Indium-mediated allylation reactions of α-chlorocarbonyl compounds and preparation of allylic epoxides

Article abstract of DOI:10.1039/b101111l

Indium-mediated allylation of α-chlorocarbonyl compounds with various allyl bromides in aqueous media gave the corresponding homoallylic chlorohydrins, which could be transformed into the corresponding epoxides in the presence of a base. These reactions w

Full text of DOI:10.1039/b101111l

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Indium-mediated allylation reactions of ꢀ-chlorocarbonyl
compounds and preparation of allylic epoxides
Jeong Ah Shin,ab Kyung Il Choi,a Ae Nim Pae,a Hun Yeong Koh,a Han-Young Kangb and
Yong Seo Cho*a
1
a Biochemicals Research Center, Korea Institute of Science and Technology,
Cheongryang P.O. Box 131, Seoul 130-650, Korea. Fax: ϩ82-2-958-5189;
E-mail: ys4049@kist.re.kr
b Department of Chemistry, Chungbuk National University Cheongju, Chungbuk 361-763,
Korea
Received 1st February 2001, Accepted 15th March 2001
First published as an Advance Article on the web 30th March 2001
Indium-mediated allylation of ꢀ-chlorocarbonyl com-
pounds with various allyl bromides in aqueous media
gave the corresponding homoallylic chlorohydrins, which
could be transformed into the corresponding epoxides
in the presence of a base. These reactions were strongly
dependent upon both the substituents at the carbon
bearing chlorine and the allyl bromides used.
reaction times specified in Table 1, the mixture was extracted
with ethyl acetate (10 mL × 2), dried and concentrated. Purifi-
cation of the crude products by silica gel chromatography gave
the desired products 1. Since the dehalogenation occurred com-
petitively, the allylation reactions were highly dependent upon
the substrates. While the allylation reactions in entries 1, 3, and
5 proceeded at 50 ЊC to provide the homoallylic chlorohydrins 1
in modest to good yields with trace amounts of reduced
products, those in entries 2 and 4 gave predominantly reduced
products under the same reaction conditions. In the cases of
entries 2 and 4, the desired allylated products were obtained in
low yields at room temperature with the recovery of starting
materials. Regarding allyl bromides, γ-substituted ones, i.e.
crotyl bromide C and 4-bromo-2-methylbut-2-ene D, gave the
corresponding products in relatively low yields. Transformation
of chlorohydrins 1 to epoxides was achieved by using appropri-
ate bases to give the corresponding epoxides (2) in good yields
(Table 1).
As shown in Table 2, the allylation reactions of α-chloro-
carbonyl compounds containing heterocycles and the conver-
sion of the resulting chlorohydrins 3 to epoxides were examined
under the same reaction conditions mentioned above. Allyl-
ation of chloroacetylthiophene (entry 1) and chloroacetylfuran
(entry 2) proceeded similarly. The chlorohydrins 3 yielded the
corresponding epoxide 4 by reacting with a base. In some cases,
however, the first generated epoxide 4 was converted to the
two compounds 5 and 6 after the epoxidation reaction was
quenched with saturated NH4Cl solution.
Introduction
Halohydrins constitute important intermediates in synthetic
organic chemistry. They have usually been prepared by addition
of hypohalous acids or hypohalites to alkenes or by opening
epoxides by hydrohalic acids.1 Recently, it has been reported
that metal-mediated addition of haloallyl or halovinyl halides
to ketones provided the corresponding halohydrin.2 Reductive
dehalogenation reactions of α-halocarbonyl compounds using
metals in organic solvents have also been studied extensively.3,4
To the best of our knowledge, however, metal-mediated allyl-
ation reactions of α-halocarbonyl compounds have never been
reported presumably due to the competing dehalogenation
reactions.
Herein, we wish to report the indium-mediated allylation of
α-chlorocarbonyl compounds, which resulted in the corre-
sponding homoallylic chlorohydrins, and synthesis of the
corresponding epoxides from the thus prepared chlorohydrins
(Scheme 1).
A plausible mechanism for the formation of 5 and 6 might
involve two types of rearrangements after the cleavage of the
C–O bond of the epoxides: path (a) hydride migration and path
(b) addition of water molecule (Scheme 2).5
Scheme 1
Results and discussion
Scheme 2
The results are summarized in Table 1. A general procedure for
the allylation reaction is as follows: a mixture of an α-chloro-
carbonyl compound (0.5 mmol), indium (0.6 mmol) and an
allyl bromide (0.75 mmol) was stirred in 6 mL of aqueous THF
(THF–H2O = 1 : 3, v/v) at rt (or 50 ЊC). After stirring for the
In summary, we have accomplished the indium-mediated
allylation of α-chlorocarbonyl compounds in aqueous media
and the preparation of epoxides from the chlorohydrins
obtained. Allylation of α-chlorocarbonyl compounds was
946
J. Chem. Soc., Perkin Trans. 1, 2001, 946–948
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101111l

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Table 1 Indium-mediated allylation reaction of α-chlorocarbonyl compounds and preparation of allylic epoxides
Entry
1
Substrate
Bromide
Temp./ЊC
Time/h
Yield (1, %)a
Base/solvent
Time/h
Yield (2, %)a
A
B
C
D
50
50
50
50
4
1
5
3
88
85
55
38
DBU/THF
DBU/THF
DBU/THF
DBU/THF
12
4
4
81
78
89
99
6
A
B
C
D
rt
rt
rt
rt
5
3
5
5
27(39)b (48/52)e NaH/DMF
31(35)b (45/55)e NaH/DMF
34(39)b (48/52)e NaH/DMF
4
4
4
79
nrc
nrc
nrc
2
3
4
5
nr
—
—
A
B
C
D
50
50
50
50
4
2
4
4
71(48/52)e
71(31/69)e
58(48/52)e
52(50/50)e
DBU/THF
DBU/THF
DBU/THF
DBU/THF
12
12
8
93
67
98
nrc
8
A
B
C
D
rt
rt
rt
rt
7
5
4
5
78(50/50)e
71(50/50)e
53(50/50)e
nr
K2CO3/acetone
K2CO3/acetone
K2CO3/acetone
—
2.5
2.5
12
87
nrc
71
—
—
A
B
C
D
50
50
50
50
2
2
4
4
97
93
65
50
NaH/DMF
NaH/DMF
NaH/DMF
NaH/DMF
1.5d
—
76
nrc
90
71
2d
1d
a Isolated yield. b Starting material recovered. c No reaction. d At 0 ЊC. e Diastereoisomers(%).
Table 2 Indium-mediated allylation reaction of α-chlorocarbonyl heterocycles and preparation of allylic epoxides
Entry
1
Substrate
Bromide
Time/h
Yield (3, %)a
Time/h
Yield (4, %)a
Yield (5, %)a
Yield (6, %)a
A
B
C
D
2.5
1.5
4.0
3.5b
65
99
67
59
1.0
2.0
2.5
2.0
—
97
—
99
30
—
79
—
22
—
16
—
A
B
C
D
5.0
4.0
3.0
5.0
64
73
62
53
1.5
0.5
2.5
7.0
—
—
—
66
24
21
23
—
40
61
28
—
2
a Isolated yield. b At rt.
strongly dependent upon both the substrates and the allyl
bromides used. With respect to the epoxide formation, hetero-
cyclic α-chlorocarbonyl compounds provided various products
via rearrangements after the formation of epoxides.
or a Hewlett Packard MSD 5972 series spectrometer coupled
with a Hewlett Packard 5890 series II gas chromatograph.
Identification of the products was made on the basis of IR,
1H NMR and mass evidence in comparison with authentic
samples.
Allylation reactions of ꢀ-chlorocarbonyl compounds. General
procedure
Experimental
All starting materials were obtained commercially from Aldrich
or prepared by the known methods. 1H (300 MHz) and 13C (75
MHz) spectra were recorded in deuteriochloroform, unless
otherwise stated, on a Varian Gemini 300 NMR spectrometer
with tetramethylsilane as internal standard. Mass spectra were
recorded on either a VG70-VSEQ (VG ANALYTICAL, UK)
Method A. To a solution of 2-chloroacetophenone (309 mg,
2.0 mmol) in 25% aq. THF (5 mL) were added allyl bromide
(260 µL, 3.0 mmol) and indium powder (276 mg, 2.4 mmol).
The solution was stirred at 40–50 ЊC for 4 h. The reaction mix-
ture was cooled at room temperature and quenched with 6 M
J. Chem. Soc., Perkin Trans. 1, 2001, 946–948
947

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HCl. It was extracted with CH2Cl2, the organic layer was dried
over anhydrous MgSO4 and concentrated. Flash chromato-
graphy of the residue (benzene–ethyl ether–hexane 2 : 1 : 6) gave
the chlorohydrin (347 mg, 88%) and acetophenone (9.5 mg, 4%).
δH(300 MHz; CDCl3) 7.37 (m, 5H, ArH), 5.61 (m, 1H,
to the reaction mixture and it was washed with H2O. The
organic layer was dried and concentrated to give the epoxide
(60 mg, 79%). δH(300 MHz; CDCl3) 7.3 (m, 5H, ArH), 5.75 (m,
1H, CH ᎐CH-), 5.16 (t, 2H, CH ᎐CH-), 3.11 (q, 1H, CH OC),
᎐
᎐
2
2
2
2.84 (q, 1H, CH ᎐CHCH -), 2.51 (q, 1H, CH ᎐CHCH -), 0.99
᎐
2
᎐
2
2
2
CH ᎐CHCH -), 5.15 (t, 2H, CH ᎐CHCH -), 3.85 (dd, J = 3.9,
(d, 3H, CH3CHCl).
᎐
᎐
2
2
2
2
9.1 Hz, 2H, -CH Cl), 2.71 (d, J = 7.5 Hz, 2H, CH ᎐CHCH -),
2.45 (s, 1H, -OH).
᎐
2
2
2
Method C. The chlorohydrin (from bromide A and entry 4 in
Table 1, 142 mg, 0.5 mmol) was dissolved in acetone and K2CO3
(110 mg, 0.8 mmol) was added. The resulting solution was at
room temperature for 2.5 h. The reaction mixture was extracted
with CH2Cl2. The organic layer was dried and concentrated to
give the epoxide (107 mg, 87%). δH(300 MHz; CDCl3) 7.35 (m,
5H, ArH), 5.73 (m, 1H, CH ᎐CHCH -), 5.09 (t, 2H, CH ᎐
Method B. To a solution of ethyl 2-chloro-3-oxo-3-phenyl-
propanoate (340 mg, 1.5 mmol) in 25% aq. THF (5 mL) were
added allyl bromide (195 µL, 2.3 mmol) and indium powder
(207 mg, 1.8 mmol). The solution was stirred at room temper-
ature for 7 h. The reaction mixture was quenched with 6 M
HCl, then was extracted with CH2Cl2. The organic layer was
dried over anhydrous MgSO4 and concentrated. Flash chrom-
atography of the residue (hexane–ethyl acetate 20 : 1) gave the
chlorohydrin (313 mg, 78%). δH(300 MHz; CDCl3) 7.42–7.27
᎐
᎐
2
2
2
CHCH2-), 4.3 (m, 2H, -OCH2CH3), 3.5 (s, 1H, COCH), 2.92
(dd, J = 7.1, 15.1 Hz, 1H, CH ᎐CHCH -), 2.78 (dd, J = 7.1, 15.1
᎐
2
2
Hz, 1H, CH ᎐CHCH -), 1.32 (t, 3H, -OCH CH ).
᎐
2
2
2
3
(m, 5H, ArH), 5.5 (m, 1H, CH ᎐CHCH -), 5.05 (t, 2H,
᎐
2
2
Acknowledgement
CH ᎐CHCH -), 4.66 (s, 1H, CCHCl), 3.97 (m, 3H, -OCH CH
᎐
2
2
2
3
and -OH), 2.85 (dd, J = 6.9, 13.9 Hz, 1H, CH ᎐CHCH -), 2.7
This work is financially supported by the Korean Ministry of
Science and Technology (Critical Technology-21) and the
Center for Molecular Design and Synthesis (CMDS), KAIST.
᎐
2
2
(dd, J = 7.4, 13.9 Hz, 1H, CH ᎐CHCH -), 0.95 (t, J = 7.14, 3H,
᎐
2
2
-OCH2CH3).
Preparation of allylic epoxides. General procedure
References
Method A. The chlorohydrin (from bromide A and entry 1 in
Table 1, 100 mg, 0.5 mmol), DBU (224 µL, 1.5 mmol) in THF
were stirred at room temperature for 14 h. The reaction mixture
was extracted with CH2Cl2 and washed 1 M HCl. The organic
layer was dried and concentrated to give the epoxide (66 mg,
81%). δH(300 MHz; CDCl3) 7.35 (m, 5H, ArH), 5.8 (m, 1H,
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᎐
2
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᎐
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4 R. Yanada, K. Bessho and K. Yanada, Chem. Lett., 1994, 1279;
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Method B. The chlorohydrin (from bromide A and entry 2 in
Table 1, 93 mg, 0.44 mmol) was dissolved in DMF and NaH
(80% dispersion in mineral oil, 40 mg, 1.32 mmol) was added.
The resulting solution was stirred at room temperature for 4 h,
then it was quenched with sat. NH4Cl. Ethyl acetate was added
948
J. Chem. Soc., Perkin Trans. 1, 2001, 946–948