An efficient protocol for the synthesis of six-membered N, O-heterocycles via a 1,3-dipolar (3+3) cycloaddition between nitrile oxide and α-diazo esters

Article abstract of DOI:10.1016/j.tet.2017.05.055

In this manuscript, we are reporting an efficient protocol for the construction of highly functionalized N, O-heterocyclic derivatives such as 1,2,4-oxadiazine and 1,4,2-dioxazine-6-carboxylate derivatives via a 1,3-dipolar (3 + 3) cycloaddition between nitrile oxide and unprotected α-diazo esters in the presence of 2 mol% Cu(OTf)₂ catalyst. The expected N, O-heterocycles were obtained in excellent yields. These N, O-heterocycles are known to exhibit insecticidal and acaricidal properties.

Full text of DOI:10.1016/j.tet.2017.05.055

Accepted Manuscript
An efficient protocol for the synthesis of six-membered N, O-heterocycles via a 1,3-
dipolar (3+3) cycloaddition between nitrile oxide and α-diazo esters
Bharath Kumar Kuruba, Dr Samuel Vasanthkumar, Professor of Chemistry
PII:
S0040-4020(17)30541-0
10.1016/j.tet.2017.05.055
TET 28721
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 November 2016
Revised Date: 12 May 2017
Accepted Date: 13 May 2017
Please cite this article as: Kuruba BK, Vasanthkumar S, An efficient protocol for the synthesis of six-
membered N, O-heterocycles via a 1,3-dipolar (3+3) cycloaddition between nitrile oxide and α-diazo
esters, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.055.
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ACCEPTED MANUSCRIPT
An efficient protocol for the synthesis of six-membered N, O-heterocycles via a
1,3-dipolar (3+3) cycloaddition between nitrile oxide and α-diazo esters
Bharath Kumar Kuruba,a Samuel Vasanthkumara*
aSchool of Science & Humanities, Department of Chemistry, Karunya University,
Coimbatore (TN) – 641114, INDIA.
R3C(Cl)NOH
Et3N DCM, RT
X
R2OC
O
X
N
N2
R3CNO (in situ)
R1
R1
R3
Cu(OTf)2, 0 oC-RT,
COR2
R3= CH3, C6H5,
90 min
14 examples
Yield upto 92%
X = O, NOMe
p-NO2-C6H4
Abstract: In this manuscript, we are reporting an efficient protocol for the
construction of highly functionalized N, O-heterocyclic derivatives such as 1,2,4-
oxadiazine and 1,4,2-dioxazine-6-carboxylate derivatives via a 1,3-dipolar (3+3)
cycloaddition between nitrile oxide and unprotected α-diazo esters in the presence of
2 mol% Cu(OTf)2 catalyst. The expected N, O-heterocycles were obtained in
excellent yields. These N, O-heterocycles are known to exhibit insecticidal and
acaricidal properties.
Keywords: α-diazo ester, nitrile oxide, N,O-heterocycles, 1,3-dipolar cycloaddition,
1,2,4-Oxadiazine and 1,4,2-dioxazine derivatives.
1

ACCEPTED MANUSCRIPT
An efficient protocol for the synthesis of six-membered N, O-heterocycles via a
1,3-dipolar (3+3) cycloaddition between nitrile oxide and α-diazo esters
Bharath Kumar Kuruba,a Samuel Vasanthkumara*
aSchool of Science & Humanities, Department of Chemistry, Karunya University,
Coimbatore (TN) – 641114, INDIA.
*Corresponding address:
Dr S. Vasanthkumar,
Professor of Chemistry, Department of Science & Humanities,
Karunya University, Coimbatore – 641 114 (IN)
Corresponding email: vasanthakumar@karunya.edu
Ph No: +91 9442429024, Fax: 0422-2615615
N, O-heterocycles are important structural motifs in a variety of natural products
exhibiting significant biological properties such as antifungal, antitumor, and
antibacterial activity.1 N,O-heterocycles also play a key role in asymmetric synthesis
as they form core structural units of several chiral ligands employed in asymmetric
catalysis. Oxadiazines are one of the less explored classes of N, O-heterocyclic
compounds exhibiting high activity as γ-secretase modulators (Fig 1) for the
treatment of Alzheimer’s disease and as an active ingredient in many biologically
active drug candidates.2 Among different types of oxadiazines classified based on the
position of the hetero atoms, 1, 2, 4-oxadiazines are of pharmacological interest and
represent useful synthetic building blocks.3 There are few reports4-6 on the
construction of these heterocyclic ring systems. Owing to their importance,
developing simple preparation methods with readily available reagents is always
desirable.
2

ACCEPTED MANUSCRIPT
O
N
MeO
F
F
N
O
N
N
F
Fig 1: γ-secretase modulators
Nitrile oxides have a long history of useful applications in the field of
organic synthesis. Their preparation, reactivity and synthetic applications are well-
documented.7-9 Although, nitrile oxides can be induced to undergo cycloaddition
with a variety of dipolarophiles to form a variety of N, O-heterocycles, their
application in the synthesis of oxadiazine ring systems has not been reported, till
date. α-diazo esters are the versatile reacting species which are known to undergo a
variety of chemical transformations,10 most of which are carried out in the presence
of transition metal catalysts11 to avoid the formation of regioisomers.
In the course of our research on diazo carbonyl esters, we have reported a
simple one-pot12 process for the synthesis of α-diazo oxyimino esters directly from
β-keto esters and successfully demonstrated them as building blocks for the synthesis
of N-methoxy imidazoles13 via (3+2) cycloaddition reaction between organo nitriles
and α-diazo oxyimino esters in the presence of Cu-catalyst. Now, we proceed to
report a 1,3-dipolar (3+3) cycloaddition reaction between α-diazo oxyimino esters
and nitrile oxides.
Recently, Doyle et al.14 have reported a (3+2) cycloaddition reaction
between methyl TBS-protected enol diazoacetate and nitrile oxide (Scheme 1) to
produce γ-lactone derivatives.
O
O
O
TBSO
2.0 mol%
Rh2(Pfb)4
ArHN
O
OR2
N
DCM, 4 Ao MS
0-25 oC, 2h
N2
R2OOC
R1
R1
Ar
Scheme 1: Synthesis of 5-aryl amino furan-2(H)-one-4-carboxylate derivatives
3

ACCEPTED MANUSCRIPT
In the above reaction, lactone derivatives were formed from the TBS-
protected enol diazoacetates, indicating the role of the protecting group in bringing
about this chemical transformation via Lossen rearrangement.
Inspired by Doyle’s work, we envisioned that the unprotected diazo ester
without an olefinic bond may undergo a 1,3-dipolar (3+3) cycloaddition with nitrile
oxide to give six-membered heterocycles like 1,2,4-oxadiazine-6-carboxylate
derivatives. As anticipated, α-diazo oxyimino ester 1 reacted with nitrile oxide 2 in
the presence of 2 mol% Cu(OTf)2 catalyst in dichloromethane to give highly
functionalized 1,2,4-oxadiazine-6-carboxylate 3 in excellent yield (Scheme 2).
To achieve the maximum yield, reaction optimisation was carried out by screening
several catalysts in different solvents and the results are given in Table 1.
Table 1: Reaction optimisationa
EtO2C
O
O
N
N
Catalyst
N2
PhCNO
Solvent, 0 oC - RT,
90 min
N
O
Ph
CO2Et
1a
2a
3a
Entry Catalyst (mol %) solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuI
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
41
57
c
Cu(hfacac)2
Pd(OAc)2
PdCl2
36
25
Rh2(OAc)4
CuOTf
92
65
91 (69)d
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
84
CHCl3
80
4

ACCEPTED MANUSCRIPT
10
11
12
13
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuCl2
THF
Et2O
59
35
59
12
DCM
DCM
aReaction conditions: α-diazo oxyimino ester (2 mmol) in a solvent (5 mL) was
added over a period of 45 min using a syringe at 0 oC to a mixture of nitrile oxide (2
mmol in 6 mL/mmol DCM) and a 2 mol % catalyst, stirred for another 45 min.
bYield corresponding to the isolated product by chromatography, cvacuum dried at 60
oC, dyield at 70 oC.
Among different catalysts employed, Rh2(OAc)4 catalysed the
cycloaddition reaction with the highest efficiency. Interestingly, competing with the
Rh catalyst, Cu(OTf)2 also catalysed the reaction very well. Whereas, moderate to
poor yields (65 – 25%) were observed with CuOTf, Cu(hfacac)2, CuI, Pd(OAc)2 and
PdCl2, respectively. Reaction performed in CuCl2 resulted in very poor yield
whereas in the presence of Cu(OAc)2, moderate yield was observed. A blank
reaction carried out under catalyst-free conditions failed completely signifying the
importance of the transition metal catalyst. Reactions carried out in halogenated
solvents gave excellent yields while poor yields were observed in THF and Et2O
solvents. On careful screening, catalyst loading was fixed at 2 mol%.
The substrate scope was scrutinised using a range of α-diazo oxyimino
esters (2 mmol/5 mL DCM), which were treated with nitrile oxide (2 mmol in 6
mL/mmol DCM) using 2 mol% Cu(OTf)2 catalyst. The alkyl or aryl functionalized
1,2,4-oxadiazine-6-carboxylates were prepared in excellent yields (Scheme 2).
5

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O
R2OC
R1
O
2.0 mol %
Cu(OTf)2
DCM, 0 oC-RT,
90 min
N
N
N2
R3CNO
R1
N
O
R3
COR2
1
2
3
R1 = Alkyl or aryl
R2 = OMe, OEt
R3 = CH3, C6H5, p-NO2-C6H4
Scheme 2: Synthesis of 1,2,4-oxadiazine-6-carboxylates
Table 2: 1,2,4-oxadiazine-6-carboxylate derivativesa
Diazo oxyimino
Nitrile
Oxide
2
Oxadiazine
Derivatives
3
Yieldb
(%)
Entry
a
ester
1
EtO2C
O
O
N
N
91
92
PhCNO
PhCNO
N2
N
O
Ph
CO2Et
MeO2C
O
O
N
N
b
c
d
N2
N
O
Ph
N
CO2Me
EtO2C
O
O
N
84
80
N2
N
O
Ph
PhCNO
PhCNO
CO2Et
O2N
O2N
EtO2C
O
O
N
N
N2
CO2Et
Bn
N
O
Ph
Bn
6

ACCEPTED MANUSCRIPT
EtO2C
O
N
O2N
O
N
N
O
Ph
N2
e
PhCNO
83
CO2Et
NO2
EtO2C
O
O
N
N
N
f
CH3CNO
90
58
N2
N
O
CO2Et
EtO2C
O
N
O
p-(NO2)-
N
O
g
N2
CO2Et
a
PhCNO
NO2
aReaction conditions: Reaction conditions: α-diazo oxyimino ester (2 mmol/5 mL
DCM), nitrile oxide (2 mmol), 2 mol % catalyst in 6 mL/mmol DCM, stirred for 90
min at 0 oC-RT. bYield corresponding to the isolated product by chromatography.
From Table 2, it was observed that the steric hindrance caused due to the
bulky groups attached to the diazo esters had little influence on the yield of the
product, with marginally higher yields observed in the case of the aliphatic
substituent. Substrates bearing –NO2 groups also underwent the expected
cycloaddition smoothly. There was a sudden drop in the yield of 3g, which can be
attributed to the resonance stabilisation of the nitrile oxide 2g bearing nitro group at
the para position of the phenyl ring.
After successful establishment of the protocol, the synthetic utility of this
cycloaddition was expanded for the synthesis of 1,4,2-dioxazine-6-carboxylate
derivatives by replacing α-diazo oxyimino ester with α-diazo carbonyl esters.
Dioxazine derivatives find important applications as fine chemicals for the synthesis
of a variety of fine art materials, pesticides etc. They are also expected to exhibit
7

ACCEPTED MANUSCRIPT
insecticidal and acaricidal properties.15 Under standard reaction conditions, α-diazo
carbonyl ester 4 was subjected to the 1,3-dipolar (3+3) cycloaddition reaction with
nitrile oxide 2 to obtain the corresponding 1,4,2-dioxazine-6-carboxylates 5 (Scheme
3).
2.0 mol %
O
R2OC
R1
O
Cu(OTf)2
N
N2
R3CNO
R1
DCM, 0 oC-RT,
90 min
O
R3
COR2
4
2
5
Scheme 3: Synthesis of dioxazine-6-carboxylates
Table 3: 1,4,2-Dioxazine-6-carboxylate derivativesa
Diazo oxyimino
Nitrile
Oxide
2
Oxadiazine
Derivatives
5
Yieldb
(%)
Entry
a
ester
4
O
EtO2C
O
N
N2
90
91
PhCNO
O
Ph
CO2Et
MeO2C
O
O
N
N2
b
c
d
PhCNO
N
O
Ph
N
CO2Me
EtO2C
O
O
N2
CO2Et
83
88
N
O
Ph
PhCNO
PhCNO
O2N
O2N
EtO2C
O
O
N
N2
CO2Et
Bn
Bn
N
O
Ph
8

ACCEPTED MANUSCRIPT
EtO2C
O
N
O2N
N
O
Ph
O
N2
e
PhCNO
84
CO2Et
NO2
EtO2C
O
O
O
N
N2
f
CH3CNO
92
62
N
O
CO2Et
EtO2C
O
N
p-(NO2)-
N2
N
O
g
PhCNO
CO2Et
NO2
a
aReaction conditions: Reaction conditions: α-diazo carbonyl ester (2 mmol/ 4-5 ml
DCM), nitrile oxide (2 mmol), 2 mol % catalyst in 6 mL/mmol DCM, stirred for 90
min at 0 oC-RT. bYield corresponding to the isolated product by chromatography.
In comparison with α-diazo oxyimino esters, α-diazo carbonyl esters
were found be more facile in undergoing the 1,3-dipolar (3+3) cycloaddition with the
nitrile oxides resulting in corresponding 1,4,2-dioxazine-6-carboxylate derivatives in
excellent yields (Table 3), presumably due to the higher electronegativity of the
oxygen than that of an amine. A similar observation was made by C.-M. Park et al.
during their study on the synthesis of pyrroles and furans.
To the best of our knowledge, till date, only TBS protected diazo esters
were employed in a reaction with nitrile oxide. A reaction of an unprotected α-diazo
ester with nitrile oxide is not known thus far. In order to throw light on the course of
the reaction, a catalytic pathway16 has been proposed (Fig 2) based on our previous
findings on 1,3-dipolar cycloaddition reaction in the presence of Cu(OTf)2 catalyst.13
9

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-N2
-N2
Cu
Cu
X
COR2
R1
R2OC
R1
Cu
X
R2OC
R1
O
O N
R3
R3
N O
N
R2OC
N2
X
R2OC
R1
N2
R3
X
A
A
B
R1
Migration
of Cu onto X via C
X
Dissociation
of Cu
Cu(II)
Cu(II)
Path B
R2OC
Path A
R2OC
R1
O
X
O
X
N
N
R3
R3
R1
Cu
D
C
Dissociation
of Cu
R2O2C
R1
O
N
X
R3
E
Fig 2. Plausible mechanism
A nucleophilic attack of the active dipolarophile, nitrile oxide on the
carbon bearing Cu(II) generates a tetrahedral intermediate B. Dissociation of Cu(I)
and the gradual migration of the charge increases the nucleophilicity on X (N or O),
which is sufficient enough to attack the electrophilic carbon in the nitrilium ion to
undergo (3+3) cycloaddition to give E (Path A). Nevertheless, Cu binding to such
systems is unprecedented and might not dissociate to generate C. Instead, it could
migrate to X (N or O) to stabilise the transition state C to generate D, which upon
cyclisation expels Cu to yield the cyclised product E (Path B). The mechanism
might be more complex also as the reason for the requirement of the catalyst with
high Lewis acidity is still under investigation.
In summary, we have developed an efficient synthetic protocol for the
synthesis of 1,2,4-oxadiazine and 1,4,2-dioxazine-6-carboxylate derivatives via 1,3-
dipolar (3+3) cycloaddition using 2 mol% Cu(OTf)2 catalyst. The scope of the
reaction is wide enough to produce highly functionalized N, O-heterocycles using a
variety of diazo esters and nitrile oxides under mild conditions. These N, O-
heterocycles exhibit interesting properties, which need further investigation.
10

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Experimental
All reagents and solvents were obtained from Merck and Aldrich are used
1
13
without any purification. H- and C- NMR spectra were recorded on Bruker
FT- 500 or 400 using tetramethylsilane (TMS) as an internal standard. The IR
spectra were recorded on Shimadzu FT-IR spectrophotometer (in KBr).The
compounds were purified by column chromatography using silica gel (100-200
mesh) and pet ether: ethyl acetate. TLC was performed using silica gel 60 F254
pre-coated on aluminium sheets, obtained from Merck. Visualisation of spots on
TLC plate was done with UV light (254 nm).
General Procedure
Preparation of nitrile oxide:
A cis:trans mixture of aldoxime generated from alkyl/aryl aldehyde (2 mmol) and
hydroxylamine hydrochloride (3 mmol), in the presence triethylamine (3.5 mmol),
refluxed at RT for 45 minutes in 6 mL EtOH:H2O (2:1) is subjected to the
chlorination with NCS (2 mmol) in 5 mL DMF (N-Chlorosuccinimide) without
further purification. The obtained hydroximoyl chloride (2 mmol) is subjected to
dehydrohalogenation by refluxing at RT in the presence of triethylamine (2.2 mmol)
in 6 mL/mmol DCM. Upon completion of the reaction, as indicated by the TLC (3:1
pet ether/ethyl acetate), the obtained nitrile oxide is used for the next step without
any further purification.
Preparation of Oxadiazine/dioxazine derivatives: α-diazo ester (2 mmol) in 5 mL
of DCM was added drop-wise over a period of 45 min through a syringe to a round
bottom flask loaded with in situ generated nitrile oxide (2 mmol) and a 2 mol%
Cu(OTf)2 catalyst at 0 o - RT and stirred for another 45 min. After the completion of
the reaction as hinted by the TLC, the reaction mixture was purified by column
chromatography using pet ether/ethyl acetate (3:1).
Ethyl-4-methoxy-5-methyl-3-phenyl-4H-1,2,4-oxadiazine-6-carboxylate(3a):
The title compound was prepared according to the general procedure and the product
11

ACCEPTED MANUSCRIPT
was obtained as brownish yellow solid. Yield: 91% (0.502 gm); M.P. 195o – 197 oC;
Rf (25 % Pet ether/ethyl acetate) 0.48; IR (cm-1): 3100, 2350, 2065, 1785, 1595,
1
1432, 1323, 1295, 1186, 895, 776, 685; H NMR (400 MHz, CDCl3) δ 8.03 – 7.89
(m, 2H), 7.63 – 7.39 (m, 3H), 4.14 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 2.38 (s, 3H),
13
1.24 (t, 3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ 159.52, 155.52, 152.75,
137.34, 128.83, 128.81, 128.78, 126.98, 126.96, 126.66, 61.69, 57.75, 15.37, 13.99;
MS (EI) m/z [M+H]+: Calcd for C14H16N2O4:276.1110, found: 276.1112.
Methyl-4-methoxy-5-methyl-3-phenyl-4H-1,2,4-oxadiazine-6-carboxylate(3b):
The title compound was prepared according to the general procedure and the product
was obtained as brownish yellow solid. Yield: 92% (0.482 gm); M.P. 194o – 195 oC;
Rf (25 % Pet ether/ethyl acetate) 0.45; IR (cm-1) 3110, 2497, 2066, 1455, 1312,
1
1278, 1194, 879, 751, 690; H NMR (400 MHz, CDCl3) δ 8.03 – 7.89 (m, 2H), 7.63
– 7.37 (m, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 158.58, 154.58, 151.81, 136.40, 127.90, 127.88, 127.84, 126.05, 126.04, 125.72,
56.81, 51.27, 14.43; MS (EI) m/z [M+H]+: Calcd for C13H14N2O4: 262.0954, found:
262.0955.
Ethyl-4-methoxy-5-(4-nitrophenyl)-3-phenyl-4H-1,2,4-oxadiazine-6-carboxylate
(3c): The title compound was prepared according to the general procedure and the
product was obtained as dark brown solid. Yield: 84% (0.644 gm); M.P. 201o – 203
oC; Rf (25 % Pet ether/ethyl acetate) 0.41; 1H NMR (400 MHz, CDCl3) δ 8.11 (dd,
2H, J = 8.3, 3.7 Hz), 7.93 (dd, 2H, J = 8.4, 3.8 Hz), 7.65 – 7.45 (m, 5H), 4.16 (q, 2H,
13
J = 7.1 Hz), 3.76 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ
154.49, 155.49, 152.72, 147.81, 137.31, 131.68, 128.78, 128.76, 128.75, 126.98,
126.97, 126.94, 126.93, 126.63, 124.58, 124.57, 61.66, 57.72, 13.96; MS (EI) m/z
[M+H]+: Calcd for C19H17N3O6: 383.1117, found: 383.1116.
Ethyl-5-benzyl-4-methoxy-3-phenyl-4H-1,2,4-oxadiazine-6-carboxylate(3d): The
title compound was prepared according to the general procedure and the product was
12

ACCEPTED MANUSCRIPT
obtained as pale brown solid. Yield: 80% (0.563 gm); M.P. 210o – 212 oC; Rf (25 %
1
Pet ether/ethyl acetate) 0.44; H NMR (400 MHz, CDCl3) δ 8.06 – 7.88 (m, 2H),
7.64 – 7.42 (m, 3H), 7.42 – 7.10 (m, 5H), 4.15 (q, 2H, J = 7.3 Hz), 3.78 (s, 3H), 3.72
13
(s, 2H), 1.26 (t, 3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ 159.67, 155.69,
152.90, 138.43, 137.49, 128.93(2), 128.71(2), 128.10(2), 127.13(2), 126.81, 61.84,
57.90, 30.25, 14.14; MS (EI) m/z [M+H]+: Calcd for C20H20N2O4: 352.1423, found:
352.1424.
Ethyl-4-methoxy-5-(4-nitrobenzyl)-3-phenyl-4H-1,2,4-oxadiazine-6-carboxylate
(3e): The title compound was prepared according to the general procedure and the
product was obtained as dirty brown solid. Yield: 83% (0.659 gm); M.P. 203o – 205
oC; Rf (25 % Pet ether/ethyl acetate) 0.45; 1H NMR (400 MHz, CDCl3) δ 8.04 (d,
2H, J = 8.1 Hz), 7.93 (dt, 2H, J = 3.8, 2.1 Hz), 7.64 – 7.41 (m, 3H), 7.38 (d, 2H, J =
8.1 Hz), 4.15 (q, 2H, J = 7.0 Hz), 3.78 (s, 3H), 3.70 (s, 2H), 1.26 (t, 3H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) δ 159.53, 155.53, 152.77, 147.86, 138.29, 137.35,
129.88, 129.86, 128.87, 128.82, 128.80, 127.01, 127.00, 126.67, 123.44, 123.42,
61.70, 57.76, 30.12, 14.01; MS (EI) m/z [M+H]+: Calcd for C20H19N3O6: 397.1274,
found: 397.1275.
Ethyl-4-methoxy-3,5-dimethyl-4H-1,2,4-oxadiazine-6-carboxylate(3f): The title
compound was prepared according to the general procedure and the product was
obtained as dark brown gum. Yield: 90% (0.385 gm); M.P. 193o – 195 oC; Rf (25 %
1
Pet ether/ethyl acetate) 0.40; H NMR (400 MHz, CDCl3) δ 4.14 (q, 2H, J = 7.2
13
Hz), 3.78 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.23 (t, 3H, J = 7.1 Hz); C NMR
(CDCl3, 125 MHz) δ 158.19, 154.19, 151.42, 136.01, 60.36, 56.42, 14.04, 12.89,
12.67. MS (EI) m/z [M+H]+: Calcd for C9H14N2O4: 214.0954, found: 214.0954.
Ethyl-4-methoxy-5-methyl-3-(4-nitrophenyl)-4H-1,2,4-oxadiazine-6-carboxylate
(3g): The title compound was prepared according to the general procedure and the
13

ACCEPTED MANUSCRIPT
product was obtained as dark brown solid. Yield: 58% (0.373 gm); M.P. 200o – 202
oC; Rf (25 % Pet ether/ethyl acetate) 0.46; 1H NMR (400 MHz, CDCl3) δ 8.15 (dd,
2H, J = 8.7, 2.3 Hz), 7.82 (dd, 2H, J = 8.7, 2.3 Hz), 4.15 (q, 2H, J = 7.0 Hz), 3.75 (s,
13
3H), 2.33 (s, 3H), 1.30 (t, 3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ 159.22,
155.22, 152.45, 147.54, 137.04, 127.11, 127.69, 126.36, 123.53, 123.51, 61.39,
57.45, 15.07, 13.69. MS (EI) m/z [M+H]+: Calcd for C15H17N3O5: 319.1168, found:
319.1167.
Ethyl-5-methyl-3-phenyl-1,4,2-dioxazine-6-carboxylate(5a): The title compound
was prepared according to the general procedure and the product was obtained as
o
dirty brown solid. Yield: 90% (0.445 gm); M.P. 199o – 201 C; Rf (25 % Pet
ether/ethyl acetate) 0.39; IR (cm-1) 3105, 2365, 2105, 1745, 1609, 1455, 1310,
1289, 1182, 850, 725; 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, 2H, J = 8.3, 1.3 Hz),
7.70 – 7.51 (m, 3H), 4.12 (q, 2H, J = 7.2 Hz), 2.45 (s, 3H), 1.24 (t, 3H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) δ 159.52, 156.59, 155.52, 152.62, 130.55, 128.79,
128.77, 126.55, 126.52, 61.69, 14.82, 14.00 MS (EI) m/z [M+H]+: Calcd for
C13H13NO4: 247.0845, found: 247.0847.
Methyl-5-methyl-3-phenyl-1,4,2-dioxazine-6-carboxylate(5b): The title compound
was prepared according to the general procedure and the product was obtained as
brown solid. Yield: 91% (0.424 gm); M.P. 197o – 199 oC; Rf (25 % Pet ether/ethyl
acetate) 0.40; IR (cm-1) 3110, 2384, 2109, 1732, 1616, 1457, 1309, 1293, 1181, 847,
728, 680; 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, 2H, J = 8.3, 1.3 Hz), 7.70 – 7.51
13
(m, 3H), 3.73 (s, 3H), 2.45 (s, 3H); C NMR (CDCl3, 125 MHz) δ 156.21, 155.14,
152.24, 130.17, 128. 43, 128.41, 126.19, 126.17, 51.84, 14.44; MS (EI) m/z [M+H]+:
Calcd for C12H11NO4: 233.0688, found: 233.0687.
Ethyl-5-(4-nitrophenyl)-3-phenyl-1,4,2-dioxazine-6-carboxylate(5c): The title
compound was prepared according to the general procedure and the product was
obtained as dark brown solid. Yield: 83% (0.588 gm); M.P. 207o – 209 oC; Rf (25 %
14

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Pet ether/ethyl acetate) 0.39; 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, 2H, J = 8.7,
3.1 Hz), 8.12 (dd, 2H, J = 6.9, 2.5 Hz), 7.87 (dd, 2H, J = 8.7, 3.1 Hz), 7.63 – 7.46 (m,
3H), 4.19 (q, 2H, J = 7.0 Hz), 1.26 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz)
δ 159.22, 155.23, 153.92, 152.32, 147.55, 130.25, 128.49, 128.48, 126.25, 126.24,
124.86, 124.85, 124.36, 124.26, 124.25, 61.40, 13.70; MS (EI) m/z [M+H]+: Calcd
for C18H14N2O6: 354.0852, found: 354.0854.
Ethyl-5-benzyl-3-phenyl-1,4,2-dioxazine-6-carboxylate(5d): The title compound
was prepared according to the general procedure and the product was obtained as
o
pale brown solid. Yield: 88% (0.569 gm); M.P. 210o – 211 C; Rf (25 % Pet
1
ether/ethyl acetate) 0.38; H NMR (400 MHz, CDCl3) δ 7.99 (dd, 2H, J = 8.2, 1.2
Hz), 7.61 (ddd, 3H, J = 35.0, 11.4, 4.4 Hz), 7.39 – 7.21 (m, 5H), 4.15 (q, 2H, J = 7.0
13
Hz), 3.56 (s, 2H), 1.23 (t, 3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ 159.06,
159.03, 155.03, 152.13, 141.58, 134.17, 130.06, 129.18, 129.16, 128.32, 128.30,
128.22, 128.21, 128.10, 128.08, 126.06, 126.04, 61.20, 32.18, 13.51; MS (EI) m/z
[M+H]+: Calcd for C19H17NO4: 323.1158, found: 323.1156.
Ethyl-5-(4-nitrobenzyl)-3-phenyl-1,4,2-dioxazine-6-carboxylate(5e): The title
compound was prepared according to the general procedure and the product was
obtained as dark brown solid. Yield: 84% (0.618 gm); M.P. 208o – 210 oC; Rf (25 %
Pet ether/ethyl acetate) 0.41; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H, J = 8.1
Hz), 7.93 (dt, 2H, J = 3.8, 2.1 Hz), 7.70 – 7.51 (m, 3H), 7.38 (d, 2H, J = 8.1 Hz),
13
4.15 (q, 2H, J = 7.0 Hz), 3.44 (s, 2H), 1.23 (t, 3H, J = 7.1 Hz); C NMR (CDCl3,
125 MHz) δ 159.52, 155.52, 152.62, 147.85, 142.07, 134.66, 130.55, 129.88, 129.86,
128.79, 128.77, 126.56, 126.55, 123.43, 123.42, 61.69, 32.67, 14.00; MS (EI) m/z
[M+H]+: Calcd for C19H16N2O6: 368.1008, found: 368.1010.
Ethyl-4-methoxy-3,5-dimethyl-4H-1,2,4-oxadiazine-6-carboxylate(5f): The title
compound was prepared according to the general procedure and the product was
o
obtained as pale brown oil. Yield: 92% (0.394 gm); M.P. 195o – 197 C; Rf (25 %
15

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1
Pet ether/ethyl acetate) 0.40; H NMR (400 MHz, CDCl3) δ 4.11 (q, 2H, J = 7.2
Hz), 2.44 (s, 3H), 2.21 (s, 3H), 1.24 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz)
δ 159.67, 159.65, 152.90, 137.49, 61.84, 57.90, 15.52, 14.36, 14.14; MS (EI) m/z
[M+H]+: Calcd for C9H14N2O4: 214.0954, found: 214.0955.
Ethyl-5-methyl-3-(4-nitrophenyl)-1,4,2-dioxazine-6-carboxylate(5g): The title
compound was prepared according to the general procedure and the product was
obtained as dark brown solid. Yield: 62% (0.362 gm); M.P. 205o – 207 oC; Rf (25 %
1
Pet ether/ethyl acetate) 0.41; H NMR (400 MHz, CDCl3) δ 8.29 (dd, 2H, J = 7.7,
2.2 Hz), 8.13 (dd, 2H, J = 8.0, 2.2 Hz), 4.12 (q, 2H, J = 7.0 Hz), 2.45 (s, 3H), 1.24 (t,
13
3H, J = 7.1 Hz); C NMR (CDCl3, 125 MHz) δ 159.67, 156.74, 155.67, 152.77,
147.99, 130.69, 130.06, 124.08, 61.84, 14.96, 14.14; MS (EI) m/z [M+H]+: Calcd
for C13H12N2O8: 324.0594, found: 324.0592.
Associated content
Supporting Information:
1
Supporting Information containing H, 13C NMR and MASS spectra of all the
compounds.
AUTHOR INFORMATION
Corresponding Author:
*Email-ID: vasanthakumar@karunya.edu; Phone: +919442429024; Fax: 0422-
2615615
Acknowledgement
The authors thank the Administration and the Management of Karunya University
for their constant support and encouragement. The authors also thank Prof. M. P.
Doyle, Dept. Of Chemistry, University of Texas, San Antonio, Texas, Dr S.
Muthusubramanian, Dept. Of Chemistry, M. K. University, Madurai (TN) and Dr L.
Emmanuvel, Dept. Of Chemistry, Karunya University, Coimbatore (TN).
16

ACCEPTED MANUSCRIPT
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Highlights
1. This is a convenient protocol for the construction of six-membered highly
substituted N,O-heterocycles.
2. For the first time, we are reporting a 1,3-dipolar cycloaddition reaction between
unprotected α-diazo esters and nitrile oxide.
3. This chemical transformation was achieved in presence of Cu(OTf)2 catalyst.
4. Highly functionalized 1,2,4-oxadiazine-6-carboxylates can be synthesized due to
its varied substrate scope (alkyl, aryl, substituted aryl) in appreciable yields (up to
92%).
5. The method also provides an access to the 1,4,2-dioxazine-6-carboxylate
derivatives in very good yields.
6. Both diazo oxyimino esters and diazo carbonyl esters underwent cyclization
smoothly to afford the desired product in high yields.