Hypervalent-Iodine(III)-Mediated Tandem Oxidative Dearomatization/Aziridination of Phenolic Amines: Synthesis of Functionalized Unactivated Aziridines

Article abstract of DOI:10.1002/chem.202100762

A new hypervalent-iodine(III)-mediated tandem reaction involving oxidative dearomatization and in situ aziridination of phenolic amines is described, providing a mild and effective method for the assembly of structurally interesting and synthetically usef

Full text of DOI:10.1002/chem.202100762

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
Hypervalent-Iodine(III)-Mediated Tandem Oxidative
Dearomatization/Aziridination of Phenolic Amines:
Synthesis of Functionalized Unactivated Aziridines
Ye-Xing Cao,[a] Patamawadee Silalai,[b] Chun-Fang Liu,[a] Ke-Yin Yu,[a] Xu Bao,[a]
Xian-He Zhao,[a] Rungnapha Saeeng,[b] and Chun-An Fan*[a]
Abstract: A new hypervalent-iodine(III)-mediated tandem
reaction involving oxidative dearomatization and in situ
aziridination of phenolic amines is described, providing a
mild and effective method for the assembly of structurally
interesting and synthetically useful aziridines. Importantly,
the densely functionalized aziridines resulting from this
unprecedented tandem reaction offer
a platform for
expeditious access to architecturally diverse aza-hetero-
cycles through transformations initiated by selective ring-
opening of aziridines.
Aziridines are a class of nitrogen-functionalized heterocyclic
compounds consisting of strained three-membered ring system
in organic chemistry.[1] Chemically, the aziridine units not only
widely exist in many natural products and drugs (e.g.,
azinomycin A, miraziridine A, and FR-900482),[1b] but also
constitute versatile building blocks for synthesizing a variety of
bioactive compounds (e.g., β-lactams, pyrrolizidines, and
tetrahydropyridines).[2] Due to the diverse reactivity arising from
the intrinsic strain of aziridine moieties, the development of
aziridination methodologies has received considerable atten-
tions in the synthetic community.[1,2] As was known, “C2+N1”
addition[1,3] employing alkenes and nitrogen sources represents
one of the most general approaches toward the construction of
aziridines. Among previous reports, several types of nitrogen-
based 1,1-dipole synthon equivalents such as azides,[4]
iminoiodinanes,[5] sulfilimines,[6] haloamine-T[7] and hydroxyl-
amine derivatives[8] (route 1, Scheme 1a) have been extensively
used in the chemistry of aziridination. Alternative methods
resulting from in situ formation of nitrenoids or nitrenoid-type
Scheme 1. Previous methods for the synthesis of aziridines and our design.
species by using electronically deficient amine derivatives (e.g.,
carbamates,[9] sulfonamides,[10] and hydrazides;[11] route 2,
Scheme 1a) in the presence of oxidants (e.g., iodine(III) and lead
(IV)) have also provided access to the aziridines. Despite much
progress in the synthesis of aziridines, the direct aziridination of
alkenes through in situ oxidation of aliphatic primary amines
has rarely been explored from a methodologic point of view
(route 3, Scheme 1a).[12] Combining this with the challenge of
straightforward azridination using primary amines as well as the
significant impact of oxidative phenol dearomatization to the
organic synthesis,[13] we recently have designed a new tandem
oxidative dearomatization/aziridination reaction of phenolic
amines A in the presence of hypervalent-iodine(III) (Scheme 1b),
thus providing an effective method for the expeditious
[a] Y.-X. Cao, C.-F. Liu, K.-Y. Yu, Prof. Dr. X. Bao, Dr. X.-H. Zhao, Prof. Dr. C.-
A. Fan
State Key Laboratory of Applied OrganicChemistry
College of Chemistry and Chemical Engineering
Lanzhou University
222 Tianshui Nanlu, Lanzhou 730000 (P. R. China)
E-mail: fanchunan@lzu.edu.cn
construction of unactivated polycyclic aziridines
B highly
functionalized with an olefinic moiety and an ortho-diketone
monoketal unit. Herein, we report our results.
The model reaction using the phenolic amine 1a (Table 1),
which was readily derived from isovanillin, was initially inves-
tigated in the presence of iodobenzene diacetate as oxidant
[b] P. Silalai, Prof. Dr. R. Saeeng
Department of Chemistry and Center for Innovation in Chemistry, Faculty of
Science
Burapha University
Chonburi 20131 (Thailand)
°
and MeOH as solvent at 0 C. Along with the quick disappear-
ance of 1a, the title reaction involving the oxidation of phenol
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100762
moiety and amino group led to the formation of the structurally
Chem. Eur. J. 2021, 27, 1–7
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
Table 1. The optimization of reaction conditions.[a,b]
Entry
Oxidant
R
Additive
Product
Yield
32%
1
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
PhI(CF3CO2)2
DMP
IBX
PhI(OAc)2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
–
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b”
2[d]
3[d]
4
Na2CO3
NaHCO3
HOAc
CF3CO2H
4-MeC6H4SO3H·H2O
Me3SiCl/MeOH
4-MeC6H4SO3H·H2O
4-MeC6H4SO3H·H2O
4-MeC6H4SO3H·H2O
4-MeC6H4SO3H·H2O
4-MeC6H4SO3H·H2O
4-MeC6H4SO3H·H2O
–
[e]
8%[e]
63%
71%
73%
70%
55%
67%
5
6
7
8
9
[f]
10
11
12
13
–
[f]
–
56% (1:1 dr)
[f]
PhI(OAc)2
iPr
–
[a] Unless otherwise noted, the reaction was performed with 1a (0.2 mmol) in the presence of additive (0.22 mmol) and PhI(OAc)2 (0.42 mmol) in MeOH
°
(2.0 mL) at 0 C. After 25 min, the reaction mixture was diluted with EtOAc (2.0 mL) and quenched with saturated aqueous solution of NaHCO3, and then
stirred for 10 min. [b] Yield of isolated product. [c] The stereochemistry of β-2a-a as major product was determined by X-ray crystallographic analysis [d]
Diluted with EtOAc (2.0 mL) and extracted directly. [e] The starting material disappeared completely, and several unidentified by-products were observed. [f]
No desired product was isolated from the complex reaction mixture. DMP=Dess-Martin periodinane, IBX=o-iodoxybenzoic acid.
interesting 5,3,6-tricyclic aziridine 2a, but in a low yield of 32%
(entry 1), and its relative configuration was unambiguously
determined by X-ray crystallographic analysis of β-2a-a result-
ing from the diastereoselective reduction of 2a.[14] Considering
the chemoselectivity between the phenol motif and the amino
unit in model substrate 1a, some additives were introduced to
probe the potential influence of the pH value of reaction system
(entries 2–7). Inorganic bases (e.g., Na2CO3, and NaHCO3), which
could neutralize the HOAc generated in situ from the oxidation
mediated by PhI(OAc)2, gave a complicated reaction mixture
(entries 2 and 3), showing the fact that the acidic medium
might be important to the oxidative dearomatization and
aziridination. In contrast to the results using basic additives
(entries 2 and 3), the employment of a stoichiometric amount
of HOAc as acidic additive afforded an improved reaction yield
of 63% (entry 4). Pleasingly, the increased acidity of organic
additives (CF3CO2H, and TsOH·H2O) could give a positive
contribution to the reaction yield (entries 5 and 6), in which
employing p-toluenesulfonic acid as additive obtained the
optimal yield of 73% (entry 6). Notably, using the stronger
inorganic acid HCl in situ formed from TMSCl and MeOH could
not further improve the reaction efficiency and only resulted in
an analogous yield of 70% (entry 7).
ability (Dess-Martin periodinane, and o-iodoxybenzoic acid) led
to unidentified complex mixture (entries 10 and 11). Following
the screening mentioned above, the solvent acting as nucleo-
phile in this oxidative dearomatization was also probed
(entries 12 and 13). In addition to MeOH as solvent (entry 6),
EtOH was suitable for this model reaction to deliver the
aziridine 2b albeit in a decreased yield of 56% (entry 12). But
the bulkier iPrOH failed to the formation of the desired aziridine
2b’’ (entry 13), demonstrating the unfavorable steric influence
of nucleophilic entity in this dearomative transformation.
With the optimized conditions in hand, as shown in Table 2,
the substrate scope of tandem oxidative dearomatization/
aziridination reaction was investigated. According to the
topological connection of the phenol unit and the amino-
containing substituent in 1, a series of meta-phenolic amines
(1a–1m) having primary amino pendant group at β position of
phenolic core were firstly considered. Compared with the result
using model substrate 1a (R1 =Me, entry 1), phenolic amine 1b
bearing a slight increased bulkiness of α’-ethoxy group (R1 =Et,
entry 3) yielded the aziridine 2b with 1:1 dr, but in a somewhat
decreased yield of 62%. When substrates with γ-substituent
group, 1c (R2 =γ-prenyl, entry 4) and 1d (R2 =γ-Br, entry 5),
were subjected to the standard conditions, the expected
functionalized aziridines 2c and 2d could be obtained in 48%
and 67% yields, respectively. In contrast to the case using 1d
with γ-bromo group (R2 =γ-Br, entry 5), the employment of 1e
with α-bromo group (R2 =α-Br, entry 6) could not deliver the
desired product 2e, mostly due to the instability of the bromo
aziridine 2e, which was chemically confirmed by the formation
of unexpected tetrahydroquinoline 2e-a[15] through in situ one-
pot reduction of 2e and its subsequent elimination and
Based on the current optimization of additives (entries 2–7,
Table 1), a series of hypervalent iodine reagents were evaluated
in the presence of TsOH·H2O as additive and MeOH as solvent
°
at 0 C (entries 8–11). Among these oxidants, iodine(III) reagents
(PhIO, and PhI(CF3CO2)2) were compatible with the current
transformation, but the decreased yields of desired aziridine 2a
were obtained (55% and 67%, entries 8 and 9). In contrast to
these results, iodine(V) reagents having stronger oxidation
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
Table 2. The generality for tandem oxidative dearomatization/aziridination reaction.[a,b]
Entry
Substrate
Product
Yield
Entry
Substrate
Product
Yield
1
2
3
1a (R1 =Me)
1b (R1 =Et)
2a
73%
69%
62% (1:1 dr)
10
11
1i (R3 =H)
1j (R3 =Br)
2i
2j
69%
55%
2a (gram scale)
2b
4
5
6
1c (R2 =γ-prenyl)
1d (R2 =γ-Br)
1e (R2 =α-Br)
2c (R2a =prenyl), R2b =H)
2d (R2a =Br, R2b =H)
2e (R2a =H, R2b =Br)
48%
12
13
1k (X=O)
1l (X=NTs)
2k
2l
52%
58%
67%
[c]
7
8
1f
2f
45%
42%
14
15
1m
1n
2m
2n
51%
39%
1g
2g
9
1h
2h
65% (1:1 dr)
16
1o
2o
77%
[a] Unless otherwise noted, the reaction was performed with 1 (0.2 mmol) in the presence of additive (0.22 mmol) and PhI(OAc)2 (0.42 mmol) in MeOH
°
(2.0 mL) at 0 C. After 25 min, the reaction mixture was diluted with EtOAc (2.0 mL) and quenched with saturated aqueous solution of NaHCO3 (2.0 mL), and
then stirred for 10 min. [b] Yield of isolated product. [c] For details, see ref. [15].
aromatization. Two examples employing phenolic amines 1f
and 1g with β’,γ-disubstituted subunit smoothly afforded the
architecturally interesting 5,3,6,6-tetracyclic aziridines 2f (en-
try 7) and 2g (entry 8) in 45% and 42% yield, respectively.
Following the structural evaluation of substituents at α, γ,
α’, β’-position of phenol unit in 1a–1g, the influence of amino-
containing pendant group at β position of phenolic core was
probed subsequently. The phenolic amine 1h (entry 9, Table 2)
having a remote ester group substituted on the propylamino
side chain was suitable to this cascade transformation to
provide the corresponding 5,3,6-tricyclic product 2h in 1:1 dr
and 65% yield, wherein the potentially competitive lactoniza-
tion of the ester group was not observed during this oxidative
reaction involving subsequent aziridination. Upon treatment of
meta-phenolic amines (1i and 1j) bearing the butylamino
substituent with identical conditions, the synthetically interest-
ing 6,3,6-tricyclic aziridines 2i and 2j could be accessed in 69%
and 55% yields (entries 10 and 11), respectively. While using
the substrates (1k and 1l) with oxygen and nitrogen-containing
amino side chains, the 6,3,6-tricyclic aziridines 2k bearing the
morpholine moiety and 2l bearing the piperazine motif could
be analogously achieved in moderate yields of 52% and 58%
(entries 12 and 13), respectively. Meanwhile, the substrate 1m
containing the benzylamine subunit was also tested for this
reaction, and the 6,6,3,6-tetracyclic aziridine 2m comprising the
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
tetrahydroisoquinoline moiety was readily afforded in 51% yield
(entry 14).
In addition to the cases employing meta-phenolic amines
(1a–1m), ortho-phenolic amine 1n with primary amino pendant
group at α position of phenolic core (entry 15, Table 2) was
subjected to present tandem oxidative dearomatization/aziridi-
nation reaction, and pleasingly the structurally rigid 5,3,6-
tricyclic aziridine 2n was delivered, albeit in 39% yield. More-
over, one example using para-phenolic amine 1o with primary
amino pendant substituent at γ position of phenolic core
(entry 16) was also conducted, and interestingly this case led to
the formation of structurally unique 7,3,6-tricyclic aziridine 2o
bearing a bridgehead double bond in good yield of 77%. To
explore the synthetic utility of this protocol, a gram-scale
reaction of 1a was performed by using finely ground PhI(OAc)2
to afford tricyclic aziridine 2a with analogous efficiency in 69%
yield (entry 2). In an attempt to increase the structural diversity
of functionalized aziridines, as shown in Scheme 2, tandem
oxidative aziridination involving p-quinone monoketal inter-
mediate was investigated,[16] and the reaction of meta-phenolic
amine 1p having γ-methoxy instead of α’-methoxy in 1a under
the standard conditions resulted in the formation of sterically
congested, chemically unstable homoallylic aziridine 2p, which
was reduced in situ to give the hydroxy-aziridine 2p-a in 58%
yield and 4:1 dr. Structurally, the stereochemistry of β-2p-a as
major isomer was clearly assigned by X-ray crystallographic
analysis.[14]
Chemically inspired by the synthetic importance of vinyl
aziridine substructure[1b] embedded in the products resulting
from tandem oxidative dearomatization/aziridination, as shown
in Scheme 3, several transformations initiated by SN2 and SN2’
ring opening were explored. Upon the reduction of 2a with
°
NaBH4 at À 78 C, the chromatographically separable hydroxy-
aziridine β-2a-a as major isomer could be obtained in 68%
yield, and its stereochemistry was characterized by X-ray
crystallographic analysis.[14] The regioselective SN2 ring opening
of aziridine β-2a-a was achieved by using MeOH as nucleophile
at room temperature under a balloon pressure of CO2,[17] giving
the functionalized octahydroquinoline 3a in 96% yield (entry 1,
Scheme 3. Synthetic transformations starting from 2a and 2o.
Scheme 3), which could not be accessed by the related control
Scheme 3) was subsequently examined under 40 atm of CO2 at
[18]
°
°
experiment (MeOH, 25 C) in the absence of CO2. To explore
50 C, the CO2 insertion carbonate 4b (71% yield) as major
the possibility of insertion mediated by CO2, the increased
pressure of CO2 (40 atm) was introduced to the ring opening of
product followed the formation of minor 3b (23% yield) could
be afforded in this case, showing unfavorable effect of the steric
hindrance of alcoholic nucleophile to the direct competitive SN2
ring opening of alcohols. Significantly, using the bulkier iPrOH
(entry 4, Scheme 3) led to the predominant formation of the
allylic carbonate 4c having the octahydroquinoline framework
in 50% yield (95% yield based on the recovery of starting
material).
°
β-2a-a in MeOH at 25 C, and pleasingly the formation of CO2
insertion carbonate 4a (15% yield) as minor product accom-
panied by the major 3a (83% yield) was observed (entry 2,
Scheme 3). While the sterically increased EtOH (entry 3,
Interestingly, the aziridine β-2a-a was subjected to the
classic elimination conditions using Burgess reagent,[19] and a
cage-like polycyclic sulfamide 5a was obtained in 45% yield via
a transannular (5+2) annulation involving SN2’ ring opening of
vinyl aziridine, to some extent demonstrating the unique
reactivity of tricyclic vinyl aziridine β-2a-a and the first example
of (5+2) annulation between vinyl aziridine and Burgess
reagent. Besides, SmI2-mediated SET reduction of β-2a-a
Scheme 2. Tandem oxidative aziridination involving p-quinone monoketal.
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
[1] For selected general reviews on the chemistry of aziridines, see: a) J. B.
Sweeney, Chem. Soc. Rev. 2002, 31, 247; b) Aziridines and Epoxides in
Organic Synthesis (Ed.: A. K. Yudin), Wiley-VCH, Weinheim, 2006; c) G. S.
Singh in Advances in Heterocyclic Chemistry, Vol. 129 (Eds.: E. F. V.
Scriven, C. A. Ramsden), Academic Press, San Diego, 2019, Chapter 4,
pp. 245–335.
[2] For selected reviews on the synthetic utility of aziridines, see: a) X. E.
Hu, Tetrahedron 2004, 60, 2701; b) G. S. Singh, M. D’hooghe, N.
De Kimpe, Chem. Rev. 2007, 107, 2080; c) P. Lu, Tetrahedron 2010, 66,
2549; d) S. Florio, R. Luisi, Chem. Rev. 2010, 110, 5128; e) C. Botuha, F.
Chemla, F. Ferreira, A. Pérez-Luna in Heterocycles in Natural Product
Synthesis (Eds.: K. C. Majumdar, S. K. Chattopadhyay), Wiley-VCH,
Weinheim, 2011, Chapter 1, pp. 3–39; f) S. Stanković, M. D’hooghe, S.
Catak, H. Eum, M. Waroquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha,
Chem. Soc. Rev. 2012, 41, 643; g) G. Callebaut, T. Meiresonne, N.
De Kimpe, S. Mangelinckx, Chem. Rev. 2014, 114, 7954; h) S. Sabir, G.
Kumar, J. L. Jat, Asian J. Org. Chem. 2017, 6, 782.
followed by N-sulfamidation delivered the densely functional-
ized bicyclic diene 6 in 72% yield, which could not be accessed
efficiently by other known methods. Upon treatment of diene 6
°
with N-Ph maleimide at 120 C, structurally complicated
tetracyclic (4+2) cycloadduct 7 could be constructed via endo-
selectivity in 89% yield. Moreover, an additional example using
7,3,6-tricyclic aziridine 2o bearing the bridgehead double-bond
was also carried out for its synthetic transformation. Under
°
hydrogenation conditions (Pd/C, H2 (balloon), THF, 25 C), a
chemoselective allylic cleavage of vinyl aziridine 2o gave α-
amino ketone 8a having an azabicyclo[5.3.1]undecane skeleton
through SN2-type reductive ring-opening. Importantly, the
unexpected lability of 8a during its chromatographic purifica-
tion and recrystallization disclosed an interesting observation
that α-amino ketone unit in 8a could partially undergo an
insertion reaction with CO2 in air, affording the tricyclic 2-
oxazolidone-hemiketal 8b.[20] Based on this serendipitous result,
a combined protocol involving hydrogenation (Pd/C, H2, THF),
carbamation (CO2, THF), and deketalization (HBF4, THF) was
then adopted to directly access to 5,6,8-tricyclic 9 bearing a
unique bridgehead double bond in 57% yield in one pot.
Notably, all relative configurations of N-(4-BrC6H4SO2)-3a, 4b,
5a, 7, 8b, and 9 resulting from the above transformations have
been confirmed by X-ray crystallographic analyses.[14]
[3] For recent reviews on the synthesis of aziridines, see: a) H. Pellissier,
Tetrahedron 2010, 66, 1509; b) J. W. W. Chang, T. M. U. Ton, P. W. H.
Chan, Chem. Rec. 2011, 11, 331; c) D. Karila, R. H. Dodd, Curr. Org. Chem.
2011, 15, 1507; d) L. Degennaro, P. Trinchera, R. Luisi, Chem. Rev. 2014,
114, 7881.
[4] For selected examples involving azides, see: a) A. L. Logothetis, J. Am.
Chem. Soc. 1965, 87, 749; b) H. Kwart, A. A. Khan, J. Am. Chem. Soc.
1967, 89, 1951; c) A. Mishra, S. N. Rice, W. Lwowski, J. Org. Chem. 1968,
33, 481; d) J. T. Groves, T. Takahashi, J. Am. Chem. Soc. 1983, 105, 2073;
e) S. A. Cramer, D. M. Jenkins, J. Am. Chem. Soc. 2011, 133, 19342; f) E. C.
McLaughlin, A. Shrestha, M. H. Fletcher, N. S. Steinauer, M. K. Shinn,
S. M. Shahid, Tetrahedron Lett. 2013, 54, 5461; g) S. O. Scholz, E. P.
Farney, S. Kim, D. M. Bates, T. P. Yoon, Angew. Chem. Int. Ed. 2016, 55,
2239; Angew. Chem. 2016, 128, 2279; h) H. Jiang, K. Lang, H. Lu, L.
Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2017, 139, 9164; i) C. L. Keller, J. L.
Kern, B. D. Terry, S. Roy, D. M. Jenkins, Chem. Commun. 2018, 54, 1429;
j) Y. Zhang, X. Dong, Y. Wu, G. Li, H. Lu, Org. Lett. 2018, 20, 4838.
[5] For selected examples involving iminoiodinanes, see: a) D. Mansuy, J.-P.
Mahy, A. Dureault, G. Bedi, P. Battioni, J. Chem. Soc., Chem. Commun.
1984, 20, 1161; b) L. Ma, D.-M. Du, J. Xu, J. Org. Chem. 2005, 70, 10155;
c) S. K.-Y. Leung, W.-M. Tsui, J.-S. Huang, C.-M. Che, J.-L. Liang, N. Zhu, J.
Am. Chem. Soc. 2005, 127, 16629; d) M. Nakanishi, A.-F. Salit, C. Bolm,
Adv. Synth. Catal. 2008, 350, 1835; e) J. Llaveria, Á. Beltrán, W. M. C.
Sameera, A. Locati, M. M. Díaz-Requejo, M. I. Matheu, S. Castillón, F.
Maseras, P. J. Pérez, J. Am. Chem. Soc. 2014, 136, 5342.
[6] For selected examples involving sulfilimines, see: a) Y. Hayashi, D.
Swern, Tetrahedron Lett. 1972, 13, 1921; b) N. Furukawa, M. Fukumura,
T. Nishio, S. Oae, J. Chem. Soc., Perkin Trans. 1 1977, 96; c) T. Fujita, T.
Maeda, B. J. Kim, A. Tatami, D. Miyamoto, H. Kawaguchi, N. Tsuchiya, M.
Yoshida, W. Kawashima, H. Morita, J. Sulfur Chem. 2008, 29, 459; d) V.
Desikan, Y. Liu, J. P. Toscano, W. S. Jenks, J. Org. Chem. 2008, 73, 4398.
[7] For selected examples involving haloamine-T, see: a) T. Ando, S.
Minakata, I. Ryu, M. Komatsu, Tetrahedron Lett. 1998, 39, 309; b) R. Vyas,
B. M. Chanda, A. V. Bedekar, Tetrahedron Lett. 1998, 39, 4715; c) D. P.
Albone, P. S. Aujla, P. C. Taylor, J. Org. Chem. 1998, 63, 9569; d) A. M. M.
Antunes, S. J. L. Marto, P. S. Branco, S. Prabhakar, A. M. Lobo, Chem.
Commun. 2001, 37, 405; e) K. A. Kumar, K. M. L. Rai, K. B. Umesha,
Tetrahedron 2001, 57, 6993.
In conclusion, an unprecedented hypervalent iodine(III)-
mediated tandem oxidative dearomatization/aziridination reac-
tion of phenolic amines has been developed for the first time,
providing
a new method for the effective synthesis of
structurally diverse functionalized unactivated aziridines. Based
on this cascade methodology, several protocols initiated by
regioselective ring opening of vinyl aziridines have been
representatively shown to efficiently lead to synthetically
versatile nitrogen-containing heterocycles; the related trans-
formations, particularly involving the incorporation of CO2 and
Burgess reagent, have been exploited for their synthetic
potential. The present tandem reaction consisting of the
oxidative dearomatization of phenols and the aziridination of
aliphatic primary amines not only enriches the synthetic
chemistry of functionalized aziridines, but also expands syn-
thetic application of the hypervalent iodine chemistry.
[8] For selected examples involving hydroxylamine derivatives, see: a) W.
Lwowski, T. J. Maricich, J. Am. Chem. Soc. 1965, 87, 3630; b) J. C. Bottaro,
J. Chem. Soc., Chem. Commun. 1980, 16, 560; c) G. Cerichelli, A. Freddi,
M. A. Loreto, L. Pellacani, P. A. Tardella, Tetrahedron 1992, 48. 2495;
d) M. Barani, S. Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella,
Tetrahedron 1994, 50, 3829; e) A. Armstrong, C. A. Baxter, S. G. Lamont,
A. R. Pape, R. Wincewicz, Org. Lett. 2007, 9, 351; f) H. Lebel, C. Spitz, O.
Leogane, C. Trudel, M. Parmentier, Org. Lett. 2011, 13, 5460; g) J. L. Jat,
M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D. Devarajan, D. H. Ess,
L. Kürti, J. R. Falck, Science 2014, 343, 61; h) Z. Ma, Z. Zhou, L. Kürti,
Angew. Chem. Int. Ed. 2017, 56, 9886; Angew. Chem. 2017, 129, 10018;
i) J. J. Farndon, T. A. Young, J. F. Bower, J. Am. Chem. Soc. 2018, 140,
17846.
[9] For selected examples involving carbamates, see: a) C. J. Hayes, P. W.
Beavis, L. A. Humphries, Chem. Commun. 2006, 42, 4501; b) J. W. Rigoli,
L. A. Boralsky, J. C. Hershberger, D. Marston, A. R. Meis, I. A. Guzei, J. M.
Schomaker, J. Org. Chem. 2012, 77, 2446.
[10] For selected examples involving sulfonamides, see: a) P. Dauban, L.
Sanière, A. Tarrade, R. H. Dodd, J. Am. Chem. Soc. 2001, 123, 7707; b) K.
Guthikonda, J. Du Bois, J. Am. Chem. Soc. 2002, 124, 13672; c) S.
Acknowledgements
We are grateful for financial support from NSFC (21825104,
22071091, 21801103, 22001104), FRFCU (lzujbky-2020-40),
PCSIRT (IRT_15R28), and the 111 Project of MOE (111-2-17).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Aziridines · cascade reactions · dearomatization ·
iodine · oxidation
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202100762
Chemistry—A European Journal
Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Chem. Commun. 2006,
42, 3337.
Centre and Fachinformationszentrum Karlsruhe Access Structures
service www.ccdc.cam.ac.uk/structures.
[15] The tetrahydroquinoline 2e-a was obtained from one-pot in situ
[11] For selected examples involving hydrazides, see: a) R. S. Atkinson, C. W.
Rees, J. Chem. Soc. C 1969, 772; b) D. J. Anderson, T. L. Gilchrist, D. C.
HorweII, C. W. Rees, J. Chem. Soc. C 1970, 576; c) J. Li, J.-L. Liang, P. W. H.
Chan, C.-M. Che, Tetrahedron Lett. 2002, 45, 2685; d) J. Li, P. W. H. Chan,
C.-M. Che, Org. Lett. 2005, 7, 5801; e) R. D. Richardson, M. Desaize, T.
Wirth, Chem. Eur. J. 2007, 13, 6745.
reductions.
[12] There is no general methodology for aziridination of alkenes with
aliphatic primary amines under chemical oxidative conditions. For
special intramolecular cases, see: a) W. Nagata, S. Hirai, K. Kawata, T.
Aoki, J. Am. Chem. Soc. 1967, 89, 5045; b) P. S. Portoghese, D. T. Sepp,
Tetrahedron 1973, 29, 2253; c) S. Takano, K. Inomata, T. Sato, M.
Takahashi, K. Ogasawara, J. Chem. Soc., Chem. Commun. 1990, 26, 290;
d) A. Roy, F. G. Roberts, P. R. Wilderman, K. Zhou, R. J. Peters, R. M.
Coates, J. Am. Chem. Soc. 2007, 129, 12453; e) R.-H. Mei, Z.-G. Liu, H.
Cheng, L. Xu, F.-P. Wang, Org. Lett. 2013, 15, 2206; f) Z.-G. Liu, H. Cheng,
M.-J. Ge, L. Xu, F.-P. Wang, Tetrahedron 2013, 69, 5431.
[13] For reviews on oxidative phenol dearomatization, see: a) H. Tohma, Y.
Kita, Top. Curr. Chem. 2003, 224, 209; b) S. Quideau, L. Pouységu, D.
Deffieux, Synlett 2008, 19, 467; c) L. Pouységu, D. Deffieux, S. Quideau,
Tetrahedron 2010, 66, 2235; d) S. K. Jackson, K.-L. Wu, T. R. R. Pettus in
Biomimetic Organic Synthesis (Eds.: E. Poupon, B. Nay), Wiley-VCH,
Weinheim, 2011, Chapter 20, pp. 723–749; e) S. P. Roche, J. A. Porco Jr,
Angew. Chem. Int. Ed. 2011, 50, 4068; Angew. Chem. 2011, 123, 4154;
f) S. Quideau, L. Pouységu, P. A. Peixoto, D. Deffieux, Top. Curr. Chem.
2016, 373, 25; g) W.-T. Wu, L. Zhang, S.-L. You, Chem. Soc. Rev. 2016, 45,
1570.
[16] para-Cyclohexadienone intermediates resulting from PhI(OAc)2-medi-
ated dearomatization of dihalogenated phenols having
a lateral
Fukuyama sulfonamide have been pioneered very recently in an
arylative aziridination process, see: K. Signo, E. Deruer, S. Coulibali, S.
Canesi, Heterocycles 2021, https://doi.org/10.3987/COM-20-S(K)44.
[17] For selected reviews, see: a) Carbon Dioxide as Chemical Feedstock (Ed.:
M. Aresta), Wiley-VCH, Weinheim, 2010; b) T. Sakakura, J.-C. Choi, H.
Yasuda, Chem. Rev. 2007, 107, 2365; c) C. Martín, G. Fiorani, A. W. Kleij,
ACS Catal. 2015, 5, 1353; d) Q.-W. Song, Z.-H. Zhou, L.-N. He, Green
Chem. 2017, 19, 3707; e) S. Wang, C. Xi, Chem. Soc. Rev. 2019, 48, 382.
[18] For details on the conditions’ optimization of CO2-mediated ring
opening reaction, see the Supporting Information.
[19] For selected reviews, see: a) K. C. Nicolaou, S. A. Snyder, D. A. Long-
bottom, A. Z. Nalbandian, X. Huang, Chem. Eur. J. 2004, 10, 5581;
b) M. M. Heravi, T. Ahmadi, A. Fazeli, N. M. Kalkhorani, Curr. Org. Synth.
2015, 12, 328.
[20] For details of the CO2 insertion, see the Supporting Information.
[14] Deposition numbers 2033467 (for β-2a-a), 2033468 (for β-2p-a),
2033470 (for N-(4-BrC6H4SO2)-3a), 2033469 (for 4b), 2033471 (for 5a),
2033472 (for 7), 2033473 (for 9), and 2063689 (for 8b) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic Data
Manuscript received: March 2, 2021
Accepted manuscript online: April 12, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATION
Y.-X. Cao, P. Silalai, C.-F. Liu, K.-Y. Yu,
Prof. Dr. X. Bao, Dr. X.-H. Zhao,
Prof. Dr. R. Saeeng, Prof. Dr. C.-A. Fan*
1 – 7
Hypervalent-Iodine(III)-Mediated
Tandem Oxidative Dearomatization/
Aziridination of Phenolic Amines:
Synthesis of Functionalized Unacti-
vated Aziridines
An unprecedented tandem reaction
(oxidative dearomatization/aziridina-
tion) of phenolic amines in the
presence of hypervalent-iodine(III)
reagent is described. This cascade
reaction shows a chemical unification
of the oxidative reactivity of phenol
and aliphatic primary amine in the
chemistry of dearomatization and azir-
idination, thus providing a new
method for the synthesis of unacti-
vated aziridines with dense function-
alization.