Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives

Article abstract of DOI:10.1002/anie.201913435

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Full text of DOI:10.1002/anie.201913435

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes.
Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone
Derivatives
Authors: Shekhar KC, Roshan Dhungana, Namrata Khanal, and
Ramesh Giri
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913435
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10.1002/anie.201913435
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed
-Carbonylalkylarylation
of
Vinylarenes.
Expedient Access to ,-Diarylcarbonyl and Aryltetralone
Derivatives
Shekhar KC,† Roshan K. Dhungana,‡ Namrata Khanal,† and Ramesh Giri ‡,*
carbonylalkylarylation of vinylarenes with primary, secondary and
tertiary -halocarbonyl compounds and arylzinc reagents. This
reaction generates ,-diarylcarbonyl compounds via the addition of
-carbonylalkyl radicals to alkenes. ,-Diarylcarbonyl motifs are
prevalent in bioactive molecules, natural products and
pharmaceuticals (Scheme 1).[13] Known molecules with ,-
diarylcarbonyl scaffolds are integrin receptor inhibitors and nitric oxide
donors.[14] These bioactive compounds display antiproliferative and
proapoptotic activity and serve as a precursor of Zoloft, a marketed
antidepressant drug.[15]
Abstract: We report
a
Ni-catalyzed regioselective -
carbonylalkylarylation of vinylarenes with -halocarbonyl compounds
and arylzinc reagents. The reaction works with primary, secondary
and tertiary -halocarbonyl molecules, and electronically varied
arylzinc reagents. The reaction generates ,-diarylcarbonyl
derivatives with -secondary, tertiary and quaternary carbon centers.
The products can be readily converted to aryltetralones, including a
precursor to Zoloft, an antidepressant drug.
Three-component vicinal dicarbofunctionalization of alkenes[1] is a
powerful tool to synthesize complex molecules rapidly from readily
available starting materials.[2] Recently, significant progress has been
made in this area by reductive coupling,[3] radical coupling,[4]
photoredox catalysis[5] and cross-coupling,[6] which have been
programmed to introduce two carbon entities across alkenes with high
regioselectivity. The success of the reaction relies upon the ability of
the carbon source to intercept in situ-generated alkylmetal species
prior to -H elimination,[7] a formidably challenging process that derails
alkene difunctionalization to form Heck products. Strategies that
stabilize alkylmetal species, such as the formation of metallacycles[8]
and -allyl/-benzylmetal species,[9] and the generation of carbon
radicals,[5] have been successful in addressing both issues of
regioselectivity and -H elimination, and executing alkene
dicarbofunctionalization on various alkene substrates.[10]
Scheme 1. Bioactive and Naturally Occurring ,-Diaryl
Esters and Aryltetralone Cores
Vinylarenes are important precursors in complex molecule synthesis,
as they are a valuable source of both alkyl and aryl scaffolds.
Vinylarenes are also excellent sources of alkenes for
difunctionalization owing to the polarizability of alkenes for
regiocontrol and the stabilization of alkylmetal species as -
benzylmetal intermediates. However, vinylarenes are still seriously
underutilized for dicarbofunctionalization, despite recent reports on
dialkylation,[4a] alkylarylation,[11] diarylation[9a, 12] and vinylarylation.[9b]
We envisioned that vinylarenes could serve as excellent precursors
to access ,-diarylcarbonyl compounds and aryltetralone derivatives.
In our efforts to generate such scaffolds, we examined
difunctionalization of indene with ethyl -bromoacetate and m-
CF3C6H4ZnI under various conditions (Table 1). We found that
Ni(cod)2 was an excellent catalyst, which enabled -
carbonylalkylarylation of indene to proceed at room temperature and
afforded the 1,2-difunctionalized indane 4 in 76% yield (entry 1). NiBr2
and (Ph3P)4Ni formed product 4 in lower yields (entries 2-3). Fe, Co,
Pd and Cu-based catalysts were ineffective (entry 4). The reaction
can also be conducted in DMA albeit with lower product yield (entry
5). Additionally, product 4 was formed in lower yield in DMF, THF,
DCM and toluene (entries 6-7). Moreover, ethyl -bromoethyl acetate
can be replaced with ethyl -chloroethyl acetate, which formed
product 4 in 63% yield (entry 8).
Herein,
we
report
a
Ni-catalyzed
regioselective
-
[*]
Mr. R. K. Dhungana, Prof. R. Giri
Department of Chemistry
Pennsylvania State University,
University Park, Pennsylvania 16802, USA
E-mail: rkg5374@psu.edu
Mr. S. KC, Ms. N. Khanal
Next, we examined the scope of the -carbonylalkylarylation reaction
with respect to arylzinc reagents (Table 2). A wide range of electron
deficient, neutral and electron-rich arylzinc reagents, along with ethyl
-bromo- and -chloroacetates, are capable of difunctionalizing
indene and affording -carbonyl- alkylarylated products in good
yields. The reaction tolerates arylzinc reagents bearing halides such
as F, Cl, di-Cl and Br (8-12 and 15). Arylzinc reagents bearing
Department of Chemistry and Chemical Biology
University of New Mexico
300 Terrace St. NE, Albuquerque, NM, USA
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201913435
Angewandte Chemie International Edition
COMMUNICATION
a0.5 mmol scale reactions. Letters in parenthesis indicate X in -
sensitive functional groups such as nitriles and esters (13 and 14) are
also good coupling partners. The reaction also works well with ortho-
substituted arylzinc and heteroarylzinc reagents (7 and 15). The -
carbonylalkylarylated products are formed as trans-stereoisomers
with high diastereoselectivity (≥ 10:1). The structure of the major
trans-diastereomer was confirmed by single crystal X-ray
crystallography of the carboxylic acid derivative of the product 10.
haloacetate. b0.2 mmol scale reaction. c10 mol% Ni(cod)2.
Various vinylarenes based on aryl, naphthyl and indenyl scaffolds
bearing both electron-donating and withdrawing functional groups
readily undergo the difunctionalization reaction (Table 3). Halides (Cl,
Br), OMe and ortho-Me are tolerated on vinylarenes (19-21, 25 and
26). -Methylstyrene and styrenes containing an aldehyde group at
the ortho-position are also good alkene substrates, in which the ortho-
aldehyde remains intact after the reaction (37). These vinylarenes are
coupled with different primary, secondary and tertiary -
bromocarboxylates along with arylzinc reagents containing various
Table 1. Optimization of reaction conditionsa
Table 3. Scope with vinylarenes, RX and ArZnIa
Entry Modified conditions
Yield of 4 (%)
1
2
3
4
None
76 (72)b
61
NiBr2 instead of Ni(cod)2
(Ph3P)4Ni instead of Ni(cod)2
Pd(OAc)2, CoCl2, FeCl2 or CuI
instead of Ni(cod)2
10
0
5
6
7
8
DMA instead of NMP
52
DMF or THF instead of NMP
DCM or Toluene instead of NMP
ethyl -chloroacetate instead of
ethyl -bromoacetate
10-15
10-16
63
a0.1 mmol scale reactions. bIsolated yield (0.5 mmol scale) in
parenthesis. dr 16:1.
Table 2. Scope with ArZnIa
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10.1002/anie.201913435
Angewandte Chemie International Edition
COMMUNICATION
a0.5 mmol scale reactions. b5 mol% Ni(cod)2 in DCM. c10 mol%
Ni(acac)2 in toluene. d10 mol% Ni(acac)2 in DCE.
Scheme 3. Reaction with TEMPO
functional groups (F, di-F, Br, CF3 and ortho-CO2Me). The reaction
also works well with -bromolactones (32), and other secondary and
tertiary -bromocarboxylates (33-35), which generate products with
-tertiary and -quaternary carbon centers.[16] An -bromoketone can
also be used instead of -bromocarboxylate, which generates a ,-
diarylketone product (23). An application of the current method is also
demonstrated by difunctionalizing vinylarene scaffolds attached to a
commercial drug, indomethacin (38 and 39).
Scheme 4. Radical clock experiment
We also propose a catalytic cycle for the -carbonylalkylarylation
reaction (Scheme 5). The reaction is initiated by the reduction of alkyl
-bromocarboxylates via single electron transfer (SET) by the Ni(y)-
catalyst (y = 0 or I), which generates -carbonylalkyl radicals,
ROC(=O)-R• (46), stabilized by resonance within the solvent cage
with Ni(y+1)X bound either to cyclooctadiene (cod), vinylarene or NMP.
The -carbonylalkyl radicals then add to vinylarenes followed by
The -carbonylalkylarylation reaction can be applied for the rapid
synthesis of aryltetralone derivatives (Scheme 2). We have
demonstrated
a
one-pot
two-step
synthesis
of
the
dichlorophenyltetralone 40, a known precursor to a commercial
antidepressant drug sertraline•HCl (Zoloft)[15] (eq. 1). In this synthesis,
styrene was difunctionalized with ethyl -bromoacetate and 3,4-
dichlorophenylzinc iodide to furnish ethyl -(3,4-dichlorophenyl)--
phenylbutyrate (18), which was then cyclized without purification to
the Zoloft precursor 40 by intramolecular Friedel-Crafts acylation. We
also synthesized a difluoroaryltetralone derivative 41 from the reaction
of styrene with ethyl -bromobutyrate and 3,5-difluorophenylzinc
iodide followed by intramolecular Friedel-Crafts acylation without
purification (Scheme 2, eq. 2).
radical recombination with Ni(y+1)
X
to form benzylnickel(II)
intermediate (48). The generation of the benzylic radical, which also
supports our hypothesis of 1e‒ reduction of -bromoester by Ni(y), is
consistent with the observation of trans-products derived from
indenes. A 2e‒ reduction of -bromoester by Ni(0), i.e. by oxidative
addition, which is generally proposed for reduction of alkyl halides by
Ni(0), would furnish cis-stereochemistry by migratory insertion of the
cyclic alkenes – an outcome inconsistent with our observation.[20] The
intermediate 48 then transmetallates with arylzinc reagents and
subsequently reductively eliminates to form the difunctionalized
product 50 and regenerate the Ni(y)-catalyst.
Scheme 2. Synthesis of aryltetralone derivatives
Moreover, we performed preliminary mechanistic studies utilizing
radical trap and radical clock experiments. Addition of 1 equiv of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radical to the reaction
of indene with ethyl -bromoacetate and 3-(trifluoromethyl)phenylzinc
iodide generated the TEMPO adduct 42 in 32% yield, along with the
diester 43,[17] by trapping an -ethoxycarbonylmethyl radical (Scheme
3). We then employed allyl -bromoacetate as a radical clock, which
was reacted with styrene and 3-(trifluoromethyl)phenylzinc iodide.
The reaction produced the uncyclized -carbonylalkylarylated product
44 in 46% yield (Scheme 4). The product 45, which would be
generated via radical cyclization on the tethered alkene, was not
observed.[18] The results from these two experiments are consistent
with the generation of a stable -carbonylalkyl radical,[19] which
undergoes radical addition to the moderately activated alkene in
styrene faster than the unactivated tethered alkene.
Scheme 5: Proposed catalytic cycle
In summary, we have developed a Ni-catalyzed regioselective -
carbonylalkylarylation of vinylarenes with -halocarbonyl compounds
and arylzinc reagents to generate ,-diarylcarbonyl and aryltetralone
derivatives. The reaction works well for the reaction of various
vinylarenes with primary, secondary and tertiary -halocarboxylates,
and a variety of arylzinc reagents, which forms products with -
secondary, tertiary and quaternary carbon centers.
Acknowledgements
We gratefully acknowledge the NIH NIGMS (R35GM133438) and the
NSF (CHE-1554299) for support of this work. We also thank The
Pennsylvania State University and the University of New Mexico
(UNM) for additional financial support. A major part of the current work
was conducted at UNM.
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10.1002/anie.201913435
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COMMUNICATION
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Keywords: Aryltetralone • diarylcarbonyl •
dicarbofunctionalization • nickel-catalyzed • vinylarenes
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10.1002/anie.201913435
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COMMUNICATION
TOC
COMMUNICATION
Shekhar KC, Roshan K. Dhungana,
Namrata Khanal, and Ramesh Giri *
Page No. – Page No.
Nickel-Catalyzed -
Carbonylalkylarylation of
Vinylarenes. Expedient Access to ,-
Diarylcarbonyl and Aryltetralone
Derivatives
A nickel-catalyzed regioselective -carbonylalkylarylation of vinylarenes with
primary, secondary and tertiary -halocarbonyl compounds and arylzinc reagents is
reported. The ,-diarylcarbonyl products can be readily converted to aryltetralones,
including a precursor to Zoloft, an antidepressant drug. Mechanistic studies indicate
that the reaction proceeds via additions of stable -carbonylalkyl radicals to
alkenes.
This article is protected by copyright. All rights reserved.