Indium(I) bromide-promoted stereoselective preparation of (E)-α,β-unsaturated ketones via sequential intermolecular aldol-type coupling/elimination reactions of α,α-dichloroketones with aldehydes

Article abstract of DOI:10.1016/j.jorganchem.2006.09.046

Indium(I) bromide promotes the reaction of α,α-dichloroketones with aldehydes to produce (E)-α,β-unsaturated ketones, exclusively. The transformation occurs via two sequential reactions, an aldol-type coupling between the two carbonylic reagents followed by an elimination process.

Full text of DOI:10.1016/j.jorganchem.2006.09.046

Journal of Organometallic Chemistry 691 (2006) 5856–5860
www.elsevier.com/locate/jorganchem
Indium(I) bromide-promoted stereoselective preparation of
(E)-a,b-unsaturated ketones via sequential intermolecular
aldol-type coupling/elimination reactions of a,a-dichloroketones
with aldehydes
*
Clovis Peppe , Rafael Pavao das Chagas
˜
ˆ
´
Laborato´rio de Materiais Inorganicos, Departamento de Quımica, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Received 17 August 2006; received in revised form 19 September 2006; accepted 19 September 2006
Available online 29 September 2006
Abstract
Indium(I) bromide promotes the reaction of a,a-dichloroketones with aldehydes to produce (E)-a,b-unsaturated ketones, exclusively.
The transformation occurs via two sequential reactions, an aldol-type coupling between the two carbonylic reagents followed by an elim-
ination process.
Ó 2006 Elsevier B.V. All rights reserved.
Keywords: Indium; Organoindium; Carbon–carbon bond formation; Aldol-type coupling; Elimination reaction; Sequential chemical reactions
1. Introduction
sidered an important improvement over the previous men-
tioned methods.
Aldol coupling between carbonyl compounds followed
by elimination and the Wittig reactions are amongst the
most important methods to prepare a,b-unsaturated car-
bonyl compounds [1]. However, both methods suffer of
undesired limitations. Self condensation products are fre-
quently encountered as by-products in the former process,
when both carbonyl starting materials are enolizable sub-
stances. Similarly, in the Wittig reactions, the phosphor-
anes and the strong bases used to generate them are not
compatible with enolizable carbonyl compounds and again
can lead to self condensation products. Recent work has
demonstrated that a,a-dihalogenocarbonyl compounds
can be reduced by samarium(II) iodide or chromium(II)
chloride; the products from these reductions couple with
aldehydes to produce, after elimination, a,b-unsaturated
carbonyl compounds [2]. The rigorous stereoselectivity of
the reaction leading exclusively to the (E)-isomers was con-
Recently, we have demonstrated that dibromoacetonit-
rile reacts with aldehydes mediated by indium monobro-
mide to afford 2-alkenenitriles, through a sequence of a
coupling followed by an elimination process [3]. In this
paper, we aim to show that indium monobromide is also
an effective reagent to promote the reaction between a,a-
dichloroketones 1 with aldehydes to produce certain (E)-
a,b-unsaturated ketones 2 (Scheme 1) via the same cou-
pling/elimination sequence.
2. Results and discussion
The reaction between equimolar amounts of a,a-dichlo-
roketones 1 and selected aldehydes promoted by 2 M equiv.
of InBr, in refluxing THF, gives rise to the (E)-a,b-unsatu-
rated ketones 2 products described at Table 1.
The stereochemistry of the olefinic products 2a–k was
1
determined by H NMR spectroscopy; the coupling con-
stants relating the two olefinic protons in the range
15.7 0.6 Hz (see Section 4) characterize the exclusive pro-
duction of the E-isomers.
*
Corresponding author. Tel.: +55 55 3220 8868; fax: +55 55 3220 8031.
E-mail address: peppe@quimica.ufsm.br (C. Peppe).
0022-328X/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.09.046

C. Peppe, R.P. das Chagas / Journal of Organometallic Chemistry 691 (2006) 5856–5860
5857
dative insertion of InBr into one of the carbon–chlorine
bonds of the a,a-dichloroketone 1, as we have determined
previously when, after aqueous work-up, we have isolated
the 2-chloro-3-hydroxy-propan-1-one derivatives 6 as a
mixture of diastereoisomers [4a]. A second oxidative inser-
tion of the monobromide into the carbon–chlorine bond of
the indium alkoxide 4 produces the dimetallic intermediate
5, which is the key species leading to the enones 2, through
an elimination process.
The rigorous stereoselectivity during elimination of the
indium(III) oxide (X2In)2O from intermediate 5 is under-
stood in terms of the chairlyke six-membered transition
state depicted at Fig. 1, in which the aldehyde R2 group
adopts equatorial orientation in relation to the dichlorok-
etone R1 substituent to avoid 1,3-diaxial repulsive interac-
O
O
O
Cl
2 InBr
R1
+
R1
R2
R2
Cl
1
2
Scheme 1. InBr-promoted synthesis of (E)-a,b-unsaturated ketones 2.
Table 1
The generality of the InBr-promoted synthesis of (E)-a,b-unsaturated
ketones 2
Entry
R1
R2
Yield
a
b
c
d
e
f
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
77
78
66
64
56
55
60
57
p-ClC6H4
p-BrC6H4
o-BrC6H4
p-CH3C6H4
p-CH3OC6H4
n-C3H7
i-C3H7
n-C9H19
p-ClC6H4
p-CH3OC6H4
n-C9H19
g
h
i
X
InX2
62
33
32
R2
O
X
In
j
R2
k
l
CH3
CH3
O
O
Traces
H
H
R1
X
O
H
R1
H
In
X
InX2
The proposed mechanism for this transformation con-
sists of two sequential reactions and it is given at Scheme
2. The first reaction is an aldol coupling between the alde-
hyde with the indium(III) enolate 3, generated by the oxi-
5A
5B
Fig. 1. Transition state model.
O
O
R2CHO + 2 InBr
Cl
R1
R2
R1
Cl
2
1
- (X2In)2O
InBr
O
OInX2
X2
In
OInX2
O
X2In
O
Cl
O
Cl
R1
R1
R2
R1
R1
InX2
R2
H
InX2
3
5
R2CHO
InBr
OInX2
O
OH
O
H+
R2
R1
R2
R1
Cl
Cl
4
6
Scheme 2. Proposed mechanism for InBr-mediated synthesis of (E)-a,b-unsaturated ketones 2.

5858
C. Peppe, R.P. das Chagas / Journal of Organometallic Chemistry 691 (2006) 5856–5860
R2CHO
tion. Such an intermediate was proposed previously by
InBr
´
Concellon and co-workers when studying similar pro-
cesses promoted by SmI2 or CrCl2 and seems very appro-
priated to explain the present InBr-mediated process [2].
A comparison between the stereoselective aspects of this
sequence of reactions involving dichloroketones and alde-
hydes with the analogous process with dibromoacetonit-
rile previously reported is important because it lends
some indirect support to the proposed cyclic intermediate
5. No cyclic intermediate is possible from the nitrile due
to the linear geometry of its CN bond. Therefore, as
expected, dibromoacetonitrile affords mixtures of both
(Z and E) diasteroisomers of the corresponding 3-orga-
nyl-2-alkenenitriles.
4
2
3
O
H+
6
1 + 3 InBr
R1
Et3N
R1
R2
7
O
R1OC
O
trans-8 (only)
Scheme 3. Products derived from indium enolate 3.
monobromide, the corresponding 1,4-butanediones, 7 [5];
alternatively, the enolate condensates with an aldehyde to
give the corresponding 2-chloro-3-hydroxy-propan-1-one
derivative, 6 [4a]; which can easily be converted into the
trans-epoxyde 8 by treatment with a convenient base
(Scheme 3) [4a].
The efficiency of the reaction is governed by the nat-
ure of both organyl groups, R1 and R2. The chalcones
2a–f and the 3-alkyl-1-phenyl-prop-2-en-1-one derivatives
2g–i derived from a,a-dichloroacetophenone were
obtained in moderate to good yields. On the other hand,
the products derived of a,a-dichloroacetone were
obtained in low yields, and only from reactions with aro-
matic aldehydes (2j–k). At this point, it is important to
notice that the major by-products which were isolated
from ineffective reactions were the aldehyde starting
material and the corresponding a-chloroketone; the
dynamic equilibrium involving the proposed intermedi-
ates 3 ꢀ 4, which was discussed in our previous work
[4a], is an important operative feature in the proposed
sequence of reactions and accounts for the observed
by-products. Successful reactions (entries a–i) seem to
be closely associated with the thermodynamic stability
of the enone product 2 and are achieved preferentially
for 1-aryl and 3-aryl substituted products. Comparison
of the results obtained from this InBr-mediated process
with the two other sequential methods to transform
a,a-dichloroketones and aldehydes into a,b-unsaturated
ketones 2 promoted by SmI2 and CrCl2 [2c] is important
to guide to the correct choice amongst these reagents.
The reaction is quite general when promoted by a sixfold
excess of CrCl2, while certain aldehydes resisted the
transformation promoted by SmI2. The present InBr-pro-
moted method does not require excess of the inorganic
reagent and shows generality similar to the process pro-
moted by CrCl2, although smaller yields were systemati-
cally obtained.
Now, we have extended this sequence of reactions to
produce the (E)-a,b-unsaturated ketones 2, through an
aldol coupling followed by an elimination reaction. The
key step in the sequence is the ejection of the b-related
chlorine and oxygen atoms of the diindium intermediate
5. The sequential reactions are conducted in neutral con-
ditions and offer a single step, one-pot, new protocol for
preparing enones 2. Despite the fact that the primary eno-
late 3 is produced as a mixture of diastereoisomers [4a],
the E-isomers of the enones 2 were obtained with com-
plete stereoselectivity, through a transition state 5 that
minimize steric repulsion between the organyl groups
attached to the aldehyde and to the dichloroketone start-
ing materials. Moreover, we expect that this work shed
some light on how to use indium(I) salts to prepare reac-
tive organoindium(III) compounds capable of useful
organic transformations.
4. Experimental section
4.1. General data
Indium monobromide was prepared by heating indium
metal and indium tribromide (molar ratio 2:1) in a vacuum
sealed tube, at 450 °C for 24 h. a,a-Dichloroacetone and
a,a-dichloroacetophenone (Aldrich) were distilled before
used under atmospheric and reduced pressures, respec-
tively. All the aldehydes were obtained from commercial
suppliers and purified, when necessary, according to stan-
dard procedures [6]. 1H and 13C NMR spectra were
acquired on a Bruker DPX 200 spectrometer (1H at
200.13 MHz and 13C at 50.32 MHz). Mass spectra were
registered in a HP 6890 GC (equipped with a split–splitless
injector and a cross-linked HP-5 capillary column measur-
ing of 30 m and with internal diameter of 0.32 mm) con-
nected to a HP 5973 MSD spectrometer, with helium as
the carrier gas.
3. Conclusion
We have demonstrated how to use indium monohalides
to produce reactive organoindium(III) species from gem-
dihalogenoketones, capable of useful organic transforma-
tions [3,4a]. The indium enolate, 3 obtained from the oxi-
dative insertion of InBr into one of the carbon–chlorine
bonds of the dichloroketone can be used for several pur-
poses: it couples with a second molecule of the dichlorok-
etone to produce, after reduction with excess of indium

C. Peppe, R.P. das Chagas / Journal of Organometallic Chemistry 691 (2006) 5856–5860
5859
4.2. Indium(I) bromide-promoted stereoselective preparation
of (E)-a,b-unsaturated ketones via sequential intermolecular
aldol-type coupling/elimination reactions of a,a-
dichloroketones and aldehydes. General experimental
procedure
(E)-3-(4-Methoxyphenyl)-1-phenyl-2-propen-1-one, 2f
(CAS: 959-33-1) [10]: 1H NMR (CDCl3): d = 3.75 (s,
3H), 6.81–6.88 (m, 2H), 7.33 (d, J = 15.6 Hz, 1H), 7.34–
7.55 (m, 5H), 7.71 (d, J = 15.6 Hz, 1H), 7.91–7.98 (m,
2H); 13C NMR (CDCl3): d = 55.22, 114.31, 119.66,
127.48, 128.26, 128.41, 130.09, 132.39, 138.39, 144.52,
161.57, 190.35; MS (EI, 70 eV): m/z (%) = 238 (100) [M],
161 (58), 108 (46), 77 (86).
A Schlenk test tube equipped with a condenser, truly
dried under high vacuum, was charged with 2 mL of dry
(sodium) THF, 195 mg (1.0 mmol) of the red solid InBr
and the a,a-dichloroketones (0.5 mmol). To this mixture
was added 0.5 mmol of the aldehyde and the reaction
was kept under reflux for l4 h. At the end of this period,
the reaction was quenched with water. The organics were
extracted with ethyl acetate. The extract was dried
(Na2SO4) and evaporated to dryness. The (E)-a,b-unsatu-
rated ketones 2 were separated by column chromatography
with hexanes or hexanes–ethyl acetate mixtures. Yields of
reactions are given in Table 1, and spectroscopic data for
products 2a–l are as follow:
(E)-1,3-Diphenyl-2-propen-1-one, 2a (CAS: 614-47-1)
[7]: 1H NMR (CDCl3): d = 7.39–7.67 (m, 8H), 7.54 (d,
J = 15.7 Hz, 1H), 7.83 (d, J = 15.7 Hz, 1H), 8.01–8.06
(m, 2H); 13C NMR (CDCl3): d = 121.82, 128.28, 128.32,
128.44, 128.77, 130.37, 132.62, 134.65, 137.97, 144.60,
190.24; MS (EI, 70 eV): m/z (%) = 208 (100) [M], 131
(76), 103 (76), 77 (100), 51 (69).
(E)-1-Phenyl-2-hexen-1-one, 2g [11]: 1H NMR (CDCl3):
d = 0.86 (t, J = 7.4 Hz, 3H), 1.44 (sex, J = 7.4 Hz, 2H),
2.12–2.24 (m, 2H), 6.77 (dt, J = 15.4 Hz, 1.0 Hz, 1H),
6.96 (dt, J = 15.4 Hz, 6.0 Hz, 1H), 7.30–7.48 (m, 3H),
7.80–7.86 (m, 2H); 13C NMR (CDCl3): d = 13.58, 21.27,
34.65, 125.86, 128.31, 128.32, 132.40, 137.83, 149.61,
190.68; MS (EI, 70 eV): m/z (%) = 174 (100) [M], 159
(36), 145 (100), 131 (84), 105 (100), 77 (100), 55 (100).
(E)-4-Methyl-1-phenyl-2-penten-1-one, 2h [12]: 1H
NMR (CDCl3): d = 1.04 (d, J = 6.8 Hz, 6H), 2.36–2.58
(m, 1H), 6.73 (dd, J = 15.5 Hz, 1.1 Hz, 1H), 6.95 (dd,
J = 15.5 Hz, 6.5 Hz, 1H), 7.32–7.50 (m, 3H), 7.81–7.89
(m, 2H); 13C NMR (CDCl3): d = 21.27, 31.40, 122.97,
128.38, 128.40, 132.45, 137.98, 155.90, 191.18; MS (EI,
70 eV): m/z (%) = 174 (86) [M], 159 (53), 145 (17), 131
(26), 105 (100), 77 (100).
(E)-1-Phenyl-2-dodecen-1-one, 2i (CAS: 100696-90-0)
[13]: 1H NMR (CDCl3): d = 0.81 (t, J = 6.7 Hz, 3H),
1.14–1.33 (m, 12H), 1.37–1.53 (m, 2H), 2.24 (q,
J = 7.0 Hz, 2H), 6.79 (d, J = 15.7 Hz, 1H), 7.00 (dt,
J = 15.7 Hz, 6.6 Hz, 1H), 7.30–7.50 (m, 3H), 7.83–7.90
(m, 2H); 13C NMR (CDCl3): d = 14.08, 22.64, 28.13,
29.22, 29.26, 29.38, 29.46, 31.83, 32.84, 125.79, 128.45,
128.48, 132.53, 137.96, 150.21, 190.96; MS (EI, 70 eV):
m/z (%) = 258 (22) [M], 159 (74), 133 (79), 120 (100), 105
(100), 77 (100), 55 (69).
(E)-3-(4-Chlorophenyl)-1-phenyl-2-propen-1-one,
2b
(CAS: 956-04-7) [8]: 1H NMR (CDCl3): d = 7.39 (d,
J = 8.0 Hz, 2H), 7.51 (d, J = 15.6 Hz, 1H), 7.49–7.62 (m,
5H), 7.76 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H);
13C NMR (CDCl3): d = 122.42, 128.47, 128.65, 129.22,
129.56, 132.91, 133.34, 136.40, 137.98, 143.29, 190.22;
MS (EI, 70 eV, for 35Cl): m/z (%) = 242 (79) [M], 207
(50), 165 (41), 105 (53), 77 (100).
(E)-3-(4-Bromophenyl)-1-phenyl-2-propen-1-one, 2c [9]:
1H NMR (CDCl3): d = 7.44 (d, J = 15.7 Hz, 1H), 7.38–
7.55 (m, 7H), 7.67 (d, J = 15.7 Hz, 1H), 7.91–7.96 (m,
2H); 13C NMR (CDCl3): d = 122.63, 124.77, 128.47,
128.65, 129.75, 132.20, 132.90, 133.84, 138.04, 143.32,
190.20; MS (EI, 70 eV, for 79Br): m/z (%) = 286 (38) [M],
207 (57), 105 (57), 77 (100).
(E)-4-(4-Chlorophenyl)-3-buten-2-one, 2j (CAS: 3160-
40-5) [14]: H NMR (CDCl3): d = 2.37 (s, 3H), 6.67 (d,
J = 16.0 Hz, 1H), 7.33–7.50 (m, 4H), 7.47 (d,
J = 16.0 Hz, 1H); 13C NMR (CDCl3): d = 27.57, 127.44,
129.19, 129.32, 132.90, 136.37, 141.76, 197.94.
1
(E)-4-(4-Methoxyphenyl)-3-buten-2-one, 2k (CAS:
1
3815-30-3) [15]: H NMR (CDCl3): d = 2.35 (s, 3H), 3.83
(E)-3-(2-Bromophenyl)-1-phenyl-2-propen-1-one,
2d:
(s, 3H), 6.60 (d, J = 16.3 Hz, 1H), 6.85–6.94 (m, 2H),
7.47 (d, J = 16.3 Hz, 1H), 7.40–7.53 (m, 2H); 13C NMR
(CDCl3): d = 27.32, 55.32, 114.37, 124.94, 126.97, 129.89,
143.21, 161.54, 198.37; MS (EI, 70 eV): m/z (%) = 176
(40) [M], 161 (100), 133 (36), 118 (18), 89 (24).
1H NMR (CDCl3): d = 7.13–7.30 (m, 2H), 7.35 (d,
J = 15.7 Hz, 1H), 7.40–7.68 (m, 5H), 7.92–7.97 (m, 2H),
8.06 (d, J = 15.7 Hz, 1H); 13C NMR (CDCl3):
d = 125.00, 125.84, 127.67, 127.83, 128.60, 128.61, 131.29,
132.91, 133.50, 135.00, 137.81, 143.16, 190.40; MS (EI,
70 eV, for 79Br): m/z (%) = 286 (5) [M], 207 (100), 105
(16), 77 (37), 51 (21).
Acknowledgement
(E)-3-(4-Methylphenyl)-1-phenyl-2-propen-1-one,
2e:
C.P. thanks CNPq for grants, and R.P.D. for the award
of a scholarship.
1H NMR (CDCl3): d = 2.40 (s, 3H), 7.24 (d, 2H), 7.50
(d, J = 15.8 Hz, 1H), 7.48–7.61 (m, 5H), 7.81 (d,
J = 15.8 Hz, 1H), 8.01–8.05 (m, 2H); 13C NMR (CDCl3):
d = 21.46, 117.94, 121.12, 128.42, 128.53, 129.65, 132.15,
132.58, 138.35, 141.01, 144.87, 190.59; MS (EI, 70 eV):
m/z (%) = 222 (33) [M], 207 (100), 145 (35), 115 (48), 105
(29), 77 (71).
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C. Peppe, R.P. das Chagas / Journal of Organometallic Chemistry 691 (2006) 5856–5860
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´
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