An Electrophilic Approach to the Palladium-Catalyzed Carbonylative C-H Functionalization of Heterocycles

Article abstract of DOI:10.1021/jacs.5b07098

A palladium-catalyzed approach to intermolecular carbonylative C-H functionalization is described. This transformation is mediated by P^tBu₃-coordinated palladium catalyst and allows the derivatization of a diverse range of heterocycles, including pyrroles, indoles, imidazoles, benzoxazoles, and furans. Preliminary studies suggest that this reaction may proceed via the catalytic formation of highly electrophilic intermediates. Overall, this provides with an atom-economical and general synthetic route to generate aryl-(hetero)aryl ketones using stable reagents (aryl iodides and CO) and without the typical need to exploit pre-metalated heterocycles in carbonylative coupling chemistry.

Full text of DOI:10.1021/jacs.5b07098

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Article
An Electrophilic Approach to the Palladium-Catalyzed
Carbonylative C-H Functionalization of Heterocycles
Jevgenijs Tjutrins, and Bruce A. Arndtsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07098 • Publication Date (Web): 31 Aug 2015
Downloaded from http://pubs.acs.org on August 31, 2015
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An Electrophilic Approach to the Palladium-Catalyzed Carbonyl-
ative C-H Functionalization of Heterocycles
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Jevgenijs Tjutrins and Bruce A. Arndtsen*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, H3A 0B8, Canada
bruce.arndtsen@mcgill.ca
Received Date- (will be automatically inserted after manuscript is accepted)
ABSTRACT: A palladium catalyzed approach to intermolecular carbonylative C-H functionalization is described. This transformation is
mediated by PtBu3-coordinated palladium catalyst, and allows the derivatization of a diverse range of heterocycles, including pyrroles,
indoles, imidazoles, benzoxazoles and furans. Preliminary studies suggest that this reaction may proceed via the catalytic formation of
highly electrophilic intermediates. Overall, this provides with an atom economical and general synthetic route to generate aryl-(hetero)aryl
ketones using stable reagents (aryl iodides and CO), and without the typical need to exploit pre-metallated heterocycles in carbonylative
coupling chemistry.
INTRODUCTION
The palladium catalyzed C-H functionalization of arenes and
heteroarenes has emerged as one of the most important new ap-
proaches in synthetic chemistry.1 Extensive research efforts have
been directed towards the discovery of new approaches to these
transformations, with examples including such powerful platforms
as chelation-assisted functionalization,2 concerted metalation
deprotonation (CMD),3 radical reactions,4 and others.5 In con-
trast, the design of methods to incorporate reactive functionalities
such as CO into C-H bond functionalization has to date presented
a challenge. Unlike reactions that generate robust and relatively
inert aryl-(hetero)aryl, -alkyl, or -heteroatom bonds, palladium
catalyzed carbonylations provide an efficient route synthesize a
number of the most easily manipulated functional groups in syn-
thetic chemistry, such as carboxylic acid derivatives or ketones.6
Unfortunately, carbon monoxide is also a π-acidic and reactive
ligand with the potential to interfere with many modes of Pd-
based bond activation. In this regard, Fujiwara and others have
demonstrated the palladium catalyzed oxidative carbonylation of
Scheme 1. An Electrophilic Approach to Pd-Catalyzed
Carbonylative C-H Bond Functionalization.
arenes and heteroarenes to carboxylic acids and esters.7,8 More
recently, examples of the application of this chemistry to coupling
with aryl halides have emerged involving either intramolecular or
In considering these issues, we postulated that the features
unique to carbonylation may offer an alternative approach to C-H
functionalization. We have recently reported that the highly steri-
cally encumbered ligands such as PtBu3 can induce the reductive
elimination and Pd-catalyzed generation of acid chlorides from
aryl halides and CO.13 In contrast to the moderate reactivity of the
palladium-acyl intermediates formed in traditional carbonylations,
acid chlorides are highly electrophilic, and have allowed the ap-
plication of carbonylation to a range of new classes of weak nu-
cleophiles. The formation of acid chlorides is driven by the unu-
sual energetics of carbon monoxide, whose reduction is sufficient-
chelation assisted carbonylations by Larock, Beller, Yu, Lei and
others (Scheme 1a),9 or the use of activated substrates, such as
perfluoroarenes, reported by Skrydstrup (Scheme 1b).10 Howev-
er, a general carbonylative coupling of heterocycles and aryl hal-
ides is to our knowledge not known. These products are instead
often prepared via palladium catalyzed cross coupling reactions,11
or via Friedel-Crafts acylations with acid chlorides and strong
Lewis acids;12 both of which require the synthesis of high energy
substrates and/or create significant waste.
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ly exothermic as to allow the formation of a weak aroyl-chloride
gard was to omit the addition of chloride to the reaction of aryl
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bond. These results led us to question if carbonylations might be
used to create even more high energy products than acid chlo-
rides, including those sufficiently electrophilic to react directly
aromatic systems (Scheme 1c). We describe here the results of
these studies. These have led to the design of what is to our
knowledge the first broadly applicable approach to perform car-
bonylative C-H functionalization of heterocycles, without direct-
ing groups, and via a mechanism that is promoted, rather than
inhibited, by carbon monoxide.
iodide, pyrrole and CO. Rather than inhibiting catalysis, this led
to a dramatic increase in aroylation and 1a yield (entries 6 and 7,
also in a 3.2:1 isomeric ratio). Examination of ligand effects re-
veals that the large cone angle PtBu3 ligand creates the most reac-
tive catalyst for this transformation, and smaller ligands show
diminished activity (entries 8-15). Bidentate ligands, which have
become common in many Pd-catalyzed carbonylation reactions,
almost fully shut down catalysis (entries 16-20). Increasing the
reaction temperature to 115 oC with the most active ligand, PtBu3,
allowed us to decrease the catalyst loading to 5 mol% and obtain
the near quantitative formation of ketone (entry 21).
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RESULTS AND DISCUSSION
The optimized catalyst system can mediate carbonylative C-H
functionalization with a range of aryl iodides and pyrroles (Table
2). Electron-acceptor and electron-donor substituents are tolerat-
ed in all positions of the aryl iodide, and lead to substituted pyr-
roles in good yield. This includes a number of palladium-reactive
functionalities (1c-d, 1f-g, 1i-j), and ortho-functionalized sub-
strates (1h-1j, 1m, 1p, 1s). Sterically encumbered arenes are also
viable in this transformation (1v), and the chemistry can be ex-
tended to the use of thiophenyl iodides (1w). With N-
methylpyrrole, the 2-derivatized isomer is obtained in all cases as
the isolated product.16 In the case of the more sterically encum-
bered N-2,6-dimethylphenyl-substituted pyrrole, both regioiso-
mers were observed in moderate yields (1z), and the further in-
creasing steric bulk to N-t-butyl pyrrole leads to the exclusive
generation of the 3-subsitututed product (1x). Substituents can
also be incorporated onto the pyrrole backbone (1y).
Our initial studies involved the carbonylation of 4-iodoanisole
in the presence of the electron rich N-benzyl pyrrole employing
the conditions we have reported for the catalytic, in situ formation
of acid chlorides (Pd/PtBu3, Bu4NCl). As shown in Table 1, this
leads to the generation of the carbonylative arene/pyrrole coupling
product 1a in 44% yield (entry 1). This reaction proceeds in
highest yields with PtBu3 (entries 2 – 5), presumably due to its
ability to facilitate acid chloride reductive elimination. The for-
mation of 1a is slow under these conditions, and generates a mix-
ture of 2- and 3-substituted isomers (3.2:1 ratio). These features
mirror the reactivity of aromatic acid chlorides with pyrroles.14
Table 1. Catalyst for Carbonylative Functionalizationa
Table 2. Pd-Catalyzed Functionalization of Pyrrolesa
%
1ac
%
1ac
entry
L
additive
entry
L
1
2
3
PtBu3
PPh3
Bu4NCl
Bu4NCl
Bu4NCl
44
0
12
13
-
45
15
PCy3
P(o-tolyl)3
27
14
9
4
PCy3
Bu4NCl
0
5
Bu4NCl
24
15
21
6
7
8
9
PtBu3
Pd(PtBu3)2
PPh3
-
-
84
79
60
62
16
17
18
19
DPPE
DPPP
DPPF
DCPE
0
0
0
0
P(o-tolyl)3
-
-
10
64
20
11
97
(73)d
b
11
-
72
21
Pd(PtBu3)2
aCH3OC6H4I (47 mg, 0.20 mmol), pyrrole (16 mg, 0.10 mmol),
Pd (0.010 mmol), L (0.010 mmol), NEtiPr2 (15 mg, 0.12 mmol) 4
b
o
c
atm CO, 0.7 mL CD3CN ; 115 C, 0.005 mmol Pd; NMR yield
of 2- and 3- isomers, all formed in a 3.2:1 ratio; disolated yield of
2-aroyl pyrrole.
While effective, the observed yields in this reaction are moder-
ate, and product scope expected to be limited to substrates reac-
tive towards acid chlorides. In probing methods to increase reac-
tivity, we questioned if acid chloride formation is indeed neces-
sary for carbonylative coupling. A simple experiment in this re-
aArI (1.0 mmol), pyrrole (0.50 mmol), NEtiPr2 (77 mg, 0.60
mmol) 4 atm CO and Pd(PtBu3)2 (13 mg, 0.025 mmol) in MeCN
(2 mL) at 115 oC for 24 h; Isolated yield of isomer shown.
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The ability to carbonylatively functionalize pyrroles with aryl
allow the subsequent reaction of aroyl iodide with pyrrole.18
Consistent with this mechanism, the introduction of CO signifi-
cantly accelerates the stoichiometric reaction (Scheme 2b).19 The
latter has been noted to facilitate reductive elimination by creating
a sterically encumbered, electron poor palladium intermediate 3.13
Kinetic analysis of the reaction of 2a with pyrrole in the presence
of CO and iodotoluene show a linear rate dependence on pyrrole
concentration (See Supporting Information). While this data is
potentially consistent with all three pathways in Scheme 2a, as
with the results with iodotoluene, it also suggests that any elimi-
nation of aroyl iodide is a rapid equilibrium strongly favoring 2a.
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iodides opens a number of mechanistic questions. As no chloride
salts are present in these transformations, acid chloride is not a
viable intermediate. Nevertheless, the reactivity and product se-
lectivity observed are consistent with an electrophilic pathway. In
light of our previously observed acid chloride synthesis, one pos-
sibility is that without chloride, aroyl iodide (ArCO-I) itself can
undergo reductive elimination (Scheme 2a, path A). Although the
latter is analogous to acid chloride formation, it is notable that
aroyl iodides are much more reactive and electrophilic products,
and have not been previously observed in Pd-catalyzed carbonyla-
tion chemistry. As such, we also consider the potential that the
palladium-aroyl intermediates of carbonylation (2) could directly
react with pyrroles, such as via a Friedel-Crafts reaction with the
aroyl ligand (path B), or the electrophilic palladation of pyrrole
(path C), in analogy to known non-carbonylative reactions.16
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As far as we are aware, the catalytic formation of potent elec-
trophilic products for carbonylative C-H bond functionalization
has not been previously described. This high reactivity provides
the ability to functionalize a variety of less reactive heterocycles.
As examples, indoles can be converted into ketones in good to
excellent yields with this catalyst system (4a-k, Table 3). Col-
lidine is required as a base in these reactions to avoid the aroy-
lation of the amine base by these reactive intermediates.20 In all
cases, the 3-substituted indole derivative is generated. The
Table 3. Pd-Catalyzed Carbonylative Functionalization
of Heterocyclesa
Scheme 2. Mechanistic Studies on the Carbonylative
Functionalization of Pyrroles
Preliminary studies shed some light on the pathway followed in
1
this reaction. Monitoring the catalytic reaction by in situ by H
and 31P NMR spectrometry reveals the formation of the three-
coordinate palladium-aroyl complex 2a (Scheme 2a) as the major
palladium containing intermediate and presumed catalyst resting
state.
Complex 2a can be independently generated from
Pd(PtBu3)2, aryl iodide and CO,17 and its reactivity examined.
Interestingly, 2a does not itself react with the pyrrole at elevated
temperatures with or without CO present (Scheme 2b). These
data suggests that the palladium-aroyl complex, even with CO
coordinated, is not sufficiently electrophilic to directly react with
pyrrole, either at the aroyl ligand or palladium. However, the ad-
dition of the other reagent present in catalysis, iodotoluene, to the
stoichiometric reaction of 2a initiates a reaction with pyrrole to
form the functionalized pyrrole product. In considering the
mechanistic postulates, while it is possible that aryl iodide reacts
directly with 2a to form a Pd(IV) intermediate, an alternative role
would be to trap any Pd(0) generated upon reversible reductive
elimination in the rate determining step (path A). Unlike even
acid chlorides, the ArCO-I bond is very weak and reactive, mak-
ing its formation an equilibrium process that would heavily favor
palladium-aroyl complex 2. In the presence of excess aryl iodide,
this palladium can be converted to palladium-aryl complex and
aArI (1.0 mmol), heterocycle (0.5 mmol), collidine (73 mg, 0.6
o
mmol), Pd(PtBu3)2 (25 mg, 0.05 mmol), 2 mL MeCN, 125 C, 24
h; b 20 atm CO; c 150 oC, 48 h.
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reaction proceeds with electron rich (4a, 4f, 4j), electron poor
directing groups, or exploit high energy building blocks. Consid-
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(4b-e), or sterically encumbered (4f-h) aryl iodides. Less reactive
heterocycles can also be functionalized, such as those containing
two heteroatoms. Benzimidazoles undergoes clean carbonylative
coupling with aryl iodides to form ketones (4l,m). Similar reac-
tivity is observed with benzoxazoles (4n,o), and with the monocy-
clic N-methyl imidazole (4p,q). It is also possible to move be-
yond nitrogen heterocycles, with simple furan undergoing car-
bonylative functionalization in good yield (4r).
ering the high electrophilicity of the intermediates in this chemis-
try, and the CO promoted, rather than diminished, reactivity, this
suggests the potential application of carbonylation in a range of
new products classes. Studies directed towards the latter are un-
derway.
ASSOCIATED CONTENT
As an illustration of the potential utility of this chemistry, we
noted that the carbonylative C-H functionalization is mechanisti-
cally orthogonal to many of the more established Pd-based meth-
ods for heterocycle derivatization. The latter can be exploited for
the selective, sequential functionalization of heterocycles. As
examples, the carbonylative functionalization of indole with or-
tho-bromoiodobenzene followed by direct arylation can allow the
selective generation of polycyclic 5 (Scheme 3a). As both of
these steps are palladium catalyzed, this reaction can be extended
to a one pot, sequential C-H functionalization reaction, where the
same palladium catalyzed is employed in both steps via the step-
wise addition of ligands (Pd(PtBu3)2 and PPh3/K2CO3) for each
functionalization. We see no evidence for cross-over in function-
alization in this chemistry (e.g. non-carbonylative coupling), pre-
sumably due to the distinct mechanisms for the two processes.
The same transformation is available with pyrroles (6), and allows
the selective functionalization of two C-H bonds via differing
methods in one pot. Alternatively, this chemistry can be applied
in synthesis, such as the preparation of Tolmetin (7, Scheme 3b),
a potent nonsteroidal anti-inflammatory agent, in two steps using
available 4-iodotoluene and CO.21
9
Supporting Information
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Experimental procedures and spectral data. This material is
available free of charge at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
Bruce.arndtsen@mcgill.ca
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank NSERC, the Canadian Foundation for Innovation (CFI),
and the FQRNT supported Centre for Green Chemistry and Catal-
ysis for funding this research.
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tive Heterocycle Functionalization
CONCLUSIONS
In conclusion, we have reported a new approach to palladium
catalyzed carbonylative C-H functionalization. This provides an
efficient method to synthesize functionalized heterocycles with
high atom economy, using stable reagents (aryl iodides and CO),
and without the need to prefunctionalize the heterocycle, install
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(18) While ArCOI selectivity between Pd(0) and pyrrole would not be
affected by iodotoluene, ArCOI presumably reacts much more rapidly
with Pd(0). The analogous reaction of benzoyl chloride and Pd(PtBu3)2
occurs within 1 h at ambient temperature (ref. 13), while reaction with
o
pyrrole requires 115 C, 24 h (ref. 14). Iodotoluene reaction with Pd(0)
9
could therefore allow small concentrations ArCOI to build-up for a slower
reaction with pyrrole.
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(19) While the reaction between pyrrole and 2a in the absence of CO is
not quantitative, the initial rate of this reaction is much slower (kobs = 1.5 x
10-3 min-1) than that in the presence of CO (kobs = 1.0 x 10-2 min-1).
o
(20) Anisoyl iodide reacts with NEtiPr2 at 125 C to form N-ethyl-N-
isopropyl-4-methoxybenzamide via a Hofmann-type elimination.
(21) (a) Carson, J. R.; McKinstry, D. N.; Wong, S. J. Med. Chem.
1971, 14, 646. (b) Reddy, L. A.; Chakraborty, S.; Swapna, R.; Bhalerao,
D.; Malakondaiah, G. C.; Ravikumar, M.; Kumar, A.; Reddy, G. S.; Na-
ram, J.; Dwivedi, N.; Roy, A.; Himabindu, V.; Babu, B.; Bhattacharya, A.;
Bandichhor, R. Org. Process Res. Dev. 2010, 14, 362.
(10) (a) Lian, Z.; Friis S. D.; Skrydstrup T. Chem. Commun., 2015, 51,
1870. For carbonylative coupling with in situ generated organocuprates
with stoichiometric copper: (b) Wu, X.-F.; Anbarasan, P.; Neumann, H.;
Beller, M. Angew. Chem. Int. Ed. 2010, 49, 7316. For in situ halogenation
of heterocycles for carbonylative coupling, see: (c) Zhao, M.-N.; Ran, L.;
Chen, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. ACS Catal. 2015, 5,
1210. (d) Lang, R.; Shi, L.; Li, D.; Xia, C.; Li, F. Org. Lett. 2012, 14,
4130. (e) Li, D.; Shan, S.; Shi, L.; Lang, R.; Xia, C.; Li, F. Chinese J
Catal. 2013, 34, 185.
(11) (a) Beletskaya, I. P.; Cheprakov, A. V. In Comprehensive Organ-
ometallic Chemistry III; Crabtree, R.H; Mings, D. M. P., Eds.; Elsevier:
Oxford, 2007, 411. (b) Beller, M.; Wu, X. F. Transition Metal Catalyzed
Carbonylation Reactions: Carbonylative Activation of C-X Bonds; Spring-
er: Berlin, Heidelberg, 2013.
(12) (a) Olah, G. A. Friedel-Crafts and Related Reactions; Interscience
Publishers: New York, 1963. b) Olah, G. A. Friedel-Crafts Chemistry;
John Wiley-Interscience: New York, 1973.
(13) (a) Quesnel, J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2013, 135,
16841. (b) Quesnel, J. S.; Kayser, L. V.; Fabrikant, A.; Arndtsen, B. A.
Chem. Eur. J. 2015, 21, 9550.
(14) The reaction of N-benzyl pyrrole (16 mg, 0.1 mmol) and p-anisoyl
chloride (21 mg, 0.12 mmol) with NEtiPr2 (16 mg, 0.12 mmol) in CD3CN
o
(0.7 mL) at 115 C for 24 h leads to the 2- and 3-substituted pyrrole in
43% yield (in an identical 3.2:1 ratio.
(15) 1H NMR analysis of reaction crude shows generation of ca. 4:1 ra-
tio of 2- and 3-substituted N-methylpyrrole. Only the major isomer is
isolated and characterized.
(16) (a) Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org. Chem. 2011,
76, 471. (b) Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org.
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