A mild and efficient procedure for asymmetric michael additions of α-bromochalcone with cyclohexanone catalyzed by different bases

Article abstract of DOI:10.14233/ajchem.2013.13457

A mild and efficient procedure for Michael addition of α- bromochalcone with cyclohexanone has been developed. In the presence of sodium ethoxide, α-bromochalcone reacted with cyclohexanone to afford Michael products in moderate to high yield and good diastereoselectivities. Especially, while CH₃CH₂ONa or t-BuOK as catalyst, the unexpected products were obtained, which were the compound 4a((8aR,9S)-4a,8a-dihydroxy-10- phenyl-tetradecahydro-phenanthren-9-yl)(phenyl)methanone) and 4b(((8aR,9R)-4a,9- dihydroxy-10-phenyl-tetradecahydrophenanthren-9-yl)(phenyl)methanone).

Full text of DOI:10.14233/ajchem.2013.13457

Asian Journal of Chemistry; Vol. 25, No. 5 (2013), 2561-2564
http://dx.doi.org/10.14233/ajchem.2013.13457
A Mild and Efficient Procedure for Asymmetric Michael Additions of
α-Bromochalcone with Cyclohexanone Catalyzed by Different Bases
*
LI-GUO GAO, DONG-ZHI LIU, WEI LI and XUE-QIN ZHOU
School of Chemical Engineering, Tianjin University, Tianjin 300072, P.R. China
*Corresponding author: Fax: +86 22 27400911; Tel: +86 22 27400911; E-mail: zhouxueqin@tju.edu.cn
(Received: 16 January 2012; Accepted: 12 November 2012)
AJC-12401
A mild and efficient procedure for Michael addition of α-bromochalcone with cyclohexanone has been developed. In the presence of
sodium ethoxide, α-bromochalcone reacted with cyclohexanone to afford Michael products in moderate to high yield and good
diastereoselectivities. Especially, while CH3CH2ONa or t-BuOK as catalyst, the unexpected products were obtained, which were the
compound 4a((8aR,9S)-4a,8a-dihydroxy-10-phenyl-tetradecahydro-phenanthren-9-yl)(phenyl)methanone) and 4b(((8aR,9R)-4a,9-
dihydroxy-10-phenyl-tetradecahydrophenanthren-9-yl)(phenyl)methanone).
Key Words: α-Bromochalcone, Cyclohexanone, Synthesis.
design and discovery of efficient ways to generate single
configuration products is still a challenge in organic synthetic
chemistry.
INTRODUCTION
Conjugate addition reactions of α,β-unsaturated ketones
with donors is one of the most important carbon-carbon bond-
forming reactions in organic synthesis1. Over the past decade,
there has been attracted increasing interest in the addition
reaction of α,β-unsaturated ketones with cyclohexanone2,
particularly in Michanel addition reactions. However, most of
the reactions used highly activated nucleophiles, such as
nitroalkenes3 or malonates4. Especially, asymmetric Michael
addition of enones with ketones is still a challenging reaction.
Ishrat5 reported the reactions of chalcones with cyclohexanone
to generate 1,5-dicarbonyl compounds catalyzed by CH3CH2ONa
with good yields (79 %) and low diastereoselectivities which
only is ((S)-2-((R)-3-oxo-1,3-diphenylpropyl)cyclohexanone:
(R)-2-((R)-3-oxo-1,3-diphenylpropyl)cyclohexanone =
86:14). Many workers6 have reported imidazolidinones as
organocatalysts to catalyze the reactions of aldehydes with
enones, which had some drawbacks such as: long reaction
time (more than 4 days) or high catalyst loading and these led
to a high cost and limited its application in the pharmaceutical
industry. The synthesis of (R)-2-((R)-3-oxo-1,3-diphenyl-
propyl)cyclohexanone with CH3COOLi as catalyst also had
the same shortcomings (poor diastereoselectivity). Melchiorre
and Jøgensen7 have shown that pyrrolidine derivatives could
promote the asymmetric conjugate addition smoothly with
good results. The reactions were complete in a short time with
a low catalyst loading (25 %), but preparation of the
organcatalysts was complex and difficult. Therefore, the
It's noticed that dehydrobromination reaction preceded
easily during Michael addition of 1,2,4-triazole to α-bromo-
chalcone producing E-1,3-diaryl-3-(1H-1,2,4-triazol-l-yl)-
2-propen-l-ones in high yields8. Considering the reactivity of
bromine atom, this paper aims at studying the asymmetric
Michael addition of α-bromochalcone with cyclohexanone
using different catalysts. The compound 1,3-diphenyl-3-(2-
oxo-cyclohexyl)-1-propanone was obtained with high
diastereoselectivity. Besides, the other products was achieved
while two mole ratio of cyclohexanones to α-bromochalcone
in the presence of t-BuOK or NaH as catalyst, which has not
been reported in the literature.
EXPERIMENTAL
All the solvents were purified according to standard
procedures. The 1H NMR spectra were recorded at 500 MHz,
13C NMR spectra were recorded at 500 MHz. 1H and 13C NMR
chemical shifts were calibrated to tetramethylsilane as an
external reference. Coupling constants are given in hertz. HRMS
were recorded on an IonSpec FT-ICR mass spectrometer with
ESI resource. Melting points were measured on an RY-I
apparatus and uncorrected. The reagents were used without
purification. 2-Bromo-1,3-diphenyl-propenone was prepared
following literature procedures9.
2-(3-Oxo-1,3-diphenyl-propyl)-cyclohexanone (3a10):
Sodium (0.35 g, 0.015 mol) was dissolved in dry ethanol (30

2562 Gao et al.
Asian J. Chem.
mL) and then cooled to 20 ºC, cyclohexanone (1.96 g, 0.02
mol) and α-bromochalcone (0.98 g, 0.01 mol) were added,
the mixture was left at same temperature for 3 h. Filtered and
the crude solid was washed with ethanol 30 mL × 3 mL, dried,
gave a white solid; yield: 80 %. (2.74 g, ), m.p. 144.5-145.8
ºC, IR: 3058, 3025, 2939, 2855, 1709, 1683, 1597, 1495 and
cooled, filtered. The crude red solid was purified by column
chromatography (petroleum ether:ethyl acetate = 20:1) to give
additional white solid. Yield: 72 %. m.p. 184.5-186.1 ºC. IR:
3445, 3060, 3021, 2930, 2854, 1647, 1595, 1578 and 1493
cm-1. 1H NMR (CDCl3, 500 MHz): δ (ppm) 1.07-1.57 (m, 7H)
1.68-1.95 (m, 4H), 2.08 (t, 2H, J = 12.5 Hz), 3.42 (t, 1H, J =
14 Hz), 4.24 (d, 1H, J = 14 Hz), 5.56 (s, 1H), 6.05 (s,1H),
6.89-6.96 (m, 2H), 7.00-7.06 (m, 4H), 7.18-7.23 (m, 4H), 7.28
(s, 2H), 7.43 (d, 2H, J = 7 Hz), 13C NMR (100 MHz, CDCl3):
δ (ppm) 19.92, 20.91, 21.34, 24.82, 25.98, 26.13, 36.07, 39.44,
45.53, 50.25, 50.34, 58.93, 72.44, 75.22, 126.08, 126.61,
128.27, 128.34, 128.37, 128.41, 128.40, 129.09, 131.11,
131.40, 133.33, 140.84, 209.10. HRMS calcd. (%) for
C27H32O3H+(M + 2Na+-H+) 449.2058, found (%) 449.2060.
1
1448 cm-1, H NMR (CDCl3, 500 MHz): δ (ppm) 1.25-1.30
(m, 1H) 1.55-1.81 (m, 4H), 1.98-2.00 (m, 1H), 2.37-2.43 (m,
1H), 2.50-2.55 (m, 1H), 2.73 (dt, 1H, J1 = 5.5 Hz, J2 = 5.0
Hz), 3.264 (dd, 1H, J1 = 10.0 Hz, J2 = 20 Hz), 3.49 (dd, 1H,
J1 = 4.0 Hz, J2 = 4.0 Hz), 3.73 (dd, 1H, J1 = 13.5 Hz, J2 = 4.0
Hz), 7.17 (t, 2H, J = 7.5 Hz), 7.258-7.274 (m, 3H), 7.399-
7.449 (m, 2H), 7.50 (t, 1H, J = 7.5 Hz),7.91 (d, 2H, J = 8 Hz).
HRMS calcd. (%) for C21H22O2H+ (M + H+) 307.1693, found
(%) 307.1686.
2-(1-Benzyl-2-oxo-2-phenyl-ethyl)-cyclohexanone
(3b11): Catalyst (0.02 mol) was dissolved in dry solvent
(20 mL), cylohexanone (1.96 g, 0.02 mol) was added, α-
bromochalcone (2.08 g, 0.01 mol) dissolved in 20 mL solvent
was added, the mixture was kept at same temperature for 12
h, filtered. The crude red solid was purified by column chroma-
tography (petroleum ether:ethyl acetate = 15:1) to give white
solid; yield: 80 %. m.p. 144.5-145.8 ºC, IR: 3058, 3025, 2939,
2855, 1709, 1683, 1597, 1495 and 1448 cm-1, 1H NMR (CDCl3,
500 MHz): δ (ppm) 1.55-1.70 (m, 4H), 1.90-1.91 (m, 1H),
2.00-2.09 (m, 2H), 2.24-2.30 (m, 1H), 2.38-2.41 (m, 1H), 2.70
(dt, 1H, J1 = 6 Hz, J2 = 5.5 Hz), 3.40 (dd, 1H, J1 = 9.5 Hz,),
3.53 (dd, 1H, J1 = 5.0 Hz, J2 = 5.0 Hz), 3.95 (dt, 1H, J1 = 4.5
Hz, J2 = 5.0 Hz), 7.149-7.184 (m, 1H), 7.258 (t, 3H, J = 4.5
Hz), 7.44 (t, 2H, J = 7.5 Hz), 7.53 (t, 1H, J = 7 Hz), 7.96 (d,
2H, J = 7.5 Hz). HRMS calcd (%) for C21H22O2H+ (M + Na+)
329.1513, found (%) 329.1514.
RESULTS AND DISCUSSION
Sodium ethoxide was employed to catalyze the conjugated
addition of cyclohexanone to α-bromochalcone firstly. When
the reaction was performed in THF, the product 3a was formed
in high diastereoselectivity (> 99:1) and low yield (21 %, Table-
1, entry 1). When the reaction temperature was increased to
80 ºC, the other configuration (3b) was obtained (dr 100 %)
in good yield (Table-1, entry 2). While performed in ethanol,
high yield was gained with lower diastereoselectivity (94:6,
Table-1, entry 3) at room temperature and good results were
observed when the temperature was increased to 80 ºC ( 80 %
yield, 99:1 diastereoselectivity) (Table-1, entry 4). However,
low diastereoselectivities were obtained if toluene was used
as solvent either in low temperature or in high temperature
(Table-1 entry 5-6). If the temperature was increased to 120
ºC, the yield of 3 nearly decreased to zero (Table-1 entry 7).
Then t-BuOK was chose as catalyst, which could catalyze the
reaction effectively in high yields, but with low diastereo-
selectivities (Table-1, entry 8-12). Using NaH as catalyst, the
yields of 3 were nearly zero at different temperature.
2-[2-(2-Hydroxy-cyclohexylidene)-1-(hydroxy-phenyl-
methyl)-2-phenyl-ethyl]-cyclohexanone (4a): Catalysts (0.02
mol) dissolved in dry THF (20 mL), cylohexanone (1.96 g,
0.02 mol) was added, α-bromochalcone (2.08 g, 0.01 mol)
dissolved in 20 mL THF was dropwised in 0.5 h. The mixture
was maintained at same temperature for 12 h and filtered. The
crude red solid was purified by column chromatography
(petroleum ether:ethyl acetate = 20:1) to give additional white
solid.Yield: 84 %. m.p. 184.3-186 ºC. IR: 3442.61, 3061, 3026,
2930, 2854, 1645, 1595, 1578 and 1493 cm-1. 1H NMR (CDCl3,
500 MHz): δ (ppm) 0.99-1.11 (m, 3H), 1.21-1.41 (m, 6H),
1.59 (d, 1H, J = 13.5 Hz), 1.58-1.86 (m, 7H), 2.07 (d, 1H, J =
13.5 Hz), 3.26 (t, 1H, J = 12.0 Hz), 3.77 (d, 1H, J = 11.5 Hz),
4.78 (s, 1H), 5.18 (s, 1H), 6.89-6.96 (m, 2H), 7.01 (dd, 2H,
J = 7.5 Hz), 7.19 (t, 1H, J = 7.5 Hz), 7.23 (t, 2H, J = 7.5 Hz),
7.39 (t, 1H, J = 7.5 Hz), 7.52 (d, 2H, J = 7 Hz), 13C NMR (100
MHz, CDCl3): δ (ppm) 19.90, 20.93, 21.30, 24.86, 25.97,
26.17, 36.06, 39.42, 45.59, 50.26, 50.37, 58.96, 72.47, 75.25,
126.02, 126.63, 128.22, 128.35, 128.35, 128.49, 128.49,
129.06, 131.15, 131.44, 133.39, 140.83, 209.14. HRMS calcd.
(%) for C27H32O3H+(M + H+) 405.2424, found (%) 405.2422.
2-[2-(2-Hydroxy-cyclohexylidene)-1-(hydroxy-phenyl-
methyl)-2-phenyl-ethyl]-cyclohexanone (4b): t-BuOK (0.02
mol) dissolved in dry ethanol (20 mL), cylohexanone (1.96 g,
0.02 mol) was added, α-bromochalcone (2.08 g, 0.01 mol)
dissolved in 20 mL ethanol was added in 0.5 h, the mixture
was left at same temperature for 2 h under N2 atmosphere,
An interesting phenomenon was found. While using
t-BuOK as the catalyst and the reaction temperature was at 80
ºC in ethanol and toluene, then new compounds (4) not 3 were
formed (Table-1, entry 13-14) in high yield and mordrate
diastereoselectivities. However, when the reaction was carried
out under nitrogen atmosphere, only one configuration was
obtained (Table-2, entry 1). Changing the catalyst to NaH,
only the compound 4a was afforded in good yield in THF and
zero yields of 3 or 4 in toluene. While changing the feeding
order, compounds 3 and 4 were obtained together as showed
in Table-4. Then, the same reactions were done with 3a and
3b as starting material to find whether they were the interme-
diates of the reactions. 4a was obtained in THF with NaH as
catalyst, but no reaction occurred when t-BuOK was used as
catalyst in ethanol (Table-4, entry 1).
This fact allowed us to hypothesize that synthesis of
compounds 4 are preceded as follows: The order also affected
the results which could be seen from the Tables 2 and 5.
From Table-1 (entry 1 and 2), we had believed that 3b
was the thermodynamic control product. But when we did the
reactions as showed in Table-3, 3a couldn't convert to 3b except
when THF was used as solvent. This revealed 3b was not the
thermodynamic control product.

Vol. 25, No. 5 (2013)
A Mild and Efficient Procedure for Asymmetric MichaelAdditions of α-Bromochalcone with Cyclohexanone 2563
TABLE-1
REACTION OF CYCLOHEXANONE WITH α-BROMOCHALOCONE UNDER AIR ATMOSPHEREa
OH
OH
H
O
O
OH
H
O
O
O
O
OH
+
+
+
+
Solvent
Br
O
O
1b
3
4
b
3a
b
4a
Yieldb (%)
Entry
Cat
Sovlent (mL)
Temp. (ºC)
Time (h)
3(drc)
4(drd)
1
2
CH3CH2ONa
CH3CH2ONa
CH3CH2ONa
CH3CH2ONa
CH3CH2ONa
CH3CH2ONa
CH3CH2ONa
t-BuOK
THF
THF
25
80
25
80
25
80
120
25
80
25
14
80
120
80
25
80
14
80
2
2
2
2
2
2
2
2
2
2
5
5
5
2
2
2
2
5
21 (>99:1)
73 (<1:99)
78 (96:4)
80 (99:1)
40 (82:18)
67 (85:15)
< 5
0
0
3
Ethanol
Ethanol
Toluene
Toluene
Toluene
THF
0
4
0
5
0
6
0
7
0
8
61 (78:22)
54 (88:12)
76 (57:43)
71 (72:28)
75 (73:27)
61 (71:29)
0
0
9
t-BuOK
THF
0
10
11
12
13
14
15
16
17
18
t-BuOK
Ethanol
Toluene
Toluene
Toluene
Ethanol
THF
0
t-BuOK
0
t-BuOK
0
t-BuOK
17 (100:0)
84 (86:14)
67 (100:0)
79 (100:0)
0
t-BuOK
NaH
0
NaH
THF
0
<5e
<5f
NaH
Toluene
Toluene
NaH
0
aUnless, special remark, the order was mix cyclohexanone and catalyst (in THF) first and stired for five minutes and then added α-bromochalcone
(in THF) slowly in 0.5 h in the given temperature. bIsolated yield. cdr (3a:3b) was determined by 1H NMR spectroscopy (500 MHz). d(4a:4b) was
determined by 1H NMR spectroscopy (500 MHz). ePer cent conversion was 0. fPer cent conversion was 100 %.
TABLE-2
REACTION OF CYCLOHEXANONE WITH α-BROMOCHALOCONE UNDER NITROGEN ATMOSPHEREa
OH
OH
H
O
O
OH
H
O
O
O
O
OH
+
+
+
+
Solvent
Br
O
O
1b
3
4
b
3a
b
4a
Yieldb (%)
Entry
Cat
Sovlent (mL)
Temp. (ºC)
Time (h)
3(drc)
4(drd)
1
2
3
t-BuOK
NaH
Ethanol
Toluene
Toluene
80
25
80
2
2
5
0
72 (0:100)
< 5e
< 5f
0
0
NaH
aUnless, special remark, the order was mix cyclohexanone and catalyst (in THF) first and stired for five minutes and then added α-bromochalcone
(in THF) slowly in 0.5 h in the given temperature. bIsolated yield. cdr (3a:3b) was determined by 1H NMR spectroscopy (500 MHz). d(4a:4b) was
determined by 1H NMR spectroscopy (500 MHz). ePer cent conversion was 0. fPer cent conversion was 100 %.
-
O
O
OH
-
O
O
O
-
O
O
O
Br
base
O
Br
Br
OH
OH
O
OH
OH
H
-
O
OH
H
-
H
O
OH
Br
O
+
Br
O
O
O
O
Fig. 1. Proposed mechanism forming compounds 4

2564 Gao et al.
Asian J. Chem.
TABLE-4
REACTION OF CYCLOHEXANONE WITH α-BROMOCHALOCONE UNDER AIR ATMOSPHEREa
OH
OH
H
O
O
OH
H
O
O
O
O
OH
+
+
+
+
Solvent
Br
O
O
1b
3
4
b
3a
b
4a
Yieldb (%)
Entry
Cat
Solvent (mL)
Temp. (ºC)
Time (h)
3(drc)
4(drd)
1
2
3
NaH
NaH
NaH
THF
THF
THF
14
25
80
2
2
2
57(79:21)
56(70:30)
50(79:21)
10(100:0)
22(100:0)
27(100:0)
aOrder was mix cyclohexanone and α-bromochalcone (in THF) first and stirred for 5 min and then added catalyst (in THF) in the given
temperature. bIsolated yield. cdr (3a:3b) was determined by 1H NMR spectroscopy (500 MHz). d(4a:4b) was determined by 1H NMR spectroscopy
(500MHz).
TABLE-3
REFERENCES
RESULTS OF COMPOUND 3a CONVERTED TO 3b
Yieldb
(%)
1. P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon: Oxford (1992).
Solvent
(mL)
Temp.
(ºC)
Time
(h)
Entry
Cat
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1
2
3
CH3CH2ONa
Ethanol
80
80
80
2
2
2
19
0
CH3CH2ONa Toluene
CH3CH2ONa THF
90
bIsolated yield.
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as solvent.
TABLE-5
REACTION OF 3(a+b) TO 4a
Solvent
(mL)
Temp.
(ºC)
Time
(h)
Yieldb
(%)
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Entry
Cat
1
2
3
NaH
t-BuOK
NaH
THF
80
80
80
2
2
5
87
0
Ethanol
Toluene
0
bIsolated yield.
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Conclusion
The reaction of α-bromochalcone with cyclohexanone
generated good results. Different catalysts get different products.
Good result was obtained when sodium ethoxide was employed
as catalyst in the presence of ethanol. The other configuration
was obtained under refluxed when performed in THF with
sodium ethoxide as catalyst. Using t-BuOK in refluxed ethanol,
new compounds 4 were genereted. The single configuration
was generated with NaH as catalyst in THF. At the same time,
the feeding order also changed the results of the reaction.
Further researches are still in progress.
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