Expeditious synthesis of 2,3,6-trisubstituted 2 H -1,3-oxazin-4(3 H)-ones via the tertiary amine-induced reaction of 2-diazo-3-oxoalkanals and imines under mild conditions

Article abstract of DOI:10.1055/s-0030-1258439

A series of 2,3,6-trisubstituted 2H-1,3-oxazin-4(3H)-one derivatives were conveniently synthesized in satisfactory to good yields by the reaction of imines with 2-diazo-3-oxoalkanals in the presence of a catalytic amount of a tertiary amine during several seconds under mild condition. Different bases and -diazo - dicarbonyl compounds were also evaluated and a reaction mechanism is proposed. Compared with the corresponding thermal- and photo-induced- reactions, the current method is a metal-free, mild, highly regioselective, and more efficient approach for the synthesis of 2H-1,3-oxazin-4(3H)-one derivatives. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258439

PAPER
887
Expeditious Synthesis of 2,3,6-Trisubstituted 2H-1,3-Oxazin-4(3H)-ones
via the Tertiary Amine-Induced Reaction of 2-Diazo-3-oxoalkanals and Imines
Under Mild Conditions
Synthesis of
2
H
-1,
e
3-Oxazin-4
n
(3
H
)
-ones gzhen Qi, Jiantao Zhang, Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology, Beijing 100029, P. R. of China
Fax +86(10)64435565; E-mail: jxxu@mail.buct.edu.cn
Received 13 January 2011
1,3-dipolar cycloaddition with nitriles.13 Diazomalonal-
Abstract: A series of 2,3,6-trisubstituted 2H-1,3-oxazin-4(3H)-one
derivatives were conveniently synthesized in satisfactory to good
yields by the reaction of imines with 2-diazo-3-oxoalkanals in the
presence of a catalytic amount of a tertiary amine during several
seconds under mild condition. Different bases and a-diazo-b-dicar-
bonyl compounds were also evaluated and a reaction mechanism is
proposed. Compared with the corresponding thermal- and photo-
induced reactions, the current method is a metal-free, mild, highly
regioselective, and more efficient approach for the synthesis of 2H-
1,3-oxazin-4(3H)-one derivatives.
dehyde reacts with trimethylsilyl vinyl ethers under the
catalysis of copper sulfate to give 4-pyrones as well.14
1,3-Oxazinone derivatives are important biologically ac-
tive compounds, showing antibacterial,15 anti-inflamma-
tory,16 antinociceptive activities,17 etc. 2H-1,3-Oxazin-
4(3H)-one derivatives have been generally prepared by
thermal heteroatom Diels–Alder reaction of imines with
acylketenes,1 which can be generated mainly from a-di-
azo-b-dicarbonyl compounds, including a-diazo-b-dike-
tones and a-diazo-b-oxoalkanals, 1,3-dioxinones, furan-
Key words: acylketene, amine-induced reaction, cycloaddition, 2-
diazo-3-oxoalkanal, Diels–Alder reaction, imine, oxazinone
O
R1
R1
R3
R2
a-Diazo-b-dicarbonyl compounds (a-diazo-b-diketones
and a-diazo-b-oxoalkanals) are important synthetic inter-
mediates in organic chemistry.1 They have been widely
used in the synthesis of heterocyclic compounds via cy-
cloadditions.1 a-Diazo-b-diketones undergo heteroatom
Diels–Alder reactions with unsaturated compounds, such
as imines,2 aldehydes and ketones,3 thiones,4 nitriles,5 iso-
cyanates,2a isothiocyanates,2a,6 carbodiimides,2a etc., re-
spectively, to afford 2H-1,3-oxazin-4-ones, 4H-1,3-
dioxin-4-ones, 4H-1,3-oxathiin-4-ones, 1,3-oxazin-4-
ones, 2H-1,3-oxazine-2,4(3H)-diones, 2-thioxo-2H-1,3-
oxazin-4(3H)-ones, 2-alkylimino-2H-1,3-oxazin-4(3H)-
ones, and so on (Scheme 1). They undergo [2+3] cycload-
ditions in the presence of transition-metal catalysts, gen-
erally dirhodium tetraacetate, with nitriles,7 carbon
disulfide,8 electron-rich olefins,5,9 and alkynes10 to pro-
duce 4-acyloxazoles, 1,3-oxathiole-2-thiones, 3-acyl-4,5-
dihydrofurans, and 3-acylfuran derivatives, respectively
(Scheme 1). However, a-diazo-b-oxoalkanals have been
seldom applied in organic synthesis. They were con-
densed with primary amines, ammonium, hydroxylamine,
and semicarbazide to yield the corresponding 1-substitut-
ed 4-acyl-1H-1,2,3-triazoles in moderate to good yields
under acidic conditions.11 Decomposition of diazoma-
lonaldehyde under catalysis of dirhodium tetraacetate
with alkyl vinyl ether leads to 2-alkoxy-2,3-dihydro-4-py-
rones, which on exposure to an acid give 4-pyrones;12 and
affords 2-substituted 1,3-oxazole-4-carboxaldehydes via
N
O
O
O
R1
R1
O
R2
N
R3(H)
R2
etc.
O
R2
R3(H)
R3
S
O
O
O
O
O
O
R1
R1
R2
N
R1
R1
R2N=C-NR2
R2
R3
R2
R3
N
S
R1
R1
R2
N2
R2CN
O
R1
R1
O
N
R1
S
O
R2
R2
O
O
R1
O
N
R1
R1
O
R2
N
α-diazo-β-diketones in heteroatom Diels–Alder reactions
O
O
O
O
R1
R1
R2
R1
R1
R2
R2CN
R2C CH
R1
R1
N
Rh2(OAc)4
Rh2(OAc)4
N2
O
O
S
O
R1
EDG
O
S
R1
R1
R1
O
O
SYNTHESIS 2011, No. 6, pp 0887–0894
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1258439; Art ID: H11211SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1
α-diazo-β-diketones in [2+3] cycloadditions
Scheme 1 Application of a-diazo-b-diketones in synthesis of hete-
rocycles via cycloadditions

888
H. Qi et al.
PAPER
2,3-diones, as well from carboxylic acid derivatives and
alkynol derivatives.1 Recently, we found that 2-diazo-3-
oxoalkanals undergo Wolff rearrangement to generate
acylketenes, which react with imines to afford 2H-1,3-ox-
azin-4(3H)-ones in satisfactory yields under photoirradia-
tion conditions.18 The cycloaddition of a-diazo-b-
diketones and/or 2-diazo-3-oxoalkanals with imines oc-
curs at high temperature under thermal conditions1,2 or in
low yields and slow reaction rates under photoirradia-
tion.18 It is desired to develop an efficient approach to con-
duct the reaction. To improve the synthetic efficiency, a
search for catalysts was done to increase the reaction rates
under mild reaction conditions. It was reported that a mere
trace of amine can cause diazomalonaldehyde to liberate
Me
Me
Cl
H
1)
N+
Cl–
Ph
O
O
O
O
CH2N2
Et3N
H
H
Ph
Ph
Cl
2) H2O
N2
N2
1a
–
NaN3
–
Et3O+BF4
–
BF4
BF4
Cl
N+
N3
N+
Et
N
Cl
Et
O
O
O
O
H
+
H
N2
1b
nitrogen to generate
a
polymer composed of
O
formylketene.19 Thus, it was assumed that organic bases
would attack the positive part of the diazo group to pro-
mote the release of nitrogen and further Wolff rearrange-
ment. Therefore, the efficiency of organic bases as
catalysts was evaluated in reactions of representative a-di-
azo-b-diketones and 2-diazo-3-oxoalkanals with imines.
Herein, we present our results on the tertiary amine-cata-
lyzed reaction of 2-diazo-3-oxoalkanals and imines to
synthesize 2H-1,3-oxazin-4(3H)-ones expeditiously.
Et3N
HClO4
H3N+CH2COOH
Cl–
POCl3
+
H
NMe2
Me2N+
N
O
O
–
ClO4
NaNO2
NaOH
Me2N
H
H
AcOH
NMe2
N2
1c
O
O
O
O
TsN3, Et3N
Representative 2-diazo-3-oxoalkanals and a-diazo-b-
diketones can be prepared conveniently from the corre-
sponding 3-oxoalkanals and b-diketones, or from a-diazo
ketones. 2-Diazo-3-oxo-3-phenylpropanal (1a) was pre-
pared from 2-diazoacetophenone and the Vilsmeier–
Haack reagent,11a which was synthesized from DMF and
oxalyl chloride.20 2-Diazo-3-oxobutanal (1b) was pre-
pared from 3-oxobutanal via the diazo transformation
with 2-azido-1-ethylpyridinium tetrafluoroborate.21 Di-
azomalonaldehyde (1c) was obtained via hydrolysis and
diazotization of N,N-dimethyl-N-[2-(dimethylamino-
methylene)amino-3-dimethylamino]prop-2-enylideneam-
monium perchlorate,11a which was prepared from DMF,
phosphorus oxychloride, and glycine hydrochloride in the
presence of perchloric acid22 (Scheme 2). a-Diazo-b-
diketones 1d–f were prepared from the corresponding b-
diketones via the diazo transformation with tosyl azide2f
(Scheme 2).
R1
R2
R1
R2
N2
1d–g
d: R1 = R2 = Me
e: R1,R2 = (CH2)2CMe2
f: R1 = Ph, R2 = Me
g: R1 = R2 = Ph
Scheme 2 Preparation of a-diazo-b-dicarbonyl compounds 1
romethane before addition of a tertiary amine. 2-Diazo-3-
oxobutanal (1b) and diazomalonaldehyde (1c) produced
complex products possibly due to their high reactivity.
However, a-diazo-b-diketones 1d–g are inert and do not
participate in any reaction under the same reaction condi-
tions.
Secondly, the reaction of 2-diazo-3-oxo-3-phenylpropa-
nal (1a) and N-benzylideneaniline (2a) was selected as a
model reaction to evaluate the catalytic efficiency of dif-
ferent bases (Table 2, entries 1–8). The results indicate
that all aliphatic tertiary amines can catalyze the reaction,
but the yield of the desired product decreases obviously
with increasing steric hindrance of bases. Under the catal-
ysis of secondary amine piperidine, only trace of the prod-
uct was obtained. However, aromatic tertiary amine N,N-
dimethylaniline and pyridine, as well triphenylphosphine,
cannot catalyze the reaction. In the case of inorganic
bases, both weak base potassium carbonate and strong
base sodium hydride are not efficient catalysts for the re-
action. To further verify the effect of organic bases on the
reaction, the reaction of 2-diazo-3-oxo-3-phenylpropanal
(1a) and N-benzylidenebenzylamine (2b) was conducted
with different tertiary amines as catalysts (Table 2, entries
9–12). The results show that the yield decreases with in-
creasing steric hindrance from triethylamine to tributyl-
The reactivity of different a-diazo-b-dicarbonyl com-
pounds 1 with benzylideneaniline (2a) was initially eval-
uated under the catalysis of triethylamine (Table 1). The
results indicate that 2-diazo-3-oxoalkanals 1a,b and di-
azomalonaldehyde (1c) are exceptionally reactive. After a
drop of triethylamine was added to a mixture of an a-di-
azo-b-keto aldehyde and an imine, the a-diazo-b-keto alde-
hyde released nitrogen rapidly. The Wolff rearrangement
and cycloaddition with the imine, for 2-diazo-3-oxo-3-
phenylpropanal (1a), took place during 1–2 second(s),
giving rise to the desired product 2,3,6-triphenyl-2H-1,3-
oxazin-4(3H)-one (3a) in a satisfactory yield. Although
the reaction can be conducted under solvent-free condi-
tions, to mix two reactants completely and to perform the
reaction smoothly, an a-diazo-b-keto aldehyde and an
imine were dissolved in a small amount of dichlo-
Synthesis 2011, No. 6, 887–894 © Thieme Stuttgart · New York

PAPER
Synthesis of 2H-1,3-Oxazin-4(3H)-ones
889
After evaluation of different a-diazo-b-dicarbonyl com-
pounds and bases, it was found that 2-diazo-3-oxo-3-phe-
nylpropanal (1a) is a suitable precursor of heteroatom-
containing diene and triethylamine is the more efficient
catalyst for the reaction. The reaction was further extend-
ed to various linear and cyclic imines 2a–i (Table 3). For
each of imines, the desired products were obtained in sat-
isfactory to good yields. For imine 2g with a chiral carbon
atom, a pair of diastereomeric products were generated in
a ratio of 6:1 of anti-isomer/syn-isomer on the basis of 1H
NMR analysis (Table 3, entry 7). In the reaction with
imine 2i, the desired Diels–Alder product 3i was obtained,
accompanied with benzoyl trans-b-lactam product 5i,
which was generated from imine 2i and benzoylketene,
produced from diazo compound 1a, via the Staudinger re-
action through the imine attack to the ketene from its exo-
side and subsequent conrotatory ring closure.23 Although
diazomalonaldehyde did not produce the desired product
with linear imine 2a, it did with cyclic imine 2i in a low
yield of 26% (Table 3, entry 10).
Table 1 Evaluation of Different a-Diazo-b-dicarbonyl Compounds
1 in the Reaction with N-Benzylideneaniline (2a) under the Catalysis
of Triethylamine
O
O
O
R2
R1
Ph
Ph
Et3N
Ph
R1
R2
N
+
Ph
N
CH2Cl2
N2
1d–g
O
2a
3
Entry
Diazo compound 1
Time
Yield (%)
1
R1
R2
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Ph
Me
H
H
2 s
2 s
54
H
complex products
complex products
no reaction
H
2 s
Me
Me
24 h
24 h
24 h
24 h
CH2CMe2CH2
no reaction
Ph
Ph
Me
Ph
no reaction
To compare the current method with the thermal and pho-
to reactions, we carried out the reaction of 2-diazo-3-oxo-
3-phenylpropanal (1a) and imine 2b under thermal and
photo conditions, respectively (Scheme 3). The results in-
dicate that the triethylamine-catalyzed reaction shows ad-
vantages not only in the reaction rate, but also in yield and
regioselectivity, revealing that benzoyl formyl carbene
generated from 2-diazo-3-oxo-3-phenylpropanal (1a) pre-
fers a hydrogen shift to give rise to benzoylketene under
triethylamine-catalyzed and thermal conditions, whereas
1g
no reaction
amine to ethyldiisopropylamine (DIPEA) although the
yield is higher than that in the reaction with N-benzylid-
eneaniline (2a). Triphenylphosphine cannot catalyze the
reaction either. However, besides the 2,3,6-trisubstituted
2H-1,3-oxazin-4(3H)-one (3b), its regioisomer, the 2,3,5-
trisubstituted 2H-1,3-oxazin-4(3H)-one (4b), was also ob-
tained in a low yield under the catalysis of triethyl- and
tributylamines.
Table 2 Evaluation of the Catalytic Efficiency of Different Bases in the Reaction of 2-Diazo-3-oxo-3-phenylpropanal (1a) with Imines 2a
and 2b
O
O
O
O
H
R
Ph
H
Bn
Ph
base
R
N
N
Ph
H
+
Ph
2a,b
N
+
CH2Cl2
N2
Ph
O
Ph
O
1a
a: R = Ph
b: R = Bn
4b
3a,b
Entry
1
Imine 2
2a
Base
Et3N
Bu3N
Time
2 s
Yield (%)
54
2
2a
10 s
2 s
36
3
2a
piperidine
PhNMe2
pyridine
Ph3P
trace
4
2a
24 h
24 h
24 h
24 h
24 h
2 s
no reaction
no reaction
no reaction
no reaction
no reaction
92 (3/4 = 93:7)
83 (3/4 = 88:12)
54 (3/4 = 100:0)
no reaction
5
2a
6
2a
7
2a
K2CO3
NaH
8
2a
9
2b
Et3N
10
11
12
2b
Bu3N
10 s
15 s
24 h
2b
DIPEA
Ph3P
2b
Synthesis 2011, No. 6, 887–894 © Thieme Stuttgart · New York

890
H. Qi et al.
PAPER
O
O
it does not show any selectivity under photoirradiation
conditions.
O
O
H
Bn Ph
+
Bn
N
Bn
N
Ph
H
+
Ph
N
As for the reaction mechanism, it is proposed that a tertia-
ry amine attacks the middle nitrogen atom of the diazo
group of 2-diazo-3-oxo-3-phenylpropanal (1a) or diazo-
malonaldehyde (1c) to generate a zwitterionic intermedi-
ate, which further undergoes an electron transfer to form
a diacylcarbene through loss of nitrogen and the amine.
The diacylcarbene undergoes the Wolff rearrangement to
produce the acylketene, which undergoes a heteroatom
Diels–Alder cycloaddition to yield the desired 2,3,6-
trisubstituted 2H-1,3-oxazin-4(3H)-one 3 (Scheme 4).
N2
1a
Ph
O
Ph
H
O
Ph
2b
3b
4b
thermal reaction: in refluxing toluene, 1 h, 76% yield, 3b/4b = 86:14
photo reaction: UV light, in CH2Cl2, 2 h, 78% yield, 3b/4b = 50:50
Et3N-catalyzed reaction: in CH2Cl2, 2 s, 92% yield, 3b/4b = 93:17
Scheme 3 Comparison of thermal, photo, and Et3N-catalyzed reac-
tions of diazo compound 1a and imine 2b
Table 3 Reaction of 2-Diazo-3-oxo-3-phenylpropanal (1a) and Diazomalonaldehyde (1c) with Various Imines 2
Entry
Diazoacetate 1 Imine 2
b-Lactam 3
Yield (%)a
54
O
H
Ph
Ph
Ph
Bn
N
1
1a
1a
Ph
N
N
2a
Ph
O
O
3a
O
H
Bn
Ph
Ph
H
Bn
Ph
N
N
+
2
86 (4b: 6%)
Ph
Ph
O
O
2b
3b
4b
OMe
O
O
N
H
N
O
3
4
5
1a
1a
1a
68
47
78
OMe
Ph
O
2c
3c
OMe
O
Ph
N
H
N
N
OMe
Ph
O
O
Ph
2d
3d
MeO
H
N
Ph
O
OMe
2e
3e
H
O
O
O2N
N
6
1a
85
N
Ph
NO2
2f
3f
Synthesis 2011, No. 6, 887–894 © Thieme Stuttgart · New York

PAPER
Synthesis of 2H-1,3-Oxazin-4(3H)-ones
891
Table 3 Reaction of 2-Diazo-3-oxo-3-phenylpropanal (1a) and Diazomalonaldehyde (1c) with Various Imines 2 (continued)
Entry
Diazoacetate 1 Imine 2
b-Lactam 3
Yield (%)a
O
O
O
H
H
N
Ph
N
Ph
Ph
N
Ph
+
7
1a
1a
90 (anti/syn = 6:1)b
Ph
O
Ph
Ph
Ph
( )
( )
2g
syn-3g
anti-3g
O
N
O
H
8
9
42
N
Ph
2h
3h
O
N
O
O
H
N
O
O
O
+
Ph
1a
35 (5i: 6%)
Ph
H
H
N
O
( )
2i
3i
5i
O
H
H
O
N
O
10
1c
26
O
N
2i
3j
a Yields of isolated products (sum of cis- and trans-product yields).
b Ratio was determined via 1H NMR analysis of the reaction mixture.
O
O
Despite a-diazo-b-keto aldehydes are active and a-diazo-
b-diketones are inert in the presence of tertiary amines, it
seems that the hydrogen atom in the formyl group plays an
important role in the reaction. We initially assumed that
the amine first abstracts the hydrogen atom to generate a
2-diazo-3-oxoacyl anion intermediate, which induces the
Wolff rearrangement to produce an acylketene anion. The
anion abstracts a proton from the generated ammonium in
the reaction system to form the acylketene, which under-
goes Diels–Alder reaction to produce the desired product.
However, a-diazo-b-keto aldehydes are inert to the strong
base sodium hydride with weak nucleophilicity, revealing
that bases, especially tertiary amines, cannot abstract the
hydrogen atom of the formyl group. On the other hand,
less steric tertiary amines (favorable nucleophiles) show
higher activity than more steric ones (unfavorable nucleo-
philes), supporting the proposed mechanism through the
amine attack to the diazo group.
O
O
O
O
–
–
R
H
R
H
R
H
N+
N+
N
N+
N–
: NEt3
+NEt3
–N
R
O
O
O
H
Wolff rearrangement
– N2
– NEt3
C
R
H
O
O
R2
H
R2
R1
N
N
R
R
O
R1
O
O
R
O
O
H
: NEt3
– H+NEt3
H+NEt3
– NEt3
–
H
R
N+
N
C
O
C
O
In summary, a series of 2,3,6-trisubstituted 2H-1,3-ox-
azin-4(3H)-one derivatives were expeditiously synthe-
sized in satisfactory to good yields from the reaction of
imines and 2-diazo-3-oxoalkanals under the catalysis of
Scheme 4 Proposed mechanism for reaction of diazo compounds 1
and imines 2 under the catalysis of triethylamine
Synthesis 2011, No. 6, 887–894 © Thieme Stuttgart · New York

892
H. Qi et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 46.5, 87.9, 97.7, 126.3, 127.4,
127.6, 127.8, 128.65, 128.66, 128.69, 129.8, 131.2, 131.8, 135.3,
136.9, 161.7, 164.0.
tertiary amine during several seconds under mild condi-
tion. Different bases and a-diazo-b-dicarbonyl com-
pounds were also evaluated, indicating that less steric
tertiary amines are efficient catalysts and 2-diazo-3-
oxoalkanals are suitable acylketene precursors. A reaction
mechanism was proposed in which tertiary amines induce
Wolff rearrangement of 2-diazo-3-oxoalkanals to gener-
ate acylketenes, which further undergo a heteroatom
Diels–Alder reaction to yield 2,3,6-trisubstituted 2H-1,3-
oxazin-3(4H)-ones. Compared with the corresponding
thermal- and photo-induced reactions, the current method
is a metal-free, mild, highly regioselective, and more effi-
cient approach to synthesis of 2H-1,3-oxazin-4(3H)-one
derivatives.
3-Benzyl-2,5-diphenyl-2H-1,3-oxazin-4(3H)-one (4b)
Yield: 22 mg (6%); colorless crystals; mp 142–143 °C.
IR (KBr): 1661 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 3.98 (d, J = 15.2 Hz, 1 H in CH2),
5.47 (d, J = 15.2 Hz, 1 H in CH2), 6.27 (s, 1 H, CH), 7.08 (s, 1 H,
CH), 7.25–7.53 (m, 15 H, ArH).
13C NMR (100 MHz, CDCl3): d = 46.9, 88.4, 116.8, 127.55, 127.59,
127.6, 128.0, 128.3, 128.7, 129.9, 132.6, 135.4, 136.8, 151.5, 162.6.
HRMS (ESI): m/z calcd for C23H20NO2 [M + H]+: 342.1489; found:
342.1503.
2-Fur-2-yl-3-(4-methoxyphenyl)-6-phenyl-2H-1,3-oxazin-
4(3H)-one (3c)
Yield: 236 mg (68%); colorless crystals; mp 151–153 °C.
IR (KBr): 1645 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H, CH3), 6.05 (s, 1 H,
CH), 6.35 (dd, J = 1.6, 3.6 Hz, 1 H, ArH), 6.58 (d, J = 3.6 Hz, 1 H,
ArH), 6.70 (s, 1 H, CH), 6.90 (d, J = 8.8 Hz, 2 H, ArH), 7.27 (d,
J = 8.8 Hz, 2 H, ArH), 9.35–7.48 (m, 4 H, ArH), 7.71 (d, J = 7.2 Hz,
2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 55.5, 85.0, 98.6, 110.6, 111.4,
114.5, 126.6, 127.2, 128.7, 131.4, 131.7, 131.8, 143.9, 149.0, 158.3,
161.2, 162.6.
Melting points were measured on a Yanaco MP-500 melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on a Varian Mercury Plus 300 (300 MHz) or Bruker AV
400 (400 MHz) spectrometer in CDCl3 with TMS as an internal
standard. HRMS data were carried out on a Bruker APEX IV Fou-
rier transform ion cyclotron resonance mass spectrometer. IR spec-
tra were determined on a Nicolet 5700 FT-IR spectrometer. All a-
diazo-b-dicarbonyl compounds were prepared according to the re-
ported methods,2f,11a,20–22 and their analytical data are identical to
those earlier reported in literatures.2f,11a,20–22 Column chromatogra-
phy was carried out on Haiyang silica gel (200–300 mesh)
(Qingdao, China). CH2Cl2 was refluxed with CaH2 and freshly dis-
tilled prior to use.
HRMS (ESI): m/z calcd for C21H18NO4 [M + H]+: 348.1230; found:
Caution: Diazomethane is toxic and potentially explosive. a-Di-
azo-b-diketones and a-diazo-b-oxoalkanals are also potentially ex-
plosive. All operations involving diazo compounds must be carried
out in a well-ventilated hood with an adequate shield for safety, al-
though no explosion had occurred in any of our experiments.
348.1228.
3-(4-Methoxystyryl)-2,6-diphenyl-2H-1,3-oxazin-4(3H)-one
(3d)
Yield: 180 mg (47%); colorless crystals; mp 115–116 °C.
IR (KBr): 1662 cm–1 (C=O).
Reaction of 2-Diazo-3-oxoalkanals and Imines under the Catal-
ysis of Tertiary Amine; General Procedure
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H, CH3), 6.10 (s, 1 H,
CH), 6.21 (d, J = 6.0 Hz, 1 H, CH), 6.52 (dd, J = 6.4, 15.6 Hz, 1 H,
CH), 6.80 (d, J = 16 Hz, 1 H, CH), 6.91–7.76 (m, 14 H, ArH).
13C NMR (100 MHz, CDCl3): d = 55.5, 90.7, 97.9, 114.6, 122.3,
126.4, 127.1, 128.1, 128.8, 128.9, 131.4, 131.6, 131.8, 135.1, 136.2,
158.5, 162.1, 163.3.
To a solution of 2-diazo-3-oxoalkanal 1 (2 mmol) and an imine 2 (1
mmol) in CH2Cl2 (3 mL) was added a drop of a tertiary amine (0.3
mmol) under stirring in an ice-water bath or at r.t. N2 was liberated
immediately and TLC monitoring indicated that the reaction com-
pleted. After stirring for 2 s (with Et3N) (10 s with Bu3N and 15 s
with DIPEA), the residue was separated on a silica gel column chro-
matographically [elution with EtOAc and petroleum ether (bp 60–
90 °C) 1:10 to 1:20, v/v] to afford the product(s) 3 (Table 3).
HRMS (ESI): m/z calcd for C25H22NO3 [M + H]+: 384.1594; found:
384.1598.
3-Isopropyl-2-(4-methoxyphenyl)-6-phenyl-2H-1,3-oxazin-
4(3H)-one (3e)
Yield: 252 mg (78%); colorless crystals; mp 142–143 °C.
IR (KBr): 1650 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.09 (d, J = 6.4 Hz, 3 H, CH3),
1.33 (d, J = 6.4 Hz, 3 H, CH3), 3.74 (s, 3 H, CH3), 4.88 (hept,
J = 6.4 Hz, 1 H, CH), 5.89 (s, 1 H, CH), 6.51 (s, 1 H, CH), 6.85–
7.58 (m, 9 H, ArH).
13C NMR (100 MHz, CDCl3): d = 20.3, 21.3, 44.3, 55.2, 83.7, 99.0,
113.7, 126.2, 128.5, 128.6, 129.6, 130.9, 132.1, 159.8, 160.2, 163.1.
2,3,6-Triphenyl-2H-1,3-oxazin-4(3H)-one (3a)
Yield: 177 mg (54%); colorless crystals; mp 161–162 °C (Lit.24 mp
146–148 °C).
IR (KBr): 1663 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 6.08 (s, 1 H, CH), 6.87 (s, 1 H,
CH), 7.22–7.74 (m, 15 H, ArH).
13C NMR (75.5 MHz, CDCl3): d = 90.1, 99.0, 125.0, 126.3, 126.4,
127.2, 128.65, 128.71, 129.1, 129.5, 131.4, 131.7, 136.5, 139.7,
161.4, 163.0.
HRMS (ESI): m/z calcd for C20H22NO3 [M + H]+: 324.1594; found:
324.1600.
3-Benzyl-2,6-diphenyl-2H-1,3-oxazin-4(3H)-one (3b)
Yield: 292 mg (86%); colorless crystals; mp 125–126 °C (Lit.25 mp
123–124 °C).
3-Isopropyl-2-(4-nitrophenyl)-6-phenyl-2H-1,3-oxazin-4(3H)-
one (3f)
Yield: 288 mg (85%); colorless crystals; mp 152–153 °C.
IR (KBr): 1652 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 3.91 (d, J = 15.6 Hz, 1 H in CH2),
5.41 (d, J = 15.6 Hz, 1 H in CH2), 6.00 (s, 1 H, CH), 6.29 (s, 1 H,
CH), 7.17–7.61 (m, 15 H, ArH).
Synthesis 2011, No. 6, 887–894 © Thieme Stuttgart · New York

PAPER
Synthesis of 2H-1,3-Oxazin-4(3H)-ones
893
1H NMR (400 MHz, CDCl3): d = 1.15 (d, J = 6.8 Hz, 3 H, CH3),
1.38 (d, J = 6.8 Hz, 3 H, CH3), 4.97 (hept, J = 6.8 Hz, 1 H, CH),
5.91 (s, 1 H, CH), 6.63 (s, 1 H, CH), 7.30–8.22 (m, 9 H, ArH).
13C NMR (100 MHz, CDCl3): d = 20.9, 53.5, 63.2, 120.1, 121.5,
121.6, 124.9, 125.1, 126.5, 128.9, 129.3, 129.6, 129.7, 130.7, 134.1,
135.0, 135.7, 144.5, 156.3, 158.8, 190.4.
13C NMR (100 MHz, CDCl3): d = 20.4, 21.4, 44.6, 82.8, 99.3, 123.6,
126.1, 128.2, 128.7, 131.3, 131.4, 144.8, 148.4, 160.2, 162.6.
HRMS (ESI): m/z calcd for C23H17NO3 + Na [M + Na]+: 378.1101;
found: 378.1111.
HRMS (ESI): m/z calcd for C19H19N2O4 [M + H]+: 339.1339; found:
339.1355.
13-Methyldibenzo[b,f][1,3]oxazino[3,2-d][1,4]oxazepin-
4(14bH)-one (3j)
Yield: 73 mg (26%); colorless crystals; mp 107–108 °C.
IR (KBr): 1680 cm–1 (C=O).
rel-(R)-2,6-Diphenyl-3-[(R)-1-phenylethyl]-2H-1,3-oxazin-
4(3H)-one (anti-3g) and rel-(R)-2,6-Diphenyl-3-[(S)-1-phenyl-
ethyl]-2H-1,3-oxazin-4(3H)-one (syn-3g)
Yield: 324 mg (90%); colorless crystals; mp 167–168 C; anti/
syn = 6:1, inseparable.
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H, CH3), 5.62 (d, J = 6.0
Hz, 1 H, CH), 6.55 (s, 1 H, CH), 7.15–7.57 (m, 7 H, ArH), 7.56 (d,
J = 6.0 Hz, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 20.7, 87.4, 104.0, 120.8, 121.1,
124.6, 124.9, 128.2, 128.7, 129.0, 129.4, 131.8, 134.1, 154.0, 155.0,
156.2, 162.2.
IR (KBr): 1642 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d (anti-3g) = 1.45 (d, J = 7.2 Hz, 3 H,
CH3), 5.95 (s, 1 H, CH), 6.13 (q, J = 7.2 Hz, 1 H, CH), 6.28 (s, 1 H,
CH), 7.10–7.58 (m, 15 H, ArH); d (syn-3g) = 1.76 (d, J = 7.2 Hz, 3
H, CH3), 5.91 (s, 1 H, CH), 5.95 (q, J = 7.2 Hz, 1 H, CH), 6.49 (s,
1 H, CH), 7.10–7.58 (m, 15 H, ArH).
HRMS (ESI): m/z calcd for C17H14NO3 [M + H]+: 280.0968; found:
280.0966.
13C NMR (100 MHz, CDCl3): d (anti-3g) = 17.7, 50.3, 84.7, 98.5,
126.4, 127.1, 127.4, 127.7, 128.4, 128.5, 128.8, 129.3, 131.1, 132.0,
137.5, 140.9, 160.3, 163.4; d (syn-3g) = 17.8, 50.3, 84.9, 99.1,
126.4, 127.1, 127.4, 127.7, 128.1, 128.5, 128.8, 129.3, 131.1, 132.0,
137.5, 140.9, 160.3, 163.4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
HRMS (ESI): m/z calcd for C24H22NO2 [M + H]+: 356.1645; found:
The project was supported partly by National Natural Science Foun-
dation of China (Nos. 20972013 and 20772005), Beijing Natural
Science Foundation (No. 2092022), and specialized Research Fund
for the Doctoral Program of Higher Education, Ministry of Educa-
tion of China.
356.1647.
2-Phenyl-6,7-dihydro[1,3]oxazino[2,3-a]isoquinolin-4(11bH)-
one (3h)
Yield: 116 mg (42%); colorless crystals; mp 197–198 °C.
IR (KBr): 1660 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 2.85 (dt, J = 15.6, 4.0 Hz, 1 H, H
in CH2), 3.07 (ddd, J = 4.8, 10.8, 15.6 Hz, 1 H in CH2), 3.36 (ddd,
J = 3.6, 10.4, 12.8 Hz, 1 H), 4.42 (dt, J = 12.8, 4.8 Hz, 1 H), 6.24 (s,
1H), 7.25–7.56 (m, 10 H, ArH).
13C NMR (100 MHz, CDCl3): d = 28.5, 37.8, 84.7, 117.4, 127.2,
127.6, 128.0, 128.3, 128.6, 128.7, 129.5, 130.1, 132.8, 136.3, 153.9,
163.6.
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azepin-4(14bH)-one (3i)
Yield: 124 mg (35%); colorless oil.
IR (KBr): 1672 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H, CH3), 6.18 (s, 1 H,
CH), 6.72 (s, 1 H, CH), 7.17–7.83 (m, 12 H, ArH).
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rel-(1R,12bR)-1-Benzoyl-11-methyl-1H-azeto[1,2-d]diben-
zo[b,f][1,4]oxazepin-2(12bH)-one (5i)
Yield: 21 mg (6%); colorless crystals; mp 167–168 °C.
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1H NMR (400 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 5.37 (d, J = 2.8
Hz, 1 H, CH), 6.38 (d, J = 2.8 Hz, 1 H, CH), 7.02–8.30 (m, 12 H,
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