Cycloaddition of α-Diazocarbonyl Compounds and N-Tosylaziridines: Synthesis of Polysubstituted 2 H-1,4-Oxazines through Synergetic Catalysis of AgOTf/Cu(OAc)2

Article abstract of DOI:10.1021/acs.orglett.9b00632

An impressive and new [3 + 3]-cycloaddition of α-diazocarbonyl compounds with N-tosylaziridines via synergetic catalysis of AgOTf and Cu(OAc)₂ has been well described, which offers efficient access to highly substituted 2H-1,4-oxazine derivatives. A variety of α-diazocarbonyl compounds and N-tosylaziridines were compatible substrates with convenient operations under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.9b00632

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
[
3 + 3]-Cycloaddition of α‑Diazocarbonyl Compounds and
N‑Tosylaziridines: Synthesis of Polysubstituted 2H‑1,4-Oxazines
through Synergetic Catalysis of AgOTf/Cu(OAc)2
Shangwen Fang, Yanwei Zhao, Haiyan Li, Yonggao Zheng, Pengcheng Lian, and Xiaobing Wan*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P.R. China
*
S Supporting Information
ABSTRACT: An impressive and new [3 + 3]-cycloaddition of α-diazocarbonyl compounds with N-tosylaziridines via
synergetic catalysis of AgOTf and Cu(OAc) has been well described, which offers efficient access to highly substituted 2H-1,4-
2
oxazine derivatives. A variety of α-diazocarbonyl compounds and N-tosylaziridines were compatible substrates with convenient
operations under mild reaction conditions.
3
2
H-1,4-oxazines are six-membered heterocycles that are present
(Scheme 1b). Recently, [3 + 3]-cycloaddition of triazoles and
in a myriad of pharmaceutical, agrochemical, biological, and
material molecules with significant activities. Several ap-
epoxides to 2H-1,4-oxazines was well developed by Chen’s
group (Scheme 1c). Despite significant progress in this field,
1
4
proaches to 2H-1,4-oxazines have been reported for the past
few years. For example, Blechert and colleagues showed the Zn-
catalyzed intramolecular hydroamination of functionalized
most systems reported so far suffered from high temperature and
tedious side reactions. Thus, the development of mild and
efficient methods for the construction of 2H-1,4-oxazine
derivatives has been both a challenge and a focus of synthetic
chemistry.
alkenes and alkynes to construct 2H-1,4-oxazines (Scheme
2
1
2
a). In 2008, Urabe et al. developed the facile preparation of
In past decades, α-diazocarbonyl compounds have received
H-1,4-oxazines through copper-catalyzed [2 + 4]-cyclo-
5
widespread attention because they can convert into metal−
addition of 1-halo-1-alkynes and hydroxyl N-tosylethanolamines
carbene complexes and then react with alkenes, alkynes, or
nitriles to deliver cycloaddition products. Doyle and co-workers
Scheme 1. Synthesis of 2H-1,4-Oxazines
6
have made great achievements in this field; they realized a series
of cyclization reaction using enoldiazo compounds and proper
7
dipoles. Aziridine, which bears a nucleophilic nitrogen and an
electrophilic carbon atom, has been widely applied in the
synthesis of heterocyclic scaffolds. As a continuation of our
8
research in diazo chemistry, we envisioned that the [3 + 3]-
cycloaddition between α-diazocarbonyl compounds and azir-
idines would afford a novel approach to the synthesis of highly
substituted 2H-1,4-oxazine derivatives (Scheme 1d). Compared
with traditional methods, this methodology was distinguished by
mild conditions and wide substrate scope.
Initially, we chose ethyl 2-diazo-3-oxobutanoate 1a and N-
tosylaziridine 2a as model substrates to test our hypothesis. It
has been widely reported that N-tosylaziridines can undergo
9
nucleophilic ring opening aided by Lewis acid. AgOTf, one of
Received: February 19, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
the most commonly used Lewis acid catalysts, was used for this
Letter
10
a
Scheme 2. Scope of α-Diazocarbonyl Compounds
2
H-1,4-oxazine formation reaction. By analyzing the reaction
mixture, the desired product 3a was detected in an isolated yield
of 43% (Table 1, entry 1). To optimize this cycloaddition
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
cocatalyst
base
yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na CO
43
45
<5
45
75
69
80
<5
75
<5
<5
69
<5
<5
<5
<5
<5
<5
<5
75
FeSO ·7H O
Co(acac)2
4
2
Ni(OTf)2
Cu(OTf)2
CuSO4
Cu(OAc)2
Cu(acac)2
CuCl
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
1
1
1
1
1
1
1
1
1
1
2
BF ·Et O
3
2
In(OTf)3
Sn(OTf)2
Pd(OAc)2
AgOAc
AgBF4
AgOTf
AgOTf
AgOTf
AgOTf
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), AgOTf (0.03
mmol, 15 mol %), Cu(OAc) (0.02 mmol, 10 mol %), and NaHCO
2
3
2
3
(0.4 mmol) in DCE (0.4 mL) at 40 °C for 12 h. Isolated yield.
KOH
DBU
DMAP
Acyl α-diazoesters bearing different ester groups and acyl
substituents were investigated, affording the corresponding
products 3a−3f in moderate to good yields. The benzoyl-
substituted diazo compound worked well and delivered the
desired product 3f in 26% yield, most probably owing to the
electronic effects. Notably, acyl α-diazoketones were suitable
substrates for this reaction, providing the corresponding
products in moderate to good yields (3g−3i), and the steric
effects were not obvious. The exact configuration of 3b was
further determined by single X-ray crystallography (for more
details, see the Supporting Information).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Lewis acid
0.03 mmol, 15 mol %), cocatalyst (0.02 mmol, 10 mol %), and base
0.4 mmol) in DCE (0.4 mL) at 40 °C for 12 h. Isolated yield.
(
(
b
reaction, a variety of Lewis acids were tested, but no better
results were obtained (for details, see Table S1 in the Supporting
Information). Because the matching of ring opening rate and
metal−carbene formation rate will be critical to the formation of
products, we next screened an appropriate cocatalyst to
control the rate of α-diazocarbonyl compound dediazoniation
1
1
(
Table 1, entries 2−9). After extensive screenings, Cu(OAc)
Next, we tested various substituted 2-aryl-N-tosylaziridines
for 2H-1,4-oxazine formation. As shown in Scheme 3, the
substrates bearing electron-donating groups or electron-with-
drawing groups could take part in this transformation smoothly,
affording the corresponding products (4b−4k) in moderate to
high yields. Additionally, the alkyl-substituted 2-aryl-N-
tosylaziridines (4b and 4c) were less efficient than others,
presumably due to the electronic effects. It was noteworthy that
this transformation showed favorable compatibility of halogen
atoms (4e−4i), such as fluoro, chloro, and bromo, and the
desired products were afforded in good yields. Based on these
results (4f, 4h, and 4i), it was noteworthy that the steric effect of
substituents on the aromatic ring did not conspicuously
influence the reaction efficiency. The variations of the
benzenesulfonyl group were also tested for this transformation
in which the 2-aryl-N-(para-methoxylsulfonyl)aziridine and 2-
aryl-N-(para-nitrosulfonyl)aziridine afforded the corresponding
products 4j and 4k in 76 and 55% yields, respectively. To further
prove the practical utility of this methodology, the reaction was
carried out on 7.0 mmol scale, and the desired product 3a (2.06
g) was obtained in good 73% yield (Scheme 4).
2
was found to be the best cocatalyst and afforded the desired
product 3a in high 80% yield (Table 1, entry 7). Notably, no
product 3a was detected in the absence of AgOTf (Table 1,
entry 10), indicating that it was indispensable for the generation
of 2H-1,4-oxazines. Other Lewis acid catalysts were tested under
Cu(OAc) conditions, but no better results were obtained for
this transformation (Table 1, entries 11−16). Based on these
results, it was reasonable to believe that AgOTf induced this
2
transformation and Cu(OAc) made this process more efficient.
For the base, Na CO , KOH, DBU, and DMAP all led to
dramatically decreased yields, compared to that with NaHCO3
2
2
3
(
Table 1, entries 16−19). Based on these screening results, the
optimal reaction conditions were established as follows: using
AgOTf (15 mol %) as the catalyst, Cu(OAc) (10 mol %) as the
cocatalyst, and NaHCO (0.4 mmol) as base for reaction of 1a
(
h.
2
3
0.2 mmol) and 2a (0.6 mmol) in 0.4 mL of DCE at 40 °C for 12
Having established the optimal reaction conditions, we next
examined a variety of α-diazocarbonyl compounds for 2H-1,4-
oxazine formation, and the results are summarized in Scheme 2.
B
DOI: 10.1021/acs.orglett.9b00632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Aziridines
oxazines through synergetic catalysis of AgOTf/Cu(OAc)2.
This methodology also successfully expands the scope of α-
diazocarbonyl compounds in the [3 + 3]-cycloaddition reaction.
Further investigations on the detailed mechanism and potential
application are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00632.
Experimental procedure, characterization data, copies of
1
13
19
H, C, and F NMR spectra (PDF)
Accession Codes
CCDC 1879327 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: wanxb@suda.edu.cn.
ORCID
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), AgOTf (0.03
Xiaobing Wan: 0000-0001-9007-2128
Notes
mmol, 15 mol %), Cu(OAc) (0.02 mmol, 10 mol %), and NaHCO
2
3
(
0.4 mmol) in DCE (0.4 mL) at 40 °C for 12 h. Isolated yield. 4c
proceeded on 0.5 mmol scale. 4i proceeded on 1.0 mmol scale.
The authors declare no competing financial interest.
Scheme 4. Gram-Scale Synthesis of 2H-1,4-Oxazines
ACKNOWLEDGMENTS
■
This project is funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD),
NSFC (21572148, 21272165).
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DOI: 10.1021/acs.orglett.9b00632
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D
DOI: 10.1021/acs.orglett.9b00632
Org. Lett. XXXX, XXX, XXX−XXX