Palladium-Catalyzed Decarbonylative Iodination of Aryl Carboxylic Acids Enabled by Ligand-Assisted Halide Exchange

Article abstract of DOI:10.1002/anie.202103269

We report an efficient and broadly applicable palladium-catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt. The use of 1-iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis, including complex drug-like scaffolds. Stoichiometric experiments and kinetic analysis suggest a unique mechanism involving C?P reductive elimination to form the Xantphos phosphonium chloride, which subsequently initiates an unusual halogen exchange by outer sphere nucleophilic substitution.

Full text of DOI:10.1002/anie.202103269

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Palladium-Catalyzed Decarbonylative Iodination of Aryl
Carboxylic Acids Enabled by Ligand-Assisted Halide Exchange
Authors: Philip Boehm, Tristano Martini, Yong Ho Lee, Bastien
Cacherat, and Bill Morandi
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.202103269
Link to VoR: https://doi.org/10.1002/anie.202103269

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
Palladium-Catalyzed Decarbonylative Iodination of Aryl
Carboxylic Acids Enabled by Ligand-Assisted Halide Exchange
Philip Boehm+, Tristano Martini+, Yong Ho Lee, Bastien Cacherat, and Bill Morandi*
In memory of Prof. Klaus Hafner.
[*]
Philip Boehm, Tristano Martini, Yong Ho Lee and Prof. Dr. Bill Morandi
Laboratorium für Organische Chemie, ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
E-mail: bill.morandi@org.chem.ethz.ch
Yong Ho Lee, Dr. Bastien Cacherat and Prof. Dr. Bill Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of the document.
Abstract: We report an efficient and broadly applicable palladium-
catalyzed iodination of inexpensive and abundant aryl and vinyl
carboxylic acids via in situ activation to the acid chloride and formation
of a phosphonium salt. The use of 1-iodobutane as iodide source in
combination with a base and a deoxychlorinating reagent gives
access to a wide range of aryl and vinyl iodides under Pd/Xantphos
catalysis, including complex drug-like scaffolds. Stoichiometric
experiments and kinetic analysis suggest a unique mechanism
involving C–P reductive elimination to form the Xantphos
phosphonium chloride which subsequently initiates an unusual
halogen exchange by outer sphere nucleophilic substitution.
general and mild methods for the installation of C(sp2)–I bonds
remain highly sought after.
Introduction
Organic halides are among the most prevalent functional groups
in organic chemistry, spanning occurrence from natural
products,[1] pharmaceuticals,[2] agrochemicals,[3] to functional
materials[4] and molecular recognition.[5] In addition, halides are
important building blocks in organic chemistry and serve as
synthetic handles, e.g. through carbon-halogen bond activation
by transition-metals,[6] metal-halogen exchange,[7] or nucleophilic
substitution.[8] Numerous methods for the ruthenium-,[9]
rhodium-,[10] nickel-,[11] copper-catalyzed,[12] and transition-metal
free[13] C(sp2)–halogen bond formation have been described.[6]
Over the last decades, Pd(0)/Pd(II) catalysis has emerged as an
attractive alternative to those protocols, since it allows for mild
reaction conditions and broad substrate scopes.[14] Systematic
stoichiometric studies by Hartwig on the reductive elimination of
aryl-Pd(II)-halide complexes have paved the way to a more
benign synthesis of aryl halides.[15] Subsequent reports by the
groups of Buchwald, Sanford and others have broadened the
spectrum of accessible Pd(0)/Pd(II) catalyzed methods for the
installation of carbon-halogen bonds.[6,16] Among aromatic halides,
aryl iodides take a privileged role, since they exhibit unique
characteristics, such as superior reactivity in cross-coupling
reactions,[17] or their potential application in hypervalent iodine
chemistry.[18] Despite recent progress on the transition-metal
catalyzed installation of carbon-halogen bonds,[6,11a,b,f,12c,d]
Scheme 1. Context of this work.
Since carboxylic acids are inexpensive, readily available, and
ubiquitously found in natural products,[19] their utilization as
synthetic
handles,
e.g.
through
decarbonylative
or
decarboxylative pathways,[20,21] holds great prospects in
streamlining target-oriented synthesis. Given those advantages of
carboxylic acids and the high synthetic utility of aryl iodides, the
direct conversion of aryl carboxylic acids into aryl iodides would
be a highly valuable transformation. Several protocols for the
decarboxylative and decarbonylative iodination of aryl carboxylic
acids have been developed since the initial report of the
Hunsdiecker reaction.[22,23,24] However, current reactions still
exhibit several drawbacks: they either require preactivation of the
carboxylic acid,[23b] stoichiometric amounts of transition
metal,[23c,d] or a tailor-made Ir-photocatalyst for the installation of
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
the carbon–iodine bond.[23b,e] In addition, several reports show
limited substrate scope,[23f,g] or afford the desired aryl iodides in
only modest yields.[23h] Larrosa et al. disclosed an elegant
transition-metal free protocol for the iodination of aryl carboxylic
acids, using potassium phosphate and molecular iodine.[24]
However, the scope was mostly limited to electron-rich substrates
with ortho-substituents or substrates with several fluorine
substituents. For example, simple benzoic acid and para-nitro
benzoic acid completely shut down the reaction. Additionally,
diiodination via C–H iodination was observed in several cases.
In 2018, our group disclosed a single-bond metathesis
reaction for the synthesis of aryl iodides from acid chlorides
(Scheme 1a).[25] It was proposed that a central, reversible C–P
reductive elimination with the Xantphos ligand enabled the aryl
group exchange between aryl iodides and aroyl chlorides. Therein,
the mechanistic studies suggested that Xantphos acts as an aryl
group storage unit to mediate facile aryl ligand exchange rather
than either halide or CO exchange. In addition to the required
activation step to transform the carboxylic acid into the acid
chloride, excess amount of the iodination reagent was necessary
in many cases to drive the reaction to high conversion.
Furthermore, stoichiometric acid chloride by-product was
generated during the reaction, complicating the purification of the
desired aryl iodide.
GC-yield after 16 hours (Table 1, entry 1). Running the reaction
in an open system proved to be crucial to achieve high yields,
presumably by helping the release of CO (entry 5). Xantphos, a
wide bite-angle bidentate phosphine ligand previously employed
in challenging reductive elimination steps,[14a,20n,25,27,28] showed
superior results among all the ligands tested (entry 6). For the in
situ activation of the carboxylic acid, the combination of proton
sponge as base and PyCIU as deoxychlorinating reagent gave
the best result (entries 7–9).[29] Switching to other Pd(0)
precursors and solvents had a deleterious effect on the reaction
yield (entries 10 and 11).
Table 1. Selected Optimization Data for the Iodination of Aryl
Carboxylic Acids.[a]
Entry
Deviations from above
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
none
88
40
37
32
10
<5
13
76
LiI instead of 1-iodobutane
NnBu4I instead of 1-iodobutane
MeI instead of 1-iodobutane
Closed 4 mL vial instead of open system
PtBu3 (20 mol%) instead of Xantphos
DIPEA instead of proton sponge
2.0 equiv. proton sponge
Based on the ability of the Pd/Xantphos catalyst system to
facilitate reductive elimination of C–I bonds,[14a,25a] we
hypothesized that broadly available aryl carboxylic acids could be
transformed into aryl iodides using readily available iodide
sources after in situ activation of the carboxylic acid to the acid
chloride. This process could unlock an exciting and more general
decarbonylative iodination of carboxylic acids (Scheme 1b).
Ghosez’s reagent instead of PyCIU/proton
sponge
9
64
Herein, we report
a
palladium-catalyzed decarbonylative
iodination of aryl and vinyl carboxylic acids using 1-iodobutane as
iodide source via in situ formation of an acid chloride. Additionally,
we report preliminary kinetic and organometallic studies which
support the unique mechanism of this reaction. A strategic C–P
reductive elimination with the ligand to form a phosphonium
chloride provides an efficient and unusual platform to facilitate
chloride/iodide exchange with the alkyl iodide in an outer sphere
nucleophilic substitution.[26]
10
11
Pd(PPh3)4 instead of Pd2(dba)3
1,4-dioxane instead of toluene
62
32
[a] Reaction conditions: benzoic acid (0.25 mmol), 1-iodobutane (0.275 mmol),
Pd2(dba)3 (5 mol%), Xantphos (10 mol%), 1,8-bis(dimethylamino)naphthalene
(proton sponge, 0.275 mmol), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium
hexafluorophosphate (PyCIU, 0.35 mmol), toluene (2.5 mL), 120 °C, 16 h. [b]
Yields in % obtained by GC-FID using n-dodecane as internal standard.
Iodination of Aryl and Vinyl Carboxylic Acids.
With these optimized reaction conditions, we set out to
explore the generality of this reaction. A broad range of aryl
carboxylic acids worked efficiently under the reaction conditions.
Indeed, both electron-neutral (3a, 3r) and electron-deficient (3d,
3g, 3j–l, 3n, 3p and 3u) substituents were tolerated, giving the
corresponding aryl iodides in moderate to very good yields (54–
88%). The fact that simple electron-neutral (such as 1a) and
electron-poor aryl carboxylic acids (such as 1g, 1j and 1l) could
be converted into the corresponding aryl iodides (3a, 3g, 3j and
3l) in good yields shows the orthogonality of this method to other
previously reported methods,[24] where electron-neutral or
electron-deficient arenes gave low yields (in the case of 3g and
3l) or did not work at all (3a and 3j). Carboxylic acids with electron-
rich functional groups in para-position (3c, 3i) were also tolerated,
albeit affording the corresponding iodobenzene in lower yield
(31% and 42%, respectively). In those cases, increased amounts
of iodobenzene (3a) were observed as side product potentially
due to scrambling with the phenyl groups of Xantphos. Moving the
electron-donating group to the meta-position (3b, 3m) partially
restored the reactivity.
Results and Discussion
Evaluation of Reaction Conditions.
We began our investigations with benzoic acid (1a) and
different iodide sources. Initial attempts with (alkali metal) iodide
salts resulted in moderate conversion of the carboxylic acid to the
desired iodobenzene (3a) (Table 1, entry 2 and 3). We reasoned
that the palladium catalyst might be deactivated via the formation
of unreactive PdI2, resulting in low turnover numbers, thus
revealing the necessity to slowly release iodide into the system.
After extensive screening of the reaction conditions (see
Supporting Information), it was found that alkyl iodides proved to
be competent iodide sources, with iodomethane giving
iodobenzene (3a) in 32% GC-yield (entry 4). Further careful
optimization of the reaction parameters led to a combination of
Pd2(dba)3, Xantphos, 1,8-bis(dimethylamino)naphthalene (proton
sponge),
1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium
hexafluorophosphate (PyCIU) and less volatile 1-iodobutane in
toluene at 120 °C, giving the desired iodobenzene (3a) in 88%
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Palladium-catalyzed Iodination of Aryl and Vinyl Carboxylic Acids.[a]
[a] Reaction conditions: benzoic acid (0.25 mmol), 1-iodobutane (0.275 mmol), Pd2(dba)3 (5 mol%), Xantphos (10 mol%), 1,8-bis(dimethylamino)naphthalene (proton
sponge, 0.275 mmol), 1-(Chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyCIU, 0.35 mmol), toluene (2.5 mL), 120 °C, 16 h. [b] GC-yield using
n-dodecane as internal standard. [c] Starting from benzoyl chloride (0.25 mmol) without PyCIU and proton sponge.
Carboxylic acids are ubiquitous in natural products and
Several substrates bearing other halogen substituents (3e,
3f and 3o) afforded the corresponding aryl iodides in moderate to
good yields, without any signs of either halogen exchange of other
C–X bonds or catalyst deactivation by oxidative addition into the
other carbon-halogen bonds. Substrates bearing ortho-
substituents did not afford the desired aryl iodides in satisfying
yields, and only activated ortho-substituted substrates, such as 1-
naphthoic acid (1q), were converted to the corresponding iodides,
giving 1-iodonaphthalene (3q) in 73% yield. Heterocycles, such
as pyridine (3w), benzofuran (3s), or benzothiophene (3t) were
well-tolerated under the reaction conditions. A protected benzylic
amine (3v), a TMS-protected alkyne (3x), and an azo-group (3y)
further demonstrate the broad functional group tolerance of this
reaction.
bioactive molecules.[19] Our method for the efficient conversion of
aryl carboxylic acids into aryl iodides is therefore highly desirable,
as the carbon–iodine bond can then serve as a platform to access
a plethora of different functional groups. To further highlight the
synthetic versatility of our method, several complex carboxylic
acids, some of which are used as drugs, were subjected to the
reaction conditions. Adapalene (1z) and a flavone derivative (1aa)
gave the corresponding iodoarenes 3z and 3aa in 79% and 53%
yield, respectively. Probenecid and Febuxostat also were
converted to the iodinated derivatives (3ab, 66% and 3ac, 74%).
Additionally, Diacerein,
a
drug for the treatment of
osteoarthritis,[30] cleanly reacted to the iodoarene derivative 3ad
in 81% yield. Our method also proved to be competent to convert
vinyl carboxylic acids into the corresponding vinyl iodides, a class
of compounds challenging to access otherwise.[14a,16f] While
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
simple cinnamic acid did not afford the product, α-phenyl-
cinnamic acid afforded vinyl iodide 3ae in 67% yield. Indene
derivative 1af gave the corresponding vinyl iodide in 75% yield
and tetrasubstituted vinyl iodide 3ag was obtained in 70% yield.
Furthermore, conducting the reaction at a larger scale (1 and 5
mmol) using carboxylic acid 1h provided a comparable yield of
the iodoarene 3h, thus illustrating the scalability of this reaction.
iodo-1,2-dimethoxybenzene (6) under known conditions for the
aminocarbonylation of aryl iodides.[33] After 16 hours, product 7,
which stems from incorporation of CO released in the first
chamber, was isolated in 71% yield. This result confirms that CO
is released in our reaction. The need to release CO is consistent
with previous reports showing that the formation of aroyl-Pd-X (X
= halogen) complexes is highly favored over aryl-Pd-X complexes
in the presence of CO.[27a,28,31e] Therefore, extrusion of CO from
the reaction mixture is necessary to avoid CO re-insertion and to
drive the equilibrium towards the aryl-Pd-X complex. Accordingly,
the yield of iodobenzene (3a) in our standard reaction dropped
significantly from 88% to 55%, when conducting the experiment
under an atmosphere of CO (see Supporting Information).
During our optimization studies, 1-chlorobutane was
observed by GC-MS analysis. This observation, paired with the
absence of olefinic by-products and the fact that tert-butyl iodide
hardly affords the desired product, iodobenzene (3a), speaks
against a mechanism involving oxidative addition into the aliphatic
carbon–iodine bond and β-hydride elimination to activate the
reagent.[27,34] To test this hypothesis, we synthesized heavier alkyl
iodide 2-(2-iodoethyl)naphthalene (10) and subjected it to our
standard reaction conditions. The corresponding halide exchange
product – alkyl chloride 11 – could be isolated in 95% yield without
any signs of olefinic by-products (Scheme 3a). This result
indicates that a pathway via oxidative addition into the aliphatic
carbon–iodine bond,[34] and subsequent β-hydride elimination is
not operating under our reaction conditions. We therefore
hypothesized that, similarly to previous reports from our group,[25a]
complex 4 could undergo C–P reductive elimination after CO de-
insertion to form a phosphonium chloride.
Mechanistic Studies
The observation that only Xantphos as ligand gave the
corresponding aryl iodides in satisfying yields, and the use of alkyl
iodides as rather unconventional iodide source prompted us to
start investigating the mechanism of this decarbonylative
iodination of aryl and vinyl carboxylic acids.
Previous reports have shown that the combination of proton
sponge and deoxychlorinating reagent efficiently produces the
acid chloride from the carboxylic acid.[20h,29] We thus started our
studies by synthesizing the oxidative addition complex 4 of
Pd(Xantphos) into the carbon–chlorine bond of benzoyl
chloride.[25b,31] Additionally, complex 5, resulting from the oxidative
addition of Pd(Xantphos) into the carbon–iodine bond of
iodobenzene was synthesized.[31d,32] Both complexes proved to be
kinetically competent under our standard reaction conditions
(Scheme 2a, see Supporting Information for details) and are thus
likely involved in the catalytic cycle.
Scheme 2. a) Catalytic and kinetic competence of isolated complexes 4 and 5
and of Pd(0) with phosphonium chloride 9. b) Detection of CO release by two-
chamber aminocarbonylation.
We envisaged that after oxidative addition, complex 4 might
lose CO. Consistent with this hypothesis is the requirement for
open reaction conditions, suggesting that CO is detrimental to the
process.[16d,31e] To further support this hypothesis experimentally,
we conducted a reaction in a sealed two-chamber system
(Scheme 2b).[33] In one chamber, our reaction for the iodination of
carboxylic acids was run; the other chamber was loaded with 4-
Scheme 3. a) Isolation of heavier alkyl chloride 10 under the standard reaction
conditions. b) Phosphonium chloride 9 observed by 31P-NMR and X-ray
structure of 9. c) Nucleophilic substitution of heavier alkyl iodide with 9. d)
Nucleophilic substitution of heavier alkyl iodide 10 with tetraphenylphosphonium
chloride 12 and with [(PPh3)2Pd(Ph)(Cl)] (14).
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
The outer sphere chloride anion could then readily substitute the
iodide of alkyl iodide 2 or 10 through a nucleophilic substitution
reaction.[35] Indeed, when we tried a stoichiometric reaction to
detect the mono-phosphonium chloride form of Xantphos (9),
traces of the salt were unambiguously observed by 31P{1H}-NMR
together with a significant amount of the deactivation complex,
(Xantphos)PdCl2 (Scheme 3b, see Supporting Information). We
next used a different route to access phosphonium chloride 9 in
preparative quantities, starting from chlorobenzene under nickel
catalysis.[36] The identity of the counter anion of 9 was confirmed
by X-ray analysis. With this salt in hand, we then tried additional
control reactions to support our hypothesis. First, phosphonium
chloride 9 proved to be a kinetically competent ligand in our model
reaction (see Scheme 2a and Supporting Information for details).
Furthermore, heavier alkyl iodide 10 was reacted with
phosphonium chloride 9. To our delight, the corresponding alkyl
chloride 11 was isolated in 77% yield, together with 13%
unreacted starting material 10 (Scheme 3c), showing that the
chloride counter ion of the phosphonium salt is indeed a
competent reagent for nucleophilic displacement.
and close the catalytic cycle. In rare cases, phenyl group
scrambling was observed after C–P oxidative addition into the
phosphorus-phenyl bond of Xantphos to give iodobenzene (3a)
(vide supra), thus further supporting the proposed mechanism.
Still, it cannot be excluded from these experiments that the
nucleophilic substitution might be mediated by a simple aryl-Pd-
Cl complex in the absence of C–P reductive elimination. We
therefore performed additional stoichiometric experiments to
probe such a pathway. To facilitate the analysis of the reaction
mixture, we chose tetraphenylphosphonium chloride (12) instead
of phosphonium chloride 9. First, the reaction of 12 with 10 to
tetraphenylphosphonium iodide (13) and alkyl chloride 11 proved
that the nucleophilic substitution is feasible and that the reaction
reaches full conversion (Scheme 3d, top). Subsequently, alkyl
iodide 10 was reacted with the synthesized complex
[(PPh3)2Pd(Ph)(Cl)] (14).[37] If this aryl-Pd-Cl complex, which is
unknown to undergo C–P reductive elimination to form a
phosphonium chloride,[36] is less capable of facilitating the halide
exchange than the phosphonium salts 9 and 14, the yield of alkyl
chloride 11 should be reduced. Indeed, the yield of alkyl chloride
11 reached only around 7%, even after prolonged reaction time
Scheme 4. Proposed catalytic cycle for the palladium-catalyzed
decarbonylative iodination.
Conclusion
In conclusion, we have reported a method for the decarbonylative
iodination of readily available aryl carboxylic acids with 1-
iodobutane. The generality of this transformation has been
demonstrated on a wide spectrum of aryl carboxylic acids and on
a number of drug molecules. In addition, electron-poor substrates
which are not compatible with conventional iodination methods,[24]
were efficiently converted to their corresponding aryl iodides. For
this operationally simple iodination process, mechanistic
experiments and kinetic studies support a phosphonium halide
intermediate which is key to enable a rapid halogen exchange via
SN2 type reaction with a primary alkyl iodide, revealing an unusual
outer sphere nucleophile exchange process. To the best of our
knowledge, this constitutes the first example of halide exchange
assisted by C–P reductive elimination,[9] followed by sequential
nucleophilic substitution and oxidative addition at a Pd center.
(Scheme 3d, bottom). This observation suggests that
a
mechanism involving a direct reaction between an aryl-Pd-Cl
intermediate and the alkyl iodide is unlikely.
Based on the results from our experiments, we propose a
mechanism for the iodination of aryl and vinyl carboxylic acids that
best explains all the findings (Scheme 4). After in situ activation
of the carboxylic acid with the proton sponge and PyCIU, facile
oxidative addition of (Xantphos)Pd(0) into the C–Cl bond occurs
to form complex I. Subsequent CO de-insertion and release gives
complex II, which could undergo C–Cl reductive elimination to
form aryl chlorides under certain conditions.[16d] However,
chlorobenzene was never observed during our studies and
experiments suggest that complex II undergoes chemoselective
C–P reductive elimination to afford III. At this point, it is unclear,
whether CO release occurs before or after C–P reductive
elimination and nucleophilic substitution. Arndtsen has shown that
CO renders the Pd center more electron-deficient, facilitating
analogous challenging reductive elimination steps,[38] which could
also be the case here in the C–P reductive elimination. Since the
chloride anion is in the outer sphere in complex III, fast
nucleophilic substitution occurs with the alkyl iodide to form
complex IV, which now has iodide as counter anion. This complex
then undergoes C–P oxidative addition to form complex V,
followed by reductive elimination to release the desired aryl iodide
Experimental Section
Experimental details and compound characterization are given in
the supporting information.
Acknowledgements
This project received funding from the European Research
Council under the European Union’s Horizon 2020 research and
innovation program (Shuttle Cat, Project ID: 757608), the FCI
(scholarship to P.B.), LG Chem (scholarship to Y.H.L.), ETH
Zürich, the Max-Planck-Society and the Max-Planck-Institut für
Kohlenforschung. We thank the NMR service, the Molecular and
Biomolecular Analysis Service (MoBiAS), and X-ray (SMoCC)
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
L. Racicot, D. Panagopoulos, S. H. Liang, M. A. Ciufolini, Angew. Chem.
Int. Ed. 2014, 53, 9637–9639.; Angew. Chem. 2014, 126, 9791–9793. e)
M. G. Suero, E. D. Bayle, B. S. L. Collins, M. J. Gaunt, J. Am. Chem. Soc.
2013, 135, 5332–5335.
service of ETH Zürich for assistance. We thank Marius Lutz and
Miguel Rivero Crespo for assistance with the kinetic studies and
our group for critical proofreading of the manuscript.
[19] a) L. J. Gooßen, N. Rodríguez, K. Gooßen, Angew. Chem. Int. Ed. 2008,
47, 3100–3120.; Angew. Chem. 2008, 120, 3144–3164. b) T. Qin, J.
Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura, B. D. Maxwell,
M. D. Eastgate, P. S. Baran, Science 2016, 352, 801–805. c) A. Noble,
S. J. McCarver, D. W. C. Macmillan, J. Am. Chem. Soc. 2015, 137, 624–
627.
Keywords: iodination • palladium • shuttle catalysis • reaction
mechanism • ligand non-innocence
[1]
[2]
G. W. Gribble, Acc. Chem. Res. 1998, 31, 141–152.
a) M. Hernandes, S. M. Cavalcanti, D. R. Moreira, W. de Azevedo Junior,
A. C. Leite, Curr. Drug Targets 2010, 11, 303–314. b) T. Kosjek, E. Heath,
Top Heterocycl Chem 2011; 27, 219–246.
[20] Selected reviews and reports on decarbonylation: a) Q. Zhao, M. Szostak,
ChemSusChem 2019, 12, 2983–2987. b) Z. Wang, X. Wang, Y.
Nishihara, Chem. – Asian J. 2020, 15, 1234–1247. c) L. Guo, M. Rueping,
Chem. – Eur. J. 2018, 24, 7794–7809. d) H. Lu, T. Y. Yu, P. F. Xu, H.
Wei, Chem. Rev. 2021, 121, 365–411. e) K. Amaike, K. Muto, J.
Yamaguchi, K. Itami, J. Am. Chem. Soc. 2012, 134, 13573–13576. f) L.
J. Gooßen, J. Paetzold, Adv. Synth. Catal. 2004, 346, 1665–1668. g) T.
Zhou, P. P. Xie, C. L. Ji, X. Hong, M. Szostak, M. Org. Lett. 2020, 22,
6434–6440. h) C. A. Malapit, J. R. Bour, C. E. Brigham, M. S. Sanford,
Nature 2018, 563, 100–104. i) N. A. Weires, E. L. Baker, N. K. Garg, Nat.
Chem. 2016, 8, 75–79. j) G. Meng, M. Szostak, M. Angew. Chem. Int.
Ed. 2015, 54, 14518–14522.; Angew. Chem. 2015, 127, 14726–14730.
k) T. Sugihara, T. Satoh, M. Miura, M. Nomura, Angew. Chem. Int. Ed.
2003, 42, 4672–4674.; Angew. Chem. 2003, 115, 4820–4822. l) L. J.
Gooßen, J. Paetzold, Angew. Chem. Int. Ed. 2002, 41, 1237–1241.;
Angew. Chem. 2002, 114, 1285–1289. m) F. Pan, G. B. Boursalian, T.
Ritter, Angew. Chem. Int. Ed. 2018, 57, 16871–16876.; Angew. Chem.
2018, 130, 17113–17118. n) S. T. Keaveney, F. Schoenebeck, Angew.
Chem. Int. Ed. 2018, 57, 4073–4077.; Angew. Chem. 2018, 130, 4137–
4141.
[3]
P. Jeschke, W. Krämer, U. Schirmer, M. Witschel, Modern Methods in
Crop Protection Research, Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2012.
[4]
[5]
M. L. Tang, Z. Bao, Chem. Mater. 2011, 23, 446–455.
T. M. Beale, M. G. Chudzinski, M. G. Sarwar, M. S. Taylor, Chem. Soc.
Rev. 2013, 42, 1667–1680.
[6]
[7]
[8]
D. A. Petrone, J. Ye, M. Lautens, Chem. Rev. 2016, 116, 8003–8104.
W. F. Bailey, J. J. Patricia, J. Organomet. Chem. 1988, 352, 1–46.
F. Terrier, F. Modern Nucleophilic Aromatic Substitution, Wiley: Hoboken,
2013.
[9]
a) Y. Imazaki, E. Shirakawa, R. Ueno, T. Hayashi, J. Am. Chem. Soc.
2012, 134, 14760–14763. b) E. Shirakawa, Y. Imazaki, T. Hayashi,
Chem. Commun. 2009, 5088–5090.
[10] a) J. Blum, H. Rosenman, E. D. Bergmann, J. Org. Chem. 1968, 33,
1928–1930. b) J. Blum, E. Oppenheimer, E. D. Bergmann, J. Am. Chem.
Soc. 1967, 89, 2338–2341. c) J. Blum, Tetrahedron Lett. 1966, 7, 1605–
1608.
[11] a) J. L. Hofstra, K. E. Poremba, A. M. Shimozono, S. E. Reisman, Angew.
Chem. Int. Ed. 2019, 58, 14901–14905.; Angew. Chem. 2019, 131,
15043–15047. b) T. Takahashi, D. Kuroda, T. Kuwano, Y. Yoshida, T.
Kurahashi, S. Matsubara, Chem. Commun. 2018, 54, 12750–12753. c)
A. A. Cant, R. Bhalla, S. L. Pimlott, A. Sutherland, Chem. Commun. 2012,
48, 3993–3995. d) S. H. Yang, C. S. Li, C. H. Cheng, J. Org. Chem. 1987,
52, 691–694. e) T. T. Tsou, J. K. Kochi, J. Org. Chem. 1980, 45, 1930–
1937. f) A. D. Marchese, T. Adrianov, M. Lautens, Angew. Chem. Int. Ed.
2021, DOI: 10.1002/anie.202101324.; Angew. Chem. 2021, DOI:
10.1002/ange.202101324.
[21] Selected reviews and reports on decarboxylation: a) N. Rodríguez, L. J.
Goossen, Chem. Soc. Rev. 2011, 40, 5030–5048. b) J. Cornella, I.
Larrosa, Synthesis 2012, 44, 653–676. c) J. T. Edwards, R. R. Merchant,
K. S. McClymont, K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A.
Shaw, D. H. Bao, F.-L. Wei, T. Zhou, M. D. Eastgate, P. S. Baran, Nature
2017, 545, 213–218. d) Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A.
G. Doyle, D. W. C. MacMillan, Science 2014, 345, 437–440. e) L. J.
Gooßen, G. Deng, L. M. Levy, Science 2006, 313, 662–664. f) J. Cornella,
P. Lu, I. Larrosa, Org. Lett. 2009, 11, 5506–5509.
[22] a) A. Borodine, Justus Liebigs Ann. Chem. 1861, 119, 121–123. b) H.
Hunsdiecker, C. Hunsdiecker, Berichte der Dtsch. Chem. Gesellschaft
1942, 75, 291–297. c) R. G. Johnson, R. K. Ingham, Chem. Rev. 1956,
56, 219–269.
[12] a) A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 14844–
14845. b) X. Feng, Y. Qu, Y. Han, X. Yu, M. Bao, Y. Yamamoto, Chem.
Commun. 2012, 48, 9468–9470. c) X. Jin, R. P. Davies, Catal. Sci.
Technol. 2017, 7, 2110–2117. d) W. Cao, S.-L. Niu, L. Shuai, Q. Xiao,
Chem. Commun. 2020, 56, 972–975.
[23] a) A. Varenikov, E. Shapiro, M. Gandelman, Chem. Rev. 2021, 121, 412–
484. b) T. Patra, S. Mukherjee, J. Ma, F. Strieth‐Kalthoff, F. Glorius,
Angew. Chem. Int. Ed. 2019, 58, 10514–10520.; Angew. Chem. 2019,
131, 10624–10630. c) Z. Fu, Z. Li, Y. Song, R. Yang, Y. Liu, H. Cai, J.
Org. Chem. 2016, 81, 2794–2803. d) J. Cornella, M. Rosillo-Lopez, I.
Larrosa, Adv. Synth. Catal. 2011, 353, 1359–1366. e) M. Jiang, H. Yang,
Y. Jin, L. Ou, H. Fu, Synlett 2018, 29, 1572–1577. f) Z. Fu, Y. Jiang, L.
Jiang, Z. Li, S. Guo, H. Cai, Tetrahedron Lett. 2018, 59, 4458–4461. g)
Synlett 2014, 25, 2508–2512. h) D. H. R. Barton, B. Lacher, S. Z. Zard,
Tetrahedron 1987, 43, 4321–4328.
[13] W. Liu, X. Yang, Y. Gao, C. J. Li, J. Am. Chem. Soc. 2017, 139, 8621–
8627.
[14] a) Y. H. Lee, B. Morandi, Angew. Chem. Int. Ed. 2019, 58, 6444–6448.;
Angew. Chem. 2019, 131, 6510–6515. b) S. G. Newman, M. Lautens, M.
J. Am. Chem. Soc. 2010, 132, 11416–11417.
[15] a) A. H. Roy, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 1232–1233.
b) A. H. Roy, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125, 13944–13945.
c) A. H. Roy, J. F. Hartwig, Organometallics 2004, 23, 1533–1541.
[16] a) D. J. Jones, M. Lautens, G. P. McGlacken, Nat. Catal. 2019, 2, 843–
851. b) X. Shen, A. M. Hyde, S. L. Buchwald, J. Am. Chem. Soc. 2010,
132, 14076–14078. c) J. Pan, X. Wang, Y. Zhang, S. L. Buchwald, Org.
Lett. 2011, 13, 4974–4976. d) C. A. Malapit, N. Ichiishi, M. S. Sanford,
Org. Lett. 2017, 19, 4142–4145. e) J. W. Verbicky, B. A. Dellacoletta, L.
Williams, Tetrahedron Lett. 1982, 23, 371–372. f) C. M. Lee, P. J. C.
Menzies, D. A. Petrone, M. Lautens, Angew. Chem. Int. Ed. 2015, 54,
254–257.; Angew. Chem. 2015, 127, 256–259.
[24] G. J. P. Perry, J. M. Quibell, A. Panigrahi, I. Larrosa, J. Am. Chem. Soc.
2017, 139, 11527–11536.
[25] a) Y. H. Lee, B. Morandi, Nat. Chem. 2018, 10, 1016–1022. b) For an
independent report on the synthesis of acid chlorides from aryl iodides,
see: M. De La Higuera Macias, B. A. Arndtsen, J. Am. Chem. Soc. 2018,
140, 10140–10144.
[26] Y. H. Lee, B. Morandi, Coord. Chem. Rev. 2019, 386, 96–118.
[27] a) P. Boehm, S. Roediger, A. Bismuto, B. Morandi, Angew. Chem. Int.
Ed. 2020, 59, 17887–17896.; Angew. Chem. 2020, 132, 18043–18052.
b) X. Fang, B. Cacherat, B. Morandi, Nat. Chem. 2017, 9, 1105–1109.
[28] V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 2006, 128, 12644–
12645.
[17] a) P. Fitton, E. A. Rick, J. Organomet. Chem. 1971, 28, 287–291. b) V.
V. Grushin, H. Alper, Chem. Rev. 1994, 94, 1047–1062. c) F. Barrios-
Landeros, B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131,
8141–8154.
[18] a) T. Wirth, Hypervalent Iodine Chemistry: Modern Developments in
Organic Synthesis; Topics in Current Chemistry Series 224; Springer:
Berlin-Tokyo, 2003. b) A. Yoshimura, V. V. Zhdankin, Chem. Rev. 2016,
116, 3328–3435. c) T. Wirth, Angew. Chem. Int. Ed. 2005, 44, 3656–
3665.; Angew. Chem. 2005, 117, 3722–3731. d) T. Kasahara, Y. J. Jang,
[29] P. M. Garcia-Barrantes, K. McGowan, S. W. Ingram, C. W. Lindsley,
Tetrahedron Lett. 2017, 58, 898–901.
[30] E. Panova, G. Jones, Drug Safety. 2015, 38, 245–252.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
[31] a) J. R. Martinelli, D. A. Watson, D. M. M. Freckmann, T. E. Barder, S. L.
Buchwald, J. Org. Chem. 2008, 73, 7102–7107. b) P. L. Lagueux-
Tremblay, A. Fabrikant, B. A. Arndtsen, ACS Catal. 2018, 8, 5350–5354.
c) F. M. Miloserdov, V. V. Grushin, Angew. Chem. Int. Ed. 2012, 51,
3668–3672.; Angew. Chem. 2012, 124, 3728–3732. d) T. L. Andersen,
S. D. Friis, H. Audrain, P. Nordeman, G. Antoni, T. Skrydstrup, J. Am.
Chem. Soc. 2015, 137, 1548–1555. e) F. M. Miloserdov, C. L. McMullin,
M. M. Belmonte, J. Benet-Buchholz, V. I. Bakhmutov, S. A. Macgregor,
V. V. Grushin, Organometallics 2014, 33, 736–752.
[32] a) P. E. Garros, R. F. Heck, J. Am. Chem. Soc. 1976, 98, 4115–4127. b)
S. L. Fraser, M. Y. Antipin, V. N. Khroustalyov, V. V. Grushin, J. Am.
Chem. Soc. 1997, 119, 4769–4770.
[33] P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp, T.
Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061–6071.
[34] a) A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674–688.;
Angew. Chem. 2005, 117, 680–695. b) N. Kambe, T. Iwasaki, J. Terao,
Chem. Soc. Rev. 2011, 40, 4937–4947. c) A. Rudolph, M. Lautens,
Angew. Chem. Int. Ed. 2009, 48, 2656–2670.; Angew. Chem. 2009, 121,
2694–2708. d) Y. Peng, B. Morandi, Angew. Chem. Int. Ed. 2017, 56,
15693–15697.; Angew. Chem. 2017, 129, 15899–15903. e) M. R.
Netherton, C. Dai, K. Neuschütz, G. C. Fu, J. Am. Chem. Soc. 2001, 123,
10099–10100.
[35] For an example of halide-substitution reactions with phosphonium salts,
see: D. Mandal, M. Jurisch, C. S. Consorti, J. A. Gladysz, Chem. Asian
J. 2008, 3, 1772–1782.
[36] D. Marcoux, A. B. Charette, Adv. Synth. Catal. 2008, 350, 2967–2974.
[37] L. K. Hwang, Y. Na, J. Lee, Y. Do, S. Chang, Angew. Chem. Int. Ed. 2005,
44, 6166–6169.; Angew. Chem. 2005, 117, 6322–6325.
[38] a) G. M. Torres, Y. Liu, B. A. Arndtsen, Science 2020, 368, 318 – 323. b)
R. G. Kinney, J. Tjutrins, G. M. Torres, N. J. Liu, O. Kulkarni, B. A.
Arndtsen, Nat. Chem. 2018, 10, 193–199.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202103269
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
8
This article is protected by copyright. All rights reserved.