Ring-opening formal hetero-[5+2] cycloaddition of 1-tosyl-2,3-dihydro-1: H-pyrroles with terminal alkynes: Entry to 1-tosyl-2,3-dihydro 2,3-dihydro-1 H-azepines

Article abstract of DOI:10.1039/c9cc05082e

A new Lewis acid catalysed formal hetero-[5+2] cycloaddition of 2,3-dihydro-1H-pyrroles to terminal alkynes is described. By employing a FeCl₃ and BF₃·OEt₂ co-catalytic strategy, the ring-opening of 1-tosyl-2,3-dihydro-1H-

Full text of DOI:10.1039/c9cc05082e

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Zhou, R. Pi, F.
Teng, Y. Li and J. Li, Chem. Commun., 2019, DOI: 10.1039/C9CC05082E.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C9CC05082E
ChemComm
COMMUNICATION
Ring-Opening Formal Hetero-[5+2] Cycloaddition of 1-Tosyl-2,3-
dihydro-1H-pyrroles with Terminal Alkynes: Entry to 1-Tosyl-2,3-
dihydro 2,3-Dihydro-1H-azepines
Received 00th January 20xx,
Accepted 00th January 20xx
Ming-Bo Zhouab‡, Rui Pia‡, Fan Teng,a Yang Li,a and Jin-Heng Li*abc
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new Lewis acid catalysed formal hetero-[5+2] cycloaddition of ring-opening and hetero-[5+2] cycloaddition reactions with alkynes
2,3-dihydro-1H-pyrroles to terminal alkynes is described. By are rare,4 although they represent straightforward synthetic
employing a FeCl3 and BF3·OEt2 co-catalytic strategy, the ring- strategies for the construction of valuable seven-membered
opening of 1-tosyl-2,3-dihydro-1H-pyrroles by selective cleavage heterocycles, such as azepine derivatives,5,6 which show strong
of the C(sp2)-N bond and subsequent annulation have been bioactivity as potent inhibitors of protein kinase C, nonpeptidic
achieved to access 1-tosyl 2,3-dihydro-1H-azepines with excellent plasmepsin II/IV and dual NET/DAT uptake, as well as urotensin-II
regioselectivity, offering a new avenue for cycloaddition through receptor antagonists and herbicides (Scheme 1).6 Stogryn4a and
the ring-opening of non-strained-ring-based units.
OMe
O
S
O
N
Et
O
H
N
N
OMe
N
N
O
The cycloaddition reaction is commonly utilized in synthesis to
build diverse complex ring systems, and it continues to attract
attention.1-3 However, the development of such a cycloaddition
reaction capable of constructing seven-membered to larger ring
systems is generally hindered by a combination of entropic
factors and the presence of non-bonding interactions in the
transition states preferentially leading to five- or six-membered
ring products instead. In past decades, selective cycloaddition
strategies that proceed by ring-opening to access seven-
membered or larger ring systems in-situ by cyclometallation
and/or heteroatom coordination have been developed to
overcome the complications caused by the aforementioned
N
N
Molinate (III,
an herbicide)
N
S
H
O
O
O
O
O
O
II (A urotensin-II receptor antagonist)
Relacatib (SB-462795; I) (A cathepsin K Inhibitor)
H
N
NH
Cl
HN
N
O
H
N
Cl
H
H
N
O
H
O
O
O
O
Ph
O
(-)-Tuberostemonine (VII;
against pulmonary tuberculosis,
bronchitis and insecticides)
O
O
O
V (A nonpeptidic
plasmepsin II and IV Inhibitor)
VI (A dual NET/DAT
uptake inhibitor)
Flueggenine A (IV)
Scheme 1. Important examples of bioactive azepine derivatives.
Hassner4b and their co-workers independently developed catalyst-
free three-membered ring-opening and hetero-[5+2] reactions of
vinylaziridines with electron-poor perfluorobut-2-yne and dimethyl
but-2-ynedioate, respectively, by cleavage of the C(sp3)-N bond for
the synthesis of 2,5-dihydro-1H-azepines (Scheme 2a top). Recently,
the Zhang and co-workers illustrated a new rhodium catalysis that
disadvantageous
interactions.1-3
entropic
factors
and
non-bonding
Among them, the [5+2] cycloaddition of ring-based five-atom
units to  systems (e.g., alkynes, alkenes and allenes) by ring-
opening and annulation to efficiently access seven-membered
carbo- and heterocyclic compounds has been the focus of attention.
However, the vast majority of such reactions have employed
strained-ring-based five-atom units that are less accessible and
versatile as synthetic building blocks.2-4 Examples of intermolecular
made such
a strategy applicable to a wide range of both
vinylaziridines and alkynes (Scheme 2a bottom).4c We have
reported a FeCl3 and BF3·OEt2 co-catalysed ring-opening and [5+2]
heteroannulation of 2-(2-aminoethyl)oxiranes with alkynes for the
synthesis of 2,3-dihydro-1H-azepines by the cleavage of two C(sp3)-
O bonds (Scheme 2b).4d Two protocols for the hetero-[5+2]
cycloaddition reactions initiated by ring-opening by cleavage of a C-
C bond have been established in which only highly active electron-
poor alkynes are viable (Scheme 2c-d).4e-g More promisingly, less
strained 2,3-dihydro-1H-pyrroles4g have been employed in hetero-
[5+2] cycloaddition reactions in which the C=C bond was selectively
broken, although this approach is limited to special 2,3-dihydro-1H-
pyrroles and electron-poor alkynes (Scheme 2d). On this basis, we
envisioned that by utilizing a potent catalytic system, common 2,3-
dihydro-1H-pyrroles might undergo ring-opening by the selectively
a Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources
Recycle, Nanchang Hangkong University, Nanchang 330063, China
b Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research
(Ministry of Education), Hunan Normal University, Changsha 410081, China
c State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, China
E-mail: jhli@hnu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡ These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
cleavage of a chemical bond to enable formal hetero-[5+2] alkynes 2 (Scheme 3). The reactions proceeded well with electron-
View Article Online
DOI: 10.1039/C9CC05082E
cycloaddition reactions with various  systems.
rich
Thus, we report herein a new Lewis acid catalysed ring-opening Table 1 Screening of optimal reaction conditionsa
and formal [5+2] cycloaddition of 1-tosyl-2,3-dihydro-1H-pyrroles to
Ph
Ts
terminal alkynes by C(sp2)-N bond cleavage (Scheme 2e). An
inexpensive FeCl3/BF3·Et2O co-catalytic system7 proved effective for
the conversion of various common 1-tosyl-2,3-dihydro-1H-pyrroles
into 1-tosyl-2,3-dihydro-1H-azepines by ring-opening and
annulation with alkynes, thus providing a catalytic hetero-[5+2]
cycloaddition triggered by selective cleavage of the C(sp2)-N bond8
using a two Lewis acids co-catalysed strategy.
Ph
Ts
N
N
Ph
FeCl3 (4 mol%)
BF3 Et2O (40 mol%)
CH2ClCH2Cl, 80 o
Ar, 24 h
Ph
+
C
2a
1a
3
Entry
Variation from the standard conditions
Yield (%)b
1
2
none
without BF3·Et2O
73
36
68
50
3
BF3·Et2O (80 mol%)
without FeCl3
Previous work: Ring-opening/[5+2] cycloaddition
via C(sp3)-heteroatom bond cleavage
via C-C bond cleavage
4
R1
R1
N
a)
c)
N
R1
5
FeCl3 (6 mol%)
71
N
N
R1
6
Fe(OTf)3 instead of FeCl3
Fe(acac)3 instead of FeCl3
AgSbF6 instead of FeCl3
70
[Rh(CO)2Cl]2
R
rt or -20 o
C
R
R'
DCE, 60 o
C
R'
R1 = alkyl R = R' = CO2Me
7
59
72
(refs. 4a-b)
R1 = H R = R' = CO2Me, CF3
(ref. 4e)
R1 = Ts, Ns, Ms
[Rh(h6-C10H8)(COD)]SbF6
DCE, 0 oC (ref. 4c)
or BF3 OEt2(ref. 4h)
O
8
R
CO2Et
R = aryl, alkyl, TMS
R' = H, alkyl, COMe
R2
R1
9
CuCl2, Sc(OTf)3, InCl3 or AlCl3 instead of FeCl3
46-51
trace
52
N
R1
R2
NH2
10
11
12
13
14
15c
Sc(OTf)3 instead of the FeCl3/BF3·Et2O system
b)
d)
R3
R'
NC
NHTs
R2
R4
CH2Cl2 instead of CH2ClCH2Cl
MeNO2 instead of CH2ClCH2Cl
N
CO2Et
CN
3 examples
R3
R2
MeO2
C
N
Ts
53
FeCl3, BF3 OEt2
CH2Cl2, rt (ref. 4d)
DMSO, rt
or xylene, reflux
(ref. 4g)
NH2
R4
At 60 oC
At 100 oC
none
38
R
6 exampes, 7%-61% yields
R = H, CO2Me R' = CO2Me
R
R'
R = aryl, alkyl R' = H, alkyl
68
e) This work: Ring-opening/[5+2] cycloaddition via selective cleavage of C(sp2)-N bond
62
R3
R1
R4
R
FeCl3 (4 mol%)
R4
R3
N
BF3 Et2O (40 mol%)
R2
+
a
R1
N
CH2ClCH2Cl, 80 oC, Ar, 24 h
Reaction conditions: 1a (0.2 mmol), 2a (4 equiv), FeCl3 (4
mol%), BF3·Et2O (40 mol%), CH2ClCH2Cl (anhydrous; 2 mL),
argon, 80 oC, and 24 h. b Isolated yield. c 1a (1 mmol) and 48 h.
R2
2
1
R
Scheme 2. [5+2] Cycloaddition via ring-opening.
We started our investigation initiated by exploring the ring-
opening/formal [5+2] cycloaddition reaction between 3-phenyl-5-
(p-tolyl)-1-tosyl-2,3-dihydro-1H-pyrrole (1a) and phenylacetylene
(2a) using different Lewis acid catalysts (Table 1). The reaction was
efficiently catalysed by combining 4 mol% FeCl3 and 40 mol%
or electron-deficient terminal arylalkynes, affording diversely
tetrasubstituted 2,3-dihydro-1H-azepines 4-16 in moderate-to-good
yields. The results showed that various substituents, including Me,
t-Bu, Br, Cl, F, CO2Me and CO2Et, on the aryl ring of terminal alkynes
were well tolerated, but the electronic nature and position of the
substituent affected the yield. Electron-rich para-alkyl (e.g., Me, t-
Bu)-substituted aryl alkynes efficiently generated azepines 4 and 5,
respectively, in high yields (75 and 81%), whereas arylalkynes
bearing either an electron-deficient para-substituent (e.g., ester) or
o
BF3·Et2O in CH2ClCH2Cl at 80 C, which gave the desired 1-tosyl-2,3-
dihydro-1H-azepine 3 in 73% yield (entry 1), whose structure was
unambiguously confirmed by X-ray crystallography analysis.9 It was
noted that the reaction could afford 3 in the absence of either
BF3·Et2O or FeCl3 (entries 2 and 4), albeit in a lower yield. Increasing
the amount of BF3·Et2O and FeCl3, respectively, did not improve the
yield (entries 3 and 5). A series of Lewis acids, including Fe(OTf)3,
Fe(acac)3, AgSbF6, CuCl2, Sc(OTf)3, InCl3 and AlCl3, were examined.
Both Fe(OTf)3 (entry 6) and AgSbF6 (entry 8) displayed high catalytic
efficiency, giving fairly good yields of the product, but Fe(acac)3 was
less effective (entry 7). The other Lewis acids (entry 9) gave similar
results to that obtained in the absence of FeCl3 (entry 4). However,
by using only Sc(OTf)3 as the catalyst (entry 10), the amount of
azepine 3 was negligible after this reaction. When the reaction was
performed in two other solvents, namely CH2Cl2 and MeNO2, lower
yields were obtained (entries 11 and 12). Reducing the temperature
(60 oC) had a negative effect (entry 13), whereas raising the
temperature (100 oC) led to a similar yield to that obtained at 80 oC
(entry 14). The optimal reaction conditions were suitable for scaling
up the reaction of 1-tosyl-2,3-dihydro-1H-pyrrole 1a to 1 mmol,
giving azepine 3 in good yield (entry 15).
a
meta- or ortho-substituent (e.g., Me, Cl) delivered the
corresponding products 9-13 in moderate yields (41-66%).
Gratifyingly, the halo groups, such as Br, Cl and F, were also
tolerated in this reaction (6-8, 13). The reaction could also be
performed smoothly with alkynes possessing other functional
groups, such as 1-naphthalenyl (15), 3-thiophenyl (16) and
cyclohex-1-enyl (17). Cyclopropylacetylene, an alkylalkyne, was also
a viable cycloaddition partner (18). However, this cycloaddition
reaction was not compatible with a common linear aliphatic
terminal alkyne (19) and internal alkyne (20).
We next assessed the generality of this formal cycloaddition
protocol with regard to 2,3-dihydro-1H-pyrroles 1 (Scheme 3). The
reaction was applicable to a variety of 1-tosyl-2,3-dihydro-1H-
pyrroles (21-36). 1-Tosyl-2,3-dihydro-1H-pyrroles possessing a
phenyl or an alkyl group at the 5 position were viable five-atom
units, giving azepines 21-23 in good yields. The reaction with 3,5-
disubstituted 2,3-dihydro-1H-pyrroles efficiently produced azepines
24-34 in yields of 55-80% depending on the nature of the
substituent and the alkyne. 3,5-Diphenyl-1-tosyl-2,3-dihydro-1H-
pyrrole reacted with phenylacetylene (2a) to afford 24 in 80% yield,
but the reaction with 1-ethynyl-3,5-dimethylbenzene gave 25 in a
With the optimal conditions in hand, we explored the scope of
this ring-opening/formal [5+2] cycloaddition reaction of 3-phenyl-5-
(p-tolyl)-1-tosyl-2,3-dihydro-1H-pyrrole (1a) with a wide range of
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 4
ChemComm
Journal Name
COMMUNICATION
reduced yield of 64%. An array of aryl groups, including Ph, para- lead to the formation of azepines (38 and 39). Both conformations
View Article Online
DOI: 10.1039/C9CC05082E
MeC6H4, para-BrC6H4, para-ClC6H4 and meta-ClC6H4, placed at the of azepines 36 and 37 adopt cis-form, which is the assumed relative
configuration from the starting materials.10 Moreover, 4-methyl-
Scheme 3. Variation of the 2,3-dihydro-1H-pyrroles (1) and 3,5-diphenyl-1-tosyl-2,3-dihydro-1H-pyrrole was also inert due to
alkynes (2)a
steric hindrance to inhibiting coordination with the Lewis acids.
As shown in Scheme 4, neither 2-phenyl-1-tosyl-1H-pyrrole [1r;
(Eqn (1), left)] nor 2-phenyl-1-tosylpyrrolidine [1s; (Eqn (2), right)]
showed any reactivity in this ring-opening/cycloaddition protocol.
because both compounds have very stable five-membered-
heterocyclic rings: the C(sp2)-N bond in 1H-pyrrole 1r has a very
high dissociation energy and its cleavage requires a challenging
dearomatization process, and the C(sp3)-N bond in pyrrolidine 1s is
extremely stable as it adopts puckered conformation to reduce the
torsional strain and small ring strain.
R
R4
FeCl3 (4 mol%)
BF3 Et2O (40 mol%)
CH2ClCH2Cl, 80 oC, Ar, 24 h
R
R3
R4
R3
N
N
R1
+
R1
R2
2
1
R2
tBu
Cl
Br
Ts
Ts
Ts
N
N
Ts
N
N
A possible mechanism for this ring-opening/formal hetero-[5+2]
cycloaddition protocol is proposed in Scheme 4.1-4,7,8 Initially,
complexation of the Lewis acids (FeCl3 and BF3·Et2O)7 with both 1-
tosyl-2,3-dihydro-1H-pyrrole 1a (through the C=C bond and the
nitrogen atom) and alkyne 2a (through the CC bond) affords the
intermediate A, and subsequent addition of the nitrogen atom to
the CC bond of alkyne 2a leads to the intermediate B. Finally,
formal hetero-[5+2] annulation of the intermediate B through
C(sp2)-N bond cleavage8 generates 1-tosyl-2,3-dihydro-1H-azepine
3.
Ph
Ph
Ph
Ph
4, 75%
6, 68%
7, 70%
5, 81%
C
MeO2
EtO2
C
F
Ts
Ts
Ts
Ts
N
N
N
N
Ph
Ph
9, 41%b
Ph
10, 47%b
Ph
11, 66%
8, 61%
Cl
Ts
Ts
Ts
Ts
Ts
N
N
N
N
Ts
Ts
Ph
Ph
13, 52%
Ph
14, 77%
R
Ph
Ph
Ph
Ph
N
N
12, 64%
15, 74%
Ph
Ph
Ph
S
Ts
Ts
1r
Ph
1s
N
N
(1)
Ts
Ph
Ph
N
FeCl3 (4 mol%)
BF3 Et2O (40 mol%)
CH2ClCH2Cl, 80 oC, Ar, 24 h
FeCl3 (4 mol%)
BF3 Et2O (40 mol%)
CH2ClCH2Cl, 80 oC, Ar, 24 h
N
2a
Ts
Ts
N
N
41, 0%
40, 0%
Ph
Ph
Ph
20, traceb
R = cPr, 18, 44b
LA
Ph
Ph
17, 50%b
Ph
16, 45%
R = nC6H13, 19, traceb
Formal [5+2] cycloaddition
via C-N bond cleavage
LA +
Ph
R
Ts
Ph
Ts
N
LA
N
2a
Ts
Ph
Ts
Ph
Ts
N
N
R5 = Me, 26, 69%
R5 = Br, 27, 60%
R5 = Cl, 28, 63%
N
R1 = Ph, 21, 73%
R1 = Et, 22, 61%b
=
nPr, 23, 53%b
Ph
Ph
LA
LA
Ts
N
LA
N
R1
R1
Ts
LA = FeCl3/BF3 Et2
O
Ph
R = Ph, 24, 80%
R = 3,5-diMeC6H3, 25, 64%
Ph
B
Ph
1a
Ph
Ph
3
A
Ph
R5
Ts
R
R
Ts
N
Scheme 4. Other pyrrole derivatives and possible mechanism.
Ph
Ph
Ts
N
N
Ts
Cl
Br
N
In summary, we have developed a general, highly effective ring-
opening/formal hetero-[5+2] cycloaddition protocol for selectively
accessing 2,3-dihydro-1H-azepines, in which two new chemical
bonds, namely a C(sp2)-N bond and a C(sp2)-C(sp2) bond, have been
formed smoothly by means of two non-precious FeCl3 and BF3·Et2O
double-activation catalysts. It is the first example of a Lewis acid co-
catalysed formal hetero-[5+2] cycloaddition reaction of 1-tosyl-2,3-
dihydro-1H-pyrroles (acting effectively as non-strained-ring-based
five-atom units) with terminal alkynes. In addition, the reaction
shows high selectivity and a broad scope. Studies on how to
selectively cleave of the C(sp2)-N bonds of 1-tosyl-2,3-dihydro-1H-
pyrroles and the utility of this formal hetero-[5+2] cycloaddition
strategy are underway in our laboratory.
Ph
Ph
Cl
R = Ph, 31, 57%
R = 4-ClC6H4, 32, 60%
R = Ph, 33, 68%
R = 4-BrC6H4, 34, 66%
Ph
30, 71%
Ph
29, 55%
Ph
Ph
Ph
Ts
H
N
Ts
N
R4
N
Ph
Ph
R4 = Ms, 37, 81%
R4 = Boc, 38, trace
R4 = H, 39, trace
Ph
N
Ph
Ph
Ph
35, 73%
40, trace
36, 77%
a
Reaction conditions: 1a (0.2 mmol), 2 (4 equiv), FeCl3 (4
mol%), BF3·Et2O (40 mol%), CH2ClCH2Cl (anhydrous; 2 mL),
argon, 80 C, and 24 h. AgSbF6 (30 mol%) instead of FeCl3 for
60 h
o
b
.
3 and 5 positions were tolerated (26-34). Notably, both halogen
atoms (e.g., Br, Cl) and the C=C bond were incorporated into the
resulting products (27-29, 31-34), which have potential for
substituent modification to access new azepine derivatives. A 1-
tosyl-2,3-dihydro-1H-pyrrole bearing three substituents, two phenyl
and a methyl group, was converted into pentasubstituted azepine
35 with a quaternary carbon centre. Interestingly, the reaction was
applicable to the construction of bicyclic compounds 36 and 37.
Employing 1-tosyl-3a,4,5,6,7,7a-hexahydro-1H-indole gave access to
six-membered-ring-fused azepine 36 in 77% yield. The 2,3-dihydro-
1H-pyrrole with N-Ms instead of N-Ts showed high reactivity (37),
but the corresponding pyrroles with N-Boc and free N-H did not
We thank the National Natural Science Foundation of China
(Nos. 21625203, 21871126 and 21602058) and the Opening Fund of
KLCBTCMR, Ministry of Education (Nos. KLCBTCMR18-02 and
KLCBTCMR201706) for financial support.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
For selected reviews, see: (a) Advances in Cycloaddition, JAI
Press, Greenwich, 1988-1999, Vols. 1-6; (b) N. E. Schore,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
Chem. Rev., 1988, 88, 1081; (c) W. Carruthers, in
Cycloaddition Reactions in Organic Synthesis, Pergamon,
Oxford, 1990; (d) B. M. Trost, Angew. Chem. Int. Ed. Engl.,
1995, 34, 259; (e) Cycloaddition Reactions in Organic
Synthesis, (Eds.: S. Kobayashi and K. A. Jørgensen), Wiley-
VCH, Weinheim, Germany, 2002; (f) N. Nishiwaki, Methods
and Applions of Cycloaddition Reactions in Organic Syntheses,
Wiley-VCH, Hoboken, 2014.
For selected reviews on cycloaddition with strain-ring-based
units, see: (a) R. I. Khusnutdinov and U. M. Dzhemilev, J.
Organomet. Chem., 1994, 471, 1; (b) G. Dyker, Angew. Chem.
Int. Ed. Engl., 1995, 34, 2223; (c) M. Harmata, Acc. Chem.
Res., 2001, 34, 595; (d) P. A. Wender, G. G. Gamber and T. J.
Williams in Modern Rhodium-Catalyzed Organic Reactions
(Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005, p. 263; (e) M.
A. Battiste, P. M. Pelphrey and D. L. Wright, Chem. Eur. J.,
2006, 12, 3438; (f) P. A. Wender, M. P. Croatt and N. M.
Deschamps, in Comprehensive Organometallic Chemistry III,
Vol. 10 (Eds.: R. H. Crabtree, D. M. P. Mingos), Elsevier,
Oxford, 2007, p. 603; (g) H. Butenschön, Angew. Chem. Int.
Ed., 2008, 47, 5287; (h) M. Harmata, Chem. Commun., 2010,
46, 8904; (i) A. G. Lohse and R. P. Hsung, Chem. Eur. J., 2011,
17, 3812; (j) K. Tanaka, Heterocycles, 2012, 85, 1017; (k) L.
Jiao, Z.-X. Yu, J. Org. Chem. 2013, 78, 6842; (l) Y. Gao, X.-F. Fu
and Z.-X. Yu, Top. Curr. Chem., 2014, 346, 195; (m) Y. Wang
and Z.-X. Yu, Acc. Chem. Res., 2015, 48, 2288.
For selected reviews on [5+2] cycloaddition, see: (a) H.
Pellissier, Adv. Synth. Catal., 2011, 353, 189; (b) K. E. O.
Ylijoki and J. M. Stryker, Chem. Rev., 2013, 113, 2244; (c) J.-J.
Feng and J. Zhang, ACS Catal., 2016, 6, 6651; (d) H. Pellissier,
Adv. Synth. Catal., 2018, 360, 1551; (e) K. Gao, Y.-G. Zhang,
Z.g Wang and H. Ding, Chem. Commun., 2019, 55, 1859.
(a) E. L. Stogryn and S. J. Brois, J. Am. Chem. Soc., 1967, 89,
605; (b) A. Hassner, R. D’Costa, A. T. McPhail and W. Butler,
Tetrahedron Lett., 1981, 22, 3691; (c) J.-J. Feng, T.-Y. Lin, C.-Z.
Zhu, H. Wang, H.-H. Wu and J. Zhang, J. Am. Chem. Soc.,
2016, 138, 2178; (d) C. Hu, R.-J. Song, M. Hu, Y. Yang, J.-H. Li
and S. Luo, Angew. Chem. Int. Ed., 2016, 55, 10423; (e) P. A.
Wender, T. M. Pedersen and M. J. C. Scanio, J. Am. Chem.
Soc., 2002, 124, 15154; (f) M. M. Montero-Campillo, E. M.
Cabaleiro-Lago and J. Ro-driguez-Otero, J. Phys. Chem. A,
2008, 112, 9068; (g) H. Matsunaga, M. Sonoda, Y. Tomika
and M. Yamazaki, Chem. Pharm. Bull., 1984, 32, 2596; (h) D.
Singh and H.-J. Ha, Org. Biomol. Chem., 2019, 17, 3093, and
references cited therein.
For representative papers on azepine synthesis via other
cycloaddition reactions, see: (a) D. J. Anderson and A.
Fiassner, J. Am. Chem. Soc., 1971, 93, 4339; (b) N. D. Shapiro
and F. D. Toste, J. Am. Chem. Soc., 2008, 130, 9244; (c) Y.
Karibe, H. Kusama and N. Iwasawa, Angew. Chem. Int. Ed.,
2012, 51, 6214; (d) L. Wang, J. Huang, S. Peng, H. Liu, X. Jiang
and J. Wang, Angew. Chem. Int. Ed., 2013, 52, 1768; (e) Z. Shi,
C. Grohmann, F. Glorius, Angew. Chem. Int. Ed., 2013, 52,
5393; (f) M.-B. Zhou, R.-J. Song, C.-Y. Wang and J.-H. Li,
Angew. Chem. Int. Ed., 2013, 52, 10805; (g) M.-B. Zhou, R.-J.
Song and J.-H. Li, Angew. Chem. Int. Ed., 2014, 53, 4196; (h) R.
Han, X.-R. Song, Y.-F. Qiu, H.-R. Zhang, L.-H. Li, D.-P. Jin, X.-Q.
View Article Online
Sun, X.-Y. Liu and Y.-M. Liang, Org. LetDt.O, I2: 0101.160,3198/C, 99C4C00; 5(q08)2YE.
Li, M. Hu and J.-H. Li, ACS Catalysis, 2017, 7, 6757; (r) J. Chen
and Y. Huang, Org. Lett., 2017, 19, 5609; (s) S. M. Thullen, D.
M. Rubush and T. Rovis, Synlett, 2017, 28, 2755; (t) Lu Bai, Y.
Wang, Y. Ge, J. Liu and X. Luan, Org. Lett., 2017, 19, 1734; (u)
B. Lang, H. Zhu, C. Wang, P. Lu and Y. Wang, Org. Lett., 2017,
19, 1630; (v) C.-Z. Zhu, J.-J. Feng and, J. Zhang, Angew. Chem.
Int. Ed., 2017, 56, 1351.
2
6
(a) T. Kametani and K. Fukumoto, Heterocycles, 1975, 3, 931;
(b) B. Renfroe, C. Harrington and G. R. Proctor, Heterocyclic
Compounds: Azepines , Wiley & Interscience, New York, 1984;
(c) C. R. Ganellin and, D. J. Triggle, Dictionary of
Pharmacological Agents, Chapman & Hall/CRC: London, 1996;
(d) J. J. Vaquero, A. M. Cuadro and B. Herradyn, Modern
Heterocyclic Chemistry, Wiley-VCH, Weinheim, 2011; (e) H.
Wang, S. N.Goodman, Q. Dai, G. W. Stockdale, W. M. and Jr.
Clark, Org. Process Res. Dev., 2008, 12, 226; (f) W. A. Kinney,
D. K. Luci, B. E. Marynoff, S. Ghosh and, E. C. Lawson,
Urotensin ii receptor antagonists, U.S. Patent 20100029616
A1, 2010; (g) W. T. Jewell, R. A. Hess and M. G. Miller, Appl.
Pharmacol., 1998, 149, 159; (h) L.-S. Gan, C.-Q. Fan, S.-P.
Yang, Y. Wu, L.-P. Lin, J. Ding and J.-M. Yue, Org. Lett., 2006,
8, 2285; (i) T. Luksch, N.-S. Chan, S. Brass, C. A. Sotriffer, G.
Klebe and W. E. Diederich, ChemMedChem, 2008, 3, 1323; (j)
B. Brem, C. Seger, P. Pacher, O. Hofer, S. Vajrodaya and H.
Greger, J. Agric. Food Chem., 2002, 50, 6383; (k) M.
Maruyama and K. Takeda, Comp. Biochem. Physiol., C:
Pharmacol., Toxicol. Endocrinol., 1994, 107C, 105.
A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633.
For selected examples on Lewis acid-catalyzed cleavage of C-
N bonds, see: (a) H. Nozaki, S. Fujita, H. Koide and T. Hiyama,
Tetrahedron, 1973, 29, 3137; (b) J. Legters, J. G. H. Willems, L.
Thijs and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1992,
111, 59; (c) S. C. Bergmeier, S. L. Fundy and P. P. Seth,
Tetrahedron, 1999, 55, 8025; (d) S. C. Bergmeier, S. J. Katz, J.
Huang, H. McPherson, P. J. Donoghue and D. D. Reed,
Tetrahedron Lett., 2004, 45, 5011; (e) R. J. Madhushaw, C.-C.
Hu and R.-S. Liu, Org. Lett., 2002, 4, 4151; (f) M. Nakagawa
and M. Kawahara, Org. Lett., 2000, 2, 953; (g) J. Fan, L. Gao
and Z. Wang, Chem. Commun., 2009, 5021; (h) B. D. Narhe, V.
Sriramurthy and V. K. Yadav, Org. Biomol. Chem., 2012, 10,
4390; (i) M.-G. Zhou, W.-Z. Zhang and S.-K. Tian, Chem.
Commun., 2014, 50, 14531; (j) S. R. Pathipati, V. Singh, L.
Eriksson and N. Selander, Org. Lett., 2015, 17, 4506; (k) F.
Zhou, E. Zhao,, Z. Yan, D. Chen and Y. Zhao, Tetrahedron Lett.,
2018, 59, 1871; (l) H. Li, S. Huang, Y. Wang, and C. Huo, Org.
Lett., 2018, 20, 92; (m) J. Cen, J. Li, Y. Zhang, Z. Zhu, S. Yang
and H. Jiang, Org. Lett., 2018, 20, 4434; (n) P. Dauban and G.
Malik, Angew. Chem. Int. Ed., 2009, 48, 9026; (o) J.-J. Feng
and J. Zhang, ACS Catal., 2016, 6, 6651; (p) A. L. Cardoso and
T. M. V. D. Pinho e Melo, Eur. J. Org. Chem., 2012, 6479.
CCDC 1867336 (3) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3
4
7
8
5
9
Shenje, M. C. Martin and S. France, Angew. Chem. Int. Ed., 10 M.-C. Chung, Y.-H. Chan, W.-J. Chang and D.-R. Hou, Org.
2014, 53, 13907; (i) A. Seoane, N. Casanova, N. Quiñones, J. L.
Mascareñas and M. Gulías, J. Am. Chem. Soc., 2014, 136, 834;
(j) D. J. Lee, H. S. Han, J. Shin and E. J. Yoo, J. Am. Chem. Soc.,
2014, 136, 11606; (k) Y. Yang, M.-B. Zhou, X.-H. Ouyang, R. Pi,
R.-J. Song and J.-H. Li, Angew. Chem. Int. Ed., 2015, 54, 6595;
(l) J.-J. Feng, T.-Y. Lin, H.-H. Wu and J. Zhang, Angew. Chem.
Int. Ed., 2015, 54, 15854; (m) J.-J. Feng, T.-Y. Lin, H.-H. Wu
and, J. Zhang, J. Am. Chem. Soc., 2015, 137, 3787; (n) Z. Zuo,
J. Liu, J. Nan, L. Fan, W. Sun, Y. Wang and X. Luan, Angew.
Chem. Int. Ed., 2015, 54, 15385; (o) T. Li, F. Xu, X. Li, C. Wang
and B. Wan, Angew. Chem. Int. Ed., 2016, 55, 2861; (p) Y.-P.
Biomol. Chem., 2017, 15, 3783.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins