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Metal-free anomalous [5+1] cycloaddition

reactions of donor–acceptor aziridines for the
Cite this: Chem. Commun., 2023,
59, 8572 synthesis of 2H-1,4-oxazines†
Received 5th May 2023,
Accepted 13th June 2023 Jianfeng Zheng, *a Jingzhi Bi,a Lan Ma,a Lvli Chen,a Luhao Tang,a Dong Xionga
and Yin Tian b
DOI: 10.1039/d3cc02193a

rsc.li/chemcomm

A new type of metal-free [5+1] cycloaddition reaction of donor– asymmetric allylic substitution reaction16 and Ag-catalyzed [3+3]-
acceptor aziridines with 2-(2-isocyanoethyl)indoles is reported cycloaddition of N-tosylaziridines17 (Scheme 1). Unfortunately, tran-
herein. This method exhibits broad substrate scope and atom- sition metal catalysts are required in the above strategies. Metal-free
economy. A series of 2H-1,4-oxazines containing an indole hetero- protocols for the efficient construction of 2H-1,4-oxazines are still
cycle skeleton were obtained in up to 92% yield under mild reaction very limited.18 Herein, we wish to develop an efficient method to
conditions. Control experiments revealed that free indole N–H is construct such 2H-1,4-oxazine skeletons.
crucial for the above transformations. The theoretical calculation Donor–acceptor aziridines are versatile building blocks for the
studies provided guidance on the in-depth insight into the reaction construction of nitrogen-containing biologically active
mechanism and the hydrogen-bond between the free indole N–H compounds.19 Their intrinsic high ring strain renders them
and carbonyl group was identified to lower the free energy barrier susceptible to undergo typical C–C bond heterolytic cleavage to
in the transition states. generate active azomethine ylides in the presence of a Lewis acid,
thus participating in [3+1],20 [3+2],21 and [3+3]22 cycloaddition
2H-1,4-oxazines and their saturated counterpart morpholine
have fascinated synthetic chemists over the past years, due to
their intriguing structures and potential biological activities in
a myriad of pharmaceutical drugs and natural products.1
Additionally, chiral morpholines also could serve as important
versatile synthetic units2 and chiral catalysts3 in organic synthesis.
In the past few decades, considerable efforts have been devoted to
the development of efficient protocols to access these interesting
frameworks,4 which mainly focus on Zn-catalyzed intramolecular
hydroamination of functionalized alkynes,5 ring-opening cyclization
of aziridines6 and oxiranes,7 Cu-catalyzed intermolecular cyclization
of N-tosylethanolamines,8 Ru-catalyzed cyclization of the N-tethered
alkynone9 and a-aryl amino ketones,10 Rh-catalyzed reaction
of 1-tosyl-1,2,3-triazoles with epoxides11/glycidols12/halohydrins,13
Au-catalyzed cyclization reaction of alkynylalcohols14 and ring-
opening reaction of aziridines,15 Ir-catalyzed intramolecular

a
School of Chemistry, School of Life Science and Engineering, Southwest Jiaotong
University, Chengdu 610031, China. E-mail: jfzheng@swjtu.edu.cn
b
State Key Laboratory of Southwestern Chinese Medicine Resources, School of
Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137,
China
† Electronic supplementary information (ESI) available: [1H NMR, 13C NMR and
19
F NMR, and X-ray crystallographic data for 3aa and 3aa 0 (CIF)]. CCDC 2123982 Scheme 1 (a) Metal catalysed transformations for the synthesis of 2H-
and 2183357. For ESI and crystallographic data in CIF or other electronic format 1,4-oxazines; (b) Lewis acid catalysed diverse [3+N] cycloaddition of
see DOI: https://doi.org/10.1039/d3cc02193a donor–acceptor aziridines and our [5+1] cycloaddition.

8572 | Chem. Commun., 2023, 59, 8572–8575 This journal is © The Royal Society of Chemistry 2023
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reactions with various dipolarophiles. In these reactions, an active
transient azomethine ylide intermediate was used as a masked
1,3-dipole. Owing to the electron-withdrawing 2,2 0 -diester group,
we wondered whether the in situ generated p–p conjugated 1C–3C
ylide could be extended to a p–p–p conjugated 1C–5O ylide, which
could function as a ‘‘1,5-dipole’’, captured by nucleophiles to
Published on 13 June 2023. Downloaded by Indian Institute of Technology Kanpur on 3/31/2024 11:16:11 AM.
without a 4 Å MS (entry 12). It should be noted that molecular
sieves play an important role in the stabilization of the azo-
methine ylide intermediate. When a 4 Å MS was replaced by a
3 Å MS and a 5 Å MS, the reaction could give rise to 79% and
68% yield, respectively (entries 13 and 14). When a 3 Å MS
(25 mg) was used, the desired product was obtained in 82%

afford the corresponding nitrogen containing heterocycles. As far
as we know, applying donor–acceptor aziridines as five-atom
synthons for the construction of 2H-1,4-oxazines via [5+1] cycload-
ditions has not been achieved to date. In line with our continued
interest in the cycloaddition reaction of aziridine,23 we herein
report metal-free [5+1] cycloaddition reaction of donor–acceptor
aziridines with 2-(2-isocyanoethyl)indoles for the efficient synth-
esis of a 2H-1,4-oxazine containing indole skeleton. This cycload-
dition reaction is metal-free, and features atom-economy, mild
reaction conditions, simple operation and broad substrate scope.
After a preliminary screening,24 the well-known donor–
acceptor aziridine 1a and 2-(2-isocyanoethyl)indole 2a were
selected as the model substrates to optimize the reaction
conditions. As shown in Table 1, 2-(2-isocyanoethyl)indole 2a
reacted with the aziridine 1a in the presence of 4 Å MS in
CH2Cl2 at 35 1C to afford the corresponding 2H-1,4-oxazine
derivative 3aa in 54% yield (entry 1). The solvents CHCl3,
ClCH2CH2Cl, THF, Toluene, EtOAc, Et2O, CH3CN and DMF
were then screened. Among them, CHCl3 showed the best result
and afforded the cyclization product in 68% yield (entries 2–9).
Adjusting the ratio of 1a to 2a to 2 : 1 with an excess of donor–
acceptor aziridine promotes more efficient transformation of
2a, resulting in 71% yield (entry 10). The yield was slightly
increased to 75% when the reaction was performed at 50 1C
(entry 11). The desired product 3aa was obtained in 53% yield
yield (entry 15).
With the optimized reaction conditions established, the
scope of the [5+1] cycloaddition reactions of a range of 2,2 0 -
diester aziridines was then investigated (Scheme 2). It was found
that the yield was slightly decreased to 63% when phenylsulfonyl
substituted 1b was used. Ortho- and meta-position-substituted aryl
aziridines were proved to be suitable in this reaction, affording
the desired 2H-1,4-oxazines 3ca-3ea in 50–77% yield. Regardless of
whether electron-withdrawing or electron-donating groups were
found on the para-position of the aryl moiety, the aziridines could
smoothly transform into the corresponding products 3fa-3na in
61–83% yield. Subsequently, aziridines with fused rings and
heterocycles were amenable to the reaction, delivering the pro-
ducts 3oa-3qa in 40–73% yields. The variation of the alkyl and
methyl ester group substituted aziridines was also performed, and
the corresponding [5+1] cycloaddition products were not smoothly
obtained. The structure of 3aa was unambiguously determined
using X-ray diffraction analysis.25
Encouraged by the aforementioned results, we then investi-
gated the scope with respect to 2-(2-isocyanoethyl)indole deriva-
tives. As depicted in Scheme 3, the electronic nature and position

Table 1 Optimization of the reaction conditionsa

Entrya Molecular Sieves 1a:2a Solvent Yield % (3aa)b

1 4Å MS 1.5 : 1 CH2Cl2 54
2 4Å MS 1.5 : 1 CHCl3 68
3 4Å MS 1.5 : 1 ClCH2CH2Cl 50
4 4Å MS 1.5 : 1 THF N.d.
5 4Å MS 1.5 : 1 Toluene 30
6 4Å MS 1.5 : 1 EtOAc N.d.
7 4Å MS 1.5 : 1 Et2O 25
8 4Å MS 1.5 : 1 CH3CN N.d.
9 4Å MS 1.5 : 1 DMF N.d.
10 4Å MS 2:1 CHCl3 71
11c 4Å MS 2:1 CHCl3 75
12c — 2:1 CHCl3 53
13c 3Å MS 2:1 CHCl3 79
14c 5Å MS 2:1 CHCl3 68
15cd 3Å MS 2:1 CHCl3 82
a
Unless otherwise noted, the reactions were carried out with 1a
(0.10 mmol), 2a (0.15 or 0.2 mmol), and molecular sieves (50 mg) in
the indicated solvents (0.5 mL) at 35 1C for 24 h. b The yield of isolated Scheme 2 Substrate Scope for 2,2 0 -diester aziridinesa aReaction condi-
product 3aa. c At 50 1C, 7 h. d With 3 Å MS (25 mg). tions: 1 (0.2 mmol), and 2a (0.10 mmol) in CHCl3 (0.5 mL) at 50 1C for 7 h.

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Scheme 3 Substrate scope for isocyanides.a a Reaction conditions: 1h

(0.2 mmol), 2 (0.10 mmol) in CHCl3 (0.5 mL) at 50 1C for 7 h.

of the substituents on the indole unit had a slight influence on

this cycloaddition reaction, and all of the substituted 2-isocyano-
ethylindoles took part in [5+1] cycloaddition well, delivering the
corresponding adducts in 56–78% yields (2b-2g). Isocyanide 2h
containing a shorter chain was also proven to be an appropriate
candidate. However, isocyanide containing a longer chain and
pyrrole derived isocyanide failed to give rise to the pure [5+1]
cycloaddition products.
To evaluate the synthetic potential of this methodology, gram-
scale synthesis and further transformations were performed
(Scheme 4). The donor–acceptor aziridine 1a and 2-(2-isocyano-
ethyl)indole 2a were performed on a gram-scale under standard
reaction conditions, furnishing the corresponding 2H-1,4-oxazine
3aa in 77% yield (1.70 g) (Scheme 4a). In the presence of HOAc,
ring-opening reaction of 3aa was performed, giving rise to the
amide product 4 in 58% yield (Scheme 4b). Then, 3aa was
subjected to reduction with DIBAL-H, resulting in the cleavage
of the C–O bond, affording the desired product 5 in 72% yield
(Scheme 4c). Scheme 5 (a) Control experiments and (b) relative energy profiles
To gain greater insights into the possible reaction mecha- (in kcal mol1) of the reaction pathway and optimized structures of
nism, several control experiments were firstly performed. When important transition states.

N–Me protected 2-(2-isocyanoethyl)indole 2i was used, the

corresponding [5+1] cycloaddition product 3ai was obtained
in 15% yield. With phenyl, tetra-butyl and phenylethyl isocya-
nides, none of the desired products were observed under the
optimization reaction conditions, thus indicating the essential
role of the free indole N–H group (Scheme 5a).
According to the above experimental study, the possible [5+1]
cycloaddition pathway was explored through density functional
theory (DFT). As described in Scheme 5b, the reaction mechanism
Scheme 4 Gram-scale synthesis and synthetic applications.
includes two steps: ring-opening and nucleophilic addition. In
step 1, the reaction starts from aziridine 1a and isocyanide 2a,
followed by the hydrogen-bonded reactant complex (RC) formed
between the sulfonyl group of 1a and free N–H of 2a, and then the
nucleophilic carbon in the isocyanide group of 2a attacks the
electrophilic carbon of aziridine 1a. Simultaneously, the carbon–
carbon bond of aziridine 1a is broken, thus generating the
intermediate IM1. In step 2, relatively stable intermediate IM2
(6.4 kcal mol1) was formed with the concomitant destruction of
the H-bond between the sulfonyl group on 1a and free N–H on 2a,
as well as the creation of a H-bond between the carbonyl oxygen on
1a and free N–H on 2a. As shown in Scheme 5, the DFT calculation
indicates that the relative free energy of TS1 (40.0 kcal mol1) is
much higher than that of TS2 (9.3 kcal mol1), which suggested
that the former is the rate-determining step. Finally, the enolization
and nucleophilic attacks of the nitrionium allow the formation of
the desired [5+1] cycloaddition reaction product.
In conclusion, we have reported metal-free [5+1]
cycloaddition reactions of donor–acceptor aziridine with

8574 | Chem. Commun., 2023, 59, 8572–8575 This journal is © The Royal Society of Chemistry 2023

Communication
2-(2-isocyanoethyl)indoles. This protocol allowed the efficient
production of a variant of 2H-1,4-oxazines bearing an indole
motif, and the corresponding products were obtained in 35–
92% yield under mild reaction conditions. The reaction could
be scaled-up and further transformations were also performed.
Insights into the mechanism were obtained via a combination
Published on 13 June 2023. Downloaded by Indian Institute of Technology Kanpur on 3/31/2024 11:16:11 AM.
of control experimental and DFT computational studies.
We acknowledge financial support from the National
Natural Science Foundation of China (No. 21901215) and the
Science and Technology Planning Project of Sichuan Province
(2022NSFSC0618).
Conflicts of interest
There are no conflicts to declare.
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tion product could be obtained in 78% yield with Y(OTf)3 as Lewis
acid catalyst. Intriguingly, a trace amount of [5+1] cycloaddition
product could be obtained without Y(OTf)3 catalyst
25 CCDC 2123982 (3aa) and 2183357 (3aa 0 ) contain the supplementary
crystallographic data for this paper†.
Chem. Commun., 2023, 59, 8572–8575 | 8575