Selective syntheses of 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones via temperature-dependent Rh(II)-carbenoid-mediated 2H-azirine-ring expansion Dedicated to Professor Armin de Meijere on the occasion of his 75th birthday

Article abstract of DOI:10.1016/j.tet.2014.03.101

The Rh(II)-catalyzed reaction of 2-carbonyl-substituted 2H-azirines with ethyl 2-cyano-2-diazoacetate or 2-diazo-3,3,3-trifluoropropionate provides an easy access to 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones. These compounds can be selectively prepared from the same starting material using temperature as the only varied parameter. The 2-azabuta-1,3-diene intermediate, a common precursor for both heterocyclic products, isomerizes into 2H-1,3-oxazine under kinetic control, while 1H-pyrrol-3(2H)-one is the sole product of the reaction at elevated temperatures. According to DFT-calculations a one-atom oxazine ring contraction involving ring-opening to a 2-azabuta-1,3-diene intermediate, followed by a 1,5- and 1,2-prototropic shift leads to the consecutive formation of imidoylketene and azomethine ylide, which then further undergo cyclization to the pyrrole derivative.

Full text of DOI:10.1016/j.tet.2014.03.101

Tetrahedron 70 (2014) 3377e3384
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective syntheses of 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones
via temperature-dependent Rh(II)-carbenoid-mediated 2H-azirine-
ring expansion
*
Kirill V. Zavyalov, Mikail S. Novikov , Alexander F. Khlebnikov, Viktoriia V. Pakalnis
Institute of Chemistry, Saint-Petersburg State University, Universitetskii Pr. 26, 198504 St. Petersburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The Rh(II)-catalyzed reaction of 2-carbonyl-substituted 2H-azirines with ethyl 2-cyano-2-diazoacetate or
2-diazo-3,3,3-trifluoropropionate provides an easy access to 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones.
These compounds can be selectively prepared from the same starting material using temperature as the
only varied parameter. The 2-azabuta-1,3-diene intermediate, a common precursor for both heterocyclic
products, isomerizes into 2H-1,3-oxazine under kinetic control, while 1H-pyrrol-3(2H)-one is the sole
product of the reaction at elevated temperatures. According to DFT-calculations a one-atom oxazine ring
contraction involving ring-opening to a 2-azabuta-1,3-diene intermediate, followed by a 1,5- and 1,2-
prototropic shift leads to the consecutive formation of imidoylketene and azomethine ylide, which
then further undergo cyclization to the pyrrole derivative.
Received 21 January 2014
Received in revised form 17 March 2014
Accepted 31 March 2014
Available online 4 April 2014
Dedicated to Professor Armin de Meijere on
the occasion of his 75th birthday
Keywords:
Azirines
Ó 2014 Elsevier Ltd. All rights reserved.
Diazo compounds
Carbenoids
Ylides
Heterocyclizations
1. Introduction
2H-Azirines are effective heterocyclic building blocks used for
the synthesis of larger heterocycles: pyrroles, indoles, azaindoles,
oxazoles, azepines, and others.1 These syntheses involve catalytic or
thermal azirine ring-opening across an NeC or CeC bond followed
by cyclization, (4þ2)-, (3þ2)-cycloadditions to a C]N bond or ad-
dition of electrophiles to a nitrogen lone pair followed by a three-
membered ring opening. In particular, the reactions of azirines
with electrophilic metallo carbenoids, derived from diazo com-
pounds can result in a one-, two- or three-atom ring expansion via
formal insertion of carbene2e4 or carbonylcarbene moieties and
this provides a short synthetic route to 4e6-membered nitrogen
heterocycles, such as azetes, pyrroles, and 2H-1,4-oxazines. In the
last case a three-atom CeCeO fragment of a carbenoid is formally
inserted into azirine to form a 1,4-oxazine ring. Recently we re-
ported a new example of a three-atom ring expansion of 2H-azir-
ines to 2H-1,3-oxazines by the Rh2(OAc)4-catalyzed reaction with
dimethyl diazomalonate (Scheme 1).5 This process was found to be
characteristic of 2H-azirines having a formyl group in the 2-
Scheme 1. Rh2(OAc)4-catalyzed reaction of azirine-2-carbaldehydes with dimethyl
diazomalonate.
position. The formyl group, along with a carbon atom of the car-
benoid, becomes incorporated into a 1,3-oxazine ring.
Functionalized non-fused 2H-1,3-oxazines containing a hemi-
aminal structural unit are of interest as appropriate building blocks
for the synthesis of various nitrogenated compounds, in particular,
aminoalcohols and azetidines.6 1,3-Oxazines having no heter-
oatomic substituent at C-2 are not readily available compounds,
though several methods for their preparation involving both cyclic
and acyclic precursors are known: phosphine-mediated reaction of
ynones with 2-azido alcohols,7 condensation of 4-amino-1-
azabutadienes with esters of glyoxylic acid,6 thermal ring-
contraction of 1,4-diazepines,8 reaction of
b-carbonyl-substituted
enamines with orthoesters,9 rhodium-catalyzed coupling of iso-
xazoles with diazocarbonyl compounds,10 and base-induced de-
composition of isoxazolium salts.11 These procedures are limited to
* Corresponding author. Tel.: þ7 812 428 4021; fax: þ7 812 428 6939; e-mail
address: m.s.novikov@chem.spbu.ru (M.S. Novikov).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.101

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K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
Table 1
those 1,3-oxazines having a restricted range of substituents and this
prompted us to search for new synthetic methods. Due to the
availability of diazocarbonyl compounds and 2-carbonyl-
substituted 2H-azirines12 the recently found Rh(II)-catalyzed re-
action of these compounds deserve attention as a promising ap-
proach to 2H-1,3-oxazines with electron-withdrawing substitutes
at C-2. To broaden the scope of the reaction, an examination of the
reactivity of cyano- and trifluoromethyl-containing diazo com-
pounds towards various 2-carbonyl-substituted azirines was car-
ried out. In the course of this work a new synthetic application of
the reaction was discovered: a two-atom azirine ring expansion to
1H-pyrrol-3(2H)-ones. Its mechanism was investigated by using
DFT-calculations.
The yields of 2H-1,3-oxazines 3aek
Azirine Diazo
compound
2a
Ar
R1 R2 R3 Reaction
conditions
Oxazine 3 Yield
of 3, %
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1g
1g
4-MeOC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN DCM, 40 ꢀC 3a
69
70
70
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2a
2b
CN DCM, 40 ꢀC 3b
CN DCM, 40 ꢀC 3c
CN DCM, 40 ꢀC 3d
CN DCM, 40 ꢀC 3e
CN TFT, 103 ꢀC 3f
CF3 DCE, 84 ꢀC 3g
CF3 DCE, 84 ꢀC 3h
CF3 DCE, 84 ꢀC 3i
CF3 DCE, 84 ꢀC 3j
CF3 DCE, 84 ꢀC 3k
67
60
Ph
31a
78
4-MeOC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
81
76
73
H
Me
78
Me
Me
Ph Me CN DCM, 40 ꢀC 3l
Ph Me CF3 DCE, 84 ꢀC 3m
60b
38c
2. Results and discussion
a
Ethyl 2-cyano-3-oxo-4,5-diphenyl-2,3-dihydro-1H-pyrrole-2-carboxylate 4f
was also isolated in 19% yield.
b
According to the 1H NMR spectrum of the reaction mixture ethyl 2-cyano-2-
2.1. Syntheses of 1,3-2H-oxazines and 1H-pyrrol-3(2H)-ones
from 2H-azirines
[(E)-4-oxo-3-phenylpent-2-en-2-ylimino]acetate 5a was also formed (3l/5a ratio
12:1).
c
According to the 1H NMR spectrum of the reaction mixture ethyl 3,3,3-trifluoro-
Aiming to broaden the scope of the carbenoid-mediated three-
atom ring expansion of 2H-azirine-2-carbaldehydes 1 to the 2H-
1,3-oxazine system we focused on diazo compounds 2a,b as car-
benoid sources transferring cyano and trifluoromethyl groups into
the target heterocycle. The reaction of azirine 1a with ethyl diaz-
ocyanoacetate 2a was carried out under standard conditions using
Rh2(OAc)4 as a catalyst in refluxing 1,2-dichloroethane (DCE). Un-
expectedly, along with the expected oxazine 3a (35%), pyrrolinone
4a (30%) was also isolated (Scheme 2). It was also found that the
latter is formed from oxazine 3a under refluxing in DCE and hence
the ratio 4a/3a is increased with the increase of heating time.
Fortunately, performing the reaction at a lower temperature
(dichloromethane, DCM, 40 ꢀC) avoided the thermal isomerization
2-[(E)-4-oxo-3-phenylpent-2-en-2-ylimino]propanoate 5b was also formed (3m/5b
ratio 2:1).
There are several methods for the preparation of N-benzyl,13 N-
methyl14 and N-unsubstituted15 1H-pyrrol-3(2H)ones with 2-alkyl,
2-aryl or 2-alkoxycarbonyl substituents.16 The thermal one-atom
1,3-oxazine ring contraction reaction provides an easy access to N-
unsubstituted 1H-pyrrol-3(2H)-ones bearing a CN or CF3 group in
the position 2. The pyrrolinones 4a,e,f with a cyano group in the 2-
position were shown to be formed quantitatively from the corre-
sponding oxazines 3a,e,f in refluxing a,a,a-trifluorotoluene (TFT)
(Scheme 4, Table 2, entries 2, 7, 9). Moreover they can be success-
fully prepared from 3-arylazirines 1aed and diazo compound 2a
without isolation of the intermediate oxazine 3 (Scheme 4, Table 2,
entries 1, 3e5).
Table 2
Syntheses of pyrrolinones 4aeg from 2H-azirines 1aef and oxazines 3a,e,f
Entry
Starting compounds
Ar
R
Yield of 4, %
1
2
3
4
5
6
7
8
9
1aþ2a
3a
4-MeOC6H4
4-MeOC6H4
Ph
4-MeC6H4
H
H
H
H
60 (4a)
100 (4a)
60 (4b)
64 (4c)
59 (4d)
36a (4e)
100 (4e)
19b (4f)
100 (4f)
1bþ2a
1cþ2a
1dþ2a
1eþ2a
3e
Scheme 2. Rh2(OAc)4-catalyzed reaction of azirine 1a with diazo compound 2a.
4-ClC6H4
H
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
of oxazine 3a, and it was isolated in 69% yield as sole product. Under
these conditions oxazines 3bee were synthesized in 60e70% yield
(Scheme 3, Table 1). According to the 1H NMR spectra of the re-
action mixtures (CHBr2CHBr2 as an internal standard) the conver-
sion of azirines 3 was 84e89%. The use of an excess of diazo
compound to raise the conversion leads, however, to a decrease in
the oxazine yield.
1fþ2a
3f
a
According to the 1H NMR spectrum ethyl 2-cyano-5-methyl-4-phenyl-2H-1,3-
oxazine-2-carboxylate 3e was also formed in 17% yield.
b
Oxazine 3f was also isolated in 31% yield.
Scheme 4. Syntheses of pyrrolinones 4aeg.
Scheme 3. Synthesis of 2H-1,3-oxazines 3aem.
Oxazine 3l with a methyl group at the C-2 atom is thermally
stable towards isomerization.
Oxazine 3n, derived from azirine 1a and dimethyl diazo-
malonate 2c, does not undergo visible changes in DCE at 84 ꢀC
(Scheme 5), but refluxing in TFT (103 ꢀC) gave pyrrolinone 4k in 16%
according to 1H NMR spectroscopy: 3.89 (s, 6H, 2ꢁ CO2CH3), 3.90 (s,
2-Acetyl-substituted azirine 1g reacts in a similar way to give
oxazine 3l, bearing a methyl group at atom C-6, in 60% yield. But in
this case the formation of azadiene 5a, in trace amounts (6% on
consumed azirine 1g), was also detected by 1H NMR spectroscopy.

K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
3379
2.2. Theoretical calculations and reaction mechanism
Previous computational studies on the mechanism of formation
of 2H-1,3-oxazine 7 in the Rh(II)-catalyzed reaction of azirine-2-
carbaldehydes 1 with dimethyl diazomalonate 6a demonstrated
that it involves consecutive generation of azirinium ylide 9, ring
opening to 2-azabuta-1,3-diene 10 followed by a 1,6-p-electro-
Scheme 5. Isomerization of oxazine 3n to pyrrolinone 4k.
cyclization.5 The selective isomerization of azirinium ylide to aza-
diene with the C]C bond in Z configuration, which is favorable for
further 1,6-cyclization, was predicted by DFT-calculations. For the
1,3-oxazine-pyrrolin-3-one isomerization 7/8 proceeding at ele-
vated temperatures we proposed the mechanism involving re-
versible oxazine 7 ring-opening to 2-azabutadiene 10 (4-azapenta-
2,4-dienal), 1,5-H-shift to imidoylketene 11, 1,2-H-shift to the NH-
azomethine ylide followed by cyclization (Scheme 7).
3H, CH3O), 5.55 (s, 1H, H-4), 5.91 (br s, 1H, NeH), 7.01 (d, 2H,
J¼8.9 Hz, ArH), 7.67 (d, 2H, J¼8.9 Hz, ArH). This compound is prone
to decomposition during silica gel chromatography and all attempts
to isolate it by chromatography failed.
Changing one of the CO2Me groups in 3n for a trifluoromethyl
group leads to a further increase in the stability of the oxazine: only
heating at 130 ꢀC in o-xylene for 3.5 h results in a full conversion of
3g to pyrrolinone 4g, which was isolated in 43% yield using chro-
matography on silica gel (Scheme 6). Under these conditions oxa-
zines 3hej were isomerized to compounds 4hej in moderate yields
(Table 3). Pyrrolinones 4 could be obtained from the corresponding
azirines 1 without isolation of the intermediate oxazines 3. Thus,
the compound 4g was obtained in 21% yield by decomposition of
diazo compound 2c in the presence of azirine 1a and Rh2(OAc)4 in
TFT at 90 ꢀC followed by additional heating of the reaction mixture
at 135 ꢀC for 3 h.
To the best of our knowledge the isomerization of 4-azapenta-
2,4-dienals to iminoketenes is unknown but the back reaction
proceeding via a [1,5]-H-shift was postulated in a gas-phase py-
rolysis of N-alkylaminomethylene derivatives of Meldrum’s acid to
4-azapenta-2,4-dienals (Scheme 8, reaction 1).17 It was also pro-
posed that a [1,5]-H-shift of the formyl hydrogen proceeds under
isomerization of penta-2,4-dienals to vinylketenes (Scheme 8, re-
action 2).18 Later the ‘ketenic’ mechanism was confirmed by
quantum-chemical calculations for the rearrangement of Zincke
aldehydes.19 The sigmatropic shift of this type can be realized under
milder conditions for penta-2,4-dienals bearing an electron-
withdrawing ester group at C-3.20
Scheme 6. Isomerization of oxazines 3gej to pyrrolinones 4gej.
Table 3
Synthesis of pyrrolinones 4gej from oxazines 3gej
Oxazine
Ar
Pyrrolinone 4
Yield of 4, %
3g
1h
1i
4-MeOC6H4
Ph
4-MeC6H4
4-ClC6H4
4g
4h
4i
43
34
18
11
1j
4j
Scheme 7. Proposed mechanism for the formation of pyrrolinones 8.
The structures of compounds 4aej were verified by 1H and 13C
NMR, IR spectroscopy, and mass-spectrometry and the structure of
4e was confirmed by X-ray analysis (Fig. 1).
Scheme 8. Penta-2,4-dienaldketene isomerization.
To verify the supposed mechanistic scheme we performed
a computational evaluation of free energies of transition states of
the key steps of the oxazine-pyrrolinone isomerization. Because of
the dramatic influence of a C-2 substituent in the 1,3-oxazine on the
Fig. 1. X-ray structure of compound 4e.

3380
K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
rate of this transformation, the substrates 7aec bearing CO2Me, CN,
and CF3 in this position were included into consideration (Scheme
7). The geometries of oxazines 7aec, azadienes 10a, E,Z-, Z,Z-10b,c,
imidoylketenes 11aec, ylides 12aec, pyrrolinones 8aec as well as
the transition states of ring opening of oxazines 7 (TS1(aec)), the
[1,5]-H-shift in azabutadienes 10 (TS2(aec)), and cyclization of
ylides 12 (TS3(aec)) to pyrrolinones 8aec were optimized at the
DFT mPWB1K/6-31þG(d,p) level21 using the PCM solvent model for
toluene. The energy of the most stable conformation of oxazines
7aec, azadienes 10 aec, imidoylketenes 11aec, and azomethine
ylides 12aec were used in the calculations of the activation free
energies (Fig. 2).
lower temperatures.25 The high acidity of 11a in comparison with
11b,c makes the stage of the formation of ylide 12a exothermic,
while 1,2-shifts in imidoylketenes 11b,c are endothermic processes
(Fig. 2).
Attempts to trap the intermediate azomethine ylide by accom-
plishing the reaction of azirine 1a with diazo compound 2a in the
presence of N-(4-bromophenyl)maleimide, as a dipolar trap failed,
probably, due to the very low activation barrier (8.2 kcal/mol) for its
cyclization to pyrrolinone 7a.
The suggested mechanistic scheme involving a [1,5]-prototropic
shift as one of the stages reasonably explains the enhanced thermal
stability of 6-methyl-substituted oxazine 3l, which thermally pro-
Fig. 2. Energy profiles (DFT mPWB1K/6-31þG(d,p), kcal/mol, 375.15 K) for the isomerization of oxazines 7aec to pyrrolinones 8aec in toluene.
As follows from Fig. 2 the activation barriers for ring-opening of
oxazines 7aec are sufficiently low (17.9e22.6 kcal/mol) and can be
overcome at room temperature. Ring-opening of oxazines 7aec is
facilitated when the C-2 substituent changes from CF3 to CO2Me,
and then to CN. Azadienes 10 in all cases are sufficiently less stable
compounds than their cyclic isomers 7 and can exist only as short-
lived intermediates. The activation barriers for the [1,5]-H-shift in
azadienes 10 (25.5e26.6 kcal/mol) practically do not depend on the
substituents R (Scheme 5). However the transition state energy for
this stage appreciably increases in the order of substituents
CN<CO2Me<CF3 (30.4, 32.6, 35.0 kcal/mol) and this is in good
agreement with the experimentally observed relationship between
the temperature needed for isomerization and the character of the
substituent at C-2 in the oxazine.
The 1,2-H-shift in imidoylketene 11, which gives rise to azo-
methine ylide 12, is an intermolecular process22 and a reliable
evaluation of its activation barrier is a rather difficult problem due
to the uncertainty in the nature of the reaction promoter. It is
known that the iminedazomethine ylide prototropy is catalyzed
both by acids and bases22 including such weak bases as the starting
imines and the final cycloaddition products of azomethine ylides.23
Most probably, the barriers for 1,2-H-prototropy in imidoylketens
are lower than those for the 1,5-H-prototropy, giving rise to aza-
dienes 10aec, due to the higher acidity of compounds 11aec. It is
well known that the facility with which the NH-azomethine ylide is
formed depends upon the CH-acidity of the starting imine,22 and
prototropy for iminomalonates usually occurs at 70 ꢀC24 or even at
duces the 2-azadiene intermediate without the hydrogen atom able
to migrate.
3. Conclusions
In conclusion, 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones can
be easily synthesized by the Rh(II)-catalyzed reaction of 2-
carbonyl-substituted 2H-azirines with ethyl 2-cyano-2-diazo
acetate or 2-diazo-3,3,3-trifluoropropionate using temperature
as the only controlled variable. The 2-azabutadiene intermediate,
a common precursor for both heterocyclic products, isomerizes
into 2H-1,3-oxazine under kinetic control, while 1H-pyrrol-3(2H)-
one is the sole product of the reaction at elevated temperatures.
According to DFT-calculations the one-atom oxazine ring con-
traction involves the ring-opening to the 2-azabuta-1,3-diene
derivative, a 1,5-/1,2-prototropic shift cascade via the formation
of imidoylketene and NH-azomethine ylide followed by
cyclization.
4. Experimental section
4.1. General methods
Melting points were determined on a hot stage microscope and
are uncorrected. 1H (300 or 400 MHz) and 13C (75 or 100 MHz) NMR
spectra were determined in CDCl3 and DMSO-d6. Chemical shifts (
d)
are reported in parts per million downfield from tetramethylsilane.

K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
3381
Electrospray ionization mass spectra were measured on a Bruker
micrOTOF mass spectrometer. IR spectra were recorded on a SPE-
CORD M80 spectrometer for tablets in KBr or solutions in CHCl3.
Single crystal X-ray data were collected on an Agilent Technologies
Xcalibur Eos diffractometer and measured at a temperature of
TOF, [MþH]þ): calcd for C15H15N2O4, 287.1026; found 287.1032. If
the reaction of azirine 1a (150 mg, 0.9 mmol) with diazo compound
2a (119 mg, 0.9 mmol) in the presence of Rh2(OAc)4 (1 mol %) is
carried out according to procedure A in refluxing DCE instead of
DCM then after chromatographic purification oxazine 3a (86 mg,
35%) and pyrrolinone 4a (73 mg, 30%) were formed.
100 K using monochromated Mo K
a radiation. An empirical ab-
sorption correction was applied in CrysAlisPro program complex
using spherical harmonics implemented in Scale 3 Abspackslaling
algorithm. The structure has been solved by direct methods using
the SHELX-97 program incorporated in the OLEX2 program pack-
age. Positions of H atoms were modeled using the ‘riding’ model.
Crystallographic data for the structures have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-970742 (for 4e). Silica gel Merck 60 was used
for column chromatography. Thin-layer chromatography (TLC) was
conducted on alumina sheets precoated with SiO2 ALUGRAM SIL G/
UV254. Compounds 1aef,12e 1g,26 2a,27 and 2b28 were prepared by
the reported procedures.
4.3.4. Ethyl 2-cyano-4-phenyl-2H-1,3-oxazine-2-carboxylate
(3b). Compound 3b was prepared according to general procedure
A, using DCM as a solvent, from azirine 1b (75 mg, 0.52 mmol) and
diazo compound 2a (72 mg, 0.52 mmol) as a yellowish solid (92 mg,
70%). Mp 50e52 ꢀC (hexane/Et2O). Rf¼0.27 (25% EtOAc/hexane). IR
(KBr): 3100, 3085, 2995, 2240, 1745, 1625, 1520, 1315, 1225, 1100,
1025 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.45 (t, 3H, J¼7.1 Hz, CH3),
4.48 (q, 2H, J¼7.1 Hz, CH2), 6.39 (d, 1H, J¼5.9 Hz, H-5), 7.21 (br s, 1H,
H-6), 7.44e7.58 (m, 3H, ArH), 7.88 (d, 2H, J¼7.3 Hz, ArH). 13C NMR
(75 MHz, CDCl3):
d 13.8 (CH3), 64.2 (CH2), 84.6 (C-2), 101.6 (C-5),
113.8 (CN), 127.3, 128.7, 132.2, 134.2 (Ar), 152.0 (C-6), 162.7, 163.6 (C-
4, C]O). HRMS (ESI-TOF, [MþNa]þ): calcd for C14H12N2NaO3,
279.0740; found 279.0730.
4.2. Calculation details
All calculations were performed with the mPWB1K density
functional method by using the Gaussian 0929 suite of quantum
chemical programs. Geometry optimizations of intermediates,
transition states, reactants, and products in toluene were per-
formed at the DFT mPWB1K/6-31þG(d,p) level using the PCM
model. Stationary points on the respective potential-energy sur-
faces were characterized at the same level of theory by evaluating
the corresponding Hessian indices. Careful verification of the
unique imaginary frequencies for transition states was carried out
to check whether the frequency indeed pertains to the desired
reaction coordinate.
4.3.5. Ethyl 2-cyano-4-(4-methylphenyl)-2H-1,3-oxazine-2-
carboxylate (3c). Compound 3c was prepared according to gen-
eral procedure A, using DCM as solvent, from azirine 1c (75 mg,
0.47 mmol) and diazo compound 2a (65 mg, 0.47 mmol) as a yel-
lowish solid (89 mg, 70%). Mp 51e53 ꢀC (hexane/Et2O). IR (KBr):
3115, 3045, 2990, 2240, 1770, 1630, 1530, 1520, 1305, 1275, 1105,
1050 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.45 (t, 3H, J¼7.1 Hz, CH3),
2.42 (s, 3H, CH3), 4.48 (q, 2H, J¼7.1 Hz, CH2), 6.38 (d,1H, J¼5.9 Hz, H-
5), 7.20 (br s, 1H, H-6), 7.27 (d, 2H, J¼7.9 Hz, ArH), 7.78 (d, 2H,
J¼7.9 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d 13.9 (CH3), 21.5 (CH3),
64.2 (CH2), 101.6 (C-5), 113.9 (CN), 127.3, 129.4, 131.5, 143.0 (Ar),
151.7 (C-6),162.9,163.3 (C-4, C]O). HRMS (ESI-TOF, [MþH]þ): calcd
for C15H15N2O3, 271.1077; found 271.1074.
4.3. Synthesis of oxazines 3aee, gel
4.3.1. General procedure A (for oxazines 3aee, l). A solution of diazo
compound 2a (69.5 mg, 0.5 mmol) in anhydrous dichloromethane
(DCM) (1 mL) was added in one portion to a stirred solution of
azirine 1aef (0.5 mmol) and Rh2(OAc)4 (1 mol %) in anhydrous
DCM (1 mL) at reflux under an argon atmosphere, and the mixture
was stirred at this temperature for 10 min. The solvent was
evaporated in vacuo, and the residue was purified by column
chromatography on silica gel (eluent hexane/EtOAc) to give com-
pound 3aee, l.
4.3.6. Ethyl 4-(4-chlorophenyl)-2-cyano-2H-1,3-oxazine-2-
carboxylate (3d). Compound 3d was prepared according to gen-
eral procedure A, using DCM as solvent, from azirine 1d (75 mg,
0.42 mmol) and diazo compound 2a (58 mg, 0.42 mmol) as a yel-
lowish solid (82 mg, 67%). Mp 50e54 ꢀC (hexane/Et2O). Rf¼0.29
(25% EtOAc/hexane). IR (KBr): 3120, 2985, 2935, 2240, 1775, 1630,
1450, 1310, 1273, 1124, 1110, 1050 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.45 (t, 3H, J¼7.1 Hz, CH3), 4.48 (q, 2H, J¼7.1 Hz, CH2), 6.35 (d, 1H,
J¼5.9 Hz, H-5), 7.20 (br s, 1H, H-6), 7.44 (d, 2H, J¼8.5 Hz, ArH), 7.83
(d, 2H, J¼8.5 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d 13.9 (CH3), 64.3
4.3.2. General procedure B (for oxazines 3gek). A solution of diazo
compound 2b (218 mg, 1.2 mmol) in anhydrous 1,2-dichloroethane
(DCE) (5 mL) was added using a syringe during 1.5 h to a stirred
solution of azirine 1aef (1.0 mmol) and Rh2(OAc)4 (1 mol %) in
anhydrous DCE (3 mL) at reflux under an argon atmosphere, and
the mixture was stirred at this temperature for an additional 5 min.
The solvent was evaporated in vacuo, and the residue was purified
by column chromatography on silica gel (eluent hexane/EtOAc) to
give compound 3gek.
(CH2), 101.2 (C-5), 113.7 (CN),128.7,129.0,132.6,138.7 (Ar),152.4 (C-
6), 162.6, 162.7 (C-4, C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
C
14H1235ClN2O3, 291.0531; found 291.0532.
4.3.7. Ethyl 2-cyano-5-methyl-4-phenyl-2H-1,3-oxazine-2-
carboxylate (3e). Compound 3e was prepared according to gen-
eral procedure A, using DCM as solvent, from azirine 1e (80 mg,
0.5 mmol) and diazo compound 2a (70 mg, 0.5 mmol) as a yel-
lowish oil (82 mg, 60%). IR (KBr): 3065, 2985, 2940, 1740, 1605,
1495, 1445, 1382, 1195, 1015 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d 1.43
4.3.3. Ethyl 2-cyano-4-(4-methoxyphenyl)-2H-1,3-oxazine-2-
carboxylate (3a). Compound 3a was prepared according to pro-
cedure A, using DCM as solvent, from azirine 1a (75 mg, 0.43 mmol)
and diazo compound 2a (60 mg, 0.43 mmol) as a yellowish oil
(85 mg, 69%). IR (KBr): 3085, 2985, 2940, 2840, 2240, 1760, 1605,
1635, 1605, 1515, 1260, 1220, 1105 cmꢂ1. 1H NMR (300 MHz, CDCl3):
(t, 3H, J¼7.1 Hz, CH3), 1.89 (s, 3H, CH3), 4.41e4.50 (m, 2H, CH2), 6.96
(s, 1H, H-6), 7.45e7.51 (m, 5H, ArH). 13C NMR (75 MHz, CDCl3):
d
13.8 (CH3), 14.1 (CH3), 64.2 (CH2), 84.1 (C-2), 112.5, 114.1 (Ar, CN),
128.1, 128.4, 130.5, 135.4 (Ar), 147.6 (C-6), 162.9, 169.9 (C-4, C]O).
HRMS (ESI-TOF, [MþNa]þ): calcd for C15H14N2NaO3, 293.0897;
found 293.0892.
d
1.44 (t, 3H, J¼7.1 Hz, CH3), 3.87 (s, 3H, CH3O), 4.48 (q, 2H, J¼7.1 Hz,
CH2), 6.37 (d, 1H, J¼5.9 Hz, H-5), 6.96 (d, 2H, J¼8.5 Hz, ArH), 7.19
4.3.8. Ethyl 2-cyano-4,5-diphenyl-2H-1,3-oxazine-2-carboxylate
(3f). Compound 3f was prepared according to general procedure
C (see below), using anhydrous TFT (5 mL) as solvent, from azirine
1f (75 mg, 0.34 mmol) and diazo compound 2b (47 mg, 0.34 mmol)
(br s,1H, H-5), 7.86 (d, 2H, J¼8.5 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d
13.9 (CH3), 55.4 (CH3O), 64.1 (CH2), 101.4 (C-5), 114.0, 126.7, 129.2
(Ar), 151.8 (C-6), 162.5, 162.96, 163.05 (C-6, C-4, C]O). HRMS (ESI-

3382
K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
as a yellowish oil (35 mg, 31%). 1H NMR (300 MHz, CDCl3):
3H, J¼7.1 Hz, CH3), 4.42 (q, 2H, J¼7.1 Hz, CH2), 7.07 (s, 1H, H-6),
7.15e7.51 (m, 10H, ArH). 13C NMR (75 MHz, CDCl3):
13.9 (CH3),
d
1.41 (t,
(ESI-TOF, [MþH]þ): calcd for C14H1235ClF3NO3, 334.0452; found
334.0448.
d
64.7 (CH2), 112.8 (CN), 123.2, 125.5, 128.3, 128.4, 128.7, 128.8, 130.5,
139.0, 131.2, 144.4, 154.7, 162.3 (C-4, C]O). HRMS (ESI-TOF,
[MþNa]þ): calcd for C20H16N2NaO3, 355.1053; found 355.1054.
4.3.13. Ethyl 5-methyl-4-phenyl-2-trifluoromethyl-2H-1,3-oxazine-
2-carboxylate (3k). Compound 3k was prepared according to gen-
eral procedure B, using DCE as solvent, from azirine 1e (150 mg,
0.94 mmol) and diazo compound 2b (206 mg, 1.13 mmol) as a yel-
lowish solid (229 mg, 78%). Mp 34e36 ꢀC (hexane/Et2O). Rf¼0.47
(25% EtOAc/hexane). IR (KBr): 3075, 2980, 1740, 1660, 1550, 1445,
4.3.9. Ethyl 4-(4-methoxyphenyl)-2-trifluoromethyl-2H-1,3-oxazine-
2-carboxylate (3g). Compound 3g was prepared according to gen-
eral procedure B, using DCE as solvent, from azirine 1a (200 mg,
1.14 mmol) and diazo compound 2b (250 mg, 1.37 mmol) as a yel-
lowish solid (293 mg, 78%). Mp 69e71 ꢀC (hexane/Et2O). Rf¼0.33
(25% EtOAc/hexane). IR (KBr): 3055, 3000, 2975, 2950, 1755, 1635,
1610, 1540, 1515, 1420, 1325, 1254, 1225, 1195, 1025 cmꢂ1. 1H NMR
1375, 1195, 1095, 1032 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d 1.35 (t,
3H, J¼7.1 Hz, CH3), 1.75 (d, 3H, J¼1.2 Hz, CH3), 4.38 (q, 2H, J¼7.1 Hz,
CH2), 6.86 (d, 1H, J¼1.2 Hz, C-5), 7.40e7.53 (m, 5H, ArH). 13C NMR
(100 MHz, CDCl3):
d 13.9 (CH3), 14.0 (CH3), 63.1 (CH2), 89.6 (q,
J¼31.8 Hz, C-2), 109.8 (C-5), 121.1 (q, J¼285 Hz, CF3), 128.0, 128.3,
130.0, 136.3 (Ar), 147.9 (C-6), 164.6, 168.1 (C-4, C]O). HRMS (ESI-
TOF, [MþH]þ): calcd for C15H15F3NO3, 314.0999; found 314.0993.
(400 MHz, CDCl3):
d
1.31 (t, 3H, J¼7.1 Hz, CH3), 3.85 (s, 3H, CH3O),
4.28e4.41 (m, 2H, CH2), 6.07 (d, 1H, J¼5.9 Hz, H-5), 6.93e6.97 (m,
2H, ArH), 7.08 (d, 1H, J¼5.9 Hz, H-6), 7.86e7.90 (m, 2H, ArH). 13C
NMR (100 MHz, CDCl3):
d
13.9 (CH3), 55.3 (CH3O), 63.0 (CH2), 90.2
4.3.14. Ethyl 2-cyano-4,6-dimethyl-5-phenyl-2H-1,3-oxazine-2-
carboxylate (3l). Compound 3l was prepared according to general
procedure A from azirine 1g (100 mg, 0.58 mmol) and diazo com-
pound 2a (80 mg, 0.58 mmol). A mixture of oxazine 3l and ethyl 2-
cyano-2-[(E)-4-oxo-3-phenylpent-2-en-2-ylimino]acetate 5a in
12:1 ratio (107 mg, 65%) was isolated. Pure oxazine 3l (98 mg, 60%)
was obtained as a yellow solid by crystallization from hexane/Et2O
(2:1). Compound 3l. Mp 43e45 ꢀC (hexane/Et2O). Rf¼0.33 (25%
EtOAc/hexane). IR (KBr): 3030, 2985, 2935, 2235, 1775, 1650, 1555,
(q, J¼32 Hz, C-2), 98.8 (C-5), 113.9 (Ar), 121.1 (q, J¼285 Hz, CF3),
127.5, 128.9 (Ar), 151.9 (C-6), 161.0, 162.6, 164.4 (Ar, C-4, C]O).
HRMS (ESI-TOF, [MþH]þ): calcd for C15H15F3NO4, 330.0948; found
330.0946.
4.3.10. Ethyl 4-phenyl-2-trifluoromethyl-2H-1,3-oxazine-2-
carboxylate (3h). Compound 3h was prepared according to gen-
eral procedure B, using DCE as solvent, from azirine 1b (100 mg,
0.69 mmol) and diazo compound 2b (188 mg, 1.03 mmol) as a col-
orless solid (167 mg, 81%). Mp 49e51ꢀC (hexane/Et2O). Rf¼0.42
(25% EtOAc/hexane). IR (KBr): 3095, 2995, 2950, 2915, 1745, 1635,
1535, 1335, 1260, 1230, 1195, 1070, 1025 cmꢂ1. 1H NMR (400 MHz,
1425, 1310, 1250, 1115, 1070 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d 1.46
(t, 3H, J¼7.1 Hz, CH3), 1.92 C (s, 3H, CH3), 1.94 (s, 3H, CH3), 4.45e4.54
(m, 2H, CH2), 7.19e7.21 (m, 2H, ArH), 7.39e7.46 (m, 3H, ArH). 13C
NMR (75 MHz, CDCl3):
d 13.9 (CH3), 17.0 (CHH3), 23.5 (CH3), 64.2
CDCl3):
1H, J¼5.9 Hz, H-5), 7.12 (d, 1H, J¼5.9 Hz H-6), 7.44e7.56 (m, 3H,
ArH), 7.88e7.92 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3):
13.9
d
1.33 (t, 3H, J¼7.1 Hz, CH3), 4.30e4.43 (m, 2H, CH2), 6.10 (d,
(CH2), 84.0 (C-2), 114.5 (CN), 116.8, 128.2, 128.9, 130.2, 133.4 (C-5,
Ar), 157.8 (C-6), 163.3, 169.3 (C-4, C]O). HRMS (ESI-TOF, [MþNa]þ):
calcd for C16H16N2NaO3, 307.1053; found 307.1054.
d
(CH3), 63.2 (CH2), 90.2 (q, J¼32 Hz, C-2), 99.0 (C-5), 121.1 (q,
J¼285 Hz, CF3), 127.1, 128.6, 131.8, 135.0 (Ar), 152.2 (C-6), 162.1, 164.1
(C-4, C]O). HRMS (ESI-TOF, [MþH]þ): calcd for C14H13F3NO3,
300.0842; found 300.0836.
4.3.15. Ethyl 4,6-dimethyl-5-phenyl-2-trifluoromethyl-2H-1,3-
oxazine-2-carboxylate (3m). Compound 3m was prepared accord-
ing to general procedure B, using DCE as solvent, from azirine 1g
(150 mg, 0.87 mmol) and diazo compound 2b (189 mg, 1.04 mmol).
A mixture of oxazine 3m and ethyl 3,3,3-trifluoro-2-[(E)-4-oxo-3-
phenylpent-2-en-2-ylimino]propanoate 5b in 2:1 ratio (186 mg,
66%) was isolated. Pure oxazine 3m (108 mg, 38%) was obtained as
a colorless solid after refluxing this mixture in o-xylene for 3 h
followed by chromatographic purification on silica gel (eluent
hexane/EtOAc). Mp 61e63 ꢀC (hexane/Et2O). Rf¼0.52 (25% EtOAc/
hexane). IR (KBr): 3070, 3010, 2985, 1750, 1655, 1570, 1495, 1380,
1335, 1245, 1190, 1130, 1070, 1045, 1020 cmꢂ1. 1H NMR (300 MHz,
4.3.11. Ethyl 4-(4-methylphenyl)-2-trifluoromethyl-2H-1,3-oxazine-
2-carboxylate (3i). Compound 3i was prepared according to
general procedure B, using DCE as solvent, from azirine 1c
(75 mg, 0.47 mmol) and diazo compound 2b (103 mg, 0.57 mmol)
as a yellowish solid (112 mg, 76%). Mp 83e85 ꢀC (hexane/Et2O).
Rf¼0.47 (25% EtOAc/hexane). IR (KBr): 3090, 2995, 1745, 1635,
1535, 1425, 1285, 1260, 1235, 1195, 1030 cmꢂ1. 1H NMR (400 MHz,
CDCl3):
d
1.32 (t, 3H, J¼7.1 Hz, CH3), 2.41 (s, 3H, CH3), 4.28e4.42
(m, 2H, CH2), 6.08 (d, 1H, J¼5.8 Hz, H-5), 7.10 (d, 1H, J¼5.8 Hz, H-
CDCl3):
CH3), 4.25e4.47 (m, 2H, CH2), 7.08e7.11 (m, 2H, ArH), 7.32e7.39 (m,
3H, ArH). 13C NMR (75 MHz, CDCl3):
14.0 (CH3), 17.1 (CH3), 23.6
d
1.35 (t, 3H, J¼7.1 Hz, CH3), 1.89 (s, 3H, CH3), 1.91 (s, 3H,
6), 7.26 (d, 2H, ArH), 7.80 (d, 2H, J¼8.1 Hz, ArH). 13C NMR
(100 MHz, CDCl3):
d
13.9 (CH3), 21.4 (CH3), 63.1 (CH2), 90.3
d
(q, J¼31.5 Hz, C2), 99.0 (C-5), 121.1 (q, J¼285 Hz, CF3), 127.1,
129.3, 132.2, 142.3 (Ar), 152.0 (C-6), 161.8, 164.3 (C-4, C]O).
HRMS (ESI-TOF, [MþH]þ): calcd for C15H15F3NO3, 314.0999;
found 314.1005.
(CH3), 63.0 (CH2), 89.6 (q, J¼31.4 Hz, C-2), 114.9 (C-5), 121.5 (q,
J¼285 Hz, CF3), 127.9, 128.7, 130.2, 134.0 (Ar), 158.2 (C-6), 164.9,
167.4 (C-4, C]O). HRMS (ESI-TOF, [MþH]þ): calcd for C16H17F3NO3,
328.1155; found 328.1157. Compound 5b (not separated), Rf¼0.52
(25% EtOAc/hexane). 1H NMR (300 MHz, CDCl3):
d
1.34 (t, J¼7.3 Hz,
4.3.12. Ethyl 4-(4-chlorophenyl)-2-trifluoromethyl-2H-1,3-oxazine-
2-carboxylate (3j). Compound 3j was prepared according to gen-
eral procedure B, using DCE as solvent, from azirine 1d (155 mg,
0.86 mmol) and diazo compound 2b (189 mg, 1.04 mmol) as a yel-
lowish solid (210 mg, 73%). Mp 52e54 ꢀC (hexane/Et2O). IR (KBr):
3095, 2985, 1760, 1640, 1595, 1575, 1540, 1423, 1325, 1280, 1245,
CH3), 2.03 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.30 (q, J¼7.3 Hz, CH2),
7.01e7.11 (m, 2H, ArH), 7.29e7.43 (m, 3H, ArH). 13C NMR (75 MHz,
CDCl3):
d 13.7 (CH3), 18.5 (CH3), 31.0 (CH3), 63.1 (CH2), 117.5 (q,
J¼279 Hz, CF3), 127.7, 128.7, 129.4, 136.1 (Ar), 144.7 (q, J¼37 Hz),
153.1, 155.9, 164.1 (C]O), 199.4 (C]O).
1205, 1078, 1025 cmꢂ1
.
1H NMR (400 MHz, CDCl3):
d
1.32 (t, 3H,
4.4. Syntheses of pyrrolinones 4aef
J¼7.15 Hz, CH3), 4.29e4.42 (m, 2H, CH2), 6.04 (d, 1H, J¼5.9 Hz, H-5),
7.12 (d, 1H, J¼5.9 Hz, H-6), 7.41 (d, 2H, J¼8.6 Hz, ArH), 7.824 (d, 2H,
4.4.1. General procedure C. A solution of diazo compound 2a
(0.5 mmol) in anhydrous TFT (5 mL) was added using a syringe over
1.5 h to a stirred solution of azirine 1aef (0.5 mmol) and Rh2(OAc)4
(2.2 mg, 1 mol %) in anhydrous TFT (5 mL) at reflux under an argon
J¼8.6 Hz, ArH). 13C NMR (100 MHz, CDCl3):
d 13.9 (CH3), 63.3 (CH2),
90.2 (q, J¼32.0 Hz, C-2), 98.6 (C-5), 121.0 (q, J¼285 Hz, CF3), 128.5,
128.9, 133.3, 138.1 (Ar), 152.6 (C-6), 161.1, 164.0 (C-4, C]O). HRMS

K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
3383
atmosphere and the mixture was stirred at this temperature for
additional 5 min. The solvent was evaporated in vacuo and the
residue was purified by column chromatography on silica gel (el-
uent hexane/EtOAc) to give compound 4aef.
According to 1H NMR spectroscopy oxazine 3e was detected in the
reaction mixture in 17% yield. Compound 4e. Mp 164e165 ꢀC
(Et2O). Rf¼0.55 (50% EtOAc/hexane). IR (KBr): 3385, 3060, 2980,
1745, 1665, 1605, 1580, 1560, 1465, 1245, 1196, 1080, 950 cmꢂ1. 1H
NMR (300 MHz, CDCl3):
4.42 (q, 2H, J¼7.1 Hz, CH2), 5.27 (s, 1H, NH), 7.55e7.71 (m, 5H, ArH).
13C NMR (75 MHz, CDCl3):
8.04 (CH3), 13.9 (CH3), 64.1 (C-2), 65.0
d
1.42 (t, 3H, J¼7.1 Hz, CH3),1.94 (s 3H, CH3),
4.4.2. Ethyl 2-cyano-5-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-
pyrrole-2-carboxylate (4a). Compound 4a was prepared according
to procedure C from azirine 1a (75 mg, 0.43 mmol) and diazo
compound 2a (60 mg, 0.43 mmol) as a yellowish oil (73 mg, 60%).
Rf¼0.36 (50% EtOAc/hexane). IR (KBr): 3260, 2985, 2925, 2850,
1755, 1665, 1605, 1580, 1555, 1495, 1465, 1270, 1185, 1160,
d
(CH2), 107.3 (C-4), 113.7 (CN), 127.9, 129.2, 130.4, 132.2 (Ar), 161.6,
174.4 (C-5, C]O), 187.7 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
C15H15N2O3, 271.1077; found 271.1080. Crystal data (CCDC-970742):
C
15H14N2O3, M¼270.28, monoclinic, space group P21/n,
1020 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.38 (t, 3H, J¼7.1 Hz, CH3),
a¼11.3003(5), b¼9.3561(3), c¼12.7239(4) A,
a¼90,
b
¼96.244(4),
ꢀ
3
ꢀ
ꢀ
3.91 (3H, CH3O), 4.40 (q, 2H, J¼7.1 Hz, CH2), 5.56 (s, 1H, C-4), 6.24 (s,
g
¼90 , V¼1337.24(9) A , Z¼4, T¼100 K,
m
(Mo K
a
)¼0.095 mmꢂ1
,
1H, NH), 7.03 (d, 2H, J¼8.8 Hz, ArH), 7.69 (d, 2H, J¼8.8 Hz, ArH). 13
C
6519 reflections measured, 3075 unique (Rint¼0.0208) were used in
NMR (75 MHz, CDCl3):
d
13.9 (CH3), 55.6 (CH3O), 64.8 (CH2), 65.4
all calculations. The final R1 was 0.0385 (2519>2s(I)) and wR2 was
(C-2), 94.8 (C-4), 113.7 (CN), 114.8, 120.7, 129.2 (Ar), 161.7, 164.0,
178.0 (Ar, C-5, C]O), 185.8 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd
for C15H15N2O4, 287.1026; found 287.1038. Compound 4a was ob-
tained in quantitative yield by refluxing a solution of oxazine 3a in
anhydrous TFT for 1 h.
0.0898 (all data). Compound 4e was obtained in quantitative yield
by refluxing a solution of oxazine 3e in anhydrous TFT for 5 h.
4.4.7. Ethyl 2-cyano-4,5-diphenyl-3-oxo-2,3-dihydro-1H-pyrrole-2-
carboxylate (4f). Compound 4f was prepared according to pro-
cedure C from azirine 1f (75 mg, 0.34 mmol) and diazo compound
2a (47 mg, 0.34 mmol) as a yellowish oil (22 mg, 19%). Rf¼0.58 (50%
EtOAc/hexane). IR (KBr): 3290, 3060, 2985, 2925, 2250, 1755, 1655,
4.4.3. Ethyl 2-cyano-3-oxo-5-phenyl-2,3-dihydro-1H-pyrrole-2-
carboxylate (4b). Compound 4b was prepared according to pro-
cedure C from azirine 1b (75 mg, 0.52 mmol) and diazo compound
2a (72 mg, 0.52 mmol) as a yellowish solid (79 mg, 60%). Mp
115e118 ꢀC (Et2O). Rf¼0.45 (50% EtOAc/hexane). IR (KBr): 3300,
2985, 1750, 1680, 1545, 1490, 1475, 1250, 1150, 1075 cmꢂ1. 1H NMR
1605, 1550, 1485, 1440, 1245, 1180, 1075, 980 cmꢂ1
(300 MHz, CDCl3):
CH2), 5.68 (s, 1H, NH), 7.21e7.55 (m, 10H, ArH). 13C NMR (75 MHz,
CDCl3): 14.0 (CH3), 64.6 (C-2), 65.1 (CH2), 111.4 (C-4), 113.5 (CN),
.
1H NMR
d
1.44 (t, 3H, J¼7.1 Hz, CH3), 4.46 (q, 2H, J¼7.1 Hz,
d
(300 MHz, CDCl3):
CH2), 5.65 (s, 1H, C-4), 6.17 (s, 1H, NH), 7.54e7.75 (m, 5H, ArH). 13
NMR (75 MHz, CDCl3): 13.9 (CH3), 65.0 (CH2), 65.4 (C-2), 96.4 (C-
d
1.39 (t, 3H, J¼7.1 Hz, CH3), 4.41 (q, 2H, J¼7.1 Hz,
127.5, 128.4, 128.5, 129.1, 129.2, 129.3, 129.9, 132.5 (Ar), 161.4, 174.6
C
(C-5, C]O), 185.2 (C]O). HRMS (ESI-TOF, [MþNa]þ): calcd for
d
C20H16N2NaO3, 355.1053; found: 355.1055. Compound 4f was ob-
4), 113.4 (CN), 127.1, 128.6, 129.4, 133.6 (Ar), 161.4, 178.5 (C-5, C]O),
186.0 (C]O). HRMS (ESI-TOF, [MþNa]þ): calcd for C14H12N2NaO3,
279.0740; found 279.0733.
tained in quantitative yield by refluxing a solution of oxazine 3f in
anhydrous TFT for 12 h.
4.5. Syntheses of pyrrolinones 4gej
4.4.4. Ethyl 2-cyano-5-(4-methylphenyl)-3-oxo-2,3-dihydro-1H-pyr-
role-2-carboxylate (4c). Compound 4c was prepared according to
procedure C from azirine 1c (75 mg, 0.47 mmol) and diazo com-
pound 2a (66 mg, 0.47 mmol) as a yellowish solid (82 mg, 64%). Mp
102e104 ꢀC (Et2O). Rf¼0.49 (50% EtOAc/hexane). IR (KBr): 3290,
2985, 2935, 1760, 1680, 1615, 1580, 1555, 1465, 1251, 1190, 1155,
4.5.1. General procedure. A solution of oxazine 3gej (100 mg) in
anhydrous o-xylene was stirred under heating at 130 ꢀC for 3.5 h.
The solvent was evaporated in vacuo and the residue purified by
column chromatography on silica gel (eluent EtOAc/hexane) to give
pyrrolinones 4gej.
1015, 970 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.38 (t, 3H, J¼7.1 Hz,
CH3), 2.46 (s, 3H, CH3), 4.40 (q, 2H, J¼7.1 Hz, CH2), 5.61 (s, 1H, C-4),
6.19 (s, 1H, NH), 7.35 (d, 2H, J¼7.8 Hz, ArH), 7.62 (d, 2H, J¼7.8 Hz,
4.5.2. Ethyl 5-(4-methoxyphenyl)-3-oxo-2-(trifluoromethyl)-2,3-
dihydro-1H-pyrrole-2-carboxylate (4g). Yield 43%. Yellowish solid.
Mp 118e120 ꢀC (hexane/Et2O). Rf¼0.44 (50% EtOAc/hexane). IR
(KBr): 3230, 3010, 2940, 2845, 1760, 1670, 1605, 1555, 1505, 1270,
ArH). 13C NMR (75 MHz, CDCl3):
d 13.9 (CH3), 21.7 (CH3), 64.9 (CH2),
65.4 (C-2), 95.6 (C-4), 113.5 (CN), 125.7, 127.1, 130.1, 144.7 (Ar), 161.5,
178.5 (C-5, C]O), 186.0 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
1180, 998 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d
1.36 (t, 3H, J¼7.1 Hz,
C
15H15N2O3, 271.1077; found 271.1083.
CH3), 3.92 (s, 3H, CH3O), 4.31e4.49 (m, 2H, CH2), 5.62 (s, 1H, C-4),
5.73 (s, 1H, NH), 7.04 (d, 2H, J¼8.9 Hz, ArH), 7.71 (d, 2H, J¼8.9 Hz,
4.4.5. Ethyl 5-(4-chlorophenyl)-2-cyano-3-oxo-2,3-dihydro-1H-pyr-
role-2-carboxylate (4d). Compound 4d was prepared according to
procedure C from azirine (75 mg, 0.42 mmol) and diazo compound
2a (58 mg, 0.42 mmol) as a yellowish solid (72 mg, 59%). Mp
150e153 ꢀC (Et2O). Rf¼0.56 (50% EtOAc/hexane). IR (KBr): 3280,
2980, 1760, 1680, 1600, 1580, 1545, 1485, 1465, 1235, 1155, 1095,
ArH). 13C NMR (100 MHz, CDCl3):
d 13.9 (CH3), 55.6 (CH3O), 64.0
(CH2), 72.5 (q, J¼28.7 Hz, C-2), 98.0 (C-4), 114.6 (Ar), 121.4 (q,
J¼283 Hz, CF3), 121.4, 129.0 (Ar), 162.1, 163.7, 177.6 (Ar, C]O, C-5),
187.3 (C]O). HRMS (ESI-TOF, [MþNa]þ): calcd for C15H14F3NNaO4,
352.0767; found: 352.0769.
Compound 4g was also obtained according to procedure C from
azirine 1a (100 mg, 0.57 mmol), diazo compound 2c (125 mg,
0.69 mmol), and Rh2(OAc)4 (3 mg, 1 mol %) at 90 ꢀC. After com-
pletion of the decomposition of the diazo compound the flask was
closed with a stopper, which was fixed so as to keep a slight excess
pressure and the reaction mixture was stirred at 135 ꢀC for 3 h. The
solvent was evaporated in vacuo, and the residue was purified by
column chromatography on silica gel (eluent hexane/EtOAc) to give
compound 4g (39 mg, 21%).
1015 cmꢂ1
.
1H NMR (300 MHz, DMSO-d6):
d
1.22 (t, 3H, J¼7.1 Hz,
CH3), 4.30 (q, 2H, J¼7.1 Hz, CH2), 5.91 (s, 1H, C-4), 7.72 (d, 2H,
J¼8.5 Hz, ArH), 7.94 (d, 2H, J¼8.5 Hz, ArH), 9.71 (s, 1H, NH). 13C NMR
(75 MHz, CDCl3):
d 13.9 (CH3), 65.1 (CH2), 65.5 (C-2), 96.6 (C-4),
113.3 (CN), 127.0, 128.4, 129.8, 140.0 (Ar), 161.3, 177.2 (C-5, C]O),
186.0 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd for C14H1235ClN2O3,
291.0531; found 291.0533.
4.4.6. Ethyl 2-cyano-4-methyl-5-phenyl-3-oxo-2,3-dihydro-1H-pyr-
role-2-carboxylate (4e). Compound 4e was prepared according to
procedure C from azirine 1e (80 mg, 0.5 mmol) and diazo com-
pound 2a (70 mg, 0.5 mmol) as a yellowish solid (49 mg, 36%).
4.5.3. Ethyl
3-oxo-5-phenyl-2-(trifluoromethyl)-2,3-dihydro-1H-
pyrrole-2-carboxylate (4h). Yield 34%. Yellowish oil. Rf¼0.49 (50%
EtOAc/hexane). IR (KBr): 3270, 2985, 2855, 1760, 1675, 1605, 1555,

3384
K.V. Zavyalov et al. / Tetrahedron 70 (2014) 3377e3384
1495, 1475, 1295, 1250, 1175, 1035 cmꢂ1. 1H NMR (400 MHz, CDCl3):
1.36 (t, 3H, J¼7.1 Hz, CH3), 4.32e4.45 (m, 2H, CH2), 5.68 (s, 1H, C-
4), 5.95 (s, 1H, NH), 7.52e7.64 (m, 3H, ArH), 7.73e7.76 (m, 2H, ArH).
13C NMR (100 MHz, CDCl3):
13.9 (CH3), 64.1 (CH2), 72.6 (q,
J¼28.8 Hz, C-2), 99.3 (C-4), 121.3 (q, J¼283 Hz, CF3), 127.0, 129.2,
129.3, 133.2 (Ar), 161.9, 178.1 (C]O, C-5), 187.6 (C]O). HRMS (ESI-
TOF, [MþK]þ): calcd for C14H12F3KNO3, 338.0401; found: 338.0399.
Org. Synth. 2004, 1, 275e292; (g) Palacios, F.; Ochoa de Retana, A. M.; Martínez
de Marigorta, E.; de los Santos, J. M. Eur. J. Org. Chem. 2001, 2401e2414.
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Tetrahedron Lett. 2012, 53, 5777e5780; (b) Khlebnikov, A. F.; Novikov, M. S.;
Amer, A. A.; Kostikov, R. R.; Magull, J. Russ. J. Org. Chem. 2006, 42, 533e544.
3. (a) Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A. Tetrahedron Lett. 2004, 45,
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69, 4546e4551.
6. Barluenga, J.; Tomas, M.; Ballesteros, A.; Kong, J.-S. Tetrahedron 1996, 52,
3095e3106.
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d
d
4.5.4. Ethyl 5-(4-methylphenyl)-3-oxo-2-(trifluoromethyl)-2,3-
dihydro-1H-pyrrole-2-carboxylate (4i). Yield 18%. Yellowish oil.
Rf¼0.56 (50% EtOAc/hexane). IR (CHCl3): 3375, 3040, 1760, 1735,
1700, 1615, 1590, 1560, 1510, 1300, 1175 cmꢂ1. 1H NMR (400 MHz,
CDCl3):
d
1.37 (t, 3H, J¼7.1 Hz, CH3), 2.47 (s, 3H, CH3), 4.32e4.47 (m,
2H, CH2), 5.65 (s, 1H, C-4), 5.83 (s, 1H, NH), 7.35 (d, 2H, J¼8.1 Hz, Ar),
7.64 (d, 2H, J¼8.1 Hz, Ar). 13C NMR (100 MHz, CDCl3):
d 13.9 (CH3),
9. Schmidt, R. R.; Schwille, D.; Wolf, H. Chem. Ber. 1970, 103, 2760e2767.
10. (a) Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130, 8602e8603; (b)
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1866e1869.
21.7 (CH3), 64.1 (CH2), 72.5 (q, J¼28.9 Hz, C-2), 98.8 (C-4), 121.1 (q,
J¼283 Hz, CF3), 126.3, 127.0, 130.0, 144.2 (Ar), 162.0, 178.1 (C]O, C-
5), 187.5 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd for C15H15F3NO3,
314.0999; found: 314.0995.
12. (a) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc. 1975, 97, 4682e4691;
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4.5.5. Ethyl 5-(4-chlorophenyl)-3-oxo-2-(trifluoromethyl)-2,3-
dihydro-1H-pyrrole-2-carboxylate (4j). Yield 11%. Yellowish solid.
Mp 134e137 ꢀC (hexane/Et2O). Rf¼0.59 (50% EtOAc/hexane). IR
(CHCl3): 3375, 3040, 1760, 1735, 1705, 1605, 1585, 1560, 1490, 1300,
ꢁ
€
Chem. 2008, 45, 311e317; (f) Batori, S.; Dopp, D.; Messmer, A. Tetrahedron 1994,
50, 4699e4708; (g) Brahma, S.; Ray, J. K. Tetrahedron Lett. 2005, 46, 6575e6578.
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2531e2534.
1180 cmꢂ1. 1H NMR (400 MHz, CDCl3):
d
1.37 (t, 3H, J¼7.1 Hz, CH3),
4.33e4.48 (m, 2H, CH2), 5.67 (s, 1H, C-4), 5.79 (s, 1H, NH), 7.53 (d,
2H, J¼8.5 Hz, ArH), 7.69 (d, 2H, J¼8.5 Hz, ArH). 13C NMR (100 MHz,
CDCl3):
d
13.9 (CH3), 64.3 (CH2), 72.7 (q, J¼28.9 Hz, C-2), 99.9 (C-4),
121.2 (q, J¼283 Hz, CF3), 127.7, 128.3, 129.7, 139.5 (Ar), 161.8, 176.8,
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(C]O, C-5), 187.5 (C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
C
14H1235ClF3NO3, 334.0452; found: 334.0456.
Acknowledgements
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We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (Grant No. 14-03-00187) and Saint
Petersburg State University (Grants No. 12.38.78.2012, No.
12.38.239.2014). This research used resources of the resource
center ‘Computer Center’, ‘Research resource center for Magnetic
Resonance’, ‘Center for Chemical Analysis and Material Research’,
and ‘Research resource Centre for X-ray Diffraction Studies’ of Saint
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~
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Supplementary data
1H, 13C NMR spectra of all new compounds and Cartesian co-
ordinates of optimized structures can be found. Supplementary
data related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2014.03.101. These data include MOL files and InChi-
Keys of the most important compounds described in this article.
29. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
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