Palladium-catalyzed secondary benzylic imidoylative reactions

Article abstract of DOI:10.1021/acs.orglett.0c02515

Reported herein is a palladium-catalyzed secondary benzylic imidoylative Negishi reaction leveraging the sterically bulky aromatic isocyanides as the imine source. This method allows the facile access of alkyl-, (hetero)aryl-, and alkynylzinc reagents to afford various α-substituted phenylacetone products under mild acidic hydrolysis, which are ubiquitous motifs in many pharmaceuticals and biologically active compounds. The diastereoselective reduction of imine can be accomplished to provide the expedient conversion of secondary benzylic halide into α-substituted phenethylamine derivatives with high atom economy.

Full text of DOI:10.1021/acs.orglett.0c02515

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Letter
Palladium-Catalyzed Secondary Benzylic Imidoylative Reactions
Chenglong Wang, Licheng Wu, Wentao Xu, Feng He, Jingping Qu,* and Yifeng Chen*
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ABSTRACT: Reported herein is a palladium-catalyzed secondary
benzylic imidoylative Negishi reaction leveraging the sterically
bulky aromatic isocyanides as the imine source. This method allows
the facile access of alkyl-, (hetero)aryl-, and alkynylzinc reagents to
afford various α-substituted phenylacetone products under mild
acidic hydrolysis, which are ubiquitous motifs in many pharmaceuticals and biologically active compounds. The diastereoselective
reduction of imine can be accomplished to provide the expedient conversion of secondary benzylic halide into α-substituted
phenethylamine derivatives with high atom economy.
improvement.12 We recently reported a Ni-catalyzed formal
α-Substituted phenylacetones are a versatile array of building
aminocarbonylative reaction of secondary benzyl chloride
using tert-butyl isocyanide, in which we identified inhibition
of the rapid β-H elimination of imidoyl metal species as a
significant challenge in developing an efficient secondary
benzyl carbonylative cross-coupling reaction to forge C−C
bond formation.13 Instead, the rapid transmetalation of
organometallic reagent with metal imidoyl intermediate should
be a superior process which also avoids a direct coupling
reaction with benzylic electrophiles. The broad functional
group tolerating organozinc reagent would be an appropriate
candidate.14 In line with our research interest in practical
carbonylation,15 we describe a Pd-catalyzed imdoylative
Negishi cross coupling of secondary benzyl halide with
modified isocyanide to provide the α-substituted arylaceti-
mines, which overcome competitive β-H elimination and direct
Negishi cross-coupling side pathways. Moreover, a wide array
of organozinc reagents containing sp, sp2, sp3, and heterocyclic
organozinc reagents can be readily accessed. In addition, both
α-substituted of phenylacetone and phenethylamine derivatives
can be divergently obtained upon the different workup
protocols: the mild acidic hydrolysis would provide the
phenylacetones, and the phenethylamines are generated in
high diastereoselective reduction with 100% atom economy
(Scheme 1).16
blocks, ubiquitous in pharmaceutically active compounds,
natural products, and agrochemicals.1 The traditional synthetic
route largely relies on the Buchwald−Hartwig α-arylation of
ketone, which often suffers from selective enolate intermediate
formation, especially for unsymmetric alkylated ketones
substrates, thus requiring the additional preformation of silyl
enol ether.2 Recently, the cross-coupling of benzylic electro-
philes via synergistic Pd/NHC-catalyzed umpolung of acyl
anions3 and Ni-catalyzed reductive cross-coupling of acyl
chloride4 have emerged as alternative synthetic approaches;
however, both methods restrict incorporation of alkylated
carbonyls. Meanwhile, phenethylamine derivatives represent
one of the top five pharmaceutical scaffolds, present in a broad
class of hormones, neurotransmitters, and psychoactive drugs.5
Thus, their diastereoselective preparation has gained consid-
erable attraction from organic chemists over several decades.6
Therefore, a divergent synthesis of α-substituted phenyl-
acetone and phenethylamine derivatives from easily accessible
benzylic electrophiles with broad substrate scope would be of
great research value.
Transition-metal-catalyzed carbonylative cross-coupling has
been classified as a powerful and straightforward protocol for
ketone synthesis with two carbon−carbon bond formations in
a single transformation.7 The majority of benzylic carbon-
ylations are mainly centered on formation of primary benzyl
ketones,8 as substituted benzyl ketone are synthetically
challenging due to the slow oxidative addition caused by
steric obstruction of the secondary benzyl electrophiles, as well
as inhibiting competitive reactions caused by the following β-H
elimination.9 More recently, Zhang and co-workers achieved
the Ni-catalyzed secondary benzylic bromide with organo-
boron reagent under mild conditions; however, the nucleo-
philes largely relied on the aromatic boronic acid.10
We initiated our studies with commercially available 2-(1-
chloroethyl) naphthalene 1a as benzyl electrophile in Table 1,
and the imidoylative reaction proceeded with treatment of tert-
butyl isocyanide 2a (1.5 equiv), n-butyl zinc chloride 3a (1.5
equiv) as nucleophile, and Pd2dba3 (2 mol %) under 60 °C in
Received: July 28, 2020
Isocyanide, as an important C1 synthon,11 has been
implemented in transition-metal-catalyzed carbonylation for
ketone synthesis, although the atom economy requires further
https://dx.doi.org/10.1021/acs.orglett.0c02515
© XXXX American Chemical Society
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With the optimized conditions in hand, we next examined
the substrate scope and functional group tolerance of Pd-
catalyzed benzylic imidolyative Negishi coupling reaction using
secondary 2-(1-chloroethyl)naphthalene 1a as a benzylic
electrophile (Table 2). A wide array of organozinc reagents
Scheme 1. General Strategy for Pd-Catalyzed Benzylic
Imidoylative Coupling of Carbon Fragments
a
Table 2. Substrate Scope of Zinc Reagents
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv), 3a
(0.3 mmol, 1.5 equiv), Pd2dba3 (0.004 mmol, 2 mol %), DMF (2
mL), 60 °C, 2 h. The reaction was quenched with 1 N HCl (2 mL)
and stirred at 25 °C for 0.25 h. Corrected GC yield was reported.
b
Isolated yield shown in parentheses.
DMF. Nevertheless, no desired imidoylative Negishi coupling
product was observed, while vinyl naphthalene was generated
as the main side product due to undesired β-H elimination.
The screening of another alkyl isocyanide (CyNC, 2b) also
failed to produce the desired product. Encouragingly, when
phenyl isocyanide (2c) was employed as the imidoyl
component, the desired product 4a was observed after 1.0 N
HCl workup, albeit with 16% GC yield. Varying the
substitution of aromatic isocyanide dramatically influenced
the efficiency of imidoylative Negishi coupling, and the
introduction of an o-methyl group at the phenyl isocyanide
(2d) greatly improved the yield to 72% presumably due to the
slow addition of isocyanide, which restricts the highly
coordinating nature of isocyanide.17 2-Ethylphenyl isocyanide
(2e) was proven as the best imidoyl source in this reaction,
resulting in a high GC yield of 80% with 78% isolated yield.
Exchanging the ethyl with an isopropyl group (2f) exhibits
similar reactivity. When the ortho-heteroatom substitution
(methoxyl 2g, methyl sufide 2h) was employed at the phenyl
group, the yield decreased to 57% and 33%, respectively. The
introduction of both a 2,6-diethyl group (2i) and a 2,6-
diisopropyl group (2j) on the phenyl ring resulted in a much
lower yield.
a
Reaction conditions: 1a (1.0 equiv), 2e (1.5 equiv), 3 (1.5 equiv),
Pd2dba3 (2 mol %), DMF, 60−80 °C, 1−24 h. The reaction was
quenched with 1 N HCl and stirred at 25 °C for 0.25 h.
containing sp, sp2, sp3, and heteroaryl zinc reagents can be
readily accessed. The scope of the sp3 zinc reagents was first
investigated. The isobutyl (4b) and 2-phenyl ethyl group (4c)
could be accessed in 61% and 76% isolated yield, respectively,
with acidic hydrolysis. Functional primary zinc reagents such as
(5-fluoropentyl)zinc bromide, (4-cyanobutyl)zinc bromide,
and (5-pivalatepentyl)zinc bromide can be successfully utilized
as the alkylated reagents to afford the corresponding ketone
products in moderate to good yield (4d−4f). It is worth noting
that the cyclic Negishi reagents such as cyclopentyl- and
cyclohexylzinc reagents worked well, furnishing 4g and 4h in
moderate yield. Next, we started to explore the substrate scope
of sp2 organozinc reagents. Coupling of 2-(1-chloroethyl)
naphthalene with phenylzinc reagents afforded the desired
product in 76% isolated yield (4l). The aryl nucleophiles
bearing electron-donating substituents such as methoxyl and
N,N-dimethyl furnished the corresponding ketones in high
yield (4i, 4j). Arylzinc reagents bearing electron-withdrawing
B
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substituents also worked well, including amide (4m),
trifluoromethyl group (4n), chloride (4o), fluoride (4p), and
cyanide (4k). Heteroarenes are among the most significant
structural backbones of pharmaceuticals. Pyridine (4q),
thiophene (4r), and benzothiophene (4s) are tolerated in
this imidoyl coupling chemistry. The protocol also extends to
sp zinc reagents. Both phenyl-substituted alkynylzinc reagents
and alkyl-substituted alkynylzinc reagents can be coupled and
obtain the product (4t, 4u). At the current stage, the
unactivated alkyl halide electrophiles were not suitable for
the Pd-catalyzed Negishi imidolylative reaction, and no
product could be observed in the reaction mixture, presumably
due to the challenge for oxidative addition for Pd(0) with alkyl
halides.
(4aa−4ad). Notably, no significant steric hindrance was
observed, as the methyl group in the ortho position had little
effect on the yield of the reaction (4aa). Finally, the primary
benzyl chloride was also investigated. We use 1-(chlorometh-
yl)-4-methoxybenzene coupled with functional phenylzinc
reagents and various heteroarylzinc reagents including
thiophene, benzofuran, and pyrazole functionalities (4ae−4aj).
It was evident that this Pd-catalyzed benzylic imidoylative
reaction proceeds via an imine intermediate, instead of the
direct acidic hydrolysis, and we hypothesized that the
corresponding phenylethylamine and phenylethanol could be
obtained by diastereoselective reduction (Scheme 2). For-
a
Scheme 2. Derivatization of Imidoylative Reaction
Next, we explored the scope of secondary benzyl chloride
(Table 3). Benzyl ketone products can also be obtained at a
a
Table 3. Substrate Scope of Benzyl Chlorides
a
Reaction conditions: 1 (1.0 equiv), 2-ethylphenyl isocyanide (1.5
equiv), R′ZnCl (1.5 equiv), Pd2dba3 (0.02 equiv), DMF, 60 °C, 2 h.
Conditions A: 1 N HCl, 0.25 h, then LiAlH4 (2.0 equiv), THF, −78
to +25 °C, 4−12 h; Conditions B: aq NH4Cl, then LiAlH4 (5.0
b
c
d
equiv), THF, −78 to +25 °C, 12 h. dr >20:1. dr = 11:1. dr = 5:1.
e
dr = 10:1.
tunately, the benzyl ketone product and imine intermediate
can smoothly convert to relevant phenyl ethanol (5a, 5b, 5c)
and phenylethylamine (6a, 6b, 6c) in high diastereoselectiv-
ities with LiAlH4 as reducing reagent. The relative stereo-
configuration of phenyl ethanol was trans, which was
confirmed via the Ns protection of 5a, and the structure of
derivative 7a was unambiguously assigned by single-crystal X-
ray analysis.
Considering the importance of phenethylamine derivatives
in the field of pharmaceutical chemistry, we further examined
the substrate scope of aromatic isocyanide (Table 4). It was
found that when various alkyl groups such as methyl, isopropyl,
n-butyl, and benzyl were introduced to the ortho-position of
aromatic rings, the corresponding phenethylamine derivatives
could be obtained with satisfactory yield and dr (6aa, 6ab, 6ac,
6ad, 6ae). Encouragingly, the chloride functionality on the
isocyanide moiety could also be tolerated under this Pd-
catalyzed imidoylative reaction, affording the amine 6af with
high diastereoselectivity. Notably, employing naphthyl iso-
cyanide can also obtain imine intermediate and achieve
a
Reaction conditions: 1 (1.0 equiv), 2e (1.5 equiv), 3 (1.5 equiv),
Pd2dba3 (2 mol %), DMF, 60−100 °C, 6−12 h. The reaction was
quenched with 1 N HCl and stirred at 25 °C for 0.25 h.
good yield when methyl groups are replaced with other alkyl
groups including ethyl (4v, 4w), n-propyl (4x), and n-butyl
(4y). When a tether alkene group was incorporated in the
starting material, the reaction did not proceed via the
intramolecular migratory insertion yet provided the desired
product 4z in 63% isolated yield, demonstrating that the
intermolecular 1,1-insertion of aryl isocyanide is a superior
reaction pathway. The scope of benzylic electrophile was
extended to phenyl-substituted benzyl chlorides, which exhibit
slightly lower reactivity than the corresponding naphthalene
benzyl chloride. Installations of various substituted phenyl
benzyl chlorides containing both electron-donating and
-withdrawing groups on the aryl rings could be tolerated
C
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a
source allows the facile synthesis of α-substituted of phenyl-
acetones under mild acidic hydrolysis. The protocol demon-
strates a broad substrate scope and functional group tolerance
and enables a variety of carbon nucleophiles including sp3, sp2,
sp, and heteroaryl zinc reagents to be successfully incorporated.
Moreover, the highly diastereoselective reductive amination of
this imidoylative process enables the expedient construction of
phenethylamine derivatives with high atom economy.
Table 4. Substrate Scope of Diastereoselective Amination
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02515.
Experimental procedures, X-ray crystallographic analysis,
and NMR spectra (PDF)
Accession Codes
CCDC 1974859 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
AUTHOR INFORMATION
Corresponding Authors
Reaction conditions: 1a (1.0 equiv), 2 (1.5 equiv), 3a (1.5 equiv),
■
Pd2dba3 (0.02 equiv), DMF, 60 °C, 2 h, aq NH4Cl, then LiAlH4 (5.0
equiv), THF, −78 to +25 °C, 12 h.
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 and 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 and Technology,
Shanghai 200237, China; orcid.org/0000-0003-3239-
6209; Email: yifengchen@ecust.edu.cn
subsequent diastereoselective reduction but with lower yield
(6ag). Utilizing phenyl isocyanide with electron-withdrawing
substituents decreases both the yield and dr of the phenethyl-
amine (6ah). The product can also be obtained in good yield
by using tetrahydronaphthalene isocyanide (6ai).
A plausible reaction mechanism is proposed in Scheme 3:
the reaction is initiated by oxidative addition of secondary
Scheme 3. Proposed Reaction Mechanism
Authors
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
and Technology, Shanghai 200237, China
Licheng Wu − 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 and Technology,
Shanghai 200237, China
benzyl chloride 1 with the palladium(0) to generate the
benzylic palladium(II) intermediate A. The selective mono-
migratory insertion of sterically bulky aryl isocyanide provides
benzyl imidoylpalladium intermediate B, which undergoes
transmetalation with Negishi reagents and subsequent
reductive elimination to produce the imine intermediate D.
The desired phenylacetone 4 could be obtained via the acidic
hydrolysis of the imine intermediate D.
Wentao Xu − 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
In summary, we have demonstrated a Pd-catalyzed
imidoylative Negishi coupling with secondary benzyl chlorides.
Harnessing of sterically bulky aryl isocyanides as the imine
D
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2018, 47, 172−194. (g) Peng, J.-B.; Wu, X.-F. Ligand-and Solvent-
Controlled Regio- and Chemodivergent Carbonylative Reactions.
Angew. Chem., Int. Ed. 2018, 57, 1152−1160. (h) Yin, Z.; Xu, J.-X.;
Wu, X.-F. No Making Without Breaking: Nitrogen-Centered
Carbonylation Reactions. ACS Catal. 2020, 10, 6510−6531.
(i) Kwiatkowski, M. R.; Alexanian, E. J. Transition-Metal (Pd, Ni,
Mn)-Catalyzed C−C Bond Constructions Involving Unactivated
Alkyl Halides and Fundamental Synthetic Building Blocks. Acc. Chem.
Res. 2019, 52, 1134−1144. (j) Wu, X.-F.; Fang, X.; Wu, L.; Jackstell,
R.; Neumann, H.; Beller, M. Transition-Metal-Catalyzed Carbon-
ylation Reactions of Olefins and Alkynes: A Personal Account. Acc.
Chem. Res. 2014, 47, 1041−1053. (k) Zhang, S.; Neumann, H.; Beller,
M. Synthesis of α,β-Unsaturated Carbonyl Compounds by Carbon-
ylation Reactions. Chem. Soc. Rev. 2020, 49, 3187−3210. (l) Sumino,
S.; Fusano, A.; Fukuyama, T.; Ryu, I. Carbonylation Reactions of
Alkyl Iodides through the Interplay of Carbon Radicals and Pd
Catalysts. Acc. Chem. Res. 2014, 47, 1563−1574. (m) Friis, S. D.;
Lindhardt, A. T.; Skrydstrup, T. The Development and Application of
Two-Chamber Reactors and Carbon Monoxide Precursors for Safe
Carbonylation Reactions. Acc. Chem. Res. 2016, 49, 594−605.
(8) (a) Wakita, Y.; Yasunaga, T.; Akita, M.; Kojima, M. Palladium-
Catalyzed Carbonylative Cross-Coupling of Organoboranes with Aryl
Iodides or Benzyl Halides in the Presence of Bis(acetylacetonato)-
Zinc(II). J. Organomet. Chem. 1986, 301, 17−20. (b) Ishiyama, T.;
Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. Palladium-Catalyzed
Carbonylative Cross-Coupling Reaction of Arylboronic Acids with
Aryl Electrophiles: Synthesis of Biaryl Ketones. J. Org. Chem. 1998,
63, 4726−4731. (c) Wu, X.-F.; Neumann, H.; Beller, M. Palladium-
Catalyzed Carbonylative Coupling of Benzyl Chlorides with Aryl
Boronic Acids in Aqueous Media. Tetrahedron Lett. 2010, 51, 6146−
6149. (d) Wu, X.-F.; Neumann, H.; Beller, M. Palladium-Catalyzed
Carbonylative Suzuki Coupling of Benzyl Halides with Potassium
Aryltrifluoroborates in Aqueous Media. Adv. Synth. Catal. 2011, 353,
788−792. (e) Jin, F.; Zhong, Y.; Zhang, X.; Zhang, H.; Zhao, Q.; Han,
W. Transition Metal-Free, Iodide-Mediated Domino Carbonylation−
Benzylation of Benzyl Chlorides with Arylboronic Acids under
Ambient Pressure of Carbon Monoxide. Green Chem. 2016, 18,
2598−2603. (f) Wu, X.-F.; Schranck, J.; Neumann, H.; Beller, M.
Palladium-Catalyzed Carbonylative Negishi-Type Coupling of Aryl
Iodides with Benzylchlorides. Chem. - Asian J. 2012, 7, 40−44.
(g) Perrone, S.; Bona, F.; Troisi, T. Palladium-Catalyzed Acylation
and/or Homo-Coupling of Aryl- and Alkyl-Acetylenes. Tetrahedron
2011, 67, 7386−7391. (h) Wu, X.-F.; Neumann, H.; Beller, M.
Palladium-Catalyzed Carbonylative Coupling of Benzyl Chlorides
with Terminal Alkynes to give 1,4-Diaryl-3-Butyn-2-Ones and Related
Furanones. Org. Biomol. Chem. 2011, 9, 8003−8005. (i) Andersen, T.
L.; Donslund, A. S.; Neumann, K. T.; Skrydstrup, T. Carbonylative
Coupling of Alkyl Zinc Reagents with Benzyl Bromides Catalyzed by
a Nickel/NN2 Pincer Ligand Complex. Angew. Chem., Int. Ed. 2018,
57, 800−804.
and Dynamic Chemistry, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China
Feng He − 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 and Technology,
Shanghai 200237, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02515
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC/China (21421004,
21702060), Shanghai Rising-Star Program, Shanghai Munici-
pal 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. We thank the
Research Center of Analysis and Test of East China University
of Science and Technology for help with the NMR analysis.
REFERENCES
■
(1) See, for example, β-blocker budavari: The Merck Index, 11th ed.;
Merck: Rahway, 1989.
(2) (a) Palucki, M.; Buchwald, S. L. Palladium-Catalyzed α-
Arylation of Ketones. J. Am. Chem. Soc. 1997, 119, 11108−11109.
(b) Hamann, B. C.; Hartwig, J. F. Palladium-Catalyzed Direct α-
Arylation of Ketones, Rate Acceleration by Sterically Hindered
Chelating Ligands and Reductive Elimination from a Transition Metal
Enolate Complex. J. Am. Chem. Soc. 1997, 119, 12382−12383.
(c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Palladium-
Catalyzed Regioselective Mono-and Diarylation Reactions of 2-
Phenylphenols and Naphthols with Aryl Halides. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740−1742.
(3) Yasuda, S.; Ishii, T.; Takemoto, S.; Haruki, H.; Oshima, H.
Synergistic N-heterocyclic Carbene/Palladium-Catalyzed Reactions of
Aldehyde Acyl Anions with Either Diarylmethyl or Allylic Carbonates.
Angew. Chem., Int. Ed. 2018, 57, 2938−2942.
(4) 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.
́
(9) (a) Liegault, B.; Renaud, J.-L.; Bruneau, C. Activation and
Functionalization of Benzylic Derivatives by Palladium Catalysts.
Chem. Soc. Rev. 2008, 37, 290−299. (b) Trost, B. M.; Czabaniuk, L.
C. Structure and Reactivity of Late Transition Metal η3-Benzyl
Complexes. Angew. Chem., Int. Ed. 2014, 53, 2826−2851. (c) Le Bras,
J.; Muzart, J. Production of Csp3−Csp3 Bonds through Palladium-
Catalyzed Tsuji-Trost-Type Reactions of (Hetero)Benzylic Sub-
strates. Eur. J. Org. Chem. 2016, 2016, 2565−2593.
(10) Cheng, R.; Zhao, H.-Y.; Zhang, S.; Zhang, X. Nickel-Catalyzed
Carbonylation of Secondary Trifluoromethylated, Difluoromethy-
lated, and Nonfluorinated Aliphatic Electrophiles with Arylboronic
Acids under 1 atm of CO. ACS Catal. 2020, 10, 36−42.
(5) Wang, J.; Hou, T. Drug and Drug Candidate Building Block
Analysis. J. Chem. Inf. Model. 2010, 50, 55−67.
(6) Bentley, K. W. β-Phenylethylamines and the Isoquinoline
Alkaloids. Nat. Prod. Rep. 2001, 18, 148−170.
(7) (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Palladium-
̈
Catalyzed Carbonylation Reactions of Aryl Halides and Related
Compounds. Angew. Chem., Int. Ed. 2009, 48, 4114−4133. (b) Wu,
X.-F.; Neumann, H.; Beller, M. Palladium-Catalyzed Carbonylative
Coupling Reactions between Ar−X and Carbon Nucleophiles. Chem.
Soc. Rev. 2011, 40, 4986−5009. (c) Peng, J.-B.; Wu, F.-P.; Wu, X.-F.
First-Row Transition-Metal-Catalyzed Carbonylative Transformations
of Carbon Electrophiles. Chem. Rev. 2019, 119, 2090−2127. (d) 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. (e) Wu, X.-F.; Neumann, H.; Beller, M.
Synthesis of Heterocycles via Palladium-Catalyzed Carbonylations.
Chem. Rev. 2013, 113, 1−35. (f) Li, Y.; Hu, Y.; Wu, X.-F. Non-noble
Metal-Catalysed Carbonylative Transformations. Chem. Soc. Rev.
(11) (a) Qiu, G.; Ding, Q.; Wu, J. Recent Advances in Isocyanide
Insertion Chemistry. Chem. Soc. Rev. 2013, 42, 5257−5269. (b) Vlaar,
T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Palladium-Catalyzed
Migratory Insertion of Isocyanides: An Emerging Platform in Cross-
Coupling Chemistry. Angew. Chem., Int. Ed. 2013, 52, 7084−709.
̈
(c) Domling, A.; Ugi, I. Multicomponent Reactions with Isocyanides.
Angew. Chem., Int. Ed. 2000, 39, 3168−3210. (d) Song, B.; Xu, B.
E
https://dx.doi.org/10.1021/acs.orglett.0c02515
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Metal-Catalyzed C−H Functionalization Involving Isocyanides. Chem.
Soc. Rev. 2017, 46, 1103−1123. (e) Lang, S. Unravelling the Labyrinth
of Palladium-Catalysed Reactions Involving Isocyanides. Chem. Soc.
Rev. 2013, 42, 4867−4880. (f) Giustiniano, M.; Basso, A.; Mercalli,
V.; Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu, J. To each his
own: Isonitriles for All Flavors. Functionalized Isocyanides as
Valuable Tools in Organic Synthesis. Chem. Soc. Rev. 2017, 46,
1295−1357. (g) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.;
Kukushkin, V. Y. Metal-Mediated and Metal-Catalyzed Reactions of
Isocyanides. Chem. Rev. 2015, 115, 2698−2779. (h) Liu, Y.-J.; Xu, H.;
Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-Q. Overcoming the
Limitations of Directed C−H Functionalizations of Heterocycles.
Nature 2014, 515, 389−393. (i) Jiang, H.; Liu, B.; Li, Y.; Wang, A.;
Huang, H. Synthesis of Amides via Palladium-Catalyzed Amidation of
Aryl Halides. Org. Lett. 2011, 13, 1028−1031. (j) Hu, W.; Li, M.;
Jiang, G.; Wu, W.; Jiang, H. Synthesis of 2,3-Difunctionalized
Benzofuran Derivatives through Palladium-Catalyzed Double Iso-
cyanide Insertion Reaction. Org. Lett. 2018, 20, 3500−3503.
(k) Zhang, R.; Gu, Z.-Y.; Wang, S.-Y.; Ji, S.-J. Co(II)/Ag(I)
Synergistically Catalyzed Monoinsertion Reaction of Isocyanide to
Terminal Alkynes with H2O: Synthesis of Alkynamide Derivatives.
Org. Lett. 2018, 20, 5510−5514. (l) Xu, P.; Wang, F.; Wei, T.-Q.; Yin,
L.; Wang, S.-Y.; Ji, S.-J. Palladium-Catalyzed Incorporation of Two C1
Building Blocks: The Reaction of Atmospheric CO2 and Isocyanides
with 2-Iodoanilines Leading to the Synthesis of Quinazoline-
2,4(1H,3H)-Diones. Org. Lett. 2017, 19, 4484−4487.
Asymmetric Negishi Arylations of Racemic Secondary Benzylic
Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes. J. Am.
Chem. Soc. 2013, 135, 16288−16291. (d) 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.
(15) (a) Weng, Y.; Zhang, C.; Tang, Z.; Shrestha, M.; Huang, W.;
Qu, J.; Chen, Y. Nickel-Catalyzed Allylic Carbonylative Coupling of
Alkyl Zinc Reagents with tert-Butyl Isocyanide. Nat. Commun. 2020,
11, 392−400. (b) Huang, W.; Wang, Y.; Weng, Y.; Shrestha, M.; Qu,
J.; Chen, Y. Nickel-Catalyzed Formal Aminocarbonylation of
Unactivated Alkyl Iodides with Isocyanides. Org. Lett. 2020, 22,
3245−3250.
(16) Trost, B. The Atom Economy-A Search for Synthetic
Efficiency. Science 1991, 254, 1471−1477.
(17) (a) Yamamoto, Y. Zerovalent Transition Metal Complexes of
Organic Isocyanides. Coord. Chem. Rev. 1980, 32, 193−233.
(b) Wang, B.; He, D.; Ren, B.; Yao, T. Synthesis of Imides via
Palladium-Catalyzed Three-Component Coupling of Aryl Halides,
Isocyanides and Carboxylic Acids. Chem. Commun. 2020, 56, 900−
903.
(12) (a) Ishiyama, T.; Oh-e, T.; Miyaura, N.; Suzuki, A. Palladium-
Catalyzed Iminocarbonylative Cross-Coupling Reaction between
Haloarenes, t-BuNC, and 9-Alkyl-9-BBN Derivatives. Synthesis of
Alkyl Aryl Ketones. Tetrahedron Lett. 1992, 33, 4465−4468.
(b) Otsuka, S.; Nogi, K.; Yorimitsu, H. Palladium-Catalyzed Insertion
of Isocyanides into the C−S Bonds of Heteroaryl Sulfides. Angew.
Chem., Int. Ed. 2018, 57, 6653−6657. (c) Dechert-Schmitt, A.-M.;
Garnsey, M. R.; Wisniewska, H. M.; Murray, J. I.; Lee, T.; Kung, D.
W.; Sach, N.; Blackmond, D. G. Highly Modular Synthesis of 1,2-
Diketones via Multicomponent Coupling Reactions of Isocyanides as
CO Equivalents. ACS Catal. 2019, 9, 4508−4515. (d) Tang, T.; Fei,
X.-D.; Ge, Z.-Y.; Chen, Z.; Zhu, Y.-M.; Ji, S.-J. Palladium-Catalyzed
Carbonylative Sonogashira Coupling of Aryl Bromides via tert-Butyl
Isocyanide Insertion. J. Org. Chem. 2013, 78, 3170−3175. (e) Chen,
Z.; Duan, H.; Jiang, X.; Wang, J.; Zhu, Y.; Yang, S. Palladium-
Catalyzed Synthesis of Biaryl Ketones via tert-Butyl Isocyanide
Insertion. Synlett 2014, 25, 1425−1430. (f) Duan, H.; Chen, Z.; Han,
L.; Feng, Y.; Zhu, Y.; Yang, S. Palladium-Catalyzed Chemoselective
Synthesis of Indane-1,3-Dione Derivatives via tert-Butyl Isocyanide
Insertion. Org. Biomol. Chem. 2015, 13, 6782−6788. (g) Li, Z.; Zheng,
J.; Hu, W.; Li, J.; Wu, W.; Jiang, H. Synthesis of 1,4-Enyne-3-Ones via
Palladium-Catalyzed Sequential Decarboxylation and Carbonylation
of Allyl Alkynoates. Org. Chem. Front. 2017, 4, 1363−1366. (h) Jiang,
X.; Wang, J.-M.; Zhang, Y.; Chen, Z.; Zhu, Y.-M.; Ji, S.-J. Palladium-
Catalyzed Formylation of Aryl Halides with tert-Butyl Isocyanide. Org.
Lett. 2014, 16, 3492−3495. (i) Fei, X.-D.; Ge, Z.-Y.; Tang, T.; Zhu,
Y.-M.; Ji, S.-J. Palladium-Catalyzed Synthesis of Isocoumarins and
Phthalides via tert-Butyl Isocyanide Insertion. J. Org. Chem. 2012, 77,
10321−10328.
(13) (a) Wang, Y.; Huang, W.; Wang, C.; Qu, J.; Chen, Y. Nickel-
Catalyzed Formal Aminocarbonylation of Secondary Benzyl Chlorides
with Isocyanides. Org. Lett. 2020, 22, 4245−4249. (b) Yang, Q.; Li,
C.; Cheng, M.-X.; Yang, S.-D. Palladium-Catalyzed Migratory
Insertion of Isocyanides for Synthesis of C-Phosphonoketenimines.
ACS Catal. 2016, 6, 4715−4719.
(14) (a) Arp, F. O.; Fu, G. C. Catalytic Enantioselective Negishi
Reactions of Racemic Secondary Benzylic Halides. J. Am. Chem. Soc.
2005, 127, 10482−10483. (b) Binder, J. T.; Cordier, C. J.; Fu, G. C.
Catalytic Enantioselective Cross-Couplings of Secondary Alkyl
Electrophiles with Secondary Alkylmetal Nucleophiles: Negishi
Reactions of Racemic Benzylic Bromides with Achiral Alkylzinc
Reagents. J. Am. Chem. Soc. 2012, 134, 17003−17006. (c) Do, H.-Q.;
Chandrashekar, E. R. R.; Fu, G. C. Nickel/Bis(oxazoline)-Catalyzed
F
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