Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 5750
COMMUNICATION
Development of strong Brønsted base catalysis: catalytic direct-type Mannich
reactions of non-activated esters via a product-base mechanism†‡
Yasuhiro Yamashita, Hirotsugu Suzuki and Shū Kobayashi*
Received 10th March 2012, Accepted 2nd April 2012
DOI: 10.1039/c2ob25522g
carbanion precursors bearing less acidic hydrogens, such as
esters with no activating functionality at the α-position, has not
been well established.5 Deprotonation of esters to form the corre-
sponding enolate species is generally conducted using a stoichio-
metric amount of a strong Brønsted base system, for example,
metallated carbon or nitrogen molecules such as alkyl lithiums,
lithium diisopropylamide (LDA), etc. However, their conjugate
acids, for example diisopropylamine in the case of LDA, are less
acidic to protonate the intermediates efficiently. On the other
hand, in the case of Mannich reactions, it has been known that
anionic nitrogen species form after the addition of carbanions to
the imino carbons, which could then subsequently deprotonate
the next ester substrate and so promote the reaction catalytically.
In this report, we describe a very rare example of strong base-
promoted catalytic Mannich reactions using simple esters as
substrates.
Based on our concept, we focused on use of N-aryl imines
containing a methoxy group as a substrate. It was anticipated
that this formed a more basic nitrogen anion as a Mannich inter-
mediate after addition of a carbanion, and that the aryl group in
the subsequently formed products could be removed by oxidative
cleavage using cerium ammonium nitrate (CAN),6 etc. Firstly we
attempted the Mannich reaction of N-o-methoxyphenyl (OMP)
benzaldehyde imine (1a) with 2 equivalents of tert-butyl isobu-
tyrate (2a) in THF (0.4 M) at 0 °C for 24 h in the presence of
5 mol% of potassium bistrimethylsilylamide (KHMDS). The
OMP group was expected to prevent undesired intramolecular
cyclization to the corresponding β-lactam by increasing steric
hindrance around the nitrogen atom. As expected, the desired
Mannich adduct was obtained in 88% yield. To simplify the
reaction system, we then employed a strong Brønsted base, pot-
assium hydride (KH, 5 mol%), whose conjugate acid is H2, not
an acidic species. To our delight, the desired product was
obtained in high yield (Table 1, entry 1). This result clearly indi-
cated that the Mannich reaction proceeded via the product base
mechanism.7 Optimization of the reaction conditions showed
that the reaction proceeds smoothly in tert-butyl methyl ether
(TBME) using a slight excess of the imine to afford the desired
product in high yield (entry 2). Next we investigated the effect
of imine substrates; other OMP imines derived from aromatic
aldehydes were also found to be reactive under the same opti-
mized reaction conditions. Imines bearing electron-donating
groups reacted with 2a smoothly, with the corresponding
A catalytic Mannich reaction of a simple ester with no acti-
vating functionality at the α-position via a product-base
mechanism was reported. The desired Mannich adducts
were obtained in high yields using a catalytic amount of KH.
This is a rare example of a Brønsted base-catalyzed Mannich
reaction of unactivated esters as substrates.
Brønsted base-catalyzed carbon–carbon bond forming reactions
are among the most fundamental and atom economical reactions
for the construction of organic molecules.1 In the reactions, one
key point for efficient promotion of the reaction is basicity of cat-
alysts, and strong Brønsted bases could enhance the reactions
smoothly and also expand the scope of available substrates sig-
nificantly. On the other hand, protonation of intermediates after
bond-forming steps is also another key point for smooth catalyst
turnover in base-catalyzed processes. When strong Brønsted base
catalysts are employed in reactions, the protonation step often is
not efficient due to the low Brønsted acidity of the corresponding
conjugate acids of their counter anions, and the catalyst turnover
could be stopped. Furthermore, when the protonation step is not
efficient, retro reactions from the formed intermediates could
occur. Therefore, base species with high Brønsted basicity have
yet to be used as effective catalysts. However, if an intermediate,
which could be preferred to be a “product-base,” had strong
Brønsted basicity, smooth deprotonation of the next substrate by
this reaction intermediate could smoothly complete the catalytic
cycle and so catalyst turnover would successfully occur even
when a strong base species is used as the catalyst.2
Direct-type Mannich reactions of enolizable carbonyl com-
pounds with imines provide an efficient method for the prep-
aration of β-aminocarbonyl compounds in a single step.3
Recently, catalytic activation of carbonyl compounds by basic
catalyst systems to form carbanions or their equivalents has been
widely developed in several carbon–carbon bond forming reac-
tions.4 However, methodology for catalytic activation of
Department of Chemistry, School of Science, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, 113-0033. E-mail: shu_kobayashi@
chem.s.u-tokyo.ac.jp; Fax: +81-3-5684-0634; Tel: +81-3-5841-4794
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: General pro-
1
cedure of the Mannich reaction, H and 13C NMR data of the products
obtained. See DOI: 10.1039/c2ob25522g
5750 | Org. Biomol. Chem., 2012, 10, 5750–5752
This journal is © The Royal Society of Chemistry 2012