Mild decarboxylative activation of malonic acid derivatives by 1,1′-carbonyldiimidazole

Article abstract of DOI:10.1021/ol200575c

Chemical equations presented. Malonic acid derivatives undergo unusually mild decarboxylation when treated with N,N′-carbonyldiimidazole (CDI) at room temperature to generate the carbonyl imidazole moiety in high yield, which can be reacted further with a variety of nucleophiles in an efficient one-pot process.

Full text of DOI:10.1021/ol200575c

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2322–2325
Mild Decarboxylative Activation
of Malonic Acid Derivatives by
1,10-Carbonyldiimidazole
Danny Lafrance,* Paul Bowles, Kyle Leeman, and Robert Rafka
Development Science and Technology, Pfizer Inc., Eastern Point Road, Groton,
Connecticut 06340, United States
Danny.lafrance@pfizer.com
Received March 3, 2011
ABSTRACT
Malonic acid derivatives undergo unusually mild decarboxylation when treated with N,N0-carbonyldiimidazole (CDI) at room temperature to
generate the carbonyl imidazole moiety in high yield, which can be reacted further with a variety of nucleophiles in an efficient one-pot process.
The synthesis of carboxylic acid derivatives via malonic
ester alkylation, hydrolysis, and subsequent decarboxyla-
tion is a well established method for carbonꢀcarbon bond
formation (Scheme1).1 Thedecarboxylation stepisusually
During our investigation of cost-effective synthetic meth-
ods for the preparation of cyclopentanecarboxylic acid, we
observed that the treatment of cyclopentane-1,1-dicar-
boxylic acid with 1 equivalent of 1-10-carbonyldiimidazole
at room temperature resulted in the clean and quantitative
formation to the monocarbonylimidazole within 30 min
(Scheme 2),6 implying that the decarboxylation step was
Scheme 1. Conversion of Malonic Ester to Carboxylic Acids
Scheme 2. Cyclopentane Carbonyl Imidazole Formation
performed under harsh thermal conditions (up to 200 °C)
using conventional2 or microwave3 heating. A milder
copper catalyzed decarboxylation of malonic acid deriva-
tives was reported to proceed in refluxing acetonitrile, but
it was later establishedthat copper had no actual impact on
the rate of carbon dioxide extrusion.4 In addition to the
thermal methods, decarboxylase enzymes can also be used
for specific substrates at room temperature.5
proceeding rapidly under unusually mild conditions. The
carbonyl imidazole prepared can then be treated with a
basic aqueous solution followed by an acidic workup to
generate the carboxylic acid, or with a variety of nucleo-
philes, taking advantage of the direct activation of the
carbonyl position. We report herein our synthetic studies
of this reaction and its application toward a variety of
malonic acid derivatives.7
(1) Carey, F. A., Sunberg, R. J. In Advanced Organic Chemistry, 3rd
ed.; Plenum Press: New York, 1990; pp 12ꢀ13 and references cited therein.
(2) (a) Oniciu, D. C.; Dasseux, J. L. J. Med. Chem. 2006, 49, 334. (b)
Chow, H.; Ng, K. Org. Lett. 2006, 8, 471. (c) Brace, N. O. J. Fluorine
Chem. 2005, 126, 7. (d) Wu, Z.; Minhas, G. S. J. Med. Chem. 2004, 47,
3281. (e) Dahan, A.; Portnoy, M. J. Org. Chem. 2001, 66, 6484.
(3) (a) Zara, C. L.; Jin, T. Synth. Commun. 2000, 30, 2099. (b) Hubbs,
J. L. U.S. Patent 7 834 034, 2006.
(4) Cu2O is acting as a base catalyst in the thermal decarboxylation:
Blanchet, J.; Baudoux, J. Eur. J. Org. Chem. 2008, 5493 and references
cited therein.
(5) (a) Okrasa, K.; Levy, C. Angew. Chem., Int. Ed. 2009, 48, 4691. (b)
Miyamato, K.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 4077.
r
10.1021/ol200575c
Published on Web 04/13/2011
2011 American Chemical Society

The volume of CO2 produced in a pilot reaction using
1 g of diethylmalonic acid as the reference starting
material was measured at 146 mL, in accordance with
the calculated volume expected for 2 mol of CO2 (150 mL)8
being produced. Using the same reaction conditions
(1.05 mol equiv of CDI at room temperature), we next
conducted the decarboxylative activation of diethylmalo-
nic acid in different solvents and looked at the in situ
yield by GCMS after 1 h (Table 1). The reaction works
equally well in all solvent screened except for toluene,
which resulted in a more sluggish conversion. This is
likely caused by poor solubility of this specific substrate
in toluene.
Table 2. Malonic Acid Derivatives Screen
Table 1. Solvent Screen Study
entry
solvent
THF
conva (%)
1
2
3
4
5
6
95
92
96
71b
95
88
DCM
Acetonitrile
Toluene
EtOAc
DMF
a In situ conversion measured by GCMS. b Precipitate forms in
toluene upon CDI addition.
As expected from reported N-acylimidazole stability
studies,9 the carbonyl imidazole 1a was found to be
relatively stable under neutral or slightly acidic aqueous
conditions, while hydrolyzing rapidly under basic condi-
tions. Compound 1a was successfully isolated in good
yield (80%) and purity (98% by GCMS) as a light yellow
oil after an aqueous citric acid workup followed by extrac-
tion with ethyl acetate. However, the isolated product
appears to degrade rapidly when left on the bench at
room temperature, the light yellow oil turning to a dark
brown color overnight. The decomposition may not be
due to hydrolysis and could rather be the results of
photodegradation.10 Given the limited stability of the
isolated carbonyl imidazole and the reactive nature of this
activated carbonyl, we decided to trap the intermediate
formed in situ with benzyl amine in order to obtain an
accurate isolated yield for this process (Table 2). Other
nucleophiles were also used with diethylmalonic acid as the
a In situ conversion measured by GCMS referenced against residual
malonic acid. b Isolated yield. c Only a mixture of bis-carbonyl imidazole
and 1-carboxylate-10-carbonylimidazole was observed. d An attempt to
trap 9a with benzyl amine yielded a mixture of desired product and
competitive Michael adduct side product. e Isolated pure product sepa-
rated by chromatography. Alternative reaction conditions were not
investigated.
(6) 1H NMR tube reaction.
(7) To the best of our knowledge, there is only one report of this
reaction in the literature, but no details or comments are provided for
this specific step: Connolly, T. J. U.S. Patent 0 269 342, 2008.
(8) An inverted graduated cylinder in a water bath was used. Pressure
stabilizes after 90 min. Parameters: n = 6.24 mmol, T = 292.5 K, p =
101.3 Kpa.
starting material to synthesize a variety of functionalized
end products in an efficient one-pot reaction (Table 3).
We were pleased to observe that the reaction proceeds
smoothly across a range of alkyl-, alkyl(aryl)-, aryl-, and
(9) Zamarella, S.; Stromberg, R. Eur. J. Org. Chem. 2002, 15, 2663.
(10) Iwasaki, S. Helv. Chim. Acta 1976, 59, 2753.
Org. Lett., Vol. 13, No. 9, 2011
2323

Diethylmalonic acid 1 was converted easily (Table 3) to
the carboxylic acid (entry 1), tert-amyl ester (entry 2),
Weinreb amide (entry 3), sulfonamide (entry 4), and
β-keto ester (entry 5) using a variety of conditions in a
practical one-pot process.
Table 3. Trapping of the Carbonyl Imidazole Intermediate with
Various Nucleophiles
We initially postulated a simple reaction mechanism
ressembling the known decarboxylation mechanism of
malonic acid derivatives,13 where an intermediate enolate
is formed through an intramolecular proton transfer. In
the case of the carbonyl imidazole, resonance stabilization
from the imidazole moiety could have explained the faster
rate compared to malonic acids (Scheme 3).
Scheme 3. Intramolecular Proton Transfer
However, when the bis-carbonyl imidazole of diethyl-
malonic acid (prepared from treatment of diethylmalonyl
dichloride with imidazole) was hydrolyzed under different
conditions (acidic, neutral and basic), only the diethylma-
lonic acid was recovered and no decarboxylated product
was formed. This suggested that monoactivation of one
carboxylic acid group to the carbonyl imidazole, followed
by a decarboxylation step as depicted in Scheme 3, was not
the actual mechanism of the reaction. In addition, the
resonance interaction from N-1 to the carbonyl carbon
(Scheme 3, structure B) has been shown to be very weak,14
with the imidazole group having a net negative charge on
theN-3atom. Thesefindingsarealsosupportedbya recent
report15 presentingthe synthesis of malonic monocarbonyl
(alkyl)imidazole and benzimidazole (similar to structure A
in Scheme 3) that were isolated in good yields without
degrading via decarboxylation to the activated carboxylic
acid. To account for the results obtained for the bis-
carbonyl imidazole control reactions, as well as the dec-
arboxylationrateobservedwhen usingavarietyofmalonic
acid starting materials (Table 2), we propose a mechanism
that involves the formation of a ketene intermediate that is
quickly trapped by the imidazole free base to form the
carbonyl imidazole 15 (Scheme 4). Considering that ketene
a In situ conversion measured by GCMS.
cycloalkylmalonic acid derivatives (Table 2, entries 1ꢀ7).
To our surprise, the rate of the key decarboxylation step is
independent of the nature of the malonic acid structure at
room temperature. For example, the first-order rate con-
stant for the thermal decarboxylation of phenylmalonic acid
in water compared to malonic acid is approximately 100
times higher.11 Despite numerous attempts to carry out the
decarboxylative activation of cyclopropane dicarboxylic
acid (Table 2, entry 8), we were unable to detect the presence
of the carbonyl imidazole product or the trapped benzyl
amine product, even at slightly higher temperature (45 °C).
Cinnamylidenemalonic acid (Table 2, entry 9) was found to
decarboxylate smoothly under the reaction conditions to
generate 93% in situ yield of the corresponding carbonyl
imidazole. Fluoromalonic acid (Table 2, entry 10) did
produce the desired product in low yield as a mixture with
a N-N0-dibenzylurea side product, which could be explained
by the poor solubility of the intermediates in THF.12 We
believe that as the reaction progresses, the free base imida-
zole generated during the process forms a salt with the
unreacted malonic acid that precipitates and prevent full
reaction conversion. This leaves unreacted CDI that gets
trapped by benzyl amine to generate the urea side product.
exhibits a strong characteristic IR signal around 2100 cmꢀ1
,
we attempted to detect the ketene intermediate by mon-
itoring a reaction using ReactIR. Although we were unable
to directly observe the ketene peak, we postulated that this
intermediate would be trapped as it forms by the free
imidazole, which would prevent it from accumulating in
(12) The reaction was also tried in DCM and DMF, but the yield
remains moderate. Factors other than solubility could be involved.
(13) Bach, R. D.; Canepa, C. J. Org. Chem. 1996, 61, 6346.
(14) Fife, T. H.; Natarajan, R. J. Org. Chem. 1987, 52, 740 and
references cited therein.
(11) Gelles, E. J. Am. Chem. Soc. 1954, 75, 6199.
(15) Chatterjee, S.; Charles, G. Y. Tetrahedron Lett. 2010, 51, 1139.
2324
Org. Lett., Vol. 13, No. 9, 2011

(1330 cmꢀ1) and CO2 gas (2340 cmꢀ1) are leveling out
within this short period of time.18
Scheme 4. Proposed Reaction Mechanism
The ketene intermediate 14(Scheme4) can be formedvia
two different paths. In path a, intermediate 12 would
undergo a cascade type decarboxylation that would se-
quentially generate 2 mol equiv of carbon dioxide and 1
mol equiv of imidazole. Such a mechanism is similar to the
ketene formation from 2-bromoisobutyryl bromide
(Scheme 5), where the enolate species generated from
bromide reduction is unstable and driven to the ketene
product by the leaving group expulsion from the carbonyl.
In path b, an intramolecular cyclization of 12 could take
place to generate the cyclotrione intermediate 13,19 which
would then undergo a concerted bis-decarboxylation di-
rectly to the ketene intermediate. A similar mechanism was
postulated to account for the formation of a related imino
ketene intermediate,20 presumably formed by pyrolytic
concerted expulsion of acetone and CO2 from a Meldrum’s
acid hydrazone derivative. Finally, the seemingly sharp
difference in reactivity between 7 and 8 could be explained
by the known propensity of the cyclobutane system to
stabilize exocyclic enolate, due to the R-carbon having
intermediate sp2/sp3 hybridization.21
In summary, we have developed a novel decarboxyla-
tive activation of malonic acid derivatives with CDI that
proceeds in near quantitative yield under unusually mild
conditions. The carbonyl imidazole thus formed can be
trapped with a variety of nucleophiles in an efficient
one-pot process. Although we could not directly observe
the ketene intermediate postulated, cumulative observa-
tions suggest a mechanism going through this key
intermediate.
thereactor andgenerating astrongsignal. Thisassumption
was confirmed by preparing dimethyl ketene (Scheme 5)
using a known method16 and reacting it with 1 mol equiv of
imidazole in THF at room temperature. The sharp peak at
2120 cmꢀ1 was completely consumed in less than 2 min.
Scheme 5. Dimethyl Ketene Formation
Acknowledgment. The authors thank the following Pfi-
zer colleagues: Juan Colberg and Stephane Caron for
helpful suggestions and discussions, and the SEG group
for analytical support.
The quick trapping of the ketene intermediate as it forms is
also consistent with the fact that none of the side products
typically associated with ketene formation, such as ketene
dimer or trimer,17 are formedinthisreaction. Interestingly,
the ReactIR results for the reaction of diethylmalonic acid
with CDI suggest that the reaction is completed in less than
5 min at room temperature, as both starting materials get
completely consumed and the formation of free imidazole
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) 1,3-Dioxane-2,4,6-triones are an unstable species that have only
been reported in theoretical studies as a hydrogen bond acceptor: Zue,
L.; Teng, Q. Chin. J. Struct. Chem. 2006, 25 (2), 143.
(20) Briehl, H.; Lukosch, A. J. Org. Chem. 1984, 49, 2772.
(21) Eames, J.; Coumbarides, G. S. Eur. J. Org. Chem. 2003, 634.
(16) Baigrie, L. M.; Lenoir, D. J. Org. Chem. 1985, 50, 2105.
(17) Hoffmann, M. R.; Eggert, U. J. Org. Chem. 1989, 54, 6096.
(18) Carbon dioxide concentration gets lower as off-gasing takes
place over a period of about 90 min.
Org. Lett., Vol. 13, No. 9, 2011
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