Reexamination of CeCl3 and InCl3 as activators in the diastereoselective mukaiyama aldol reaction in aqueous media

Article abstract of DOI:10.1021/jo026713c

A search for suitable reaction conditions in Mukaiyama-type aldol condensations activated by CeCl₃ and InCl₃ revealed that the reaction proceeds best in i-PrOH/ H₂O (95:5). Contrary to literature precedent, no reaction was

Full text of DOI:10.1021/jo026713c

advantage in the Mukaiyama approach is the potential
for catalytic, enantioselective reactions.3
Reexa m in a tion of CeCl3 a n d In Cl3 a s
Activa tor s in th e Dia ster eoselective
Mu k a iya m a Ald ol Rea ction in Aqu eou s
Med ia
Omar Mun˜oz-Mun˜iz, Martina Quintanar-Audelo, and
Eusebio J uaristi*
A variety of Lewis acids have been used as catalysts
in the Mukaiyama reaction (eq 2), including triarylcar-
benium ions,4a boron Lewis acids,4b tin Lewis acids,4c,d
palladium Lewis acids,4e titanium Lewis acids,4f and
copper Lewis acids.4g Most of these Lewis acids react
rapidly with water and become deactivated in the pro-
cess; thus, the reactions must be carried out under strict
anhydrous conditions. Nevertheless, Kobayashi et al.5
have recently shown that lanthanide triflates [Ln(OTf)3]
can be used as efficient Lewis acids in aqueous media
(typically, H2O-THF (1:4) or H2O-EtOH (1:9)], as their
hydrolysis by water is generally slow. This development
is quite remarkable because, in regard to the topic of
interest in the present report, Mukaiyama-type aldol
reactions can be carried out in aqueous media, avoiding
the use of potentially toxic solvents and allowing the easy
recovery of the active Lewis acid catalyst.
Departamento de Quı´mica, Centro de Investigacio´n y de
Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado Postal 14-740, 07000 Me´xico, D.F., Me´xico
ejuarist@mail.cinvestav.mx
Received November 14, 2002
Abstr a ct: A search for suitable reaction conditions in
Mukaiyama-type aldol condensations activated by CeCl3 and
InCl3 revealed that the reaction proceeds best in i-PrOH/
H2O (95:5). Contrary to literature precedent, no reaction was
observed in pure water, and the encountered destruction of
the starting silyl enol ether can be ascribed to initial
hydrolysis of the Lewis acid. As anticipated from the dual
parameter (pKh, WERC value) characteristics of CeCl3 and
InCl3, the former proved more efficient as Lewis acid-
promoter, in terms of reaction speed and yield. Nevertheless,
InCl3 was a superior catalyst during evaluation of the
diastereoselectivity of the process. In this regard, determi-
nation of diastereoselectivity as a function of time showed
that the InCl3-catalyzed reaction is irreversible, whereas the
CeCl3-catalyzed reaction is a reversible process. In both
cases, formation of the syn product is kinetically pre-
ferred, although ∆∆G2q73K(InCl3) ) 1.50 kcal/mol versus
Very recently, from a systematic examination of the
catalytic activity exhibited by group 1-15 metal chlo-
rides, perchlorates, and triflates in the Mukaiyama aldol
reaction of benzaldehyde with silyl enol ether Z-1 in
water-THF (1:9) (eq 3), Kobayashi concluded that the
∆∆Gq273K(CeCl3)
) 0.38 kcal/mol. Molecular modeling
(semiempirical PM3, ab initio HF/3-21G*, hybrid B3LYP/3-
21G*, and B3LYP/LANL2DZ) of the diastereoselective aldol
reaction promoted by InCl3 supports a “closed”, Zimmer-
mann-Traxler transition state.
catalytic activity of the metal cations depends on two
parameters: (1) the hydrolysis constants, Kh, and (2)
water exchange rate constants, WERC. In particular,
highest catalytic activity was found in those metal cations
with pKh values in the range from about 4 to 10, and
The aldol reaction is well-recognized as one of the most
important carbon-carbon bond-forming reactions in
organic synthesis. As can be appreciated in eq 1, two
WERC values greater than 3.2 × 106 M-1 s-1 5d
.
As anticipated from the previous analysis, “borderline”
indium(III) salts gave the aldol products in modest
yields.5d Nevertheless, an influential review by Cintas6
has elicited much interest in the utility of indium
stereogenic centers are generated in the aldol reaction
and useful protocols must fulfill satisfactory levels of
reaction yield, diastereoselectivity, and enantioselectiv-
ity.1
A most relevant variant of the classical aldol reaction
(eq 1) was developed by Mukaiyama et al.,2 who found
that silyl enol ethers react with carbonyl compounds in
the presence of Lewis acids to give aldol products in a
highly chemoselective manner (eq 2). The other main
(3) (a) Mukaiyama, T. Aldrichim. Acta 1996, 29, 59. (b) Kobayashi,
S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102,
2227. (c) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
(4) (a) Denmark, S. E.; Chen, C.-T. Tetrahedron Lett. 1994, 35, 4327.
(b) For two comprehensive reviews, see: Deloux, L.; Srebnik, M. Chem.
Rev. 1993, 93, 763. Wallbaum, S.; Martens, J . Tetrahedron: Asymmetry
1992, 3, 1475. (c) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T.
Tetrahedron 1993, 49, 1761. (d) Evans, D. A.; McMillan, D. W.;
Campos, K. R. J . Am. Chem. Soc. 1997, 119, 10859. (e) Sodeoka, M.;
Ohrai, K.; Shibasaki, M. J . Org. Chem. 1995, 60, 2648. (f) Carreira, E.
M.; Singer, R. A.; Lee, W. J . Am. Chem. Soc. 1994, 116, 8837. (g) Evans,
D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem. Soc. 1996, 118,
5814.
(1) Some representative reviews: (a) Heathcock, C. H. Aldrichim.
Acta 1990, 23, 99. (b) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top.
Stereochem. 1982, 13, 1. (c) Paterson, I. Org. React. 1997, 51, 1. (d)
Mahrwald, R. Chem. Rev. 1999, 99, 1095. (e) Denmark, S. E.;
Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
(2) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1012. (b) Mukaiyama, T. Org. React. 1982, 28, 203.
(5) (a) Kobayashi, S. Chem. Lett. 1991, 2087. (b) Kobayashi, S.;
Hachiya, I. J . Org. Chem. 1994, 59, 3590. For Ln(OTf)3-catalyzed
asymmetric aldol reactions in aqueous media, see: (c) Kobayashi, S.;
Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001, 3, 165. (d)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (e) Manabe,
K.; Kobayashi, S. Chem. Eur. J . 2000, 6, 4095.
(6) Cintas, P. Synlett 1995, 1087.
10.1021/jo026713c CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
1622
J . Org. Chem. 2003, 68, 1622-1625

TABLE 1. Solven t Effect on th e Mu k a iya m a -Typ e Ald ol
Con d en sa tion
TABLE 2. Dia ster eoselectivity of Ald ol Rea ction s
P r om oted by CeCl3 a n d In Cl3
MCl3
(mol %)
temp
(°C)
time
(h)
yield
(%)
dr
Lewis acid
entry (20 mol %)
temp time yield yield
(°C) (h) of 3 of 4
entry
(syn:anti)
solvent(s)
CH2Cl2
toluene
CH3CN
H2O
H2O/EtOH (1:9)
1
2
3
4
5
6
InCl3 (100)
InCl3 (20)
InCl3 (20)
CeCl3 (100)
CeCl3 (20)
CeCl3 (20)
0
0
25
0
0
25
6
24
24
3
18
24
63
65
71
91
85
88
96:4
92:8
92:8
41:59
44:56
48:52
1
2
3
4
5
6
7
8
9
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
0
0
0
25
25
24
24
24
24
18
18
24
24
24
24
12
12
14
17
39
9
43
55
H2O/i-PrOH (1:19) 25
CH2Cl2
toluene
CH3CN
H2O
0
0
0
25
25
28
35
in a water-2-propanol (1:19) solvent mixture (entries 6
and 12 in Table 1). As anticipated from pKh/WERC value
dual parameter considerations,5d CeCl3 proved more
efficient than InCl3 as a Lewis acid activator (compare
entries 5 and 11, as well as entries 6 and 12 in Table 1).
(See, however, next section.)
45 16
traces
10
11
12
H2O/EtOH (1:9)
67
90
H2O/i-PrOH (1:19) 25
reagents in synthesis. Furthermore, Loh and co-workers7
reported in 1996 that InCl3 was an efficient catalyst in
aldol reactions of silyl enol ethers with aldehydes in pure
water. This report was subsequently questioned by Koba-
yashi et al.,8 who repeated the experiments and found
that hydrolysis of the Mukaiyama silyl enol ethers is
faster than the desired condensation, unless the Lewis
acid (InCl3) is used neat or in micellar systems.
Lew is Acid Effect on Dia ster eoselectivity. Once
we had established suitable reaction conditions for the
Mukaiyama-type aldol condensation promoted by CeCl3
and InCl3 [i-PrOH-H2O (19:1), rt, 12 and 18 h, respec-
tively], we proceeded to evaluate the diastereoselectivity
of the process. To this end, the trimethylsilyl ether
derived from propiophenone, Z-1,9 was reacted with
benzaldehyde, with the results collected in Table 2.
Diastereomeric ratios were determined by measurement
With this background, we would like to communicate
our own results in the area, in particular the evaluation
of signal ratios in H and 13C NMR spectra. The assign-
ment of the relative configuration of products syn-5 and
anti-5 was done by analysis of vicinal coupling constants,
as described by Denmark et al.11
1
of InCl3 (pKh ) 4.0; WERC value ) 4.0 × 104 M-1 s-1
)
and CeCl3 (pKh ) 8.3; WERC value ) 2.17 × 108 M-1
s-1) as Lewis acid catalysts in Mukaiyama-type aldol
reactions.
Inspection of Table 2 confirms that CeCl3 is a more
efficient Lewis acid activator than InCl3. Indeed, yields
with CeCl3 fall in the 85-91% range (entries 4-6),
whereas moderate yields are seen with InCl3, 63-71%
(entries 1-3). Nevertheless, much better diastereoselec-
tivities were achieved with InCl3: dr ) 92-96:8-4. By
comparison, diastereomeric ratios with CeCl3 are a
disappointing 41-48:59-42.
Resu lts a n d Discu ssion
Solven t Effect. First of all, a search was undertaken
for the best reaction conditions (solvent, temperature,
reaction time) in the aldol condensation of trimethylsilyl
enol ether 29 with benzaldehyde, in the presence of 0.2
equiv of the Lewis acid activator (Table 1).
Interestingly, determination of the diastereomeric
product ratio with time indicates that such ratio remains
constant in the case of the InCl3-promoted reaction (i.e.,
the reaction is kinetically controlled, with great predomi-
nance of the syn product), whereas the CeCl3-activated
reaction initially affords a syn:anti ratio equal to 67:33
that then gradually changes until an equilibrium syn:
anti ratio of 47:53 dr is attained (Figure 1).
The epimerization process syn-5 h anti-5 observed
with CeCl3 could in principle be ascribed to a retro-Aldol
reaction; however, a control experiment in which syn-5
was treated with CeCl3 in the presence of p-nitrobenz-
aldehyde afforded varying amounts of anti-5, but no
appreciable formation of aldol product 6 (Scheme 1).
The above observation, together with literature pre-
cedent,12 leads to the conclusion that CeCl3 most likely
promotes the epimerization syn-5 h anti-5 via keto-
Salient observations are the following: (1) No aldol
reaction takes place in pure water (entries 4 and 10 in
Table 1), presumably as a consequence of partial hy-
drolysis of the Lewis acid, which induces destruction of
the silyl enol ether. This result is contrary to Loh’s
reports,7 but in line with Kobayashi’s analysis.8 (2) Poor
to moderate yields of the silylated aldol product 3 were
found in aprotic solvents CH2Cl2, toluene, or CH3CN.
Essentially quantitative desilylation of 3 to give 4 was
achieved with tetrabutylammonium fluoride.10 (3) The
best yields of the desired aldol product 4 were obtained
(7) (a) Loh, T.-P.; Pei, J .; Cao, G.-Q. Chem. Commun. 1996, 1819.
(b) Loh, T.-P.; Chua, G.-L.; Vittal, J . J .; Wong, M.-W. Chem. Commun.
1998, 861.
(8) Kobayashi, S.; Busujima, T.; Nagayama, S. Tetrahedron Lett.
1998, 39, 1579.
(9) Prepared according to literature procedures: (a) House, H. O.;
Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org. Chem. 1969, 34, 2324.
(b) Matano, Y.; Azuma, N.; Suzuki, H. J . Chem. Soc., Perkin Trans. 1
1994, 1739.
(10) Cf.: (a) Greene, T. W. Protective Groups in Organic Synthesis;
Wiley: New York, 1981; pp 39-43. (b) Kocienski, P. J . Protecting
Groups; Thieme: Stutgart, Germany, 1994.
(11) Denmark, S. E.; Wang, K.-T.; Stavenger, R. A. J . Am. Chem.
Soc. 1997, 119, 2333 and Supporting Information for this paper.
(12) See, for example: Ward, D. E.; Sales, M.; Sasmal, P. K. Org.
Lett. 2001, 3, 3671.
J . Org. Chem, Vol. 68, No. 4, 2003 1623

F IGURE 1. Diastereomeric (syn-5/anti-5) product ratios as a function of time. The reactions were carried out at 0 °C, with 20
mol % of Lewis acid catalyst.
TABLE 3. Dia ster eoselectivity of Ald ol Rea ction s w ith
Both Alip h a tic a n d Ar om a tic Ald eh yd es, P r om oted by
CeCl3 a n d In Cl3
SCHEME 1
temp time prod- yield
dr
entry
aldehyde
MX3 (°C) (h) uct (%) (syn:anti)
1
2
3
4
5
6
7
8
9
benzaldehyde
CeCl3 25
18 rac-5
12 rac-6
18 rac-7
15 rac-8
12 rac-9
85
78
73
66
83
44:56
39:61
34:66
40:60
45:55
36:64
44:56
92:8
68:32
95:5
90:10
96:4
p-nitrobenzaldehyde CeCl3 25
p-anisaldehyde CeCl3 25
p-chlorobenzaldehyde CeCl3 25
acetaldehyde
CeCl3
CeCl3
CeCl3
0
0
0
isobutyraldehyde
pivalaldehyde
benzaldehyde
18 rac-10 47
18 rac-11 39
SCHEME 2
InCl3 25
24 rac-5
18 rac-6
24 rac-7
18 rac-8
18 rac-9
71
60
61
51
63
p-nitrobenzaldehyde InCl3 25
InCl3 25
11 p-chlorobenzaldehyde InCl3 25
10 p-anisaldehyde
12 acetaldehyde
13 isobutyraldehyde
14 pivalaldehyde
InCl3
InCl3
InCl3
0
0
0
18 rac-10 42
18 rac-11 31
95:5
98:2
enolization (Scheme 2). Epimerization via ketoenolization
is presumably favored by the greater Lewis acidity of
Ce(III), with respect to In(III).13
reaction times is 67:33, which indicates a smaller
∆∆Gq273K ) 0.38 kcal/mol. Again, the activation energy
is lower for the transition state leading to syn-5.
Table 3 collects diastereoselectivity data obtained with
additional aldehydes, both aliphatic (acetaldehyde, iso-
butyraldehyde, and pivalaldehyde) and aromatic (p-
anisaldehyde, p-nitrobenzaldehyde, and p-chlorobenz-
aldehyde). It is appreciated that similar observations
were recorded: faster but less stereoselective aldol ad-
dition in the presence of CeCl3, and slower and highly
diastereoselective addition with InCl3 as Lewis acid
catalyst.
Molecu la r Mod elin g of th e Lew is Acid -Activa ted
Com p lexes. From the kinetic studies discussed above
(cf. Figure 1 and text), it is apparent that the difference
in activation energies for the aldol reactions catalyzed
by InCl3 and CeCl3 is substantial. Indeed, with InCl3 as
Lewis acid, silyl enol ether Z-1 reacts with benzaldehyde
under kinetic control to give a ca. 94:6 ratio of the syn
and anti aldol products; this suggests a ∆∆Gq273K ) 1.50
kcal/mol, favoring formation of syn-5. By contrast, the
syn:anti ratio of diastereomeric products 5 at short
In his recent review, Mahrwald1d concluded that the
described stereochemical outcome of the Mukaiyama
reaction cannot be explained by classical “closed” transi-
tion state models (Zimmermann-Traxler models); in-
stead, “open” transition state models offer best agreement
with the experimental data. To gain some mechanistic
insight into the indium chloride catalyzed Mukaiyama
reaction of interest,14 we performed semiempirical (PM3),15
ab initio (HF/3-21G*),16 and hybrid (B3LYP/3-21G* and
B3LYP/LANL2DZ)16 theoretical calculations on the six
“open” Lewis acid-activated arrangements that can in
principle afford the anti and syn products 5 (Scheme 3).
Table 4 collects the calculated energies for optimized
geometries of the “open” transition states leading to anti
(I-III) and syn (IV-VI) aldol products in the reaction
(14) For meaningful computational comparison of diastereomeric
transition states, it is recommended that relative energies differ by at
least 0.5 kcal/mol: J uaristi, E. Introduction to Stereochemistry and
Conformational Analysis; Wiley: New York, 1991; p 170.
(15) PC Spartan-Pro, version 1.0; Wavefunction, Inc.: Irvine, CA,
1999.
(13) Cf.: Fukuzumi, S.; Ohkubo, K. Chem. Eur. J . 2000, 6, 4532.
1624 J . Org. Chem., Vol. 68, No. 4, 2003

SCHEME 3
TABLE 4. Ca lcu la ted Rela tive En er gies for “Op en ”
In Cl3-P r om oted Tr a n sition Sta tes Lea d in g to a n ti-5
(I-III) a n d syn -5 (IV-VI) (See Sch em e 3)
SCHEME 4
Erel (kcal/mol)
PM3
HF/3-21G* B3LYP/3-21G* B3LYP/LANL2DZ
I
II
6.313
4.103
8.804
7.759
0.000
3.055
0.000
4.597
2.822
7.701
7.177
0.000
10.253
0.000
5.669
6.115
5.082
12.599
11.290
0.000
5.178
0.000
6.909
14.940
6.835
9.324
12.405
0.000
11.008
0.000
4.889
III
IV
V
VI
VII
Con clu sion s. (1) Evaluation of both aprotic (CH2Cl2,
toluene, CH3CN) and aqueous media as solvents for
Mukaiyama-type aldol condensations promoted by CeCl3
and InCl3 showed i-PrOH/H2O (95:5) to give the highest
yields.
(2) As anticipated by Kobayashi’s dual parameter
generalization, CeCl3 proved to be a superior Lewis acid
activator than InCl3 in terms of reaction speed and
chemical yield. Nevertheless, InCl3 should be the catalyst
of choice since high diastereoselectivity is then achieved.
(3) Kinetic studies revealed that the InCl3-catalyzed
aldol reaction is irreversible, whereas the CeCl3-catalyzed
process is reversible. In both cases, kinetic control favors
formation of the syn-5 diastereomeric product, although
the difference in activation energy is much larger with
InCl3.
VIII 5.539
of silyl enol ether Z-1 with benzaldehyde, and activated
by InCl3.17 All methods predict that transition state V is
lowest in energy, affording aldol product syn-5, as
experimentally observed.
Interestingly, geometry reoptimization of V at the
B3LYP/3-21G* level of theory afforded “closed” transition
state VII (Scheme 4a). By comparison, optimization of
the corresponding Zimmermann-Traxler transition state
leading from III to anti-5 (VIII in Scheme 4b) is
estimated to be 6.9 kcal/mol higher in energy. Therefore,
at the levels of theory explored in this work, we conclude
that syn isomers are generated via a chelated (closed)
model in the InCl3-activated reactions. By contrast, open
transition structure II is calculated to be the most
favorable structure leading to the anti isomer, but this
TS is estimated to be significantly higher in energy.
(4) Molecular modeling at various levels of theory
supports a “closed” transition state in the highly diaste-
reoselective aldol condensation of Z-1 with PhCHO, when
promoted by InCl3.
(16) Gaussian 98, Revision A.7; Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrsewski, V. G.; Montgomery, J . A.; Stratmann, R. E., J r.; Burant,
J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas. O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennuci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petterson, G. A.; Ayala, P. Y.; Cui, Q.; Ortiz, J . V.; Baboul, A. G.;
Stefanov, B. B.; Lui, G.; Liashenko, A.; Piskorz, P.; Komaroni, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, D. J .; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc.:
Pittsburgh, PA, 1998.
Ack n ow led gm en t. We are grateful to Conacyt
(Me´xico) for financial support via grant No. 33023-E.
We are also indebted to Marı´a Luisa Kaiser for technical
assistance.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, general procedures for Mukaiyama aldol
reactions catalyzed with CeCl3 and InCl3, general procedure
for desilylation of aldol products, physical and spectroscopic
data for Z-1, 2, 3, 4, syn-5, anti-5, and 6-11, and com-
putational results (Cartesian coordinates for intermediates
I-VIII). This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Nuclei beyond the third row such as Ce(III) require an ap-
proximate treatment, via effective core potentials which include some
relativistic effects. Although the LANL2DZ is the best known basis
set for this purpose, so far we have been unable to manage cerium at
this level of theory.
(18) Curran, D. P. J . Am. Chem. Soc. 1983, 105, 5826.
J O026713C
J . Org. Chem, Vol. 68, No. 4, 2003 1625