Nickel-Catalyzed Formal Aminocarbonylation of Secondary Benzyl Chlorides with Isocyanides

Article abstract of DOI:10.1021/acs.orglett.0c01284

Phenylacetamides represent versatile feedstocks in synthetic chemistry, widely existing in drug molecules and natural products. Herein, we disclose a nickel-catalyzed formal aminocarbonylation of secondary benzyl chlorides with isocyanides yielding α-substituted phenylacetamide with steric hindrance, which is synthetically challenging via palladium-catalyzed aminocarbonylation. The reaction features wide functional group tolerance under mild conditions, highlighted by the tolerance of various aromatic halide (-Cl, -Br, -I) and heteroaromatic rings (pyridine and pyrazine).

Full text of DOI:10.1021/acs.orglett.0c01284

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Letter
Nickel-Catalyzed Formal Aminocarbonylation of Secondary Benzyl
Chlorides with Isocyanides
Yun Wang, Wenyi Huang, Chenglong Wang, Jingping Qu,* and Yifeng Chen*
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ABSTRACT: Phenylacetamides represent versatile feedstocks in
synthetic chemistry, widely existing in drug molecules and natural
products. Herein, we disclose a nickel-catalyzed formal amino-
carbonylation of secondary benzyl chlorides with isocyanides
yielding α-substituted phenylacetamide with steric hindrance,
which is synthetically challenging via palladium-catalyzed amino-
carbonylation. The reaction features wide functional group tolerance under mild conditions, highlighted by the tolerance of various
aromatic halide (−Cl, −Br, −I) and heteroaromatic rings (pyridine and pyrazine).
feasible and effective synthetic approach to synthesize the
henylacetamide is a quintessential functional group in
Porganic chemistry and also plays a versatile role as phenylacetamide derivatives. Since the pioneering work by
Heck in 1974, palladium-catalyzed carbonylation with various
electrophiles and CO gas as a C1 building block has become
the standard procedure for syntheses of carbonyl compounds
(ketone, ester, amide, etc.).2 Not surprisingly, the access to
phenylacetamide via palladium-catalyzed aminocarbonylation
of benzylic electrophiles has also received much attention
(Scheme 1b).3 However, the scope of benzylic halides3a−c and
benzylic ammonium salts3d of the reported three-component
aminocarbonylation reaction limited on the use of the primary
ones, most likely due to the undesired β-H elimination of
benzyl palladium intermediate via oxidative addition. Recently,
Pd-catalyzed oxidative aminocarbonylation with benzylic C−H
activation under elevated CO atmosphere has emerged as an
appealing strategy.4 Nevertheless, the bulky toluene and
ethylbenzene are the only two substrates which could capable
of selective formation of benzylic palladium intermediate.
More recently, earth-abundant nickel-catalyzed cross-cou-
pling of benzylic electrophiles, including secondary benzylic
electrophile, has emerged as a robust platform for benzyl-
substituted compounds synthesis.5−7 Among these, nickel-
catalyzed carbonylation of benzylic electrophiles is less
developed with only a few research groups reporting the
synthesis of benzylic ketones via the insertion of CO.8 To the
best of our knowledge, the facile synthesis of phenylacetamide
via nickel-catalyzed aminocarbonylation of benzylic electro-
philes remains elusive.
scaffolds in drugs, natural products, and bulk chemicals
(Scheme 1a).1 Owing to their ubiquitous nature, chemists
are still exploring novel strategies to synthesize phenyl-
acetamides, especially the method for the α-position-
substituted phenylacetamide with restricted steric hindrance.
Among them, the transition-metal-catalyzed aminocarbonyla-
tion of easily accessible benzyl electrophiles represents a
Scheme 1. Overview of Aminocarbonylation of Benzylic
Electrophile
Received: April 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01284
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Isocyanides as an efficient CO surrogate and C1 synthon are
frequently employed as a carbonyl source in transition metal
catalyzed carbonylations and heterocycle synthesis.9 Pioneered
by Saegusa and Zhu,10 Yang and co-workers reported an
elegant Pd-catalyzed migratory insertion of α-halo phospho-
nates with isocyanides to provide the C-phosphonoketeni-
mines, which could undergo an additional hydrolysis to
generate the corresponding amides, while all the secondary
benzyl chlorides do not possess the β-hydrogen atom adjacent
to the benzylic positions.11 We have recently achieve the
nickel-catalyzed regioselective allylic carbonylative Negishi
reactions with isocyanides to afford the β,γ-unsaruated
ketones,12 and the aminocarbonylation to access alkyl amides
leveraging isocyanide as both a carbonyl and amine source,
whereas the secondary electrophiles limits on the relative and
less stable alkyl iodides.13 Thereby, we envisaged implement-
ing isocyanide to achieve nickel-catalyzed aminocarbonylation
of secondary benzylic electrophiles to tackle the challenge
aforementioned for palladium catalysis. Herein, we report an
efficient aminocarbonylation employing readily available
secondary benzyl chloride as the feedstocks under nickel-
catalyzed conditions to afford a series of hindered α-
substituted phenylacetamides, exhibiting broad functional
group tolerance under mild conditions (Scheme 1c).
naphthalene 1a as the benzylic electrophile, and the reaction
efficiency greatly improved and the product 3a was obtained in
73% GC yield (Scheme 2, entry 2). Investigation of the
activate oxygen-containing leaving groups, including −OPiv,
−OBoc, and −OTs, did not provide any desired amide 3a
(Scheme 2, entries 3−5). With the determination of the
leaving group, we conducted the base screening, it was found
that the type of base affected the formation of the elimination
side products. When NaOtBu was employed as the base, the
amide 3a could be produced in 86% GC yield without
formation of alkene 4a, and the isolated yield was 77%
(Scheme 2, entry 6). When stronger base KOtBu was utilized,
the GC yield of amide 3a dramatically dropped to 14% as well
as 15% side product 4a (Scheme 2, entry 7). Minimal product
could be observed with treatment of LiOtBu as base (Scheme
2, entry 8). The examination of other common inorganic bases
(Na2CO3, K3PO4, NaOEt) was also detrimental (Scheme 2,
entries 9−11).
With the optimized conditions in hand, the substrate scope
of the nickel-catalyzed aminocarbonylation of secondary benzyl
chlorides with isocyanides was examined (Scheme 3). It was
found that various naphthyl chloroalkanes were well tolerated
under the optimized conditions; when the ethyl group was
incorporated, the corresponding amide 3b was isolated in 84%
yield. Gratefully, when the cyclohexyl group was introduced,
the desired product 3c could still be obtained as moderate
yield. It was well known that the naphthalene functionality
would significantly increase the aromaticity of the benzyl
electrophiles. When the commercially available (1-chloro-
ethyl)benzene 1d was employed as the benzylic electrophile,
the amide 3d was still isolated with 80% yield, demonstrating
that this protocol did not rely on the naphthalene substitution
effect. The isopropyl-substituted benzyl chloride 1e also
worked under the standard conditions, although with moderate
reaction efficiency (52%) likely due to the increased steric
hindrance. This ligandless Ni-catalyzed amionacarbonylation
protocol allowed the various aromatic halide substitutions
(−Cl, −Br, −I) which were suitable and inert to the low-valent
nickel species, especially for iodide substitution (3h) which
would be extremely challenging for palladium catalysis,
demonstrating the merits for this synthetic methodology, and
the tolerance of activate aromatic halide allows for the various
further functionalizations. The nitrogen-containing heteroar-
enes are among the most significant structural backbones of
pharmaceuticals.14 Furthermore, this catalytic system tolerated
secondary heterobenzyl chloride, including several of the
nitrogen-containing six-membered heteroarenes, such as
pyridines (3i−3k) and pyrazines (3l), the corresponding
secondary amide could be smoothly obtained in 58−71%
isolated yield. Notably, the substitution on the pyridines has
minimal effect on this carbonylative reaction, the ortho-, meta-,
and para-substituted 1-chloroethylpyridines all worked. The
tertiary amide could be traditionally synthesized via the
Buchwald−Hartwig α-arylation of the enolized amides with
the heteroarmoatic halide.15 However, the secondary amide
was extremely challenging for direct deprotonation for
formation of enolate.15b Hence, the success of the hetero-
benzylic electrophile reveals its potential application in
pharmaceuticals. In addition, analogues of (chloromethylene)-
dibenzene could also be converted into amides (3m, 3n, 3o),
respectively, albeit in moderate yield. By changing the
We initiated the nickel-catalyzed aminocarbonylation using
2-(1-bromoethyl)naphthalene as the starting material and tert-
butyl isocyanide as the carbonyl and amine source; the desired
aminocarbonylative product N-(tert-butyl)-2-(naphthalen-2-
yl)propenamide 3a was obtained in 37% corrected GC yield,
as no other detective side products was observed (Scheme 2,
entry 1). The lack of mass balance revealed that the benzylic
bromide electrophiles underwent the significant decomposi-
tion. Thus, we selected less reactive 2-(1-chloroethyl)-
Scheme 2. Optimization of the Ni-Catalyzed
a
t
Aminocarbonylation of 1a with BuNC
a
Reaction conditions: 1 (0.1 mmol), tert-butyl isocyanide 2a (0.15
mmol), Ni(cod)2 (0.01 mmol), NaOtBu (0.2 mmol), toluene (1.0
mL), at 100 °C, 5 h. Then 1 M HCl (1.0 mL), rt, 5 min. Corrected
GC yield with dodecane as an internal standard. Isolated yield.
t
b
isocyanide from BuNC to AdNC, amide 3p was available in
c
45% yield. When CyNC and 2-ethylphenyl isocyanide were
B
https://dx.doi.org/10.1021/acs.orglett.0c01284
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 3. Scope of Ni-Catalyzed Aminocarbonylation of
Secondary Benzyl Chlorides with Isocyanides
Scheme 4. Mechanistic Hypothesis
a
In conclusion, we have developed a nickel-catalyzed formal
aminocarbonylation of secondary benzyl chlorides, capitalizing
on the selective insertion of isocyanide. A range of potentially
useful phenylacetamides are accessible under mild conditions,
allowing the deployment in synthesis of medicinal chemistry
and natural products. Further exploration on nickel-catalyzed
carbonylation utilizing isocyanide as the carbonyl source is
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01284.
Experimental details, NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1c, 1l, and 3a−3p (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Jingping Qu − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China; orcid.org/0000-0002-7576-
0798; Email: qujp@dlut.edu.cn
Yifeng Chen − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China; orcid.org/0000-0003-3239-
6209; Email: yifengchen@ecust.edu.cn
a
Reaction conditions: secondary benzyl chloride 1 (1.0 equiv),
isocyanide 2 (1.1−1.5 equiv), Ni(cod)2 (10 mol %), NaOtBu (1.0−
2.0 equiv), toluene (0.1 M), 80−120 °C. Then 1 M HCl, rt, 5 min.
c
d
Saturated aq NaHCO3 was added until pH > 7. Three M HCl, rt, 1
h.
employed as the carbonyl and amine source, the desired
product (3q, 3r) could not be detected and the starting
material largely remained, which revealed that the less bulky
isocyanides might serve as ligand to deactivate the nickel
catalyst.
On the basis of the Ni-catalyzed benzylation chemistry6,7
and prior work on aminocarbonylation with isocyanides,13
a
plausible mechanism is proposed in Scheme 4. The Ni(0)
species reacts with benzyl chloride 1 via oxidative addition to
generate benzylic nickel intermediate A. After the selective 1,1-
migratory insertion of isocyanide 2, the imidoyl nickel species
B is furnished, which further undergoes successive β-hydride
elimination to offer the key ketenimine D intermediate.16
Under the weak acidic condition, ketenimine D is hydrolyzed
to produce the desired amide 3 product. Finally, the reductive
elimination of C regenerates the Ni(0) species.
Authors
Yun Wang − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
C
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Esters via C−N Bond Activation. Org. Biomol. Chem. 2018, 16, 3099−
3103.
Engineering, East China University of Science & Technology,
Shanghai 200237, China
(4) (a) Xie, P.; Xia, C.; Huang, H. Palladium-Catalyzed Oxidative
Aminocarbonylation: A New Entry to Amides via C−H Activation.
Org. Lett. 2013, 15, 3370−3373. (b) Xie, P.; Xie, Y.; Qian, B.; Zhou,
H.; Xia, C.; Huang, H. Palladium-Catalyzed Oxidative of Benzylic C-
H Bonds via Nondirected C(sp3)−H Activation. J. Am. Chem. Soc.
2012, 134, 9902−9905. (c) Liu, H.; Laurenczy, G.; Yan, N.; Dyson, P.
J. Chem. Commun. 2014, 50, 341−343.
Wenyi Huang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, Frontiers Science Center for Materiobiology
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science & Technology,
Shanghai 200237, China
(5) Sergeev, A. G.; Hartwig, J. F. Selective, Nickel-Catalyzed
Hydrogenolysis of Aryl Ethers. Science 2011, 332, 439−443.
(6) (a) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Stereospecific
Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers and
Esters. Acc. Chem. Res. 2015, 48, 2344−2353. (b) Pound, S. M.;
Watson, M. P. Asymmetric Synthesis via Stereospecific C−N and C−
O Bond Activation of Alkyl Amine and Alcohol Derivatives. Chem.
Commun. 2018, 54, 12286−12301. (c) Wang, Z.-X.; Yang, B.
Chemical Transformations of Quaternary Ammonium Salts via C-N
Bond Cleavage. Org. Biomol. Chem. 2020, 18, 1057−1072. (d) Zhou,
Q.; Cobb, K. M.; Tan, T.; Watson, M. P. Stereospecific Cross
Couplings to Set Benzylic, All Carbon Quaternary Stereocenters in
High Enantiopurity. J. Am. Chem. Soc. 2016, 138, 12057−12060.
(e) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.; Tomlin, J. W.;
Garnsey, M. R.; Watson, M. P. Transforming Benzylic Amines into
Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C-
N Bond Activation. Org. Lett. 2018, 20, 3030−3033. (f) Michel, N.
W. M.; Jeanneret, A. D. M.; Kim, H.; Rousseaux, S. A. L. Nickel-
Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters. J. Org.
Chem. 2018, 83, 11860−11872. (g) Tsuji, H.; Hashimoto, K.;
Kawatsura, M. Nickel-Catalyzed Benzylic Substitution of Benzyl
Esters with Malonates as a Soft Carbon Nucleophile. Org. Lett. 2019,
21, 8837−8841. (h) Plunkett, S.; Basch, C. H.; Santana, S. O.;
Watson, M. P. Harnessing Alkylpyridinium Salts as Electrophiles in
Deaminative Alkyl-Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019,
141, 2257−2262. (i) Chen, P.-P.; Lucas, E. L.; Greene, M. A.; Zhang,
S.; Tollefson, E. J.; Erickson, L. E.; Taylor, B. L.; Jarvo, E. R.; Hong, X.
A Unified Explanation for Chemoselecivity and Stereospecificity of
Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of
Benzylic Ethers: A Combined Computational and Experimental
Study. J. Am. Chem. Soc. 2019, 141, 5835−5855.
(7) (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic
Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioen-
riched Acyclic α, α-Disubstituted Ketones. J. Am. Chem. Soc. 2013,
135, 7442−7445. (b) Cherney, A. H.; Reisman, S. E. Nickel-
Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and
Benzyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365−14368.
(c) Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Intra- and Intermolecular
Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of
Benzylic Esters with Aryl Halides. Angew. Chem., Int. Ed. 2016, 55,
6730−6733. (d) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman,
S. E. Nickel-Catalyzed Enantioselective Cross-Coupling of N-
Hydroxyphthalimide Esters with Vinyl Bromides. Org. Lett. 2017,
19, 2150−2153. (e) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.;
Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric
Reductive Cross-Coupling to Access 1,1-Diarylalkanes. J. Am. Chem.
Soc. 2017, 139, 5684−5687. (f) Hofstra, J. H.; Cherney, A. H.;
Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic
Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem.
Soc. 2018, 140, 139−142. (g) Liao, J.; Basch, C. H.; Hoerrner, M. E.;
Talley, M. R.; Boscoe, B. P.; Tucker, J. W.; Garnsey, M. R.; Watson,
M. P. Deaminative Reductive Cross-Electrophile Couplings of
Alkylpyridinium Salts and Aryl Bromides. Org. Lett. 2019, 21,
2941−2946. (h) DeLano, T. J.; Reisman, S. E. Enantioselective
Electroreductive Coupling of Alkenyl and Benzyl Halides via Nickel
Catalysis. ACS Catal. 2019, 9, 6751−6754. (i) He, R.-D.; Li, C.-L.;
Pan, Q.-Q.; Guo, P.; Liu, X.-Y.; Shu, X.-Z. Reductive Coupling
between C−N and C−O Electrophiles. J. Am. Chem. Soc. 2019, 141,
12481−12486.
Chenglong Wang − Key Laboratory for Advanced Materials
and Joint International Research Laboratory of Precision
Chemistry and Molecular Engineering, Feringa Nobel Prize
Scientist Joint Research Center, Frontiers Science Center for
Materiobiology and Dynamic Chemistry, School of Chemistry
and Molecular Engineering, East China University of Science &
Technology, Shanghai 200237, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01284
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC/China (21421004,
21702060), Shanghai Municipal Science and Technology
Major Project (Grant No.2018SHZDZX03), the Program of
Introducing Talents of Discipline to Universities (B16017),
and the Fundamental Research Funds for the Central
Universities. The authors thank the Research Center of
Analysis and Test of East China University of Science and
Technology for the help with NMR analysis.
REFERENCES
■
(1) Katzung, B.; Masters, S.; Trevor, A. In Basic and Clinical
Pharmacology, 12th ed.; McGraw-Hill: New York, 2011.
(2) (a) Schoenberg, A.; Heck, R. F. Palladium-Catalyzed
Formylation of Aryl, Heterocyclic, and Vinylic Halides. J. Am.
Chem. Soc. 1974, 96, 7761−7764. (b) Schoenberg, A.; Heck, R. F.
Palladium-Catalyzed Amidation of Aryl, Heterocyclic, and Vinylic
Halides. J. Org. Chem. 1974, 39, 3327−3331. (c) Schoenberg, A.;
Bartoletti, I.; Heck, R. F. Palladium-Catalyzed Carboalkoxylation of
Aryl, Benzyl, and Vinylic Halides. J. Org. Chem. 1974, 39, 3318−3326.
(d) Brennfuhrer, A.; Neumann, H.; Beller, M. Palladium-Catalyzed
̈
Carbonylation Reactions of Aryl Halides and Related Compounds.
Angew. Chem., Int. Ed. 2009, 48, 4114−4133. (e) Wu, L.; Fang, X.;
Liu, Q.; Jackstell, R.; Beller, M.; Wu, X.-F. Palladium-Catalyzed
Carbonylative Transformation of C(sp3)−X Bonds. ACS Catal. 2014,
4, 2977−2989. (f) Barnard, C. F. J. Palladium-Catalyzed Carbon-
ylation-A Reaction Come of Age. Organometallics 2008, 27, 5402−
5422. (g) Grigg, R.; Mutton, S. P. Pd-Catalysed Carbonylations:
Versatile Technology for Discovery and Process Chemists. Tetrahe-
dron 2010, 66, 5515−5548. (h) Tsuji, J. In Palladium Reagents and
Catalysts: Innovations in Organic Synthesis; John Wiley & Sons, Inc.:
New York, 1995.
(3) (a) Troisi, L.; Pindinelli, E.; Strusi, V.; Trinchera, P.
Stereoselective Synthesis of 3,4-Diaryl β-Lactams. Tetrahedron:
Asymmetry 2009, 20, 368−374. (b) Troisi, L.; Granito, C.; Rosato,
F.; Videtta, V. One-Pot Amide Synthesis from Allyl or Benzyl Halides
and Amines by Pd-Catalysed Carbonylation. Tetrahedron Lett. 2010,
51, 371−373. (c) Wu, X.-F.; Schranck, J.; Neumann, H.; Beller, M.
Palladium-Catalyzed Aminocarbonylation of Benzyl Chlorides Using
Ammonia. ChemCatChem 2012, 4, 69−71. (d) Yu, W.; Yang, S.;
Xiong, F.; Fan, T.; Feng, Y.; Huang, Y.; Fu, J.; Wang, T. Palladium-
Catalyzed Carbonylation of Benzylic Ammonium Salts to Amides and
D
https://dx.doi.org/10.1021/acs.orglett.0c01284
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