Palladium(II)-catalyzed direct arylation of enaminones using organotrifluoroborates

Article abstract of DOI:10.1021/ja710221c

A Pd(II)-catalyzed reaction for the direct arylation of cyclic enaminones is reported. The reactivity of electron-rich, electron-poor, and sterically encumbered organotrifluoroborates was investigated. This reaction represents a unique use for organotrifluoroborates as coupling partners and discloses the utility of enaminones for direct-functionalization reactions. It provides immediate access to arylpiperidine, indolizidine, and quinolizidine scaffolds from the corresponding mono- and bicyclic, unattenuated enaminones. Copyright

Full text of DOI:10.1021/ja710221c

Published on Web 03/06/2008
Palladium(II)-Catalyzed Direct Arylation of Enaminones Using
Organotrifluoroborates
Haibo Ge,† Micah J. Niphakis,‡ and Gunda I. Georg*,§
Department of Medicinal Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Lawrence, Kansas 66045,
Center for Chemical Methodologies and Library DeVelopment, UniVersity of Kansas, 1501 Wakarusa DriVe,
Lawrence, Kansas 66047, and Department of Medicinal Chemistry and the Institute for Therapeutics DiscoVery and
DeVelopment, UniVersity of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414
Received November 11, 2007; E-mail: georg239@umn.edu
The direct conversion of C-H to C-C bonds is an exceedingly
valuable process in contemporary organic synthesis. Recent devel-
opments in this field have allowed concise and economical routes
to useful materials and synthetic intermediates.1 The current rise
of palladium-catalyzed methods,2,3 in particular, is evidence of this
transformation’s versatility. The well-known liabilities of C-H
functionalization, namely overfunctionalization and regioselectivity,2c
Figure 1. Examples of 3-arylpiperidine medicinal agents.
have limited its applicability. Indeed, the need for a broader pool
of viable C-H donors as well as reagent choices is clear.
In light of the advances in this area, our interest in the synthesis
of biologically active natural products and lead discovery libraries
inspired us to explore the 3-arylpiperidine system. Many compounds
which feature this scaffold are known to have high affinity for an
array of validated targets (Figure 1).4 Expanding upon our recently
developed method for the enantiospecific construction of cyclic
enaminones5 we sought a general method for C-3 arylation. This
transformation has been achieved via a two-step sequence involving
halogenation and subsequent coupling using Pd(0).6 We envisaged
a more direct protocol, which allowed us to avoid preactivation of
the enaminone. We hoped to take advantage of the innate
nucleophilic character of the enaminone and reasoned that the same
putative transition-metal species as in the two-step process could
be accessed in a catalytic, one-step fashion. Furthermore, we
planned to intercept this intermediate with a suitable coupling
partner. We describe here the realization of this proposal as well
as a unique use of organotrifluoroborates7 as coupling partners in
palladium-catalyzed C-H functionalization.
Table 1. Reaction Optimization for C-H Functionalization of
Enaminones
To our delight, initial attempts to couple enaminone 1a and
trifluoroborate 2 using Pd(OAc)2 were successful despite the
observation of the biphenyl homocoupled product (Table 1, entry
1). 4-Methoxyboronic acid, used in place of the trifluoroborate 2,
gave poor yields of enaminone 3a (Table 1, entry 2). It should be
noted that the use of an acidic cosolvent, thought to promote
palladation by increasing the electrophilicity of the Pd(II) center,8
consequently limits the potential of basic or nucleophile-promoted
organometallic coupling partners (i.e., boronic acids, organozinc
reagents, silanes, etc.). Additionally, Molander et al. have found
organotrifluoroborates to be robust equivalents of organoboronic
acids7a and therefore were deemed to be apposite reagents for further
optimization studies.
a Reaction conditions unless otherwise specified: enaminone 1a (0.1 M),
trifluoroborate 2 (2-3 equiv), Pd(II) (0.3 equiv), oxidant (3 equiv) at 60
°C. b Isolated yield. c 2:3 3a/homodimer ratio. d 4-Methoxyphenylboronic
acid (3 equiv) was used in the place of trifluoroborate 2. e 1.0 equiv.
f Complete in 3 h at 30 °C. g Trifluoroborate (2-3 equiv) was added slowly
(see the Supporting Information for details).
long reaction times and high temperatures which were otherwise
required to drive the reaction to completion. The addition of
trifluoroacetate salts (Table 1, entries 10-12) also reduced the
reaction time but resulted in lower yields. The slow addition of the
trifluoroborate was found to give the desired product in excellent
yield and was most effective for suppressing homocoupling (Table
1, entry 13).
With optimized conditions in hand, we embarked on an
investigation of the reaction scope. Electron-rich trifluoroborates
undergo rapid (2-6 h) and high-yielding cross-coupling as com-
pared to their electron-deficient counterparts (Table 2). Sterically
encumbered trifluoroborates (Table 2, entries 3 and 4) require longer
reaction times (24 h) and proceed in moderate yields. Furthermore,
aryl halides (Table 2, entries 7 and 8) are tolerant under these
conditions demonstrating a unique feature of this reaction compared
We first identified Cu(OAc)2 as being an economic and effica-
cious reoxidant (Table 1, entries 3-7). Furthermore, Pd(OAc)2 was
found to be a superior catalyst compared with PdCl2 and Pd(OTFA)2
(Table 1, entries 8 and 9). Considering the limited stability of our
substrate, a higher Pd(II)-catalyst loading was used to circumvent
† Department of Medicinal Chemistry, University of Kansas.
‡ Center for Chemical Methodologies and Library Development, University of
Kansas.
§ University of Minnesota.
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J. AM. CHEM. SOC. 2008, 130, 3708-3709
10.1021/ja710221c CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Aryltrifluoroborates in C-H Functionalization
a Reaction conditions: enaminone 1a (0.1 M), R-BF3K (2-3 equiv),
Pd(OAc)2 (0.3 equiv), Cu(OAc)2 (3 equiv), K2CO3 (2 equiv) in t-BuOH/
AcOH/DMSO (20:5:1) at 60 °C. Isolated yield.
Figure 2. Proposed catalytic cycle for direct arylation of enaminones.
b
palladium on the enaminone (6, Figure 2) and subsequent depro-
tonation. In the presence of an appropriate organometallic substrate,
transmetalation and reductive elimination would provide the desired
coupled product. Finally, in situ oxidation of Pd(0) to Pd(II) by
Cu(OAc)2 completes the catalytic cycle. Alternatively, transmeta-
lation may precede enaminone palladation providing an intermediate
that could favor homocoupling.
Table 3. Scope of Enaminones in C-H Functionalization
In summary, this methodology provides a direct method for the
construction of 3-arylpiperidine scaffolds, a privileged structure and
prevalent motif in many natural products. This method is a
significant advance over the existing two-step method. This reaction
also represents an unprecedented example of C-H functionalization
on enaminones (a nonaromatic enamine system).
Acknowledgment. We thank the National Institutes of Health
(CA90602, GM069663, and GM076302) and the Kansas Masonic
Cancer Research Institute for their support of our programs.
Supporting Information Available: Representative experimental
procedures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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a Reaction conditions: enaminone (0.1 M), trifluoroborate 2 (2-3 equiv),
Pd(OAc)2 (0.3 equiv), Cu(OAc)2 (3 equiv), K2CO3 (2 equiv) in t-BuOH/
AcOH/DMSO (20:5:1) at 60 °C. b Isolated yield. c Starting material was
recovered. PMP ) 4-methoxyphenyl.
to classical Suzuki-Miyaura protocols. We have also had success
in the oxidative Heck coupling of enaminones with alkenes (eq 1)
and will disclose our results in due time.9
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An initial investigation of enaminone compatibility revealed that
monocyclic and bicyclic, unattenuated enaminones were viable
substrates in this reaction. These mildly acidic conditions are
suitable for diastereomeric enaminones (Table 3, entries 3 and 4),
which react with no observable epimerization. N-Boc-protected
enaminones, however, were found to be unreactive under our
optimized conditions, which we suggest is due to their decreased
nucleophilicity (Table 3, entry 7).
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(9) Unoptimized conditions.
We believe that the mechanism for palladation of enaminones
resembles that of indoles,1e initiated by an electrophilic attack of
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