Iron-Catalyzed, Iminyl Radical-Triggered Cascade 1,5-Hydrogen Atom Transfer/(5+2) or (5+1) Annulation: Oxime as a Five-Atom Assembling Unit

Article abstract of DOI:10.1002/anie.202007825

By integration of iminyl radical-triggered 1,5-hydrogen atom transfer and (5+2) or (5+1) annulation processes, a series of structurally novel and interesting azepine and spiro-tetrahydropyridine derivatives have been successfully prepared in moderate to good yields. This method utilizes FeCl₂ as the catalyst and readily available oximes as five-atom units, while showcasing broad substrate scope and good functional group compatibility. The annulation products can be easily converted into many valuable compounds. Moreover, DFT calculation studies are performed to provide some insights into the possible reaction mechanisms for the (5+2) and (5+1) annulations.

Full text of DOI:10.1002/anie.202007825

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Iron-Catalyzed, Iminyl Radical-Triggered Cascade 1,5-Hydrogen
Atom Transfer/(5+2) or (5+1) Annulation: Oxime as a Five-Atom
Assembling Unit
Authors: Ye Wei, Wu Liang, Kun Jiang, Fei Du, Jie Yang, Li Shuai, Qin
Ouyang, and Ying-Chun Chen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007825
Link to VoR: https://doi.org/10.1002/anie.202007825

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
Iron-Catalyzed, Iminyl Radical-Triggered Cascade 1,5-Hydrogen
Atom Transfer/(5+2) or (5+1) Annulation: Oxime as a Five-Atom
Assembling Unit
Wu Liang, Kun Jiang, Fei Du, Jie Yang, Li Shuai, Qin Ouyang,* Ying-Chun Chen,* and Ye Wei*
[a]
W. Liang, K. Jiang, F. Du, J. Yang, L. Shuai, Dr. Q. Ouyang, Prof. Dr. Y.-C. Chen, Prof. Dr. Y. Wei
College of Pharmacy, Army Medical University,
Chongqing, 400038 (China)
E-mail: ouyangq @tmmu.edu.cn
ycchen@scu.edu.cn
weiye712@swu.edu.cn
involve radical-triggered cascade 1,5-hydrogen atom transfer[7,8]
(1,5-HAT)/annulation processes. In this scenario, remote
C(sp3)−H bonds can be converted into reactive carbon radicals,
which subsequently occur annulation reactions with unsaturated
compounds to afford the N-heterocycles (Scheme 1b).
Considering the ubiquity of the C(sp3)−H bonds in organic
compounds, the exploration of such a radical-triggered cascade
1,5-HAT/annulation strategy may enable an array of readily
available compounds to participate in the synthesis of the N-
heterocycles.
Abstract: By integration of iminyl radical-triggered 1,5-hydrogen
atom transfer and (5+2) or (5+1) annulation processes, a series of
structurally
novel
and
interesting
azepine
and
spiro-
tetrahydropyridine derivatives have been successfully prepared in
moderate to good yields. This method utilizes FeCl2 as the catalyst
and readily available oximes as five-atom units, and showcases
broad substrate scope and good functional group compatibility. The
annulation products can be easily converted into many valuable
compounds. Moreover, DFT calculation studies are performed to
provide some insights into the possible reaction mechanisms for the
(5+2) and (5+1) annulations.
Introduction
N-heterocycles are ubiquitous in natural products,
pharmaceuticals, agrochemicals, and functional materials.[1]
Consequently, a plethora of methods toward these molecules
have been developed.[2] Among these methods, radical
cyclizations have been emerged as a useful synthetic tool.[3]
However, many reactions require the use of potentially toxic
and/or explosive compounds as the radical precursors (e.g.,
organic halides, diazonium salts, and azides), or the use of
stoichiometric amounts of radical initiators (e.g., peroxide and
Bu3SnH). Therefore, the development of new and concise
synthetic strategy for the synthesis of the N-heterocycles is of
high significance. To this end, some interesting protocols
involving C-C bond cleavage followed by radical annulation have
been recently disclosed (Scheme 1a).[4,5] For example, Zuo
realized visible-light-induced, cerium-catalyzed annulations of
cycloalkanols with electron-deficient alkenes or di-tert-butyl
azodicarboxylate.[6] In these reactions, the C-C bonds of
unstrained cyclic alcohols can be cleaved by the highly oxidizing
CeIV species. Another fascinating yet unexplored tactic would
Scheme 2. Reactions involving iminyl radical-triggered 1,5-HAT.
Nitrogen-centered radicals have great capability in the
construction of carbon-nitrogen bonds and the N-heterocycles,[9]
as exemplified by the well-known Hofmann-Löffler-Freytag
reaction[10] that has been applied in the synthesis of various
cyclic amines. As one of the most significant classes of nitrogen-
centered radicals, iminyl radicals have gained increased
attention from synthetic organic chemists in the past few
decades. Many synthetic strategies and reactions based on the
iminyl radical have been successfully explored, such as
cyclization, cycloaddition, and 1,5-HAT.[11] In the field of the
iminyl radical-triggered 1,5-HAT, Forrester reported
a few
seminal works, in which the iminyl radicals were generated by
oxidation of phenylalkylideneamino-oxyacetic acids.[12] The
resulting iminyl radical species can be transformed into
tetralones through tandem 1,5-HAT and intramolecular C−C
Scheme 1. N-heterocycle synthesis through cascade C-C cleavage/annulation
and cascade 1,5-HAT/annulation. A=B indicates unsaturated compounds.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
bond formation (Scheme 2a). However, elevated temperature
and the use of stoichiometric amounts of strong oxidant resulted
in poor functional group compatibility and narrow substrate
scope. With the advent of new methods toward the formation of
the iminyl radicals via cleavage of the oxime N−O bond,
including visible-light photoredox catalysis and transition metal
catalysis, the iminyl radical-triggered 1,5-HAT has recently
achieved remarkable progress. For instance, carbon radicals
generated by 1,5-HAT could be trapped by intramolecular imine
group to deliver pyrrolines or dihydroimidazoles (Scheme 2a).[13]
Besides intramolecular reactions, the carbon radicals could also
be intermolecularly captured by some substrates to form C−C,
C−N, and C−halide bonds (Scheme 2b).[14] In these reactions,
the in situ formed imine group is generally converted into ketone
group upon hydrolysis. As such, the intermolecular scenario
based on the iminyl radical-triggered 1,5-HAT remains largely
restricted to the synthesis of substituted ketones. In considering
the synthetic potential of the iminyl radicals and related 1,5-HAT
strategies, as well as the importance of the N-heterocycles, it is
highly desirable to apply the iminyl radical-triggered 1,5-HAT to
the intermolecular annulation reactions to construct the N-
heterocyclic compounds.
The construction of seven-membered N-heterocyclic rings is
important and desirable due to their interesting biological and
pharmaceutical properties.[15] Among the reported approaches
toward these compounds, (5+2) annulation reactions are
particularly fascinating, because alkenes and alkynes,
structurally diverse and readily available compounds, could
serve as two-atom units in the transformations. Nonetheless,
most of the known (5+2) annulation reactions toward the seven-
membered N-heterocycles require the utilization of structurally
specific substrates, such as vinylaziridines, pyridinium
zwitterions, and oxiranes, which would result in limited molecular
diversity.[16] Motivated by the aforementioned work related to the
iminyl radical-triggered 1,5-HAT[13,14] and our ongoing research
on N−O bond transformations toward the N-heterocycles,[17] we
envisaged to develop a new approach involving the iminyl
radical-triggered cascade 1,5-HAT/(5+2) annulation for the
synthesis of the seven-membered N-heterocyclic rings, in which
the oxime serves as a five-atom unit. To our best knowledge,
such a protocol remains unexplored. As depicted in Scheme 2c,
an iminyl radical induces the formation of a γ-carbon radical via
1,5-HAT. Subsequently, the γ-carbon radical undergoes an
addition step to an alkene to deliver a new carbon radical that
might be trapped by the intramolecular imine group to form a
seven-membered cyclic imine. In addition, a (5+1) annulation
process might also occur if the alkene can act as a one-atom
unit. These processes appear deceptively simple, but are
challenging because some critical problems need to be
addressed: 1) inhibition of the γ-carbon radical to take part in
intramolecular C−N and C−C bond-forming reactions,[13,18] and
2) suppression of the hydrogen elimination from carbon radicals
to yield alkenes.[8a] Herein, we present an iron-catalyzed 1,5-
HAT/(5+2) or (5+1) annulation cascade protocol with oximes and
alkenes as readily accessible starting materials. This
transformation produces various structurally interesting azepine
and spiro-succinimide-tetrahydropyridine derivatives, which are
the core structures of many natural products and biologically
active molecules,[19] and exhibits broad substrate scope and
good functional group compatibility.
Results and Discussion
Table 1. Optimization of the reaction conditions.[a]
Entry
R
Catalyst
Additive
Solvent
Yield [%][b]
1
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
Bz
FBz
Ac
Piv
Bz
CuBr
none
THF
0
2
NiCl2
none
THF
0
3
CoCl2
FeCl3
Fe(acac)3
Fe(OAc)2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
none
none
THF
0
4
none
THF
20
26
21
28
33
trace
14
6
5
none
THF
6
none
THF
7
none
THF
8
none
1,4-dioxane
MeCN
9
none
10
11
12
13
14
15
16
17
18
none
toluene
DMSO
none
PhCO2Na
AcONa
PivONa
PivONa
PivONa
PivONa
PivONa
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
52
63
82
58
51
53
0
[a] Reaction conditions: oxime 1 (0.1 mmol), acrylonitrile 2a (0.2 mmol),
catalyst (10 mol%), additive (0 or 1 equiv), solvent (1 mL), 100 °C, 12 h, in a
sealed tube, under Ar. Abbreviation: FBz = pentafluorobenzoyl. [b] Isolated
yields.
We commenced our investigation by choosing oximes (1a)
and acrylonitrile (2a) as model substrates to develop an effective
catalytic system to realize the (5+2) annulation reaction.
Considerable experimentation has been conducted, and some
important results are shown in Table 1.[20] Among different kinds
of transition metals,[21] including copper, nickel, cobalt, and iron
salts, FeCl2 exhibited the best catalytic reactivity toward 3a
formation (entries 1−7). The structure of 3a was unambiguously
confirmed by single-crystal X-ray diffraction.[22] The reaction
afforded 3a in 33% yield with 1,4-dioxane as the solvent (entry
8), while showed significantly lower yields in MeCN, toluene, and
DMSO (entries 9−11). A further improvement was achieved by
using 1 equiv of sodium pivalate as an additive (82%, entry 14).
Considering the influence of the oxime group on the
transformation, several O-substituted oximes were studied
(entries 15−17); however, all the reactions produced the target
product in moderate yields. A control experiment demonstrated
that catalytic amount of FeCl2 was indispensable, because 3a
cannot be observed in its absence (entry 18). Thus, the optimal
reaction conditions were concluded to be the following: FeCl2
(10 mol%) as the catalyst, PivONa (1 equiv) as the additive, and
1,4-dioxane as the solvent at 100 °C for 12 h.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Substrate scope of oximes.[a]
Scheme 3. A two-fold annulation reaction.
oxime bears two potentially reactive sites for 1,5-HAT, the
reaction preferred to occur at the methyl group (3ak), probably
due to the relatively high stability of the benzylic carbon radical.
Our method can be scaled up to 10 mmol scale with a slightly
lower yield (75% yield). Interestingly, a two-fold annulation
reaction between bis-oxime 4 and 2a readily provided the target
product 3al in 65% yield (Scheme 3).
Table 3. Substrate scope of alkenes.[a]
[a] Reaction conditions: oxime 1a (0.2 mmol), alkene 2 (0.24 mmol), FeCl2 (10
mol%), PivONa (0.2 mmol), 1,4-dioxane (2 mL), 100 °C, 12 h, in a sealed tube,
under Ar. [b] Alkene (0.4 mmol) was used.
[a] Reaction conditions: oxime 1 (0.2 mmol), acrylonitrile 2a (0.4 mmol), FeCl2
(10 mol%), PivONa (0.2 mmol), 1,4-dioxane (2 mL), 100 °C, 12 h, in a sealed
tube, under Ar. [b] FeCl2 (20 mol%) was used.
Subsequently, we turned our attention to evaluate the
substrate scope of alkenes (Table 3). Cinnamonitriles
participated in the annulation reactions to generate the desired
products in moderate yields (3am−3ap). In addition, acrylamides,
acrylates, and fumaronitrile can react with 1a to give rise to the
final products in synthetically useful yields (3aq−3at).
Unfortunately, other alkenes, such as styrene and methyl
cinnamate were unreactive in the transformation.
After identifying the optimal reaction conditions, we surveyed
the substrate scope with respect to oximes (Table 2). Substrate
1 reacted well with acrylonitrile, giving rise to the corresponding
products in 43−90% yields (3b−3r), with tolerance of a series of
functional groups, including methoxy (3b and 3r), trimethylsilyl
(3c), ester (3d), cyano (3e), trifluoromethyl (3f), trifluoromethoxy
(3i), difluoromethoxyl (3n), chloro (3g and 3j), iodo (3h), bromo
(3k), fluoro (3q), morpholino (3l), olefinic (3m), cyclopropyl (3n),
hydroxyl (3o), and naphthyl groups (3p). An oxime with a
ferrocene functionality displayed moderated reactivity in the
transformation, which produced 3s in 60% yield. Our approach
was also amenable to several heterocycle-derived oximes,
which include the ones derived from benzodioxole (3t), pyridine
(3u), quinoline (3v), isoquinoline (3w), thiophene (3x),
benzothiazole (3y), furan (3z), and benzofuran (3aa). In terms of
the substituents (R1 and R2) at the γ position of the oxime moiety,
they can be ethyl/ethyl (3ab), phenyl/methyl (3ac). The
substituents can also be cyclic moieties. As such, the annulation
method can furnish structurally interesting spiro-azepine
derivatives in moderate yields (3ad−3af). Furthermore, the
newly developed approach was suitable for the estrone-derived
oxime, and the corresponding product 3ag was obtained in 75%
yield. The iminyl radical-triggered 1,5-HAT was also suitable for
the generation of secondary (3ah and 3ai) and primary carbon
radicals (3aj and 3ak), which can take part in the annulation
reactions to deliver the target products. Note that, when an
Interestingly, when maleimides were utilized as the substrates,
the
(5+1)
annulation
products,
spiro-succinimide-
tetrahydropyridine derivatives, were observed (Table 4). A series
of N-aryl maleimides with different functionalities on the aryl ring,
including nitro (3av), trifluoromethoxy (3aw), trifluoromethyl
(3ax), fluoro (3ay), bromo (3ay), and chloro groups (3az),[23]
were amenable to the reaction, affording the corresponding
products in moderate yields. In addition, the reactions betwen N-
(2,4,6-trichlorophenyl)maleimide and various oximes can also
generate the desired products (3aaa−3aae). Besides N-aryl
maleimides, N-Me maleimide (3aaf) and NH-maleimide (3aag)
can take part in the reactions to deliver the target products in
synthetically useful yields.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 4. (5+1) Annulation reactions.[a]
Scheme 5. Mechanistic investigations.
To gain insights into the reaction mechanism, some
experiments were conducted (Scheme 5). A radical clock
reaction was performed with oxime 8 as the substrate (Scheme
5a). Under the standard reaction conditions, the reaction
produced a ring-opening product 9 in 28% yield. In addition, the
addition of 3 equiv of radical scavenger TEMPO into the model
reaction totally inhibited the formation of seven-membered
product 3a, and significant amounts of radical-trapping product
10 was observed (Scheme 5b). These results supported the
involvement of a γ-carbon radical in the (5+2) annulation
reaction.
[a] Reaction conditions: oxime 1a (0.2 mmol), alkene 2 (0.24 mmol), FeCl2 (10
mol%), PivONa (0.2 mmol), 1,4-dioxane (2 mL), 100 °C, 12 h, in a sealed tube,
under Ar.
Scheme 6. Proposed mechanism for cascade 1,5-HAT/(5+2) annulation.
Based on the aforementioned results and the previous work
on iminyl radical transformations,
a
plausible reaction
mechanism is illustrated for the cascade 1,5-HAT/(5+2)
annulation reactions (Scheme 6). Single electron transfer from
Fe(II) to the oxime results in N−O bond cleavage to generate
Fe(III) and an iminyl radical A.[14e,21g-i] The latter undergoes 1,5-
HAT to form an alkyl carbon radical B. Through the addition of
the γ-carbon radical to the alkene, a new carbon radical C can
be produced. The carbon radical would add to the intramolecular
imine group to give rise to an intermediate D,[24] which could be
oxidized by the Fe(III) to form an iminium ion E with concurrent
regeneration of the Fe(II) catalyst. After deprotonation, the
azeping derivative 3 would be generated. Fe(III) salts can also
induce the reaction (entries 4 and 5, Table 1), and a possible
reason might be that the Fe(III) salts were firstly reduced to
Fe(II) species under the reaction conditions (e.g., 1,4-
dioxane).[18]
Scheme 4. Synthetic transformations. Reaction conditions: a) 3a (0.1 mmol),
NaOH (0.3 mmol), EtOH (1 mL), H2O (1 mL), reflux, 10 h. b) 1) 3a (0.1 mmol),
LiAlH4 (0.4 mmol), THF (2 mL), 0 °C, 5 h; 2) BzCl (0.15 mmol), Et3N (0.2
mmol), DCM (5 mL), RT, 2 h. c) 3a (0.1 mmol), acrylonitrile (0.2 mmol),
AgOAc (0.01 mmol), Cs2CO3 (0.02 mmol), toluene (1 mL), reflux, 8 h. d) 1) 3a
(0.1 mmol), conc. HCl (1 mL), 1,4-dioxane (2 mL), H2O (1 mL), 100 °C, 10 h;
2) SOCl2 (0.5 mmol), MeOH (5 mL), 70 °C, 5 h.
Besides the structural importance of the azepine derivatives,
their synthetic utility would also be attractive. As illustrated in
Scheme 4, 3a was converted into a cyclic enamide 5 in 51%
yield under basic conditions (Scheme 4a). Through sequential
reduction by lithium aluminum hydride and acylation by benzoyl
chloride, 3a can be transformed into an azepane 6 in 65% yield
(Scheme 4b). In addition, a Michael addition reaction between
3a and acrylonitrile furnished the corresponding product 7 in
72% yield (Scheme 4c). The CN group of 3a can also be
efficiently converted into an ester group upon hydrolysis and
esterification (Scheme 4d).
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
scope and good functional group compatibility. The survey of
more iminyl radical-triggerred cascade 1,5-HAT/(5+n) annulation
reactions with the oximes as the five-atom units to access N-
heterocycles is ongoing in our group.
Acknowledgements
Financial support from the NSFC (No. 21772231), the National
Key R&D program of China (No. 2018YFA0507900), China
Postdoctoral Science Foundation (No. 2018M633761) and the
Army Medical University is greatly appreciated.
Keywords: oximes • N-heterocycles • cascade reaction • iron
catalysis • synthetic methods
[1]
a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103,
893; b) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem.
2014, 57, 5854; c) T. Y. Zhang, Adv. Heterocycl. Chem. 2017, 121, 1.
[2]
[3]
Comprehensive Heterocyclic Chemistry III (Ed.: A. R. Katritzky, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor), Elsevier, Amsterdam, 2008.
Radicals in Organic Synthesis (Ed.: P. Renaud, M. P. Sibi), Wiley-VCH,
Weinheim, 2001.
[4]
[5]
For recent review, see: H.-M. Huang, M. H. Garduño-Castro, C. Morrill,
D. J. Procter, Chem. Soc. Rev. 2019, 48, 4626.
For recent examples involving C-C bond cleavage followed by radical
annulation for the construction of alicyclic compounds, see: a); A. G.
Amador, E. M. Sherbrook, T. P. Yoon, J. Am. Chem. Soc. 2016, 138,
4722; b) W. Hao, J. H. Harenberg, X. Xu, S. N. MacMillan, S. Lin, J. Am.
Chem. Soc. 2018, 140, 3514; c) X. Huang, J. Lin, T. Shen, K. Harms, M.
Marchini, P. Ceroni, E. Meggers, Angew. Chem. Int. Ed. 2018, 57,
5454; Angew. Chem. 2018, 130, 5552.
Scheme 7. Energy profile of annulation reactions with relative Gibbs free
energies [kcal/mol].
[6]
[7]
a) J.-J. Guo, A. Hu, Y. Chen, J. Sun, H. Tang, Z. Zuo, Angew. Chem. Int.
Ed. 2016, 55, 15319; Angew. Chem. 2016, 128, 15545; b) A. Hu, Y.
Chen, J.-J. Guo, N. Yu, Q. An, Z. Zuo, J. Am. Chem. Soc. 2018, 140,
13580.
For recent reviews, see: a) J. Robertson, J. Phillaia, R. K. Lush, Chem. Soc.
Rev. 2001, 30, 94; b) Ž. Čeković, Tetrahedron 2003, 59, 8073; c) S. Chiba,
H. Chen, Org. Biomol. Chem. 2014, 12, 4051; d) M. Yan, J. C. Lo, J. T.
Edwards, P. S. Baran, J. Am. Chem. Soc. 2016, 138, 12692; e) L. Capaldo, D.
Ravelli, Eur. J. Org. Chem. 2017, 2056; f) X.-Q. Hu, J.-R. Chen, W.-J. Xiao,
Angew. Chem. Int. Ed. 2017, 56, 1960; Angew. Chem. 2017, 129,
1988; g) X. Wu, C. Zhu, Chem. Commun. 2019, 55, 9747.
For recent examples, see: a) A.-F. Voica, A. Mendoza, W. R. Gutekunst,
J. O. Fraga, P. S. Baran, Nat. Chem. 2012, 4, 629; b) Y.-F. Wang, H.
Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134, 11980; c) P. Yu, J.-S.
Lin, L. Li, S.-C. Zheng, Y.-P. Xiong, L.-J. Zhao, B. Tan, X.-Y. Liu, Angew.
Chem. Int. Ed. 2014, 53, 11890; Angew. Chem. 2014, 126, 12084; d) G.
J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539, 268;
e) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272; f) J. Zhang, Y. Li, F. Zhang,
C. Hu, Y. Chen, Angew. Chem. Int. Ed. 2016, 55, 1872; Angew. Chem.
2016, 128, 1904; g) C. Wang, K. Harms, E. Meggers, Angew. Chem. Int.
Ed. 2016, 55, 13495; Angew. Chem. 2016, 128, 13693; h) E. A.
Wappes, K. M. Nakafuku, D. A. Nagib, J. Am. Chem. Soc. 2017, 139,
10204; i) W. Yuan, Z. Zhou, L. Gong, E. Meggers, Chem. Commun.
2017, 53, 8964; j) A. Hu, J.-J. Guo, H. Pan, H. Tang, Z. Gao, Z. Zuo, J.
Am. Chem. Soc. 2018, 140, 1612; k) Y. Xia, L. Wang, A. Studer, Angew.
Chem. Int. Ed. 2018, 57, 12940; Angew. Chem. 2018, 130, 13122; l) H.
Guan, S. Sun, Y. Mao, L. Chen, R. Lu, J. Huang, L. Liu, Angew. Chem.
Int. Ed. 2018, 57, 11413; Angew. Chem. 2018, 130, 11583; m) S. P.
Morcillo, E. M. Dauncey, J. H. Kim, J. J. Douglas, N. S. Sheikh, D.
Leonori, Angew. Chem. Int. Ed. 2018, 57, 12945; Angew. Chem. 2018,
130, 13127; n) X.-X. Wu, H. Zhang, N.-N. Tang, Z. Wu, D.-P. Wang, M.-
S. Ji, Y. Xu, M. Wang, C. Zhu, Nat. Commun. 2018, 9, 3343; o) Z. Li, Q.
Wang, J. Zhu, Angew. Chem. Int. Ed. 2018, 57, 13288; Angew. Chem.
2018, 130, 13472; p) D. Kurandina, D. Yadagiri, M. Rivas, A. Kavun, P.
Chuentragool, K. Hayama, V. Gevorgyan, J. Am. Chem. Soc. 2019, 141,
8104; q) S. Wu, X. Wu, D. Wang, C. Zhu, Angew. Chem. Int. Ed. 2019,
58, 1499; Angew. Chem. 2019, 131, 1513; r) K. Wu, L. Wang, S. Colón
Next, we sought to use density functional theory (DFT)
calculations at B2PLYP/def2-TZVPPD/SMD//M06-2X/def2-TZVP
level to understand the chemoselectivity for the formation of
seven-membered and six-membered rings (Scheme 7).[25] After
1,5-HAT and the addition to the alkene, a key intermediate INT-
C was formed. The seven-membered ring could be generated by
intramolecular cyclization of the 2a-INT-C for acrylonitrile 2a.
After proposing and calculating four different pathways, the
computational results suggested that the 2q-INT-C would
produce the six-membered ring via sequentially 1,4-HAT, 1,4-
HAT, 1,6-HAT and intramolecular cyclization for NH-maleimide
2q (see Scheme S4 in the Supporting Information for the
details).[26] The energy barriers of the annulation reactions of 2a
and 2q were calculated. The highest energy barrier (2a-TS14)
among the process to produce six-membered ring was 9.7
kcal/mol higher than that of 2a-TS1, suggesting the formation of
seven-membered ring from 2a was more favorable. On the other
side, for the substrate 2q, the energy of 2q-INT-D was slightly
higher (2.1 kcal/mol) than 2q-INT-C, while the energies of 2q-
INT-C’’ and 2q-INT-D’ were 4.7 and 10.1 kcal/mol lower than
2q-INT-C, respectively. Moreover, the energy barrier of 2q-TS1
was 0.9 kcal/mol higher than the highest energy barrier (2q-TS14)
among the process to produce six-membered ring. These results
implied that the reaction of 2q was favorable to form the six-
membered ring.
[8]
Conclusion
‐Rodríguez, G.-U. Flechsig, T. Wang, Angew. Chem. Int. Ed. 2019, 58,
1774; Angew. Chem. 2019, 131, 1788.
We have successfully exploited oximes as five-atom units for
the iminyl radical-triggered cascade 1,5-HAT/(5+2) or (5+1)
annulation reactions with various electron-deficient alkenes,
which allow for the rapid assembly of over 50 examples of
structurally new and interesting azepine and spiro-
tetrahydropyridine derivatives as potentially attractive privileged
scaffolds in drug discovery. The method exhibits broad substrate
[9]
For recent reviews, see: a) S. Z. Zard, Chem. Soc. Rev. 2008, 37,
1603; b) S. B. Höfling, M. R. Heinrich, Synthesis 2011, 173; c) T. Xiong,
Q. Zhang, Chem. Soc. Rev. 2016, 45, 3069; d) J.-R. Chen, X.-Q. Hu,
L.-Q. Lu, W.-J. Xiao, Chem. Soc. Rev. 2016, 45, 2044; e) H. Jiang, A.
Studer, CCS Chem. 2019, 1, 38.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
[10] a) A. W. Hofmann, Ber. Dtsch. Chem. Ges. 1883, 16, 558; b) K. Löffler,
C. Freytag, Ber. Dtsch. Chem. Ges. 1909, 42, 3427.
[11] For recent reviews, see: a) M. Kitamura, K. Narasaka, Bull. Chem. Soc.
Jpn. 2008, 81, 539; b) J. C. Walton, Acc. Chem. Res. 2014, 47, 1406;
c) H. Huang, X. Ji, W. Wu, H. Jiang, Chem. Soc. Rev. 2015, 44, 1155;
d) X. Zhu, S. Chiba, Chem. Soc. Rev. 2016, 45, 4504; e) D. S. Bolotin,
N. A. Bokach, M. Y. Demakova, V. Y. Kukushkin, Chem. Rev. 2017,
117, 13039; f) N. J. Race, I. R. Hazelden, A. Faulkner, J. F. Bower,
Chem. Sci. 2017, 8, 5248; g) L. M. Stateman, K. M. Nakafuku, D. A.
Nagib, Synthesis 2018, 50, 1569; h) J. Davies, S. P. Morcillo, J. J.
Douglas, D. Leonori, Chem. Eur. J. 2018, 24, 12154; i) S. P. Morcillo,
Angew. Chem. Int. Ed. 2019, 58, 14044; Angew. Chem. 2019, 131,
14182.
[12] A. R. Forrester, M. Gill, R. J. Napier, R. H. Thomson, J. Chem. Soc.,
Perkin Trans. 1 1979, 632.
[13] a) H. Chen, S. Chiba, Org. Biomol. Chem. 2014, 12, 42; b) W. Shu, C.
Nevado, Angew. Chem. Int. Ed. 2017, 56, 1881; Angew. Chem. 2017,
129, 1907.
[14] a) E. M. Dauncey, S. P. Morcillo, J. J. Douglas, N. S. Sheikh, D. Leonori,
Angew. Chem. Int. Ed. 2018, 57, 744; Angew. Chem. 2018, 130, 752;
b) H. Jiang, A. Studer, Angew. Chem. Int. Ed. 2018, 57, 1692; Angew.
Chem. 2018, 130, 1708; c) X. Shen, J.-J. Zhao, S. Yu, Org. Lett. 2018,
20, 5523; d) Z.-Y. Ma, L.-N. Guo, Y.-R. Gu, L. Chen, X.-H. Duan, Adv.
Synth. Catal. 2018, 360, 4341; e) R. O. Torres-Ochoa, A. Leclair, Q.
Wang, J. Zhu, Chem. Eur. J. 2019, 25, 9477; f) Y.-R. Gu, X.-H. Duan, L.
Chen, Z.-Y. Ma, P. Gao, L.-N. Guo, Org. Lett. 2019, 21, 917.
[15] a) P. A. Evans, A. B. Holmes, Tetrahedron 1991, 47, 9131; b) E. Vitaku,
D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257.
[16] a) H. Pellissier, Adv. Synth. Catal. 2011, 353, 189; b) H. Pellissier, Adv.
Synth. Catal. 2018, 360, 1551.
[17] a) B. Zhao, H.-W. Liang, J. Yang, Z. Yang, Y. Wei, ACS Catal. 2017, 7,
5612; b) H.-W. Liang, Z. Yang, K. Jiang, Y. Ye, Y. Wei, Angew. Chem.
Int. Ed. 2018, 57, 5720; Angew. Chem. 2018, 130, 5822; c) J. Yang, B.
Zhao, Y. Xi, S. Sun, Z. Yang, Y. Ye, K. Jiang, Y. Wei, Org. Lett. 2018,
20, 1216; d) Z. Yang, K. Jiang, Y.-C. Chen, Y. Wei, J. Org. Chem. 2019,
84, 3725.
[18] Y. Zhang, Z. Yin, X.-F. Wu, Adv. Synth. Catal. 2019, 361, 3223.
[19] a) B. Renfroe, C. Harrington, G. R. Proctor in Chemistry of Heterocyclic
Compounds: Azepines, Vol. 43 (Ed.: A. Rosowsky), Wiley
&
Interscience, New York, 1984, pp. 637−768; b) S. Tomas, J. Renault, B.
Martin, S. Duhieu, V. Cerec, M. Le Roch, P. Uriac, J.-G. Delcros, J.
Med. Chem. 2010, 53, 7647; c) Y. Dudognon, J. Rodriguez, T.
Constantieux, X. Bugaut, Eur. J. Org. Chem. 2018, 2432.
[20] Please see the Supporting Information for more details.
[21] Several transition metals can induce the oxime N−O cleavage. [Cu]: a)
K. Tanaka, M. Kitamura, K. Narasaka, Bull. Chem. Soc. Jpn. 2005, 78,
1659; b) Y. Wei, N. Yoshikai, J. Am. Chem. Soc. 2013, 135, 3756; [Pd]:
c) W. P. Hong, A. V. Iosub, S. S. Stahl, J. Am. Chem. Soc. 2013, 135,
13664;d) A. Faulkner, J. S. Scott, J. F. Bower, J. Am. Chem. Soc. 2015,
137, 7224; [Ni]: e) Y.-R. Gu, X.-H. Duan, L. Yang, L.-N. Guo, Org. Lett.
2017, 19, 5908; f) H.-B. Yang, S. R. Pathipati, N. Selander, ACS Catal.
2017, 7, 8441; [Fe]: g) M.-N. Zhao, Z.-H. Ren, L. Yu, Y.-Y. Wang, Z.-H.
Guan, Org. Lett. 2016, 18, 1194; h) H.-B. Yang, N. Selander, Chem.
Eur. J. 2017, 23, 1779; i) T. Shimbayashi, D. Nakamoto, K. Okamoto, K.
Ohe, Org. Lett. 2018, 20, 3044.
[22] CCDC 1955189 (3a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[23] CCDC 1971469 (3az) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[24] D. W. Peacock, C. B. Roos, J. F. Hartwig, ACS Cent. Sci. 2016, 2, 647.
[25] Please see the Supporting Information for the details.
[26] For the radical-triggered 1,n-HAT (n≠5), see a recent review: M. Nechab,
S. Mondal, M. P. Bertrand, Chem. Eur. J. 2014, 20, 16034.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202007825
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
With readily available oximes as five-atom units, a variety of azepine and spiro-tetrahydropyridine derivatives have been synthesized
through the iminyl-radical triggered 1,5-hydrogen atom transfer/(5+2) or (5+1) annulation cascade protocol. This method exhibits
broad substrate scope and good functional group compatibility.
7
This article is protected by copyright. All rights reserved.