by
the gradual addition of 30% aqueous H2O2 (5.25 mmol, 1.5
equiv) for 1 h and then reflux for 5 h. GC-MS analysis showed
100% desired bromohydrin formation, and it was isolated in
93% yield. The same procedure was followed for reutilization
of aqueous part (from Table 3) for the corresponding bromohydrin synthesis as mentioned in Table 4.
General Procedure for the Oxidation of Benzylic/Secondary Alcohols to Corresponding Carbonyl Compounds. Representative procedure for 4-methylbenzaldehyde (Table 5, entry
8): To a solution of 4-methylbenzyl alcohol (0.5 g, 4.1 mmol)
in dioxane (5 mL) was added 0.1 equiv of 46% aqueous HBr
and 1.2 equiv of 30% aqueous H2O2. The mixture was stirred
at room temperature for 15 h (TLC). After completion of the
reaction, the product was extracted with ethyl acetate (15 mL
× 3). The combined organic extracts were washed with 2%
sodium thiosulfate solution if required and dried over anhydrous
sodium sulfate. The organic solvent was evaporated, and the
crude product thus obtained was subjected to column chromatography to get 88% (0.432 g) isolated yield. The spectroscopic
data (IR, 1H NMR, and 13C NMR) are in good agreement with
the reported values.19 The above procedure followed for the
oxidation of secondary alcohols to ketones (Table 6).
3. Results and Discussion
In our previous studies, we have screened different solvent
conditions for the synthesis of bromohydrins and observed that
the dibromo impurity is inevitably formed.6a,c In the reaction
of alkenes with aqueous HBr-NaNO2, J. Iskra and co-workers
obtained dibromo derivatives as sole products under optimized
conditions,5a but they also achieved 53% bromohydrin with
aqueous HBr alone at room temperature.5d The presence of the
dibromo impurity not only decreased the yield of the desired
bromohydrin but also demanded the purification of products
particularly in case of bromohydrin synthesis. In view of our
ongoing search for sustainable processes for the regioselective
synthesis of bromohydrins, we found that using the appropriate
conditions allows the synthesis of regioselective bromohydrins
from olefins (Scheme 1), and oxidation of benzyl alcohols to
aldehydes, and secondary alcohols to ketones, without using
any transition metals, by simply employing 10 mol % hydrobromic acid (HBr) (Scheme 2) under aqueous conditions.
Initially, the synthesis of styrene bromohydrin was carried
out by stirring the reaction mixture of styrene, aqueous
hydrobromic acid (46 wt %), and hydrogen peroxide (30 wt
%) at room temperature. GC-MS analysis showed the formation
of 65% bromohydrin, 19% bromoketone, and 15% dibromo
derivatives. When the same reaction was carried out by the
controlled addition of H2O2 at room temperature (1 h) and the
Table 1. Synthesis of Bromohydrins with HBr-H2O2
8101
a
a
Conditions: Styrenes/indene (5.0 mmol), HBr (1.2 equiv), H2O2 (1.5
equiv), 1.0 h RT, and 5.0 h reflux. b GC conversions. c GC yields of
desired bromohydrin; yields in parentheses refer to isolated products.
d
96:4 and 98:2 regioisomers observed in entries 2 and 8, respectively.
reaction mixture was refluxed at 100 °C for 5 h in water, styrene
bromohydrin was obtained with 100% selectivity (Table 1, entry
1). Under reflux conditions, the initially formed dibromo
derivative (at room temp) underwent debromination selectively
(under reflux) at the benzylic position20 to provide further
bromohydrin, thereby eliminating the dibromo impurity during
the reaction. A further advantage of the reaction at reflux is the
avoidance of bromoketone formation probably due to decomposition of excess H2O2. Simple organic extraction and evaporation of solvent provides analytically pure bromohydrins in many
cases. In this way, neat bromohydrin could be obtained as a
sole product without any tedious purification.
However, at room temperature the initially formed bromohydrin undergoes further oxidation and provides bromoketone.
Further, when the reaction was carried out in organic solvents
(for example, 1,4-dioxane, dichloromethane, dichloroethane,
acetonitrile), the dibromo derivative was observed as the major
product, which does not undergo further debromination even
under reflux conditions to provide the bromohydrin as indicated
above. Hence, water is the only choice for the selective synthesis
of bromohydrins. Considering the wide utility of these bromohydrins, we undertook the study for the synthesis of bromohydrins from olefins employing HBr-H2O2 as a cost-effective
reagent under mild reaction conditions which can be implemented in industry as well as undergraduate laboratories.
Inspired by the high yield and selectivity of the above reaction,
we extended our study toward other styrenes. All the styrenes
were selectively converted to corresponding bromohydrins in
excellent yields, and results are presented in Table 1. As shown
in Table 1, styrenes with electron-releasing (Table 1, entries 2
and 3) and electron-withdrawing (Table 1, entries 4 and 5)
substituents were neatly converted to the corresponding bromohydrins. However, 2-chlorostyrene provided 91% of the
8102
Ind. Eng. Chem. Res., Vol. 49, No. 17, 2010
Table 2. Optimization of Conditions for r-Bromoketone Synthesis
Scheme 3
product distribution (%)c
entry
conditions
conversionb
2
3
4
1a
2a
3a
4d
5e
6
1.5HBr-3H2O2, water, 25 h
1.7HBr-3H2O2, water, 25 h
2HBr-3H2O2, water, 25 h
2BrOH, water, 25 h
2NBS, water, 24 h
1.7HBr-2.5H2O2, water,
10 h, RT
1.7HBr-2.5H2O2,
water-dioxane (1:1),
10 h, RT
1.7HBr-2.5H2O2,
dioxane, 10 h, RT
100
100
100
100
100
100
78
94
93
92
81
25
22
04
02
05
19
61
00
00
00
00
00
10
100
28
52
18
99
18
24
57
7
8
Table 3. Synthesis of r-Bromoketones from Olefins with
HBr-H2O2a
a
Initially 1.5 eqv 30% aqueous H2O2 was added gradually at RT for
1.0 h then 5 h reflux and followed by the addition of rest of H2O2 at
RT, 19 h (for entries 1-3). b By GC conversion. c Yields based on GC
area %. d Reagent from our previous reference,7 and reaction carried out
under the present conditions. e Data taken from refence.5d
corresponding bromohydrin along with 6% bromoketone (Table
1, entry 6). In the case of 3-nitrostyrene, 87% bromohydrin
formation was observed along with 13% dibromo derivative
(Table 1, entry 7). Particularly, only in the case of 3-nitrostyrene
debromination was not observed due to the strong electronwithdrawing property of nitro group at the meta position. Other
substrates such as indene were also neatly (100%) converted to
the corresponding bromohydrin (Table 1, entry 8).
To broaden the scope of the present system, and for the access
to R-bromoketones from olefins, we optimized the reaction
conditions in a single-step synthesis of bromoketomes from
olefins (Table 2). As shown in Table 2, by increasing the amount
of HBr from 1.5 to 2.0 equiv, the desired bromoketone yield
(by GC) was also increased from 78% to 94% (Table 2, entries
1-3). When the reaction of entry 2 was conducted at room
temperature, bromohydrin was obtained as the major product
rather than the desired bromoketone (entry 6). Further, conducting the reaction in organic solvent led to bromohydrin (entry
7) and dibromo derivatives (entry 8) as major products. The
results from Table 2 suggest that to obtain the desired bromoketone, the conditions of entry 2 were considered optimal.
We subjected various styrenes and indene to these optimized
conditions to obtain the corresponding R-bromoketones. The
results are shown in Table 3. The lower yields of bromoketones
in the cases of 3-nitrostyrene and indene are due to the low
miscibility of the corresponding bromohydrin intermediate in
water compared to the rest of the substrates. To the best of our
knowledge, as indicated in the Table 3, the direct single-step
synthesis of R-bromoketones from olefins with HBr-H2O2
under mild conditions is a new and efficient process not yet
reported in the literature.
Even though 1.7 equiv of HBr is employed for the synthesis
of bromoketones from styrenes, only 1 equiv of bromide is
consumed for the desired conversion, the rest of the bromide
(0.7 equiv) remaining in the water phase after workup. To ensure
maximum atom efficiency as mentioned above, we added a
further 0.7 equiv of the corresponding styrene and H2O2 (1.5
equiv w.r.t. styrene) to the water phase containing the unreacted
0.7 equiv of bromide and used the same reaction conditions as
mentioned in Table 1, to obtain the complete yield of bromohydrin. Thus, maximum bromide atom efficiency results in either
a
Under the optimized conditions of Table 2 (entry 2); yields are
based on GC area %. b 1.0 equiv of HBr was used. cRest is a dibromo
impurity.
bromoketone and/or bromohydrin with zero effluent discharge,
representing an environmentally benign process. The schematic
representation for obtaining either bromohydrin and/or bromoketone is shown in Scheme 3, and the representative
examples for utilization of the bromide from the effluent (water
phase from Table 3) to obtain bromohydrins are presented in
Table 4. As evidenced from the results of Table 4, maximum
bromide atom efficiency was achieved and the corresponding
bromohydrins were obtained in excellent yields and with high
selectivity. The aqueous effluent containing bromide could be
utilized either for the same or different styrenes as desired.
Finally, to evaluate the efficiency of the present reagent
system, we also carried out the selective oxidation of benzylic
alcohols to aldehydes, and secondary alcohols to ketones, using
a catalytic amount of HBr (0.1 equiv) and aqueous H2O2 (1.2
equiv) in aqueous dioxane at room temperature. It is known
that at room temperature HBr-H2O2 generates molecular
bromine, and in aqueous medium the molecular bromine
disproportionates to HBr and HOBr (eqs 1 and 2).5c HOBr is a
good selective and mild oxidizing agent for a number of organic
substrates (eq 3).7,18 Thus, a general mechanism for the synthesis
of bromohydrins/R-bromoketones with the present system is
Ind. Eng. Chem. Res., Vol. 49, No. 17, 2010
Table 4. Synthesis of Bromohydrin from the Aqueous Effluent
Containing Bromide (from Table 3) under the Conditions of Table 1
8103
Table 5. Oxidation of Benzylic Alcohols to Aldehydes
a
GC conversions. b GC yields of bromohydrins based on area %
yields in parentheses refer to isolated products. c 89:4, 95:2, and 87:4
regioisomers are obtained in entries 2-4, respectively.
a
Isolated yields after separation by column chromatography.
benzoic acid.
Scheme 4
b
15%
Table 6. Oxidation of Secondary Alcohols to Ketones
proposed (Scheme 4). A similar mechanism operates for the
oxidation of alcohols.
2HBr + H2O2 f Br2 + H2O
(1)
Br2 + H2O f HOBr + HBr
(2)
RCH(OH)R1 + HOBr f RC(O)R1 + HBr + H2O
(3)
HBr-H2O2 has been reported to oxidize a number of
secondary alcohols at 80 °C,21 but the reported procedure does
not include the oxidation of benzylic alcohols to aldehydes with
this system. We observed that the present system is effective
for the selective oxidation of benzylic alcohols to aldehydes as
well as secondary alcohols to ketones in aqueous dioxane at
room temperature. We further observed that when the oxidation
of benzyl alcohol was carried out under the present conditions
(HBr: 0.1 equiv and aqueous H2O2: 1.2 equiv) with only water
at room temperature, the conversion of alcohols to aldehydes
was not efficient as in case of dioxane medium (Table 5, entry
1), where complete conversion was observed. Under the
conditions of aqueous dioxane as solvent with HBr (0.1 equiv)
and aqueous 30% H2O2 (1.2 equiv) at room temperature, a series
of benzylic alcohols were selectively converted to the corresponding aldehydes in excellent yields. These results are
summarized in Table 5.
Benzyl alcohol provided 78% isolated yield of benzaldehyde
along with 15% benzoic acid. Except for benzyl alcohol, other
alcohols neatly converted to the corresponding aldehydes. Both
electron-withdrawing as well as electron-releasing alcohols
a
Isolated yields after separation by column chromatography.
provided selective aldehydes in good isolated yields. Since HBr
is a nonprecious and broadly available in common chemical
laboratories, it can be generally used for the oxidation of various
benzylic alcohols to aldehydes in a catalytic amount (10 mol
%) as an alternate to the precious metal catalysts.8-11 The
generality of the present catalytic system proved to be very
fruitful for the oxidation of secondary alcohols to ketones under
the same reaction conditions (Table 6). All secondary alcohols
were selectively and efficiently converted to the corresponding
ketones in excellent yields. The oxidation reactions of secondary
alcohols were completed within 8 h, compared to 20 h reaction
time for the oxidation of benzyl alcohols (Table 5) studied in
the present investigation.
4. Conclusions
In summary, the present method describes an efficient,
selective, and environmentally benign method for the synthesis
8104
Ind. Eng. Chem. Res., Vol. 49, No. 17, 2010
of bromohydrins and R-bromoketones using the HBr-H2O2
system in water under mild conditions. The dibromo impurity
generated during the bromohydrin synthesis is selectively
converted to bromohydrin by refluxing in water. This conversion
is possible only when the reaction is carried out in water but
not in any organic solvent media. Further, the HBr (0.7 equiv)
generated during the conversion of bromohydrin to R-bromoketones is utilized to get back bromohydrin by charging a fresh
substrate under the conditions specified. Therefore, the present
system generates absolutely zero effluent, representing an
environmentally benign process. Catalysis with HBr (10 mol
%) is a highly efficient and selective method for the oxidation
of various benzylic alcohols to aldehydes, and secondary
alcohols to ketones, in aqueous dioxane medium at room
temperature. Furthermore, the versatility toward a range of
styrenes to obtain either bromohydrins or R-bromoketones and
for the selective oxidation of benzylic/secondary alcohols to
carbonyl compounds, simple reaction conditions, and excellent
yields of the products make this method a facile, ideal, and
attractive synthetic tool.
Acknowledgment
The authors gratefully acknowledge DST, New Delhi, India,
for the financial support of this project under the Green
Chemistry Task Force Scheme [No.SR/S5/GC-02A/2006]. We
thank Miss Daksha Kuvadia, H. Brahmbhatt, and Mr. Hitesh
of our Analytical Division for conducting GC-MS and NMR
analyses. We thank Dr. S. H. R. Abdi and Dr. R. I. Kureshi for
chiral HPLC analysis of a sample. R.D.P. and G.J. are thankful
to CSIR, New Delhi, India, for the award of Senior Research
Fellowships.
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ReceiVed for reView March 5, 2010
ReVised manuscript receiVed July 1, 2010
Accepted July 6, 2010
IE100492R
Tetrahedron Letters 50 (2009) 2529–2532
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile one-pot synthesis of a-bromoketones from olefins using bromide/
bromate couple as a nonhazardous brominating agent
Rajendra D. Patil a, Girdhar Joshi a, Subbarayappa Adimurthy a,*, Brindaban C. Ranu b,*
a
b
Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002, Gujarat, India
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e
i n f o
Article history:
Received 19 January 2009
Revised 6 March 2009
Accepted 10 March 2009
Available online 13 March 2009
a b s t r a c t
A new method for the preparation of a-bromoketones from olefins using bromide/bromate couple as a
nonhazardous brominating agent has been developed. Several a-bromoketones were successfully prepared from a variety of olefins by this method. This procedure is an alternative to conventional molecular
bromine.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkenes
Bromide/bromate couple
a-Bromoketones
Bromine-free procedure
a-Bromoketones are versatile intermediates in organic synthesis.1 Numerous methods have been developed for the preparation
of a-bromoketones from ketones with liquid bromine in the presence of protic and Lewis acids.2 Bromine is hazardous with associated risks in handling and transport. However, it is still being used
by industry as well as academia due to its easy availability, low
cost, and lack of a better alternative. A few other alternative procedures for a-bromination of carbonyl compounds avoiding liquid
bromine involve N-bromosuccinimide (NBS)3 and 4,4-dibromo2,6-di-tert-butyl-cyclohexa-2,5-dienone.4 Nevertheless, these brominating reagents have some limitations including their low atom
efficiency and use of molecular bromine for their preparation.
A survey of the existing literature revealed that a-bromoketones have been synthesized mainly from ketones.2–4 Surprisingly,
we have found limited reports for the preparation of a-bromoketones from olefins.5 The direct conversion of alkenes to a-chloroketones is reported with chromyl chloride.6 However, the same
strategy for a-bromoketones is not explored in the literature.
Despite the fact that, the reactions of olefins with NBS is well
documented in the literature to obtain bromohydrins,7 it is seldom
extended to get a-bromoketones. As olefins substituted with a
variety of functionalities are easily accessible we assumed that a
convenient procedure from olefins using an alternative mild brominating agent will be appreciated.
* Corresponding authors. Fax: +91 278 2567562 (S.A.); tel.: +91 3324734971; fax:
+91 33 24732805 (B.C.R.).
E-mail addresses: [email protected] (S. Adimurthy), [email protected] (B.C.
Ranu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.047
Our continuous efforts to achieve maximum bromide atom efficiency and minimize waste generation, as well as elimination of
the use of hazardous liquid bromine led us to develop a versatile
brominating reagent, a bromide–bromate couple, and we have already demonstrated a few useful applications.8
Herein, we report further results using this brominating reagent for the direct synthesis of a-bromoketones from olefins
Table 1
Optimization of reaction conditions for a-bromoketone synthesis
O
Solvent
+
1
2 BrOH
Solvent
Time (h)
1
2
3
4
5
6
7b
8c
9d
Dioxane
Acetonitrile
THF
CH2Cl2
Et2O
DMSO
Dioxane
Dioxane
Dioxane
8
8
8
8
8
8
7.5
7.5
8
a
c
d
Br
GC yields unless otherwise stated.
Isolated yield with 2.5 equiv of BrOH.
Isolated yield with 3.0 equiv of BrOH.
Reaction with NBS.
Br
5
4
3
Entry
b
+
Br
2
Br
OH
+
R.T.
Product ratioa
3
4
5
71
40
3
—
13
—
60
61
36
17
47
39
19
3
60
11
10
52
12
8
24
77
76
8
1
2
3
2530
R. D. Patil et al. / Tetrahedron Letters 50 (2009) 2529–2532
Table 2
Synthesis of various a-bromoketones from olefins
Entry
Substrate
Time (h)
Isolated yields (%)
Bromoketone
Bromohydrin
O
7.5
1
12
OH
87
4
6
t-Bu
Br
O
OH
86
Br
6.5
Cl
6.5
Br
t-Bu
11
12
01
Br
15
OH O
Br O
10
03
Br
Br
OH
Br
Br07
C4H9
8
11
C6H13
7
12
C7H15
13
13
C8H17
13
14
C9H19
7.5
15
C10H21
14
O
Br 82
C10H21
OHBr
06
C 10H21
Br Br
02
C10H 21
16
C 12H25
15
O
Br 65
C 12H25
OH Br
08
C12H 25
C 12H25
O
C6H13
O
C7H15
O
C8H17
O
C9H19
Br 50
Br 68
Br 64
Br 70
Br 70
C4H9
Br17
OH
C 6H13
OH
C7H15
OH
C 8H17
C9H19
8a
Br
10
C4H9
10
Br
64
O
02
Br
10
2e
Br
OH
77
O O
O
11
NO 2
Br
9
03
Br
Br
NO2
NO2
7
Br
09
Br
11
Br
OH
40
02
Br
25
Br
O
8
Br
Cl
Br
OH
Br
68
O
NO2
02
Br
O
15
Br
Br
OH
Cl
77
Br
7
2i
t-Bu
Br
O
Br
01
OH
82
Br
6
10
Br
O
Cl
Br
10
Br
t-Bu
02
Br
Br
5
Br
11
Br
10
Br
O
6
01
Br
6
3
Br
OH
60
Br
2
Ref.
Dibromo
Br20
Br08
Br07
OH Br
07
C4H9
Br
C 6H13
Br
C7H 15
Br
C 8H17
C9H19
Br04
Br03
Br03
Br Br
03
Br
Br03
10
2531
R. D. Patil et al. / Tetrahedron Letters 50 (2009) 2529–2532
Table 2 (continued)
Entry
Substrate
Time (h)
17
C14H29
14
18
C16H33
14
19
Isolated yields (%)
Bromohydrin
Dibromo
O
Br 67
C14H 29
OH Br
09
C 14H29
C14H29
O
OH
Br08
C16H 33
Br
Br03
C16H33
Br 65
C16H33
O
8
OH
46
O
9
under ambient conditions. In our earlier communication,8a we
showed the generation of active species BrOH by reacting
bromide–bromate and acid in the ratio of 2:1:3, respectively
(Eq. 1):
The reaction of BrOH with olefins to provide a-bromoketones is
investigated. To optimize the reaction conditions we initiated our
studies with styrene 1 as a representative olefin in different solvents at room temperature. When the reaction was carried out with
1,4-dioxane as solvent with 2.0 equiv of brominating reagent, the
products a-bromoacetophenone 3, 2-bromo-1-phenylethanol 4,
and styrene dibromide 5 were obtained in 71%, 17%, and 12% yields,
respectively (GC) (Table 1, entry 1). When the reaction was performed in acetonitrile, the yield of product 3 was reduced to 40%
(entry 2), bromohydrin 4 being the major product in 47% along with
8% of product 5. Whereas THF, dichloromethane, and diethyl ether
provided desired product 3 in 3%, 0%, and 13% yields, respectively,
and products 4 and 5 are obtained as major ones. When the reaction
was conducted in dimethylsulfoxide (DMSO) at room temperature,
the reaction does not yield bromoketone; however, it gave bromohydrin (4) as the major product (60% isolated yield) and dibromo
derivative (5) in 8% yield and the rest constituted unidentified bromo impurities (entry 6). To optimize the amount of the reagent 2,
we performed two reactions in dioxane employing 2.5 and 3.0 equiv
of reagent 2. The gradual increase of the reagent from 2 to 2.5 and
3 equiv gave the desired product (3) in 60% and 61% isolated yields,
respectively (entries 7 and 8). The results clearly indicate that the
best yield of the desired product could be obtained in dioxane with
2.1 equiv of reagent BrOH. Therefore the following experiments
Br
06
Br
HO
H O
R
Br + + OH -
Br
+
BrOH
Br
R
+
H O
R
06
8b
8b
were performed under these optimized conditions in dioxane, unless otherwise required.9
When we carried out the reaction of styrene with N-bromosuccinimide7 (2.1 equiv) under identical conditions the desired product (3) was obtained only in 36% yield (Table 1, entry 9). This
study further supports the significance of the present reagent for
obtaining a-bromoketones directly from olefins in good yields.
Several alkenes were subjected to this procedure to produce the
corresponding a-bromoketones (Table 2). 4-Methyl styrene and indene (Table 2, entries 2 and 3.) showed high selectivity to provide
4-methyl-a-bromoacetophenone and 2-bromo-indan-1-one in 87%
and 86% isolated yields. These transformations are associated with
undesired products during bromination using HBr/H2O2.10 When
this methodology was applied to 3-nitro styrene (Table 2, entry
7) the corresponding 3-nitro-a-bromoacetophenone was obtained
in 40% yield. Such deactivated substrates are reported to be tedious
by other methods.3a The internal olefins stilbene and chalcone
were smoothly converted to 2-bromo-1,2-diphenyl-ethanone and
2-bromo-1,3-diphenylpropane-1,3-dione, respectively, in good
yields (Table 2, entries 8 and 9). Under the same experimental conditions straight chain as well as cyclic olefins underwent brominations without any difficulty to provide the corresponding abromoketones in moderate to good yields (Table 2, entries 10–20).
As indicated in Eq. 1, the active species BrOH reacts with olefins
to provide bromohydrin8a which further reacts with another equivalent of BrOH to give the corresponding a-bromoketones as outlined in Scheme 1.
In conclusion, the bromide/bromate couple in aqueous acidic
medium serves as an efficient and green reagent for the synthesis
of the a-bromoketone by direct oxybromination of olefins avoiding
ð1Þ
R
Br Br
03
Br
OH
07
Br
46
Br
2Br þ BrO3 þ 3Hþ ! 3BrOH
Br
07
Br
Br
20
Ref.
Bromoketone
Br
O
Br
+ OH-H2 O
Br
O
R
Br
-HBr
Br
R
Scheme 1. Proposal of the mechanism for the synthesis of a-bromoketones from olefins.
2532
R. D. Patil et al. / Tetrahedron Letters 50 (2009) 2529–2532
hazardous molecular bromine. In addition, this procedure offers
significant improvements with regard to reaction conditions (room
temperature), good yields, and user-friendly operations compared
to conventional methods. These results also highlight the significant scope for the synthesis of a-bromoketones from easily accessible olefins, which is inadequately reported in the literature.
Acknowledgment
We gratefully acknowledge DST, New Delhi, India, for the financial support of this project under the Green Chemistry Task Force
scheme [No. SR/S5/GC-02A/2006].
Supplementary data
Characterization data for products at entries 4, 10, 11 and 13–
18 in Table 2. Copies of 1H NMR and 13C NMR of all products listed
in Table 2. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.03.047.
References and notes
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Y.; Chi, D. Y. Org. Lett. 2003, 5, 411–414; (f) Paul, S.; Gupta, V.; Gupta, R. Synth.
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9. (Caution: All the compounds are lachrymators and proper care should be taken
while handling.) General procedure for the synthesis of a-bromoketone from
olefins. Representative procedure for 2-bromo-1-phenyl-ethanone (Table 1, entry
1): To a solution of styrene (1.0 g, 9.6 mmol) in 1,4-dioxane (5.0 mL) was added
an aqueous solution (20 ml) containing a 2:1 mole ratio of NaBr (1.38 g,
13.4 mmol)—NaBrO3 (1.01 g, 6.7 mmol) (2.1 equiv) reagent at room
temperature. To the above mixture, 98% sulfuric acid (10.5 mmol) was added
slowly under stirring at room temperature during 2.5 h. After complete
addition of the acid, stirring was continued for further 4 h (TLC). The product
was extracted with CH2Cl2 (3 25 ml). The combined organic layers were
washed with aqueous Na2S2O3 and dried over Na2SO4. Evaporation of solvent
left the crude product which was purified by column chromatography over
silica gel (ethyl acetate–hexane 5:95) to afford the pure white solid product
(1.15 g, 5.76 mmol) 2-bromo-1-phenyl-ethanone 3 in 60% yield; melting point
48 °C, (Lit 48.8–49.3 °C).10 The side products, styrene bromohydrin 4 (0.31 g,
12%) and styrene dibromide 5 (0.022 g, 1%) were also obtained. The
spectroscopic data (IR, 1H NMR and 13C NMR) are in good agreement with
the reported values.10
2-bromo-1-(4-tert-butylphenyl) ethanone (Table 2, entry 4): Yellow oil. IR:
mmax (Neat). 3042, 2965, 2870, 1680, 1605, 1566, 1465, 1428, 1407, 1365, 1284,
1194, 1104, 1008, 992, 847, 733, 665, 643, 578. 1H NMR (CDCl3-500 MHz)—(d):
1.32 (s,9H), 4.43 (s, 2H), 7.47 (d, 2H, J = 8.5 Hz), 7.91 (d, 2H, J = 8.5 Hz) ppm. 13C
NMR (CDCl3-125 MHz) (d): 30.9, 31.2, 35.1, 125.7, 128.8, 131.2, 157.6,
190.7 ppm. HRMS Calcd for C12H15BrO [M+1]+: 255.0384; Found: 255.0385.
1-Bromo-hexan-2-one (Table 2, entry 10): Colorless liquid. IR: mmax (Neat).
2956, 2931, 2859, 1718, 1462, 1403, 1377, 1255, 1124, 1057, 758, 631. 1H NMR
(CDCl3-500 MHz)—(d): 0.66 (s, 3H), 1.08 (d, 2H, J = 5.0 Hz), 1.34 (s, 2H), 2.40 (s,
2H), 3.65 (s, 2H) ppm. 13C NMR (CDCl3-125 MHz) (d): 13.7, 22.1, 25.8, 34.4,
39.5, 202.1 ppm. HRMS Calcd for C6H11BrO [M+1]+: 179.0071; Found:
179.0072.
1-Bromo-octan-2-one (Table 2, entry 11): yellow oil. IR: mmax (Neat). 2930,
2858, 1716, 1464, 1213, 1055, 878, 671, 487. 1H NMR (CDCl3-500 MHz)—
(d) = 0.89 (s, 3H), 1.29 (s, 6H), 1.61 (s, 2H), 2.65 (s, 2H), 3.89 (s, 2H) ppm. 13C
NMR (CDCl3-125 MHz) (d): 13.9, 22.4, 23.8, 28.6, 31.4, 34.3, 39.8, 202.2 ppm.
LRMS Calcd for C8H15BrO [M]+: 207.0384; Found: 207.0385.
1-Bromo-decan-2-one (Table 2, entry 13): Pale yellow oil. IR: mmax (Neat). 2928,
2857, 1719, 1462, 1401, 1065, 894, 634. 1H NMR (CDCl3-500 MHz)—(d): 0.87 (s,
3H), 1.29 (d, 10H, J = 4 Hz), 1.61 (t, 2H, J = 7 Hz), 2.64 (t, 2H, J = 7 Hz), 3.89 (s,
2H) ppm. 13C NMR (CDCl3-125 MHz) (d): 14.0, 22.6, 23.8, 29.0, 29.2, 31.7, 34.3,
39.8, 202.1 ppm. HRMS Calcd for C10H19BrO [M]+: 235.0697; Found: 235.0698.
1-Bromo-undecan-2-one (Table 2, entry 14): White crystalline solid melting
point observed 40-41 °C. IR: mmax (Neat). 2925, 2854, 1719,1468, 1406, 1243,
1128, 1086, 1038, 719, 693, 638, 469. 1H NMR (CDCl3-500 MHz)—(d): 0.87 (t,
3H, J = 7 Hz), 1.28 (t, 12H, J = 6 Hz), 1.62 (t, 2H, J = 3.5 Hz), 2.64 (t, 2H, J = 7 Hz),
3.88 (s, 2H) ppm. 13C NMR (CDCl3-125 MHz) (d): 14.1, 22.6, 23.8, 29.0,29.2,
29.3, 29.4, 31.8, 34.3, 39.8, 202.3 ppm. Elemental Anal. Calcd for C11H21BrO is C,
53.02; H, 8.49. Found: C, 53.26; H, 9.21. LRMS Calcd for C11H21BrO [M]+:
249.19; Found: 248.67.
1-Bromo-dodecan-2-one (Table 2, entry 15): White crystalline solid melting
point observed 41–42 °C. IR: mmax (Neat). 2925, 2855, 1720, 1468, 1408, 1238,
1128, 1090, 1049, 719, 693, 639. 1H NMR (CDCl3-500 MHz)—(d): 0.88 (t, 3H,
J = 6 Hz), 1.27 (s, 14H), 1.61 (t, 2H, J = 7 Hz), 2.64 (t, 2H, J = 7 Hz), 3.89 (s,
2H) ppm. 13C NMR (CDCl3-125 MHz) (d): 14.1, 22.7, 23.8, 29.0, 29.3, 29.4, 29.6,
31.9, 34.3, 39.8, 202.2 ppm. Elemental Anal. Calcd for C12H23BrO is C, 54.76; H,
8.81. Found: C, 55.03; H, 9.09. LRMS Calcd for C12H23BrO [M]+: 263.21; Found:
262.68.
1-Bromo-tetradecan-2-one (Table 2, entry 16): White solid melting point
observed 54–55 °C. IR: mmax (Neat). 2925, 2853, 1720, 1469, 1410, 1249, 1129,
1097, 1061, 719, 640. 1H NMR (CDCl3-500 MHz)—(d): 0.88 (t, 3H, J = 5 Hz), 1.25
(s, 18H), 1.61 (t, 2H, J = 7.5 Hz), 2.64 (t, 2H, J = 7 Hz), 3.89 (s, 2H) ppm. 13C NMR
(CDCl3-125 MHz) (d): 14.1, 22.7, 23.8, 29.0, 29.36, 29.38, 29.4, 29.62, 29.66,
29.67, 31.9, 34.3, 39.8, 202.2 ppm. Elemental Anal. Calcd for C14H27BrO is C,
57.73; H, 9.34. Found: C, 57.98; H, 7.91. LRMS Calcd for C14H27BrO [M]+:
291.27; Found: 290.74.
1-Bromo-hexadecan-2-one (Table 2, entry 17): White solid melting point
observed 58–59 °C. IR: mmax (Neat). 2923, 2822, 1720, 1469, 1409, 1254, 1129,
1090, 1034, 718, 640. 1H NMR (CDCl3-500 MHz)—(d): 0.88 (t, 3H, J = 6 Hz), 1.25
(s, 22H), 1.61 (d, 2H, J = 6 Hz), 2.64 (t, 2H, J = 7 Hz), 3.88 (s, 2H) ppm. 13C NMR
(CDCl3): (d): 14.1, 22.7, 23.8, 29.0, 29.3, 29.4, 29.6, 31.9, 34.3, 39.8, 202.2 ppm.
Elemental Anal. Calcd for C16H31BrO is C, 60.18; H, 9.79. Found: C, 60.23; H,
10.72. LRMS Calcd for C16H31BrO [M+ Na]+: 342.31; Found: 341.46.
1-Bromo-octadecan-2-one (Table 2, entry 18): White solid melting point
observed 62-63 °C. IR: mmax (Neat). 2922, 2852, 1725, 1465, 1389, 1249, 1081,
724, 638. 1H NMR (CDCl3-500 MHz)—(d): 0.88 (t, 3H, J = 6 Hz), 1.25 (s, 26H),
1.60 (d, 2H, J = 6.5 Hz), 2.64 (t, 2H, J = 7.5 Hz), 3.88 (s, 2H) ppm. 13C NMR
(CDCl3): (d): 14.1, 22.7, 23.8, 29.0, 29.35, 29.39, 29.4, 29.61, 29.67, 29.69, 29.7,
31.9, 34.3, 39.8, 202.2 ppm. Elemental Anal. Calcd for C18H35BrO is C, 62.24; H,
10.16. Found: C, 62.50; H, 9.93. LRMS Calcd for C18H35BrO [M+Na]+: 370.36;
Found: 369.47.
10. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Green Chem. 2007, 9, 1212–1218.
11. Pauchert, C. J.; Behnke, J. In The Aldrich Library of 13C and 1H—FT NMR Spectra, I
ed.; Aldrich Chemical: Milwaukee, USA, 1993, Vol. 2.
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Green Oxidation of Methylarenes to Benzoic Acids with Bromide/Bromate
in Water
Rajendra D. Patila; Sukalyan Bhadrab; Subbarayappa Adimurthya; Brindaban C. Ranub
a
Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research,
G. B. Marg, Bhavnagar, Gujarat, India b Department of Organic Chemistry, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata, India
Online publication date: 25 August 2010
To cite this Article Patil, Rajendra D. , Bhadra, Sukalyan , Adimurthy, Subbarayappa and Ranu, Brindaban C.(2010) 'Green
Oxidation of Methylarenes to Benzoic Acids with Bromide/Bromate in Water', Synthetic Communications, 40: 19, 2922
— 2929
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DOI: 10.1080/00397910903340678
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GREEN OXIDATION OF METHYLARENES TO BENZOIC
ACIDS WITH BROMIDE/BROMATE IN WATER
Rajendra D. Patil,1 Sukalyan Bhadra,2
Subbarayappa Adimurthy,1 and Brindaban C. Ranu2
1
Central Salt and Marine Chemicals Research Institute, Council of Scientific
and Industrial Research, G. B. Marg, Bhavnagar, Gujarat, India
2
Department of Organic Chemistry, Indian Association for the Cultivation of
Science, Jadavpur, Kolkata, India
An efficient and convenient procedure has been developed for the oxidation of methylarenes
to the corresponding benzoic acids using a bromide/bromate-based reagent system in water.
Regeneration and reusability of the bromide/bromate reagent is demonstrated.
Keywords: Benzoic acids; bromide=bromate; methylarenes; oxidation
INTRODUCTION
The oxidation of methyl aromatics into the corresponding benzoic acids is an
important transformation in organic synthesis as these carbonyl derivatives constitute
versatile building blocks in pharmaceutical and polymer industries.[1] A variety of
oxidizing agents such as KMnO4, CrO3, Na2Cr2O7, TiO2, NaIO4, and HNO3 are
available to effect this key reaction.[2–6] However, these metallic reagents are often
required in stoichiometric amounts, and these procedures are associated with
environmental pollution because of the large amounts of hazardous metallic wastes.
Moreover, purification of the reaction products is often very tedious because of the
difficulty in separation of the metal residues from the product. Despite the industrial
importance of this process and ever-growing environmental concerns, efficient
catalytic systems have been rarely described.[7] Recently, WO3=70% tert-butyl hydroperoxide (TBHP)=aqueous NaOH has been reported.[8] Although several methods are
known for the synthesis of aromatic carboxylic acids, preparation under mild conditions
without use of heavy-metal catalysts and generation of waste is an ultimate goal in view
of technical, economical, and industrial aspects. As a part of our continuing activities to
develop green procedures that avoid hazardous reagents,[9] we report herein a novel,
heavy-metal-free, and recyclable reagent system for the oxidation of methylarenes to
Received July 10, 2009.
Address correspondence to Subbarayappa Adimurthy, Central Salt and Marine Chemicals
Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002,
Gujarat, India. E-mail: [email protected]
2922
OXIDATION OF METHYLARENES
2923
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Scheme 1. Oxidation of methyl arenes to benzoic acids.
their corresponding benzoic acids using a bromide=bromate reagent under mild conditions in an open atmosphere with water as solvent (Scheme 1).
RESULTS AND DISCUSSION
To gain more insight into this process, the oxidation of methylarenes with
bromide=bromate under an aqueous acidic medium was investigated. In our earlier
studies, we showed that the reactions of bromide=bromate and acid in a 2:1:3 molar
ratio [Eq. (1)] generates the reactive species BrOH.[9] We think that this species is also
responsible for the oxidation of methylarenes.
þ
2Br þ BrO
3 þ 3 H ! 3BrOH
ð1Þ
A study for the oxidation of toluene by this reagent in different organic solvents such
as CH2Cl2, ClCH2CH2Cl, CCl4, and CH3OH demonstrated that the best result with
regard to the formation of carboxylic acid was achieved using water as solvent. To
optimize the reaction parameters, such as the amount of reagent system and reaction
temperature, the reaction of toluene was investigated under various conditions as
illustrated in Table 1. The best yield was obtained using 3 equivalents of bromide=
bromate=acid in a 2:1:3 molar ratio (Table 1, entry 3).
The present transformation, 1 to 2, proceeds through the intermediates of
benzyl alcohol 4 and aldehyde 3 [Eqs. (2)–(4)]. Thus, this transformation needs 3
equivalents of the reagent [Eq. (5)].
ArCH3 þ BrOH ! ArCH2 OH þ HBr
ð2Þ
ArCH2 OH þ BrOH ! ArCHO þ HBr þ H2 O
ð3Þ
ArCHO þ BrOH ! ArCO2 H þ HBr
ð4Þ
ArCH3 þ 3BrOH ! ArCO2 H þ 3HBr þ H2 O
ð5Þ
It clearly indicates that the intermediates 3 and 4 could be avoided completely by
using 3 equivalents of the reagent, and the desired product 2 was obtained in 72%
isolated yield (Table 1, entry 3). When the reaction was conducted at room temperature, it took a prolonged period of time to consume the total reagent and undesired
products were formed (Table 1, entry 4). This indicates that the selective activation
of aromatic alkyl C-H group at room temperature will be difficult without any metal
catalyst.[4,10] It is further observed that in the absence of visible light, nuclear
2924
R. D. PATIL ET AL.
þ
Table 1. Oxidation of toluene (1) with Br =BrO
3 =H reagent under different conditions
Downloaded By: [Adimurthy, Subbarayappa][CSIR eJournals Consortium] At: 04:45 30 August 2010
Run
1
2
3
4c
5e
Reagent (eqv.)
Conv (%)a
2
3
4
5
Others
1.0
2.0
3.0
3.0
3.0
100
100
100
100
100
22.6
41.1
90 (72)b
9.0
32.6
10.7
7.3
—
4.4
—
25.4
22.4
—
—
—
10.2
9.6
4.6
26.4
58.6
Rest
Rest
Rest
59.4d
Rest
þ
Notes. Conditions: 10.86 mmol of 1, Br =BrO
3 =H are in a 2:1:3 molar ratio, water, 100 C, 8.00 h, in
visible light. Product distribution is based on GC area percentages.
a
GC-MS.
b
Isolated yield.
c
Reaction carried out at rt for 16 h.
d
Constituted with multinuclear brominated and oxidized products not mentioned in the table.
e
Without visible light.
brominated products were formed (Table 1, entry 5). Presumably, the presence of
visible light is necessary to initiate the reaction if it proceeds via a free-radical mechanism.[11] To check whether the present transformation proceeds via the benzylic
bromide mechanism,[6e] we performed the reaction of toluene under the same conditions in dichloromethane and water. In the former case, benzylic brominated products 6 and 7 were formed, and in the latter case, the desired product benzoic acid 2
(Scheme 2) was produced. Thus, the transformation of toluene to benzoic acid is
facilitated in water rather than in organic solvents. Based on all these observations,
the oxidations were carried out in water at 100 C using 3 equivalents of reagent system. The isolation of the product is very simple. The completion of the reaction is
indicated by the disappearance of the color of the reactive species BrOH=Br2. The
reaction mixture was allowed to cool to room temperature, and the solid was filtered.
The solid was washed with cold water and dried to get the product.
Several substituted methylarenes were subjected to oxidation by this procedure
to provide the corresponding benzoic acids in good yields. The results are summarized in Table 2. The position of substitution (o, m, p) does not affect the oxidation
process. The hindered o-substituted toluenes (Table 2, entries 8 and 13) were also
Scheme 2. Effect of H2O and CH2Cl2 on oxidation of toluene.
OXIDATION OF METHYLARENES
2925
Table 2. Oxidation of alkylarenes to the corresponding benzoic acids
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Entry
Substrate
Time (h)
Product
Yield (%)a
Mp (Lit. mp) ( C)
Ref.
1
8
72
122 (121–125)
12
2
5
84
236 (237–240)
12
3
9
69
137 (139–141)
12
4
7
82
167 (163–165)
13
5
8
83
212 (208–209)
14
6
5
75
238 (238–241)
12
7
6
70
155 (153–157)
12
8
6
73
142 (138–140)
12
9
10
73
180 (182–184)
12
10
7
70
160 (155–158)
12
11
8
66
189 (185–187)
12
12
9
67
268 (270–273)
12
13
10
63
164 (160–162)
12
(Continued )
2926
R. D. PATIL ET AL.
Table 2. Continued
Entry
Time (h)
Product
Yield (%)a
Mp (Lit. mp) ( C)
Ref.
14
9
71
155 (157–160)
12
15
10
64
122 (121–125)
12
a
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Substrate
Isolated yields of pure products (1H and
13
C NMR).
oxidized without any difficulty. In general, the deactivated methylarenes were more
facile in this oxidation process. The highly deactivated toluenes such as nitrotoluenes
were not always easy to oxidize.[6a] The unactivated arenes such as a-methyl naphthalene (Table 2, entry 14) and ethyl benzene (Table 2, entry 15) also produced
the corresponding carboxylic acids. However, oxidations of highly activating methylarenes were not encouraged, being associated with considerable amounts of ring
brominated products.
Because bromide is not consumed as such in the oxidation process, both the
bromide=bromate ions ended up in the aqueous effluent as total bromide ions, and
we reoxidized a part of the bromide ion with NaOCl to bromate to regenerate the
reagent to its original form [Eq. (6)] under ambient conditions (Scheme 3). Sodium
chloride produced in the course of regeneration caused no problem in the oxidation
reactions. The regenerated reagent was successively used for oxidation of methylarenes under similar conditions. For a representative example, 4-nitrotoluene was
subjected to oxidation by this regenerated reagent system with three consecutive
cycles, and the results (Table 3) are same as with the fresh reagent.
3Br þ 3 OCl ! 2Br þ BrO
3 þ 3Cl
ð6Þ
In conclusion, we have developed a very simple and efficient procedure for the
oxidation of methylarenes to the corresponding benzoic acids using an inexpensive
Scheme 3. Regeneration of bromide=bromate.
OXIDATION OF METHYLARENES
2927
Table 3. Oxidation of p-nitrotoluene with regenerated reagent
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Cycle
1
2
3
a
Time (h)
Yield (%)a
5.0
7.0
7.0
84
76
72
Isolated yield.
and easily available bromide=bromate reagent system. The most significant and
green feature of this methodology is the simple operation in water and use of no hazardous organic solvent or toxic reagent in the entire process. The recyclability of the
reagent also adds to its green merit. Thus, this cost-effective and environmentally
friendly procedure is a practical alternative to the existing ones and will find useful
applications in academia as well as industry.
EXPERIMENTAL
General Experimental Procedure for the Oxidation of Methylarenes
to Benzoic Acids: Representative Procedure for 4-Nitrobenzoic Acid
(Table 2, Entry 2)
An aqueous solution of NaBr (3.00 g, 29.1 mmol) and H2SO4 (2.14 g,
21.8 mmol) was added at 100 C (oil bath) to a stirred solution of 4-nitrotoluene
(2.0 g, 14.5 mmol), water (20 ml), and NaBrO3 (2.20 g, 14.5 mmol) during a period of 3 h in the presence of visible light. Stirring was continued for 2 h until the
brown color disappeared at the same temperature. The reaction mixture was
allowed to attain room temperature (25 C). The solid separated was filtered
off, washed with water, and dried to afford 4-nitrobenzoic acid (2.03 g, 84%).
Recrystallization from hot water provided the analytically pure sample. The
spectroscopic data [infrared (IR), 1H NMR, and 13C NMR)] are in good agreement with the reported values.[6e] The aqueous part left after workup of the first
cycle was neutralized and thereafter treated with NaOCl solution (81.5 ml of 4%
available chlorine) to oxidize 1=3 of total Br- into BrO
3 and to regenerate the
original 2:1 Br =BrO
couple.
Fresh
4-nitrotoluene
(2.0
g,
14.5 mmol) was added
3
to it, followed by H2SO4 (2.14 g, 21.8 mmol) at 100 C (oil bath) during a period
of 3 h, and stirring was continued for 4 h. After workup (as mentioned previously), pure 4-nitrobenzoic acid was obtained (1.84 g, 76%). A similar procedure was followed for the third cycle. All of the products are known
compounds and were easily identified by comparison of their spectroscopic data
with the reported values.[12]
2928
R. D. PATIL ET AL.
ACKNOWLEDGMENT
The authors gratefully acknowledge the Department of Science and
Technology, New Delhi, India, for financial support of this project under the Green
Chemistry Task Force Scheme [No. SR=S5=GC-02A=2006].
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Easy Access to α-Bromoketones and Epoxides from vic-Dibromides Under
Aqueous Conditions
Rajendra D. Patila; Subbarayappa Adimurthya; Brindaban C. Ranub
a
Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research,
Bhavnagar, Gujarat, India b Department of Organic Chemistry, Indian Association for the Cultivation
of Science, Jadavpur, Kolkata, India
Online publication date: 04 October 2010
To cite this Article Patil, Rajendra D. , Adimurthy, Subbarayappa and Ranu, Brindaban C.(2010) 'Easy Access to α-
Bromoketones and Epoxides from vic-Dibromides Under Aqueous Conditions', Synthetic Communications, 40: 21, 3233
— 3239
To link to this Article: DOI: 10.1080/00397910903398643
URL: http://dx.doi.org/10.1080/00397910903398643
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Synthetic Communications1, 40: 3233–3239, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903398643
EASY ACCESS TO a-BROMOKETONES AND EPOXIDES
FROM vic-DIBROMIDES UNDER AQUEOUS
CONDITIONS
Rajendra D. Patil,1 Subbarayappa Adimurthy,1 and
Brindaban C. Ranu2
Downloaded By: [Adimurthy, Subbarayappa] At: 05:59 8 November 2010
1
Central Salt and Marine Chemicals Research Institute, Council of Scientific
and Industrial Research, Bhavnagar, Gujarat, India
2
Department of Organic Chemistry, Indian Association for the Cultivation of
Science, Jadavpur, Kolkata, India
The conversion of vic-1,2 dibromides to a-bromoketones and epoxides using H2O2/dioxane
and NaOH/water respectively under mild conditions has been described.
Keywords: a-Bromoketones; bromohydrins; epoxides; vic-dibromides
INTRODUCTION
Organic reactions in water have received increased attention primarily because
of their environmental acceptability, abundance, and low cost.[1] Water as the reaction
medium is certainly the best choice in the constant search for cheaper, cleaner, and
more efficient technologies for the transformations of organic molecules.[2] Moreover,
water also exhibits unique reactivity and selectivity that cannot be attained in conventional organic solvents.[3]
Vicinal halohydrins, a-bromoketones, and epoxides are versatile intermediates
for the synthesis of a variety of biologically important natural products, fine chemicals, and pharmaceuticals.[4] Thus, a number of procedures have been developed for
preparation of bromohydrins, which involve either ring opening of epoxides by hydrogen bromide or metal bromides[5] or addition of BrOH to an olefin.[6] The procedures
reported for the preparation of a-bromoketones are primarily based on the reaction of
carbonyl compounds with elemental bromine,[7] N-bromosuccinimde (NBS),[8] and
4,4-dibromo-2,6-di-tert-butyl-cyclohexa-2,5-dienone.[9] Although a number of methods have been reported for these transformations, development of an efficient
procedure in water without any catalyst will be highly appreciated.
Received August 3, 2009.
Address correspondence to Subbarayappa Adimurthy, Central Salt and Marine Chemicals
Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002,
Gujarat, India. E-mail: [email protected] and Brindaban C. Ranu, Department of Organic
Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
E-mail: [email protected]
3233
3234
R. D. PATIL, S. ADIMURTHY, AND B. C. RANU
Downloaded By: [Adimurthy, Subbarayappa] At: 05:59 8 November 2010
RESULTS AND DISCUSSION
A current interest in our laboratory is the functionalization of alkenes for
diverse applications (Scheme 1).[10] In anticipation of the easy accessibility of
vic-dihalides from the corresponding alkenes by simple addition of bromine or other
reagents,[10b] we describe the amenability to exploit these vic-dibromides to obtain
the more versatile intermediates bromohydrins, a-bromoketones, and epoxides under
mild conditions using H2O2 or a base in water (Scheme 2). The vic-dibromides were
easily converted to bromohydrins by refluxing in water at 100 C. (After refluxing
the vic-dibromide in water at 100 C, the corresponding bromohydrin was obtained
through SN2 reaction, and bromide ions remain present in the system as HBr).
Recently, we reported a one pot-synthesis of a-bromoketones from olefins using a
bromide=bromate couple under aqueous acidic medium, where we obtained dibromide
and bromohydrin as minor side products.[10e] Our idea of obtaining a-bromoketones
from vic-dibromides is based on the fact that on heating in water vic-dibromides lead
to the corresponding bromohydrin, which can be converted to a-bromoketones by
simple oxidizing agents such as H2O2.[11] On the other hand, on treatment with a base
the bromohydrin can provide an epoxide. Accordingly, we initiated our studies with
styrene dibromide 1 as model substrate. Gas chromatographic (GC) analysis of the
product obtained by heating 1 under reflux in water for 3 h showed 100% conversion
to the styrene bromohydrin 2. Interestingly, no elimination product was observed
under these conditions. Certainly, achievement of 100% selectivity and quantitative
yield of the desired product without any catalyst is very promising. The direct conversion of an alkene to a halohydrin by many known reagents leads to its dihaloderivative
as a side product. To the same flask containing 2, we further added H2O2 in dioxane
and continued the stirring at room temperature. After 10 h (as monitored by thin-layer
chromatography, TLC), 2-bromo-1-phenylethanone 3 was obtained in 64% isolated
yield. The yield of bromoketone obtained by this protocol is better than that obtained
by the previous method.[10e] In another set of experiments (Scheme 2), we obtained the
epoxide 4 in 90% isolated yield by stirring 2 at room temperature in the presence of
NaOH for 2 h in pure water. Even though many reports are available in the literature
for the synthesis of epoxides, we report herein a simple method of obtaining epoxides
from vic-dibromides at room temperature (24 C) without use of any catalyst or
organic solvent. To the best of our knowledge, the conversion of dibromides to epoxides has been rarely reported in the literature. As a variety of substituted dibromides
are easily accessible, we felt that a convenient and alternate procedure for preparation
of epoxides from dibromides is highly desirable.
Scheme 1. Functionalization of alkenes.
a-BROMOKETONES AND EPOXIDES
3235
Scheme 2. Synthesis of a-bromoketones and epoxides from vic-dibromides.
Downloaded By: [Adimurthy, Subbarayappa] At: 05:59 8 November 2010
Under this optimized condition, a variety of a-bromoketones and epoxides
were obtained from the corresponding vic-dibromides (Table 1). The bromide ion
present in solution is the source for the in situ generation of mild oxidizable species
such as Br2=BrOH by H2O2 [Eq. (1)]. BrOH is shown to be a mild and good reagent
for converting bromohydrins into a-bromoketones.[10e]
HBr þ H2 O2 ! BrOH þ H2 O
Table 1. Conversion of vic-1,2 dibromides to a-bromoketones and epoxides
ð1Þ
3236
R. D. PATIL, S. ADIMURTHY, AND B. C. RANU
Downloaded By: [Adimurthy, Subbarayappa] At: 05:59 8 November 2010
Scheme 3. Proposed mechanism for the conversion of vic-1,2-dibromides to a-bromoketones and
epoxides.
All the reactions are very clean, and good to excellent yields of epoxides were
obtained. Representative examples are illustrated in Table 1. The present reaction
conditions are compatible with different substituents in the aromatic ring (entries
1–5, Table 1). However, with highly electron-releasing substituents like methoxy,
subsequent nuclear bromiation was observed (entry 6, Table 1).
With alkyl and cyclic 1,2-dibromides, these transformations are sluggish
(entries 7 and 8, Table 1). The mechanistic pathways for both of these transformations are shown in Scheme 3.
In conclusion, the present procedure provides an efficient and convenient
method for the transformation of vic-1,2 dibromides to a-bromoketones and epoxides.
It provides an easy and alternative method to obtain a-bromoketones and epoxides.
The notable advantages offered by this method are simple operation under aqueous
medium, mild reaction conditions, excellent yields of products, and cost-effectiveness.
EXPERIMENTAL
1
H NMR spectra were recorded on a Bruker 200-MHz Fourier transform
(FT)–NMR DPX-200 instrument in CDCl3 with tetramethylsilane (TMS) as an internal standard, and 13C NMR was performed at 50 MHz. Melting points were recorded
on a Veego capillary instrument and may be uncorrected. Analytical thin-layer chromatography (TLC) was performed on Aluchrosep silica gel 60=UV254 with ultraviolet
(UV) light purchased from Merck. vic-1,2-Dibromides were prepared by our own
previously reported procedure.[10a,b] Purification of the reaction products was carried
out by column chromatography using silica gel (100–200 mesh).
General Procedure for the Synthesis of a-Bromoketones
(2-Bromo-1-phenylethanone 3 is as a representative procedure. Styrene dibromide (0.50 g; 1.9 mmol) was refluxed in water (10 mL) for 3 h to obtain styrene bromohydrin (progress of the reaction was monitored by TLC), and the reaction mixture
was allowed to attain room temperature. To this mixture, 5.0 mL dioxane and
H2O2 (1.0 equiv.) were added, and stirring was continued for a further 10 h at room
a-BROMOKETONES AND EPOXIDES
3237
temperature (25 C). The product was extracted with ethyl acetate, and the solvent
was evaporated to leave the crude product, which was purified by column chromatography on silica gel with ethyl acetate in hexane (1:25 v=v) to get pure 2-bromo-1phenylethanone 3 (0.24 g) in 64% yield.
General Procedure for the Synthesis of Epoxides
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Styrene epoxide 4 is as a representative procedure. The styrene bromohydrin
was obtained from the styrene dibromide as described, and the reaction mixture
was made basic with NaOH (1.1 equiv.) and stirred for another 2 h at room temperature (25 C). Similar workup as mentioned previously provided pure styrene epoxide 4
in 90% yield.
ACKNOWLEDGMENT
The authors gratefully acknowledge the Department of Science and Technology,
New Delhi, India, for the financial support of this project under the Green Chemistry
Task Force, Scheme No. SR=S5=GC-02A=2006.
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Direct and Selective Conversion of Benzyl Bromides to Benzaldehydes
with Aqueous H2O2 Without Catalyst
Rajendra D. Patila; Subbarayappa Adimurthya
a
Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research,
Bhavnagar, Gujarat, India
Online publication date: 21 June 2011
To cite this Article Patil, Rajendra D. and Adimurthy, Subbarayappa(2011) 'Direct and Selective Conversion of Benzyl
Bromides to Benzaldehydes with Aqueous H2O2 Without Catalyst', Synthetic Communications, 41: 18, 2712 — 2718
To link to this Article: DOI: 10.1080/00397911.2010.515347
URL: http://dx.doi.org/10.1080/00397911.2010.515347
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distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss,
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Synthetic Communications1, 41: 2712–2718, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515347
DIRECT AND SELECTIVE CONVERSION OF BENZYL
BROMIDES TO BENZALDEHYDES WITH AQUEOUS
H2O2 WITHOUT CATALYST
Rajendra D. Patil and Subbarayappa Adimurthy
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Central Salt and Marine Chemicals Research Institute, Council of Scientific
and Industrial Research, Bhavnagar, Gujarat, India
GRAPHICAL ABSTRACT
Abstract The facile and selective conversion of benzylic bromides to benzaldehydes using
H2O2 as a benign oxidizing agent in an aqueous medium is described. Under these conditions, good yields of benzaldehydes were obtained.
Keywords Benzyl bromides; hydrogen peroxide; oxidation benzaldehydes
INTRODUCTION
Organic reactions in water have received increased attention primarily because
of their environmental acceptability, abundance, and low cost.[1] Water as the reaction medium is certainly the best choice in the constant search for cheaper, cleaner,
and more efficient technologies for the transformations of organic molecules.[2]
Moreover, water also exhibits unique reactivity and selectivity that cannot be
attained in conventional organic solvents.[3]
The development of sustainable, efficient, and selective catalysts and reagents
for the oxidation of alcohols to aldehydes is an important and fundamental reaction
in academia and industry. During the past decade, many transition-metal-catalyzed
reactions[4–8] have been uncovered for direct oxidation of benzylic alcohols to aldehydes. The scarcity of these precious metals and their high price limits their applications. The conversion of benzyl halides to benzaldehydes is the best alternate as
benzyl halides are easily accessible from methyl arenes.[9] Many methods have been
Received April 7, 2010.
Address correspondence to Subbarayappa Adimurthy, Central Salt and Marine Chemicals
Research Institute, Council of Scientific and Industrial Research, G. B. Marg, Bhavnagar 364 002,
Gujarat, India. E-mail: [email protected]
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CONVERSION OF BENZYL BROMIDES
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Scheme 1. Oxidation of benzyl bromides to benzaldehydes.
developed for the conversion of benzyl halides to benzaldehydes.[10] The Kornblum
reaction is the most notable method for this transformation.[11] In continuation of
our work on the oxidation of benzylic=secondary alcohols to corresponding carbonyl compounds,[12–14] we report here the direct conversion of benzyl bromides
to benzaldehydes using H2O2 as a benign oxidizing agent, without any catalyst
and in organic solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
Various benzyl bromides (both electron-deficient and electron-rich) participated
in this reaction, yielding the corresponding benzaldehydes in good yields (79–85%).
The products are summarized in Table 1. In general, all the reactions were very neat
and simple, as indicated by TLC. By refluxing benzyl bromides in water using hydrogen
peroxide as a benign oxidizing agent, benzaldehydes were obtained directly. It should be
noted that it is possible to oxidize selectively one group without affecting the other
group in the same molecule (Table 1, entry 9). This is a unique advantage of the present
method. This method does not require the use of expensive or corrosive reagents.
The reaction of benzyl bromides proceeds smoothly, independent of the nature of
substituents (electron-deficient or electron-rich) present in the aromatic ring. The
hydrolysis of benzyl bromides yield the corresponding benzylic alcohol and hydrobromic acid [Eq. 1]. It is known that HBr-H2O2 generates molecular bromine under
aqueous medium [Eq. 2]. Further, in an aqueous medium, the molecular bromine is disproportionate to HBr and HOBr [Eq. 3].[15,16] The reactive species BrOH is reported to
be a very mild and selective oxidizing agent for the conversion of various benzylic=secondary alcohols to aldehydes=ketones.[14] Thus, in the present system, the reactive species BrOH generated in situ will effect the oxidation of benzylic alcohols to aldehydes
[Eqs. (1–3)] under mild conditions. However, the present system is not applicable for
the conversion of aliphatic bromide to corresponding aldehydes because of the stability
effects in the case of aliphatic bromides, unlike benzylic bromides.[17]
ArCH2 Br þ H2 O ! ArCH2 OH þ HBr
ð1Þ
HBr þ H2 O2 ! Br2 þ H2 O
ð2Þ
Br2 þ H2 O ! HOBr þ HBr
ð3Þ
ArCH2 OH þ BrOH ! ArCHO þ HBr þ H2 O
ð4Þ
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R. D. PATIL AND S. ADIMURTHY
Table 1. Conversion of benzyl bromides to benzaldehydes
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Entry
Benzylbromide
Time (h)
Product
Yield (%)a
1
12
83
2
14
84
3
11
84
4
14
82
5
14
83
6
16
79
7
17
80
8
18
79
9
14
82
10
16
85
11
08
No reaction
—
12
00
No reaction
—
a
Isolated yields.
CONVERSION OF BENZYL BROMIDES
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CONCLUSIONS
In conclusion, the present method describes an efficient, selective, and environmentally friendly method for the conversion of benzylic bromides to benzaldehydes
using H2O2 as a benign oxidizing agent in water under mild conditions. Although the
present system does not work for the aliphatic bromides, it eliminated the hash reaction conditions employed in earlier procedures for these oxidations. Simple reaction
conditions and excellent yields of the products make this method a facile and attractive protocol.
EXPERIMENTAL
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1
H NMR spectra were recorded on a Bruker 200-MHz Fourier transform
(FT)–NMR DPX-200 instrument in CDCl3 with tetramethylsilane (TMS) as an
internal standard, and 13C NMR was determined at 50 MHz. Melting points were
recorded on a Veego capillary instrument and may be uncorrected. Analytical
thin-layer chromatography (TLC) was performed on Aluchrosep silica gel 60=
UV254 purchased from Merck with ultraviolet light. Benzyl bromides were prepared
according to our previously reported procedure.[9] Purification of the reaction products was carried out by column chromatography using silica gel (100–200 mesh).
General Procedure for the Conversion of Benzyl Bromides to
Benzaldehydes (Benzaldehyde as Representative)
Benzyl bromide (0.5 g, 2.9 mmol) was refluxed in water (10.0 mL) for 5 h (progress of the reaction was monitored by TLC), and the reaction mixture was allowed
to attain room temperature. H2O2 (0.4 mL, 3.5 mmol) was added slowly to this reaction mixture over 2 h, and stirring was continued for a further 5 h at room temperature. After completion of the reaction, the product was extracted with ethyl acetate
(3 15 mL). The combined organic extracts were washed with sodium thiosulfate
and dried over anhydrous sodium sulfate, and the solvent was stripped out under
reduced pressure. The crude product obtained was subjected to column chromatography on silica gel to afford the pure colorless liquid (0.26 g, 2.4 mmol), benzaldehyde, in 83% yield. The spectroscopic data (IR, 1H NMR, and 13C NMR) are
in good agreement with the reported values.[14] (Caution: All the benzyl bromides
are lachrymatic, and proper care should be taken for handling.)
ACKNOWLEDGMENT
R. D. Patil is thankful to the Council of Scientific and Industrial Research,
New Delhi, India, for his senior research fellowship award.
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