Regio- and stereoselective reaction of α-epoxyketones with AlCl 3: An efficient approach for the synthesis of functionalized β-chlorohydrines

Article abstract of DOI:10.1002/jccs.200900059

A simple and efficient synthesis of functionalized β-chlorohydrins is described from the regio- and stereoselective reaction of α-epoxyketones with AlCl₃ in acetonitrile at room temperature.

Full text of DOI:10.1002/jccs.200900059

4
04
Journal of the Chinese Chemical Society, 2009, 56, 404-407
Regio- and Stereoselective Reaction of a-Epoxyketones with AlCl : An
3
Efficient Approach for the Synthesis of Functionalized b-Chlorohydrines
Farzad Nikpour,* Roya Mozafari and Baran Mohammadi Mogaddam
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box 66315-416,
Sanandaj, Iran
A simple and efficient synthesis of functionalized b-chlorohydrins is described from the regio- and
3
stereoselective reaction of a-epoxyketones with AlCl in acetonitrile at room temperature.
Keywords: a-Epoxyketones; Chalcone oxides; b-Chlorohydrins; Stereoselective reaction; Ring
opening reaction.
INTRODUCTION
Epoxides are versatile intermediates in a broad vari-
compounds or to modify the reactions.
ety of syntheses and special attentions have been focused
on their reactions. Their meaningful utilization depends on
the availability of stereo- and regioselective Lewis acid
catalyzed ring opening reactions with nucleophiles such as
the regioselective formation of amino- and azido alcohols
RESULTS AND DISCUSSION
Here, we report the regio- and stereoselective forma-
tion of functionalized b-chlorohydrins 2 from the reaction
3
of chalcone oxides 1 with AlCl in MeCN at room tempera-
ture (Scheme I). The procedure is simple and the reaction
conditions are mild. Good product yields obtain with good
to high stereoselectivity (with the exception of 2g) in short
reaction times. Results are summarized in Table 1.
1
and b-halohydrins. The vicinal halohyrins are useful syn-
thetic intermediates and have found wide applications in
2
organic transformations and in the synthesis of marine nat-
3
ural products. The b-chlorohydrins preparation by direct
The stereochemistry of the major products was iden-
tified as erythro. The erythro-configuration of these b-
5
chlorohydrines is more stable than the threo. Also, based
reaction of an epoxide with a metal chloride has been re-
4
ported. However, only in few of these reports the con-
certed improvement is observed in all of the characteristic
on our previous investigation on the acetolysis of a-epoxy-
6
features of the reaction. For example, CeCl
3
in acetonitrile
ketones 1, in the erythro-configuration, the C
a
-H and
-H) appear in lower field in H NMR, in
comparison with those in threo-orientation, because of the
anisotropic effect of C -aroyl and C -aryl groups; further-
more, the coupling-constants of H in the erythro-con-
4
d
1
failed to give any product at room temperature. Further-
more, the unsymmetrical 1,2-disubstituted epoxides such
as a-epoxyketones have been rarely tested and both of the
regio- and stereoselectivity of the reactions have not been
b a
C -H (especially C
a
b
a
H
b
4
a,4c,4d,4i,4j
satisfactorily observed concertedly.
Therefore, as
figurations are larger than of those in the threo (Fig. 1).
Although we made no attempts to characterize the
produced organoaluminum intermediates in the reactions,
the proposed mechanism is shown in Scheme II. It is rea-
there is a continued interest in the selective ring opening of
epoxides to give b-halohydrins, it is important to use suit-
able reagents or effective methodology to synthesize these
Scheme I

Synthesis of Functionalized b-Chlorohydrines
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 405
Table 1. Reaction of the a-epoxyketones 1a-1h with AlCl in MeCN at room temperature
3
c
Ratio/%
a
Time/min Conversion/% Yield 2/%
b
Ar
Ar¢
erythro
threo
a
b
c
d
e
f
Ph
4-MePh
4-MePh
4-ClPh
4-MeOPh
Ph
Ph
Ph
30
20
15
20
15
10
10
45
100
090
095
100
100
100
100
070
75
79
83
83
80
75
84
60
086
100
063
100
100
092
049
100
14
-
4-MePh
Ph
37
-
Ph
-
2-MeOPh
4-MeOPh
08
51
-
g
h
Ph
Ph
3-NO Ph
2
a
b
c
Based on consumed a-epoxyketones.
Isolated yield based on consumed a-epoxyketones.
1
Estimated from H NMR.
sonable to assume that 2 results from an initial acid-base re-
nient reagent for regio- and stereoselective synthesizing of
the functionalized b-chlorohydrins 2 from a-epoxyketones
1. In comparison to the previous reports, significant im-
provements are observed in the reaction times and the
regio- and stereoselectivy of the reaction.
3
action of AlCl with a-epoxyketones 1 and subsequent ring
opening of the intermediate 3 through the transition state 4
or the intermediate 6. Nucleophilic attack of the chloride
b
anion to the C of 4 with inversion of configuration follow-
ing with hydrolysis of the intermediate 5 under the reaction
conditions employed leads to the erythro-configuration 2.
However, Nucleophilic attack of the chloride anion to the
EXPERIMENTAL
Melting points were measured with an Electrothermal
9100 apparatus. IR spectra were measured with a Shimadzu
IR-460 spectrometer. NMR spectra were recorded with a
b
C of 6 may leads to the equal ratio of erythro and threo-
configuration. This is observed in the case of 2g in which
the very strong electron-donating group in para-position
stabilizes the benzyl carbocation and eliminates the stereo-
selectivity. Since the observed stereoisomers of the prod-
ucts have more erythro-configuration (with the exception
of 2g), the transition state 4 is more probable for progres-
sion of the reaction.
1
Bruker DRX-250 AVANCE instrument (250.1 MHz for H
1
3
and 62.9 MHz for C). Chemical shifts are given in ppm
(d) relative to internal TMS, and coupling constants J are
reported in Hz. Mass spectra were recorded with a Finnigan-
MAT 8430 mass spectrometer operating at an ionization
potential of 70 eV. Elemental analyses C, H, and N were
performed using a Heraeus CHN-O-Rapid analyzer. The
synthesis of the a-epoxyketones was achieved by using the
Acetonitrile seems to be the solvent of choice since 1
3 3 2 2
did not react with AlCl in CHCl , CH Cl , toluene, DMF
7
or in solvent free conditions.
published methods.
General reaction procedure
CONCLUSION
In a 10 mL round bottom flask, 1 mmol of a-epoxy-
ketones 1a-1h was dissolved in 2 mL of MeCN. To this so-
3
In conclusion, AlC1 in acetonitrile can be a conve-
3
lution, 0.133 g (1 mmol) of anhydrous AlCl was added and
the mixture was stirred for the times as indicated in Table 1.
Then, the solvent was removed under reduced pressure and
the residue was washed with cold water. The products were
separated and purified by thin-layer chromatography on 20
´
20 plates of silicagel 60 GF254 with n-hexane/EtOAc as
eluent.
3
-Chloro-2-hydroxy-1,3-diphenylpropanone (2a)
Fig. 1
Mp 88-90 °C (Ref. [4j] 90 °C).

4
06 J. Chin. Chem. Soc., Vol. 56, No. 2, 2009
Nikpour et al.
Scheme II
3
-Chloro-2-hydroxy-1-(4-methylphenyl)-3-phenylpro-
for C17
H
17ClO
2
(288.77): C, 70.71; H, 5.93. Found: C,
70.68; H, 5.90%.
3-Chloro-1-(4-chlorophenyl)-2-hydroxy-3-phenylpro-
panone (2d)
3
Hz, 2H, Ar-H), 7.31 (d, JHH = 8.0 Hz, 2H, Ar-H), 7.28-
Mp 88-90 °C. IR (KBr): n = 3450 (OH), 1681 (CO)
3
): d = 7.79 (d, JHH = 7.8
3
.15 (m, 5H, Ar-H), 5.53 (dd, JHH = 7.5 Hz, JHH = 3.5 Hz,
3
-1
cm ; H NMR (250 MHz, CDCl
1
7
1
3
3
3
3
Hz, 2H, Ar-H), 7.46 (d, JHH = 7.8 Hz, 2H, Ar-H), 7.32-
H, C
7.5 Hz, 1H, OH), 2.46 (s, 3H, CH
MHz, CDCl ): d = 197.0, 145.7, 135.5, 131.6, 129.8, 128.8,
28.2, 128.1, 128.0, 76.8, 63.4, 21.9 ppm; MS (EI): m/z
a
-H), 5.28 (d, JHH = 3.5 Hz, 1H, C
b
-H), 3.72 (d, JHH
1
3
3
=
3
) ppm; C NMR (69.2
a
7.18 (m, 5H, Ar-H), 5.47 (d, JHH = 4.0 Hz, 1H, C -H), 5.24
3
13
3
(d, JHH = 4.0 Hz, 1H, C
NMR (69.2 MHz, CDCl
130.1, 129.4, 129.0, 128.3, 128.0, 76.7, 63.2 ppm; MS
b
-H), 3.62 (bs, 1H, OH) ppm;
C
1
3
): d = 196.6, 141.0, 135.5, 132.7,
+
×
(
(
%) = 275 (M , 5), 239 (9), 224 (10), 223 (8), 208 (19), 105
100), 77 (62); Anal. Calcd. for C16 (274.75): C,
+
×
+×
H
15ClO
2
(EI): m/z (%) = 299 [(M + 4), 3], 297 [(M + 2), 10], 295
+
×
6
9.95; H, 5.50. Found: C, 69.91; H, 5.52%.
(M , 15), 276 (2), 260 (1), 258 (3), 139 (100), 125 (96),
120 (76), 91 (50); Anal. Calcd. for C15 (295.16):
C, 61.04; H, 4.10. Found: C, 60.98; H, 4.08%.
3
-Chloro-2-hydroxy-1,3-bis(4-methylphenyl)propanone
2 2
H12Cl O
(
mixture of erythro- and threo-2c)
Mp 99-101 °C. IR (KBr): n = 3360 (OH), 1680, 1661
3
): d = 7.83 (d, JHH
3-Chloro-2-hydroxy-1-(4-methoxyphenyl)-3-phenylpro-
panone (2e)
-
1
1
CO) cm ; H NMR (250 MHz, CDCl
(
3
=
3
.0 Hz, 2H, Ar-H), 7.79 (d, JHH = 8.0 Hz, 2H, Ar-H), 7.45
8
Mp 108-110 °C. IR (KBr): n = 3435 (OH), 1667 (CO)
3
3
d, JHH = 8.0 Hz, 2H, Ar-H), 7.36 (d, JHH = 8.0 Hz, 2H,
3
-1
cm ; H NMR (250 MHz, CDCl
1
(
3
): d = 7.86 (d, JHH = 6.7
3
Ar-H), 7.32 (d, JHH = 8.0 Hz, 2H, Ar-H), 7.19 (d, JHH = 8.0
3
Hz, 2H, Ar-H), 7.05 (m, 4H, Ar-H), 5.51 (d, JHH = 3.5 Hz,
3
Hz, 2H, Ar-H), 7.28-7.23 (m, 3H, Ar-H), 7.21-7.18 (m, 2H,
3
Ar-H), 6.99 (d, JHH = 6.7 Hz, 2H, Ar-H), 5.50 (d, JHH = 3.7
3
3
-H erythro), 5.36 (d, JHH = 1.7 Hz, 1H, C
3
1
5
1
H, C
a
a
-H threo),
Hz, 1H, C
3H, OCH
CDCl ): d = 195.6, 164.6, 135.6, 131.2, 128.9, 128.2,
a
-H), 5.27 (d, JHH = 3.7 Hz, 1H, C
b
-H), 3.89 (s,
3
3
13
.25 (d, JHH = 3.5 Hz, 1H, C
.7 Hz, 1H, C -H threo), 4.15 (bs, 1H, OH), 3.70 (bs, 1H,
), 2.36 (s, 3H, CH ), 2.31 (s, 3H,
) ppm; C NMR (69.2 MHz, CDCl ): d = 197.2, 197.0,
45.7, 145.5, 138.8, 135.4, 132.5, 131.6, 130.9, 129.8
2C), 129.3, 129.2, 128.9 (2C), 128.7, 127.9, 127.8, 76.9,
6.5, 63.9, 63.2, 21.8 (2C), 21.2 (2C) ppm; MS (EI): m/z
b
-H erythro), 5.23 (d, JHH
=
3
), 3.86 (bs, 1H, OH) ppm; C NMR (69.2 MHz,
b
3
OH), 2.47 (s, 6H, 2CH
3
3
128.1, 126.9, 114.3, 76.8, 63.5, 55.6 ppm; MS (EI): m/z
+×
(%) = 291 (M , 1), 272 (1), 254 (4), 165 (18), 135 (100),
1
3
CH
3
3
1
120 (35), 107 (17), 92 (24); Anal. Calcd. for C16
H15ClO
3
(
(290.75): C, 66.10; H, 5.20. Found: C, 66.01; H, 5.18%.
7
3-Chloro-2-hydroxy-3-(2-methoxyphenyl)-1-phenylpro-
+
×
+×
(
(
%) = 291 [(M + 2), 4], 289 (M , 10), 270 (2), 252 (1), 149
panone (mixture of erythro- and threo-2f)
-1 1
IR (Liquid film): n = 3435 (OH), 1667 (CO) cm ; H
12), 139 (55), 119 (100), 105 (25), 91 (34); Anal. Calcd.

Synthesis of Functionalized b-Chlorohydrines
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 407
3
): d = 8.12 (d, JHH = 7.5 Hz, 2H,
3
Ar-H), 8.04 (d, JHH = 8.0 Hz, 1H, Ar-H), 7.93 (d, JHH = 7.7
3
Hz, 1H, Ar-H), 7.84 (d, JHH = 8.0 Hz, 1H, Ar-H), 7.72 (d,
13
3
OH) ppm; C NMR (69.2 MHz, CDCl ): d = 197.3, 147.8,
NMR (250 MHz, CDCl
3
3
137.7, 134.9, 134.2, 133.9, 129.4, 129.2, 128.7, 123.8,
+×
123.2, 76.8, 61.7 ppm; MS (EI): m/z (%) = 308 [(M + 2),
3
3
HH = 8.0 Hz, 2H, Ar-H), 7.66 (d, JHH = 8.0 Hz, 1H, Ar-
+×
67], 306 (M , 25), 272 (1), 254 (4), 165 (18), 135 (22), 105
J
3
H), 7.59 (d, JHH = 7.7 Hz, 2H, Ar-H), 7.56 (d, JHH = 7.5
3
4
(100), 77 (55); Anal. Calcd. for C15H12ClNO (305.72): C,
3
Hz, 1H, Ar-H), 7.49 (d, JHH = 7.5 Hz, 1H, Ar-H), 7.34 (dd,
58.93; H, 3.96; N, 4.58. Found: C, 58.89; H, 4.00; N,
4.56%.
3
3
HH = 7.7 Hz, JHH = 8.0 Hz, 2H, Ar-H), 7.08 (d, JHH = 7.5
3
J
3
Hz, 1H, Ar-H), 7.04 (d, JHH = 7.7 Hz, 1H, Ar-H), 6.92 (d,
3
3
HH = 8.0 Hz, 1H, Ar-H), 6.76 (d, JHH = 8.0 Hz, 1H,
J
ACKNOWLEDGMENT
3
Ar-H), 5.91 (d, JHH = 2.7 Hz, 1H, C
a
-H erythro), 5.85 (s,
-H erythro),
), 3.99 (s, 3H,
We are thankful to the University of Kurdistan Re-
search Council for the partial support of this work.
3
1
H, C
.46 (s, 1H, C
), 3.57 (s, 1H, OH), 3.39 (s, 1H, OH) ppm; C NMR
69.2 MHz, CDCl ): d = 197.8, 155.0, 134.0, 133.3, 129.8,
29.5, 128.9, 128.8, 125.9, 121.0, 109.9, 74.7, 59.0, 55.6
a
-H threo), 5.62 (d, JHH = 2.7 Hz, 1H, C
b
5
b
-H threo), 4.08 (s, 3H, OCH
3
1
3
OCH
3
Received September 19, 2008.
(
3
1
REFERENCES
+
×
+×
1
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ppm; MS (EI): m/z (%) = 293 [(M + 2), 5], 291 (M , 2),
72 (3), 254 (5), 165 (32), 135 (33), 107 (39), 105 (100), 77
55); Anal. Calcd. for C16 (290.75): C, 66.10; H,
2
(
H15ClO
3
5
3
.20. Found: C, 66.03; H, 5.22%.
-Chloro-2-hydroxy-3-(4-methoxyphenyl)-1-phenylpro-
2
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-
1 1
IR (Liquid film): n = 3455 (OH), 1681 (CO) cm ; H
3. (a) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D.,
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3
3
NMR (250 MHz, CDCl ): d = 8.91 (d, JHH = 7.7 Hz, 2H,
3
Ar-H), 7.93 (d, JHH = 7.5 Hz, 2H, Ar-H), 7.83 (d, JHH = 8.5
3
Hz, 2H, Ar-H), 7.60-7.43 (m, 5H, Ar-H), 7.07 (d, JHH = 8.7
3
Hz, 2H, Ar-H), 6.99 (d, JHH = 8.5 Hz, 2H, Ar-H), 6.87-
3
.72 (m, 3H, Ar-H), 5.31 (d, JHH = 4.5 Hz, 1H, C
3
erythro), 5.13 (d, JHH = 3.0 Hz, 1H, C
3
4
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2
6
a
-H
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a
-H threo), 4.62 (d,
3
3
J
HH = 3.0 Hz, 1H, C
b
-H threo), 4.49 (d, JHH = 4.5 Hz, 1H,
), 3.77
), 3.61 (bs, 1H, OH) ppm; C NMR (69.2
): d = 192.6, 192.1, 169.5, 158.5, 133.4, 133.0,
32.0, 130.1, 128.8, 128.6, 128.5 (2CH), 128.3, 128.2,
16.1, 114.3, 113.7, 113.6, 76.6, 76.5, 65.1 (2CH), 55.6,
C
b
-H erythro), 4.14 (bs, 1H, OH), 3.86 (s, 3H, OCH
3
1
3
(
s, 3H, OCH
3
MHz, CDCl
3
1
1
5
2
061. (h) Weidmann, B.; Seebach, D. Helv. Chim. Acta.
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+
×
5.5 ppm; MS (EI): m/z (%) = 291 (M , 2), 272 (3), 254
1
(
7), 165 (18), 135 (27), 107 (35), 105 (100), 77 (64); Anal.
Calcd. for C16 (290.75): C, 66.10; H, 5.20. Found:
C, 66.11; H, 5.17%.
-Chloro-2-hydroxy-3-(3-nitrophenyl)-1-phenylpro-
panone (2h)
IR (Liquid film): n = 3450 (OH), 1681 (CO), 1526,
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15ClO
3
5
6
7
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3
. Memarian, H. R.; Nikpour, F. J. Chin. Chem. Soc. 2002, 49,
4
01.
-
1 1
1
3
347 (NO
2
) cm ; H NMR (250 MHz, CDCl
3
): d = 8.14 (d,
. (a) Payne, G. B. J. Am. Chem. Soc. 1959, 81, 4901. (b)
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3
HH = 7.7 Hz, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 7.57 (d, JHH
J
3
7.7 Hz, 2H, Ar-H), 7.70 (2d, JHH = 7.5 Hz, JHH = 7.2 Hz,
3
=
3
H, Ar-H), 7.58-7.43 (m, 4H, Ar-H), 5.57 (d, JHH = 2.5 Hz,
1
1
3
a b
H, C -H), 5.32 (d, JHH = 2.5 Hz, 1H, C -H), 3.83 (bs, 1H,