The direct aldol reaction using bifunctional catalysts

Article abstract of DOI:10.1016/S0040-4039(03)01332-7

In this paper, we describe an approach to the direct aldol reaction using a bifunctional catalyst containing Lewis acidic and basic functional groups. To achieve this novel means of catalysis we have developed new tertiary amine-zinc catalysts, which perform the aldol reaction between acetone and p-nitrobenzaldehyde.

Full text of DOI:10.1016/S0040-4039(03)01332-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5699–5701
The direct aldol reaction using bifunctional catalysts
Michael A. Calter* and Robert K. Orr
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
Received 14 May 2003; accepted 29 May 2003
Abstract—In this paper, we describe an approach to the direct aldol reaction using a bifunctional catalyst containing Lewis acidic
and basic functional groups. To achieve this novel means of catalysis we have developed new tertiary amine–zinc catalysts, which
perform the aldol reaction between acetone and p-nitrobenzaldehyde.
© 2003 Elsevier Ltd. All rights reserved.
In recent years, the direct aldol reaction has received
the attention of a number of synthetic groups.1 Inspired
by nature, two different approaches have evolved for
the construction of aldol adducts from unactivated
ketones and aldehydes. Based on the class I aldolases,
several researchers have utilized proline to perform the
direct aldol reaction.2 The class II aldolases have stimu-
lated work with lanthanide–binapthoxide complexes3
and zinc-alkoxides.4 We report here an approach that
closely mimics the class II aldolase, using a complex
containing a triaza binding pocket for Zn(II), along
with a leaving group that can serve as both a weakly
bound ligand and a base.5
reaction. However, the reaction proved to be irrepro-
ducible. While the aldol adduct was formed, although
in much lower conversion than reported, the product
was always racemic. Investigation revealed that the
amine condensed with the aldehyde to afford a Schiff
base, in which the acidity of a-proton of the ester is
increased (Scheme 2). Furthermore, the chiral ligand
epimerized during the course of the reaction at a rate
higher than that for the aldol reaction. The use of
Zn(II)-dimethyl-a-amino-ester complexes as catalysts
for the reaction also failed to afford any
enantioselectivity.
At the onset of this project, only two examples of a
direct aldol reaction were known.6 Initially, we choose
to explore the reaction described by Watanabe and
co-workers (Scheme 1). This Zn(II)-amino ester-cata-
lyzed reaction was reported to give modest conversions
and enantioselectivities.
The Watanabe reaction appeared to provide an easy
entry point into the relatively unexplored direct aldol
Scheme 2.
Given these results, we decided that a more thorough
study of the reaction parameters was necessary. Thus, a
variety of tertiary amines were screened as ligands for
zinc following Watanabe’s general procedure (Eq. 1).7
This series consisted of triethylamine, tetramethyl-
ethylenediamine 3, pentamethyldiethylenetriamine 4,
and hexamethyltriethylenetetraamine 5 (Fig. 1). In the
case of triethylamine, very little aldol product was
observed after 24 h, using metal to ligand ratios rang-
ing from 1:1 to 1:4 (entry 1, Table 1). With the chelat-
ing ligands 3–5, the aldol reactions were success
Scheme 1.
* Corresponding author. Tel.: +1-585-275-1626; fax: +1-585-506-0205;
e-mail: calter@chem.rochester.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01332-7

5700
M. A. Calter, R. K. Orr / Tetrahedron Letters 44 (2003) 5699–5701
ful, the conversion of the reactions decreased as an
additional amino group was added to the chain of the
ligand (entries 2–4). The amount of condensation
product also decreased with increasing number of
amino groups on the ligand. This decrease could either
be attributed to the decreasing amount of free-amine in
solution or to the degree of saturation of the Lewis
acid. To test this hypothesis, 10 mol% of triethylamine
was added to the reaction mixture of 5 (entry 5). The
reaction proceeded to give more aldol adduct than
without base, albeit at lower conversion rates than
reactions employing 3 and 4.
(1)
We then turned our attention to the use of cyclic
tetra-amines, such as the tripodal ligand trimethyl-tri-
azacyclononane (Me3TACN, 6), as well as the closely
related trimethyltriazacyclododecane (7), and tetra-
methyl-tetraazacyclododecane (8). In the case of
Me3TACN 6 (entry 6, Table 1), the reaction with zinc
nitrate in methanol failed to give any products, even
after several days. The lack of reactivity perhaps stems
from the stability of the Zn(II)-TACN complex, as free
Scheme 3.
Me3TACN would potentially act as a base.8 Upon the
addition of Et3N, the reaction occurred rapidly (entry
7), suggesting a bifunctional mechanism. Weaker bases
such as sodium acetate and pyridine failed to give aldol
products with this metal and ligand. The other two
cyclic ligands were ineffective in the aldol reaction
(entries 10 and 11).
Encouraged by the results with Me3TACN, 6, we
decided to synthesize a series of TACN complexes
bearing a tethered base (10a–e). We hoped that the
preorganization of a TACN-tethered base would fur-
ther accelerate the reaction. These compounds were
synthesized by the following sequence (Scheme 3): the
commercially available TACN is first bis-acylated with
2 equiv. of the reactive agent BOC-ON (2-(t-butoxycar-
boyloxyimino)-2-phenylacetonitrile)9 to yield 9, and
then acylated with the N,N-Boc,Me-amino acids10
using DCC/DMAP.11 Finally, tetraamines 10a–e were
prepared by reduction with LiAlH4.12
Figure 1. Achiral polyamine ligands.
Table 1. Achiral ligands for direct aldol reaction with
The catalytic activity of the Zn(II)-tetraamine com-
plexes varied with the length of the tether (Table 2).
The reaction catalyzed by the complex of 10a did not
afford any products after several days. Reactions with
the same complex and external base gave minimal
conversion after 24 h (entries 1 and 2). While the
a
Zn(NO3)2
Entry
Ligandb
Additive
Time
% 1c
% 2c
1d
2
3
4
5
6
7
8
9
None
Et3N
24
6
6
5
72
66
8
42
8
64
0
0
0
20
14
0
0
0
24
0
0
0
0
3
4
5
5
6
6
6
6
7
8
None
None
None
Et3N
None
Et3N
Pyridine
NaOAc
Et3N
Table 2. Aldol reaction with TACN tethered basea
42
24
42
6
24
24
24
24
Entry
Ligandb
n
Additive
Time (h)
% 1c % 2c
1
2
3
4
5
6
10a
10a
10b
10c
10d
10e
2
2
3
4
5
6
None
Et3N
None
None
None
None
24
24
24
24
24
24
0
12
30
24
66
36
0
0
0
0
0
0
10
11
0
12
Et3N
a See Eq. (1) for reaction conditions.
b Ligands 3 and 4 were used as 2:1 complexes with zinc nitrate. All
others were used as 1:1 complexes unless noted.
c Conversion by 1H NMR.
a See Eq. (1) for the reaction conditions.
b Reactions run with Zn(NO3)2:ligand=1:1.
c Conversion by 1H NMR.
d Reaction run with Et3N:Zn(NO3)2=4:1.

M. A. Calter, R. K. Orr / Tetrahedron Letters 44 (2003) 5699–5701
5701
reactions catalyzed by compounds containing three and
four carbon tethers, 10b and 10c, did furnish some
aldol adduct (entries 3 and 4), the conversion of the
aldol reaction peaked with the five carbon tether, and
then decreased at six (entries 5 and 6).
Soc. 2003, 125, 2852–2853; (b) Nakadai, M.; Saito, S.;
Yamamoto, H. Tetrahedron 2002, 58, 8167–8177.
2. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am.
Chem. Soc. 2000, 122, 2395–2396; (b) Notz, W.; List, B.
J. Am. Chem. Soc. 2000, 122, 7386–7387; (c) Hoang, L.;
Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc.
2003, 125, 16–17; (d) Northrup, A. B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 6798–6799.
3. (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168–4178;
(b) Kumagai, N.; Matasunaga, S.; Kinoshita, T.; Harada,
S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 2169–2178.
Contrary to our original hypothesis, the reactions of
the tethered amines were slower than that of the simple
TACN and Et3N system. Sterics may have been the
cause of this rate reduction. This trend has also been
observed using TACN derivatives bearing larger but
non-chelating groups pendant to the TACN nitrogens.
Our most recent endeavors have been in the develop-
ment of an enantioselective version of this reaction
using chiral tertiary amine catalysts. Unfortunately, we
have found that none of the TACN-derived complexes
synthesized thus far afforded any asymmetric induc-
tion. A variety of achiral di- and triamines were also
screened. Our best results were with tetra-
methyldiaminocyclohexane, 11 (Eq. (2)).
4. (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003–12004; (b) Trost, B. M.; Ito, H.; Silcoff, E. R. J.
Am. Chem. Soc. 2001, 123, 3367–3368.
5. Dreyer, M. K.; Schulz, G. E. J. Mol. Biol. 1996, 458–466.
6. (a) Nakagawa, M.; Nakao, H.; Watanabe, K. Chem.
Lett. 1985, 391–394; (b) Watanabe, K.; Yamada, Y.;
Goto, K. Bull. Chem. Soc. Jpn. 1985, 55, 1401–1406; (c)
Yumada, Y.; Watanabe, K.; Yasuda, H. Usonomiya
Daiguku Kyoikugabubu Kiyo 1989, 39, 25–31; (d) Ito, Y.;
Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
6405–6406.
7. Procedure: To a solution of ligand (0.2 equiv.) in MeOH
(0.1 M with respect to the aldehyde) at room temperature
was added zinc nitrate hexahydrate (0.1 equiv.). To the
complex was then added p-nitrobenzyaldehyde (1 equiv.)
and acetone (5 equiv.). The solution was then stirred
under nitrogen atmosphere overnight. Conversion was
(2)
1
determined by H NMR of concentrated aliquots.
8. Fry, F. H.; Fallon, G. D.; Spiccia, L. Inorg. Chim. Acta
2003, 57–66.
In conclusion, we have shown the pitfalls of using
a-aminoesters in the direct aldol reaction. We have also
explored a variety of new tertiary amine ligands for the
direct aldol reaction with acetone and p-nitrobenzalde-
hyde. Both tetramethylethylenediamine- and triazacy-
clononane-derived ligands accelerate the reaction
efficiently. In the case of the TACN ligands, it has been
demonstrated that additional base is necessary to per-
form the reaction, supporting a bifunctional mecha-
nism. Excellent selectivity for the aldol adduct versus
the aldol condensate can be achieved by using base-
tethered TACN derivatives.
9. Zoltan, K.; Sherry, A. D. Tetrahedron Lett. 1995, 36,
9269–9272.
10. N,N-BOC,Me-amino acids were prepared via BOC pro-
tection of the parent amino acid. The BOC protected
compounds were then treated with NaH and MeI (3 and
5 equiv., respectively) in THF overnight. The solvent was
removed, water was added to the resulting solid, and the
mixture was acidified and extracted with CH2Cl2. The
organic extract was concentrated and chromatographed
(silica gel, EtOAc/hexanes) to yield the N,N-BOC,Me-
amino acids.
11. To a 0.1 M solution of Bis-BOC-TACN in CH2Cl2 was
added the N,N-BOC,Me-amino acid (1.2 equiv.), then
DCC (1.5 equiv.), and DMAP (0.1 equiv.). The reaction
was stirred overnight, filtered through a cotton plug, and
the volume was reduced in vacuo. The product was then
purified by chromatography (silica gel, EtOAc/hexanes).
The tris-BOC compound was then refluxed overnight in
THF (0.1 M) with excess LiAlH4 (10 equiv., n grams). To
the reaction mixture was added n mL of H2O, n mL of
15% NaOH, and, after 10 min, 3n mL of H2O. The solid
formed was washed with CH2Cl2 and EtOAc. The com-
bined organic washes were evaporated to give the tetra-
mines, which were used directly in the aldol reaction.
12. All new compounds gave satisfactory analytical and spec-
tral data.
Acknowledgements
The authors thank the Chemistry Departments of Vir-
ginia Tech and the University of Rochester for funding
this work.
References
1. For recent advances in the direct aldol reaction, see:
Lalic, G. L.; Aloise, A. D.; Shair, M. D. J. Am. Chem.