Facile cleavage of C-C bond: Conversion of pyrane derivative to 1,3-oxazin derivative

Article abstract of DOI:10.1016/j.tet.2012.05.089

A cascade reaction that involves a unique C-C bond cleavage has been discovered. This protocol affords an unusual and facile method for the synthesis of 1,3-oxazin derivatives under mild conditions.

Full text of DOI:10.1016/j.tet.2012.05.089

Tetrahedron 68 (2012) 6759e6764
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile cleavage of CeC bond: conversion of pyrane derivative to 1,3-oxazin
derivative
*
Zhilan Lin, Xueli Zhang, Xinkui You, Yuan Gao
College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 March 2012
Received in revised form 15 May 2012
Accepted 22 May 2012
A cascade reaction that involves a unique CeC bond cleavage has been discovered. This protocol affords
an unusual and facile method for the synthesis of 1,3-oxazin derivatives under mild conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 30 May 2012
Keywords:
Pyridine-mediated
Pyrane
1,3-Oxazin
CeC bond cleavage
1. Introduction
cycloaddition of an alkene and an N-acylimine,13 intramolecular
hydroamination of trichloroacetimidate,14 cycloaddition reactions
Carbonecarbon bond cleavage is a challenging target in modern
organic chemistry.1 Up to date, the carbonecarbon bond cleaving
reactions have been achieved by the following catalytic methods:
of 2-azadienes with alkenes,15 Ritter reaction of a diol with a ni-
trile,16 intramolecular cyclization of N-thioacyl 1,3-amino alcohols
with Bu4NF and EtI.17 However, most of these reactions require
harsh reaction conditions, expensive starting materials or reagents
and longer reaction times.
Since organocatalytic cascade reaction has demonstrated several
advantages including operational simplicity, significant reduction in
reaction time, less formation of by-products, and easier work-up
compared to transition-metal catalyzed reactions, it has been rec-
ognized as an efficient, green chemical method for building up the
diversity of the compound library.18 Recently, we have found an un-
usual cascade reaction. This reaction could convert pyran ring into
1,3-oxazin ring during the reaction of pyrane derivatives with acetic
anhydride in the presentof pyridine (Scheme 1). The attractive aspect
of the cascade reaction is that the novel construction of 1,3-oxazine
and the direct CeN bond formation from CeC bond can be easily
achieved via pyridine-mediated acylation in a one-pot operation.
enzyme-catalyzed,2
photocatalytic,3
organocatalytic,4
and
transition-metal catalyzed reactions.5 Most of these reactions
reported are classified into ring strain, -carbon elimination, che-
b
lation assistance, skeletal rearrangement, the stabilization of the
aromatic system, and miscellaneous phenomena.6 However, those
reports focused on the metal-catalyzed approaches, while the de-
sign of new CeC bond cleaving reactions without the use of metal
catalysts, especially those can avoid the use of expensive catalyst
and harsh reaction conditions, has not been placed a high value.
Various 1,3-oxazine derivatives have shown a wide variety of
bioactivities, such as anti-human coronavirus activity,7 inhibition of
cholesterol esterase and acetylcholinesterase,8 inhibition of human
leukocyte elastase,9 and nonsteroidal progesterone receptor an-
tagonists.10 A well-known oxazine is Efavirenz, a non-nucleoside
reverse transcriptase inhibitor that was approved by the FDA in
1998 and is currently in clinical use for treatment of AIDS.11 These
biological activities have prompted synthetic chemists to establish
novel 1,3-oxazine ring formation methods to find promising bio-
active oxazine compounds.12 There are several synthetic methods
for preparation of 1,3-oxazine derivatives, such as the [4þ2]
* Corresponding author. Tel.: þ86 755 26557379; fax: þ86 755 26536141; e-mail
Scheme 1.
address: szgaoy@tom.com (Y. Gao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.089

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Z. Lin et al. / Tetrahedron 68 (2012) 6759e6764
2. Results and discussion
The 2-amimo-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile 1 is a versatile and readily available
reagent, and its chemistry has received considerable attention
in recent years.19 As we reported before, our strategies of syn-
thesizing this compound were through the reaction of
aromatic aldehydes, malononitrile with 5,5-dimethyl-1,3-
cyclohexanedione.19e In order to further modify this com-
pound, we recently investigated the reaction of the compound 1
with acetic anhydride 3 in the presence of a substoichiometric
amount of pyridine. The product of this reaction was expected to
be compound 6.20 However, to our surprise the sole product was
2-benzo[e][1,3]oxazine derivatives 4.
In the initial studies, the mixtures of compound 1 and acetic
anhydride 3 were heated at the temperature in the range of
60e120 ꢀC without a catalyst. Only trace amount of products were
formed even extending the reaction time to 12 h. To improve the
yield, the reaction conditions were optimized by varying the cata-
lysts. The results showed that the pyridine-catalyzed reaction gave
the highest yields, as illustrated in Table 1.
Table 1
Catalyst optimization for the synthesis of 4a
Entry
Catalyst (mol %)
T (ꢀC)
Time (h)
Yield (%)
Fig. 1. ORTEP drawing of the X-ray crystal structure of 4c.
1
2
3
4
5
d
120
95
85
85
80
12
8
6
7
7
Trace
34
68
51
58
Sodium acetate (0.15)
Pyridine(0.1)
Diethylamine(0.1)
Triethylamine(0.1)
4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile 2 were used to react
with acetic anhydride 3 under the same reaction conditions, 2-(4-
aryl-7-methyl-5-oxo-3,4-dihydropyrano[3,4-e][1,3]oxazin-2(5H)-
ylidene)-3-oxobutanenitrile 5 were produced in high yields with
the results listed in Table 3. The new products were characterized
with 1H NMR, 13C NMR and elemental analysis. Furthermore, the
structure of 5b was further confirmed by single-crystal X-ray
analysis (Fig. 2).
The results of the reaction of 1 with 3 in the presence of pyr-
idine are summarized in Table 2. The structures of 4 have been
confirmed by 1H NMR, 13C NMR, and elemental analysis. Fur-
thermore, the structure of 4c was proven by single-crystal X-ray
analysis (Fig. 1).
Single-crystal X-ray diffraction analysis reveal that classical
hydrogen bonds, N(1)eH(1).O(3) and N(1)eH(1).O(5), exist in
the molecular structure of 4c and 5b, respectively. The hydrogen
Inspired by the interesting results, we further explore the ap-
plicability of this method. The 2-amino-4-aryl-7-methyl-5-oxo-
ꢀ
bond length is 2.66 A.
Although the detailed mechanism of the above reaction re-
mains to be unclear, a possible mechanism was proposed in
Table 2
Synthesis of compounds 4a
Table 3
Synthesis of compounds 5a
Entry
1
R
Time (h)
Yield (%)b
Entry
2
R
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
6
7
6.5
7
6
7.5
5
5.5
6
4a (68)
4b (65)
4c(72)
4d (52)
4e (73)
4f (55)
4g (74)
4h (71)
4i (64)
4j (71)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
5
5
6
5
6.5
5.5
7
5
5.5
7
5a (68)
5b (77)
5c (71)
5d (76)
5e (52)
5f (73)
5g (55)
5h (74)
5i (65)
5j (71)
3-NO2C6H4
3,4-(MeO)2C6H3
3-MeC6H4
4-MeC6H4
3,4-(Me)2C6H3
4-ClC6H4
4-BrC6H4
3-MeOC6H4
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
3-NO2C6H4
3-MeC6H4
4-MeC6H4
3,4-(Me)2C6H4
3-MeOC6H4
4-BrC6H4
10
1j
5.5
10
2j
3,4-(MeO)2C6H4
a
a
The reactions were carried out with 1 (1 mmol), pyridine(0.1 mL), acetic an-
hydride (1 mL) under reflux at 85 ꢀC.
The reactions were carried out with 2(1 mmol), pyridine(0.1 mL), acetic
anhydride(1 mL) under reflux at 85 ꢀC.
b
b
All the yields were isolated yields.
All the yields were isolated yields.

Z. Lin et al. / Tetrahedron 68 (2012) 6759e6764
6761
4. Experimental section
4.1. General
All reagents purchased from commercial sources were used as
received. 2-amimo-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile 1 and 2-amino-4-aryl-7-methyl-5-
oxo-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile
2 were pre-
pared according to literature procedures, respectively.19e,21 TLC
analysis was run on commercial TLC plates (Qingdao, China, 60
F254) using UV light to visualize the compounds. Melting points
were measured on an X-4 microscopic melting point apparatus and
are uncorrected. The 1H NMR and 13C NMR spectra were recorded
on a Varian INOVA-400 MHz spectrometer and are referenced to
the residual solvent signals. Elemental analysis were performed on
an Elementar Vario EL cube instrument.
4.2. Synthesis
4.2.1. General procedure for the synthesis of 4. In an oven-dried
25 mL flask, 2-amimo-4-phenyl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-benzo[b]pyran-3-carbonitrile (1 mmol), acetic an-
hydride (1 mL), and pyridine (0.1 mL) were mixed and stirred at
85 ꢀC until TLC indicated total consumption of the starting material.
Upon completion, the reaction mixture was cooled to room tem-
perature and then poured into 250 mL water. The solid product was
removed by filtration and purified by recrystallization from 95%
ethanol to afford the pure product 4a.
Fig. 2. ORTEP drawing of the X-ray crystal structure of 5b.
Scheme 2. Initially, pyridine rapidly reacts with the anhydride to
form N-acyl pyridine onium salt. Then nucleophilic attack of the
active carbonyl of acyl pyridine cation by compound A gives in-
termediate B, eliminating 1 equiv of pyridine to form the unstable
intermediate C. Due to the strongly electron-withdrawing group
(C]O) at the b-position of cyclic double bonds in the compounds
C, an additioneelimination reaction occurs when pyridine attacks
a vinylic carbon atom of C; this leads to open chain E-enamine
isomer E because of intramolecular hydrogen bond. The in-
termediate E undergoes cyclization to afford the final products 4
or 5.
4.2.1.1. 2-(7,7-Dimethyl-5-oxo-4-phenyl-3,4,5,6,7,8-hexahydro-
2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
(4a). Colorless crystals. Mp 242e243 ꢀC. IR (KBr, , cmꢁ1): 3412,
n
2911, 2209, 1690, 1666, 1577, 1450, 1373, 1208, 969, 832. 1H NMR
(400 MHz, CDCl3) (ppm): 11.80 (s,1H, NH), 7.27e7.38 (m, 5H, ArH),
d
5.37 (s, 1H, CH), 2.61e2.63 (m, 2H, CH2), 2.34 (s, 3H, CH3), 2.28 (d,
J¼5.3 Hz, 2H, CH2), 1.15 (s, 3H, CH3), 1.06 (s, 3H, CH3). 13C NMR
O
O
O
O
+
N
+
(100 MHz, DMSO-d6) d: 195.0, 194.0, 162.1, 161.8, 141.0, 129.3, 128.9,
O
O
N
127.6, 118.1, 113.1, 71.3, 50.2, 48.9, 32.6, 28.5, 28.2, 27.4. Anal. calcd
for C20H20N2O3: C 71.41, H 5.99, N 8.33; found: C 71.22, H 5.68, N
8.27.
O
R
O
OH
N
OH
R
O
O
R
CN
CN
CN
N
-Py
O
O
NH2
H
N
O
B
NH
4.2.1.2. 2-(7,7-Dimethyl-4-(3-nitrophenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
N
O
A
C
(4b). A colorless solid. Mp 253e255 ꢀC. IR (KBr, , cmꢁ1): 3402,
n
O
R
2957, 2203, 1665, 1577, 1374, 1208, 1057, 971, 823. 1H NMR
(400 MHz, CDCl3) (ppm): 11.97 (s, 1H, NH), 8.19e8.21 (m,1H, ArH),
R
O
H
OH
R
O
CN
HN
O
d
-Py
-H
NH
O
H-Bond
O
8.14 (s, 1H, ArH), 7.66e7.68 (m, 1H, ArH), 7.55e7.59 (m, 1H, ArH),
5.49 (s, 1H, CH), 2.65e2.68 (m, 2H, CH2), 2.37 (s, 3H, CH3), 2.29 (d,
J¼9.2 Hz, 2H, CH2), 1.17 (s, 3H, CH3), 1.08 (s, 3H, CH3). 13C NMR
O
H
N
N
CN
N
CN
(100 MHz, DMSO-d6) d: 195.1, 194.1, 162.4, 161.9, 148.2, 142.9, 134.3,
4 or 5
E
D
131.0, 123.8, 123.0, 118.0, 112.0, 71.6, 50.1, 48.5, 32.6, 28.5, 28.3, 27.5.
Anal. calcd for C20H19N3O5: C 62.99, H 5.02, N 11.02; found: C 62.78,
H 4.53, N 11.05.
Scheme 2. Possible reaction mechanism of the reaction.
4.2.1.3. 2-(4-(3,4-Dimethoxyphenyl)-7,7-dimethyl-5-oxo-
3,4,5,6,7,8-hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-
3. Conclusion
oxobutanenitrile (4c). Colorless crystals. Mp 209e211 ꢀC. IR (KBr,
n,
In summary, a novel cascade reaction to convert pyrane de-
rivatives into 1,3-oxazine derivatives bearing an exocyclic double
bond has been discovered. The reaction involves an unusual
carbonecarbon bond cleavage, and a facile CeN bond formation
in one pot. We believe this method will broaden the scope of the
synthesis of 1,3-oxazine moiety. Further studies for exploration
of the detailed mechanism and changing the cyanide group
to other electron-withdrawing group are underway in our
laboratory.
cmꢁ1): 3430, 2960, 2199, 1691, 1664, 1585, 1375, 1207, 1139, 974,
801. 1H NMR (400 MHz, CDCl3)
(ppm): 11.78 (s,1H, NH), 6.76e6.83
d
(m, 3H, ArH), 5.31 (s, 1H, CH), 3.87 (s,3H, OCH3), 3.85 (s,3H, OCH3),
2.61e2.62 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.29 (d, J¼3.5 Hz, 2H,
CH2), 1.16 (s, 3H, CH3), 1.08 (s, 3H, CH3).
13C NMR (100 MHz, DMSO-d6)
d: 195.1, 194.0, 161.9, 161.8, 149.3,
149.2, 133.2, 119.6, 118.2, 112.9, 112.4, 111.5, 71.2, 56.0, 56.0, 50.2,
48.6, 32.5, 28.6, 28.2, 27.4. Anal. calcd for C22H24N2O5: C 66.65, H
6.10, N 7.07; found: C 66.51, H 5.66, N 7.10.

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Z. Lin et al. / Tetrahedron 68 (2012) 6759e6764
4.2.1.4. 2-(7,7-Dimethyl-4-(3-methylphenyl)-5-oxo-3,4,5,6,7,8-
d
(ppm): 11.79 (s, 1H, NH), 7.24e7.28 (m, 1H, ArH), 6.80e6.84 (m,
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
3H, ArH), 5.33 (s, 1H, CH), 3.79 (s, 3H, OCH3), 2.60e2.63(m, 2H,
CH2), 2.34 (s, 3H, CH3), 2.29 (d, J¼2.3 Hz, 2H, CH2), 1.15 (s, 3H,
(4d). A colorless solid. Mp 251e253 ꢀC. IR (KBr, , cmꢁ1): 3446,
n
2956, 2207, 1666, 1575, 1370, 1204, 969, 814. 1H NMR (400 MHz,
CDCl3) (ppm): 11.76 (s, 1H, NH), 7.22 (m, 1H, ArH), 7.11 (m, 1H,
CH3), 1.08 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
d: 195.0,
d
194.0, 162.0, 160.0, 142.3, 130.5, 119.3, 118.1, 113.8, 113.7, 112.8,
71.3, 55.6, 50.2, 48.7, 32.5, 28.5, 28.2, 27.4. Anal. calcd for
C21H22N2O4: C 68.83, H 6.05, N 7.65; found: C 68.51, H 5.99, N
7.71.
ArH), 7.04 (m, 2H, ArH), 5.32 (s, 1H, CH), 2.61e2.64 (m, 2H, CH2),
2.34 (s, 6H, 2CH3), 2.28 (d, J¼3.1 Hz, 2H, CH2), 1.15 (s, 3H, CH3),
1.08 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
d: 195.0, 194.0,
162.0, 161.8, 140.8, 138.5, 129.5, 129.2, 128.1, 124.6, 118.1, 112.9,
71.3, 50.2, 48.9, 32.6, 28.5, 28.2, 27.4, 21.4. Anal. calcd for
C21H22N2O3: C 71.98, H 6.33, N 7.99; found: C 70.21, H 6.07, N
7.65.
4.2.1.10. 2-(7,7-Dimethyl-4-(4-nitrophenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
(4j). A colorless solid. Mp 227e229 ꢀC. IR (KBr, , cmꢁ1): 3542,
n
2975, 2207, 1665, 1526, 1375, 1203, 1051, 875, 810, 734. 1H NMR
(400 MHz, CDCl3)
4.2.1.5. 2-(7,7-Dimethyl-4-(4-methylphenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
d
(ppm): 11.96 (s, 1H, NH), 8.23 (d, J¼8.8 Hz, 2H,
ArH), 7.49 (d, J¼8.8 Hz, 2H, ArH), 5.49 (s, 1H, CH), 2.64 (s, 2H, CH2),
2.37 (s, 3H, CH3), 2.23 (d, J¼12.1 Hz, 2H, CH2), 1.17 (s, 3H, CH3), 1.05
(4e). A colorless solid. Mp 226e228 ꢀC. IR (KBr, , cmꢁ1): 3448,
n
2952, 2209, 1664, 1575, 1371, 1209, 968, 820. 1H NMR (400 MHz,
CDCl3) (ppm): 11.76 (s, 1H, NH), 7.26 (s, 2H, ArH), 7.14 (s, 2H, ArH),
(s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
d: 195.0, 194.1, 162.2,
d
162.0, 147.8, 147.7, 129.3, 124.4, 118.0, 112.2, 71.7, 50.1, 48.5, 32.6,
28.5, 28.3, 27.5. Anal. calcd for C20H19N3O5: C 62.99, H 5.02, N 11.02;
found: C 63.03, H 4.75, N 10.96.
5.33 (s, 1H, CH), 2.60e2.62 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.32 (s,
3H, CH3), 2.27 (d, J¼5.9 Hz, 2H, CH2), 1.15 (s, 3H, CH3), 1.06 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6)
d: 195.0, 194.0, 162.0, 161.7,
138.3, 138.1,129.8,127.5,118.2,113.1, 71.3, 50.2, 48.7, 32.6, 28.6, 28.2,
27.4, 21.1. Anal. calcd for C21H22N2O3: C 71.98, H 6.33, N 7.99; found:
C 71.70, H 5.97, N 7.93.
4.2.2. General procedure for the synthesis of 5. In an oven-dried
25 mL flask, 2-amino-4-aryl-7-methyl-5-oxo-4H,5H-pyrano[4,3-b]
pyran-3-carbonitrile (1 mmol), acetic anhydride (1 mL), and pyri-
dine (0.1 mL) were mixed and magnetically stirred at 85 ꢀC until
TLC indicated total consumption of the starting material. Upon
completion, the reaction mixture was cooled to room temperature
and then poured into 250 mL water. The solid product was removed
by filtration and purified by recrystallization from 95% ethanol to
afford the pure product 5a.
4.2.1.6. 2-(4-(3,4-Dimethylphenyl)-7,7-dimethyl-5-oxo-
3,4,5,6,7,8-hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-
oxobutanenitrile (4f). A colorless solid. Mp 210e212 ꢀC. IR (KBr,
n,
cmꢁ1): 3491, 2956, 2210,1662,1571,1451,1374,1205,1152, 931, 892.
1H NMR (400 MHz, CDCl3)
(ppm): 11.73 (s, 1H, NH), 7.08e7.10 (m,
d
1H, ArH), 6.96e7.00 (m, 2H, ArH), 5.28 (s, 1H, CH), 2.61e2.64 (m,
2H, CH2), 2.33 (s, 3H, CH3), 2.28 (d, J¼3.5 Hz, 2H, CH2), 2.24 (s, 3H,
CH3), 2.22 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3). 13C NMR
4.2.2.1. 2-(7-Methyl-5-oxo-4-phenyl-3,4-dihydropyrano[3,4-e]
[1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5a). A colorless
(100 MHz, DMSO-d6)
d: 195.0, 194.0, 161.9, 161.7, 138.3, 137.1, 137.1,
solid. Mp 229e232 ꢀC. IR (KBr, , cmꢁ1): 3106, 2362, 2213, 1714,
n
130.4, 128.6, 124.9, 118.2, 113.0, 71.2, 50.2, 48.7, 32.6, 28.6, 28.2, 27.5,
19.9, 19.5. Anal. calcd for C22H24N2O3: C 72.50, H 6.64, N 7.69;
found: C 72.12, H 6.39, N 7.71.
1671, 1649, 1492, 1396, 1159, 982, 833, 758, 693. 1H NMR
(400 MHz, DMSO-d6) (ppm): 11.57(s, 1H, NH), 7.33e7.40 (m, 5H,
ArH), 6.62 (s, 1H, CH), 5.55 (s, 1H, CH), 2.27 (s, 3H, CH3), 2.23 (s,
3H, CH3). 13C NMR (100 MHz, DMSO-d6)
: 194.3, 165.3, 161.7,
d
d
4.2.1.7. 2-(4-(4-Chlorophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
160.1, 157.0, 140.1, 129.3, 129.1, 127.8, 117.7, 100.4, 98.1, 71.7, 49.7,
28.2, 19.9. Anal. calcd for C18H14N2O4: C 67.07, H 4.38, N 8.69;
found: C 67.32, H 4.36, N 8.29.
(4g). A colorless solid. Mp 252e253 ꢀC. IR (KBr, , cmꢁ1): 3735,
n
2949, 2209, 1664, 1574, 1374, 1208, 969, 826. 1H NMR (400 MHz,
CDCl3)
d
(ppm): 11.82 (s, 1H, NH), 7.33 (d, J¼8.4 Hz, 2H, ArH), 7.21 (d,
4.2.2.2. 2-(4-(4-Methoxyphenyl)-7-methyl-5-oxo-3,4-dihydropy-
J¼8.4 Hz, 2H, ArH), 5.35 (s, 1H, CH), 2.61e2.62 (m, 2H, CH2), 2.35 (s,
3H, CH3), 2.28 (d, J¼7.4 Hz, 2H, CH2), 1.15 (s, 3H, CH3), 1.05 (s, 3H,
rano[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5b). A yel-
low solid. Mp 221e222 ꢀC. IR (KBr, , cmꢁ1): 3446, 3102, 2205, 1731,
n
CH3). 13C NMR (100 MHz, DMSO-d6)
d: 195.1, 194.0, 162.0, 162.0,
1672, 1576, 1391, 1244, 1023, 984, 810. 1H NMR (400 MHz, DMSO-d6)
(ppm): 11.54(s, 1H, NH), 7.30 (d, J¼8.8 Hz, 2H, ArH), 6.92 (d,
J¼8.8 Hz, 2H, ArH), 6.60 (s, 1H, CH), 5.49 (s, 1H, CH), 3.74(s, 3H, CH3),
2.27 (s, 3H, CH3), 2.22 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
140.0, 133.5, 129.7, 129.3, 118.1, 112.7, 71.5, 50.2, 48.4, 32.6, 28.5,
28.3, 27.5. Anal. calcd for C20H19ClN2O3: C 64.78, H 5.16, N 7.55;
found: C 64.59, H 5.23, N 7.64.
d
d:
194.3, 165.1, 161.5, 160.1, 156.0, 156.8, 132.2, 129.2, 117.8, 114.7, 100.5,
98.1, 71.6, 55.7, 49.1, 28.2, 19.9. Anal. calcd for C19H16N2O5: C 64.86, H
4.56, N 7.94; found: C 64.52, H 4.42, N 8.18.
4.2.1.8. 2-(4-(4-Bromophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
(4h). A colorless solid. Mp 243e244 ꢀC. IR (KBr, , cmꢁ1): 3421,
n
2948, 2208, 1664, 1578, 1373, 1207, 1056, 823. 1H NMR (400 MHz,
CDCl3)
4.2.2.3. 2-(4-(4-Chlorophenyl)-7-methyl-5-oxo-3,4-dihydropyrano
d
(ppm): 11.83 (s, 1H, NH), 7.48 (d, J¼8.4 Hz, 2H, ArH), 7.15 (d,
[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5c). A yellow
J¼8.4 Hz, 2H, ArH), 5.34 (s, 1H, CH), 2.61e2.62 (m, 2H, CH2), 2.35 (s,
3H, CH3), 2.28 (d, J¼7.4 Hz, 2H, CH2), 1.15 (s, 3H, CH3), 1.05 (s, 3H,
solid. Mp 219e220 ꢀC. IR (KBr, , cmꢁ1): 3436, 3101, 2213, 1716, 1648,
n
1574, 1394, 1160, 983, 837, 781. 1H NMR (400 MHz, DMSO-d6)
(ppm): 11.59(s, 1H, NH), 7.43 (d, J¼8.4 Hz, 2H, ArH), 7.32 (d,
J¼8.4 Hz, 2H, ArH), 6.61 (s, 1H, CH), 5.52 (s, 1H, CH), 2.27 (s, 3H, CH3),
2.23 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
: 194.3, 165.4, 161.5,
CH3). 13C NMR (100 MHz, DMSO-d6)
d
: 195.0, 194.0, 161.9, 140.3,
d
132.1, 129.9, 122.1, 118.1, 112.6, 72.9, 63.5, 50.1, 48.4, 32.6, 28.5, 28.2,
27.5. Anal. calcd for C20H19BrN2O3: C 57.84, H 4.61, N 6.75; found: C
54.079, H 4.74, N 6.51.
d
160.1, 157.1, 139.1, 133.8, 130.0, 129.2, 117.8, 99.9, 98.2, 71.8, 49.1, 28.3,
20.0. Anal. calcd for C18H13Cl N2O4: C 60.60, H 3.67, N 7.85; found: C
59.84, H 3.59, N 7.77.
4.2.1.9. 2-(7,7-Dimethyl-4-(3-methoxyphenyl)-5-oxo-3,4,5,6,7,8-
hexahydro-2H-benzo[e][1,3]oxazin-2-ylidene)-3-oxobutanenitrile
(4i). A colorless solid. Mp 218e220 ꢀC. IR (KBr,
n
, cmꢁ1): 3745,
4.2.2.4. 2-(7-Methyl-4-(3-nitrophenyl)-5-oxo-3,4-dihydropyrano
[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5d). A light
2360, 2207, 1668, 1559, 939, 821. 1H NMR (400 MHz, CDCl3)

Z. Lin et al. / Tetrahedron 68 (2012) 6759e6764
6763
yellow solid. Mp 242e245 ꢀC. IR (KBr,
1724, 1673, 1643, 1536, 1352, 1184, 1162, 983, 823, 744. 1H NMR
(400 MHz, DMSO-d6) (ppm): 11.64(s, 1H, NH), 8.19e8.33 (m, 2H,
n
, cmꢁ1): 3088, 2362, 2208,
4.2.2.10. 2-(4-(3,4-Dimethoxyphenyl)-7-methyl-5-oxo-3,4-
dihydropyrano[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile
d
(5j). A colorless solid. Mp 217e220 ꢀC. IR (KBr, , cmꢁ1): 3735, 3567,
n
ArH), 7.86 (d, J¼7.8 Hz, 1H, ArH), 7.68 (t, J¼7.8 Hz, 1H, ArH), 6.63 (s,
2369, 2212, 1711, 1668, 1578, 1391, 1288, 1016, 986, 838. 1H NMR
(400 MHz, DMSO-d6)
1H, CH), 5.71 (s, 1H, CH), 2.29 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C NMR
d
(ppm): 11.55(s, 1H, NH), 7.02 (d, J¼2.2 Hz,
(100 MHz, DMSO-d6)
d: 194.3, 165.6, 161.5, 160.2, 157.3, 148.1, 142.0,
1H, ArH), 6.92e6.94 (m, 1H, ArH), 6.82e6.85 (m, 1H, ArH), 6.61 (s,
134.7, 130.9, 124.0, 123.4, 117.8, 99.2, 98.2, 71.9, 49.2, 28.3, 19.9. Anal.
calcd for C18H13N3O6: C 58.86, H 3.57, N 11.44; found: C 58.81, H
3.56, N 7.88.
1H, CH), 5.49 (s, 1H, CH), 3.74 (s,3H, OCH3), 3.73 (s,3H, OCH3), 2.23
(s, 3H, CH3), 2.22(s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
d:
194.2, 165.0, 161.4, 160.1, 156.9, 149.5, 149.1, 132.4, 119.9, 117.8, 112.4,
111.9, 100.2, 98.1, 71.5, 56.1, 56.0, 49.3, 28.2, 19.9. Anal. calcd for
C20H18N2O6: C 62.82, H 4.74, N 7.33; found: C 62.78, H 4.78, N 7.45.
4.2.2.5. 2-(7-Methyl-4-(3-methylphenyl)-5-oxo-3,4-dihydropyrano
[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5e). A colorless
solid. Mp 237e239 ꢀC. IR (KBr, , cmꢁ1): 3166, 2366, 2214, 1719, 1670,
n
Acknowledgements
1393,1186, 982, 959, 823, 776. 1H NMR (400 MHz, DMSO-d6)
d (ppm):
11.56(s, 1H, NH), 7.25e7.29 (m, 1H, ArH), 7.15e7.19 (m, 3H, ArH), 6.61
We are grateful to financial support from the National Natural
Science Foundation of China (No. 81071144) and Natural Science
Foundation of the Guangdong Province (No. 9451806001002961).
(s, 1H, CH), 5.50 (s, 1H, CH), 2.30 (s,3H, CH3), 2.28 (s,3H, CH3), 2.22 (s,
3H, CH3). 13C NMR (100 MHz, DMSO-d6)
d: 194.2, 165.2, 161.4, 160.1,
156.9, 140.0, 138.6, 129.8, 129.2, 128.2, 125.0, 117.8, 100.2, 98.1, 71.6,
49.6, 28.2, 21.4, 19.9. Anal. calcd for C19H16N2O4: C 67.58, H 4.79, N
8.33; found: C 67.91, H 4.68, N 8.27.
Supplementary data
Copies of 1H NMR and 13C NMR spectra for all new compounds.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.089.
4.2.2.6. 2-(7-Methyl-4-(4-methylphenyl)-5-oxo-3,4-dihydropyrano
[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile (5f). A light yel-
low solid. Mp 217e219 ꢀC. IR (KBr, , cmꢁ1): 3442, 3105, 2361, 2215,
n
1715,1646,1607,1397,1185, 983, 842, 787. 1H NMR (400 MHz, DMSO-
d6)
(ppm): 11.54(s, 1H, NH), 7.25 (d, J¼7.8 Hz, 2H, ArH), 7.17 (d,
J¼8.0 Hz, 2H, ArH), 6.61 (s, 1H, CH), 5.55 (s, 1H, CH), 2.28 (s,3H, CH3),
2.27 (s,3H, CH3), 2.22 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
References and notes
d
1. For selected reports on carbonecarbon bond cleavage. (a) Rybtchinski, B.;
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kin, G. Nature 2010, 463, 523e526; (f) Nakai, K.; Kurahashi, T.; Matsubara, S. J.
Am. Chem. Soc. 2011, 133, 11066e11068.
d:
194.3, 165.2, 161.5, 160.1, 156.9, 138.6, 137.2, 129.8, 127.7, 117.8, 100.4,
98.1, 71.6, 49.4, 28.3, 21.2, 19.9. Anal. calcd for C19H16N2O4: C 67.58, H
4.79, N 8.33; found: C 67.26, H 4.63, N 7.99.
2. (a) Kluger, R. Chem. Rev. 1990, 90, 1151e1169; (b) Johnson, A. E.; Tanner, M. E.
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Arif, A. M.; Berreau, L. M. J. Am. Chem. Soc. 2005, 127, 17186e17187; (c) Meci-
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4.2.2.7. 2-(4-(3,4-Dimethylphenyl)-7-methyl-5-oxo-3,4-
dihydropyrano[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile
(5g). A colorless solid. Mp 227e229 ꢀC. IR (KBr, , cmꢁ1): 3101,
n
3002, 2361, 2213, 1724, 1673, 1606, 1395, 1185, 981, 813, 771. 1H
NMR (400 MHz, DMSO-d6) (ppm): 11.54(s, 1H, NH), 7.12e7.14 (m,
d
2H, ArH), 7.06e7.08 (m, 1H, ArH), 6.61 (s, 1H, CH), 5.47 (s, 1H, CH),
2.28 (s, 3H, CH3), 2.19e2.21 (m, 9H, 3CH3). 13C NMR (100 MHz,
DMSO-d6) d: 194.3,165.1,161.4,160.1,156.9,137.5,137.4,137.2,130.3,
128.7, 125.3, 117.8, 100.3, 98.1, 71.5, 49.4, 28.2, 19.9, 19.9, 19.5. Anal.
calcd for C20H18N2O4: C 68.56, H 5.18, N 8.00; found: C 68.25, H
4.88, N 7.91.
4.2.2.8. 2-(4-(3-Methoxyphenyl)-7-methyl-5-oxo-3,4-
dihydropyrano[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile
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(5h). A light yellow solid. Mp 219e221 ꢀC. IR (KBr, , cmꢁ1): 3429,
n
3094, 2966, 2210, 1723, 1672, 1645, 1393, 1183, 1043, 983, 872, 788.
1H NMR (400 MHz, DMSO-d6)
(ppm): 11.57(s, 1H, NH), 7.30 (t,
J¼8.2 Hz, 1H, ArH), 6.90e6.96 (m, 3H, ArH), 6.61 (s, 1H, CH), 5.52 (s,
1H, CH), 3.75 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.23 (s, 3H, CH3). 13
NMR (100 MHz, DMSO-d6) : 194.3, 165.3, 161.6, 160.2, 159.9, 157.1,
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J.; Wilhelm, J. M.; Wolfrom, S.; Zhu, Y.; Zhang, Z.; Zhang, P.; Winneker, R. C.;
Wrobel, J. J. Med. Chem. 2005, 48, 5092e5095; (b) Kern, J. C.; Terefenko, E. A.;
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d
C
d
141.6,130.6,119.6,117.8, 114.2,114.1, 100.1, 98.2, 71.7, 55.7, 49.5, 28.3,
20.0. Anal. calcd for C19H16N2O5: C 64.77, H 4.58, N 7.95; found: C
64.60, H 4.43, N 7.93.
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4.2.2.9. 2-(4-(4-Bromophenyl)-7-methyl-5-oxo-3,4-
dihydropyrano[3,4-e][1,3]oxazin-2(5H)-ylidene)-3-oxobutanenitrile
(5i). A yellow solid. Mp 224e226 ꢀC. IR (KBr, , cmꢁ1): 3445, 3108,
n
2217, 1726, 1652, 1574, 1395, 1162, 987, 832, 793. 1H NMR (400 MHz,
DMSO-d6)
(ppm): 11.55(s,1H, NH), 7.58 (d, J¼8.6 Hz, 2H, ArH), 7.36
(d, J¼8.6 Hz, 2H, ArH), 6.62 (s, 1H, CH), 5.53 (s, 1H, CH), 2.27 (s, 3H,
CH3), 2.23 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6)
: 194.3,
d
d
165.3, 161.5, 160.1, 157.0, 139.0, 133.8, 130.0, 129.2, 117.8, 99.8, 98.2,
71.7, 49.1, 28.3, 20.0. Anal. calcd for C18H13Br N2O4: C 53.89, H 3.27,
N 6.98; found: C 53.74, H 3.31, N 6.95.
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