Decarboxylation with Carbon Monoxide: The Direct Conversion of Carboxylic Acids into Potent Acid Triflate Electrophiles

Article abstract of DOI:10.1002/anie.201814660

We report a new strategy for the conversion of carboxylic acids into potent acid triflate electrophiles. The reaction involves oxidative carbonylation of carboxylic acids with I₂ in the presence of AgOTf, and is postulated to proceed via acyl hypoiodites that react with CO to form acid triflates. Coupling this chemistry with subsequent trapping with arenes offers a mild, room temperature approach to generate ketones directly from broadly available carboxylic acids without the use of corrosive and reactive Lewis or Bronsted acid additives, and instead from compounds that are readily available, stable, and functional group compatible.

Full text of DOI:10.1002/anie.201814660

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Decarboxylation with Carbon Monoxide: The Direct Conversion of
Carboxylic Acids into Potent Acid Triflate Electrophiles
Authors: Bruce Alan Arndtsen and R. Garrison Kinney
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814660
Angew. Chem. 10.1002/ange.201814660
Link to VoR: http://dx.doi.org/10.1002/anie.201814660
http://dx.doi.org/10.1002/ange.201814660

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
Decarboxylation with Carbon Monoxide: The Direct Conversion
of Carboxylic Acids into Potent Acid Triflate Electrophiles
R. Garrison Kinney and Bruce A. Arndtsen*
Abstract: We report a new strategy for the conversion of carboxylic
acids into potent acid triflate electrophiles. The reaction involves
oxidative carbonylation of carboxylic acids with I2 in the presence of
AgOTf, and is postulated to proceed via acyl hypoiodites that react
with CO to form acid triflates. Coupling this chemistry with
subsequent trapping with arenes offers a mild, room temperature
approach to generate ketones directly from broadly available
carboxylic acids without the use of corrosive and reactive Lewis or
Bronsted acid additives, and instead from compounds that are all by
themselves available, stable, and functional group compatible.
combination of these two broadly available reagents: carboxylic
acids and carbon monoxide. There has been significant recent
effort directed towards the replacement of organic halides with
carboxylic acids, giving rise to various transition-metal catalyzed
decarboxylative cross-coupling and related transformations.9 In
contrast, metal catalyzed decarboxylative carbonylations are
rare, and to date limited to the use of alkynyl carboxylic acids or
activated benzylic/allylic carbonate derivatives.10 An intriguing
alternative to metal catalyzed decarboxylations is the
Hunsdiecker reaction, wherein halogenation of carboxylic acids
can lead to decarboxylation to generate aryl halides (Figure
1c).11 This transformation has been recently shown by the
Larossa lab to offer efficient metal free access to aryl halides.12
In addition to generating aryl halides, the aroyl hypohalite
intermediates generated in these systems are themselves
reactive, and can associate with Lewis bases such as pyridine to
form adducts A.13 In this light, we questioned if this platform
might be used in an alternative fashion, where the interception of
the hypoiodite intermediate with carbonylation chemistry could
offer a route to generate high energy acylating agents (Figure
1d). This would both replace aryl halides with carboxylic acids in
carbonylations, and at the same time create a new route to
perform acylation reactions directly from carboxylic acids.
Described below are our efforts to develop this reaction. This
has led to a new, carbonylative approach to convert aromatic
Carboxylic acids are broadly available, low cost, and often
accessible from renewable resources, making them attractive
building blocks in organic synthesis. A classic use of carboxylic
acids is their conversion to other carbonyl-containing derivatives,
including amides, esters and ketones.1 Such acylation reactions
have been estimated to account for 22% of all pharmaceutical
transformations,2 and are also heavily employed in large scale
polymer syntheses and other applications.3 As carboxylic acids
are themselves stable, they must be transformed into reactive
acylating agents, which can lead to limitations.4 The in situ
activation of carboxylic acids with coupling reagents is broadly
employed in esterification and amidation reactions (e.g. with
carbodiimides, hydroxytriazoles; Figure 1a), but these reagents
are synthetic, can present purification challenges, and generate
significant chemical waste. In addition, the modest
electrophilicity of the intermediates in this chemistry limits its
scope. Alternatively, acyl halides are potent electrophiles
capable of rapid reaction with a diverse array of nucleophiles.5
Their preparation in this case requires the use of high energy
and caustic reagents such as thionyl chloride, oxalyl chloride, or
PCl3, none of which are desirable in synthesis, and can lead to
significant difficulty when used on large scale. These features
have made more efficient acylation protocols a high priority,
especially as we move towards creating more efficient, less
waste-intensive syntheses.6
An alternative approach for the preparation of carboxylic acid
derivatives is the carbonylation of organic halides (Figure 1b).7
These reactions typically exploit transition metal catalysis to
incorporate carbon monoxide, a stable and abundant C1
building block, into a variety of carbonyl-containing products.
This includes research in our lab and others that has
demonstrated that acyl halide and even potent acyl triflate
electrophiles can be generated from carbonylations.8 A limitation
here is the required use of aryl- or vinyl-halides as reagents.
Although a number of organic halides are commercially available,
they are rarely naturally occurring.
In considering methods to more efficiently access acylating
agents one attractive possibility would be to do so by
[a]
R.G. Kinney and Prof. Dr. B. A. Arndtsen
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, QC, Canada, H3A 0B8
E-mail: bruce.arndtsen@mcgill.ca
Supporting information for this article is given via a link at the end of
the document
Figure 1. Approaches to Carboxylic Acid Activation and Derivatization
This article is protected by copyright. All rights reserved.

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
carboxylic acids directly into electrophilic acid triflates. The
transformation combines the useful features of classical acyl
electrophile synthesis (carboxylic acid reagents), with those of
transition metal catalyzed carbonylations (exploiting broadly
available CO). In addition, the high reactivity of the electrophiles
offers a method to use carboxylic acids in Friedel-Crafts
acylation reactions under mild conditions, and without the
classical use of reactive, caustic reagents.
Our initial studies involved the use of benzoic acid in concert
with I2 as replacement feedstocks for aryl iodides in the
previously reported palladium catalyzed carbonylative synthesis
of acid triflates.8d Thiophene was employed to trap any
electrophile generated to form ketone 1a. After examining a
number of reaction conditions, it was found that reaction of
sodium benzoate and iodine in the presence of CO, silver triflate
and the [Pd(allyl)Cl]2 catalyst leads to ketone 1a in 29% yield
(Table 1, entry 1). Added ligands have only a minimal effect of
the reaction (entries 2-4). In an attempt to further improve the
yield, a simple control experiment was to remove the palladium
catalyst. To our surprise, not only did the reaction still proceed,
but did so as effectively as with palladium (entry 6), and in good
yield at 60 oC (80%, entry 7). Moreover, and in contrast to
previous reports of carboxylic acid iodination, the reaction can
proceed at ambient temperature when starting directly from the
carboxylic acid, and allows the high yield formation of 1a (entry
10).
155.5 ppm), while 19F NMR reveals the presence of the triflate (δ
-77.5 ppm). All other data are consistent with previously
reported 3a.14
Benzoyl triflates are a high energy electrophiles that can
undergo uncatalyzed Friedel-Crafts reactions with a range of
arenes, yet only rarely exploited, presumably due to their
synthesis from also reactive acid chlorides.15 Control
experiments show that carbon monoxide, I2 and AgOTf are all
needed for the formation of 3a (Figure 2a). In order to probe the
role of carbon monoxide in this transformation, the reaction was
performed with 13C-labeled CO (Figure 2b). This leads to no
detectable 13C-label in ketone 1a, and we instead observe the
generation of 13CO2. Alternatively, the use of 13C-labeled benzoic
acid results in the exclusive formation of the 13C-labeled ketone
1a. As such, unlike the Hunsdiecker reaction, decarboxylation
does not occur directly from the hypoiodite, and instead CO is
required to remove the oxygen in this intermediate. Further
control experiments show no reaction between CO, I2 and
AgOTf by themselves, implying that iodine reacts with the
carboxylic acid rather than CO (Figure S1).16 In order to probe
the reactivity of CO with the acyl hypoiodite intermediate, the
pyridine-stabilized adduct
4 was generated via previously
reported procedures.13 As shown in Figure 2c, the addition of
carbon monoxide to 4 does indeed result in its ambient
temperature decarboxylation to generate benzoic anhydride 2a
Table 1. Development of a Decarboxylative Synthesis of Acid Triflatesa
The generation of ketone 1a directly from a carboxylic acid
under such mild reaction conditions, and without a palladium
catalyst, led us to question what electrophilic intermediate is
generated in this system. To probe this, the reaction was
monitored by in situ 1H, 13C, and 19F NMR analysis, which shows
the rapid initial generation of benzoic anhydride 2a within 90 min
at ambient temperature (Figure 2a). This is followed by a slower
conversion of 2a to
a new product 3a that has been
characterized to be benzoyl triflate Of note, 13C NMR analysis of
Figure 2. Mechanistic and Control Experiments.
3a shows a diagnostic carbonyl signal for an aroyl triflate (δ
This article is protected by copyright. All rights reserved.

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
arising from the rapid reaction of in situ generated benzoyl
triflate 3a and 4.
a potent electrophile with reagents (CO, I2, AgOTf) that are each
readily available.
Together, these data are consistent with a mechanism
similar to that shown in Figure 2d. In this, the AgOTf mediated
iodination of benzoic acid allows the formation of hypoiodite
intermediate 6. While 6 can undergo decarboxylation to form
aryl iodide, it is also Lewis acidic at iodine. We therefore
postulate that carbon monoxide can intercept this Hunsdiecker
intermediate via an acid-base adduct 7. The reaction of carbon
monoxide with organic reagents without transition metal
catalysts is rare, especially at ambient temperature. The ability
of 6 to do so presumably reflects its high electrophilicity, as well
as its potential for subsequent rearrangement to 8, followed by
decarboxylation to form aroyl triflate. The latter is in equilibrium
with the observed anhydride prior to complete formation of the
high energy aroyl triflate electrophile.17,18 Overall, this provides
a platform to convert a carboxylic acid under mild conditions into
With a method to generate potent acyl triflate electrophiles
from carboxylic acids in hand, we directed our attention to the
use of this reaction. A wide range of aromatic carboxylic acids
can be converted to aroyl triflates and ketones under these
conditions (Table 2).
Electron neutral and electron rich
substrates react rapidly to generate the corresponding aroyl
triflate at room temperature (1a-1f). Alternatively, electron poor
carboxylic acids require mild heating to 40 °C (1g-1t). Due to
the lack of the transition metal catalyst that is normally used in
decarboxylative coupling reactions, aryl-chloride, -bromide, -
iodide or -triflate functionalities are all compatible with the
reaction (1d-1j). Substituents at all positions of the aromatic ring
are tolerated, including even highly sterically congested 2,6-
disubstituted benzoic acid derivatives (1f-1g). Potentially
Table 2. CO Mediated Synthesis of Ketones from Arenes and Carboxylic Acidsa
This article is protected by copyright. All rights reserved.

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
reactive functionalities can also be incorporated into the
carboxylic acid unit, such as thioether (1f), esters (1k), nitro (1l),
and nitrile (1c, 1m) groups.
We thank NSERC, the Canadian Foundation for Innovation
(CFI), and the FQRNT supported Centre for Green Chemistry
and Catalysis for funding this research
In addition to variation of the carboxylic acid, aroyl triflates
are exceptional electrophiles that offer the ability to functionalize
a wide range electronically diverse arenes. This includes
electron rich benzene derivatives, which react at room
temperature (1u-1cc), and also more deactivated arenes such
as 1,3-dichlorobenzene (1dd) and 1,3,5-trifluorobenzene (1ee)
at elevated temperatures (100 °C). The latter are typically
sluggish in Friedel-Crafts acylation chemistry. Heterocycles can
also be easily functionalized to heteroaryl ketones using this
methodology. Examples include thiophenes (1ll), furans (1jj),
benzothiophene (1kk) and pyrroles (1ii). A feature of this
transformation is its ability to generate ketones directly from
carboxylic acids without multiple synthetic steps, or the use of
high energy, caustic and strongly acidic reagents, and instead
from compounds that are each relatively benign and bench
stable.19 As a result, it is also possible to perform Friedel-Crafts
acylations under basic conditions in the presence of sensitive
functionalities, such as with N-tosyl aniline. The latter undergoes
deprotection under acidic conditions to form various products,20
but is cleanly acylated with the carbonylative reaction (1aa).
Finally, we have explored the application of this chemistry to the
targeted synthesis of Oxybenzone, a UV active reagent found in
a broad array of personal care products, sunscreens, and
plastics as a stablizer.21 In contrast to its classical synthesis from
high energy acid chlorides in the presence of Lewis acid
catalysts (e.g. AlCl3), which can lead to demethylation, 1ll can
be formed directly from benzoic acid using this protocol in high
overall yield.22
Keywords: Carbonylation • Acylation • Decarboxylation•
Iodination • Ketones
Conflict of Interest
The Authors declare no conflict of interest.
[1]
a) A. R. Katritzky, O. Meth-Kohn, C. W. Rees in Comprehensive
Organic Group Transformation, Vol. 5 Pergamon Press: Oxford, U.K.,
1995, pp. 1-229. b) A. El-Faham, F. Albericio, Chem. Rev. 2011, 111,
6557-6602. c) G. Sartori, R. Maggi, Advances in Friedel-Crafts
acylation reactions : catalytic and green processes, CRC Press, Boca
Raton, 2010. d) R. K. Dieter, Tetrahedron 1999, 55, 4177-4236
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451-3479.
B. L. Deopura in Polyesters and Polyamides; B. L. Deopura, R.
Alagirusamy, M. Joshi, B. Gupta, Eds, Woodhead Publishing, Boca
Raton, 2008.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
a) J. R. Dunetz, J. Magano, G. A. Weisenburger, Org. Process Res.
Dev. 2016, 20, 140-177. b) E. Valeur, M. Bradley, Chem. Soc. Rev.
2009, 38, 606-631.
S. G. Nelson Science of Synthesis: Compounds with Four and Three
Carbon Heteroatom Bonds, Vol. 20a (Ed.: J. S. Panek), Thieme,
Stuttgart, 2006.
D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A.
Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411-420.
a) M. Beller, X. F. Wu in Transition Metal Catalyzed Carbonylations –
Carbonylative Activation of C–X Bonds, Springe, Berlin, 2013. b) Y. Li,
Y. Hu, X.-F. Wu, Chem. Soc. Rev. 2018, 47, 172-194.
a) J. S. Quesnel, B. A. Arndtsen, J. Am. Chem. Soc. 2013, 135, 16841-
16844. b) J. S. Quesnel, L. V. Kayser, A. Fabrikant, B. A. Arndtsen,
Chem. Eur. J. 2015, 21, 9550-9555. c) J. Tjutrins, B. A. Arndtsen, J.
Am. Chem. Soc. 2015, 137, 12050-12054. d) R. Garrison Kinney, J.
Tjutrins, G. M. Torres, N. J. Liu, O. Kulkarni, B. A. Arndtsen, Nat.
Chem. 2018, 10, 193-199. e) T. A. Cernak, T. H. Lambert, J. Am.
Chem. Soc. 2009, 131, 3124-3125. For metathesis routes to acid
chlorides: f) X. Fang, B. Cacherat, B. Morandi, Nat. Chem. 2017, 9,
1105. g) M. De La Higuera Macias, B. A. Arndtsen, J. Am. Chem. Soc.
2018, 140, 10140-10144. h) Y. H. Lee, B. Morandi, Nat. Chem. 2018,
10, 1016-1022. i) D. R. Gauthier, N. R. Rivera, H. Yang, D. M. Schultz,
C. S. Shultz, J. Am. Chem. Soc. 2018, 140, 15596-15600.
Scheme 1. Application to the synthesis of Oxybenzone from benzoic acid.
In conclusion, we have described a general approach to
form aroyl triflate electrophiles directly from carboxylic acids.
This proceeds via a carbon monoxide mediated deoxygenation,
wherein carbon monoxide is postulated to intercept the
iodination intermediate of the Hunsdiecker reaction. Overall, this
offers a method to generate a diverse array of aroyl electrophiles
from carboxylic acids under mild conditions with reagents that
are each available and functional group compatible, and could
prove of utility in situations where working with highly Lewis or
Bronsted acidic reagents is undesirable. Studies towards
exploiting this approach to create alternative classes of
carbonyl-containing products are currently underway.
[9]
a) R. Shang, in New Carbon–Carbon Coupling Reactions Based on
Decarboxylation and Iron-Catalyzed C–H Activation, Springer
Singapore, Singapore, 2017, pp. 3-47. b) N. Rodríguez, L. J. Goossen,
Chem. Soc. Rev. 2011, 40, 5030-5048. c) Y. Wei, P. Hu, M. Zhang, W.
Su, Chem. Rev. 2017, 117, 8864-8907. d) J. Xuan, Z.-G. Zhang, W.-J.
Xiao, Angew. Chem. Int. Ed. 2015, 54, 15632-15641. For
representative recent examples: e) Y. Liang, X. Zhang, D. W. C.
MacMillan, Nature 2018, 559, 83-88. f) C. Li, J. Wang, L. M. Barton, S.
Yu, M. Tian, D. S. Peters, M. Kumar, A. W. Yu, K. A. Johnson, A. K.
Chatterjee, M. Yan, P. S. Baran, Science 2017, 7355. g) C. P.
Johnston, R. T. Smith, S. Allmendinger, D. W. C. MacMillan, Nature
2016, 536, 322. h) X. Sun, J. Chen, T. Ritter, Nat. Chem. 2018, 10,
1229-1233. i) W. Zhao, R. P. Wurz, J. C. Peters, G. C. Fu, J. Am.
Chem. Soc. 2017, 139, 12153-12156.
[10] For examples of coupling of alkynyl carboxylic acids:. a) J. Hwang, J.
Choi, K. Park, W. Kim, K. H. Song, S. Lee, Eur. J. Org. Chem. 2015,
2235-2243; b) C.-L. Li, W.-Q. Zhang, X. Qi, J.-B. Peng, X.-F. Wu, J.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
Organomet. Chem. 2017, 838, 9-11. c) W. Kim, K. Park, A. Park, J.
Choe, S. Lee, Org. Lett. 2013, 15, 1654-1657. d) A. Park, K. Park, Y.
Kim, S. Lee, Org. Lett. 2011, 13, 944-947. For examples of
decarboxylative carbonylation of carbamates and carbonates:. e) J J.-X.
Xu, X.-F. Wu, Org. Lett. 2018, 20, 5938-5941. f) J. G. Knight, I. M.
Lawson, C. N. Johnson, Synthesis 2006, 227-230. For other examples:
g) Q.-Q. Zhou, W. Guo, W. Ding, X. Wu, X. Chen, L.-Q. Lu, W.-J. Xiao,
Angew. Chem., Int. Ed. 2015, 54, 11196-11199. h) Z. Zheng, H. Alper,
Org. Lett. 2009, 11, 3278-3281.
[11] a) A. Borodine. Justus Liebigs Ann. Chem. 1861, 119, 121−123. b) H.
Hunsdiecker, C. Hunsdiecker. Ber. Dtsch. Chem. Ges. B 1942, 75,
291−297. c) R. G. Johnson, R. K. Ingham, Chem. Rev. 1956, 56, 219-
269. d) C. Wilson in Organic Reactions; John Wiley & Sons, Inc., New
Jersey, 2011, p 332−387. e) D. Crich, K. Sasaki in Comprehensive
Organic Synthesis II; P. Knochel, G. A. Molander, Eds, Elsevier:
Amsterdam, 2014; pp 818−836.
[12] a) G. J. P. Perry, J. M. Quibell, A. Panigrahi, I. Larrosa, J. Am. Chem.
Soc. 2017, 139, 11527-11536. b) Jacob M. Quibell, G. J. P. Perry, D.
M. Cannas, I. Larrosa, Chem. Sci. 2018, 9, 3860-3865.
[13] H. Hartl, M. Hedrich, Zeitschrift für Naturforschung B, 36, 1981, 922-
929.
[14] F. Effenberger, G. Epple, J. K. Eberhard, U. Bühler, E. Sohn, Chem.
Ber. 1983, 116, 1183-1194.
[15] For examples: a) F. Effenberger, J. K. Eberhard, A. H. Maier, J. Am.
Chem. Soc. 1996, 118, 12572-12579. b) F. Effenberger, A. H. Maier, J.
Am. Chem. Soc. 2001, 123, 3429-3433.
[16] This contrasts with the high temperature synthesis of phosgene from
CO and Cl2, and is likely related to the instability of ICOI: W. Schneider
and W. Diller (2000), Phosgene, in Ullmann’s Encyclopedia of Industrial
Chemistry, Wiley-VCH, Weinheim, Germany, 2000, pp.411-414
[17] We postulate that this equilibrium can be catalyzed by HOTf.
Alternatively, benzoic anhydride may be directly iodinated by I2/AgOTf.
[18] The acylation of arenes with 3 presumably proceeds via a similar
mechanism to that reported by Effenberger et al using acyl triflates,
which has been suggested to involve ionization of 6 to the acylium ion
in the presence of triflic acid: see reference 15a.
[19] a) M. M. Khodaei, A. Alizadeh, E. Nazari, Tetrahedron Lett. 2007, 48,
4199-4202. b) T.R. Forbus, Jr., S. L. Taylor, J. C. Martin, J. Org. Chem.
1987, 52, 4156-4159.
[20] Protection for Phenols and Catechols, In Greene's Protective Groups in
Organic Synthesis, P. G. Wuts, Ed, John Wily & sons, Inc., Hoboken,
2014
[21] a) J. B. Mancuso, R. Maruthi, S. Q. Wang, H. W. Lim, Am. J. Clin.
Dermatol. 2017, 18, 643-650. b) J. C. DiNardo, C. A. Downs, J.
Cosmet. Dermatol. 2018, 17, 15-19.
[22] The formation of 1ll presumably proceeds via the initial O-benzoylation,
which subsequently converts to ketone under acidic conditions, in
analogy to related syntheses: a) R. Murashige, Y. Hayashi, S. Ohmori,
A. Torii, Y. Aizu, Y. Muto, Y. Murai, Y. Oda, M. Hashimoto, Tetrahedron
2011, 67, 641-649; b) S. Hashem, E. Hossien, Bull. Chem. Soc. Jpn.
1993, 66, 135-139; c) R. Martin, Org. Prep. Proced. Int. 1992, 24, 369-
435.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814660
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
R. Garrison Kinney and Bruce A.
Arndtsen*
Page No. – Page No.
Decarboxylation with Carbon
Monoxide: The Direct Conversion of
Carboxylic Acids into Potent Acid
Triflate Electrophiles
A new route to transform carboxylic acids directly into potent acyl triflate
electrophiles is reported. This transformation exploits oxidative carbonylation of
carboxylic acids with I2, and is postulated to involve the interception of the
Hunsdiecker reaction with CO. Coupling this chemistry with arene trapping offers a
mild, room temperature approach to generate ketones from carboxylic acids using
available reagents, and with only CO2 and salts as by-products.
This article is protected by copyright. All rights reserved.