A convenient halogenation of α,β-unsaturated carbonyl compounds with OXONE and hydrohalic acid (HBr,HCl)

Article abstract of DOI:10.1055/s-2004-831232

Mixtures of OXONE and hydrobromic acid or hydrochloric acid afford solutions of bromine or chlorine, respectively, α-Bromo- or α-chloro-α,β-unsaturated carbonyl compounds were prepared by addition of hydrobromic acid or hydrochloric acid to the mixture of

Full text of DOI:10.1055/s-2004-831232

PAPER
2641
A Convenient Halogenation of a,b-Unsaturated Carbonyl Compounds with
OXONE® and Hydrohalic Acid (HBr, HCl)
Halogenation of
a
,
y
b
-Unsaturate
o
d Carbonyl
C
u
ompounds
w
nith OX ®
O
NEg-Mahn Kim,* In-Hwan Park
Korea Research Institute of Chemical Technology, Yusong P. O. Box 107, Taejon 305-600, Korea
Fax +11(8)428614151; E-mail: kmkim@pado.krict.re.kr
Received 17 June 2004; revised 16 July 2004
CH2Cl2 enough to dissolve OXONE®, the 97% yield of 2
Abstract: Mixtures of OXONE® and hydrobromic acid or hydro-
chloric acid afford solutions of bromine or chlorine, respectively. a-
Bromo- or a-chloro-a,b-unsaturated carbonyl compounds were pre-
pared by addition of hydrobromic acid or hydrochloric acid to the
was achieved (Scheme 1). The results showed that molec-
ular bromine is effectively generated by oxidation of hy-
drobromic acid with OXONE® in aqueous medium. In the
mixture of a,b-unsaturated carbonyl compounds and OXONE® in reaction it was found to be easy to control the amount of
CH2Cl2 followed by treatment of Et3N in moderate to good yields.
bromine generated by adjusting concentration of hydro-
bromic acid with OXONE®.
Key words: halogenation, OXONE®, hydrobromic acid, hydro-
chloric acid, a,b-unsaturated carbonyl compounds
O
O
O
OXONE
2 N HBr
Et3N
Br
Ph
Br
Ph
a-Halo-a,b-unsaturated carbonyl compounds are a class
of important intermediates for the synthesis of a-carbon
substituted enones1 and natural products.2 They are gener-
ally prepared by direct addition-elimination reaction with
halogen (Br2, Cl2).3 The use of molecular halogen suffers
from potentially environmental hazard and the utilization
in large scale operation often causes problem. Several in-
direct methods for the preparation of a-halo-a,b-enones
have been studied such as addition-elimination of expen-
sive phenylselenenyl halides,4 deoxygenation of a,b-ep-
oxy ketones with BF3·Et2O and tetraethylammonium
bromide,5 and the reaction of secondary alkynols with N-
halosuccinimide in the presence of Koser’s reagent6 have
been reported. Oxidative halogenation includes the reac-
tion with HBr and hydrogen peroxide promoted by phase
transfer catalyst,7 with OXONE® and sodium halides,8
with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxol-3(1H)-
one (DMP) and tetraethylammonium bromide,9 and with
anhydrous HCl in DMF and mCPBA.10 For recycling in-
dustrial by-product HCl or HBr, we have studied the oxi-
dative halogenation of a,b-unsaturated carbonyl
compounds and alkenes with hydrohalic acid (HBr and
HCl) and OXONE® which is cost-effectiveness, efficient
and mild oxidant with stable and nontoxic nature.
CH2Cl2
r.t. 2 h,
97%
CH2Cl2
r.t. 15 h,
92%
Br
Ph
3
2
1
Scheme 1
When the chlorination of 1 with 2 N HCl and OXONE® in
CH2Cl2 was attempted, the product was the corresponding
3,4-dichloro-4-phenyl-2-butanone which was difficult to
isolate due to its spontaneous dehydrochlorination during
the purification procedure or upon standing neat at room
temperature to afford stable 3-chloro-4-phenyl-3-buten-2-
one.8,10a In an effort to optimize the yields of the halogen
addition product, dehydrochlorination was conducted by
cautious addition of Et3N to afford 3-chloro-4-phenyl-3-
buten-2-one (3b) in 77% of yield (E/Z ratio is 37:63).
Similarly, treatment of 2 N HBr to a mixture of 4-phenyl-
3-buten-2-one and OXONE® in CH2Cl2 followed by dehy-
drobromination with excess use of Et3N afforded (E)-3-
bromo-4-phenyl-3-buten-2-one (3a, 15%) and (Z)-3-bro-
mo-4-phenyl-3-buten-2-one (3a, 77%), respectively
(Table 1, entry 1). The structures of steroisomers are sup-
ported by the appearance of singlet vinylic proton in its
NMR spectrum at d = 7.37 (E-form) and d = 8.03 (Z-
form).3a The reaction of trans-cinnamaldehyde under the
same condition was stereoselective and afforded exclu-
sively Z-isomers of trans-2-bromo- or trans-2-chloro-cin-
namaldehyde (3c and 3d) in modest yields (entry 2). The
bromination of sterically hindered 4-methyl-3-penten-2-
one under the same condition gave excellent yield of di-
bromo adduct (isolated in 99% yield), but dehydrobromi-
nation with Et3N was inefficient giving only 37% yield of
3-bromo-4-methyl-3-penten-2-one (3e, entry 3).
In continuation of our studies,10a we have examined the
bromination of trans-4-phenyl-3-buten-2-one (1) with hy-
drogen bromide (30% in HOAc) in DMF and OXONE®,
and found that the product was 3,4-dibromo-4-phenyl-2-
butanone (2) in 67% yield. When the reaction with hydro-
gen bromide in DMF was replaced by hydrobromic acid
(48% in water) in DMF with OXONE®, the isolated yield
of dibromo-adduct (2) increased to 83%. When the same
reaction was repeated with aqueous 2 N HBr (2 equiv) in
In a similar manner, treatment of other acyclic or cyclic
enones such as n-4-hexen-3-one, 2-cyclohexenone and
4,4-dimethyl-2-cyclohexenone gave the corresponding a-
halo enones in modest to good yields (entries 4–6). The
SYNTHESIS 2004, No. 16, pp 2641–2644
Advanced online publication: 11.10.2004
DOI: 10.1055/s-2004-831232; Art ID: F09104SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

2642
K.-M. Kim, I.-H. Park
PAPER
work for NaBr or NaCl with OXONE® in two phase or-
ganic solvent and water.7 Thus, the treatment of 2 N HBr
or 2 N HCl with a mixture of ethyl trans-cinnamate and
OXONE® in CH2Cl2 followed by dehydrohalogenation
yielded the desired ethyl a-bromocinnamate (3o) or ethyl
a-chlorocinnamate (3p) were obtained as a mixture of ste-
reoisomers in good yields (entry 9). Similarly, when the
reaction was repeated with sterically hindered ethyl 3,3-
dimethacrylate under the same conditions, ethyl 2-bromo-
3,3-dimethacrylate (3q) was isolated in 79% yield (entry
10).
Table 1 Halogenation of a,b-Unsaturated Carbonyl Compounds
Using OXONE® and Hydrobromic Acid or Hydrochloric Acida
Entry Substrate
HX
Product
(X = Br, Cl)
Yield (%)b
(E/Z ratios)c
1
HBr
HCl
3a (92) (16:84)d
3b (77) (37:63)d
O
X
O
Ph
Ph
2
3
HBr
HCl
3c (70) (0:100)d
3d (64) (0:100)d
O
O
O
X
H
H
Ph
O
O
O
O
OXONE
Ph
Et3N
Br
Br
2 N HBr
Br
OH
HBr
3e (37)
O
CH2Cl2
84%
Br
OH
1 h
7
5
6
Scheme 2
4
5
6
HBr
HCl
3f (74)
3g (48)
O
O
X
The reaction of 5,5-dimethyl-3-hydroxy-cyclohex-2-
enone (5) with 2 N HBr and OXONE® gave exclusively
2,2-dibromo compound 6 which was treated with Et3N
without isolation to afford 2-bromo-5,5-dimethyl-3-hy-
droxycyclohex-2-enone (7) in 84% yield (Scheme 2). On
the other hand, the reaction of 5,5-dimethyl-3-methoxy
cyclohexen-2-one (8) with 2 N HBr and OXONE® gave
mixtures of 2,2-dibromo compound 6 and 2,6-dibromo
compound 9, which were treated with Et3N to afford com-
pound 7 and 2-bromo-5,5-dimethyl-3-methoxycyclohex-
en-2-one (10) in 37% and 48% yields, respectively
(Scheme 3).11
HBr
HCl
3h (99)
3i (63)
O
X
O
HBr
HCl
3j (98)
3k (61)
O
O
X
7
HBr
HCl
O
X
3l (55)
3m (20)
O
O
O
8
9
HBr
3n (92)
Br
O
O
O
O
Br
O
O
O
O
OXONE
Br
Br
HBr
HCl
3o (89) (46:54)
3p (82) (27:73)
+
O
O
2 N HBr
O
O
Br
X
EtO
EtO
EtO
EtO
OMe
1 h
OMe
9 (52%)
Ph
Ph
6 (41%)
8
O
10
HBr
3q (79)
O
Et3N
Br
Br
OH
7 (37%)
Br
OMe
+
CH2Cl2
a Substrate (5 mmol), OXONE® (3.7 g, 6 mmol) in CH2Cl2 (20 mL)
and 2 N HX (X = Br or Cl, 11 mmol) were allowed to react for 2 h
and Et3N (3 equiv) was stirred for 2 h for dehydrohalogenation.
b Isolated yield determined by silica gel (70–230 mesh) column chro-
matography. All compounds showed satisfactory spectroscopic data
(NMR, IR, Mass).
10 (48%)
Scheme 3
Similarly, the reaction proved to be effective in alkenes.
The reaction of 1,4-dihydroxy-2-butene (11) and 2 N HBr
in the presence of OXONE® afforded 2,3-dibromo-1,4-di-
hydroxybutane (12) in 87% yield in 5 minutes
(Equation 1). Thus, the method appears to be quite gener-
al for a-halo-a,b-unsaturated carbonyl compounds and
alkenes.
c The values in parenthesis are isolated yields of the stereoisomers.
d The ratios of stereoisomers were determined by 1H NMR analysis.
reaction with chromone gave low yields of a-chloro- and
a-bromo-chromone in 20% and 55% yields, respectively,
together with the recovered chromone (entry 7), whereas
the reaction with coumarin, a class of cyclic lactone, gave
excellent yield of a-bromo compound 3n even in the reac-
tion condition of 2 N HBr and OXONE® in DMF system
(entry 8).
OXONE
Br
Br
2 N HBr
HO
OH
HO
OH
r.t., 5 min
87%
11
12
Equation 1
The strongly acidic condition may provide advantage for
the halogenation of a,b-unsaturated esters, which does not
Synthesis 2004, No. 16, 2641–2644 © Thieme Stuttgart · New York

PAPER
Halogenation of a,b-Unsaturated Carbonyl Compounds with OXONE®
2643
3-Bromo-4-phenyl-3-buten-2-one; General Procedure
To a mixture of 4-phenyl-3-buten-2-one (0.73 g, 5 mmol) and
OXONE® (3.7 g, 6 mmol) in CH2Cl2 (20 mL) was added 2 N HBr
(5.5 mL, 11 mmol of HBr) in one portion resulting in dark red col-
ored solution. After stirring for 2 h at r.t., the color disappeared and
Et3N (4 mL) was added cautiously. After stirring for further 12 h
and usual work-up, purification of the crude product by silica gel
column chromatography afforded (E)-3-bromo-4-phenyl-3-buten-
2-one (0.17g, 15%) and (Z)-3-bromo-4-phenyl-3-buten-2-one
(0.86 g, 77%) as oil.
4-Chloro-hex-4-en-3-one (3g)
1H NMR (CDCl3): d = 1.13 (t, 3 H), 1.98 (d, J = 6.8 Hz, 3 H), 2.76
(q, 2 H), 7.05 (q, J = 6.8 Hz, 1 H).
2-Bromocyclohex-2-en-1-one (3h)
IR (KBr): 1681 (s), 1652 (s), 1598 (s), 1318 (m), 1425 (m), 1125
(m) cm–1.
1H NMR (CDCl3): d = 2.02–2.15 (m, 2 H), 2.44–2.49 (m, 2 H),
2.52–2.67 (m, 2 H), 7.45 (t, J = 4.5 Hz, 1 H).
MS (70 ev): m/z (%) = 176 (24) [M + 2], 174 (23) [M+], 148 (26),
146 (26), 86 (64), 84 (100).
(E)-3-Bromo-4-phenyl-3-buten-2-one (3a)
IR (NaCl): 2347 (s), 1726 (m), 1710 (s), 1668 (s) cm–1.
2-Bromo-4,4-dimethylcyclohexeneone (3j)
IR (NaCl): 1697 (s), 1597 (m), 1468 (w), 1323 (m), 1145 (m), 813
(m) cm–1.
1H NMR (CDCl3): d = 2.27 (s, 3 H), 7.23–7.37 (m, 6 H).
MS (70 eV): m/z (%) = 226 (23) [M + 2], 224 (25) [M+], 145 (73),
102, 43 (100).
1H NMR (CDCl3): d = 1.17 (s, 6 H), 1.87 (t, J = 6.8 Hz, 2 H), 2.60
(t, J = 6.8 Hz, 2 H), 7.08 (s, 1 H).
MS (70 ev): m/z (%) = 205 (3.82) [M + 2], 203 (3.76) [M+], 123
(Z)-3-Bromo-4-phenyl-3-buten-2-one (3a)
IR (NaCl): 2347 (m), 1726 (m), 1630 (s), 1467 (m) cm–1.
(100).
1H NMR (CDCl3): d = 2.61 (s, 3 H), 7.41–7.46 (m, 3 H), 7.85–7.90
(m, 2 H), 8.03 (s, 1 H).
MS (70 eV): m/z (%) = 226 (15) [M + 2], 224 (16) [M+], 145 (73),
2-Bromochromone (3l)
Mp 94–98 °C.
102 (100).
IR (KBr): 1624 (s), 1529 (m), 1482 (m), 1089 (m) cm–1.
1H NMR (CDCl3): d = 7.24–7.49 (m, 2 H), 7.66–7.75 (m, 1 H), 8.22
3,4-Dibromo-4-phenyl-2-butanone (2)
1H NMR (CDCl3): d = 2.45 (s, 3 H), 4.93 (d, J = 11.8 Hz, 1 H), 5.32
(d, J = 11.8 Hz, 1 H), 7.37–7.43 (m, 5 H).
(s, 1 H), 8.22–8.29 (m, 1 H).
MS (70 eV): m/z (%) = 226 (20) [M+], 224 (24) [M], 145(13), 120
(38), 63 (100).
MS (70 eV): m/z (%) = 306 (5) [M + 2], 304 (15) [M], 302 (5) [M –
2], 225 (85).
2-Bromocoumarine (3n)
Mp 110–111 °C.
1H NMR (CDCl3): d = 7.28–7.35 (m, 2 H), 7.46–7.62 (m, 2 H), 8.11
(s, 1 H).
(E)-3-Chloro-4-phenyl-3-buten-2-one (3b)
1H NMR (CDCl3): d = 2.27 (s, 3 H), 7.17 (s, 1 H), 7.26–7.53 (m, 5
H).
MS (70 eV): m/z (%) = 180 (15) [M+], 84 (100).
MS (70 eV): m/z (%) = 226 (73) [M + 2], 224 (73) [M + 2], 198 (21),
196 (21), 145 (27).
(Z)-3-Chloro-4-phenyl-3-buten-2-one (3b)
1H NMR (CDCl3): d = 2.50 (s, 3 H), 7.25–7.41 (m, 3 H), 7.72 (s, 1
H), 7.81–7.85 (m, 2 H).
Ethyl a-Bromocinnamate (3o)
IR (NaCl): 1763 (s), 1636 (m), 1482 (m), 1247 (s), 1064 (s) cm–1.
(E)-Ethyl a-Bromocinnamate: 1H NMR (CDCl3): d = 1.18 (t, 3 H),
(Z)-2-Bromo-3-phenylpropanal (3c)
4.21 (q, 2 H), 7.26–7.36 (m, 6 H).
IR (KBr): 2348 (s), 1725 (m), 1669 (s), 1530 (s) cm–1.
(Z)-Ethyl a-Bromocinnamate: 1H NMR (CDCl3): d = 1.39 (t, 3 H),
4.36 (q, 2 H), 7.39–7.45 (m, 3 H), 7.83–7.88 (m, 2 H), 8.22 (s, 1 H).
MS (70 eV): m/z = 256 (24) [M + 2], 254 (25) [M+], 175 (84),
147(100), 129 (33), 102 (81).
1H NMR (CDCl3): d = 7.45–7.52 (m, 3 H), 7.90 (s, 1 H), 7.97–8.02
(m, 2 H), 9.34 (s, 1 H).
MS (70 eV): m/z (%) = 212 (47) [M + 2], 210 (49) [M+], 103 (100),
102 (91).
(E)-Ethyl a-Chlorocinnamate (3p)
(Z)-2-Chloro-3-phenylpropanal (3d)
1H NMR (CDCl3): d = 1.17 (t, 3 H), 4.21 (q, 2 H), 7.25–7.36 (m, 6
IR (KBr): 2348 (s), 1694 (s), 1609 (s), 1121 (s) cm–1.
H).
1H NMR (CDCl3): d = 7.45–7.53 (m, 3 H), 7.55 (s, 1 H), 7.91–7.98
(m, 2 H), 9.51 (s, 1 H).
MS (70 eV): m/z (%) = 167 (39) [M+], 165 (100), 103 (89), 102 (55).
(Z)-Ethyl a-Chlorocinnamate (3p)
IR (NaCl): 1728 (s), 1618 (m), 1492 (m), 1263 (s), 1199 (s) cm–1.
1H NMR (CDCl3): d = 1.38(t, 3 H), 4.36 (q, 2 H), 7.39–7.45 (m, 3
H), 7.82–7.87 (m, 2 H), 7.91 (s, 1 H).
MS (70 eV): m/z = 245 (7) [M+], 244 (8), 210 (59), 147 (55), 129
3-Bromo-4-methyl-3-penten-2-one (3e)
1H NMR (CDCl3): d = 2.02 (s, 3 H), 2.03 (s, 3 H), 2.47 (s, 3 H).
(21), 102 (100).
4-Bromo-hex-4-en-3-one (3f)
IR (NaCl): 1693 (s), 1597 (m), 1619 (w), 1323 (m), 1188(m), 1158
Ethyl 2-Bromo-3,3-dimethylacrylate (3q)
IR (NaCl): 1728 (s), 1464 (m), 1371 (m), 1266 (s), 1182 (s), 1030
(m) cm–1.
1H NMR (CDCl3): d = 1.30 (t, 3 H), 1.92 (s, 3 H), 2.03 (s, 3 H), 4.39
(q, 2 H).
(m) cm–1.
1H NMR (CDCl3): d = 1.14 (t, 3 H), 2.00 (d, J = 6.8 Hz, 3 H), 2.79
(q, 2 H), 7.25 (q, J = 6.8 Hz, 1 H).
MS (70 eV): m/z (%) = 178 (22.5) [M+], 121 (22.8), 84 (46), 58
(58.6), 43 (100).
Synthesis 2004, No. 16, 2641–2644 © Thieme Stuttgart · New York

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K.-M. Kim, I.-H. Park
PAPER
MS (70 ev): m/z (%) = 209 (16) [M + 2], 207 (18) [M+], 135 (14),
55 (100).
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2,2-Dibromo-5,5-dimethylcyclohexane-1,3-dione (6)
1H NMR (CDCl3): d = 1.02 (s, 6 H), 3.01 (s, 4 H).
MS (70 eV): m/z (%) = 300 (2.42) [M + 2], 298 (2.77) [M+], 83
(100).
2-Bromo-5,5-dimethyl-3-hydroxycyclohex-2-en-1-one (7)
Mp 158–163 °C.
IR (KBr): 2347 (s), 1629 (s), 1529 (m), 1319 (s) cm–1.
1H NMR (CDCl3): d = 1.12 (s, 6 H), 2.44 (s, 2 H), 2.53 (s, 2 H), 6.61
(s, 1 H).
MS (70 eV): m/z (%) = 220 (19) [M + 2], 218 (20) [M+], 164 (70),
162 (61), 83 (66), 55 (100).
2,6-dibromo-5,5-dimethyl-3-methoxycyclohex-2-en-1-one (9)
1H NMR (CDCl3): d = 1.25 (s, 3 H), 1.32 (s, 3 H), 2.41 (dd, J = 1.7
Hz, J = 16.8 Hz, 1 H), 2.45 (dd, J = 1.7 Hz, J = 16.8 Hz, 1 H), 4.11
(s, 3 H), 4.61 (d, J = 1.7 Hz, 1 H).
MS (70 eV): m/z (%) = 314 (11.81) [M + 2], 312 (11.87) [M+], 124
(100).
2-Bromo-5,5-dimethyl-3-methoxycyclohex-2-en-1-one (10)
Mp 95–102 °C.
IR (KBr): 2347 (s), 1690 (s), 1610 (s), 1482 (m), 1385 (m), 1328
(m), 1269 (s) cm–1.
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(s, 3 H).
MS (70 eV): m/z (%) = 234 (17.03) [M + 2], 232 (18.87) [M+], 178
(22.29), 175 (29.67), 68 (91), 67 (100).
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Synthesis 2004, No. 16, 2641–2644 © Thieme Stuttgart · New York