Iron(II)-derived lewis acid/surfactant combined catalysis for the enantioselective mukaiyama aldol reaction in pure water

Article abstract of DOI:10.1002/cctc.201402029

The catalytic asymmetric Mukaiyama aldol reaction in pure water was performed by using a combination of iron(II) dodecyl sulfate, a chiral bipyridine ligand, and benzoic acid. By using the obtained iron(II)-derived Lewis acid/surfactant combined catalyst,

Full text of DOI:10.1002/cctc.201402029

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DOI: 10.1002/cctc.201402029
Iron(II)-Derived Lewis Acid/Surfactant Combined Catalysis
for the Enantioselective Mukaiyama Aldol Reaction in Pure
Water
Mathieu Lafantaisie, Anaꢀs Mirabaud, Baptiste Plancq, and Thierry Ollevier*[a]
The catalytic asymmetric Mukaiyama aldol reaction in pure
water was performed by using a combination of iron(II) dode-
cyl sulfate, a chiral bipyridine ligand, and benzoic acid. By
using the obtained iron(II)-derived Lewis acid/surfactant com-
bined catalyst, the desired products were afforded in good
yields with high diastereo- and enantioselectivities.
aldol reactions in aqueous media,[4] we herein disclose a new
Lewis acid surfactant combined catalyst for this reaction by
using environmentally benign iron(II) dodecyl sulfate [Fe(O-
SO3C12H25)2, Fe(DS)2] and a chiral bipyridine ligand, that is,
Bolm’s ligand.[3] To the best of our knowledge, this is the first
example of the use of Fe(DS)2 as a Lewis acid in organic syn-
thesis.[9] Iron is one of the most abundant metals on Earth; it is
inexpensive, environmentally benign, and relatively nontoxic in
comparison with other metals.[10] The iron catalyst is easily pre-
pared and generates chiral metallomicelles that are stable in
pure water. The results suggest that the LASC catalyst acts
both as a chiral catalyst to activate the substrate and as a sur-
factant to form colloidal particles.
Since its discovery in 1973, the Mukaiyama aldol reaction has
been studied extensively, and many efforts have been invested
for better stereocontrol of the process.[1] Since the first reports
with the use of a chiral tin(II)-derived Lewis acid,[1c,d] many de-
velopments have been made to get greener and more efficient
catalysts and to use environmentally benign solvents. A few
studies, initiated by Kobayashi’s pioneering work,[2] reported
conditions for the catalytic asymmetric Mukaiyama aldol reac-
tion under aqueous conditions, but all of them either
First, we screened various iron-derived Lewis acids with
Bolm’s ligand 1 (Table 1). It was found that Fe(DS)2 was an ef-
fective catalyst for the reaction of silyl enol ether 2 with ben-
afforded moderate enantioselectivities[2a–e] or lacked
Table 1. Determination of the optimal catalytic micellar system.[a]
substrate generality.[2f–i] Recently,
a very efficient
system involving iron(II) and Bolm’s ligand[3] showed
large generality and wide scope but still needed di-
methoxyethane as an organic cosolvent.[4] In addition
to these results usually requiring an organic cosol-
vent (EtOH or 1,2-dimethoxyethane), the use of sur-
factants and Lewis acid surfactant combined (LASC)
catalysts have emerged as promising systems for the
asymmetric Mukaiyama aldol reaction in pure
water.[2c,5] However, only moderate enantioselectivi-
ties (<70%ee) have been reported.[5a] Thus, there is
clearly place for improvements towards the develop-
ment of the Mukaiyama aldol reaction in water with-
out using any organic solvent.
Entry FeXn
Additive (mol%)
Yield 4a [%] dr[b]
er[c]
1
Fe(DS)2
–
33
81:19 83:17
2
3
4
5
6
7
8
Fe(DS)2
Fe(DS)2
Fe(DS)2
Fe(DS)2
Fe(DS)2
Fe(DS)2
Fe(DS)3
PhCO2H
HCl
CH3CO2H
C11H25CO2H
PhCO2H+NaDS (15)
80
91:9
–
85:15 89:11
80:20 95:5
90:10 95:5
96:4
–
24[d]
44
84
70
Water has many advantages as a solvent for organ-
ic reactions regarding cost, safety, and environmental
concerns, but it is also known for its exceptional reac-
tivity and selectivity enhancements.[6] As most chiral
Lewis acids decompose rapidly in an aqueous envi-
ronment, their development is a real challenge.[7]
LASC catalysts have the unique particularity of acting
both as Lewis acids and as surfactants to form hydro-
phobic colloidal particles in water.[8] In the context of
our ongoing research on enantioselective Mukaiyama
PhCO2H+n-hexyl alcohol (10) 90
PhCO2H
91:9
94:6
77
71
75
27[d]
82:18 89:11
90:10 95:5
90:10 88:12
9
10
11
Fe(OSO3C8H17)2 PhCO2H
Fe(OSO3C18H37)2 PhCO2H
Fe(ClO4)2·6H2O PhCO2H
–
–
[a] Reaction conditions: silyl enol ether (1.2 equiv.), aldehyde (1.0 equiv.), 258C, 24 h.
[b] The syn/anti diastereoisomeric ratio was determined by 1H NMR spectroscopy.
[c] The enantiomeric ratio (syn) was determined by HPLC analysis on a chiral station-
1
ary phase. [d] Conversion calculated by H NMR spectroscopy.
zaldehyde (3a); corresponding aldol 4a was afforded in low
yield with moderate stereoselectivities (Table 1, entry 1). The
role of benzoic acid as an additive (1.2 equiv. relative to the
iron salt) has already been highlighted in previous work.[2k,4] By
using this additive, the yield and enantioselectivities were sig-
[a] M. Lafantaisie, A. Mirabaud, B. Plancq, Prof. T. Ollevier
Dꢀpartement de Chimie, Universitꢀ Laval
1045 avenue de la Mꢀdecine, Quꢀbec, Quꢀbec, G1V 0A6 (Canada)
E-mail: thierry.ollevier@chm.ulaval.ca
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nificantly increased (Table 1, entry 2). Replacing benzoic acid
with hydrochloric or acetic acid led to a decrease in the yield,
diastereoselectivity, and enantioselectivity (Table 1, entries 3
and 4). Lauric acid,[11] which may act both as a surfactant and
as an acid additive, afforded the desired product with slightly
better conversion but with decreased stereoselectivities
(Table 1, entry 5). The effect of the addition of sodium dodecyl-
sulfate (NaDS) was then investigated (Table 1, entry 6). A slight
erosion of the stereoselectivity occurred in parallel to a de-
crease in the yield in 4a, presumably owing to a reduction in
the local concentration of FeII. As the addition of alkyl-chain al-
cohols can sometimes increase the solubilizing properties of
micelles for reagents,[12] we tested n-hexyl alcohol as an addi-
tive for the reaction. Effectively, the micelles appeared to be
much more stable during the reaction with the use of this ad-
ditive. Although the conversion increased, the enantioselectivi-
ty eroded (94:6er compared to 96:4 without the additive;
Table 1, entry 7 vs. 2). A similar yield but with lower stereo-
selectivities were obtained by using Fe(DS)3 instead of Fe(DS)2
(Table 1, entry 8).
Table 2. Optimization of the reaction conditions.[a]
Entry
Fe/1
[mol%]
T
[8C]
Conc.[b]
[mmolLÀ1
]
Yield
[%]
dr[c]
er[d]
1
2
3
4
5
6
7
8[e]
5:15
5:6
1:3
5:15
5:15
5:15
5:15
5:15
25
25
25
25
25
0
15
15
15
7.5
25
15
15
15
80
74
56
80
72
16
40
85
91:9
96:4
90:10
89:11
90:10
90:10
93:7
89:11
86:14
95:5
95:5
92:8
40
25
58:42
89:11
80:20
92:8
[a] Reaction conditions: silyl enol ether (1.2 equiv.), benzaldehyde
(1.0 equiv.), benzoic acid [1.2 equiv. relative to Fe(DS)2], 24 h. [b] Concen-
tration of Fe(DS)2. [c] The syn/anti diastereoisomeric ratio was determined
Given that alkyl chain length of surfactants is known to have
an effect on both the critical micellar concentration and the
maximum reactant concentration inside the micelle, we tested
other long-chain aliphatic sulfates as iron(II) counterions. It was
found that Fe(DS)2 was the most appropriate catalyst for this
reaction. Longer and shorter linear alkyl chains did not appear
to be optimal for our model reaction (Table 1, entries 9 and
10). The reaction without a surfactant [using Fe(ClO4)2·6H2O] in
pure water showed that the LASC catalyst was essential to cat-
alyze the reaction and to avoid the hydrolysis of the silyl enol
ether (Table 1, entry 11). All these results suggest that sub-
strates are concentrated into the hydrophobic phase of the mi-
celles, which greatly accelerates the addition of the silyl enol
ether to the carbonyl partner. Presumably, water is kept out of
the organic phase, and this leads to reduced hydrolysis rate for
the silyl enol ether, and also, the aqueous environment helps
the rapid hydrolysis of the iron–aldolate to ensure better cata-
lytic turnover.[6i] We assume that the Fe+2 cation, bound to the
tetradentate bipyridine ligand and surrounded by the two sul-
fates, keeps an ideal hydrolysis constant and water exchange
rate constant to ensure good catalytic activity in water.[7]
Further optimization of the conditions regarding catalyst
concentration showed that the optimal concentration was
5 mol% Fe+2 with a Fe/ligand ratio of 1:3 (Table 2, entry 1). By
using a smaller ratio of 1:1.2 (Table 2, entry 2), the reaction pro-
ceeded more slowly, which occurred together with an erosion
in the enantioselectivity, presumably because a part of the
metallomicelle was not coordinated to the chiral ligand. In-
creasing the ratio up to 1:4 did not give better results.[13] The
use of a catalytic charge of 1 mol% of Fe+2 resulted in a de-
crease in both the conversion and the enantioselectivity
(Table 2, entry 3). Concentration, relative to Fe(DS)2, was then
studied. Slightly lower selectivities were obtained under more
diluted (Table 2, Entry 4) and more concentrated (Table 2,
Entry 5) conditions. A concentration of 15 mm relative to
Fe(DS)2 appeared to be optimal for the reaction. Decreasing
the temperature did not improve the enantioselectivity and
1
by H NMR spectroscopy. [d] The enantiomeric ratio (syn) was determined
by HPLC analysis on
benzaldehyde.
a chiral stationary phase. [e] With 2 equiv. of
this also led to a very poor yield (Table 2, entry 6). A higher
temperature dramatically affected the stereoselectivities and
did not improve the conversion, as decomposition of the silyl
enol ether was observed (Table 2, entry 7). We observed that
Fe(DS)2 was insoluble in both pure water and benzaldehyde.
As mentioned in an earlier work, the LASC catalyst presumably
forms a monolayer around the substrates, and thus it is neces-
sary for the appearance of colloidal particles in water.[8] Accord-
ingly, we tested the addition of an excess amount of benzalde-
hyde to the reaction. In this case, a better yield was observed,
but the enantioselectivity dropped (Table 2, entry 8).
Subsequently, various aldehydes were tested under the opti-
mized conditions (Table 2, entry 1) by using the new LASC
chiral catalyst. In all cases, the aldol products were reproduci-
bly formed in moderate to very good yields with high stereo-
selectivities. Various benzaldehydes substituted with electron-
donating and electron-withdrawing groups were examined
(Table 3, entries 1 to 7). An aldehyde bearing an unprotected
alcohol was even used (Table 3, entry 5). Despite a lower yield,
a high enantioselectivity was obtained. Naphthaldehyde was
less reactive than benzaldehyde but afforded a very good
enantioselectivity (Table 3, entry 8). A conjugated aldehyde
such as cinnamaldehyde was a good substrate (Table 3,
entry 9). High enantioselectivities were obtained with aliphatic
n-butanal and 3-phenylpropanal (Table 3, entries 10 and 11).
Our conditions were finally applied to heteroaromatic alde-
hydes, which provided the aldol products in good yields with
excellent enantioselectivities (95:5er; Table 3, entries 12 and
13). We studied the reactivity of the silyl enol ether derived
from acetophenone under our conditions to verify the intrinsic
enantiocontrol of the reaction. In this case, the substrate was
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Table 3. Catalytic Mukaiyama aldol reaction with the use of Fe(DS)2 as
LASC catalyst: Substrate scope.[a]
Entry
1
Aldehyde
Yield [%]
80
dr[b]
er[c]
91:9
96:4
2
3
4
63
63
82
92:8
94:6
93:7
93:7
Figure 1. Appearance of the reaction mixture before and after
centrifugation.
84:16
89:11
any organic solvents for extraction (see Figure 1). Compared to
the ethyl acetate workup procedure, the yield of the isolated
product was identical and no erosion of the enantioselectivity
was detected. We then scaled up our reaction 50-fold (3.65 g
of silyl enol ether and 1.56 g of benzaldehyde) and obtained
exactly the same enantioselectivity and a slightly decreased
yield of the desired product (71 vs. 80% on a 0.5 mmol scale).
Centrifugation was used as the only workup procedure, which
was followed by silica gel column chromatography, and this af-
forded the aldol product along with the recycled ligand.
In conclusion, we were able to develop an efficient catalytic
system that proceeds in pure water and affords good yields
and high enantioselectivities (up to 98:2er). Compared with
other methods that employ chiral CuII or ScIII, our system is ad-
vantageous in that it is the most efficient in the Mukaiyama
aldol reaction in pure water with the use of a chiral LASC cata-
lyst. To the best of our knowledge, this is the first report of the
use of Fe(DS)2 as a Lewis acid in organic synthesis. Both
Fe(DS)2 and the chiral ligand could be easily prepared, and
they formed a very efficient catalyst under aqueous conditions.
The generality of our system was highlighted by the wide
range of aldehydes that could be used in this process (aromat-
ic, conjugated, heteroaromatic, and aliphatic). Centrifugation
makes the isolation process easier and allows solvent and time
economy. A scale up of the reaction showed that the enantio-
selectivity was maintained at the same level. Our methodology
could be therefore applied on a multigram scale for the asym-
metric Mukaiyama aldol reaction in the synthesis of drugs or
pharmaceutical products as nontoxic metals are involved and
no organic solvents are used in the reaction process. These re-
sults pave the way for new developments in asymmetric catal-
ysis by using iron(II) dodecylsulfate as a Lewis acid in pure
water.
5
39
89:11
91:9
6
7
8
78
88
65
85:15
89:11
84:16
93:7
96:4
95:5
9
75
64
85
78:22
86:14
91:9
88:12
98:2
97:3
10
11
12
13
75
78
90:10
85:15
95:5
95:5
[a] Reaction conditions: silyl enol ether (1.2 equiv.), aldehyde (1.0 equiv.),
258C, 48 h. [b] The syn/anti diastereoisomeric ratio was determined by
1H NMR spectroscopy. [c] The enantiomeric ratio (syn) was determined by
HPLC analysis on a chiral stationary phase.
hydrolyzed faster, which led to a low yield of the aldol product
and a very low enantioselectivity (11% yield, 52:48er).
With the objective of making our methodology more envi-
ronmentally benign, we used centrifugation to separate the
products from the aqueous layer.[8] Rotation of the reaction
medium for 20 min at 3500 rpm allowed us to separate the or-
ganic products from the aqueous phase without the need for
Experimental Section
Preparation of Fe(DS)2
A 0.1m aqueous solution of FeCl2 (28.8 mgmLÀ1 water) was added
to an equal proportion of a 0.1m aqueous solution of sodium do-
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decyl sulfate (12.7 mgmLÀ1 water) at room temperature. The solu-
tion was mixed until complete dissolution and placed at 28C. The
precipitate was washed several times with 0.1m FeCl2. The solid
was recrystallized in water and dried under high vacuum to afford
Fe(DS)2 as white crystals.[9a]
Mukaiyama aldol reaction, see Ref. [2j] and l) J. Mlynarski, S. Bas, Chem.
Soc. Rev. 2014, 43, 577.
[3] a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem. Int. Ed. Engl. 1990, 29, 205;
Angew. Chem. 1990, 102, 206; b) C. Bolm, M. Ewald, M. Felder, G.
Schlingloff, Chem. Ber. 1992, 125, 1169; c) S. Ishikawa, T. Hamada, K.
Manabe, S. Kobayashi, Synthesis 2005, 2176.
[4] a) T. Ollevier, B. Plancq, Chem. Commun. 2012, 48, 2289; b) B. Plancq, T.
Ollevier, Aust. J. Chem. 2012, 65, 1564.
Mukaiyama aldol reaction of silyl enol ethers with various
aldehydes
[5] a) S. Kobayashi, Y. Mori, S. Nagayama, K. Manabe, Green Chem. 1999, 1,
175; b) S. Kobayashi, T. Hamada, S. Nagayama, K. Manabe, J. Braz. Chem.
Soc. 2001, 12, 627; c) H. J. Li, H. Y. Tian, Y. J. Chen, D. Wang, C.-J. Li, J.
Chem. Res. Synop. 2003, 153; a scandium-catalyzed hydroxymethylation
of ketones has more recently been disclosed: d) S. Kobayashi, M.
Kokubo, K. Kawasumi, T. Nagano, Chem. Asian J. 2010, 5, 490.
[6] a) R. Breslow, Acc. Chem. Res. 1991, 24, 159; b) C.-J. Li, Chem. Rev. 2005,
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2177; f) R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302; g) U. M.
Lindstrçm in Organic Reactions in Water: Principles, Strategies and Appli-
cations, Oxford, Blackwell Publishing, 2007; h) P. P. Garner in Organic
Synthesis in Water (Ed.: P. A. Grieco), London, 1998, pp. 1–41; i) Science
of Synthesis: Water in Organic Synthesis (Ed.: S. Kobayashi), Georg
Thieme Verlag, 2012; j) C.-J. Li, T.-H. Chan, Comprehensive Organic Reac-
tions in Aqueous Media, Wiley, Hoboken, 2007; k) M.-O. Simon, C.-J. Li,
Chem. Soc. Rev. 2012, 41, 1415.
General procedure: In a glass tube, the iron salt and the ligand
were added to distilled water (1 mL). The mixture was stirred for
1 h at 258C to ensure complexation. Aldehyde 3a–l (0.30 mmol),
benzoic acid (2.2 mg, 0.018 mmol), and silyl enol ether (0.36 mmol)
were subsequently added to the mixture. The mixture was stirred
at 258C for the desired time. The resulting mixture was either cen-
trifuged for 20 min at 3500 rpm or extracted with ethyl acetate (3ꢂ
10 mL), and the combined organic layer was dried with anhydrous
MgSO4. The solvents were evaporated under reduced pressure,
and the residue was purified by column chromatography (hexane/
ethyl acetate) to give the aldol product. The enantiomeric excess
of the product was determined by HPLC analysis on a chiral
stationary phase.
[7] a) S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc. 1998, 120,
8287; b) S. Kobayashi, T. Busujima, S. Nagayama, Chem. Eur. J. 2000, 6,
3491; c) A. E. Martell in Coordination Chemistry, Vol. 2, ACS Monograph
168, American Chemical Society, Washington, DC, 1978; d) K. B. Yatsi-
mirskii, V. P. Vasil’ev in Instability Constants of Complex Compounds, Per-
gamon, New York, 1960; e) C. F. Baes Jr., R. Mesmer in The Hydrolysis of
Cations, Wiley, New York, 1960.
Acknowledgement
This work was financially supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Centre in
Green Chemistry and Catalysis (CGCC), the Canada Foundation
for Innovation (CFI), and Universitꢀ Laval. M.L. thanks NSERC and
the Fonds Quꢀbꢀcois de la Recherche—Nature et technologies
(FQRNT) for M.Sc. scholarships.
[8] K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama, S. Kobayashi, J. Am.
Chem. Soc. 2000, 122, 7202.
[9] Fe(DS)2 has been prepared according to the procedure described in:
a) N. Moumen, P. Pileni, J. Phys. Chem. 1996, 100, 1867. Only Fe(DS)3 has
been disclosed as LASC catalyst for various reactions: b) M. A. Zolfigol,
P. Salehi, A. Ghaderi, M. Shiri, Z. Tanbakouchian, J. Mol. Catal. 2006, 259,
253; c) L. Zhang, J. Wu, Adv. Synth. Catal. 2007, 349, 1047; d) M. A. Zolfi-
gol, P. Salehi, M. Shiri, Z. Tanbakouchian, Catal. Commun. 2007, 8, 173;
e) K. Pradhan, S. Paul, A. R. Das, Tetrahedron Lett. 2013, 54, 3105; f) for
the use of FeCl3 and SDS: N. Aoyama, K. Manabe, S. Kobayashi, Chem.
Lett. 2004, 33, 312.
Keywords: aldol reaction · enantioselectivity · iron · Lewis
acids · surfactants
[1] a) T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett. 1973, 1011; b) T. Mu-
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Mukaiyama, S. Kobayashi, H. Uchiro, I. Shiina, Chem. Lett. 1990, 129;
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[2] a) T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro, S. Kobaya-
shi, J. Am. Chem. Soc. 2003, 125, 2989; b) J. Mlynarski, J. Jankowska, Adv.
Synth. Catal. 2005, 347, 521; c) S. Kobayashi, S. Nagayama, T. Busujima,
Tetrahedron 1999, 55, 8739; d) S. Nagayama, S. Kobayashi, J. Am. Chem.
Soc. 2000, 122, 11531; e) Y. Mei, P. Dissanayake, M. J. Allen, J. Am. Chem.
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Chem. Commun. 2002, 2994; g) S. Ishikawa, T. Hamada, K. Manabe, S.
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47, 6909; Angew. Chem. 2008, 120, 7015; j) T. Kitanosono, S. Kobayashi,
Adv. Synth. Catal. 2013, 355, 3095; k) T. Kitanosono, T. Ollevier, S. Ko-
bayashi, Chem. Asian J. 2013, 8, 3051; For good reviews on catalytic
[10] For reviews of iron catalysis, see: a) S. Enthaler, K. Junge, M. Beller,
Angew. Chem. Int. Ed. 2008, 47, 3317; Angew. Chem. 2008, 120, 3363;
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[11] Lauric acid has already proved to enhance yield and enantioselectivities
in a CuII/bis-oxazoline-catalyzed asymmetric Mukaiyama aldol reaction
(ee <69%); see: K. Manabe, Y. Mori, S. Nagayama, K. Odashima, S. Ko-
bayashi, Inorg. Chim. Acta 1999, 296, 158 and ref. [5a].
[12] T. Dwars, E. Paetzold, G. Oehme, Angew. Chem. Int. Ed. 2005, 44, 7174;
Angew. Chem. 2005, 117, 7338.
[13] 71% yield and 92% ee were obtained for the reaction with benzalde-
hyde using 5 mol% Fe(DS)2 and 20 mol% of ligand.
Received: February 10, 2014
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M. Lafantaisie, A. Mirabaud, B. Plancq,
T. Ollevier*
&& – &&
Iron(II)-Derived Lewis Acid/Surfactant
Combined Catalysis for the
Enantioselective Mukaiyama Aldol
Reaction in Pure Water
On a slippery slope: The catalytic
asymmetric Mukaiyama aldol reaction in
pure water is performed by using a
combination of iron(II) dodecyl sulfate
[Fe(DS)2], a chiral bipyridine ligand, and
benzoic acid. By using the obtained
iron(II)-derived Lewis acid/surfactant
combined catalyst, the desired products
are afforded in good yields with high
diastereo- and enantioselectivities.
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