Full text of DOI:10.1021/acscatal.8b00757

Subscriber access provided by Kaohsiung Medical University
Letter
Palladium Catalyzed Carbonylation of Aryl
Chlorides to Electrophilic Aroyl-DMAP Salts
Pierre-Louis Lagueux-Tremblay, Alexander Fabrikant, and Bruce A. Arndtsen
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00757 • Publication Date (Web): 04 May 2018
Downloaded from http://pubs.acs.org on May 4, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
ACS Catalysis
1
2
3
4
5
6
7
8
9
Palladium Catalyzed Carbonylation of Aryl Chlorides to Electrophilic
Aroyl-DMAP Salts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pierre-Louis Lagueux-Tremblay, Alexander Fabrikant, and Bruce A. Arndtsen*
Department of Chemistry, McGill University, 801 Sherbrooke St. W. Montreal, Quebec, Canada H3A 0B8
ABSTRACT: The palladium catalyzed carbonylative coupling of aryl chlorides and 4-dimethylaminopyridine (DMAP) to
generate electrophilic aroyl-DMAP salts is described. In contrast to classical carbonylation reactions, which often require
nucleophiles to react with weakly electrophilic palladium-acyl intermediates, the high electrophilicity of aroyl-DMAP
salts allows the acylation of a broad range of substrates. This transformation is mediated by a palladium-Xantphos cata-
lyst, and mechanistic studies suggest the combination of ligand steric strain together with Pd(0) stabilization allows both
the reductive elimination of a reactive ArCO-DMAP product, and oxidative addition of the strong aryl-chloride bond.
Overall, this transformation allows the generation of amides and esters from aryl chlorides with an array of nucleophiles,
and with good functional group compatibility.
KEYWORDS Palladium catalysis, Carbonylation, Acylation, Aryl Chlorides, DMAP, Amides, Esters
Palladium catalyzed carbonylative coupling reactions
have become of growing importance in organic synthe-
sis.1,2 Relative to classical methods to prepare carbonyl-
containing products with activated carboxylic acid deriva-
tives, which typically requires the use of synthetic, high
energy reagents (e.g. carbodiimides, SOCl2, PCl3, etc),
carbonylations offer a route to these same products using
simply CO and organic halides. These transformations
are postulated to proceed in a fashion similar to palladi-
um catalyzed cross coupling reactions, wherein oxidative
addition of an aryl halide generates a palladium-aryl
complex that can undergo CO insertion followed by nu-
cleophile coordination to palladium for reductive elimina-
tion.3 While effective, the required addition of the nucle-
ophile to palladium for elimination can also lead to limi-
tations. For example, weakly coordinating or sterically
encumbered nucleophiles can be difficult to employ in
carbonylation reactions, and often require either pressing
reaction conditions or are simply not viable reagents.2
Buchwald, Skrydstrup, Grushin, and Manabe have previ-
ously demonstrated that the palladium catalyzed for-
mation of aryl esters, thioesters, and related carbonyla-
tion products followed by the addition of stronger nucle-
ophiles can be used to expand the scope of these trans-
formations (Scheme 1a).4-8 We have recently shown that
aryl-iodides and -bromides can undergo carbonylation in
the presence of a chloride anion to build-up highly elec-
Scheme 1. Palladium-Catalyzed Carbonylative For-
mation of Electrophiles
trophilic acid chlorides (Scheme 1b).9,10
A
PtBu3-
In principle, an even more efficient approach to catalyt-
ic acid chloride formation would be the direct carbonyla-
tion of aryl chlorides. Relative to other aryl halides, aryl
chlorides are inexpensive and broadly available building
blocks, and their carbonylation would obviate the need
for a chloride additive in the reaction. Unfortunately, the
combination of a strong aryl-chloride bond and deactivat-
ing CO coordination often makes aryl chlorides much less
coordinated palladium catalyst mediates this transfor-
mation, and is believe to allow the rapid and favor reduc-
tive elimination of the weak RCO-Cl bond as a mecha-
nism to relieve steric strain.11 By coupling the formation
of acid chlorides with their high reactivity, a range of new
classes of carbonylation products can be generated.
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 7
reactive towards palladium catalyzed carbonylation reac-
(entry 16). Increasing the temperature with Xantphos
leads to the formation of 1a in high yield (85%, entry 14).
tions.2,12 This challenge is even more problematic in acid
chloride synthesis due to the ability of the acid chloride
product itself to re-add back to palladium more rapidly
than the substrate (Scheme 1b). The latter limits catalyst
activity with reactive aryl iodides,13 and has to date made
less reactive aryl chlorides not viable substrates in these
reactions.
1
2
3
4
5
6
7
Table 1 : Palladium-Catalyzed Carbonylation of PhCl
with DMAPa,b
8
9
A potential approach to avoid these limitations with ar-
yl chlorides would be to generate another class of potent
electrophile: aroyl-DMAP (4-dimethylaminopyridine)
salts (Scheme 1c). Aroyl-DMAP salts are common inter-
mediates formed in situ to facilitate acylation reactions.14
We have previously reported that aryl iodides and bro-
mides can be carbonylated into these salts by using PtBu3-
coordinated palladium catalysts to facilitate reductive
elimination.15 A useful feature of catalytically forming
DMAP salt products is their ionic character, which can
lead to their precipitation from non-polar solvents as easi-
ly isolable salts, and help drive the reaction under more
mild conditions without product inhibition. We describe
herein our efforts towards using aryl chlorides in this car-
bonylative coupling chemistry. In contrast to our previous
results, these show that the sterically encumbered PtBu3
ligand is not sufficient to allow this transformation to
occur with the less reactive aryl chloride bond. Neverthe-
less, modification to the catalyst system to stabilize palla-
dium can allow the design of an efficient route to potent
aroylating electrophiles form simple, inexpensive and
commercially available substrates.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our initial studies towards this reaction involved the
carbonylation of chlorobenzene in the presence of DMAP
with a Pd(PtBu3)2 catalyst. Unfortunately, this does not
lead to the formation of DMAP salt 1a even under press-
ing conditions (Table 1, entries 1-3). The use of a range
other monodentate phosphine ligands led to similar re-
sults (entries 4-8). This includes simple triaryl phos-
phines as well strong donor or sterically encumbered lig-
ands, many of which have been employed in activation of
aryl chlorides.16 Instead, the aryl chloride reagent is ob-
served intact at the end of the reaction.
a
PhCl (141 mg, 1.25 mmol), DMAP (30 mg, 0.25 mmol),
Pd(PtBu3)2 (6 mg, 12.5 μmol), ligand (25 μmol), CO (4
atm), toluene (1 ml), 150 °C, 24 h. b Isolated yield. c 100 °C.
d 170 °C. e with [Pd(allyl)Cl]2 (2 mg, 6.3 μmol).
The unique ability of Xantphos to allow catalysis of this
reaction raises a number of mechanistic questions.18,19
Firstly, the transformation employs a Pd(PtBu3)2 precur-
sor, which therefore has PtBu3 as well as Xantphos present
in the reaction. Replacing the Pd(PtBu3)2 catalyst with
other palladium precursors such as [Pd(allyl)Cl]2 or
Pd2dba3 leads to a significant loss in product yield (Table
2, entries 1, 2). This can be partially recovered by the ad-
dition of PtBu3 (entries 3, 4). While these data suggests
that the PtBu3 ligand may play a direct role in the reaction
together with Xantphos, an alternative is the ease of acti-
vation and greater solubility of Pd(PtBu3)2 in the non-
polar reaction solvent. This was demonstrated by prepar-
ing the Xantphos-coordinated palladium catalyst precur-
sor (Xantphos)Pd(COPh)Cl (2a).7, 19 The use of 2a as cata-
lyst leads to the formation of 1a in similar yields than with
Pd(PtBu3)2/Xantphos and with no side products (entry 7).
In the reactions above, we noted the formation of sig-
nificant amounts of Pd black precipitate at even early
times of catalysis, suggesting that the oxidative addition
of aryl chlorides in the presence of CO is not sufficiently
rapid to compete with Pd(0) deactivation. We therefore
turned next to chelate ligands, as these can more strongly
coordinate to palladium in the presence of CO. The use
of bidentate ligands such as dcpp and dppf, which have
been found to allow carbonylations of aryl chlorides in
other systems,17 leads to the formation of trace amounts
of product (entries 10, 11). However, increasing the ligand
bite angle with Xantphos leads to a significant enhance-
ment in catalytic activity, and the formation of DMAP salt
1a in 67% yield (entry 14). Lower bite angle diphosphine
ligands with similar electronic properties to Xantphos do
not convert the aryl chloride in the desired product (en-
t
tries 13), nor does the more electron rich BuXantphos
ACS Paragon Plus Environment

Page 3 of 7
ACS Catalysis
Table 2. Palladium Catalyst Precursors for the Syn-
dium to generate the cationic DMAP-palladium complex
3, which undergoes reductive elimination of 1 under mild
conditions. Alternatively, the direct attack of DMAP on
the electrophilic acyl ligand is also possible. The insolubil-
ity of the aroyl-DMAP product in toluene makes this step
irreversible, and helps drive product formation and cata-
lyst turnover. The importance of this precipitation driv-
ing the reaction forward is also shown in Scheme 2a,
where the use of a solvent in which the DMAP salt 1b is
soluble (CD2Cl2) leads to its rapid, ambient temperature
re-oxidative addition to Pd(0).
thesis of Aroyl-DMAP Saltsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Control Experiments and Proposed Mech-
anism of Catalysis
a PhCl (141 mg, 1.25 mmol), DMAP (30 mg, 0.25 mmol), Pd
(5 %, 12.5 μmol), xantphos (14 mg, 25 μmol), 4 atm CO, 1
mL toluene, 150 °C, 24 h. b Isolated. c No Xantphos added.
A series of mechanistic experiments were performed to
gain further insight into this transformation. Monitoring
1
the catalytic reaction of Table 1 by periodic H and 31P
NMR analysis shows no evidence for the palladium-aroyl
complex (2), and instead we see signals assigned as free
PtBu3 and (Xantphos)2Pd (Figure S1). This observation is
unlike previous results with aryl iodide carbonylation to
aroyl-DMAP salts,15 where the catalyst resting state is a
palladium-aroyl complex, and suggests that reductive
elimination from a Xantphos coordinated palladium in-
termediate is no longer rate limiting in catalysis. To fur-
ther probe this step, the palladium-aroyl complex 2b was
prepared by the reaction of Xantphos/Pd2dba3 and acid
chloride.19 As shown in Scheme 2a, heating this complex
together with DMAP and aryl iodide (the later to trap the
resultant Pd(0)) to 60 °C, well below catalyst tempera-
tures, leads to the elimination of 1b in 50% yield.20 In
addition, the conversion of 2b to its triflate salt, which
would presumably favor the coordination to DMAP to
palladium, results in the rapid, room temperature for-
mation of 1c.
Together, the data above is consistent with the mecha-
nism shown in Scheme 2b. In this, the coordination of
the chelating Xantphos ligand to palladium creates a
Pd(0) complex sufficiently stabilized in the presence of
carbon monoxide to mediate a rate limiting aryl chloride
oxidative addition. While a range of bidentate ligands
could in principle stabilize palladium(0) towards precipi-
tation, a second important feature of Xantphos is its large
bite angle.21 We postulate that the steric encumbrance of
Xantphos creates a bidentate alternative to the PtBu3 lig-
and to favor the reductive elimination of the reactive
aroyl-DMAP bond kinetically competent. As demonstrat-
ed in the more rapid reaction of 2c relative to 2b (Scheme
2a), the latter may occur via DMAP coordination to palla-
Finally, with a catalytic method to prepare aroyl-DMAP
salt 1a in hand, we have probed the ability of this system
to allow aryl chloride to be used in challenging carbonyla-
tion reactions. As an example, weakly nucleophilic and
sterically encumbered substrates such as sterically hin-
dered anilines and secondary amines have not been found
to be viable coupling partners in typical aryl chloride
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 7
Table 3. Palladium Catalyzed Carbonylative Coupling
carbonylations, presumably do to the weak coordinating
ability of these substrates to palladium. However, aroyl-
DMAP salts are potent electrophiles. Thus, the addition
of this amine to an in situ generated 1 can allow the build-
up of a range of secondary and tertiary amides from aryl
chlorides, amine and CO (Table 3, 4b,e,k,l,m).22 Alterna-
tively, nucleophiles incorporating palladium reactive
functionalities, which would be challenging to employ in
carbonylative coupling reactions, can also be incorpo-
rated into this system. Examples of the latter include nu-
cleophiles containing other aryl chlorides (4a,g,i,j) or
even aryl-bromides and -iodides (4c,f,h) or terminal al-
kynes (4d). A range of either electronically neutral or
activated aryl chlorides can participate in this chemistry
(4am). Electron rich aryl chlorides are also viable sub-
strates with the addition of NaPF6 (4n-r). The latter is
postulated to aid in the build-up of 1 by creating a more
reactive cationic acyl complex 2 (e.g. Scheme 2a).23 While
catalysis is typically performed with an excess of aryl
chloride to drive the build-up of 1, the reaction can also
be accomplished with near stoichiometric aryl chloride at
slightly lower yields (4a, 54%). These reactions are gen-
erally complete within 24 hours, and provide the amide or
ester products in good overall yields.
via Aroyl DMAP Saltsa,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have developed a novel carbonylation
of aryl chlorides into aroyl-DMAP salts. This transfor-
mation is driven by the use of the large bite angle
Xantphos ligand, which can both stabilize palladium to-
wards precipitation and, at the same time, favor product
elimination. Overall, this provides an efficient method to
create electrophilic aroyl-DMAP salts, and new classes of
carbonylation products, from broadly available aryl chlo-
rides.
ASSOCIATED CONTENT
1
Details of experimental procedures and H, 13C, 31P and 19F
NMR spectra of synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*bruce.arndtsen@mcgill.ca
ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), NSERC CREATE in Green
Chemistry, and the Centre for Green Chemistry and Catalysis
(supported by Fonds de Recherche du Québec – Nature et
Technologies) for funding this research.
REFERENCES
1.
(a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. Palladium-
Catalyzed Carboalkoxylation of Aryl, Benzyl, and Vinylic
Halides. J. Org. Chem. 1974, 39, 3318–3326; (b) Schoenberg,
A.; Heck, R. F. Palladium-Catalyzed Amidation of Aryl,
Heterocyclic, and Vinylic Halides. J. Org. Chem. 1974, 39,
3327–3331.
a
Aryl chloride (1.25 mmol), DMAP (30 mg, 0.25 mmol),
Pd(PtBu3)2 (6 mg, 12.5 μmol), xantphos (14 mg, 25 μmol), 4
atm CO, 1 mL toluene, 150 °C, 24 h, then addition of NuH
(0.38 mmol), NEtiPr2 (65 mg, 0.50 mmol), 1 mL MeCN, 25 °C,
b
c
d
4-16 h. Isolated yield, DMAP as limiting reagent, 170 °C,
0. 37 mmol aryl chloride, 10 mol% Pd(PtBu3)2, 10 mol%
Pd(PtBu3)2, NaPF6 (63 mg,0.375 mmol), g 130 °C, h 120 °C.
e
f
2. Reviews: (a) Barnard, C. F. J. Palladium-Catalyzed Car-
bonylations–A Reaction Come of Age. Organometallics
2008, 27, 5402–5422; (b) Grigg, R.; Mutton, S. P. Pd-
ACS Paragon Plus Environment

Page 5 of 7
ACS Catalysis
catalysed carbonylations: versatile technology for discovery
yl Bromides. Chem. Eur. J. 2015, 21, 9550–9555. (c) Kinney,
G. R.; Tjutrins, J.; Torres, G. M.; Liu, N. J.; Kulkarni, O.;
Arndtsen, B. A. A general approach to intermolecular car-
bonylation of arene C–H bonds to ketones through catalyt-
ic aroyl triflate formation. Nat. Chem. 2018, 10, 193–199; (d)
Torres, G. M.; Quesnel, J. S.; Bijou, D.; Arndtsen, B. A.
From Aryl Iodides to 1,3-Dipoles: Design and Mechanism
of a Palladium Catalyzed Multicomponent Synthesis of
Pyrroles. J. Am. Chem. Soc. 2016, 138, 7315–7324; (e)
Tjutrins, J.; Arndtsen B. A. An Electrophilic Approach to
the Palladium-Catalyzed Carbonylative C−H Functionali-
zation of Heterocycles. J. Am. Chem. Soc. 2015, 137, 12050–
12054; (f) Bontemps, S.; Quesnel, J. S.; Worrall, k.;
Arndtsen, B. A. Palladium-Catalyzed Aryl Iodide Carbonyl-
ation as a Route to Imidazoline Synthesis: Design of a Five-
Component Coupling Reaction. Angew. Chem. Int. Ed. 2011,
50, 8948–8951.
and process chemists. Tetrahedron 2010, 66, 5515–5548; (c)
Wu, X.-F.; Neumann, H.; Beller, M. Palladium-catalyzed
carbonylative coupling reactions between Ar–X and carbon
nucleophiles. Chem. Soc. Rev. 2011, 40, 4986–5009; (d) Wu,
L.; Fang, X.; Liu, Q.; Jackstell R.; Beller, M.; Wu, X.-F. Pal-
ladium-Catalyzed Carbonylative Transformation of
C(sp3)−X Bonds. ACS Catal. 2014, 4, 2977–2989; (e) Peng,
J.-B.; Wu, X.-F. Ligand- and Solvent-Controlled Regio- and
Chemodivergent Carbonylative Reactions. Angew. Chem.
Int. Ed. 2018, 57, 1152–1160.
1
2
3
4
5
6
7
8
9
3. For representative mechanistic studies: (a) Hu, Y. H.; Liu,
J.; Lu, Z. X.; Luo, X. C.; Zhang, H.; Lan, Y.; Lei, A. W. Base-
Induced Mechanistic Variation in Palladium-Catalyzed
Carbonylation of Aryl Iodides. J. Am. Chem. Soc. 2010, 132,
3153–3158; (b) Xu, T.; Alper, H. Pd-Catalyzed Chemoselec-
tive Carbonylation of Aminophenols with Iodoarenes:
Alkoxycarbonylation vs Aminocarbonylation. J. Am. Chem.
Soc. 2014, 136, 16970–16973; ; (c) Lin, Y. S.; Yamamoto, A.
Studies Relevant to Palladium-Catalyzed Carbonylation
Processes. Mechanisms of Formation of Esters and Amides
from Benzylpalladium and (Phenylacetyl)palladium Com-
plexes on Reactions with Alcohols and Amines. Organome-
tallics 1998, 17, 3466–3478; (d) Hidai, M.; Hikita, T.; Wada,
Y.; Fujikura, Y.; Uchida Y. Carboxymethylation of Organic
Halides by Palladium Complexes under Mild Conditions.
Bull. Chem. Soc. Jpn. 1975, 48, 2075–2077; (e) Ozawa, F.;
Kawasaki, N.; Okamoto, H.; Yamamoto, T.; Yamamoto, A.
Mechanisms of Double and Single Carbonylation Reactions
of Aryl Iodides Catalyzed by Palladium Complexes To Give
α-Keto Esters and Esters. Organometallics 1987, 6, 1640–
1651; (f) Moser, W. R.; Wang, A. W.; Kildahl, N. K. Mecha-
nistic Studies of the Palladium-Catalyzed Reaction of
Methanol with Bromobenzene and CO To Produce Methyl
Benzoate. 1. Stoichiometric Study. J. Am. Chem. Soc. 1988,
110, 2816–2820.
4. (a) Martinelli, J.R.; Clark, T. P.; Watson, D. A.; Munday, R.
H.; Buchwald, S. L. Palladium-Catalyzed Aminocarbonyla-
tion of Aryl Chlorides at Atmospheric Pressure: The Dual
Role of Sodium Phenoxide. Angew. Chem. Int. Ed. 2007, 46,
8460–8463; (b) Watson, D. A.; Fan, X.; Buchwald, S. L.
Carbonylation of Aryl Chlorides with Oxygen Nucleophiles
at Atmospheric Pressure. Preparation of Phenyl Esters as
Acyl Transfer Agents and the Direct Preparation of Alkyl
Esters and Carboxylic Acids. J. Org. Chem. 2008, 73, 7096–
7101.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. For catalytic approaches to acid chlorides with alkenes or
allylic substrates: (a) Cernak, T. A.; Lambert, T. H. Multi-
catalytic Synthesis of α-Pyrrolidinyl Ketones via a Tandem
Palladium(II)/ Indium(III)-Catalyzed Aminochlorocar-
bonylation/Friedel-Crafts Acylation Reaction. J. Am. Chem.
Soc. 2009, 131, 3124–3125; (b) Fang, X.; Cacherat, B.; Moran-
di, B. CO- and HCl-free synthesis of acid chlorides from
unsaturated hydrocarbons via shuttle catalysis. Nat. Chem.
2017, 9, 1105–1109. (c) Dent, W. T.; Long, R.; Whitefield, G.
H. The Carbonylation of Allylic Chlorides. J. Chem. Soc.
1964, 1588–1594; (d) Tsuji, J.; Morikawa, M.; Kiji, J. Organic
Syntheses by Means of Noble Metal Compounds. VII.1 Re-
actions of Olefin-Palladium Chloride Complexes with Car-
bon Monoxide. J. Am. Chem. Soc. 1964, 86, 4851–4853; (e)
Medema, D.; van Helden, R.; Kohll, C. F. Palladium-
Catalysed Carbonylation of Unsaturated Compounds. In-
org. Chim. Acta 1969, 3, 255–265.
11. (a) Petrone, D. A.; Ye, J.; Lautens, M. Modern Transition-
Metal-Catalyzed Carbon−Halogen Bond Formation. Chem.
Rev. 2016, 116, 8003–8104; (b) Chen, C.; Tong, X. Synthesis
of organic halides via palladium(0) catalysis. Org. Chem.
Front. 2014, 1, 439–446; (c) Jiang, X.; Liu, H.; Gu, Z. Car-
bon–Halogen Bond Formation by the Reductive Elimina-
tion of PdII Species. Asian J. Org. Chem. 2012, 1, 16–24.
12. (a) Vikse, K.; Naka, T.; McIndoe, J. S.; Besora, M.; Maseras,
F. Oxidative Additions of Aryl Halides to Palladium Pro-
ceed through the Monoligated Complex. ChemCatChem
2013, 5, 3604–3609; (b) Miloseredov, F. M.; McMullin, C. L.;
Belmonte, M. M.; Benet-Buchnolz, J.; Bakhmutov, V. I.;
Macgregor, S. A.; Grushin, V. V. The Challenge of Palladi-
um-Catalyzed Aromatic Azidocarbonylation: From Mech-
anistic and Catalyst Deactivation Studies to a Highly Effi-
cient Process. Organometallic 2014, 33, 736–752.
5. Burhardt, M.N.; Taaning, R. H.; Skrydstrup, T. Pd-
Catalyzed Thiocarbonylation with Stoichiometric Carbon
Monoxide: Scope and Applications. Org. Lett. 2013, 15, 948–
951.
6. De Almeida, A. M.; Andersen, T. L.; Lindhardt, A. T.; de
Almeida, M. V.; Skrydstrup, T. General Method for the
Preparation of Active Esters by Palladium-Catalyzed
Alkoxycarbonylation of Aryl Bromides. J. Org. Chem. 2015,
80, 1920–1928.
7. Miloserdov, F. M.; Grushin, V. V. Palladium-Catalyzed Ar-
omatic Azidocarbonylation. Angew. Chem. Int. Ed. 2012, 51,
3668–3672.
8. Ueda, T.; Konishi, H.; Manabe, K. Palladium-Catalyzed
Fluorocarbonylation Using N-Formylsaccharin as CO
Source: General Access to Carboxylic Acid Derivatives.
Org. Lett. 2013, 15, 5370–5373.
9. (a) Quesnel, J. S.; Arndtsen, B. A. A Palladium-Catalyzed
Carbonylation Approach to Acid Chloride Synthesis. J. Am.
Chem. Soc. 2013, 135, 16841–16844, (b) Quesnel, J. S.; Kayser,
L. V.; Fabrikant, A.; Arndtsen, B. A. Acid Chloride Synthe-
sis by the Palladium-Catalyzed Chlorocarbonylation of Ar-
13. Quesnel, J. S.; Moncho, S.; Ylijoki, K. E. O.; Martin Torres,
G.; Brother, E. N.; Bengali, A. A.; Arndtsen, B. A. Computa-
tional Study of the Palladium-Catalyzed Carbonylative
Synthesis of Aromatic Acid Chlorides: The Synergistic Ef-
fect of PtBu3 and CO on Reductive Elimination Chem. Eur.
J. 2016, 22, 15107–15118.
14. (a) de Rycke, N.; Couty, F.; David, O. R. P. Increasing the
Reactivity of Nitrogen Catalysts. Chem. Eur. J. 2011, 17,
12852–12871; (b) Spivey, A. C.; Arseniyadis, S. Nucleophilic
Catalysis by 4-(Dialkylamino)pyridines Revisited—The
Search for Optimal Reactivity and Selectivity. Angew.
Chem. Int. Ed. 2004, 43, 5436–5441; (c) Ragnarsson, U.;
Grehn, L. Novel Amine Chemistry Based on DMAP-
Catalyzed Acylation. Acc. Chem. Res. 1998, 31, 494–501.
15. Quesnel, J. S.; Fabrikant, A.; Arndtsen, B. A. A flexible ap-
proach to Pd-catalyzed carbonylations via aroyl dimethyl-
aminopyridinium salts. Chem. Sci. 2016, 7, 295–300.
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 7
16. (a) Littke, A. F.; Fu, G. C. Palladium-Catalyzed Coupling
(Hetero)Aryl Bromides with a Palladacycle Precatalyst.
Org. Lett. 2014, 16, 4296–4299; (g) Zeng, F.; Alper, H. Pd-
Catalyzed Direct Coupling of Indoles with Carbon Monox-
ide and Alkynes: Selective Synthesis of Linear α,β-
Unsaturated Ketones Org. Lett. 2013, 15, 2034–2037.
19. Martinelli, J. R.; Watson, D. A.; Freckmannm, D. M. M.;
Barder, T. E.; Buchwald, S. Palladium-Catalyzed Carbonyla-
tion Reactions of Aryl Bromides at Atmospheric Pressure:
A General System Based on Xantphos J. Org. Chem. 2008,
73, 7102–7107.
Reactions of Aryl Chlorides. Angew. Chem. Int Ed. 2002, 41,
4176–4211; (b) Christmann, U.; Vilar, R. Monoligated Palla-
dium Species as Catalysts in Cross-Coupling Reactions.
Angew. Chem. Int. Ed. 2005, 44, 366–374; (c) Fleckenstein,
C. A.; Plenio, H. Sterically demanding trialkylphosphines
for palladium-catalyzed cross coupling reactions—
alternatives to PtBu3. Chem. Soc. Rev. 2010, 39, 694–711; (d)
Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines in
Pd-catalyzed amination: a user’s guide. Chem. Sci. 2011, 2,
27–50.
1
2
3
4
5
6
7
8
9
20. DMAP salt 1 is soluble in the CD Cl solvent and re-adds
2
2
17. For review on ligands in carbonylation reactions see: Fang,
W.; Zhu, H.; Deng, Q.; Liu, S.; Liu, X.; Shen, Y.; Tu, T. De-
sign and Development of Ligands for Palladium-Catalyzed
Carbonylation Reactions. Synthesis 2014, 46, 1689–1708.
18. For recent uses of Xantphos in Pd catalyzed carbonyla-
tions: (a) Shen, C; Wei, Z.; Jiao, H.; Wu, X.-F. Ligand- and
Solvent-Tuned Chemoselective Carbonylation of Bromoar-
yl Triflates. Chem. Eur. J. 2017, 23, 13369–13378; (b) Wang,
D.-L.; Yand, D.; Wang, P.; Lu, Y.; Liu, Y. Aminocarbonyla-
tion of Aryl Halides to Produce Primary Amides by Using
NH4HCO3 Dually as Ammonia Surrogate and Base. Chem-
CatChem 2017, 9, 4206–4211; (c) Cabrera-Pardo, J. R.;
Trowbridge, A.; Nappi, M.; Ozaki, K.; Gaunt, M. J. Selective
Palladium(II)-Catalyzed Carbonylation of Methylene β-
C−H Bonds in Aliphatic Amines. Angew. Chem. Int. Ed.
2017, 56, 11958–11962; (d) Li, H.; Neumann, H.; Beller, M.
Palladium-Catalyzed Aminocarbonylation of Allylic Alco-
hols Chem. Eur. J. 2016, 22, 10050–10056; (e) Yu, H.; Zhang,
G.; Huang, H. Palladium-Catalyzed Dearomative Cyclocar-
bonylation by C−N Bond Activation. Angew. Chem. Int. Ed.
2015, 54, 10912–10916; (f) Friis, S. D.; Skrydstrup, T.; Buch-
wald, S. L. Mild Pd-Catalyzed Aminocarbonylation of
to Pd(0) without aryl iodide present.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21. (a) van Leeuwen, P. W. N. M.; Kamer, P. C. J. Featuring
Xantphos. Catal. Sci. Technol. 2018, 8, 26–113; (b) Adams,
G. M.; Weller, A. S. POP-type ligands: Variable coordina-
tion and hemilabile behaviour. Coor. Chem. Rev. 2018, 355,
150–172; (c) van Leeuwen, P. W. N. M.; Freixa, Z. in Mod-
ern Carbonylation Methods; Kollàr, L., Eds.; WILEY-VCH:
Weinheim, 2008, p. 1–26.
22. While the catalytic reaction is set-up under an inert at-
mosphere, the solid aroyl-DMAP salts is stable. Thus, the
addition of nucleophile can be performed in air.
23. The addition of NaPF6 also inhibits a competing exchange
of aromatic groups from the Xantphos ligand, presumably
via a more rapid reductive elimination from a cationic
complex (e.g. 2c): Goodson, F.E.; Wallow, T.I.; Novak,
B.M., Mechanistic Studies on the Aryl-Aryl Interchange
Reaction of the ArPdL2I (L = Triarylphosphine) Complexes.
J. Am. Chem. Soc. 1997, 119, 12441-12453.
ACS Paragon Plus Environment

Page 7 of 7
ACS Catalysis
Insert Table of Contents artwork here
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment