Boron-heck reaction of cyclic enaminones: Regioselective direct arylation via oxidative palladium(II) catalysis

Article abstract of DOI:10.1021/ol500105d

An oxidative boron-Heck reaction of cyclic enaminones with arylboronic acids is reported. This protocol provides a regioselective arylation at the C6 position of cyclic enaminones. When an N-carbamylated cyclic enaminone was employed, a switch to a conjugate addition reaction occurred in the presence of acid.

Full text of DOI:10.1021/ol500105d

Letter
pubs.acs.org/OrgLett
Boron−Heck Reaction of Cyclic Enaminones: Regioselective Direct
Arylation via Oxidative Palladium(II) Catalysis
Yong Wook Kim and Gunda I. Georg*
Department of Chemistry, Department of Medicinal Chemistry, and the Institute for Therapeutic Discovery and Development,
University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
S
* Supporting Information
ABSTRACT: An oxidative boron−Heck reaction of cyclic
enaminones with arylboronic acids is reported. This protocol
provides a regioselective arylation at the C6 position of cyclic
enaminones. When an N-carbamylated cyclic enaminone was
employed, a switch to a conjugate addition reaction occurred
in the presence of acid.
ix-membered cyclic enaminones (2,3-dihydropyridin-
4(1H)-ones) are versatile intermediates for the preparation
Cyclic enaminones are considered to be challenging
substrates for Heck-type reactions. Cyclic systems often
generate a mixture of the Heck product and the conjugate
addition product because the syn β-hydride elimination step
needed for a Heck reaction is unfavorable.9 In addition,
electron-rich olefins are poor olefin donors for Heck-type
reactions, and the scope of the substrates is limited to simple
olefins and enamides.10 Another challenge of a Heck reaction
with the cyclic enaminone system is the competing electrophilic
palladation (C5 functionalization)3b−f particularly with an
electron-donating group at the nitrogen. In our previous
research,3f a preference for C5 arylation was observed under the
typical Jeffery conditions,11 which was successfully used in
intramolecular Heck reactions.8b,d
S
of piperidine-containing molecules including indolizidines and
quinolizidines alkaloids (Scheme 1).1 These heterocyclic
Scheme 1. Utility of Cyclic Enaminones
Recently, boron reagents have emerged as alternative halide
surrogates in Heck-type reactions.12 These oxidative boron−
Heck reactions proved to be successful with a few cyclic
systems.12c,13 In parallel with our previous C5 arylation reaction
with arylboronic acids,3e it was envisioned that an oxidative
boron−Heck reaction could be employed to install an aryl
group at the C6 position of cyclic enaminones by a slight
modification of the C5 arylation conditions (Scheme 2). As
shown in our previous studies,3f it is necessary to increase the
electron density of the palladium catalyst to prevent C5
arylation. An electron-donating N,N′-bidentate ligand14 was
selected with the expectation that this would lead to a switch in
the regioselectivity of the reaction. While the palladation is
suppressed at the C5 position with an electron-enriched
catalytic system, transmetalation will occur with an arylboronic
acid to form the arylpalladium(II) complex, and then the
insertion with the alkene should take place. Therefore, direct
arylation at the C6-position could be accomplished. Herein, the
direct C6 arylation using arylboronic acids under Pd(II)
catalysis is described.
compounds are known to possess a variety of biological
activities.2 In our efforts to diversify cyclic enaminone
scaffolds,3 C5 arylation and olefination reactions have been
developed and used to prepare biologically active compounds
and natural products.4 For alkylation/arylation reactions at the
C6 position of cyclic enaminones, conjugate addition reactions
can be employed to afford 4-piperidones.5 C6 arylation with
retention of the enaminone system has been achieved by cross-
coupling of C6-halo derivatives6 or organocuprate addition
followed by oxidation.7 A few cases of direct arylation involving
a Heck-type reaction have been reported, but they are limited
to intramolecular reactions.8 Considering the utility of this
scaffold, the development of an efficient Pd-mediated
intermolecular C6 arylation would be a beneficial process.
Received: January 12, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
homocoupling. To address this issue, another equivalent of the
arylboronic acid was added after 6 h (entry 14).
Scheme 2. Regioselective Arylation of Cyclic Enaminones
The scope of cyclic enaminones and arylboronic acids
(Scheme 3) was investigated using the optimized reaction
a
Scheme 3. Scope of the Reaction
We initiated the optimization of the reaction using cyclic
enaminone 1 and 4-methoxyphenylboronic acid (2) as model
substrates (Table 1).15 First, the reaction conditions without
a
Table 1. Reaction Optimization
g
solvent
ligand
bpy
oxidant
yield (3/4) (%)
b
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMSO
THF
Cu(OAc)2
34 (1.8/1)
25 (1/12)
46 (<1/20)
21 (>20/1)
33 (>20/1)
4 (>20/1)
7 (>20/1)
40 (>20/1)
49 (>20/1)
39 (>20/1)
47 (>20/1)
0
Cu(CO2CF3)2
benzoquinone
PhCO3tBu
bpy
bpy
f
bpy
O2
f
bpy
O2
f
bpy
O2
f
DMA
NMP
NMP
NMP
NMP
NMP
NMP
bpy
O2
f
bpy
O2
a
Reaction conditions: cyclic enaminone (0.2 M), arylboronic acid (3
f
10
11
12
13
14
1,10-phen
dmbpy
bpy
O2
equiv), Pd(OAc)2 (10 mol %), ligand (11 mol %), oxygen (balloon
pressure).
f
O2
c
f
O2
d
e
f
bpy
O2
27 (>20/1)
68 (>20/1)
f
bpy
O2
a
conditions. Electron-rich as well as electron-deficient arylbor-
onic acids provided moderate to good yields (3a−k). However,
2-methoxyphenyl derivative 3l was not observed, presumably
due to steric hindrance. Other cyclic enaminones bearing N-
phenyl (3n) or N-methyl (3o and 3p) groups were suitable
substrates for this reaction. Bicyclic enaminones with
indolizidine and quinolizidine scaffolds also furnished the C6
arylated products 3q and 3r in good yields. While the Heck-
type products were obtained exclusively with the substrates
containing electron-donating groups at the nitrogen, the N-
carbamylated cyclic enaminone produced the Heck product 5a
as well as conjugate addition product 5b.
While investigating the factors for the conjugate addition
reactions for a N-carbamylated cyclic enaminone, it was found
that the addition of acid can switch the outcome (Table 2). As
the acidity of the acid was increased, more conjugate addition
product 5b was formed while the yield of the Heck product 5a
decreased. A complete shift to the conjugate addition product
5b was observed with 2 equiv of TFA (entry 7), albeit in lower
yield than with 1 equiv. It is worth noting that the
stereochemistry of 5b was confirmed as trans by X-ray
crystallography. Therefore, this protocol provides another
route toward the synthesis of trans-2,6-disubstituted piper-
Reaction conditions: 1 (0.2 M), 2 (2 equiv), Pd(OAc)2 (10 mol %),
b
c
ligand (11 mol %), oxidant (2 equiv). Ag2O (1 equiv). Cs2CO3 (1
d
e
equiv). AcOH (1 equiv). Additional 2 (1 equiv) was added after 6 h.
f
g
1
Balloon pressure. Yields and ratios were determined by H NMR.
PMP = p-methoxyphenyl, bpy = 2,2′-bipyridine, 1,10-phen = 1,10-
phenanthroline, dmbpy = 4,4′-dimethyl-2,2′-bipyridine.
the ligand were investigated, and a mixture of C6 arylated 3 and
C5 arylated 4 was observed (entry 1). The choice of oxidant
was essential. It should be noted that C5-arylated derivative 4
was formed preferentially when a copper salt or benzoquinone
was used as an oxidant (entries 2 and 3). The conditions with
tert-butyl perbenzoate or oxygen provided Heck-type product 3
exclusively, although the yields were moderate (entries 4 and
5). The reaction was affected significantly by the solvent
selection. Amide solvents such as DMF and NMP gave the best
yields (entries 5−9). As expected, the use of a bidentate ligand
is necessary to accomplish the regioselective reaction, and the
use of 2,2′-bipyridine provided best results (entries 9−11).
Furthermore, the addition of any acid or base additives did not
improve the reaction efficiency (entries 12 and 13). Time-
monitoring experiments revealed that the reaction decelerated
after 6 h, resulting from the depletion of the arylboronic acid by
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Letter
yield (Scheme 4). The analytical and spectral data of
compound 8 are consistent with the literature report,17 which
establishes the formal synthesis of lasubine II.
Table 2. Acid-Controlled Conjugate Addition of Cyclic
Enaminones
a
Scheme 4. Formal Synthesis of Lasubine II
c
acid (equiv)
yield (5a/5b) (%)
b
d
1
2
3
4
5
6
7
8
91 (2.8/1)
AcOH (1.0)
AcOH (5.0)
AcOH (10.0)
TsOH·H2O (1.0)
TFA (1.0)
86 (1/1.9)
87 (1/3.8)
82 (1/6.5)
72 (1/6.2)
88 (1/12)
60 (<1/20)
87 (1/2.8)
TFA (2.0)
HCO2H (1.0)
a
Reaction conditions: cyclic enaminone (0.2 M), arylboronic acid (2
equiv), Pd(OAc)2 (10 mol %), ligand (11 mol %), oxygen (balloon
b
c
1
pressure). 20 h. Yields and ratios were determined by H NMR.
d
In summary, we have developed a C6 arylation protocol for
2,3-dihydropyridin-4(1H)-ones using the oxidative boron−
Heck reaction that proceeds with excellent selectivity over C5
arylation and conjugate addition reactions.18 This boron−Heck
reaction provides a complementary protocol to previously
developed arylations at the C6 position. Furthermore, an acid-
controlled reactivity switch to a conjugate addition reaction was
observed when the reaction was carried out with a N-
carbamylated enaminone in the presence of a strong acid.
Isolated yield.
idones, which have been previously prepared via conjugate
addition using Grignard reagents.5f,g
A plausible mechanism is depicted in Figure 1. The electron-
rich palladium ligand complex favors transmetalation with the
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data for all new
1
compounds, ORTEP plot for 5b, and copies of H/13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: georg@umn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Victor Young (Department of Chemistry,
University of Minnesota) for providing the X-ray structure
and data analysis for compound 5b. We also thank Dr.
Subhashree Francis (Institute for Therapeutic Discovery and
Development, University of Minnesota) for providing MS data.
We greatly appreciate the financial support from the National
Institutes of Health (GM081267) and the University of
Minnesota through the Vince and McKnight Endowed Chairs
(to G.I.G.).
Figure 1. Proposed reaction mechanisms.
arylboronic acid rather than C5 palladation of the cyclic
enaminone. Carbopalladation would take place trans to Ar1,
followed by a palladotropic shift to generate the palladium
enolate.12c,16 In the presence of acid, this intermediate would
undergo protonolysis to furnish the conjugate addition product.
The oxidative Heck product would be obtained via elimination
reactions.
C6-arylated cyclic enaminones can serve as an intermediate
in natural product synthesis. For example, lasubine II was
obtained from compound 8 following the protocol developed
by Rovis.17 Reaction of 3,4-dimethoxyphenylboronic acid (7)
with bicyclic enaminone 6 gave C6-arylated product 8 in 62%
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(18) General Procedure for the Synthesis of Compounds 3a−r and
5a−b (Table 2). Pd(OAc)2 (4.5 mg, 0.02 mmol) and 2,2′-bipyridine
(3.4 mg, 0.022 mmol) in NMP (1.0 mL) were stirred for 30 min. To
this solution were added the cyclic enaminone (0.20 mmol) and the
arylboronic acid (0.40 mmol), and the reaction mixture was stirred
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