Mukaiyama Aldol Reactions of Silyl Enolates Catalyzed by Iodine

Article abstract of DOI:10.1081/SCC-120028638

Iodine catalyzed Mukaiyama aldol reaction of silyl enol ethers and silyl ketene acetal with aldehydes, ketones and acetals in good yield with preferential antiselectivity has been described.

Full text of DOI:10.1081/SCC-120028638

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Mukaiyama Aldol Reactions of Silyl Enolates
Catalyzed by Iodine
Prodeep Phukan a
a Department of Chemistry , Gauhati University , Guwahati, 781014, Assam, India
Published online: 21 Aug 2006.
To cite this article: Prodeep Phukan (2004) Mukaiyama Aldol Reactions of Silyl Enolates Catalyzed by Iodine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:6, 1065-1070, DOI:
10.1081/SCC-120028638
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1065–1070, 2004
Mukaiyama Aldol Reactions of Silyl
Enolates Catalyzed by Iodine
*
Prodeep Phukan
Department of Chemistry, Gauhati University, Guwahati, Assam, India
ABSTRACT
Iodine catalyzed Mukaiyama aldol reaction of silyl enol ethers and silyl
ketene acetal with aldehydes, ketones and acetals in good yield with
preferential antiselectivity has been described.
Key Words: Iodine; Mukaiyama aldol; Silyl enol ether; Silyl keten
acetal; Aldehydes; ketones.
The aldol addition reaction has long been considered as one of the most
versatile carbon–carbon bond forming reactions in organic synthesis. In
particular, cross aldol reactions of silyl enol ethers which proceed in a highly
regioselective manner to afford adducts in high yield. Since the discovery of
Mukaiyama aldol reaction[1] promoted by TiCl4, a variety of catalysts have
been used to activate this process.[2] Many catalysts are fraught with
*
Correspondence: Prodeep Phukan, Department of Chemistry, Gauhati University,
Guwahati-781014, Assam, India; E-mail: pphukan@yahoo.com.
1065
DOI: 10.1081/SCC-120028638
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Phukan
limitations such as the use of stoichiometric amount of catalyst, moisture
sensitivity of the catalyst, expensive reagents etc. Although recent reports
claimed significant improvement circumventing these drawbacks, new
methods are still desirable. Recently, Li and co-workers reported2k the use
of Et2O : MgI2 as a catalyst for aldol reactions, however this method suffers
from a draw back related to stringent dry reaction medium. In recent times,
iodine has been emerging as an effective catalyst for various organic
transformations.[3] The advantages in the use of iodine are (1) mild neutral
condition (2) inexpensive reagent (3) no stringent dry conditions required. We
describe herein an efficient and convenient procedure for Mukaiyama aldol
reactions in the presence of a catalytic amount of iodine (Sch. 1).
The catalytic effect of iodine was evaluated for three representative silyl
enol ethers viz. 1-[(trimethylsilyl)oxy]-1-cyclohexene, 1-[(trimethylsily-
l)oxy]-1-phenylethylene and 1-methoxy-2-methyl-1-(trimethylsilyloxy)-1-
propene with various carbonyl compounds (Sch. 1). Reaction proceeds well
with different carbonyl compounds such as aldehyde, ketones, and acetals
with good yields (Table 1). The optimum amount of iodine needed to catalyze
the reaction is only 2 mol% based on the electrophile used. Initially, the
reaction was performed with 1-[(trimethylsilyl)oxy]-1-cyclohexene and
banzaldehyde. In a typical procedure, the enol ether, electrophile and iodine
were stirred in dichloromethane at room temperature for appropriate time. In
general, the crude product contains alcohol in a major amount and the
trimethyl silylolxy compound in a minor amount. After completion of the
reaction, methanol was added to ensure complete deprotection of the silyl
group.[4] Selectivity is temperature dependent as seen from the Table 1 (entry
2 and 3). The ratio of the stereo-isomers (syn/anti) was determined by
comparing the intensities of the methine proton signal (22CH22O) in the 1H-
NMR spectrum of the crude product and matching the data reported[2]
elsewhere. As expected, aromatic aldehydes react faster than aliphatic one.
From the results, it could be observed that there is a general trend for
antiselectivity, irrespective of the nature of aldehydes. The aldol reaction was
Scheme 1.

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Mukaiyama Aldol Reactions of Silyl Enolates Catalyzed by Iodine
1067
Table 1. Iodine catalysed Mukaiyama aldol reactions of different silyl enolates with
electrophiles.
Entry
1.
Enol ether
Electrophiles
Time (h) Yield (%)a Syn/antib,c
PhCHO
1.5
84
24 : 76d
1
1
1
1
1
1
2.
3.
4.
5.
6.
PhCHO
PhCHO
1.5
2
84
87
78
79
79
30 : 70e
48 : 52f
28 : 72g
30 : 70h
30 : 70i
p-MeO-PhCHO
p-NO2-PhCHO
p-Cl-PhCHO
1.5
1.5
1.5
7.
8.
1
1
1.5
2
82
73
25 : 75j
34 : 66k
(CH3)2CHCHO
PhCHO
9.
1.5
87
—
2
2
2
2
2
2
10.
11.
12.
13.
14.
(CH3)2CHCHO
HCH(OMe)2
PhCH(OMe)2
CH3COCH3
2
75
68
78
71
68
—
—
—
—
—
1.5
1.5
5
CH3(CH2)2COC
5
15.
PhCHO
2.5
80
—
3
3
3
3
16.
17.
18.
p-NO2-PhCHO
p-Cl-PhCHO
(CH3)3CH2CHO
2.5
2.5
3
80
77
70
—
—
—
aIsolated yield after chromatographic purification.
bProducts are characterized by 1H, 13C NMR, IR spectroscopy and mass spectrometry.
cStereoisomer ratios are determined by 1H NMR analysis.
dRef.[1b,2b,2l,2m]
.
eTemp. 08C.
fTemp. 2788C.
gRef.[2g,2l]
hRef.[2g,2l]
.
.
iRef.[2g,2l]
.
jRef.[2b,2m]
kRef.[1b,2b]
.
.

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also performed with acetal (Table 1, entry 11, 12) and ketones (Table 1, entry
13, 14). Reaction proceeds well with acetals as well as ketones in good yield.
Mechanism of the reaction is not yet studied. There are two mechanisms
known[1b,5] in the literature in case of metal catalyzed aldol reaction. The most
well accepted mechanism is the formation of a six-membered transition state
at the intermediate stage.[1b] The second pathway was observed by Seto[5]
which proceeds via an initial electron transfer from the enol-ether to the co-
ordinated metal. In our case, the second pathway is most likely wherein the
reaction proceeds via initial co-ordination of iodine with aldehyde and then
electron transfer between silyl enol ether and iodine.
In conclusion, a simple process for aldol reactions catalyzed by iodine has
been demonstrated.
EXPERIMENTAL
1
Iodine was purified by sublimation before use. H NMR and 13C NMR
spectra were recorded in Bruker 400 MHz instrument in CDCl3, using TMS as
internal standard. IR spectra were recorded in Perkin-Elmer Spectrum RXI
FT-IR spectrometer. Mass spectra were recorded on a Finnigan mass
spectrometer using ionization energy of 70 eV and elemental analysis was
carried out in Perkin-Elmer 2400 Series II elemental analyzer.
Typical Procedure
Silyl enol ether (1.1 mmol) in dichloromethane (1 mL) was added to a
solution of aldehyde (1 mmol), and iodine (0.02 mmol) in dichloromethane
(1 mL) and stirred at room temperature. After completion of reaction (TLC),
of methanol (10 mL) was added and stirred for 1 hr. Sodium thiosulfate
(20 mg) was added, the reaction mixture stirred for 10 min and evaporated.
The residue was taken up in ether, washed with brine, dried (Na2SO4) and
concentrated. Purification of the crude product by flash chromatography on
silica gel (230–400 mesh) with petroleum ether 2EtOAc as eluent gave the
pure product (70–87%).
3-Hydroxy-3-methyl-1-phenyl-1-hexanone. IR (neat): 3492, 2960,
1
2933, 1670, 1597, 1449, 1374, 1213 cm21. H NMR (400 MHz, CDCl3):
0.91 (t, J ¼ 7.3 Hz, 3H), 1.31–1.47 (m, 2H), 1.52–1.61 (m, 2H), 3.11 (dd,
J ¼ 23.6, 17.1 Hz), 4.1 (s, 1H), 7.45 (t, J ¼ 8.1 Hz, 1H), 7.94 (d, J ¼ 7.3 Hz,
2H); 13C NMR (100 MHz, CDCl3): 14.57, 17.33, 27.03, 44.7, 46.9, 71.97,
128.04, 128.68, 133.56, 137.35, 202.06. MS: (m/z, % rel. intensity) 191(4),
163(31), 145(2), 129(5), 120(20), 105 (100), 91 (3), 77 (38), 71 (20), 43 (42).

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Mukaiyama Aldol Reactions of Silyl Enolates Catalyzed by Iodine
1069
Analysis: C13H18O2 requires C, 75.69 and H, 8.79 %; found: C, 75.64 and H,
8.72%.
Methyl 3-hydroxy-2,2-dimethyl-3-(4-nitrophenyl)propanoate. Mp.
115–1178C (Lit6 114–1168C); IR (CHCl3, cm21): 3461, 3055, 2986, 1732,
1606, 1523, 1470, 1435, 1349, 1265. 1H NMR (400 MHz, CDCl3): 1.11(s, 3H),
1.12(s,3H), 3.43 (bs, 1H), 3.72 (s, 3H), 4.99 (s, 1H), 7.47 (d, J ¼ 8.59 Hz, 2H),
8.16 (d, J ¼ 8.84 Hz, 2H); 13C NMR (100 MHz, CDCl3): 19.13, 22.74, 47.60,
52.36, 77.69, 122.9, 128.56, 174.23, 174.47, 177.74. MS: (m/z, % rel.
intensity): 254 (68), 236 (77), 194 (2), 180 (6), 166 (8), 128 (4), 115 (11), 105
(26), 102 (100), 87 (34), 73 (24).
ACKNOWLEDGMENT
I am thankful to Dr. N. C. Barua of RRL, Jorhat, India, for constant
encouragement and DST, New Delhi for financial support.
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Received in India September 22, 2003

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