Iron(III) chloride as a water-compatible lewis acid for diastereoselective aldol reactions in water in the presence of a surfactant

Article abstract of DOI:10.1246/cl.2004.312

Diastereoselective aldol reactions of various aldehydes with silicon enolates in water have been successfully carried out using iron(III) chloride and a surfactant. Contrary to previous understanding, iron(III) chloride has been shown to be a water-compat

Full text of DOI:10.1246/cl.2004.312

312
Chemistry Letters Vol.33, No.3 (2004)
Iron(III) Chloride as a Water-Compatible Lewis Acid for Diastereoselective Aldol Reactions
in Water in the Presence of a Surfactant
Naohiro Aoyama, Kei Manabe, and Shu¯ Kobayashiꢀ
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
(Received December 1, 2003; CL-031169)
Diastereoselective aldol reactions of various aldehydes with
silicon enolates in water have been successfully carried out using
iron(III) chloride and a surfactant. Contrary to previous under-
standing, iron(III) chloride has been shown to be a water-com-
patible Lewis acid. In this catalytic system, epimerization of
the product was not observed, and this result indicates that the
diastereoselectivity was controlled kinetically.
estingly, the yield and selectivity of the reaction in water were
superior to that of the reaction in an H2O/THF mixed solvent
(Entry 3). The higher yield in water is ascribed to heterogeneity
of the water/surfactant system which suppressed Hþ-promoted
hydrolysis of silicon enolate 1, while hydrophobic interaction
between the substrates worked to promote the aldol reaction.
Table 2. Reaction profiles for aldol reactions in water
catalyst (10 mol %)
SDS (30 mol %)
OH
O
OSiMe3
+
PhCHO
Ph
Ph
Organic reactions in water without using harmful organic
solvents are of significant current interest, especially in relation
to today’s environmental concerns.1 In the course of our inves-
tigations to develop water-compatible Lewis acids, we have
demonstrated that rare earth metal cations (Sc3þ, Yb3þ, etc.)
combined with anionic surfactants can be used as Lewis acids
in water.2 These Lewis acid–surfactant-combined catalysts such
as Sc(DS)3 and Yb(DS)3 (DS: dodecyl sulfate) have been ap-
plied to various organic reactions including aldol,2 allylation,3
and Michael reactions4 in water. On the other hand, in order to
elucidate and expand the Lewis acid catalysis and also other cat-
alysis in water, more precise investigations on the behavior of
other metals with various ligands are necessary. We then reex-
amined water-compatible Lewis acids5 using aldol reactions of
benzaldehyde with silicon enolates as model reactions.6 As a re-
sult, iron(III) chloride (FeCl3), which had been regarded as a wa-
ter-incompatible Lewis acid,7 was found to catalyze aldol reac-
tions diastereoselectively in water in the presence of a
surfactant.8 Herein, we report that FeCl3 catalyzed aldol reac-
tions in water.
Ph
H2O, rt
1
(1.5 equiv)
Catalyst: FeCl3
Catalyst: Sc(OTf)3
Yield/% syn/anti
23 51/49
Time/min
Yield/%
46
syn/anti
86/14
86/14
85/15
10
60
74
95
50/50
50/50
57
720
53
Table 3. Treatment of the product with the catalytic systems
catalyst (10 mol %)
SDS (30 mol %)
OH
O
OH
O
Ph
Ph
Ph
Ph
H2O, rt, 12 h
syn/anti
Entry
Catalyst
before reaction
after reaction
82/18
Sc(OTf)3
FeCl3
84/16
1
2
84/16
82/18
Next, we were interested in the differences in diastereoselec-
tivities between the FeCl3- and Sc(OTf)3-catalyzed reactions.
Quite recently, Juaristi et al. have reported that epimerization
of the product was observed in a CeCl3-catalyzed aldol reaction
in aqueous media (H2O/i-PrOH = 1/19).10 However, in each
case of the FeCl3- and Sc(OTf)3-catalyzed reaction, the diaster-
eomeric ratio of the product remained unchanged in the course
of the reaction (Table 2). In addition, the diastereomeric ratio
was retained when the diastereomerically enriched, isolated
product was directly treated with each catalyst (Table 3). There-
fore, it was concluded that an epimerization process did not oc-
cur in either catalytic system. These results indicate that the di-
astereoselectivities of these reactions are kinetically controlled,
and thus reflect the characteristics of the catalysts.
Table 1. Aldol reactions in aqueous media
OH
O
catalyst (10 mol %)
solvent, rt, 12 h
OSiMe3
+
PhCHO
Ph
Ph
Ph
1
(1.5 equiv)
Entry
Catalyst/mol %
Solvent
H2O
Yield/%
95
syn/anti
50/50
85/15
71/29
1
2
3
Sc(OTf)3 (10) + SDS (30)
FeCl3 (10) + SDS (30)
FeCl3 (10)
H2O
53
H2O/THF = 1/9
45
To optimize the conditions of the FeCl3-catalyzed aldol re-
actions, we examined the effect of surfactants (Table 4). Interest-
ingly, decreasing the amounts of SDS improved the yield signif-
icantly, and 10 mol % of SDS was found to give a good result
(Entry 3). When 30 or 20 mol % of SDS was used, the hydrolysis
of silicon enolate 1 occurred rapidly (Entries 1 and 2). On the
other hand, when 5 mol % of SDS was used, both the hydrolysis
and the aldol reaction became slower (Entry 4). The aldol reac-
tion as well as the hydrolysis of the silicon enolate hardly occur-
red in the absence of the surfactant (Entry 5). As for surfactants,
both CTAB and Triton1 X-100 resulted in poor yields (Entries 6
Initially, we screened various metal salts for the aldol reac-
tion of benzaldehyde with silicon enolate 1 in water in the pres-
ence of SDS (sodium dodecyl sulfate). Among Lewis acids test-
ed, FeCl3 was found to give the product in moderate yield with
relatively good syn/anti selectivity compared with Sc(OTf)3
(Table 1, Entries 1 and 2). It is noted that FeCl3 was a water-
compatible Lewis acid here, contrary to previous understand-
ing.7 Furthermore, FeCl3 is an inexpensive, environmentally be-
nign, and relatively strong Lewis acid.9 Although silicon enolate
1 was rapidly hydrolyzed under the reaction conditions because
of strong acidity, the reaction proceeded in moderate yield. Inter-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.3 (2004)
313
Table 4. Effect of surfactants
tivity (Entry 5). Disappointingly, silicon enolate (Z)-2 or 3 af-
forded each product with lower diastereoselectivity (Entries 6
and 7). However, this catalytic system worked well for diaster-
eoselective construction of a quaternary center by using silicon
enolate 4 (Entry 8).11 These results indicate that the substituent
at the same side of the trimethylsiloxy group is important for in-
ducing high diastereoselectivity.
In conclusion, FeCl3 was found to catalyze highly diastereo-
selective aldol reactions in water in the presence of a surfactant.
The fact that epimerization of the product was not observed in-
dicates that the diastereoselectivity is controlled kinetically in
this catalytic system. When rapid hydrolysis of silicon enolates
resulted in lower yields, the addition of NaOH was effective
for improving the yields. Although the transition state structure
and the real catalytic species have not been clear yet, the use of
strong Lewis acids such as FeCl3 in water will add a new aspect
to organic reactions in water/surfactant systems.
FeCl3 (10 mol %)
surfactant
OH
O
OSiMe3
+
PhCHO
Ph
Ph
Ph
H2O, 0 °C, 12 h
1
(1.5 equiv)
Entry
Surfactant/mol %
SDS (30)
Yield/%
syn/anti
84/16
86/14
87/13
87/13
87/13
92/8
1
2
3
4
5
6
7
8
9
71
81
SDS (20)
SDS (10)
83
SDS (5)
71
−
trace
21
CTABa
Triton X-100
20
80/20
90/10
91/9
C8H17C6H4SO3Na (10)
92
C
12H25C6H4SO3Na (10)
89
aCetyltrimethylammonium bromide.
and 7). Among anionic surfactants, benzenesulfonates with long
alkyl chains gave higher yields and selectivities compared with
SDS (Entries 8 and 9).
This work was partially supported by CREST, SORST, and
ERATO, Japan Science and Technology Agency (JST), and a
Grant-in-Aid for Scientific Research from Japan Society of the
Promotion of Science. N. A. thanks the JSPS fellowship for
Japanese Junior Scientists.
Several examples of FeCl3-catalyzed aldol reactions in wa-
ter are summarized in Table 5. In the case of silicon enolate 1,
the reactions with aromatic, ꢀ,ꢁ-unsaturated, and aliphatic alde-
hydes afforded the corresponding products in moderate to good
yields with high diastereoselectivities (Entries 1 to 3). When sil-
icon enolate (E)-2 derived from S-tert-butylthiopropionate was
applied to this catalytic system, high diastereoselectivity was at-
tained although the rapid hydrolysis of (E)-2 resulted in lower
yield (Entry 4). To prevent the rapid hydrolysis of silicon eno-
lates, we tried addition of a base. Among the bases tested, NaOH
improved the yield up to 61% without losing the diastereoselec-
References and Notes
1
For review, see: C.-J. Li and T.-H. Chan, ‘‘Organic Reactions
in Aqueous Media,’’ John Wiley & Sons, New York (1997); P.
A. Grieco ‘‘Organic Synthesis in Water,’’ Blackie Academic
and Professional, London (1998); S. Kobayashi and K.
Manabe, Acc. Chem. Res., 35, 209 (2002).
2
For Sc(DS)3, see: K. Manabe, Y. Mori, T. Wakabayashi, S.
Nagayama, and S. Kobayashi, J. Am. Chem. Soc., 122, 7202
(2000); S. Kobayashi and T. Wakabayashi, Tetrahedron Lett.,
39, 5389 (1998); For other Lewis acid–surfactant-combined
catalysts, see: K. Manabe, Y. Mori, and S. Kobayashi, Tetrahe-
dron, 55, 11203 (1999); K. Manabe and S. Kobayashi, Synlett,
1999, 547.
Table 5. FeCl3-catalyzed aldol reactions in water
OSiMe3
FeCl3 (10 mol %)
OH
O
R1
surfactant (10 mol %)
R3
R3
RCHO
+
R
R2
(1.5 equiv)
R2
H2O, 0 °C, 12−24 h
R1
Entry
1
Aldehyde
Silicon Enolate
Yield/%
86
syn/anti
Surfactant
3
4
5
S. Kobayashi, T. Wakabayashi, and H. Oyamada, Chem. Lett.,
1997, 831.
Y. Mori, K. Kakumoto, K. Manabe, and S. Kobayashi, Tetra-
hedron Lett., 41, 3107 (2000).
We have already found that Fe2þ, Cu2þ, Zn2þ, Cd2þ, Pb2þ
salts are water-compatible Lewis acids. S. Kobayashi, S.
Nagayama, and T. Busujima, J. Am. Chem. Soc., 120, 8287
(1998).
OSiMe3
p-MeOC6H4CHO
C
12H25C6H4SO3Na
91/9
1
Ph
OSiMe3
C12H25C6H4SO3Na
CH2=CHCHO
Ph(CH2)2CHO
PhCHO
2
66
76
37
61
87/13
89/11
94/6
Ph
OSiMe3
C
12H25C6H4SO3Na
3
Ph
OSiMe3
(E)-2a
(E)-2a
SDS
SDS
4
6
7
8
We like to use this system to evaluate Lewis acid catalysis in
water because decomposition (hydrolysis) of silicon enolates
is competitive to the desired aldol reactions.
When the effects of metal salts in the aldol reaction were stud-
ied in H2O/THF = 1/9 at rt, FeCl3 (20 mol %) gave only 21%
yield. See Ref. 5.
For our recent examples of diastereoselective aldol reactions in
water, see: Y. Mori, K. Manabe, and S. Kobayashi, Angew.
Chem., Int. Ed., 40, 2816 (2001); Y. Mori, J. Kobayashi, K.
Manabe, and S. Kobayashi, Tetrahedron, 58, 8263 (2002).
StBu
OSiMe3
5b
PhCHO
95/5
StBu
OSiMe3
6b
(Z)-2c
24
73
67/33
53/47
PhCHO
PhCHO
SDS
SDS
StBu
OSiMe3
7b
3
OSiMe3
8b
4d
SDS
6/94e
p-ClC6H4CHO
48
9
For review, see: E. P. Kundig and C. M. Saudan, in ‘‘Lewis
¨
acids in Organic Synthesis,’’ ed. by H. Yamamoto, WILEY-
VCH, Weinheim (2000), Vol. 2, Chap. 14, p 597.
10 O. Mun˜oz-Mun˜iz, M. Quintanar-Audelo, and E. Juaristi, J.
Org. Chem., 68, 1622 (2003).
aE/Z = 95/5. bNaOH (10 mol %) was added.cE/Z = 2/98. dMixture of regio isomers = 88/12.
eThe stereochemistry was assigned by analogy from the benzaldehyde adduct as follows.
OH
O
OH O
p-ClC6H4
syn
p-ClC6H4
anti
11 For an example, see: S. Yamago, D. Machii, and E. Nakamura,
J. Org. Chem., 56, 2098 (1991).
Published on the web (Advance View) February 14, 2004; DOI 10.1246/cl.2004.312