One-pot reduction-aldol reaction of esters

Article abstract of DOI:10.1055/s-2004-834808

We have developed a new protocol for making aldol adducts in a one-pot reaction between esters and silyl enol ethers in the presence of DIBALH without isolating the intermediate aldehydes. Lewis acid activation of the initially formed aluminated hemiacetals produces highly reactive electrophilic aldehyde equivalents in situ. Using this protocol, various aldol adducts can be readily obtained in up to 90% yield on a large scale.

Full text of DOI:10.1055/s-2004-834808

CLUSTER
2443
One-Pot Reduction–Aldol Reaction of Esters
O
ne-Pot Reduction–A
l
i
dol Re
k
E
st
i
ers o Sasaki, Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6,
Canada
E-mail: ayudin@chem.utoronto.ca
Received 27 July 2004
R4
Abstract: We have developed a new protocol for making aldol ad-
R1
R3
R1
OR2
1) DIBALH (1.1 equiv) in toluene, –78 °C
ducts in a one-pot reaction between esters and silyl enol ethers in the
presence of DIBALH without isolating the intermediate aldehydes.
Lewis acid activation of the initially formed aluminated hemiacetals
produces highly reactive electrophilic aldehyde equivalents in situ.
Using this protocol, various aldol adducts can be readily obtained in
up to 90% yield on a large scale.
OH
O
OTMS
R4
O
2) THF, BF3/Et2O (1.1 equiv),
–78 °C r.t.
R3
Equation 1 One-pot reduction–aldol process
Key words: aldol reaction, reduction, esters, aldehydes, aluminat-
ed hemiacetals, one-pot reaction
The scope of the reduction–aldol process was investigated
and the results are shown in Table 1. Primary esters gave
good to excellent yields (Table 1, entry 1–3 and 6), while
secondary esters gave lower yields (Table 1, entry 4). The
a,b-unsaturated esters gave reduced alcohols instead of
the aldol adducts (Table 1, entry 5). Both aromatic and
aliphatic groups (R3) gave comparable yields (Table 1,
entry 3 and 6). The 1,1,2-trisubstituted enol ethers gave
lower yields with low diastereoselectivities, while typical
Mukaiyama-aldol reaction gives high diastereoselectivity
(Table 1, entry 7).
The aldol reaction is one of the most important carbon–
carbon bond forming processes in contemporary organic
synthesis.1 In addition, the aldol fragments or their deriv-
atives are often present in the structures of natural prod-
ucts and pharmaceuticals.2 Typically, an aldol reaction is
accomplished by reacting an aldehyde and an enolate
equivalent in the presence of a Lewis acid.3,4 The alde-
hydes are prepared by either oxidation of alcohols or by
reduction of esters. The traditional method of generating
aldol products from the ester-containing starting materials
is based on reducing the ester to the corresponding alde-
hyde using DIBALH followed by treating the isolated al-
dehyde with a silyl enol ether in the presence of a suitable
Lewis acid.5 However, aldehyde isolation can be trouble-
some, especially on a large scale, because of the sensitiv-
ity of aldehydes and/or difficulty commonly encountered
during their purification. In this regard, one-pot processes
that avoid isolation of aldehyde building blocks are highly
desirable, especially in the case of low boiling point alde-
hydes.
Table 1 The Scope of the Reduction–Aldol Reaction
Entry R1
R2
R3
R4
Yield
(%)
1a
2a
3
CH2=CH(CH2)2-
Et
Ph
Ph
Ph
Ph
Ph
Me
Ph
H
90
89
75
25
0
CH3CH2=CH(CH2)2-
PhCH2-
Et
H
Me
Me
Me
Me
Et
H
4
Cyclopropyl
PhCH=CH-
PhCH2-
H
5
H
6
H
63
38b
At the outset of our investigation, our hope was that the
silyl enol ether would attack the aluminated hemiacetal
which is formed upon initial reduction of the aldehyde
with DIBALH.6,7 Using this protocol, ethyl 4-pentenoate
was converted to the corresponding aldol in excellent
yield by the DIBALH reduction followed by the in situ al-
dol reaction with 1-phenyl-1-(trimethylsilyloxy)ethylene
in the presence of boron trifluoride without isolating the
corresponding aldehyde (Equation 1). Remarkably, the
formation of a,b-unsaturated ketone was not observed in
this reaction. The presence of boron trifluoride was found
to be mandatory as no reaction took place in its absence.
7
CH2=CH(CH2)2-
Me
a 1.1 equiv TMS ether was used. 1.5 equiv TMS ether was used in
other entries.
b Diastereomeric ratio = 1.4:1.
The proposed mechanism is shown in Scheme 1. The ester
is first reduced by DIBALH to give the aluminated hemi-
acetal, which coordinates to boron trifluoride, producing
a highly electrophilic aluminated intermediate. There are
two possible routes from this complex: in the first possi-
bility, the silyl enol ether attacks the complex to give the
aluminated aldol, which is hydrolyzed to the correspond-
ing aldol. In the other route, the initially produced com-
plex is decomposed to give aluminated aldehyde, which is
subsequently attacked by the silyl enol ether to give the
aluminated aldol adduct, which is subsequently hydro-
SYNLETT 2004, No. 13, pp 2443–2444
0
3
.1
1
.2
0
0
4
Advanced online publication: 07.10.2004
DOI: 10.1055/s-2004-834808; Art ID: Y04004ST
© Georg Thieme Verlag Stuttgart · New York

2444
M. Sasaki, A. K. Yudin
CLUSTER
successively added at –78 °C, and the reaction mixture was allowed
to warm up to around 0 °C under stirring. After completion (judged
by TLC), 1 N HCl (240 g), cooled in an ice bath, was added to the
reaction mixture and separated to two layers and the water layer was
extracted with toluene (50 mL). The combined organic layers were
washed with H2O (150 mL) and dried over NaSO4. The solvent was
removed in vacuo and 3-hydroxy-1-phenylhept-6-en-1-one was ob-
tained as a crude yellow oil (16.2 g). The purity was 88% and con-
lyzed to the corresponding aldol. As a result, the aldol
adduct is produced in a one-pot reaction from the corre-
sponding ester without isolating the intermediate alde-
hyde.
BF3
OR2
1
R1
taining 12% of acetophenone (yield: 90%). H NMR (300 MHz,
R3
CDCl3): d = 7.97–8.00 (m, 2 H), 7.59–7.64 (m, 1 H), 7.48–7.53 (m,
2 H), 5.83–5.96 (m, 1 H), 5.00–5.14 (m, 2 H), 4.24–4.32 (m, 1 H),
3.05–3.24 (m, 2 H), 2.20–2.34 (m, 2 H), 1.58–1.82 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): d = 200.8, 138.3, 136.8, 133.6, 128.7,
128.1, 115.0, 67.2, 45.0, 35.6, 29.8 ppm.
O
Bu2Al
O
TMS
R1
OR2
DIBALH
or
BF3
OR2
O
R1
Acknowledgment
R1
R3
O
We thank the Natural Sciences and Engineering Research Council
(NSERC), Canada Foundation for Innovation, ORDCF, and the
University of Toronto for financial support. Sumitomo Chemical
Co, Ltd. is gratefully acknowledged for a fellowship (MS). Andrei
K. Yudin is a Cottrell Scholar of Research Corporation.
O
Bu2Al
Bu2Al
O
TMS
R1
R3
H+
R1
R3
O
O
OH
O
Bu2Al
References
(1) For reviews, see: (a) Heathcock, C. H. In Comprehensive
Organic Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991, 133–275. (b) Braun, M. In
Houben-Weyl: Methods of Organic Chemistry, Vol. E21;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; George Thieme Verlag: Stuttgart, 1995, 1603.
(2) For example, see: (a) Evans, D. A.; Starr, J. T. J. Am. Chem.
Soc. 2003, 125, 13531. (b) Heathcock, C. H.; McLaughlin,
M.; Hubbs, J. L.; Wallace, G. A.; Scott, R.; Claffey, M. M.;
Hayes, C. J.; Ott, G. R. J. Am. Chem. Soc. 2003, 125, 12844.
(c) Kiyooka, S.; Shahid, K. A.; Goto, F.; Okazaki, M.; Shuto,
Y. J. Org. Chem. 2003, 68, 7967. (d) Gaul, C.; Njardarson,
J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042.
(e) Kalesse, M.; Chary, K. P.; Quitschalle, M.; Burzlaff, A.;
Kasper, C.; Scheper, T. Chem.–Eur. J. 2003, 9, 1129.
(3) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503.
Scheme 1 Proposed mechanism of the reduction–aldol reaction
The obtained aldols can be converted to the corresponding
b-ketoaziridines (Equation 2), which have found a range
of applications as important starting materials for various
saturated nitrogen-containing heterocycles.8
1) TsOH
2) NH2OMe
R
Ph
R
Ph
N
H
O
OH
O
3) NaOMe
Overall yield: 63% (R = H)
64% (R = Me)
Equation 2 Aldols as the starting materials to b-ketoaziridines
(4) For recent development of the aldol reaction, for example,
see: (a) Yanagisawa, A.; Sekkiguchi, T. Tetrahedron Lett.
2003, 44, 7163. (b) Nagasawa, T.; Fujiwara, H.;
Mukaiyama, T. Chem. Lett. 2003, 44, 6187. (c) Calter, M.
A.; Orr, R. K. Tetrahedron Lett. 2003, 44, 5699.
(5) For example, see: (a) Evans, D. A.; Hu, E.; Burch, J. D.;
Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654. (b) Wong,
Y.-S. Chem. Commun. 2002, 686. (c) Evans, D. A.; Fitch,
D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122,
10033.
In conclusion, we have developed a new method to syn-
thesize aldol adducts from esters in a one-pot reaction
without isolating the corresponding aldehydes. Further
studies such as asymmetric version of this reaction are in
progress. Particularly exciting is the possibility of apply-
ing the highly reactive aluminated intermediates in other
types of nucleophilic addition processes.
(6) For one-pot reaction of lactones to give aldol derivatives,
see: Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2001,
1169.
(7) For one-pot reduction–Wittig reaction of esters, see: Takacs,
J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27,
1257.
Representative Procedure of 3-Hydroxy-1-phenylhept-6-en-1-
one (Table 1, Entry 1):
To a mixture of ethyl 4-pentenoate (10.0 g, 78 mmol) and toluene
(100 mL), 1.5 M DIBALH in toluene (57 mL, 86 mmol) was slowly
added at –78 °C, and the mixture was stirred for 1 h at –78 °C. To
this reaction mixture THF (240 mL), BF3·OEt2 (11 mL, 86 mmol),
and 1-phenyl-1-trimethylsilyloxyethylene (16.5 g, 86 mmol) were
(8) Sasaki, M.; Yudin, A. K. J. Am. Chem. Soc. 2003, 125,
14242.
Synlett 2004, No. 13, 2443–2444 © Thieme Stuttgart · New York