Catalytic conjugate additions of carbonyl anions under neutral aqueous conditions

Article abstract of DOI:10.1021/ja0520161

The conjugate addition of carbonyl anions catalyzed by thiazolium salts that is fully operative under neutral aqueous conditions has been accomplished. The combination of α-keto carboxylates and thiazolium-derived zwitterions produces reactive carbonyl an

Full text of DOI:10.1021/ja0520161

Published on Web 10/04/2005
Catalytic Conjugate Additions of Carbonyl Anions under
Neutral Aqueous Conditions
Michael C. Myers, Ashwin R. Bharadwaj, Benjamin C. Milgram, and Karl A. Scheidt*
Contribution from the Department of Chemistry, Northwestern UniVersity,
EVanston, Illinois 60208
Received March 29, 2005; E-mail: scheidt@northwestern.edu
Abstract: The conjugate addition of carbonyl anions catalyzed by thiazolium salts that is fully operative
under neutral aqueous conditions has been accomplished. The combination of R-keto carboxylates and
thiazolium-derived zwitterions produces reactive carbonyl anions in a buffered protic environment that readily
undergo conjugate additions to substituted R,â-unsaturated 2-acyl imidazoles. The scope of the reaction
has been examined and found to accommodate various R-keto carboxylates and â-aryl substituted
unsaturated 2-acyl imidazoles. The optimal precatalyst for this process is the commercially available
thiazolium salt 5, a simple analogue of thiamin diphosphate. In this process, no benzoin products from
carbonyl anion dimerization are observed. The corresponding 1,4-dicarbonyl compounds can be efficiently
converted into esters and amides by way of activation of the N-methylimidazole ring via alkylation.
Introduction
proaches can efficiently construct the desired carbon-carbon
bond under strongly basic conditions, but also require postre-
Chemical processes in nature catalyzed by enzymes are not
only essential for the efficient implementation of life processes,
but also serve as elegant inspirations for the development of
new strategies regarding bond-forming reactions.1,2 The bio-
chemical investigations of many fundamental enzymatic pro-
cesses have influenced recent advances in efficient chemical
transformations. A particularly intriguing biological pathway
involves the production of acetylCoA from pyruvic acid (1, eq
1). This reaction efficiently converts 1 into a carbonyl anion in
the presence of thiamin diphosphate contained within an R-keto
acid dehydrogenase active site.3-7 This elegant transformation
is the archetype of an Umpolung process: a polarity reversal
manifold that converts a normally electrophilic carbonyl carbon
atom into a nucleophilic species.8-12 Stoichiometric carbonyl,
or acyl, anions have been traditionally accessed using protected
cyanohydrins13-16 or metalated dithianes.10,17-19 These ap-
action manipulations to unmask the desired carbonyl functional-
ity. In contrast, a number of successful systems have been de-
veloped to access carbonyl Umpolung reactivity under catalytic
conditions promoted by heteroazolium carbenes.20-23 These
highly nucleophilic heterocyclic zwitterions/carbenes possess
unique reactivity characteristics and have recently been em-
ployed as catalysts for various reactions, including acyl transfer
processes,24-30 isocyanate trimerizations,31 the addition of CF3
anions to aldehydes,32 and the generation of homoenolates.33-35
There are two established and mechanistically related reactions
that employ catalytically generated carbonyl anions as nucleo-
philes. The first process involves aldehydes as the electrophile
and is called the benzoin reaction.23,36-39 The second type of
(19) Lever, O. W. Tetrahedron 1976, 32, 1943-1985.
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A R T I C L E S
Myers et al.
addition, called the Stetter reaction, employs conjugate acceptors
and produces 1,4-dicarbonyl products.40,41 The continued de-
velopment of these two related reactions has received significant
attention recently and offers new opportunities for unconven-
tional synthetic strategies.
nation R-keto acids in the presence of thiamin diphosphate-
dependent enzymes address these criteria well (eq 1). Although
the biochemical aspects of these enzymes have been studied
extensively, significant potential exists to utilize this process
for carbon-carbon bond-forming reactions.6,7,59-62 The genera-
tion of carbonyl anions in this manner has been applied to both
the benzoin and the Stetter reaction. For example, Mu¨ller63-65
and Patel66 have separately reported cross-benzoin reactions
between R-keto acids and aldehydes catalyzed by various
decarboxylase enzymes. In a seminal study, Stetter demonstrated
that R-keto acids add to unsubstituted vinyl ketones in organic
media catalyzed by thiazolium salts in the presence of an amine
base.67 These mechanistically related systems provided the
impetus for us to initiate a study to fully explore this carbonyl
anion strategy in the broadest context possible. In general, the
addition of nucleophiles to â-substituted conjugate acceptors is
considerably more challenging than adding to related vinyl
ketones because they are far less reactive due to steric
congestion.68 Furthermore, we anticipated that the investigation
of this reaction manifold with various classes of conjugate
acceptors would expand the synthetic utility of this process. We
also predicted that the neutral aqueous environment of the
original thiamin-dependent enzymes would ultimately be the
best conditions to generate useful carbonyl anions. These
buffered catalytic conditions would have the potential to tolerate
base- or acid-labile functionality and/or protecting groups that
could be present when combining complex and/or sensitive
fragments.69-71 We report herein that simple analogues of
thiamin diphosphate catalyze the conjugate addition of R-keto
salts (2) to R,â-unsaturated 2-acyl imidazoles (3) under neutral
aqueous conditions to afford 1,4-dicarbonyl compounds in
excellent yield (eq 2).
Many catalytic benzoin and Stetter reactions utilize aldehydes
as the nucleophilic precursor. These approaches can be com-
plicated by the intrinsic high reactivity of the aldehyde because
the intermediate carbonyl anion produced during the reaction
can undergo addition to the starting aldehyde, thereby affording
self-condensation products. A successful strategy to minimize
this potential problem is to generate an intramolecular system
by tethering the aldehyde functional group to the electrophile.42-45
An alternative approach is to utilize a carbonyl anion precursor
that does not possess an aldehyde, thus removing this reactive
moiety from the reaction completely. The identification and
development of such a precursor should consequently provide
the opportunity for a general intermolecular carbonyl anion
process. In general, this strategy should allow for a broad
inclusion of many classes of electrophiles, and the carbonyl
anion generated in situ would not compete between addition to
the desired substrate and addition to the aldehyde precursor.
Our laboratory has recently reported that intermolecular con-
jugate addition reactions and additions to activated imines with
acylsilanes as the carbonyl anion precursors can be catalyzed
by thiazolium-derived carbenes.46-48 The use of these silicon-
based carbonyl anion precursors avoids self-condensation, and
we have demonstrated that acylsilanes undergo 1,2-silyl shifts
(Brook rearrangements)49-51 in the presence of neutral Lewis
bases, which in turn generate competent carbonyl anions. The
use of acylsilanes as carbonyl anions is well documented, and
this strategy can offer distinct advantages over aldehydes when
employing this Umpolung reactivity pattern.52-58
During our studies with acylsilanes, we initiated an investiga-
tion of additional carbonyl anion precursors that would undergo
Stetter-type reactions under catalytic conditions and avoid any
potential self-condensation problems. Interestingly, the combi-
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Results and Discussion
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Our initial investigations focused on combining R-keto acids
and thiazolium salts with a conjugate acceptor that would
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9
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Catalytic Conjugate Additions of Carbonyl Anions
A R T I C L E S
Scheme 1
Scheme 2
base problem was to remove the acidic proton on the R-keto
acids by forming the corresponding sodium carboxylates. The
use of sodium salts (1b) in methanol created much more robust
reaction conditions (Table 1, entry 3) that provided homoge-
neous reactions conditions. While there are a number of
commercially available thiazolium salts with various counterions
and substitution around the heterocyclic core, thiazolium 5 was
superior in terms of conversion and product yields in aqueous
media. Replacing the thiazolium salt with alternative hetero-
azolium salts as possible catalysts (e.g., imidazolium or tria-
zolium salts) does not afford product, underscoring the delicate
balance of reactive components for this process.
Table 1. Investigation of Pyruvic Acid/Sodium Pyruvate as a
Carbonyl Aniona
entry
X
solvent
base
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
H (1a)
Na (1b)
Na
Na
Na
Na
Na
Na
Na
THF
THF
MeOH
DBU
DBU
DBU
pH 12.0
pH 9.4
pH 7.2
pH 4.8
pH 2.2
-
24
-
2
12
15
8
15
-
11
85
-
89
93
94
92
91
-
MeOH/bufferc
MeOH/bufferd
MeOH/bufferc
MeOH/buffere
MeOH/bufferc
MeOH/H2O
Driven by our goal to realize this process under aqueous
conditions, DBU was replaced with aqueous pH 12 buffer (Table
1, entry 4). Gratifyingly, the reaction proceeds in excellent yield
(93%) in a buffered aqueous methanol solution at 70 °C. The
methanol was added initially for solubility purposes, and
elevated temperature is necessary to induce the reaction; gas
evolution, presumably carbon dioxide, initiates at approximately
63 °C.75 Lower temperatures significantly reduce the rate of
product formation, and the reaction does not proceed to 100%
conversion over extended periods of time. An examination of
various phosphate buffers indicated that the overall process is
operative at pH 7.2 to afford the desired 1,4-dicarbonyl
compound 7 (entry 6). Under these neutral aqueous conditions,
only the carboxylate salt (1b) is an effective carbonyl anion,
presumably because the absence of the proton keeps the balance
of pH within a level that an effective concentration of the
thiazolium zwitterion is present. In general, sodium carboxylate
R-keto salts preformed the best under our optimized reaction
conditions. Surprisingly, the reaction proceeds at pH 4.8 (entry
7) or without any external base (entry 10), although longer times
are necessary. Reducing the catalyst loading to 10 or 5 mol %
does afford product, but 100% conversion is not achieved.
The possibility of the imidazole ring of the substrate/product
acting as an internal base for the reaction was addressed by
subjecting trans-chalcone to the same reactions conditions as
in Table 1. Interestingly, using sodium pyruvate, 20 mol %
thiazolium 5 in MeOH/pH 7.2 phosphate buffer mixture afforded
78% of the 1,4-dicarbonyl compound (Scheme 2). In a second
control experiment, DBU was replaced with N-Me-imidazole
as the base under the organic media conditions (Table 1, entry
3), and no product was observed.
91
a Reactions performed at 0.5 M with 1.3:1 (v:v) mixture of MeOH and
100 mM phosphate-based buffer solution. b Isolated yields after column
chromatography. c 100 mM phosphate-based buffer solution. d Pyrophos-
phoric acid-based buffer solution. e 100 mM acetate-based buffer solution.
ultimately provide synthetically valuable products. At the onset,
unsaturated ester, amides, and related conjugate acceptors were
not viable substrates under a variety of conditions. Additionally,
substrates possessing ester termini complicated later studies
under aqueous environments. Consequently, we imposed two
key requirements during this search to make the overall
transformation valuable: (1) the conjugate acceptor possesses
substitution at the â-position, and (2) the products be easily
converted into an ester equivalent. Initial studies suggested that
unsaturated imidazole substrates were competent conjugate
acceptors meeting all of our key requirements.72,73 Another
attractive feature of these substrates was that they are easily
synthesized on a large scale by a simple aldol condensation of
2-acetyl-1-methylimidazole and the corresponding aromatic
aldehydes (Scheme 1).
After considerable experimentation using pyruvic acid (1a)
and 20 mol % thiazolium salt 5, we observed that R,â-
unsaturated 2-acyl N-methyl-imidazole (e.g., 3) as the electro-
phile while using DBU74 as the base afforded an excellent yield
of the carbonyl anion addition product 7 (Table 1, entry 1).
Subsequent studies found that optimization of this mixed
Bronsted acid/base system was limited to the â-phenyl substrate
(6). For example, substituted â-aryl substrates gave low conver-
sions of the carbonyl addition products when using pyruvic acid
and DBU. An operationally simple solution to the Bronsted acid/
With these neutral aqueous conditions identified for additions
to â-substituted conjugate acceptors, pyruvate (1b) was exam-
ined as the acyl nucleophile reagent. Generally, the reaction
affords high yields of the corresponding 1,4-diketones when
â-aryl substituents are employed (Table 2, eq 4). The process
is not affected to an appreciable degree by electron-rich or
electron-poor aromatic rings in the â-position. Conjugate
acceptors with heterocycles appended in the â-position also work
well (entries 9 and 10). Electrophilic substrates with â-alkyl
(66) Guo, Z. W.; Goswami, A.; Mirfakhrae, K. D.; Patel, R. N. Tetrahedron:
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(67) Stetter, H.; Lorenz, G. Chem. Ber. 1985, 118, 1115-1125.
(68) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Perga-
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(69) Katritzky, A. R.; Nichols, D. A.; Siskin, M.; Murugan, R.; Balasubramanian,
M. Chem. ReV. 2001, 101, 837-892.
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Heterocycles 1988, 27, 457-473.
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8942-8943.
(75) Carbon dioxide evolution is observed at 63 °C under the reaction conditions.
10 mol % of the thiazolium salt affords good yields of products, but <100%
conversion over 24 h.
(74) 1,8-Diazabicyclo[5.4.0]undec-7-ene.
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A R T I C L E S
Myers et al.
Table 2. Catalytic Reactions with Sodium Pyruvate (1b) and
â-Aryl 2-Acylimidazolesa
Table 4. Conjugate Additions of R-Keto Carboxylatesa
entry
R
time (h)
yield (%)b
product
1
2
3
4
5
6
7
8
9
4-MePh
4-MeOPh
4-ClPh
4-BrPh
2-MeOPh
2-ClPh
2-BrPh
2-CF3Ph
2-furyl
12
11
7
20
16
18
16
18
24
24
87
87
87
71
87
95
89
76
80
90
8
9
10
11
12
13
14
15
16
17
10
2-thiophene
a Reactions performed at 0.5 M with 1.3:1 (v:v) mixture of MeOH and
100 mM phosphate-based buffer solution. b Isolated yields after column
chromatography.
Table 3. Reactions with Crotyl-2-acylimidazole Acceptorsa
entry
X
conditions
time (h)
yield (%)a
1
H
THF, 70 mol% DBU,
30 mol% 5
26
35
2
Na
THF, pH 7.2 buffer,
28
23
40 mol% 5
a Reactions performed at 0.4 M. b Isolated yields after column chroma-
tography.
substituents deliver low levels of 1,4-dicarbonyl products (Table
3, eq 5), and efforts are underway to understand this divergence
in reactivity. Under organic solvent conditions (THF, DBU),
pyruvic acid adds to the crotyl derived imidazole substrate in
only 35% yield. Potentially, the presence of enolizable protons
on the electrophilic component of the reaction with DBU upsets
the balance of acids and bases in solution. Switching the solvent
to THF and pH 7.2 buffer to remove the amine base from
solution did not provide an improved yield of the addition
product, but instead afforded a lower yield. The use of methanol
was avoided because the methanol addition product is isolated
in good yield (not shown) with either methanol/DBU or
methanol/pH 7 buffer conditions.
a See Table 2 for details. b IM ) N-methyl imidazole. c Performed in
MeOH with DBU. d NR ) no reaction.
acids with R-branching give low conversions of 1,4-dicarbonyl
products, presumably due to steric congestion around the
carbonyl carbon. Interestingly, the use of sodium trifluoromethyl
pyruvate (Table 4, entry 8) does not afford any appreciable level
of product and importantly did not exhibit any CO2 gas
emissions. This R-keto carboxylate is presumably forming a
hydrate or hemiketal under the reaction conditions, and this
prohibits carbene addition to the ketone.79
The heightened reaction temperatures for the transformations
above provide good to high levels of products in a minimal
time period. However, a survey of altered reaction conditions
was conducted to promote the reaction at lower temperatures.
It was established in our related studies that the newly formed
stereogenic center of the addition products undergoes epimer-
ization under the standard reaction conditions (pH 7.2 buffer,
methanol, 70 °C). To investigate the possibility of a stereocon-
trolled variant of this bond-forming process, a modified approach
was investigated. Using unsaturated acylimidazoles 8a and 10a
as the conjugate acceptors, a variety of Lewis acids and solvents
were screened under a host of reaction conditions. We envi-
sioned that both the acylimidazole substrate and the R-keto
carboxylate have coordination sites that could interact with an
electron-deficient metal and promote a beneficial effect. While
a broad survey of Lewis acids has not been successful to date
We have also explored the impact of structural variations on
the carbonyl anion for this process (Table 4, eq 6). Many R-keto
acids are commercially available and can be easily converted
to the corresponding sodium salts.76-78 Generally, alkyl and aryl
keto carboxylates work well in this reaction. In some cases
(entries 2 and 6), our original organic media conditions (MeOH,
DBU, thiazolium salt) provide much higher yields than the
buffered aqueous conditions. The reason for this is currently
not well understood, although variation in solubilities of
substrates and products between 100% methanol and a buffered
aqueous/methanol combination may play a role. Currently, keto
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9
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Catalytic Conjugate Additions of Carbonyl Anions
A R T I C L E S
Table 5. Catalytic Reactions with Pyruvate (1b) in Ethylene
Glycola
entry
R
time (h)
yield (%)b
product
1
2
4-MePh (8a)
4-ClPh (10a)
10
8
90
86
8
10
a Reactions performed at 0.4 M in ethylene glycol at 23 °C. b Isolated
yields after filtration and water wash.
Scheme 3 a
Figure 1. Proposed reaction pathway.
a [a] MeOH, DABCO, 78%; [b] morpholine, DMAP, 94%.
enol ether formation of the pendant ketone moiety or trapping
of the activated ester by the ketone to deliver furan heterocycles.
Our proposed reaction pathway is similar to the benzoin-type
processes involving thiamine-dependent enzymes (Figure 1). The
interaction of a thiazolium zwitterion/ylide (I) generated in situ
with an R-keto carboxylate generates tetrahedral intermediate
(II). The observation that sodium trifluoropyruvate as the hy-
drate under aqueous conditions does not undergo nucleophilic
additions to electrophiles (Table 4, entry 8) is evidence that the
addition to the ketone carbon initiates the catalytic cycle. The
loss of carbon dioxide affords the enanamine/carbon nucleophile
species III,82-85 which in very select cases has been isolated.86,87
Our considerable efforts to generate and study this species have
not been successful to date. A contributing factor in this pursuit
is the potential for III to revert to an aldehyde and thiazolium
zwitterion I when there are no electrophiles present in solution.
This situation is present in the thiazolium-catalyzed benzoin
reaction in which the addition of a nucleophilic thiazolium to
an aldehyde (giving III) is reversible.83,84 Slow gas evolution
is observed during these reactions at approximately 60 °C by
way of an oil bubbler directly attached to the reaction flask.
The interaction of the electron-rich enamine III with the unsatu-
rated electrophile induces carbon-carbon bond formation at the
desired â-position. A subsequent deprotonation of the resulting
tertiary alcohol IV initiates the formation of the ketone moiety
in the product and releases I. Importantly, products arising from
the addition of the nucleophilic thiazolium species to the
conjugate acceptor are not observed.88-91 Further investigations
into the generation and determination of the level of reactivity
of nucleophilic species such as III are currently ongoing.
in lowering the reaction temperature in these carbonyl anion
conjugate additions, a change in solvent from methanol to
ethylene glycol allowed the reaction to proceed cleanly and in
good yield at room temperature. In these reactions, the dicar-
bonyl products (8 and 10) precipitate directly from solution and
are obtained by a simple filtration followed by washing with
water and drying in vacuo. In these cases, the product isolated
1
is >95% pure as judged by H NMR (500 MHz).
Under the full organic media reactions conditions (MeOH,
DBU, 70 °C), the 1,4-dicarbonyl products (e.g., 8 and 10) do
not precipitate from the solution and most likely undergo
reversible interactions with the thiazolium zwitterion/carbene
derived from 5. To probe this hypothesis, we conducted the
organic reaction conditions on substrate 8a and 10a at 23 °C
with and without the addition of the products as an additive
(Table 5, eq 6). We observed that product inhibition is occurring
under the organic reactions conditions where the products do
not precipitate from solution. For example, at all reaction times
the conversion of 8a to 8 is higher when no additive (product
8) is in the reaction solution. The rate of product formation in
both experiments also slows as the reaction progresses.80 This
effect can also be explained by product inhibition, and presum-
ably these observations account for the lack of 100% conversion
at room temperature. Product inhibition would also explain the
requirement of increased reaction temperatures when using
methanol and DBU and operative lower temperatures in ethylene
glycol where 8 and 10 precipitate from solution. In the latter
case when the products precipitate from solution, the carbene
catalyst has minimal interactions with the resulting carbonyl
groups of the product, and thus limited product inhibition occurs
when using ethylene glycol (Table 5, entries 1, 2).
(81) Davies, D. H.; Hall, J.; Smith, E. H. J. Chem. Soc., Perkins Trans. 1 1991,
2691-2698.
(82) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
(83) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241-8242.
(84) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124-5131.
(85) Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J. T.; Jordan, F. J. Org.
Chem. 1994, 59, 7714-7722.
The N-methyl imidazole architecture of the carbonyl addition
products allows for smooth access to activated ester reactivity
by way of an imidazolium intermediate (Scheme 3). The
nucleophilic lone pair on the imidazole ring provides a handle
for selective functionalization with activated electrophiles. For
example, treatment of diketone 7 with methyl trifluoromethane-
sulfonate (MeOTf) followed by either methanol or morpholine
affords high yields of the methyl ester (26, 78%) or amide (27,
94%), respectively.73,81 In these processes, we do not observe
(86) Krampitz, L. O.; Greull, G.; Miller, C. S.; Bicking, J. B.; Skeggs, H. R.;
Sprague, J. M. J. Am. Chem. Soc. 1958, 80, 5893-5894.
(87) Risinger, G. E.; Gore, W. E.; Pulver, K. Synthesis 1974, 659-660.
(88) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005, 7, 2297-
2300.
(89) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130-
5135.
(90) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen,
J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899-907.
(91) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5, 665-
667.
(80) See Supporting Information for details.
9
J. AM. CHEM. SOC. VOL. 127, NO. 42, 2005 14679

A R T I C L E S
Myers et al.
Conclusions
Experimental Section
General Procedure for the Thiazolium-Catalyzed Carbonyl
Addition to Unsaturated Imidazoles. A screw-capped tube was
charged with 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride
(5) (22 mg, 0.08 mmol, 20 mol %), R-keto carboxylate sodium salt
(0.72 mmol), and R,â-unsaturated-keto-N-methylimidazole substrate
(0.40 mmol). Next, methanol (450 µL) and pH 7.2 phosphate buffer
(350 µL, 100 mM) were added via syringe to the screw-capped tube.
The resulting mixture was heated to 70 °C and allowed to stir for the
allotted time (8-24 h). Upon 100% conversion of the reaction (as
judged by thin-layer chromatography, 90% ether/hexanes), the reaction
was cooled to room temperature, diluted with ethyl acetate (10 mL),
and transferred to a separatory funnel. Saturated sodium chloride (10
mL), saturated sodium bicarbonate (10 mL), and H2O (10 mL) were
added, and the aqueous layer was extracted with ethyl acetate (3 × 40
mL). The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo on a rotary evaporator. The resulting
residue was purified by flash column chromatography on silica gel.
In summary, we have developed a robust catalytic car-
bonyl anion reaction that is fully operative over a broad range
of pH values. Under neutral aqueous conditions, the combina-
tion of R-keto carboxylates and thiazolium salts produces
reactive carbonyl nucleophiles that readily undergo conjugate
additions to versatile â-substituted unsaturated 2-acyl imidazoles.
The reaction is tolerant of aryl substitution on the conjugate
acceptors and accommodates a variety of functionality on the
carbonyl anion precursors. When the conjugate acceptor pos-
sesses enolizable protons, the reaction affords 1,4-dicarbonyl
products, but the isolate yields are currently in the 25-35%
range. Typical reaction conditions require heat at 70 °C for
efficient conversion to products, and product inhibition is
observed in the system. Specialized conditions that promote the
precipitation of the products allow for the reaction to afford
100% conversion and high yields at 23 °C. The 1,4-dicarbonyl
products can be efficiently converted into esters and amides
while avoiding furan formation by activation of the imidazole
ring. Mechanistic investigations indicate that loss of carbon
dioxide is necessary for the reaction to proceed and that the
process can be enhanced by modifying the solvent of the
reaction. This study details that R-keto acids and R-keto
carboxylates undergo nucleophilic conjugate addition to sub-
stituted acceptors efficiently under mild conditions using
commercially available thiamin analogues as catalysts. Further-
more, the operation of this process over a wide range of acidities
(pH 4-12) can be useful with acid- and base-sensitive substrates
as well as reaction methodology that incorporate acid-pro-
moted steps. Current work is focused on developing stereose-
lective variants of this process and expanding the utility of
R-keto acids as carbonyl anion reagents in additional bond-
forming processes.
Acknowledgment. This work is dedicated to the memory of
Professor Irving M. Klotz (Northwestern University), a friend,
mentor, and exemplary scientist. Financial support for this work
has been partially provided by Northwestern University and the
NSF (CHE-0348979). K.A.S. gratefully acknowledges Amgen,
Abbott Laboratories (New Faculty Awards), 3M (Nontenured
Faculty Award), and Boehringer-Ingelheim for research support,
and FMCLithium for providing organolithiums used in this
research. M.C.M. acknowledges Abbott Laboratories for a
graduate fellowship, and B.C.M. thanks Sigma-Aldrich for a
Summer Undergraduate Research Fellowship.
Supporting Information Available: Detailed experimental
procedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0520161
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