The catalytic asymmetric Knoevenagel condensation

Article abstract of DOI:10.1002/anie.201006319

116 years after the discovery of the Knoevenagel condensation, the first catalytic asymmetric variant has been developed. Dynamic kinetic resolution in the reaction of α-branched aldehydes with malonates in the presence of a newly designed and readily available modified cinchona amine catalyst gives the corresponding alkylidene malonates in high enantioselectivity (see scheme).

Full text of DOI:10.1002/anie.201006319

DOI: 10.1002/anie.201006319
Aminocatalysis
The Catalytic Asymmetric Knoevenagel Condensation**
Anna Lee, Anna Michrowska, Sarah Sulzer-Mosse, and Benjamin List*
The Knoevenagel condensation[1] is a powerful, general, and
frequently used reaction for the formation of carbon–carbon
bonds, but is also the archetype of modern organocatalysis.[2]
Surprisingly, however, despite its long history and numerous
industrial applications, there has not been a single example of
an asymmetric variant, neither by using chiral auxiliaries nor
catalysts. Here we report an asymmetric Knoevenagel
condensation that proceeds through dynamic kinetic resolu-
tion of a-branched aldehydes and is catalyzed by a newly
designed and readily available cinchona-derived primary
amine catalyst.
Recent progress in asymmetric aminocatalysis has led to
several highly useful transformations, including aldol, Man-
nich, and Michael reactions, a-alkylations, a- and b-function-
alizations, Diels–Alder reactions, transfer hydrogenations,
epoxidation reactions, and many more.[3] Remarkably though,
while the Knoevenagel reaction, as the historic basis of all
these processes, has been incorporated into asymmetric
organocascades and domino reactions,[4] and even malonates
Scheme 1. A proline-catalyzed asymmetric Knoevenagel reaction.
derived from chiral auxiliaries have been studied,[5]
a
variation in which the Knoevenagel reaction itself is utilized
to establish asymmetry has remained elusive.
or Mannich products B (if generated reversibly) reacted with
different rates to give the Knoevenagel product (Scheme 1).
In the event we found that proline (3a) indeed catalyzes
the reaction of hydratropaldehyde (1a) with diethylmalonate
(2a) to furnish the corresponding Knoevenagel product 4a in
good yield and moderate enantioselectivity (68:32), which in
principle confirms our kinetic resolution hypothesis. How-
ever, in addition to the moderate enantioselectivity, the
previously observed formation of significant amounts of the
isomeric olefin by-product 5 complicated the situation even
further. A broader screen of aminocatalysts to improve the
enantioselectivity and product 4a/5 ratio was, therefore,
initiated.
We investigated various types of aminocatalysts, of which
selected examples are summarized in Table 1. In contrast to
proline (entry 1), imidazolidinone catalysts such as 3b[3d] and
prolinol catalyst 3c proved to be essentially ineffective in
catalyzing this reaction (entries 2 and 3).[9] Pyrrolidine-
derived catalyst 3d was found to be active, but the enantio-
selectivity was only slightly improved compared to proline
and the olefin/isomer ratio was still only 62:38 (entry 4). We
next focused on primary amine catalysts. Diamine 3e was
tested, but unfortunately by-product 5 was now obtained as
the major product (entry 5). Since amine 3e turned out to be
quite active, we also screened different primary amine
catalysts derived from cinchona alkaloids (entries 6–13).[10]
Although quinidine derivative 3 f gave the desired product 4a
in reasonable yield and significantly improved 4a/5 ratio, the
enantioselectivity was still only moderate (entry 6). An
improvement in the enantioselectivity was observed with
quinine derivative 3j (entry 10), which provided product 4a
The lack of previous catalytic and stoichiometric asym-
metric Knoevenagel condensations may be partly due to the
absence of apparent stereogenic elements created in the
process. An asymmetric version should nonetheless be
realizable. Recently, we designed several catalytic enantiose-
lective reactions that are based on nucleophilic additions to
chiral, a-branched aldehydes through dynamic kinetic reso-
lution (DKR).[6] Encouraged by these studies, we envisioned
an extension of our DKR strategy to the Knoevenagel
reaction.[7]
At the onset we hypothesized that Knoevenagel condi-
tions could be established under which a-branched aldehydes
such as hydratropaldehyde (1a) would readily undergo
racemization in the presence of an aminocatalyst such as
proline,[8] via an equilibrium between an iminium ion and an
enamine. An enantioselective reaction with DKR could then
be realized if the intermediary diastereomeric iminium ions A
[*] A. Lee, Dr. A. Michrowska, Dr. S. Sulzer-Mosse, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1
45470 Mꢀlheim an der Ruhr (Germany)
Fax: (+49) 208-306-2982
E-mail: list@mpi-muelheim.mpg.de
[**] Generous support from the Max-Planck-Society, the DFG (Priority
Program Organocatalysis SPP1179), and the Fonds der Chemischen
Industrie is gratefully acknowledged. We also thank our HPLC and
GC departments for their support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006319.
Angew. Chem. Int. Ed. 2011, 50, 1707 –1710
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1707

Communications
Table 1: Catalyst screening.[a]
described an interesting new modification of the cinchona
skeleton, in which the 2’-position of the quinoline ring can be
alkylated upon the addition of organometallic reagents,
followed by an in situ oxidation.[12]
We were pleased to find that this method can easily be
extended with similar efficiency to the corresponding amino-
cinchona catalysts, specifically to compound 3j. Accordingly,
simply treating quinoline 3j with different organolithium and
Grignard reagents, followed by an in situ reoxidation, pro-
vided analogues 3k–q in moderate to good yields. Remark-
ably, even sterically demanding reagents such as tert-butyl-
lithium could be added without difficulty (Table 2, see also
the Supporting Information for details).
Table 2: Knoevenagel reaction using novel catalysts.[a]
Entry
Catalyst
Yield [%][b]
4a/5[b]
e.r.[c]
1
2
3
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3j
3j
3j
83
–
8
73:27
–
n.d.
68.0:32.0
–
n.d.
72.0:28.0
n.d.
23.0:77.0
78.0:22.0
82.0:18.0
82.0:18.0
84.0:16.0
92.5:7.5
92.0:8.0
94.0:6.0
4[d,e]
5
91
97
34
51
63
60
61
54
80
90
62:38
4:96
93:7
77:23
57:43
60:40
52:48
52:48
95:5
98:2
6
7
8
9
10
11[f]
12[f,g]
13[h]
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst 3
(0.02 mmol), DMSO (1.0 mL), RT, 72 h. [b] Determined by GC-MS
analysis. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] 10 mol% catalyst was used. [e] Reaction was carried out for 20 h.
[f] 60 mol% benzene-1,3,5-tricarboxylic acid was added. [g] 30 equiva-
lents of 2a were used. [h] Reaction conditions: 1a (0.1 mmol), 2a
(5.0 mmol), catalyst 3j (0.01 mmol), benzene-1,3,5-tricarboxylic acid
(0.06 mmol), DMSO (1.0 mL), 208C, 168 h.
Entry
Catalyst
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
3k
3l
87
89
85
92
91
86
91
95.5:4.5
91.0:9.0
95.0:5.0
95.0:5.0
95.0:5.0
94.5:5.5
95.5:4.5
3m
3n
3o
3p
3q
[a] Reaction conditions: 1a (0.1 mmol), 2a (5.0 mmol), catalyst 3
(0.01 mmol), benzene-1,3,5-tricarboxylic acid (0.06 mmol), DMSO
(1.0 mL), 208C, 120–168h. In all cases, only traces of by-product 5
were detected by GC-MS. [b] Yield of isolated product. [c] Determined by
HPLC analysis on a chiral stationary phase.
with an enantiomeric ratio of 84:16; this catalyst was,
therefore, selected for further optimization.
During these studies (see the Supporting Information for
details) we found the addition of 60 mol% benzene-1,3,5-
tricarboxylic acid to be beneficial, with the enantiomeric ratio
improving to 92.5:7.5 (entry 11). However, the yield was only
moderate (54%) and the ratio of the desired product 4a to
by-product 5 was still disappointing (52:48). A significant
improvement in yield and selectivity was realized when we
used an excess of diethylmalonate 2a (30 eqiuv). The desired
product 4a was obtained in 80% yield with an excellent 4a/5
selectivity (95:5) and good enantioselectivity (e.r. = 92:8) at
room temperature (entry 12). Optimized conditions were
then established by using 50 equivalents of diethylmalonate,
which improved the yield and selectivity even further
(entry 13).
However, despite these enhancements in enantiomeric
ratio, and especially the isomeric ratio of the olefins, we were
still curious if the reaction could be further improved through
systematic modification of the catalyst. Such modifications of
cinchona-based catalysts have mostly been limited to N-
alklyation of quinuclidine, O-alkylation of alcohols, and
demethylation of quinoline.[11] Recently, Hintermann et al.
Upon testing the newly synthesized catalysts in our model
reaction we were delighted to obtain product 4a in generally
high enantioselectivity (e.r. up to 95.5:4.5) and very good
yield (85–92%, Table 2). Among the investigated catalysts,
amine 3q proved to be the most promising one, also with
different substrates, and was therefore chosen for our further
studies.
The screening experiments of different substrates in the
presence of the novel catalyst 3q under our optimized
conditions are summarized in Table 3. Diverse substituted
a-branched aromatic and aliphatic aldehydes were applied to
the reaction with diethylmalonate under these conditions
(Table 3, entries 1–11).
The reaction turned out to be tolerant of both electron-
deficient and electron-rich aromatic substrates, and the
products were obtained in good yields (81–92%) and
enantioselectivities (e.r. up to 95.5:4.5). 2-Phenylbutanal can
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Angew. Chem. Int. Ed. 2011, 50, 1707 –1710

Table 3: Substrate scope.[a]
In conclusion, we have developed the first catalytic
asymmetric Knoevenagel condensation. Racemic a-branched
aldehydes can be converted in a dynamic kinetic resolution
into the corresponding enantiomerically enriched products
with enantiomeric ratios of up to > 95:5 . Our reaction also
features a new cinchona amine catalyst, which can be easily
synthesized and which may be of use for other catalysts and
reactions.
Entry R1
R2
R3
R4
Product Yield
[%][b]
e.r.[c]
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4a
4b
4c
4d
4e
4 f
4g
4h
4i
91
81
87
86
90
91
92
90
91
95.5:4.5
87.0:13.0
93.5:6.5
93.5:6.5
89.5:10.5
93.5:6.5
94.5:5.5
95.0:5.0
91.5:8.5
4-OMeC6H4
4-MeC6H4
4-ClC6H4
2-FC6H4
3-FC6H4
4-FC6H4
3-MeC6H4
Ph
Experimental Section
General procedure for the catalytic asymmetric Knoevenagel con-
densation reaction: The catalyst 3q (0.02 mmol, 0.1 equiv) and
additive
6 (0.12 mmol, 0.6 equiv) were dissolved in DMSO
(2.0 mL). The solution was cooled to 208C and 1a (0.2 mmol,
1 equivalent) was added. The reaction mixture was stirred for 10 min
and then 2a (10.0 mmol, 50 equiv) was added at the same temper-
ature. After stirring the reaction mixture for 120–168 h it was poured
into water (3 mL) and extracted with ethyl acetate (3 ꢀ 5 mL). The
organic fractions were dried over anhydrous MgSO4 and concentrated
under reduced pressure. Purification by column chromatography on
silica gel (n-pentane/diethyl ether, 90:10) afforded 4a as a colorless oil
(91% yield).
10
11
c-C6H11
4-iPrC6H4CH2 Me
Me
Et
Et
Et
Et
4j
4k
92
90
60.0:40.0
52.5:47.5
12
13
Ph
Ph
Ph
Ph
Me Me Me
Me nPr nPr
Me nBu nBu
4l
4m
4n
4o
97
96
96
94
94.5:5.5
95.0:5.0
94.5:5.5
93.5:6.5
92.5:7.5
90.5:9.5
14
Received: October 8, 2010
Published online: January 20, 2011
15[d]
Me Bn
Et
16
Ph
Me Bn
Bn
4p
84
Keywords: a-branched aldehydes · dynamic kinetic resolution ·
enantioselectivity · Knoevenagel condensation · organocatalysis
.
[a] Reaction conditions: 1 (0.2 mmol), 2 (10.0 mmol), catalyst 3q
(0.02 mmol), additive 6 (0.12 mmol), DMSO (2.0 mL), 208C, 120–
168 h. [b] Yield of isolated product. [c] Determined by HPLC analysis on a
chiral stationary phase. [d] Product 4o (E/Z=1:1), measured by HPLC
analysis.
[1] a) E. Knoevenagel, Chem. Dtsch. Ber. Ges. 1894, 27, 2345 – 2346;
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[2] B. List, Angew. Chem. 2010, 122, 1774 – 1779; Angew. Chem. Int.
Ed. 2010, 49, 1730 – 1734.
also be used, and leads to the formation of a-ethyl-branched
alkylidene malonate 4i in good yield and enantiomeric ratio
(Table 3, entry 9). Aliphatic aldehydes are also suitable
substrates in the dynamic kinetic resolution, although the
enantiomeric ratios are significantly lower (Table 3, entries 10
and 11).
We also explored a variety of different malonates in the
reaction with 2-phenylpropanal (Table 3, entries 12–16). In all
cases, good to excellent yields (84–97%) were observed and
the products were obtained with high enantioselectivities.
Benzylethylmalonate gave E and Z products as a 1:1 mixture,
both in high enantioselectivity (entry 15).
[3] For reviews on aminocatalysis, see a) B. List, Synlett 2001, 1675 –
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[4] For Knoevenagel, enantioselective hetero Diels–Alder reactions
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Knoevenagel/hetero Diels–Alder reactions with chiral sub-
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To illustrate the utility of our reaction products compound
4a was converted into (R)-ethyl-4-phenylpentanoate (7b) by
a
hydrogenation and
a
Krapcho reaction sequence
(Scheme 2). The absolute configuration of product 4a was
determined to be R after transformation to 2-phenyl-1-
propanol by ozonolysis followed by reductive work up and
comparison of its GC retention time on a chiral stationary
phase (see the Supporting Information).
[6] a) S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem. Soc. 2006,
128, 13074 – 13075; b) X. Li, B. List, Chem. Commun. 2007,
Scheme 2. Synthetic utility of product 4a.
Angew. Chem. Int. Ed. 2011, 50, 1707 –1710
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Communications
1739 – 1741; c) X. Cheng, R. Goddard, G. Buth, B. List, Angew.
[10] For reviews of the catalysis using chichona-derived primary
amines, see a) G. Bartoli, P. Melchiorre, Synlett 2008, 1759 –
1772; b) Y-C. Chen, Synlett 2008, 1919—1930; for studies from
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[7] For an example of an organocatalytic aldol reaction with DKR,
see D.-E. Ward, V. Jheengut, O.-T. Akinnusi, Org. Lett. 2005, 7,
1181 – 1184.
[8] For examples of proline-catalyzed Knoevenagel reactions, see
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[11] C. E. Song, Cinchona Alkaloids in Synthesis
& Catalysis,
Ligands, Immobilization and Organocatalysis, Wiley-VCH,
Weinheim, 2009, pp. 359 – 418.
[12] L. Hintermann, M. Schmitz, U. Englert, Angew. Chem. 2007,
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see also J. P. Yardley, R. E. Bright, L. Rane, R. W. A. Rees, P. B.
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