Palladium-Mediated Remote Functionalization in γ- And ?-Arylations and Alkenylations of Unblocked Cyclic Enones

Article abstract of DOI:10.1021/acs.orglett.9b03462

We report herein an extensive investigation of simple and regioselective endo- as well as exo-γ-arylations of silyl-dienol ethers of unblocked cyclic enones with the utilization of palladium-catalyzed, modified Kuwajima-Urabe conditions. We have also successfully explored a new exo-?-arylation of silyl-trienol ethers of π-extended cyclic enones. In addition, we also report, herein, exclusive γ- and ?-alkenylation of silyl-dienol and silyl-trienol ethers of cyclic enones.

Full text of DOI:10.1021/acs.orglett.9b03462

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Mediated Remote Functionalization in γ- and ε‑Arylations
and Alkenylations of Unblocked Cyclic Enones
Gaurav Saini, Arpan Mondal, and Manmohan Kapur*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462066,
MP, India
S
* Supporting Information
ABSTRACT: We report herein an extensive investigation of simple and regioselective endo- as well as exo-γ-arylations of silyl-
dienol ethers of unblocked cyclic enones with the utilization of palladium-catalyzed, modified Kuwajima−Urabe conditions. We
have also successfully explored a new exo-ε-arylation of silyl-trienol ethers of π-extended cyclic enones. In addition, we also
report, herein, exclusive γ- and ε-alkenylation of silyl-dienol and silyl-trienol ethers of cyclic enones.
emote functionalization via the formation of a carbon−
R
carbon bond is one of the most challenging aspects of
synthetic organic chemistry.1 Biologically relevant molecules or
pharmaceutical drugs can be derived from commercially
available sources by C−C bond formation via remote
functionalization.2 Difficulties in achieving such transforma-
tions led to the emergence of innovative metal-catalyzed
methodologies involving cross-coupling reactions3 or C−H
functionalizations.4
Enones, in particular, cyclic ones, are the core building
blocks in numerous alkaloids, especially amaryllidaceae
alkaloids and natural products containing carbazole moieties.
The assembly of the core structures of such compounds are
often achieved by organic transformations of these enones
(Figure 1).5−7 Remote functionalization, particularly at the γ-
positions of dienolates and ε-positions of trienolates, is rather
inefficient due to the reduced nucleophilicity at these positions
when compared to α-enolates.8
Figure 1. Representative γ-arylated natural products.
substituted and as well as unsubstituted cyclic enones and
achieved aromatized γ-arylated products. Research groups of
Yamamoto,13 Hartwig,14 and Buchwald15 achieved γ-arylations
on β- and γ-substituted conjugated esters, respectively.
Research groups of Miura16 and Mazet17 reported γ-arylations
on α-monosubstituted and α,γ-disubstituted unsaturated
terminal aldehydes, respectively. Li, Zhang and co-workers18
reported γ-arylations on β-substituted amides involving an
olefin shift when using ortho-substituted aromatic halides.
Despite this progress, there has been no advancement made
toward the controlled γ- and ε-arylations with simple enones as
the coupling partners. To solve this unaddressed problem, we
Challenges for installing an aryl group at sp3 γ-carbon of
enones include the formation of other regioisomeric products
at α′-, α-, and β-sites. Similarly, possibilities of regioisomers at
α′-, α-, β-, and δ-positions during ε-arylation of vinylogous
enones exhibit a problem. Other problems exist in the form of
facile multiple arylations that occur at the remote sp3 positions
of enones.9 Another drawback of dienolates is that they are
highly prone toward self-condensation.10
Despite these challenges, there have been seminal works in
this area by various research groups. Buchwald and co-workers
reported γ-arylations on γ-substituted cyclic enones to generate
quaternary carbon centers.8 Similarly, the groups of Maier11
and Imahori12 attempted to achieve tertiary γ-arylations on α-
Received: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03462
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Endocyclic sp3 γ-Arylation of
Enones
designed a remote functionalization utilizing palladium-
catalyzed γ- and ε-arylations with silyl-dienol and trienol
ethers of unblocked enones and π-extended enones while other
competing nucleophilic sites in the system remain unaffected
(Scheme 1). Our work commenced with the initial screening
a
Scheme 1. γ- and ε-Arylation of Dienol- and Trienol-Ethers
of Enones
a
Unless otherwise mentioned, all reactions were performed with 1
(0.3 mmol), 4 (0.84 mmol), in 3.0 mL of degassed solvent, in a sealed
b
tube. All reagents were added in a glovebox. Reaction performed on
1 mmol scale.
was found to be the most efficient one for this transformation,
with some other phosphine ligands also performing decently
well. With the optimized reaction conditions in hand, the
generality of the regioselective γ-arylations was investigated
with various aryl bromides 1 and silyl-dienol ethers of enones 4
(Scheme 3). Initially, variation in substitution on the aryl
bromides was examined with silyl-dienol ether of 2-cyclohexen-
1-one, and the γ-arylated products 6a−6m were obtained in
excellent yield. X-ray crystallographic analysis of 6f confirmed
the structure of the γ-arylated product (CCDC 1884281).
Notable failures were 6n−6p, where no product was obtained
in the coupling reaction.
on the coupling of silyl-dienol ether of unblocked acyclic
enone 10a with aryl bromide by employing modified
Kuwajima−Urabe conditions19,20 to synthesize an exclusively
γ-arylated product (Scheme 2). To our disappointment, an
Scheme 2. Initial Attempts towards γ-Arylation of Acyclic
Enones
Interestingly, the heteroaryl bromide bearing a free N−H
group was also found to be a suitable coupling partner for the
reaction, resulting in 6q in high yield. Substrates bearing
sterically bulky mesityl, naphthyl, and phenanthrene groups
were well-tolerated and furnished the corresponding products
(6r−6t, Scheme 3) in very good yields. Both electronic and
steric factors had the least impact on the process. The scope of
the reaction was further explored with a diverse set of
substituents on 2-cyclohexen-1-one. Electron-donating as well
as electron-neutral substituents on the cyclic enones performed
well with a variety of bromides to yield the γ-arylated products
6u−6aa (Scheme 3). The methodology was further expanded
to the seven-membered cyclic enone 2-cyclohepten-1-one to
achieve the γ-arylated products 6ab−6ad in excellent yields.
We also performed the reaction of dienol ether of 4-methyl-2-
cyclohexen-1-one with aryl and heteroaryl bromides to give
6ae, 6af which are essential frameworks in the synthesis of
natural products. This also indicated that substitution at the γ-
position was also tolerated and the arylation occurred at the
desired position. We also successfully synthesized ketoindoline
skeletons 6ag, 6ah in a one-pot transformation by reaction
inseparable complex mixture of regioisomers was observed in
rather low yield along with the decomposition of the silyl-
dienol ether. Despite extensive efforts to optimize this
transformation, success eluded us and an inseparable mixture
of regioisomeric arylation products was obtained in each
attempt. This led us to switch over to cyclic enones, and after a
careful optimization study (see the Supporting Information for
details), a regioselective γ-arylation of unblocked α,β-
unsaturated cyclic enones was successfully achieved (Scheme
3).
The initial optimization was carried out with palladium
catalysts. Later nickel complexes were also scanned for this
transformation but without any success. The absence of the
palladium catalyst expectedly led only to the cleavage of the
silylenol ether, and no coupling product was detected. The
fluoride source was necessary for the transformation as was the
requirement of the cesium fluoride as well as the tributyltin
fluoride. The synergistic effect of this system has been well-
documented by Hartwig and co-workers.19b The DtBPF ligand
B
DOI: 10.1021/acs.orglett.9b03462
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Organic Letters
Letter
Scheme 5. Substrate Scope of Exocyclic sp3 ε-Arylation of
Enones
with simple 2-bromoaniline derivatives in which the 1,4-
conjugate addition occurred after the γ-arylation.8 In addition,
γ-alkenylation was performed with a cyclic alkenyl bromide
(6ai, Scheme 3), but the γ-alkenylation was not as efficient as
the γ-arylation and the minor isomerization product 6aj was
also isolated in this case. In the same fashion, γ-alkynlation was
also attempted but the reaction failed to yield the desired
product (6ak, Scheme 3).
a
To further explore the utility of this strategy, we attempted
the reaction of 3-methyl substituted cyclic enones which have
two enolizable carbons at the γ-positions (Scheme 4). The
Scheme 4. Substrate Scope of Exocyclic sp3 γ-Arylation of
a
Enones
a
Unless otherwise mentioned, all reactions were performed with 1
(0.3 mmol), 5 (0.84 mmol), in 3.0 mL of degassed solvent, in a sealed
tube. All reagents were added in a glovebox.
a
Unless otherwise mentioned, all reactions were performed with 1
silyl-dienol ethers formed on the exo sp3 carbon instead of the
endo sp3 carbon. The silyl-dienol ethers of 3-methyl and 3,5-
dimethyl-2-cyclohexen-1-one (5a, 5b respectively) reacted
with electron-rich as well as electron-deficient aryl bromides
to provide the products 7a−7h in excellent yields with
exclusive regioselectivity. We were thus able to demonstrate a
single reaction condition needed to produce exclusive exo-γ-
monoarylated products. Similarly, γ-alkenylation was also
performed on the exocyclic system by reaction with a vinyl
bromide (7i, Scheme 4).
We then turned our attention to further remote function-
alizations at the sp3 ε-carbon of silyl-trienol ether of vinylogous
enones (Scheme 5). To the best of our knowledge, to date,
there is no report on the site-selective ε-arylation of unblocked
or blocked side chains of cyclic enones. The silyl-trienol ether
of π-extended 2-cyclohexen-1-one 8a reacted without any need
for substituents on the parent chain to yield the cross-coupling
products 9a−9c (Scheme 5) with exclusive ε-regioselectivity.
The tetrahydroindole moiety 9d was successfully synthesized
in a one-pot fashion from 2-bromo-N-methylaniline in which
the 1,6-conjugate addition occurred after the ε-arylation. The
generality of the reaction was demonstrated by the highly
efficient transformations of six-membered enones to 9e−9j
(Scheme 5). X-ray crystallographic analysis of 9j confirmed the
ε-selectivity (CCDC 1922702). ε-Arylations in cyclic enones
of varied ring sizes were equally effective and yielded 9k−9m
in an efficient manner. In seven-membered systems, however,
γ-arylation 9m′ was also observed in a minor amount. A highly
efficient ε-alkenylation was also achieved on the exocyclic six-
membered vinylogous enones by reaction with 2-bromoindene
(9n, 9o, Scheme 5). In the same fashion, ε-alkynlation was also
attempted but the reaction failed to yield the desired product
(9p, Scheme 5).
(0.3 mmol), 8 (0.84 mmol), in 3.0 mL of degassed solvent, in a sealed
tube. The E/Z ratio was determined by 1H NMR of the crude
b
reaction mixture. All reagents were added in a glovebox. Reaction
performed on 1 mmol scale.
A plausible mechanism for the transformation is depicted in
Scheme 6.19,21 The Pd(0) generated in situ undergoes an
oxidative addition with aryl bromide 1 followed by trans-
metalation with the reactive stannyl-enol ether of the enone 13
to give organopalladium species 15. Finally, reductive
elimination affords the ε-arylation 9.
Scheme 6. Plausible Mechanism for ε-Arylation
C
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Organic Letters
Letter
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Modified Kuwajima−Urabe conditions were utilized to resolve
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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new compounds (PDF)
Accession Codes
̈
Knolker, H.-J. Occurrence, Biogenesis, and Synthesis of Biologically
CCDC 1884281 and 1922702 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mk@iiserb.ac.in.
ORCID
Gaurav Saini: 0000-0002-5755-4333
Arpan Mondal: 0000-0001-9192-7255
Manmohan Kapur: 0000-0003-2592-6726
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from SERB-India (EMR/2016/004298) and CSIR
India (02(0361)/19/EMR-II) is gratefully acknowledged. G.S.
thanks IISERB for a Research Fellowship. We thank Dr. Sanjit
Konar (IISERB) for the assistance in X-ray analysis and CIF,
IISERB for the analytical data. We also thank the Director,
IISERB for funding and infrastructural facilities.
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