Direct reversible decarboxylation from stable organic acids in dimethylformamide solution

Article abstract of DOI:10.1126/science.abb4129

Many classical and emerging methodologies in organic chemistry rely on carbon dioxide (CO₂) extrusion to generate reactive intermediates for bond-forming events. Synthetic reactions that involve the microscopic reverse-the carboxylation of reactive intermediates-have conventionally been undertaken using very different conditions. We report that chemically stable C(sp³) carboxylates, such as arylacetic acids and malonate half-esters, undergo uncatalyzed reversible decarboxylation in dimethylformamide solution. Decarboxylation-carboxylation occurs with substrates resistant to protodecarboxylation by Br?nsted acids under otherwise identical conditions. Isotopically labeled carboxylic acids can be prepared in high chemical and isotopic yield by simply supplying an atmosphere of ¹³CO₂ to carboxylate salts in polar aprotic solvents. An understanding of carboxylate reactivity in solution enables conditions for the trapping of aldehydes, ketones, and a,b-unsaturated esters.

Full text of DOI:10.1126/science.abb4129

REPORTS
Cite as: D. Kong et al., Science
10.1126/science.abb4129 (2020).
Direct reversible decarboxylation from stable organic acids
in dimethylformamide solution
Duanyang Kong*, Patrick J. Moon*, Erica K. J. Lui, Odey Bsharat, Rylan J. Lundgren†
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
*These authors contributed equally to this work. †Corresponding author. Email: rylan.lundgren@ualberta.ca
Many classical and emerging methodologies in organic chemistry rely on CO2 extrusion to generate reactive
intermediates for bond-forming events. Synthetic reactions that involve the microscopic reverse, the
carboxylation of reactive intermediates, have conventionally been undertaken using very different
conditions. We report that chemically stable C(sp3) carboxylates, such as arylacetic acids and malonate
half-esters, undergo uncatalyzed reversible decarboxylation in dimethylformamide solution.
Decarboxylation/carboxylation occurs with substrates resistant to protodecarboxylation by Brønsted acids
under otherwise identical conditions. Isotopically labeled carboxylic acids can be prepared in high chemical
and isotopic yield by simply supplying an atmosphere of 13CO2 to carboxylate salts in polar aprotic solvents.
An understanding of carboxylate reactivity in solution enables conditions for the trapping of aldehydes,
ketones, and α,β-unsaturated esters.
Decarboxylation is a fundamental step in biochemical pro- carboxylic acids are restricted to specialized substrate/medi-
cesses and synthetic organic chemistry. Fermentation, respi- ator pairs (20, 21). Exchange of carboxylate groups in simple
ration, and the biosynthesis of many secondary metabolites aliphatic acids with CO2 has been documented, but requires
involve the loss of CO2 from organic acids (1, 2). Decarbox- heating of neat substrates at 280–400°C (22, 23). Nonethe-
ylase enzymes accelerate these reactions by stabilizing devel- less, in the course of our studies on catalytic decarboxylative
oping intermediates (typically carbanions) and promoting cross-coupling reactions (24, 25), we questioned whether the
CO2 diffusion from the active site, thereby enabling otherwise apparent stability of organic carboxylates could arise from re-
unfeasible decarboxylations to occur under physiological versible decarboxylation/carboxylation events in solution.
conditions (Fig. 1A) (3, 4). Acid substrates lacking strong an- Supporting this hypothesis, we observed that certain simple
ion-stabilizing groups adjacent to the reactive carbon center organic acids that are stable toward protodecarboxylation in
have been construed to be inert toward spontaneous decar- solution undergo spontaneous incorporation of 13CO2 when
boxylation without resorting to thermolysis conditions (Fig. this heavier isotope is supplied at atmospheric pressure (Fig.
1B) (5). As a result, synthetic reactions driven by decarboxy- 1C).
lation are often carried out using high reaction temperatures
(6), added oxidizing agents (7, 8), or prior stoichiometric versible decarboxylation/carboxylation behavior of otherwise
chemical modification of the carboxylate unit (9–12). chemically stable carboxylic acids. A 0.1 M solution of 1 in
The potassium salt of arylacetic acid 1 exemplifies the re-
Carboxylation reactions, the microscopic reverse of decar- dimethylformamide (DMF) at 20°C underwent CO2 exchange
boxylations, are equally valuable processes in biology and when placed under an atmosphere of 13CO2. In a reaction
13
synthetic chemistry. Despite the possibility of a shared reac- where approximately six equivalents of CO2 were supplied
tion pathway, the biochemical machinery that promotes car- (13 mL of CO2 at ~1 atm, dissolved [CO2] = 0.20 M), equilib-
12
13
boxylation in CO2 fixation pathways operates with a distinct rium between C and C was achieved in 15 hours (Fig. 1C,
set of substrates and enzymes from those that promote de- red trace). Quantitative recovery of carboxylate 1 with 83%
carboxylation in all but a few cases (13–17). Similarly, syn- 13C-enrichment was possible by acid/base extractive workup.
thetic techniques that generate carboxylic acid derivatives Under similar conditions at 20°C with five equivalents of a
from CO2 have tended to apply strongly nucleophilic organo- weak Brønsted acid (MeOH) no protodecarboxylation of 1
metallics and/or in-situ stoichiometric (electro)chemical sub- was observed (Fig. 1C, black trace). These results demonstrate
strate reduction (18, 19).
that capture of the putative nucleophilic intermediate gener-
The potential for the reversibility of decarboxylation/car- ated from 1 with dissolved CO2 is significantly more favorable
boxylation mechanisms is largely ignored in reports of syn- than protonation. The process tolerates up to 0.01 M H2O and
thetic methodologies that rely on these elementary steps. does not require rigorous exclusion of air (see fig. S2). During
Reports of direct non-enzymatic reversible CO2-exchange of the review of this work, isotopic exchange of carboxylate
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groups in cesium arylacetic acid salts with 14C-, 13C-, and 11C- 10), ketones (11), aldehydes (12), esters (14), amides (13), sul-
labeled CO2 in DMSO at 80–190°C was reported (26). fonyls (15), and potentially reactive heterocycles (chrome-
The counter-cation of the carboxylate salt impacts carbox- none 25, NH-indole 26, pyridines 27, 29, pyrimidine 28,
ylate exchange reactivity (Fig. 1D). The carboxylic acid of 1 isoxazole 30, thiophene 31). Alkyl and aryl substitution adja-
13
manifested no evident CO2 exchange or protodecarboxyla- cent to the carboxylate was tolerated, including examples of
tion in DMF at 70°C. Li+ and Na+ salts of 1 reacted more trisubstituted, non-enolizable arylacetic acid salts (23, 24).
slowly, while the Cs+ salt reacted more quickly. Divalent Other classes of potassium carboxylates that underwent re-
metal salts of 1 (Zn2+ or Cu2+) were inert and the addition of versible decarboxylation include malonate half-esters (32-
M2+Cl2 salts completely inhibited the reaction (MgCl2, CaCl2,
35), keto acids (36), β-carboxysulfonyls (37, 38), cyanoace-
MnCl2, see fig. S3). The use of polar aprotic solvents (DMF,
tates (39), and carboxylactams (40). Alkene and terminal al-
DMA, DMSO; dielectric constant ε > 30) is essential for the kyne functional groups did not interfere with the process (34,
transformation: reactions conducted in THF, DCE, or water 35). Potassium malonates underwent CO2 exchange at higher
resulted in recovery of unlabeled 1 at 20°C. The addition of temperature (135°C) to give a mixture of mono- and doubly-
18-crown-6 (18-C-6) led to an approximate two-fold rate en- labeled product along with 13C-enriched monoacid (41, 42).
hancement of carboxylate exchange (see fig. S4) (27). The free
Carboxylate exchange could also be used to directly pre-
acid underwent carboxylate exchange when 1.5 equivalents of pare isotopically labeled drug molecules, including arylacetic
K2CO3 and 18-C-6 were added (>90% yield and 13C incorpora- acid salts and propionate NSAIDs of varying complexity (43-
tion in 19 hours). Collectively, these observations suggest that 52, Fig. 2). Pharmaceuticals featuring amide or ester groups
the generation of a solvent-separated ion pair leads to en- were obtained via derivatization of the acid group (Zolpidem
hanced decarboxylative reactivity.
53, Aprofene 55) or could be prepared according to estab-
Reversible decarboxylation occurred for an array of car- lished literature protocols (Propiverine 54, Netupitant 56,
boxylate containing molecules that contain adjacent aryl, car- Repaglinide 57). Consistent with the generation of a carban-
bonyl, cyano, or sulfonyl groups, including valuable synthetic ion, racemization of enantiopure Naproxen (46) was ob-
precursors, drug molecules, and amino acid derivatives (Fig. served (fig. S6). Reversible decarboxylation may explain
2). The incorporation of 13CO2 and product recovery remained reports of aryl propionate racemization required for kinetic
high (>80%) across several substrate classes. The degree of resolution manufacturing processes (36, 37). Simple alkyl car-
incorporation is largely a function of the amount of 13CO2 sup- boxylates did not undergo CO2 exchange; however isotopi-
plied: >95% enrichment can be obtained when ~50 equiva- cally labeled products of this class can be readily obtained by
lents is provided (see fig. S5). For successful cases, this
carboxylate exchange process compares favorably in terms of
operational simplicity to current state-of-the-art methods to
prepare C(sp3)–13/14CO2 labeled carboxylic acid-derivatives
sought after in (pre)clinical absorption, distribution, metab-
olism, and excretion (ADME) studies (28). Reported ap-
proaches require either chemical activation-decarboxylation-
metalation-carboxylation sequences mediated by transition
metals (29–31), indirect nucleophilic substitution reactions
with labeled cyanide followed by hydrolysis (32), or introduc-
tion of labeled carbon monoxide in place of CO2 (33, 34). The
direct exchange of C(sp2)-carboxylate groups catalyzed by
transition metals has been demonstrated; however, reactivity
is restricted to nitro- or sulfonyl-containing arenes or 2-het-
eroatom substituted electron-rich heterocycles at high tem-
perature (≥150°C) (35).
carboxylate exchange/desulfonylation reactions of β-sulfonyl
acids or exchange/decarboxylation sequences of malonic ac-
ids in three steps (58–60). The facile generation of 13C-diphe-
nylmethylidene glycine at room temperature (61 93%
incorporation, 76% yield) serves as a starting point for the
synthesis of other labeled amino acids (38).
The reversible CO2 exchange process likely involves the
formation of a carbon nucleophile either from direct decar-
boxylation, or potentially in the case of enolizable substrates,
through an enolate intermediate. The reaction rates and re-
quired temperatures for 12CO2/13CO2 interconversion correlate
with the substrate’s capacity to stabilize negative charge and
not with oxidation potential (compare 1, 14, 16, and 17). The
addition of radical inhibitors (TEMPO, BHT) had no impact
on the decarboxylative reactivity of 1 nor was cyclization of
the pendant olefin in 34 detected.
(Hetero)arylacetic acid salts with anion-stabilizing groups
underwent exchange at moderate temperatures (Fig. 2, 1–4,
9, 10, 11–15 at 20 to 80°C), whereas arylacetates with
strongly electron-donating OMe or NMe2 groups required
higher temperatures (17–20 at 100 to 130°C) and benefitted
from the addition of 18-C-6. The simplicity of the process en-
abled broad functional group compatibility, including toler-
ance to boronic esters (6), aryl halides (I, Br, Cl, F; 4, 7, 8,
Exchange of CO2 via carbanion equivalents without com-
peting quenching by other electrophiles (ketones, aldehydes,
weak Brønsted acids) likely stems in part from the relatively
high solubility of CO2
in DMF and the slow kinetics of CO2
evaporation into the reaction vessel headspace. For example,
a 0.25 M solution of 13CO2 in DMF retains a concentration of
0.2 M under a headspace of N2 over one day (measured by 13C
NMR). For substrate 1 the rate of CO2 exchange at 70°C was
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2

~10-fold faster than for reaction with benzaldehyde. Perhaps reactions. The potential for reversible decarboxylation should
counterintuitively, the rate of protodecarboxylation by weak be considered more generally when designing and executing
Brønsted acids is inversely related to acidity (Fig. 3A, in order decarboxylative functionalization processes.
of decreasing rate of protonolysis: piperidine, aniline, meth-
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ACKNOWLEDGMENTS
We thank A. Speed for analysis of this manuscript and experimental suggestions. We
thank J. Takats for the gift of 13CO2 to initiate this project and B. Reiz for
assistance in mass spectrometry data analysis. Funding: Support was provided
by NSERC Canada (RGPIN-2019-06050, RGPAS-2019-00051) the Canadian
Foundation for Innovation (IOF 32691), the University of Alberta, and the Killam
Trusts Author contributions: P.J.M. and R.J.L. conceived the study.
Experiments and data analysis were conducted by D.K., P.J.M, E.J.K.L, and O.B.
The manuscript was written by R.J.L. with consultation from all co-authors.
Competing interests: P.J.M. and R.J.L. (University of Alberta) are pursuing a
provisional patent on this work. Data and materials availability: All
experimental data are available in the supplementary materials.
SUPPLEMENTARY MATERIALS
science.sciencemag.org/cgi/content/full/science.abb4129/DC1
Materials and Methods
Figs. S1 to S9
HRMS and NMR Spectra
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Fig. 1. Overview of decarboxylative processes and carboxylate exchange. (A) Decarboxylation
catalyzed by enzymes under physiological conditions (PDB ID: 2INF). (B) Comparison of conditions
used for thermal decarboxylation of different substrates. (C) Comparison of CO2 exchange (red) and
protonation with MeOH (black) for 4-cyanophenylacetate (1). (D) Impact of salt and reaction
conditions. E+, electrophile; DMF, dimethylformamide; THF, tetrahydrofuran; DCE, 1,2-
dichloroethane; DMSO, dimethylsulfoxide; DMA, dimethylacetamide; 18-C-6, 18-crown-6.
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5

Fig. 2. Carboxylate exchange scope and application. Unless noted yields are of isolated material.
*Calibrated 1H NMR spectroscopy yield. †1 Equivalent 18-C-6 added. ‡%13C Incorporation and yield
determined by analysis of the corresponding methyl or benzyl ester. § DMSO used instead of DMF.
See the supplementary materials for complete details. NMR, nuclear magnetic resonance.
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6

Fig. 3. Mechanistic control experiments and electrophile trapping. (A) Relative rates for arylacetic
acid salt protodecarboxylation by Brønsted acids and decarboxylative trapping by benzaldehyde.
(B) Net carboxylate/proton metathesis of 1 in the absence of additional CO2. (C) CO2 transfer
between arylacetic acid salt and alkylarene does not occur. (D) The presence of CO2 accelerates the
rate of methylene C–H/D exchange in 1. (E) Scope examples for the decarboxylative trapping of
alternative classes of electrophiles. See the supplementary materials for complete details and full
reaction conditions. *Yield determined by 1H NMR spectroscopy. Ar, (4-CN)C6H4.
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Direct reversible decarboxylation from stable organic acids in dimethylformamide solution
Duanyang Kong, Patrick J. Moon, Erica K. J. Lui, Odey Bsharat and Rylan J. Lundgren
published online June 18, 2020
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