Mild aerobic oxidative palladium (II) catalyzed C-H bond functionalization: Regioselective and switchable C-H alkenylation and annulation of pyrroles

Article abstract of DOI:10.1021/ja058141u

A palladium catalyzed C-H bond functionalization system that operates under ambient and aerobic conditions can be used to alkenylate pyrroles with control of regioselectivty. A steric and electronic control strategy can be used to influence positional con

Full text of DOI:10.1021/ja058141u

Published on Web 02/02/2006
Mild Aerobic Oxidative Palladium (II) Catalyzed C-H Bond Functionalization:
Regioselective and Switchable C-H Alkenylation and Annulation of Pyrroles
Elizabeth M. Beck, Neil P. Grimster, Richard Hatley,† and Matthew J. Gaunt*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
Received November 30, 2005; E-mail: mjg32@cam.ac.uk
The development of direct C-H bond functionalization strategies
for the facile generation of compounds with useful molecular
architecture remains of high interest to academic and industrial
chemists.1 Such processes preclude the need for a prior function-
alization step, making the overall chemical transformation highly
efficient. We are particularly interested in the development of new
methods for direct metal catalyzed oxidative C-H transformations
of organic molecules under mild and operationally simple condi-
tions. Catalytic reactions of this nature would be very useful for
the elaboration of molecules that may be sensitive to the harsh
conditions that can often be required for C-H functionalization
processes. Recently, a number of groups,2 including ourselves,2e
have reported C-H bond transformations of indole. In contrast,
the use of pyrrole in similar processes is rare,3 and yet these
heterocycles are ubiquitous in natural products4 and medicinal
agents5 and are useful as intermediates in multistep synthesis.6
Despite their potential in chemical synthesis, the instability of
pyrroles toward acidic and oxidative environments has limited their
utility in metal catalyzed C-H transformations. Herein, we report
an efficient aerobic palladium (II) oxidation system for C-H bond
functionalization of sensitiVe molecules under ambient conditions.
Table 1. Effect of N-Protecting Group on Pyrrole C-H
Alkenylation
entry
catalyst loading (%)
R
yield of C2
yield of C3
ratio 2:3
1
2
3
4
5
6
10
10
10
10
10
10
Bn
SEM
Ac
Boc
Ts
TIPS
48
48
65
73
70
-
23
21
-
2.1:1
2.3:1
>95:5
>95:5
>95:5
<5:95
-
-
78
Scheme 1. Stereoelectronic Control Concept: Proposed
Mechanism
coordinating N-SEM pyrrole derivative also failed to improve the
selectivity (entry 2). We speculated that introduction of an electron-
withdrawing N-protecting group would reduce the reactivity of the
pyrrole and yield a more selective process. Accordingly, N-Ac,
N-Ts, and N-Boc pyrrole afforded only the C2 product in good
yield (entries 3-5) under mild conditions. In contrast, reaction with
N-TIPS pyrrole gave only the C3 product (entry 6).8 The switch in
selectivity is attributed to the sterically demanding nature of the
TIPS group that shields the C2 position from reaction with the
palladium catalyst, forcing the reactive pyrrole to palladate at C3.
To our knowledge this stereoelectronic strategy represents a new
method for controllable catalytic actiVation and functionalization
of pyrroles under mild conditions (see Scheme 1).
The catalyst loading can also be lowered to 5 mol %, and N-Boc
pyrrole 2 was isolated in 70% yield after 36 h. The loading can be
reduced to 1 mol % catalyst; however, the complete conversion
takes longer to achieve. The turnover number (TON) at 60% (96
h) conversion is 55, suggesting that the process displays a high
efficiency for palladium (II) processes.
This method can be used to directly generate a range of
functionalized and annulated pyrrole architectures and it is possible
to control the position of C-H bond functionalization via simple
steric and electronically tuned N-pyrrole protecting groups to form
products with either C2 or C3 elaboration.
At the outset of our studies we were guided by our discovery
that the solvent media could control positional selectivity during
palladium catalyzed C-H bond functionalizations of indoles.2e
Despite the success in the indole series the corresponding pyrrole
systems suffered from unselective and polyalkenylation as well as
significant polymerization. With this in mind we speculated that
the reactivity of the pyrrole nucleus may enable a catalytic C-H bond
functionalization at room temperature or under ambient conditions.
To test this hypothesis, we focused our attention on oxidative
alkenylations of simple pyrroles. After initial optimization studies
we identified that 10 mol % Pd(OAc)2 in a dioxane-AcOH-
DMSO solvent system and tBuOOBz as oxidant provided an
effective system for pyrrole functionalization.7 We found that N-Bn
pyrrole reacted smoothly with benzyl acrylate at only 35 °C to form
the alkenylated products. Although it was expected that the natural
reactivity of pyrrole would direct reaction to the C2 position, we
observed a 2:1 ratio of C2 to C3 isomers (Table 1, entry 1). A
With the goal of developing a more efficient process we
investigated the nature of the oxidant in this C-H alkenylation
process. When tBuOOBz was replaced with oxygen as oxidant,
both N-Boc and N-TIPS pyrroles gave 2 and 3 in 73 and 75%,
respectively (Table 2, entry 1). The ability of molecular oxygen to
effect the facile oxidation of Pd(0) is ascribed to the presence of
DMSO in the solvent media.7 Furthermore, this process also works
† Present address: GSK Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertsfordshire SG1 2NY, UK.
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10.1021/ja058141u CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Catalytic Aerobic Regioselective C-H
Alkenylation
6a is treated with Pd(OAc)2 under the aerobic conditions, the C-H
annulation is observed at C2 position as predicted by our model,
leading to pyrrole 7. However, by switching to N-TIPS derivative
6b the annulation reaction formed the cycle at the C4 position,
affording the alternative pyrrole molecular architecture, 8. The
annulation process works well and provides a facile method for
the generation of complex polycyclic ring systems. Importantly,
reaction occurs exclusively at the position predicted by our model.
Table 3. Scope of Regioselective C-H Alkenylation
In summary, we have developed a new mild aerobic palladium
(II) catalyst system for C-H bond functionalization. This catalyst
system enables a direct and regioselective pyrrole C-H bond
alkenylation and annulation process where reaction at either the
C2 or C3 position can be effected. We are currently investigating
the application of this mild aerobic catalyst system in other
palladium (II) transformations as well as exploring the utility of
pyrrole C-H bond transformation as a versatile platform for
complex molecule synthesis.
Acknowledgment. We gratefully acknowledge GSK and EPSRC
for studentship (to E.M.B.), the Royal Society for University
Research Fellowship (to M.J.G.), and the EPSRC Mass Spectrom-
etry service (University of Swansea). We also thank Professor
Steven Ley for support and useful discussion.
Supporting Information Available: Experimental data and pro-
cedures for all compounds. The material is available free of charge via
the Internet at http://pubs.acs.org.
at room temperature, highlighting the ambient nature of this C-H
bond functionalization process (entry 2). Remarkably, conducting
the reaction in a flask that is left open to the atmosphere forms 2
or 3 respectively in 72 and 75% yield after 96 h with 10 mol %
catalyst (entry 3). The use of air as oxidant without any further
additives significantly increases the efficiency of this process.
The utility of our oxidative pyrrole C-H alkenylation was
evaluated using the N-Boc and N-TIPS derivatives with a range of
alkenes. Table 2 shows alkene coupling partners that can be
exploited in this new process with good yields obtained in most
cases using either O2 or air as the oxidizing system.
The aerobic conditions work well for reactive alkenes (entries
1-7), but the process is less effective when the reaction is slower
(entries 7, 8) as the precipitation of the Pd(0) becomes a problem
over the prolonged reaction time. To address this limitation we
returned to the tBuOOBz oxidant that had been used during
optimization. With this catalytic system we were pleased to find
that a range of alkenes could be successfully used in the regio-
selective coupling (Table 3).
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Trisubstituted alkene products were also formed from TIPS
pyrrole in good yields with more substituted alkenes using this
process (entries 8, 9).9 In all cases N-Boc pyrrole underwent C-H
alkenylation at C2, whereas N-TIPS directed reaction to C3.
The substituted pyrrole products can be differentially elaborated
through catalytic regioselective functionalization. Accordingly,
pyrroles 2 and 3 undergo selective C-H bond alkenylation forming
only 4 and 5, respectively, in good yield.
(9) We speculate that a clash between the Boc group and the tri-substituted
alkene is responsible for the poor reaction in the C2 alkenylation of entries
8-9.
Intramolecular pyrrole C-H alkenylation can also be effected
with complete control of the sense of cyclization. When Ts pyrrole
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