Merging C-H Activation and Strain-Release in Ruthenium-Catalyzed Isoindolinone Synthesis

Article abstract of DOI:10.1021/acs.orglett.1c02131

The merger of strain-release of 1,2-oxazetidines with carboxylic acid directed C-H activation in catalytic synthesis of isoindolinones is reported for the first time. This reaction opens a new and sustainable avenue to prepare a range of structurally dive

Full text of DOI:10.1021/acs.orglett.1c02131

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Letter
Merging C−H Activation and Strain−Release in Ruthenium-
Catalyzed Isoindolinone Synthesis
Xiao-Qiang Hu,* Zi-Kui Liu, Ye-Xing Hou, Ji-Hang Xu, and Yang Gao*
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ABSTRACT: The merger of strain−release of 1,2-oxazetidines with
carboxylic acid directed C−H activation in catalytic synthesis of
isoindolinones is reported for the first time. This reaction opens a new
and sustainable avenue to prepare a range of structurally diverse
isoindolinone skeletons from readily available benzoic acids. The success
of late-stage functionalization of some bioactive acids, and concise synthesis
of biologically important skeletons demonstrated its great synthetic
potential in drug discovery. Mechanistic studies indicated a plausible C−H activation/β-carbon elimination/intramolecular
cyclization cascade pathway.
Scheme 1. Cross-Coupling Reactions between Benzoic
Acids and Small Ring Systems
mall (typically three- and four-membered) ring systems are
important and versatile building blocks for rapidly
S
accessing complex molecular architectures in organic chem-
istry.1 The strain energies of cyclopropane and cyclobutane are
27.5 and 26.5 kcal/mol, respectively, which are much larger
than those of cyclohexane (0.0 kcal/mol) and cyclopentane
(7.4 kcal/mol).2 The selective strain−release of small rings
offers a unique opportunity and thermodynamic driving force
for the transformation of these reactive feedstocks into value-
added chemicals and functional materials.3 In this context, the
synergistic combination of transition-metal-catalyzed C(sp2)−
H activation and strained ring cleavage has been widely
exploited for the reconstruction of small rings over the past
decades.2b,4 While these reactions can be efficient and useful,
their applications are often hampered by the inevitable
requirement of strong N-directing groups, expensive metal
catalyst (Rh, Pd, etc.), or high loading of Ag or Cu
additives.2b,5 Therefore, the practicality and cost issues in
this field have spurred ongoing efforts to explore novel catalytic
technologies that rely upon readily available substrates, an
inexpensive metal catalyst, and simple operation.
Benzoic acids are among the most widely occurring and
easily available feedstock chemicals in metal-catalyzed cross-
coupling reactions.6 In recent years, the merger of benzoic
acids with ring opening of strained rings has emerged as an
attractive strategy to invent valuable cross-coupling reactions,
which are currently elusive with the use of other strong N-
directing groups. In 2015, Yu et al. reported the first example
of Pd(II)-catalyzed C−H alkylation of benzoic acids with
epoxides, delivering a range of dihydroisocoumarins in high
efficiency (Scheme 1a).7 By employing aliphatic aziridines as
efficient coupling partners, the group of Zhao achieved a Pd-
catalyzed carboxylic acid directed C(sp2)−H alkylation of
benzoic acids for the synthesis of β-arylethylamine skeletons.8
Very recently, Yang and Huang et al. disclosed a novel C−H
activation/cyclization cascade of carboxylic acids with cyclo-
propanols enabled by a cooperative [Cp*RhCl2]2/AgOAc
catalytic system.9 Moreover, Goossen and we demonstrated a
Received: June 24, 2021
https://doi.org/10.1021/acs.orglett.1c02131
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Ru-catalyzed C−H allylation of benzoic acids with vinyl-
cyclopropanes.10 Despite the success in benzoic acid-mediated
ring-opening reactions of three-membered rings, there is still
no example of strain-enabled cross-coupling reaction between
benzoic acids and four-membered rings to date.
Table 1. Optimization of Reaction Conditions
b
1,2-Oxazetidines are highly strained four-membered rings,
which perform a higher ring strain energy even than
oxaziridines (calcd 25.2 kcal/mol vs 22.9 kcal/mol).11 The
first synthesis of 1,2-oxazetidines date back to 1970, but the
development of catalytic systems for their transformation is a
recent achievement.12 To the best of our knowledge, only four
examples have been reported to date. Orentas13 and Hu14 et al.
independently employed 1,2-oxazetidines as an efficient source
of electrophilic oxygen to react with nucleophilic organo-
metallic agents and β-keto esters. The groups of Loh15 and
Hu16 applied 1,2-oxazetidines in Co- and Ru-catalyzed C−H
aminomethylation of heteroarenes and enamides, respectively.
Among these protocols, the addition of expensive silver salts is
inevitably required. Based on the insight gained from these
important works, we recently questioned if the strain−release
of 1,2-oxazetidines and carboxylic acid directed C−H
activation can be successfully combined to create a convenient
access to bioactive isoindolinone skeletons (Scheme 1b). The
proposed reaction is quite challenging due to the weakly
coordinated carboxylate group for C−H activation step.
Moreover, the carboxylate group is a strong nucleophile,
which may directly attack 1,2-oxazetidine to deliver the
undesired ring-opening byproducts. According to our ongoing
efforts in catalytic transformation of benzoic acids and
heterocycle synthesis,17 we believe that the rational combina-
tion of metal catalyst and solvent may provide a solution to the
aforementioned problems. In should be noted that isoindoli-
nones are widely found in natural products and bioactive
molecules (Scheme 1c).18 The established methods mainly
rely on the use of stoichiometric oxidants, high temperatures
(>200 °C), and specialized N-directing groups.19 The success
of this reaction opens a new and sustainable avenue to prepare
isoindolinones.
To test the possibility of proposed reaction, we commence
the study with the reaction of 2-methylbenzoic acid 1a and N-
tosyl-1,2-oxazetidine 2a. To our delight, the desired
isoindolinone product 3aa can be obtained in 17% yield by
employing [{Ru(p-cymene)Cl2}]2 as the catalyst and K2CO3
as the base in toluene at 110 °C (Table 1, entry 1). The
screening of solvents demonstrated that toluene was the
optimal solvent, while other solvents such as CH3CN and
dioxane were ineffective. To further improve the reaction
efficiency, the effect of bases has been systematically
investigated. By using Na2CO3 and K3PO4, the yields of 3aa
can be slightly increased to 20% and 24% yields, respectively
(entries 5 and 6). KOPiv significantly improved the reaction
efficiency to give 3aa in 30% yield. Other commonly used
metal catalysts such as [RhCp*Cl2]2 and [IrCp*Cl2]2 delivered
inferior results (entries 9 and 10). It was found that this
reaction was sensitive to the amount of 2a and reaction
temperature. Increasing the loading of 2a and reaction
temperature (120 °C) dramatically improved the outcome of
3aa (entry 11, 55% yield). Fortunately, the yield of 3aa can be
further improved to 88% (entry 13), when the reaction was
conducted at 140 °C.
entry
solvent
base
T (°C)
yield (%)
1
2
3
4
5
6
7
8
toluene
CH3CN
dioxane
mesitylene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
KOPiv
KOPiv
KOPiv
KOPiv
KOPiv
KOPiv
110
110
110
110
110
110
110
110
110
110
120
130
140
17
trace
trace
15
20
24
15
30
26
0
c
9
d
10
e
11
55
62
88
e
12
e
13
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [{Ru(p-
cymene)Cl2}]2 (4 mol %), base (50 mol %), solvent (2.0 mL) at 110
°C for 16 h. Isolated yields. [RhCp*Cl2]2 (4 mol %) was used.
b
c
d
e
[IrCp*Cl2]2 (4 mol %) was used. 2a (0.25 mmol) was used.
tolerance, furnishing the expected isoindolinone products in
useful to good yields (38−96% yield). Aromatic acids bearing
different alkyl groups such as methyl, ethyl, benzyl, and
phenylethyl smoothly reacted with 2a. Leaving groups such as
Cl (3fa, 3ja, 3na, 3ra, and 3va), Br (3ia and 3ma), and I (3oa
and 3pa) were well-tolerated in this catalytic system. It should
be mentioned that benzoic acid bearing a 3-Br or 3-Cl at the
aromatic ring resulted in a mixture of C2- and C6-
functionalized products with moderate regioselectivity. Im-
portantly, sensitive groups such as ester (3sa), nitro (3ta), and
N,N-dimethyl groups (3ha) were retained after the reaction,
which are ineffective in our previous protocol.17d In addition,
simple benzoic acid was also compatible in this reaction (3wa).
Both tetrahedro-1-naphthoic acid and 2-naphthoic acid were
successfully coupled with N-tosyl-1,2-oxazetidine 2a, affording
structurally complex isoindolinones 3ya and 3za in 87% and
96% yields, respectively. Moreover, this catalytic system can be
further applied to the late-stage modification of some bioactive
benzoic acids such as adapalene (4aa), probenecid (4ba),
flufenamic acid (4ca), and bexarotene (4da), which strongly
demonstrated its synthetic potential in medicinal chemistry.
However, heteroaromatic carboxylic acids such as thiophene-2-
carboxylic acid and 1H-indole-3-carboxylic acid were not
suitable for this reaction at the current stage (see SI for more
information). Of note, this reaction can be successfully scaled
up to 1 mmol without the loss of efficiency (3aa, 86% yield).
Furthermore, the effect of the N-protecting group of 1,2-
oxazetidine 2 has also been investigated. As outlined in Scheme
2b, aromatic rings of 1,2-oxazetidines bearing electron-
donating groups (methoxyl and trimethyl) and electron-
withdrawing groups (CF3, Br, Cl, and F) were well-tolerated
in this catalytic system, delivering the desired isoindolinone
products (3ab−3ag) in generally good yields (40−95% yield).
However, the substituents on the oxazetidine ring were not
compatible in this catalytic system (see SI for more
information).
With the optimal conditions in hand, we next explored the
generality of this cascade reaction. As shown in Scheme 2, this
reaction exhibited a broad scope with good functional group
To further demonstrate the synthetic utility of this
methodology, we first removed the Ts protecting group from
isoindolinone product 3wa under the Na/naphthalene
B
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a b
,
Scheme 2. Scope of Benzoic Acids and 1,2-Oxazetidines
Scheme 3. Synthetic Application of This Methodology
Scheme 4. Mechanistic Study
the reaction did not occur in the absence of KOPiv. In
addition, the mixture of potassium 2-methylbenzoate 10 and
1a delivered the desired product 3aa in 53% yield. These two
reactions demonstrated the importance of base, which may
promote the initial generation of potassium 2-methylbenzoate
from benzoic acid. Bis(tosylamido)methane 11 is a precursor
of the reactive formaldimine compound.22 The reaction of 1a
with 11 proceeded well under the standard conditions,
suggesting the intermediacy of a formaldimine species in this
transformation. In the absence of 2a, 90% deuterium of 1a was
observed when 10 equiv of D2O were added to the reaction
system. This result confirmed that the formation of the five-
membered ruthenacycle was a reversible step (Scheme 4b).
Moreover, no significant kinetic isotope effects (KIEs) were
observed in competitive (kH/kD = 1.40:1) and parallel (kH/kD
= 1.12:1) experiments at the early stage of this reaction (20
min), which indicated the C−H bond activation might not be
the rate-determining step for this reaction (Scheme 4c and 4d).
a
Conditions: 1 (0.1 mmol), 2a (0.25 mmol), [{Ru(p-cymene)Cl2}]2
(4 mol %), KOPiv (0.05 mmol), toluene (2.0 mL), 140 °C, 10 h.
b
c
Isolated yields after flash chromatography. 1 mmol scale.
reductive system at −78 °C. In the presence of CuI catalyst,
the resulting N-free isoindolinone 5 smoothly coupled with 4-
bromoiodobenzene to give product 6 in a useful yield, which
shows good antiviral activity (Scheme 3a, left).20 Moreover,
exposure of product 5 to 6 M HCl easily offers the ring-
opening product 7 in 80% yield (Scheme 3a, right).
Significantly, the reaction of 3aa with PhMgBr efficiently
gives rise to aminomethylbenzophenone 8. It should be
mentioned that product 8 is the core skeleton of a important
anti-inflammatory compound 9 (Scheme 3b).21
To investigate the reaction mechanism, first, a series of
control experiments were conducted. As shown in Scheme 4a,
C
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Based on these observations and literature precedents,15,16
plausible Ru-catalyzed C−H activation/β-carbon elimination/
intramolecular cyclization cascade mechanism was proposed in
Scheme 5. In the presence of KOPiv, the rapidly deprotonation
a
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; orcid.org/
0000-0001-9094-2357; Email: huxiaoqiang@
mail.scuec.edu.cn
Yang Gao − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0001-9513-6899;
Email: gaoyang@gdut.edu.cn
Scheme 5. Plausible Catalytic Cycle
Authors
Zi-Kui Liu − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education & Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China
Ye-Xing Hou − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education & Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China
Ji-Hang Xu − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education & Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China
of benzoic acid offers potassium 2-methylbenzoate 1-A,
following by a Ru-catalyzed C−H activation to form a five-
membered ruthenacycle intermediate 1-B. Then, the coordi-
nation of 1,2-oxazetidine 2 to 1-B generates intermediate 2-A,
which performs a β-carbon elimination to afford Ru-imine
complex 2-B along with the formation of formaldehyde as the
byproduct. The formaldehyde byproduct can be detected by
GC-MS (see SI for more information). Subsequently, the
migratory insertion of 2-B results in a Ru-complex 2-C, which
then proceeds in an intramolecular cyclization to give
intermediate 2-D. The resulting 2-D delivers the final
isoindolinone product by release of H2O with the regeneration
of the Ru catalyst for the next catalytic cycle.
In summary, we successfully combined the strain−release of
1,2-oxazetidines with carboxylic acid directed C−H activation
in Ru-mediated isoindolinone synthesis for the first time,
furnishing a range of structurally diverse isoindolinone
skeletons. The attractive advantages of this reaction include
simple operation, broad scope, and highly functional group
tolerance, which obviates the use of external oxidants.
Importantly, this methodology can be successfully applied to
the late-stage modification of some bioactive acids and concise
synthesis of biologically important skeletons, demonstrating its
great synthetic potential in drug discovery.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02131
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Natural Science Foundation of China
(21901045, 21901258), the Technology Plan of Guangdong
Province (2018A030310570), and South-Central University of
Nationalities (YZZ19003) for financial support. The authors
also thank Prof. Lin Hu (Chongqing University) for generous
donation of 1,2-oxazetidines.
REFERENCES
■
(1) (a) Pirenne, V.; Muriel, B.; Waser, J. Catalytic Enantioselective
Ring-Opening Reactions of Cyclopropanes. Chem. Rev. 2021, 121,
227−263. (b) Biletskyi, B.; Colonna, P.; Masson, K.; Parrain, J. L.;
Commeiras, L.; Chouraqui, G. Small Rings in the Bigger Picture: Ring
Expansion of Three- and Four-membered Rings to Access Larger All-
carbon Cyclic Systems. Chem. Soc. Rev. 2021, 50, 7513. (c) Li, D.;
Zang, W.; Bird, M. J.; Hyland, C. J. T.; Shi, M. Gold-Catalyzed
Conversion of Highly Strained Compounds. Chem. Rev. 2021, 121,
8685. Please see SI ref 5 for more related references.
(2) (a) Magers, D.; Davis, S. Ring Strain in the Oxazetidines. J. Mol.
Struct.: THEOCHEM 1999, 487, 205−210. (b) Wang, F.; Yu, S.; Li,
X. Transition Metal-catalysed Couplings between Arenes and Strained
or Reactive Rings: Combination of C−H Activation and Ring
Scission. Chem. Soc. Rev. 2016, 45, 6462−6477.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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sı
(3) Murakami, M.; Ishida, N. Cleavage of Carbon−Carbon σ-Bonds
of Four-Membered Rings. Chem. Rev. 2021, 121, 264−299.
Detailed experimental procedures and NMR spectra for
all compounds (PDF)
(4) (a) Deng, L.; Dong, G. Carbon−Carbon Bond Activation of
Ketones. Trends in Chemistry 2020, 2, 183−198. (b) Bai, D.; Yu, Y.;
Guo, H.; Chang, J.; Li, X. Nickel(0)-Catalyzed Enantioselective [3 +
2] Annulation of Cyclopropenones and α,β-Unsaturated Ketones/
Imines. Angew. Chem., Int. Ed. 2020, 59, 2740−2744. (c) Shi, P.; Tu,
Y.; Wang, C.; Kong, D.; Ma, D.; Bolm, C. Synthesis of
Benzothiadiazine-1-oxides by Rhodium-Catalyzed C−H Amidation/
AUTHOR INFORMATION
Corresponding Authors
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Xiao-Qiang Hu − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education & Hubei Key
D
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Organic Letters
pubs.acs.org/OrgLett
Letter
Cyclization. Org. Lett. 2020, 22, 8842−8845. (d) Xu, S.; Takamatsu,
K.; Hirano, K.; Miura, M. Angew. Chem., Int. Ed. 2018, 57, 11797−
11801. (e) Xu, S.; Takamatsu, K.; Hirano, K.; Miura, M. Synthesis of
Seven-Membered Benzolactones by Nickel-Catalyzed C−H Coupling
of Benzamides with Oxetanes. Chem. - Eur. J. 2019, 25, 9400−9404.
Please see SI ref 6 for more related references.
Ruthenium-catalyzed Aminomethylation of Enamides. Chem. Com-
mun. 2020, 56, 7969−7972.
(17) (a) Hu, X.-Q.; Hu, Z.; Zhang, G.; Sivendran, N.; Gooßen, L. J.
Catalytic C−N and C−H Bond Activation: Ortho-Allylation of
Benzoic Acids with Allyl Amines. Org. Lett. 2018, 20, 4337−4340.
(b) Hu, X.-Q.; Liu, Z. K.; Hou, Y. X.; Zhang, G.; Gao, Y. Ru-catalysed
C(sp2)−H Vinylation/annulation of Benzoic Acids and Alkynes:
Rapid Access to Medium-sized Lactones. Chem. Commun. 2021, 57,
1113−1116. (c) Gao, Y.; Nie, J.; Li, Y.; Li, X.; Chen, Q.; Huo, Y.; Hu,
X.-Q. Rh-Catalyzed C−H Amination/Annulation of Acrylic Acids and
Anthranils by Using − COOH as a Deciduous Directing Group: An
Access to Diverse Quinolines. Org. Lett. 2020, 22, 2600−2605.
(d) Hu, X.-Q.; Hou, Y. X.; Liu, Z. K.; Gao, Y. Ruthenium-catalysed
C−H/C−N Bond Activation: Facile Access to Isoindolinones. Org.
Chem. Front. 2021, 8, 915−921. (e) Hu, X.-Q.; Hu, Z.; Trita, A. S.;
Zhang, G.; Gooßen, L. J. Carboxylate-directed C−H Allylation with
Allyl Alcohols or Ethers. Chem. Sci. 2018, 9, 5289−5294. (f) Gao, Y.;
Yang, S.; Huo, Y.; Chen, Q.; Li, X.; Hu, X.-Q. NiH-Catalyzed
Hydroamination/Cyclization Cascade: Rapid Access to Quinolines.
ACS Catal. 2021, 11, 7772−7779.
(5) (a) Yu, S.; Li, X. Mild Synthesis of Chalcones via Rhodium(III)-
Catalyzed C−C Coupling of Arenes and Cyclopropenones. Org. Lett.
2014, 16, 1220−1223. (b) Zhou, X.; Yu, S.; Kong, L.; Li, X.
Rhodium(III)-Catalyzed Coupling of Arenes with Cyclopropanols via
C−H Activation and Ring Opening. ACS Catal. 2016, 6, 647−651.
(6) (a) Hu, X.-Q.; Liu, Z. K.; Hou, Y. X.; Gao, Y. Single Electron
Activation of Aryl Carboxylic Acids. iScience 2020, 23, 101266.
(b) Zeng, Z.; Feceu, A.; Sivendran, N.; Gooßen, L. J. Decarbox-
ylation-Initiated Intermolecular Carbon-Heteroatom Bond Forma-
tion. Adv. Synth. Catal. 2021, 363, 2678−2722. (c) Das, J.; Mal, D. K.;
Maji, S.; Maiti, D. Recent Advances in External-Directing-Group-Free
C−H Functionalization of Carboxylic Acids Without Decarboxyla-
tion. ACS Catal. 2021, 11, 4205−4229. (d) Wei, Y.; Hu, P.; Zhang,
M.; Su, W. Metal-Catalyzed Decarboxylative C−H Functionalization.
Chem. Rev. 2017, 117, 8864−8907. (e) Font, M.; Quibell, J. M.; Perry,
G. J. P.; Larrosa, I. The Use of Carboxylic Acids as Traceless Directing
Groups for Regioselective C−H Bond Functionalisation. Chem.
Commun. 2017, 53, 5584−5597. Please see SI ref 7 for more related
references.
(7) Cheng, G.; Li, T. J.; Yu, J. Q. Practical Pd(II)-Catalyzed C−H
Alkylation with Epoxides: One-Step Syntheses of 3,4-Dihydroisocou-
marins. J. Am. Chem. Soc. 2015, 137, 10950−10953.
(8) Zhou, K.; Zhu, Y.; Fan, W.; Chen, Y.; Xu, X.; Zhang, J.; Zhao, Y.
Late-Stage Functionalization of Aromatic Acids with Aliphatic
Aziridines: Direct Approach to Form Β-Branched Arylethylamine
Backbones. ACS Catal. 2019, 9, 6738−6743.
(9) Wang, S.; Miao, E.; Wang, H.; Song, B.; Huang, W.; Yang, W.
Rh-Catalyzed Cascade C−H Activation/C−C Cleavage/cyclization of
Carboxylic Acids with Cyclopropanols. Chem. Commun. 2021, 57,
5929−5932.
(18) (a) Speck, K.; Magauer, T. The chemistry of isoindole natural
products. Beilstein J. Org. Chem. 2013, 9, 2048−2078. (b) Csende, F.;
Miklós, F.; Porkoláb, A. Design and synthesis of some isoindoline
derivatives as analogues of the active anti-inflammatory Indoprofen.
ARKIVOC 2013, 2013, 378−388.
(19) (a) Murahashi, S. Synthesis of Phthalimidines from Schiff bases
and carbon monoxide. J. Am. Chem. Soc. 1955, 77, 6403−6404.
(b) Rosenthal, A.; Astbury, R. F.; Hubscher, A. Reaction of aromatic
ketoximes with carbon monoxide and hydrogen1. J. Org. Chem. 1958,
́
23, 1037−1039. (c) Hernando, E.; Villalva, J.; Martínez, A. M.;
Alonso, I.; Rodríguez, N.; Gómez Arrayás, R.; Carretero, J. C.
Palladium-Catalyzed Carbonylative Cyclization of Amines via γ-
C(sp3)−H Activation: Late-Stage Diversification of Amino Acids and
Peptides. ACS Catal. 2016, 6, 6868−6882. Please see SI ref 8 for
more related references.
(20) Wang, Y.; Wang, H.; Jiang, X.; Jiang, Z.; Guo, T.; Ji, X.; Li, Y.;
Li, Y.; Li, Z. Synthesis and Broad Antiviral Activity of Novel 2-aryl-
isoindolin-1-ones Towards Diverse Enterovirus A71 Clinical Isolates.
Molecules 2019, 24, 985.
(21) Coombs, R.; Houlihan, W. J.; Nadelson, J.; Takesue, E. I.
Synthesis and Antiinflammatory Activity of tert-aminomethylbenzo-
phenones. J. Med. Chem. 1971, 14, 1072−1074.
(22) Li, Z. Y.; Chaminda Lakmal, H. H.; Cui, X. Enabling Catalytic
Arene C−H Amidomethylation via Bis(tosylamido)methane as a
Sustainable Formaldimine Releaser. Org. Lett. 2019, 21, 3735−3740.
(10) Hu, Z.; Hu, X.-Q.; Zhang, G.; Gooßen, L. J. Ring-Opening
Ortho-C−H Allylation of Benzoic Acids with Vinylcyclopropanes:
Merging Catalytic C−H and C−C Activation Concepts. Org. Lett.
2019, 21, 6770−6773.
(11) (a) Luo, Y.-R. Handbook of Bond Dissociation Energies in
Organic Compounds; CRS Press: Boca Raton, FL, 2002. (b) Alcamí,
̃
M.; Mó, O.; Yánez, M. G2 Ab Initio Calculations on Three-
Membered Rings: Role of Hydrogen Atoms. J. Comput. Chem. 1998,
19, 1072−1086.
(12) (a) Barker, M. W.; Gill, J. T. Heterocycles from Ketenimines.
IV. 3-Iminosubstituted-1,2Oxazetidines. J. Heterocycl. Chem. 1970, 7,
1203−1204. (b) Baldwin, J. E.; Bhatnagar, A. K.; Choi, S. C.;
Shortridge, T. J. Rearrangement of Strained Dipolar Species, Aziridine
N-Oxides II. J. Am. Chem. Soc. 1971, 93, 4082−4083.
̇
̌
(13) Javorskis, T.; Sriubaite, S.; Bagdziunas, G.; Orentas, E. N-
̅
Protected 1,2-Oxazetidines as a Source of Electrophilic Oxygen:
Straightforward Access to Benzomorpholines and Related Hetero-
cycles by Using a Reactive Tether. Chem. - Eur. J. 2015, 21, 9157−
9164.
(14) (a) Wu, B.; Yang, J.; Gao, M.; Hu, L. Ring-Strain-Enabled
Catalytic Asymmetric Umpolung C−O Bond-Forming Reactions of
1,2-Oxazetidines for the Synthesis of Functionalized Chiral Ethers.
Org. Lett. 2020, 22, 5561−5566. (b) Wu, B.; Chen, H.; Gao, M.;
Gong, X.; Hu, L. Synthesis of 1,3-Aminoalcohols and Spirocyclic
Azetidines via Tandem Hydroxymethylation and Aminomethylation
Reaction of Β-Keto Phosphonates with N-Nosyl-O-(2-bromoethyl)-
hydroxylamine. Org. Lett. 2021, 23, 4152−4157.
(15) Li, S.; Shi, P.; Liu, R. H.; Hu, X. H.; Loh, T. P. Cobalt-
Catalyzed N−O and C−C Bond Cleavage in 1,2-Oxazetidines:
Solvent-Controlled C−H Aminomethylation and Hydroxymethyla-
tion of Heteroarenes. Org. Lett. 2019, 21, 1602−1606.
(16) Li, S.; Shan, Q. C.; Hu, L. M.; Ma, X. Q.; Hu, X. H. Merging
Alkenyl C−H Activation with the Ring-opening of 1,2-oxazetidines:
E
https://doi.org/10.1021/acs.orglett.1c02131
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