Palladium-catalyzed decarboxylative cyanation of aromatic carboxylic acids using [13C] and [14C]-KCN

Article abstract of DOI:10.1002/jlcr.3330

The development of robust and straightforward methods to efficiently label aromatic moieties starting from simple and convenient radio-synthetic sources still represents a considerable challenge. In this report, a new palladium-catalyzed decarboxylative cyanation protocol has been described. This procedure utilizes [¹⁴C]-labeled potassium cyanide, one of the simplest and commercially available sources of carbon-14. Under the optimized reaction conditions, a series of [¹³C] and [¹⁴C]-aromatic nitriles were easily prepared (12-74% yield starting from potassium cyanide). The usefulness of this methodology is highlighted by a rare example of a formal two-step [¹²C]-[¹⁴C] carbon isotope exchange. The current synthetic approach may represent a promising alternative to traditional preparations of relevant building blocks such as labeled aromatic nitriles.

Full text of DOI:10.1002/jlcr.3330

Research article
Received 17 March 2015,
Revised 29 June 2015,
Accepted 29 July 2015
Published online 28 August 2015 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3330
Palladium-catalyzed decarboxylative cyanation
13
of aromatic carboxylic acids using [ C] and
14
[ C]-KCN
*
Olivier Loreau, Dominique Georgin, Frédéric Taran, and Davide Audisio
The development of robust and straightforward methods to efficiently label aromatic moieties starting from simple and
convenient radio-synthetic sources still represents a considerable challenge. In this report, a new palladium-catalyzed
decarboxylative cyanation protocol has been described. This procedure utilizes [14C]-labeled potassium cyanide, one of
the simplest and commercially available sources of carbon-14. Under the optimized reaction conditions, a series of [13C]
and [14C]-aromatic nitriles were easily prepared (12–74% yield starting from potassium cyanide). The usefulness of this
methodology is highlighted by a rare example of a formal two-step [12C]–[14C] carbon isotope exchange. The current
synthetic approach may represent a promising alternative to traditional preparations of relevant building blocks such as
labeled aromatic nitriles.
Keywords: isotopic labeling; carbon; cyanide; cyanation; palladium catalyzed; carbon isotope exchange
Reagents (Val de Reuil, France) or VWR Chemicals (Fontenay-sous-Bois,
Introduction
France). Silica gel 60 (40–63 μm) for column chromatography was from
Aromatic nitriles are highly important intermediates in organic Merck (Darmstadt, Germany). Potassium [13C]cyanide (99% isotopic
enrichment) and NMR solvents were from Euriso-Top (Saint Aubin,
France). Potassium [14C]cyanide with low specific activity was prepared
from unlabeled KCN, and potassium [14C]cyanide (specific activity:
31.6 MBq mgÀ1) from Quotient Bioresearch (Cardiff, UK). NMR spectra
synthesis as well as relevant building blocks frequently
encountered in pharmaceutical and agrochemical industrial
compounds.1 As a direct consequence, the preparation of
carbon-14-labeled aryl nitriles has drawn much attention over
the years.2 To date, several methods exist to prepare aryl nitriles,
the most conventional being the Sandmeyer and the
Rosenmund-von Braun reactions.3 More recently, transition
metal-catalyzed cyanation of aryl halides has become a valuable
alternative to traditional methods, allowing the use of milder
reaction conditions and a broader functional group tolerance.4
were measured on
a Bruker Avance 400 spectrometer (Bruker
Wissembourg, France), and chemical shifts (δ) are given in parts per
million. Mass spectra were obtained by gas chromatography/mass
spectrometry analyses on an HP 6890 Series gas chromatograph system
(Hewlett-Packard, Les Ulis, France) coupled to an HP 5973 mass selective
detector. Liquid scintillation analysis was performed on a Wallac 1409
counter using Ultima Gold cocktail from Perkin-Elmer (Waltham, MA).
In 2010, our group published
a
palladium-catalyzed
decarboxylative cyanation of aromatic carboxylic acids.5,6 This
methodology was successfully applied to the synthesis of [13C] General procedure for the synthesis of labeled aryl nitriles
and [14C]-arene nitriles. Although the protocol proved satisfactory, (method A)
the use of [14C]-cyclohexanone cyanohydrin7 as cyanide source
Labeled potassium cyanide (0.5 mmol, 1 eq), arene carboxylic acid
was necessary for the success of the reaction. Although the
(1 mmol, 2 eq), Ag2CO3 (3 mmol, 6 eq), and Pd(OCOCF3)2 (0.2 mmol,
preparation of [14C]-cyanohydrins from [14C]-KCN is straightforward,
40 mol%) were suspended in DMF-DMSO (95:5, 10 mL) under air. The
the storage and manipulation of [14C]-cyanohydrins is not easy that
flask was connected to a reflux condenser, and the reaction mixture
was heated to 120 °C for 3 h. After cooling, the reaction mixture was
poured into AcOEt and filtered. The filtrate was sequentially washed with
is a clear limitation to our previously described procedure.
Looking for a more direct [14C]-cyanation protocol, we
decided to further investigate this transformation. In this an aqueous NaHCO3 solution (1 M) and H2O then dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (heptane : AcOEt – 80:20) giving the desired
labeled aryl nitrile.
communication, we disclose a straightforward decarboxylative
cyanation of aromatic carboxylic acids using commercially
available K14CN, which is a rare example of a formal two-step
carbon isotope exchange involving [12C]–[12C] bond breaking
and [14C]–[12C] bond formation in the same synthetic process.
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette
F-91191, France
Experimental
*Correspondence to: Davide Audisio, CEA, iBiTecS, Service de Chimie
Bioorganique et de Marquage, Gif sur Yvette, F-91191, France.
E-mail: davide.audisio@cea.fr
Unlabeled starting materials and chemical reagents were purchased from
Aldrich (Saint Quentin Fallavier, France). Solvents were from Carlo Erba
J. Label Compd. Radiopharm 2015, 58 425–428
Copyright © 2015 John Wiley & Sons, Ltd.

O. Loreau et al.
Method B: yellow solid; 34 mg; 67% yield from K13CN, isotopic
enrichment: 99% (based on K13CN).
General procedure for the synthesis of labeled aryl nitriles
(method B)
1H NMR (400 MHz, CDCl3): δ = 7.59 (t, J = 7.4 Hz, 2H), 7.73 (t, J = 7.4 Hz,
2H), 8.09 (d, J = 8.6 Hz, 2H), 8.43 (d, J = 8.6 Hz, 2H), 8.69 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ = 117.18 (13C-enriched). MS (EI): m/z = 204 (100, [M]+).
Labeled potassium cyanide (0.25 mmol, 1 eq), arene carboxylic acid
(1 mmol, 4 eq), Ag2CO3 (3 mmol, 12 eq), and Pd(OCOCF3)2 (0.2 mmol,
0.8 eq) were suspended in DMF-DMSO (95:5, 10 mL) under air. The flask
was connected to a reflux condenser, and the reaction mixture was
heated to 120 °C for 3 h. After cooling, the reaction mixture was treated
and purified as described earlier.
[14C-Cyano]-3,6-dichloro-2-methoxybenzonitrile ([14C]-2e)
Method B: white solid; 14 MBq; 12% yield from K14CN (462.2 MBq mmolÀ1
based on K14CN, 7.1 MBq mgÀ1, 17 mg, 120.7 MBq).
1H NMR (400 MHz, CDCl3): δ = 4.09 (s, 3H), 7.21 (d, J = 8.7 Hz, 1H), 7.53
(d, J = 8.7 Hz, 1H). MS (EI): m/z = 201 (100, [M]+).
[13C-Cyano]-2,4-dimethoxybenzonitrile ([13C]-2a)
Method A: white solid; 56 mg; 68% yield from K13CN, isotopic
enrichment: 98.3% (based on MS-EI+).
Procedure for the synthesis of labeled 2,4-dimethoxybenzoic
acid
1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3H), 3.92 (s, 3H), 6.46 (s, 1H), 6.52
(dd, J = 2.1, 8.6 Hz, 1H), 7.48 (dd, J = 5.6, 8.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ = 116.91 (13C-enriched). MS (EI): m/z = 164 (100, [M]+).
Labeled 2,4-dimethoxybenzonitrile (41.5 mg of [13C]-2a or 110.3 MBq of
[
14C]-2a) was reacted overnight at 80 °C with an aqueous KOH solution
[14C-Cyano]-2,4-dimethoxybenzonitrile ([14C]-2a)
Method A: white solid; 110.3 MBq; 74% yield from K14CN
(307.1 MBq mmolÀ1 based on [14C]-3a, 4.4 MBq mgÀ1, 34 mg, 149.6 MBq).
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3H), 3.90 (s, 3H), 6.46 (d,
J = 2.2 Hz, 1H), 6.52 (dd, J = 2.4, 8.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H). MS
(EI): m/z = 163 (100, [M]+).
[13C-Cyano]-2,6-dimethoxybenzonitrile ([13C]-2b)
Method A: white solid; 61 mg; 74% yield from K13CN, isotopic
enrichment: 99% (based on K13CN).
1H NMR (400 MHz, CDCl3): δ = 3.91 (s, 6H), 6.55 (dd, J = 1.4, 8.5 Hz, 2H),
7.44 (t, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 114.03 (13C-enriched).
MS (EI): m/z = 164 (100, [M]+).
[13C-Cyano]-2,6-dimethoxynicotinonitrile ([13C]-2c)
Method A: white solid; 31 mg; 37% yield from K13CN, isotopic
enrichment: 99% (based on K13CN).
Method B: white solid; 21 mg; 51% yield from K13CN.
1H NMR (400 MHz, CDCl3): δ = 3.97 (s, 3H), 4.04 (s, 3H), 6.36 (d,
J = 8.3 Hz, 1H), 7.69 (dd, J = 5.2, 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ = 116.05 (13C-enriched). MS (EI): m/z = 165 (100, [M]+).
[13C-Cyano]-anthracene-9-carbonitrile ([13C]-2d)
Scheme 1. Synthesis of labeled aryl nitriles (isolated yields from K*CN); * labeling
13C or 14C). Method A: K*CN (0.5 mmol), ArCOOH (1 mmol), Ag2CO3 (3 mmol), Pd
(OCOCF3)2 (0.2 mmol). Method B: K*CN (0.25 mmol), ArCOOH (1 mmol), Ag2CO3
(3 mmol), Pd(OCOCF3)2 (0.2 mmol).
(
Method A: yellow solid; 19 mg; 19% yield from K13CN, isotopic
enrichment: 99% (based on K13CN).
Table 1. Optimization of the model reaction
Entry
KCN (mmol)
1a (mmol)
Ag2CO3 (mmol)
Pd(OCOCF3)2 (mmol)
Time (h)
Yield (2a)a,b (%)
1
2
3
4
5
1
1
0.5
0.5
0.25
1 (1 eq)
1 (1 eq)
1 (2 eq)
1 (2 eq)
1 (4 eq)
3 (3 eq)
3 (3 eq)
3 (6 eq)
3 (6 eq)
3 (12 eq)
0.2 (0.2 eq)
0.5 (0.5 eq)
0.2 (0.4 eq)
0.2 (0.4 eq)
0.2 (0.8 eq)
3
3
3
1
3
38
45
79
61
78
aIsolated yield from KCN.
bThis optimization was performed using [12C]KCN.
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O. Loreau et al.
Scheme 2. Carbon exchange procedure; * labeling (13C or 14C). Method A: K*CN (0.5 mmol), 2,4-dimethoxybenzoic acid 1a (1 mmol), Ag2CO3 (3 mmol), Pd(OCOCF3)2
(0.2 mmol).
functionality was necessary;5 nevertheless, electron-rich
(34%, 2 mL) and EtOH (2 mL). After cooling, the reaction mixture was
diluted with water and extracted with diethyl ether. The aqueous fraction
was acidified to pH 2 with a 6N HCl solution and then extracted twice
carboxylic acids as well as heteroaromatic acids were well
tolerated in the transformation, and also halogens provided the
with diethyl ether. The combined organic layers were washed with water
desired product, albeit in rather low yields (2e, Scheme 1).
until washes were of neutral pH, dried over Na2SO4, filtered, and
In contrast to hydrogen isotope exchange techniques,8 [12C]–
concentrated to give labeled 2,4-dimethoxybenzoic acid.
[14C] replacement strategies are more challenging and were only
[13C-Carboxyl]-2,4-dimethoxybenzoic acid ([13C]-3a)
sporadically described.2a,9 We sought to take advantage of our
protocol to develop a formal two-step carbon isotope exchange.
The first step involves the Pd-catalyzed decarboxylative
cyanation reaction, and the second step the hydrolysis of the
White solid; 37 mg; 80% yield from [13C]-2a, isotopic enrichment: 99%
(based on K13CN).
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3H), 4.05 (s, 3H), 6.54 (s, 1H), 6.65
(dd, J = 2.2, 8.8 Hz, 1H), 8.14 (dd, J = 4.5, 8.8 Hz, 1H). 13C NMR (100 MHz, corresponding labeled nitrile to reconstruct the carboxylic acid
CDCl3): δ = 165.66 (13C-enriched). MS (EI): m/z = 183 (100, [M]+).
starting material. To validate this strategy, 2,4-dimethoxybenzoic
[14C-Carboxyl]-2,4-dimethoxybenzoic acid ([14C]-3a)
acid 1a was used as model substrate. As anticipated, the formal
carbon isotopic exchange was successfully performed with an
White solid; 80.6 MBq; 73% yield from
307.1 MBq mmolÀ1 (based on MS EI+).
[
14C]-2a, specific activity:
overall 54% yield for both carbon-13 and À14 isotopes
(Scheme 2).
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3H), 4.05 (s, 3H), 6.54 (d,
J = 2.2 Hz, 1H), 6.66 (dd, J = 2.2, 8.8 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H). MS
(EI): m/z = 182 (100, [M]+).
Conclusions
We have developed a palladium-catalyzed decarboxylative
cyanation of aromatic carboxylic acids that allows the synthesis
of [13C] and [14C]-labeled nitrile derivatives. This protocol utilizes
[14C]-labeled potassium cyanide, one of the simplest
commercially available sources for radio-synthesis. The
usefulness of this methodology was showcased by a successful
example of carbon isotope exchange in two steps with 54%
overall yield.
Results and discussion
In order to improve the applicability of our previously developed
palladium-catalyzed decarboxylative cyanation, we decided to
use [14C]-KCN as isotopic cyanide source on the model substrate
1a. Potassium cyanide is one of the simplest [14C]-labeled
starting materials, commercially available, and a very convenient
source for radio-synthesis.
An initial attempt using 1 mmol of KCN, 1 mmol of 2,4-
dimethoxybenzoic acid 1a, 3 mmol of silver carbonate, and
20 mol% of palladium(II) trifluoroacetate in 10 mL of DMF-DMSO
(95/5) allowed the isolation of 2,4-dimethoxybenzonitrile 2a with
a moderate yield of 38% (Table 1, entry 1). Taking into
consideration the poisoning effect of cyanide on the palladium
catalysts, we decided to increase the amount of Pd(OCOCF3)2.
Carrying out the reaction with 50 mol% of the palladium catalyst
only slightly ameliorated the yield of the transformation, and 2a
was isolated in 45% yield (Table 1, entry 2). The reaction was
successfully improved by increasing the amount of the
carboxylic acid substrate in the reaction mixture. With 2 eq of
1a (Table 1, entry 3) and 40% of catalyst loading, the
corresponding aryl nitrile 2a was isolated in satisfying 79% yield.
Acknowledgements
The authors thank Céline Puente and David-Alexandre Buisson
(CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage)
for liquid scintillation measurements.
Conflict of interest
The authors did not report any conflict of interest.
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J. Label Compd. Radiopharm 2015, 58 425–428