Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenzamides

Article abstract of DOI:10.1002/anie.202011342

A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.

Full text of DOI:10.1002/anie.202011342

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Accepted Article
Title: Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenzamides
Authors: Sergio Cuesta-Galisteo, Johannes Schörgenhumer, Xiaofeng
Wei, Estibaliz Merino, and Cristina Nevado
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011342
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10.1002/anie.202011342
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Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenzamides
Sergio Cuesta-Galisteo,ǂ Johannes Schörgenhumer,ǂ Xiaofeng Wei, Estibaliz Merino† and Cristina
Nevado*[a]
[a]
S. Cuesta-Galisteo, Dr. J. Schörgenhumer, Dr. Xiaofeng Wei, Dr. E. Merino, Prof. Dr. C. Nevado
Department of Chemistry, University of Zurich
Winterthurerstrasse 190, CH 8057, Zurich
E-mail: cristina.nevado@chem.uzh.ch
These authors contributed equally to this work
Current address: Department of Organic and Inorganic Chemistry, University of Alcala, 28805-Alcala de Henares (Madrid), Spain.
ǂ
†
́
́
Supporting information for this article is given via a link at the end of the document.
Abstract: A nickel-catalyzed asymmetric reductive hydroarylation of
vinyl amides to produce enantioenriched α-arylbenzamides is
reported. The use of a chiral bisimidazoline (BIm) ligand, in
combination with diethoxymethylsilane and aryl halides, enables
regioselective introduction of aryl groups to the internal position of the
olefin, forging a new stereogenic center α to the N atom. The use of
neutral reagents and mild reaction conditions provides simple access
to pharmacologically relevant motifs present in anticancer, SARS-
CoV PLpro inhibitors and KCNQ channel openers.
Based on these results, we set out to explore the asymmetric
formal hydroarylation of functionalized olefins, particularly vinyl
amides.
α-Arylbenzamides are ubiquitous motifs in bioactive molecules
[1b-c]
such as anti-cancer agents[1a], SARS-CoV PLpro inhibitors
and anti-depressants[1d] among many others[1e-g] (Scheme 1a).
Access to enantiomerically enriched versions of these motifs is
nonetheless far from straightforward. Rh-catalyzed hydrogenation
of vinyl amides[2], C-N coupling between carboxylic acid
derivatives and chiral α-aryl substituted amines[3], hydride
opening of N-acylaziridines[4] are some of the methods currently
at hand to assemble these challenging motifs.[5] Limited reaction
scope, relatively harsh conditions and risk of epimerization restrict
the applicability of these methodologies in synthesis. Recently, a
Ni/photoredox dual catalyzed α-arylation of benzamides has also
been realized[6] (Scheme 1b). An alternative disconnection for this
motif would stem from a three-component formal hydroarylation
reaction involving readily available vinylbenzamides, arene
halides and an
H
source (Scheme 1c).[7] Asymmetric
Scheme 1. α-Arylbenzamides: examples of bioactive molecules and general
strategies towards their asymmetric synthesis.
hydroarylation reactions of alkenes are nonetheless scarce.
Successful examples have been reported relying on the
combination of Pd and/or Cu complexes, and aryl halides or
boranes.[8] Recently, highly selective Ni-catalyzed intramolecular
Mechanistically, our design relies on the activation of a silane with
nickel to produce, upon addition to the double bond, a chiral Csp3-
Ni(I) intermediate. Further, the Csp2-X precursors are activated
via oxidative addition, forming a chiral alkylarylNi(III) complex (I in
Scheme 1c), and outcompeting the potential direct reduction of
the aryl precursors.[13] The C-C bond-forming reductive
elimination occurs at the internal position of the olefin delivering
the new stereogenic center with high levels of stereocontrol. Thus,
Csp2-halides and a hydride are added to vinyl benzamides with
high regio- and stereoselectivity. This process avoids sensitive
organometallic reagents and proceeds at room temperature,
delivering enantioenriched α-arylbenzamides, whose subsequent
derivatization enables the straightforward assembly of
pharmacologically relevant scaffolds.[1]
[9]
cyclizations have been reported.
Formal hydroarylations
employing boronic acids and aryl iodides under asymmetric Ni
catalysis have also proven fruitful.[10] Despite their obvious
synthetic utility, these transformations are mostly amenable only
to styrene-based substrates and thus, introduction of aryl groups
to the α-position to a heteroatom remains an unconquered
challenge.
In recent years, our group has explored the use of nickel catalysis
towards the efficient difunctionalization of π-systems[11a-b] with a
particular focus on olefins[11c-e]. We have recently reported an
asymmetric alkene dicarbofunctionalization reaction in which a
chiral bisoxazoline ligand and the presence of coordinating sites
on the alkene can be synergistically combined to ensure
stereodefined Csp3-Csp2 bond formation.[12]
To select the appropriate chiral ligand, vinyl benzamide and
phenyl iodide were chosen as benchmark reaction partners using
1
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NiCl2·DME (10 mol%), diethoxymethylsilane (3 equiv), sodium
carbonate (3 equiv) and trifluoroethanol[15] (3 equiv) in THF, as
these had been found to deliver the desired benzamide 1 in
racemic form. Different chiral bisoxazoline, pyridine-oxazoline
and isoquinoline-oxazoline ligands (L1-11[14], 12.5 mol%) were
tested, however, no more than 64% ee was achieved. When we
turned our attention to bisimidazoline ligands (BIm), which have
recently gained attention in asymmetric nickel catalysis[16], we
were delighted to see that different aromatic substituents on the
nitrogen atoms and an isopropyl side chain (Scheme 2, L12-14)
resulted in the formation of the chiral benzamide 1 in moderate
yields with high levels of stereocontrol (up to 88%ee ).
furnished the amides 19 and 20 in yields of 53% and 55% with 77%
ee and 84% ee, respectively.
It is important to note that activated Csp2-bromides such as 2-
bromo-1H-indene could also be converted into the desired
product under the standard reaction conditions as demonstrated
by the successful isolation of amide 21. Interestingly, amide 22
could be obtained from β-bromostyrene, albeit with low
stereoselectivity.
Scheme 2. Ligand screening. Unless otherwise stated, reactions were carried
under the indicated conditions. Isolated yields are shown. The enantiomeric
excess was determined by chiral HPLC. For detailed experimental conditions,
see SI.[14]
Finally, implementation of an isoleucine-derived side chain in
ligand L15 resulted in the formation of the desired amide 1 in 58%
yield and 94 ee%. The same conditions were applied to 2-
methoxy-N-vinylbenzamide furnishing chiral amide 2 in 72% yield
and 89% ee.
After additional optimization of the reaction conditions in order to
reduce the catalyst loading,[14] we set out to explore the scope of
this transformation (Scheme 3). First, we assessed the reactivity
of different aryl iodides with 2-methoxy-N-vinylbenzamide as the
olefin. Reaction with 2-naphthyl iodide delivered the
corresponding α-naphthylbenzamide 3 in 75% yield and 84% ee.
Different phenyl iodides were tested next. Both electron-donating
(Me, OMe, tBu) and electron-withdrawing (CN, F, CO2Me, COMe)
groups in the para position of the aromatic ring were tolerated, as
demonstrated by the isolation of the corresponding benzamides
4-10 in good yields and high ee. Meta substituents (methoxy, 3,5-
difluoro and 3-fluoro and 3,5-dimethyl dicarboxylate) were equally
tolerated delivering the corresponding chiral amides 11-14 with
good stereocontrol and in high yields. Next, we aimed to explore
the compatibility of our protocol with functional groups typically
used in classical cross coupling reactions. To our delight, the
Scheme 3. Reaction scope on the Csp2-X. For detailed experimental conditions,
see SI. * Reactions run for 40 h. ** Reactions run for 40 h with 4 equiv of aryl or
benzyl halide.
More complex substrates bearing additional stereocenters were
also compatible with this mild reductive hydroarylation protocol.
L-Phenylalanine-, estrone- and D-glucose-derived aryl iodides
delivered products 23-25 with excellent diastereomeric ratios
(≥95:5 d.r.). Finally, derivatization of the Csp2-I bond in adduct 18
under classical Pd-catalyzed cross-coupling reaction conditions
delivered analogue 26 in 76% yield without noticeable erosion of
the enantiomeric purity. Interestingly, benzyl bromide could also
be used for the reaction to deliver the amide 27 in 90% yield, albeit
with only 60% ee.
reaction
of
2-(4-iodophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane and 1-chloro-3-iodobenzene was completely
chemoselective for the Csp2-I bond, delivering the corresponding
boron- and chloro-containing amides 15 and 16 in 83% and 82%
yield with 90% ee and 91% ee, respectively. Interestingly, mono-
reaction took place in the case of 1,4- and 1,3-diiodobenzenes,
delivering the iodo-containing chiral amides 17 and 18,
respectively, in excellent yield. Prolonged reaction times and 4
equiv. of the aryl iodides, 2-iodotoluene and 1-iodonaphthalene
Next, a variety of vinyl amides were examined (Scheme 4).
Unsubstituted (28) as well as ortho-substituted vinyl benzamides
were excellent substrates for this formal hydroarylation. Thus,
2
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vinyl- and ortho-methyl substituted benzamides reacted with
phenyl iodide and dimethyl 5-iodoisophthalate to deliver amides
29 and 30 in 68% and 58% yield and 96% and 93% ee,
respectively. Both ortho- and meta-chloro- as well as ortho-fluoro-
containing substrates afforded products 31-36 in high yields and
with excellent ee. Para-substitution of the benzamide, with both
electron-donating (OMe, Me) and electron-withdrawing groups
(CF3, Cl) delivered adducts 37-43 with similar efficiency in terms
of yield and absolute stereocontrol.
and carboxylation reactions among other transformations.[19],[20]
Stoichiometric treatment of pre-formed L15NiX2 complex (X = Cl,
Br, I) with Me(OEt)2SiH produced a significant broadening of the
1H NMR signals and a rapid color change of the reaction to dark
blue-purple, possibly indicating the formation of reactive
intermediates[21]
.
DFT calculations were performed using
vinylbenzamide, phenyl iodide, Me(OEt)2SiH and L15 as model
structures to gain additional insights onto the regio- and
stereochemical outcome of this process (Scheme 5).[14] These
studies confirm the pivotal role of the amide group for the high
stereo- and regioselectivity and lead to a plausible mechanistical
proposal involving an olefin insertion before oxidative addition and
reductive elimination.
Scheme 5. Mechanistic proposal including DFT calculations. Reaction free
energies (kcal/mol) calculated at UB3LYP/6-31G(d) (C,H,N), LANL2DZ (Ni, I)
level. Indicated distances are given in Å. [13]
Scheme 4. Reaction scope on the vinyl amide.* Reactions run for 40 h. **
Reactions run for 40 h at 40 ºC. For detailed experimental conditions, see SI.
In summary, we present here a highly efficient asymmetric
reductive hydroarylation of vinyl amides. A variety of readily
available Csp2-halides are added across the corresponding
The established protocol was applied to a pyridine-containing
substrate to afford the desired chiral amide 44, albeit in moderate
yield. Alkyl vinyl amides could also be asymmetrically
hydroarylated, as shown by the isolation of amide 45, although
extended reaction time was required in this case. Finally, we also
explored the substitution pattern at the terminal position of the
olefin. It is well established that metal-mediated insertions as well
as radical additions to olefins are sensitive to the terminal
substituents.[7j],[17] Interestingly, (E)- and (Z)-N-(prop-1-en-1-yl)-
benzamides displayed markedly different reactivity: while the
former offered the product in only 29% yield[14], the cis substrate
furnished the desired chiral amide 46 in good yield (54%) with
excellent levels of stereocontrol (94% ee). Similarly, (E)-N-
styrylbenzamide delivered amide 47 in comparatively moderate
yield, but with excellent enantioselectivity (96% ee).
alkenes at room temperature in
a
highly regio- and
enantioselective manner. The reaction proceeds through an alkyl
Ni(III)-intermediate involving a chiral bisimidazoline ligand (BIm).
DFT calculations confirm that the amide group plays a crucial role
in stabilizing the Ni center, contributing to stereodefined Csp3-
Csp2 bond formation. Our method represents a de novo approach
towards the efficient assembly of chiral α-arylbenzamides,
pharmacologically relevant motifs present in anticancer, SARS-
CoV PL proteosome inhibitors and KCNQ channel openers.
Acknowledgements
We thank the European Research Council (ERC Starting grant
agreement no. 307948) and the Swiss National Science
Foundation (SNF 200020_146853) for financial support. We
thank Dr. Jaime Martín and Marc Lennon for their contributions to
the mechanistic studies and preparation of starting materials,
respectively.
Control experiments and DFT calculations were performed to
unravel the reaction mechanism. The presence of radical
scavengers had no significant impact on the reaction outcome.[14]
Previous reports have also described the reaction of silanes with
Ni complexes to produce Ni hydride species.[18] Further, such
hydrides have been invoked in recent reports of cross-couplings
3
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DOI: 10.1002/anie.202010386
Keywords: Nickel • Hydroarylation • Asymmetric • α-Aryl amides
• Vinyl amides
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4
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Entry for the Table of Contents
A novel approach towards the efficient assembly of chiral α-arylbenzamides is presented here based on an enantioselective, nickel-
catalyzed reductive hydroarylation protocol. The use of neutral reagents and mild reaction conditions enabled the synthesis of α-
arylbenzamides in high enantiomeric purity providing an alternative access to pharmacologically relevant motifs present in anticancer,
SARS-CoV PLpro inhibitors and KCNQ channel openers.
5
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