Palladium catalyzed carbonylative generation of potent, pyridine-based acylating electrophiles for the functionalization of arenes to ketones

Article abstract of DOI:10.1039/d0sc03129a

We describe here the design of a palladium catalyzed route to generate aryl ketones via the carbonylative coupling of (hetero)arenes and aryl- or vinyl-triflates. In this, the use of the large bite angle Xantphos ligand on palladium provides a unique avenue to balance the activation of the relatively strong C(sp2)-OTf bond with the ultimate elimination of a new class of potent Friedel-Crafts acylating agent: N-acyl pyridinium salts. The latter can be exploited to modulate reactivity and selectivity in carbonylative arene functionalization chemistry, and allow the efficient synthesis of ketones with a diverse array of (hetero)arenes. This journal is

Full text of DOI:10.1039/d0sc03129a

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Palladium Catalyzed Carbonylative Generation of Potent,
Pyridine-Based Acylating Electrophiles for the Functionalization of
Arenes to Ketones
Received 00th January 20xx,
Accepted 00th January 20xx
Yi Liu, Angela M. Kaiser and Bruce A. Arndtsen*
DOI: 10.1039/x0xx00000x
We describe here the design of a palladium catalyzed route to generate aryl ketones via the carbonylative coupling of
(hetero)arenes and aryl- or vinyl-triflates. In this, the use of the large bite angle Xantphos ligand on palladium provides a
unique avenue to balance the activation of the relatively strong C(sp2)-OTf bond with the ultimate elimination of a new class
of potent Friedel-Crafts acylating agent: N-acyl pyridinium salts. The latter can be exploited to modulate reactivity and
selectivity in carbonylative arene functionalization chemistry, and allow the efficient synthesis of ketones with a diverse
array of (hetero)arenes.
Introduction
The design of catalytic methods for the efficient and selective
functionalization of aromatic C-H bonds represents an
important current thrust in synthetic chemistry.1 Despite many
significant recent advances in this area, adapting these
transformations to carbonylative ketone synthesis has seen less
success.2 Aryl ketones are instead often generated from arenes
with traditional Friedel-Crafts acylations using potent acyl
electrophiles (Fig. 1a).3 Friedel-Crafts reactions have several
attractive features, including their versatility, ability to proceed
in an intermolecular fashion, predictable selectivity, and
reactivity without directing groups. Nevertheless, a limitation of
this chemistry is the need to generate the electrophiles
themselves. The latter can require multiple steps and use high
energy reagents (e.g. thionyl chloride, oxalyl chloride, or
carbodiimides).4 Moreover, stoichiometric Lewis acids are
usually employed to mediate Friedel-Crafts couplings, which
leads to compatibility problems with basic functionalities or
even decomposition, and generates significant metal-
containing waste.5 These limitations are of relevance, since aryl
ketones are useful motifs in a range of areas, including
pharmaceuticals, photosensitizers and polymers.6
a. Friedel-Crafts Acylation
O
O
MXn
R2
R1
X
+
R2
R1
b. Catalyst Design for Carbonylative Acyl Electrophile Formation
Step A
Step B
O
Ar
O
Ar
fast
slow
LnPd(0)
LnPd OTf
LnPd OTf
O
-
Ar OTf
CO
Ar
OTf
vs.
Ln = (PR3)2
L = CO
c. This Work:
OTf
O
[Pd] /
Xantphos
H
R1
Ar
R1
Ar
+
+
CO
N
available reagents
R
O
OTf tunable
electrophile
N
Recent studies by a number of labs including our own have
described how carbonylations can offer an efficient alternative
approach to the generation of potent acylating electrophiles.7-
R1
R
1
Fig. 1 Friedel-Crafts acylations and this work: Carbonylative generation of N-acyl
pyridinium salts for C-H functionalization.
10
The reactivity of these products has allowed the application
of carbonylation reactions to a range of challenging substrates,
including the direct functionalization of arenes with acyl
triflates.8e However, as with classical Friedel- Crafts chemistry,
the reaction here also requires the use of stoichiometric metal
additives: in this case silver triflate salts, in concert with reactive
aryl iodides. In addition, the acyl triflates generated are potent
electrophiles, and offer little opportunity to control their
reactivity without changing the substrate itself.
Department of Chemistry, McGill University, 801 Sherbrooke Street West,
Montreal, QC H3A 0B8, Canada. E-mail: bruce.arndtsen@mcgill.ca
From an efficiency standpoint, a potential solution to these
issues would be to directly carbonylate aryl triflates to aroyl
Electronic
Supplementary
Information
(ESI)
available:.
See
DOI: 10.1039/x0xx00000x
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Journal Name
Bn
N
O
electrophiles. Such a system would obviate the need for metal
triflate salts, and also allow the use of broadly available aryl- or
vinyl-triflate building blocks, which can be generated in an
efficient fashion from the corresponding phenols or ketones,
respectively.11,12 Unfortunately, this transformation presents a
significant catalyst design challenge (Fig. 1b). The aryl triflate
bond is much more robust than that in aryl iodides (ca. 100 vs.
65 kcal/mol),13 and typically requires strong donor and
chelating ligands on palladium to favor its activation in the
presence of coordinating and π-acidic CO (Fig. 1b, Step A).14 The
counter to this step, the product liberating reductive
elimination of the highly electrophilic aroyl triflate from
palladium, is a strongly disfavoured equilibrium, and has only
been noted with the opposite catalyst, an electron deficient
palladium species (e.g. (CO)nPd, Step B).8e This leads to the
seemingly contradictory, and to our knowledge unprecedented,
need for a catalyst that can activate a relatively strong C(sp2)-
OTf bond, at the same time eliminate a kinetically reactive
acylating agent, and do so under the conditions required for
arene functionalization.
10% (COD)Pd(CH2TMS)2
Bn
View Article Online
OTf
N
DOI: 10.1039/D0SC03129A
20% ligand
+ CO +
4 atm
Collidine (1 equiv.)
CD3CN, 130 oC, 24 h
MeO
MeO
2a
Ligand Effects:a
PPh2
PPh2
PCy2
iPr
PPh2
PPh2
iPr
-
PR3
Fe
R=tBu: 1%
0%
4%
0%
0%
iPr
R=C6F5: 0%
O
O
O
O
PtBu2
PtBu2
PPh2
PPh2
PPh2
PPh2 PR2
PR2
0%
1%
3%
13%
(R = o-tolyl)
Pyridine Effects:a
OMe
Me
N
N
N
Me
N
N
N
N
We describe herein our studies towards such a system.
These illustrate how balancing ligand steric and electronic
features, in concert with the correct additives, can open a
palladium catalyzed route to build-up highly reactive acylating
electrophiles from C(sp2)-triflates. Synthetically, the reactivity
of these electrophiles offers an efficient route to form ketones
from broadly available (hetero)arenes, aryl/vinyl triflates and
carbon monoxide, and do so without the need for
stoichiometric metal additives or expensive reagents. In
addition, mechanistic studies suggest this reaction generates a
new class of Friedel-Crafts electrophile: N-acyl pyridinium salts
(1, Fig. 1c). These acylating agents possess several useful
features, including the ability to functionalize arenes under non-
acidic conditions, do so without Lewis acid additives, and tune
reactivity or selectivity with the pyridine employed.
83%c
82%
87%c
77%d
13%
13%b
CF3
CN
none
0%
N
N
6%e
Cl
N
F
N
12%
10%
5%
Fig. 2 Ligand and pyridine effects on palladium catalyzed carbonylative pyrrole
a.
b.
functionalization. NMR yields, ca. 2 : 1 ratio of 2- : 3-isomers of 2a. with 5%
[Pd(allyl)Cl]2 and 2 equiv. of DMAP; c. 46 h; d. 40 h; e. 17 h.
In probing approaches to enhance the yield of the reaction,
one simple modification was to change the base employed. This
was found to dramatically influence reactivity. For example,
catalysis with electron deficient pyridines such as 4-
trifluoromethyl-, 2-chloro- or 2-fluoropyridine leads to
diminished yields (5-10%, Fig. 2). Electron rich 4-
dimethylaminopyridine (DMAP) is also poorly effective (13%),
and no ketone 2a is observed without a pyridine additive (see
Fig. S1 for full list of pyridines examined). However, using
pyridines between these two extremes of nucleophilicity, such
as 4-methoxypyridine and simple pyridine, can allow the overall
functionalization of pyrrole and ketone generation with high
efficiency (up to 87% yield).16
The dramatic influence of the pyridine derivative employed
in these reactions is unusual, and suggests it may play a more
direct role than simply that of a base. Acylating electrophiles are
established to react with pyridine to form N-acyl pyridinium
salts.17 Indeed, control experiments show this association
occurs between an in situ generated aroyl triflate and 4-
methoxypyridine within minutes at ambient temperature (Fig.
S2). More conclusive evidence for the formation of N-acyl
pyridinium salts (1) as intermediates can be seen by performing
the palladium catalyzed carbonylation in the absence of the
pyrrole trap. While aryl triflates react under these conditions to
form a mixture of products (Fig. S3), the carbonylation of a more
Results and discussion
Our initial studies examined the palladium catalyzed coupling of
an aryl triflate with N-benzyl pyrrole and carbon monoxide (Fig.
2). Using a palladium catalyst without any added phosphine
ligand, in analogy to results with aryl iodide reagents,8e leads to
no ketone product, nor does the use of various monodentate
phosphine ligands. Instead, the unreacted aryl triflate is
recovered. We next turned to bidentate ligands, as these have
been demonstrated to allow the oxidative addition of aryl
triflates in traditional carbonylations.14 Many of these were
similarly ineffective, which may reflect the now difficult
reductive elimination of the reactive aroyl triflates from
palladium.8e We considered using steric effects to balance the
electronic needs of oxidative addition with the ultimate
reductive elimination of a reactive acyl electrophile.8 After
examining various sterically encumbered bidentate ligands, we
were pleased to find that the large bite angle, moderate donor
Xantphos allowed the intermolecular functionalization of N-
benzyl pyrrole to afford ketone 2a in low yield (13%).15
2 | J. Name., 2012, 00, 1-3
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a. Catalytic build-up of N-acyl pyridinium salt
the electron rich 4-dimethylamino substituted pyridinium salt
requires even more pressing conditions (130 °C) to form ketone.
View Article Online
DOI: 10.1039/D0SC03129A
O
OTf
5% Pd2dba3•CHCl3
20% Xantphos
OTf
+
N
Based upon this data, we postulate that this carbonylative
functionalization reaction proceeds as shown in Fig. 3c. The
reactivity observed with the Xantphos ligand is presumably
related in part to its ability to associate in a bidentate fashion to
palladium and better activate the relatively strong C(sp2)-OTf
bond towards carbonylation, in concert with its large bite angle,
which can favor the reductive elimination.8,19 The combination
of these features offers an avenue to build-up kinetically
reactive acylating agents from C(sp2)-triflates.20 The importance
of pyridine, and the specific pyridine structure, in catalysis is
tied to its ability to stabilize the reductive elimination product
relative to a highly reactive acid triflate. The adducts 1 represent
a new class of Friedel-Crafts acylating reagent, and incorporate
several attractive features, including the ability to react with
(hetero)arenes without added Lewis acids, and tune Friedel-
Crafts acylation reactivity with the pyridine employed (vide
infra).
N
+
CO
RT, 24 h
OMe
4 atm
OMe
1a, 99%
b. Relative electrophilicity studies
O
Bn
N
O
Bn
CD3CN
24 h
N
X
+
MeO
O
MeO
2a
(2 equiv.)
Increasing reactivity
O
O
O
O
OTf
OTf
OTf
<
<
<
<
N
Ar
OMe
Ar
Cl
Ar
Ar
OTf
N
Ar
N
CF3
NMe2
0% (80 oC)
0% (RT)a
0% (RT)
95%
(RT, 5 min)
99%
(RT, 5 min)
17% (130 oC)
99% (80 oC 8 h)
14% (80 oC)
w/ thiophene instead of pyrrole: 14% (RT)
86% (80 oC)b
91% (RT)
The in situ generation of N-acyl pyridinium salts offers a
versatile approach to the overall carbonylative conversion of
arenes to ketones. As shown in Fig. 4, various pyrroles can be
employed in this reaction in concert with 4-methoxypyridine,
such as those with N-benzyl, -methyl and -aryl substituents.
These each lead to the favored formation of the 2-substituted
ketone product (2a-2c), which is consistent with a Friedel-Crafts
mechanism of reaction.4a,21 The more sterically encumbered N-
tert-butyl pyrrole is functionalized with high selectivity at the 3-
position (2d-i). Disubstituted pyrroles such as 2,5-dimethyl-N-
phenyl pyrrole also undergo efficient reaction to form ketone
2j. This chemistry can be applied to other nitrogen heterocycles
such as substituted indoles, (2k-n), and N-substituted
benzimidazole (2o). In addition to the variation of the
heteroarenes, a number of aryl triflates can be employed in the
reaction, including 4-methoxy, -phenyl (2g) and -alkyl
substituted (2h) reagents. Meta-substituted aryl triflates are
tolerated (2i, 2m, and 2n), albeit with diminished yields.
Catalysis also proceeds with less electron rich substrates, such
as simple phenyl (2d) or naphthyl triflate (2f). However, the use
of aryl triflates with electron-withdrawing substituents such as
4-cyano and 4-trifluoromethyl substituted aryl triflates leads
instead to significant amounts of the phenyl-substituted ketone
(2d) (44% and 43%, respectively, see Fig. S5) The latter
presumably arises from the ability of the palladium-aryl
intermediate to scramble substituents with the Xantphos
ligand.8h-i,22 Similarly, less polar aryl mesylates are not reactive
under these conditions (Fig. S6).
c. Proposed mechanism
bidentate ligand
R2
N
O
PPh2
PPh2
OTf
R3
N
OTf
O
ketone
Pd(CO)n
R1
1
R1
R3
N
CO
N
OTf
R3
H
R1
O
PPh2
Pd
PPh2
R1
O
O
Pd
OTf
OTf
PPh2
PPh2
large bite angle
CO
Fig. 3 Mechanistic experiments on the carbonylative formation and reactivity of N-
a.
acyl pyridinium salts. reactions with acid chlorides were performed in the
presence of 1 equivalent of 2,4,6-collidine. b 1 h.
reactive vinyl triflate leads to the formation of the N-acyl
pyridinium salt 1a (Fig. 3a).9n,18 The formation of 1a provides a
rationale for the significant role of the pyridine base in the
chemistry, where the more nucleophilic pyridine can
presumably favor reductive elimination relative to the potential
build-up of
a
labile acyl triflate. However, this is
counterbalanced by the ability of these systems to react with
arenes. The latter can be seen as well in control experiments
(Fig. 3b). The 4-trifluoromethyl substituted pyridinium salt
reacts within minutes at ambient temperature with N-benzyl
pyrrole to form ketone. Replacing the pyrrole with thiophene
also leads to ketone (Fig. S4), although the latter requires more
pressing conditions than acyl triflates themselves. In contrast,
the more electron rich 4-methoxy substituted pyridinium salt
does not react with pyrrole at ambient temperature, and
requires heating to 80 °C to form product. For comparison, acid
chlorides show low reactivity, 14%, under these conditions, and
We next explored the compatibility of this system with vinyl
triflates as a route to access α,β-unsaturated ketones. The
transformation here is more efficient than reactions with aryl
triflates, and coupling with pyrroles and indoles can proceed at
ambient temperature with some substrates (e.g. 3f). As with the
aryl triflates, the reaction is compatible with N-substituted (3a)
or 2,5-disubstituted pyrroles (3b), and similarly functionalized
indoles using cyclic (3c-e) or acyclic (3b and 3f) vinyl triflate
reagents. These allow access to various α- or β,β-substituted
acyclic enones.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0SC03129A
O
5% Pd2dba3•CHCl3
H
OTf
20% Xantphos
+
+
Ar
Ar
CO
N
/ MeCN
100-130 o
R1
OMe
4 atm
R1
C
R
N-Heterocycles
MeO
O
O
O
Bn
Me
O
O
N
N
N
MeO
N
N
OMe
MeO
MeO
2e,
74%
O
tBu
2d, 63%
2b, 84%
2:1 2-:3-isomers
2a, 80%
1.7:1 2-:3-isomers
N
2c, 76%
tBu
1.8:1 2-:3-isomers
O
MeO
Me
O
O
O
N
Ph
N
tBu
N
MeO
MeO
tBu
N
Ph
Me
N
tBu
tBu
tBu
2i, 35%b
2j,
67%
2h, 44% (70% NMR)a
2f, 63%
2g, 47%
O
O
R
O
O
N
tBu
N
O
Me
MeO
N
MeO
N
Me
Me
O
N
Me
R = H, 2k, 66%
R = Me, 2l, 54%
2o, 62%
2m, 52%
2n, 38%
O
O
Me
N
O
O
Me
N
O
Me
Me
N
N
Ph
C5H11
Me
3f, 79%g
N
R
Me
R = H, 3c, 52%d Me
R = Me, 3d, 60%c,e
3b, 64%f
3e, 60%
3a, 56%
Me
Thiophenes, furans, arenes
O
O
O
O
O
O
S
S
S
N
S
O
R
Me
R
Me
Me
C5H11
R= H, 3i, 43%
CF3
O
Me
3k, 81%b
R = H, 3g, 74%
R = Me, 3h, 75%b
3l, 41%b
MeO
3m, 55%e
3n, 74%b
R = Me, 3j, 37%b, f
OTf
O
OMe
O
OMe
O
OMe
O
tBu
OMe
Ph
MeO
OMe
MeO
MeO
O
OMe
OMe
OMe
MeO
3o, 93%
3r, 76%
3p, 70%
3q, 53%
O
OMe
O
O
OMe
O
OMe
MeO
OMe
3w, 53%
OMe
MeO
OMe
3u, 49%b
3t, 56%
3v, 53%
3s, 43%
Fig. 4 Diversity of products available from the Pd catalyzed C-H functionalization of (hetero)arenes with organotriflates. Performed with 2 equiv. aryl or vinyl triflates for
pyrroles and indoles, 1 equiv. with other (hetero)arenes, 4 atm CO, 130 °C; 10% (COD)Pd(CH2TMS)2, 48 h for aryl triflates; using 5% Pd2dba3∙CHCl3, for vinyl triflates. a.
difficult isolation due to the presence of phenyl ketone 2d; b. 10% Pd(Xantphos)2; c. 1.25% Pd2dba3∙CHCl3; d. 150 °C; e. 100 °C; f. 80 °C; g. 25 °C
.
In addition, the pyridine unit can be used to modulate trimethoxybenzene (3o-s, 3w) and anisole (3t-v), each of which
electrophilic reactivity. Thus, while less activated undergo C-H functionalization to afford the corresponding α,β-
(hetero)arenes (e.g. thiophenes or substituted arenes) do not unsaturated ketone. This reactivity is compatible with a range
lead to product formation using 4-methoxypyridine, the use of of cyclic vinyl triflates (3g, 3l, 3p). Moreover, acyclic vinyl
the weakly nucleophilic 4-trifluoromethylpyridine can allow the triflates bearing α- or/and β- (3b, 3f), alkyl- (3f, 3k) or aryl- (3b)
carbonylative C-H functionalization of various other classes of substituents can also proceed to generate ketone products.
aromatic reagents. The more reactive vinyl triflates are Interestingly, by using 4-trifluoromethylpyridine, the vinyl
employed here to allow the build-up of these less stable N-acyl triflate bond can be selectively activated in the presence of an
pyridinium salts. Examples of hetero(arenes) that can now be aryl triflate (3w). Together, this system provides access to an
functionalized include substituted thiophenes (3g-l), furans array of ketones via the palladium catalyzed carbonylative
(3m, 3n), and even substituted arenes, such as 2,4,6- functionalization of arenes with accessible organic triflates.
4 | J. Name., 2012, 00, 1-3
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reaction to instead generate cyclized products of indoles,
View Article Online
tBu
N
a.
pyrroles and thiophenes (4a-c). The DOgeI:n1e0.r1a0t3i9o/nD0SoCf03412a9-Ac
presumably arises from the ability of these systems to undergo
acid catalyzed Nazarov cyclization,24 and offers a method to
functionalize two C-H bonds at once to build up polycyclic
products from heterocycles, CO and vinyl triflates.
tBu
N
10%
O
OTf
(COD)Pd(CH2TMS)2
20% Xantphos
CO
+
+
MeO
MeCN
130 oC, 48 h
4 atm
MeO
2e
3-isomer 2-isomer
N
2 equiv.: 66%
1 equiv.: 74%
12%
0%
OMe
Conclusions
b.
OTf
In summary, we have described a new approach to the
palladium catalyzed carbonylative generation of potent
electrophiles with aryl and vinyl triflates for the overall
functionalization of arenes. The reaction offers a route to access
ketones from combinations of available substrates
(organotriflates, (hetero)arenes, CO), and without the typical
need for Lewis acids or stoichiometric metal-containing
reagents. Mechanistic analysis shows that the Pd/Xantphos
catalyst system, in concert with pyridine additives, can provide
an unusual avenue to balance the activation of relatively strong
C(sp2)-OTf bonds with the ultimate elimination of reactive
acylating agents. In this, the pyridine additive serves not only as
a base, but more crucially as a building block to drive the
formation of a new class of Friedel-Crafts reagent: N-acyl
pyridinium salts. The latter can be exploited to modulate
reactivity and product selectivity in carbonylative
4 atm CO
(2 equiv.)
O
O
5%
OMe
+
Me
Pd2dba3•CHCl3
20% Xantphos
N
+
Me
N
Me
3d
MeCN
OMe
MeO
3o
130 oC, 3 h
Me
MeO
+
N
R = CF3:
64%
53%
0%
OMe
R
R = OMe:
38%
(3 equiv.)
(87%)a
(5 equiv.)
MeO
c.
O
10% (COD)Pd(CH2TMS)2
20% Xantphos
OTf
X
X
H
+ CO
+
4-R-C5H5N
MeCN, 130 o
4 atm
H
C
O
O
O
Me
S
N
N
Me
functionalization chemistry with
(hetero)arenes.
a
diverse array of
OMe
CF3
N
3a 56%c
3c, 52%b
Me
3h, 75%d
O
O
O
Me
N
N
S
Conflicts of interest
There are no conflicts to declare.
Me
N
4b, 60%f
4c, 57%g
4a, 66%e
Me
Fig. 5 Selectivity control in carbonylative C-H functionalization with pyridine
employed. 1.1 equiv. 4-methoxypyridine, 100 °C, 2.5 h, 17% 3o also formed;
Acknowledgements
a.
b.
c.
d.
5% Pd2dba3∙CHCl3,150 °C, 12 min;
5% Pd2dba3∙CHCl3, 20 min;
10%
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Canadian Foundation for
Innovation (CFI), McGill University (James McGill Research
Fund), and the Fonds de recherche du Québec – Nature et
Technologies (FQRNT) supported Centre for Green Chemistry
and Catalysis for funding this research.
Pd(Xantphos)2, 4-trifluoromethylpyridine, 16 h; e. 20 h; f. 4 h; g. 48 h
.
Finally, we have preliminarily probed the ability of the
pyridine to fine-tune product selectivity. One simple effect is
through concentration, where lowering the amount of pyridine
employed favours the formation of 3-substituted ketone 2e for
pyrrole bearing bulky N-substituents (Fig. 5a). The latter may
affect the rate of deprotonation of the Wheland intermediate, Notes and references
and thereby allow migration of the aroyl fragment to the
favoured 3-position under less basic conditions.23 Alternatively,
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Table of Content Entry
O
[Pd]
H
OTf
Xantphos
Ar
R1
Ar
+
+
CO
R1
N
R
O
tunable
electrophile
OTf
N
R1
R
Available reagents
Controlled reactivity
Broadly applicable
A palladium catalyzed approach to the overall carbonylative functionalization of arenes to form ketones with aryl- and vinyl-
triflates is described.
8 | J. Name., 2012, 00, 1-3
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