Construction of heterocycles via 1,4-dipolar cycloaddition of quinoline-DMAD zwitterion with various dipolarophiles

Article abstract of DOI:10.1016/j.tet.2008.01.106

Quinoline forms 1,4-zwitterion with dimethyl acetylenedicarboxylate, which is trapped by various dipolarophiles to yield a variety of pyridoquinoline and oxazinoquinoline derivatives.

Full text of DOI:10.1016/j.tet.2008.01.106

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3567e3577
www.elsevier.com/locate/tet
Construction of heterocycles via 1,4-dipolar cycloaddition of
quinolineeDMAD zwitterion with various dipolarophiles
a
c
Vijay Nair a,b, , S. Devipriya , Eringathodi Suresh
*
a Organic Chemistry Section, Chemical Sciences Division, NIIST (CSIR), Industrial Estate PO, Papanamcode, Trivandrum 695 019, India
b Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-560 004, India
c Analytical Science Discipline, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India
Received 16 October 2007; received in revised form 5 January 2008; accepted 24 January 2008
Available online 31 January 2008
Abstract
Quinoline forms 1,4-zwitterion with dimethyl acetylenedicarboxylate, which is trapped by various dipolarophiles to yield a variety of
pyridoquinoline and oxazinoquinoline derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
CO2Me
CO2Me
CO2Me
DMAD
N
1,4-Dipolar cycloaddition provides an efficient and conve-
nient route for the synthesis of six-membered heterocyclic
compounds. However, these reactions have received only scant
attention when compared to the related 1,3-dipolar cycloaddi-
tion reactions. The advent of 1,4-dipolar cycloaddition reactions
dates back to 1932, when Diels and Alder showed that pyridine
reacts smoothly with dimethyl acetylenedicarboxylate (DMAD)
to form an adduct of unknown structure.1 Three decades later,
Acheson et al. established the structure of the adduct as the
4H-quinolizine 4 (Scheme 1).2 It was Huisgen who recognized
this reaction as the 1,4-dipolar variant of the classical Dielse
Alder reaction involving the intermediate 3.3 Reports of the
intermolecular trapping of the 1,4-dipole 3 by Winterfeldt,4
Acheson and Plunkett,5 and Huisgen et al.6 are noteworthy.
Extensivework has been done by our group on the reactivities
of 1,4-dipoles derived from DMAD and nucleophiles such as
phosphines,7 isocyanides,8 dimethoxycarbene,9 nitrogen hetero-
cycles,10 and nucleophilic heterocyclic carbenes (NHC).11
These studies have led to a number ofinteresting carbonecarbon
bond forming reactions and heterocyclic constructions.12 Recent
N
CO2Me
CO2Me
N
MeO2C
CO2Me
CO2Me
1
2
3
4
Scheme 1.
investigations in our laboratory have shown that the zwitterionic
intermediate generated by the reaction of quinoline and DMAD
undergoes facile addition to aldehydes and diaryl 1,2-diones to
affordoxazinoquinolinederivativesingoodyields(Scheme2).13
In view of the success of this reaction, and in the context of
our general interest in the chemistry of zwitterions in general
and quinolineeDMAD zwitterion in particular, we have car-
ried out a systematic study of the reaction of the quinolinee
DMAD zwitterion with various dipolarophiles. The results
of these studies are presented here.
2. Results and discussion
2.1. Reaction with activated olefins
Our detailed studies commenced with the reaction of quino-
line and DMAD with the aryl cyanoacrylate 11a. A mixture of
* Corresponding author. Tel.: þ91 471 2490406; fax: þ91 471 2491712.
E-mail address: vijaynair_2001@yahoo.com (V. Nair).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.106

3568
V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
CHO
H
N
O
F3C
7
Toluene, 110 °C
Sealed tube, 12 h
4:1. 92%
MeO2C
MeO2C
CF3
CO2Me
8
N
O
S
CO2Me
S
5
2
N
O
S
O
9
S
Toluene, 110 °C
Sealed tube, 12 h
52%
MeO2C
MeO2C
O
10
N
via
MeO2C
CO2Me
Figure 1. ORTEP diagram of 12a.
6
and DMAD yielding the pyridoquinoline derivatives in good
yields (Table 1). The diastereomeric ratios of the products
Scheme 2.
1
were determined on the basis of H NMR spectroscopy of
the mixtures.
the three in dry toluene, when heated under reflux in a sealed
tube for 12 h, afforded the pyridoquinoline derivatives 12a and
13a in 62% total yield in the ratio 4:1 (Scheme 3).
Table 1
Reaction of quinoline and DMAD with aryl cyanoacrylates
CO2Me
CN
CO2Me
CN
CO2Et
CN
Toluene, 110 °C
12 h
N
H
CO2Et
Toluene, 110 °C
sealed tube, 12 h
62%, 4:1
CO2Et
F
N
N
MeO2C
MeO2C
12 & 13
CO2Me
R
CO2Me
5
2
11a
R
4
2
11
H
N
H
N
CO2Et
CN
CO2Et
CN
Entry
R
Products
Ratio
Yield (%)
1
2
3
4
5
6
7
11b, 4-chloro
11c, 4-trifluoromethyl
11d, 4-nitro
12b/13b
12c/13c
12d/13d
12e/13e
12f/13f
4:1
3.6:1
4:1
56
58
54
56
65
49
44
MeO2C
MeO2C
MeO2C
MeO2C
F
F
12a
13a
11e, 4-bromo
11f, naphthyl
11g, H
4:1
4:1
Scheme 3.
12g/13g
12h/13h
4:1
4:1
11h, 4-methoxy
The product 12a was obtained in the pure form by fractional
crystallization and was characterized on the basis of spectro-
scopic data. In the IR spectrum, the ester carbonyls showed
strong absorptions at 1740 and 1744 cmꢀ1 and the cyano group
displayed its characteristic signal at 2229 cmꢀ1. In the 1H NMR
spectrum, the methoxy carbonyl protons were visible at d 3.54
and 3.81 as sharp singlets. The ring junction proton signal was
observed as a doublet at d 4.52 (J¼4.2 Hz) and the benzylic pro-
ton displayed a singlet at d 4.59. The signals due to the olefinic
protons of the dihydroquinoline moiety were visible as a doublet
of doublet at d 6.05 (J1¼4.2 Hz, J2¼9.6 Hz) and as a multiplet
in the region d 6.65e6.71. The 13C NMR spectrum was also in
good agreement with the assigned structure. The peaks at
d 163.9, 164.2, and 165.3 were typical of the ester carbonyls.
The nitrile carbon was found to resonate at d 111.2. X-ray crys-
tallographic analysis15 revealed the relative configuration of the
isomer 12a as depicted in Figure 1.
In the absence of any theoretical studies, the mechanistic
details of the reaction are not fully understood. The initial
event is the formation of the 1,4-dipole 6 from quinoline
and DMAD. The trapping of 6 with the electrophilic car-
bonecarbon double bond of the aryl cyanoacrylate affords
pyridoquinolines. Alternatively, the reaction may take place
in two steps. The zwitterion may add to the cyanoacrylate to
form the intermediate 15, which then undergoes cyclization
to give the products (Scheme 4).
In the light of these results, attention was directed toward
arylidenemalononitriles. In the first instance, the reaction of
quinoline and DMAD with 16a in toluene at 110 ꢁC in a sealed
tube for 12 h afforded the corresponding pyridoquinoline
derivatives 17a and 18a in 72% total yield in the ratio 5:1
(Scheme 5).
Similar reactivity was observed with other aryl cyanoacryl-
ates 11beh, which underwent facile reaction with quinoline
The major isomer was isolated by repeated chromatography
and characterized by spectroscopic techniques. A strong

V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
3569
Table 2
Reaction of quinoline and DMAD with arylidene malononitriles
CO2Me
N
CO2Me
CN
CN
CO2Me
2
CN
Toluene, 110 °C
12 h
N
5
H
CN
N
MeO2C
MeO2C
17 & 18
R
CO2Me
R
4
2
16
CN
CN
CO2Et
N
N
CO2Et
14
Entry
R
Products
Ratio
Yield (%)
MeO2C
MeO2C
Ar
CO2Me
Ar
CO2Me
1
2
3
4
5
16b, 4-fluoro
17b/18b
17c/18c
17d/18d
17e/18e
17f/18f
5:1
4:1
5:1
6:1
2:1
70
71
78
68
55
6
15
16c, 4-trifluoromethyl
14d, 4-bromo
16e, 4-nitro
Addition-Cyclization
Cycloaddition
16f, 4-methyl
CN
N
H
CO2Et
treatment of N-allyl, 5-bromoisatin 19a with quinoline and
DMAD in dry toluene in a sealed tube at 110 ꢁC for 12 h
resulted in the formation of oxazinoquinoline derivatives 20a
and 21a in 71% yield as a diastereomeric mixture, in the ratio
4:1 (Scheme 6).
MeO2C
Ar
CO2Me
12/13
Scheme 4.
CO2Me
O
CN
CN
CO2Me Br
Toluene, 110 °C
sealed tube, 12 h
72%, 5:1
O
Cl
N
N
CO2Me
2
Toluene, 110 °C
sealed tube, 12 h
71%, 4:1
N
4
16a
CO2Me
2
19a
4
H
N
H
N
CN
CN
CN
CN
O
O
N
N
O
N
O
MeO2C
MeO2C
MeO2C
H
H
MeO2C
MeO2C
MeO2C
N
MeO2C
Cl
Cl
17a
18a
MeO2C
Br
Scheme 5.
Br
21a
20a
absorption at 1744 cmꢀ1 in the IR spectrum of 17a indicated the
presence of ester carbonyl groups, whereas the absorption at
2235 cmꢀ1 corresponded to the cyano groups. In the 1H NMR
spectrum, the methoxy carbonyl protons were visible as singlets
at d 3.52 and 3.84. The benzylic proton displayed a singlet at
d 4.62 and the ring junction proton resonated as a doublet at
d 5.93 (J¼4.5 Hz). The signals due to the protons of the dihydro-
quinoline moiety were visible as a doublet of doublet at d 6.00
(J1¼4.2 Hz, J2¼9.0 Hz) and as a multiplet in the region
d 6.63e6.69. The 13C NMR spectrum displayed the characteris-
tic signals of the ester carbonyls at d 164.1 and 164.5 and that of
the nitrile carbon at d 110.2. The resonance signals at d 51.2 and
52.1 were attributed to the carbomethoxy carbons.
Scheme 6.
The diastereomers were separated by column chromatogra-
phy and the major isomer 20a was obtained pure by fractional
crystallization. The structure of the product 20a was assigned
on the basis of spectroscopic analysis. In the IR spectrum, the
ester carbonyl absorptions were seen at 1732 and 1726 cmꢀ1
and that of the amide carbonyl at 1685 cmꢀ1. In the H NMR
1
spectrum, signals due to the methoxy carbonyl protons were
observed as sharp singlets at d 3.92 and 3.61. The ring junction
proton was discernible as a doublet at d 6.63 (J¼4.2 Hz). The
olefinic protons of the dihydroquinoline moiety were visible
as a doublet of doublet at d 5.60 (J1¼5.7 Hz, J2¼9.9 Hz) and
as a multiplet in the region d 6.65e6.78. The amide carbonyl
displayed the 13C resonance signal at d 172.8 and the methoxy-
carbonyls at d 165.2 and 163.6. The signal due to the spirocar-
bon was observed at d 79.2. All other signals were also in
agreement with the designated structure. Finally, the structure
of 20a was unequivocally established by single crystal X-ray
analysis15 (Fig. 2).
The reaction was found to be general with various aryl-
idenemalononitriles affording diastereomeric mixtures of the
corresponding pyridoquinolines in good yields (Table 2).
The diastereomeric ratios of the products were determined
1
on the basis of H NMR spectroscopy of the mixtures.
2.2. Reaction with cyclic 1,2-diones
Evidently, the regiospecificity observed in this reaction is
attributable to the higher electrophilicity of the keto group
vis-a-vis the amide carbonyl. The reaction was found to be
general with respect to various N-substituted isatins and the
2.2.1. Reaction with isatins
Subsequently we have investigated the reaction of the zwit-
terionic intermediate with isatins. In an illustrative example,

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V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
CMe3
oxazinoquinoline derivatives were obtained in good yields.
The results are summarized in Table 3.
CO2Me
O
Toluene, 110 °C
sealed tube, 7 h
66%, 4:1
N
Me3C
O
O
CO2Me
4
2
22a
O
O
N
O
N
CMe3
MeO2C
MeO2C
Me3C
MeO2C
MeO2C
CMe3
CMe3
23a
24a
Scheme 7.
moiety were visible as a doublet of doublet at d 5.91
(J1¼4.2 Hz, J2¼9.8 Hz) and as a multiplet in the region
d 6.95e6.98. The ring junction proton signal was observed
as a doublet at d 5.42 (J¼4.2 Hz). The methoxycarbonyls dis-
played the 13C resonance signals at d 164.4 and 164.9 and the
keto carbonyl at d 196.6. The spirocarbon signal was observed
at d 78.4. The compound gave satisfactory HRMS data also.
In order to obtain additional support for the structure of
23a, HMBC experiment was carried out (Fig. 3). The keto car-
bonyl at d 196.6 correlates with the proton at d 6.05. This
means that the carbon atom, which is a to the carbonyl carbon
bears a proton. The spirocarbon at d 78.4 does not show any
correlation with protons. The carbon atom in the a-position
has no attached proton and so there is no correlation to it
from the spirocarbon.
Figure 2. ORTEP diagram of 20a.
Table 3
Reaction of quinoline and DMAD with isatins
O
CO2Me
O
R
N
O
H
Toluene, 110 °C
O
N
R1
MeO2C
12 h
N
N
R1
CO2Me
MeO2C
R
4
2
19
20 & 21
Entry
Isatin
R
R1
Products
Ratio
Yield (%)
1
2
3
4
5
19b
19c
19d
19e
19f
H
Allyl
Methyl
20b/21b
20c/21c
20d/21d
20e/21e
20f/21f
4:1
4:1
4:1
5:1
5:1
70
65
63
69
68
Br
Br
H
Propargyl
Propargyl
Ethyl
Br
2.2.2. Reaction with 1,2-benzoquinones
Inspired by the results obtained in the trapping of qui-
nolineeDMAD zwitterion with diaryl 1,2-diones and isatins,
we focused our attention on another class of dicarbonyl com-
pounds, i.e., 1,2-benzoquinones. In a pilot experiment, a solu-
tion of 3,5-di-tert-butyl-1,2-benzoquinone 22a, quinoline, and
DMAD in dry toluene was taken in a sealed tube and was
stirred at 110 ꢁC for 7 h. The reaction mixture when subjected
to column chromatography afforded the oxazinoquinoline de-
rivatives 23a and 24a in 66% yield as a regioisomeric mixture
in the ratio 4:1 (Scheme 7).
Figure 3. HMBC spectrum of compound 23a.
The regioisomers were characterized by spectroscopic tech-
niques. The product 23a was characterized on the basis of
spectroscopic data. In the IR spectrum, the ketone carbonyl
absorption was seen at 1738 cmꢀ1 and the ester carbonyl ab-
sorptions at 1748 and 1755 cmꢀ1. The peaks corresponding
to the protons of the tert-butyl groups resonated as singlets
at d 1.16 and 1.20 in the 1H NMR spectrum. Signals due to the
methoxy carbonyl protons were observed as sharp singlets at
d 3.60 and 3.86. The olefinic protons of the dihydroquinoline
1
In the H NMR spectrum of 24a, the methoxy carbonyl
protons exhibited sharp signals at d 3.63 and 3.88, supporting
the absorptions at 1749 and 1757 cmꢀ1. The olefinic protons
of the dihydroquinoline moiety were observed as a doublet
of doublet at d 5.93 (J1¼4.2 Hz, J2¼9.8 Hz) and as a multiplet
in the region d 6.91e6.94. The ring junction proton signal was
observed as a doublet at d 5.46 (J¼4.3 Hz). The 13C resonance
signals for the ester and keto carbonyls were seen at d 164.6,

V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
3571
Table 4
Reaction of quinoline and DMAD with 1,2-benzoquinones
Entry Quinone
Products
Yield (%)
O
O
O
N
O
MeO2C
1
55
MeO2C
23b
22b
O
O
O
N
O
2
58
MeO2C
MeO2C
22c
23c
O
N
O
O
Me3C
O
O
O
N
O
MeO2C
MeO2C
3
70 (2:1)
MeO2C
MeO2C
CMe3
CMe3
CMe3
22d
23d
24d
CMe3
O
O
N
O
N
O
OMe
Me3C
O
MeO2C
MeO2C
MeO2C
Me3C
4
65 (2:1)
OMe
22e
CMe3
MeO
CO2Me
23e
CMe3
24e
CH(Ph)2
O
O
O
O
N
N
O
OMe
CH(Ph)2
CH(Ph)2
MeO2C
MeO2C
(Ph)2HC
23f
MeO2C
MeO2C
5
60 (2:1)
(Ph)2HC
O
MeO
OMe
CH(Ph)2
24f
22f
165.5, and 192.6. The spirocarbon signal was discernible at
d 79.4.
4. Experimental
The reaction was found to be applicable to other 1,2-benzo-
quinones as well and the results are summarized in Table 4.
A mechanistic rationalization as suggested for the reaction
of activated olefins may be invoked in the case of isatins and
benzoquinones also.
4.1. General
Melting points were recorded on a Buchi melting point appa-
¨
ratus. NMR spectra were recorded at 300 (1H) and 75 (13C) MHz
on a Bruker Avance DPX-300 MHz NMR spectrometer. Chem-
¨
ical shifts are reported (d) relative to TMS (1H) and CDCl3 (13C)
as the internal standards. Coupling constants (J) are reported in
hertz (Hz). High resolution mass spectra were recorded under
EI/HRMS (at 5000 resolution) resolution using JEOL JMS
600H mass spectrometer. IR spectra were recorded on Nicolet
Impact 400D FT-IR spectrophotometer. Quinoline and dimethyl
acetylenedicarboxylate were purchased from Aldrich Chemical
Co. and were used without further purification. Commercial
grade solvents were distilled prior to use. Analytical thin layer
chromatography was performed on glass plates coated with sil-
ica gel containing calcium sulfate as the binder. Gravity column
3. Conclusion
In conclusion, we have observed some new and efficient
1,4-dipolar cycloaddition reactions leading to the synthesis
of oxazinoquinolines and pyridoquinolines. Operational sim-
plicity and good yields are the salient features of these one
pot reactions leading to the synthesis of novel functionalized
heterocyclic compounds. It is worthy of mention that a wide
range of biologically active molecules contain oxazino and
pyridoquinoline moieties as the central core.14

3572
V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
chromatography was performed using 100e200 mesh silica gel
and mixtures of hexaneeethyl acetate were used for elution.
1H NMR: d 7.35e7.22 (m, 2H), 7.19e7.15 (m, 2H), 7.00e
6.94 (m, 3H), 6.77 (d, J¼9.0 Hz, 2H), 5.79 (dd, J1¼4.2 Hz,
J2¼9.6 Hz, 1H), 5.73 (s, 1H), 5.34 (d, J¼4.2 Hz, 1H), 4.11
(q, J¼4.8 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H), 1.01 (t, 3H).
13C NMR: d 167.5, 165.9, 164.7, 144.7, 144.4, 144.3, 136.1,
129.8, 129.7, 127.4, 122.5, 119.2, 115.3, 114.2, 112.3,
111.6, 104.4, 96.2, 70.5, 61.6, 54.9, 53.4, 53.1, 51.7, 50.6,
14.8. HRMS (EI) m/z calcd for C28H23F3N2O6, 540.1508;
found, 540.1504.
4.2. Experimental procedure for the synthesis of
pyridoquinoline derivatives by the reaction of quinoline,
DMAD, and aryl cyanoacrylates
Quinoline (0.53 mmol), DMAD (0.53 mmol), and aryl cya-
noacrylate (0.44 mmol) were taken in a sealed tube in dry tolu-
ene (3 mL) and the mixture was heated at 110 ꢁC for 12 h. After
removal of the solvent under vacuum using a rotary evaporator,
the residue was subjected to chromatography on a silica gel
(100e200 mesh) column using hexaneeethyl acetate (85:15)
solvent mixtures to afford a diastereomeric mixture of the pyr-
idoquinolines (the ratio was determined from 1H NMR).
1
Key H NMR values for the minor isomer, 13c: 5.77 (dd,
J1¼4.2 Hz, J2¼9.6 Hz, 0.28H), 5.72 (s, 0.29H), 5.37 (d,
J¼4.2 Hz, 0.28H), 3.82 (s, 0.83H), 3.66 (s, 0.82H).
4.2.4. 4-Ethyl 1,2-dimethyl 4-cyano-3-(4-nitrophenyl)-4,4a-
dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-tricarboxylate,
12d
4.2.1. 4-Ethyl 1,2-dimethyl 4-cyano-3-(4-fluorophenyl)-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-
tricarboxylate, 12a
Yellow solid (222 mg, 43%). Mp¼144e146 ꢁC. IR (KBr)
nmax: 3019, 2238, 1741, 1700, 1638, 1552, 1335, 1325, 1229,
1
1111, 989 cmꢀ1. H NMR: d 8.01e7.96 (m, 2H), 7.39e7.28
Yellow crystalline solid (245 mg, 50%). Mp¼116e118 ꢁC
(recrystallized from CH2Cl2ehexane). IR (KBr) nmax: 3012,
2229, 1744, 1740, 1611, 1222, 1116 cmꢀ1. 1H NMR: d 7.85e
7.82 (m, 2H), 7.80e7.74 (m, 2H), 6.71e6.65 (m, 3H), 6.53
(d, J¼9.0 Hz, 2H), 6.05 (dd, J1¼4.2 Hz, J2¼9.6 Hz, 1H), 4.59
(s, 1H), 4.52 (d, J¼4.2 Hz, 1H), 4.13 (q, J¼4.8 Hz, 2H), 3.81
(s, 3H), 3.54 (s, 3H), 0.98 (t, 3H). 13C NMR: d 165.3, 164.2,
163.9, 146.9, 144.3, 140.3, 136.5, 128.7, 128.5, 122.2, 119.5,
118.6, 114.5, 111.2, 107.7, 99.2, 88.3, 66.5, 61.6, 61.5, 54.7,
54.4, 53.1, 52.2, 51.1, 45.4, 14.7. HRMS (EI) m/z calcd for
C27H23FN2O6, 490.1540; found, 490.1544.
(m, 2H), 7.06e6.92 (m, 3H), 6.69 (d, J¼9.1 Hz, 2H), 5.75
(dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.69 (s, 1H), 5.32 (d,
J¼4.2 Hz, 1H), 4.13 (q, J¼4.8 Hz, 2H), 3.83 (s, 3H), 3.66 (s,
3H), 1.06 (t, 3H). 13C NMR: d 166.7, 165.9, 164.4, 151.0,
144.8, 144.3, 132.3, 129.7, 128.3, 128.0, 118.2, 117.4, 115.7,
99.0, 95.5, 77.5, 77.3, 61.1, 54.3, 53.2, 53.0, 52.7, 50.9, 15.0.
HRMS (EI) m/z calcd for C27H23N3O8, 517.1485; found,
517.1489.
1
Key H NMR values for the minor isomer, 13d: 5.73 (dd,
J1¼4.2 Hz, J2¼9.8 Hz, 0.24H), 5.70 (s, 0.24H), 5.33 (d,
J¼4.2 Hz, 0.25H), 3.84 (s, 0.75H), 3.68 (s, 0.75H).
1
Key H NMR values for the minor isomer, 13a: 5.98 (dd,
J1¼4.2 Hz, J2¼9.5 Hz, 0.27H), 4.57 (s, 0.24H), 4.48 (d,
4.2.5. 4-Ethyl 1,2-dimethyl 3-(4-bromophenyl)-4-cyano-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-
tricarboxylate, 12e
J¼4.2 Hz, 0.25H), 3.80 (s, 0.76H), 3.53 (s, 0.75H).
4.2.2. 4-Ethyl 1,2-dimethyl 3-(4-chlorophenyl)-4-cyano-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-
tricarboxylate, 12b
Yellow solid (247 mg, 45%). Mp¼128e130 ꢁC. IR (KBr)
nmax: 3012, 2235, 1744, 1710, 1644, 1309, 1233, 1111,
1
1088 cmꢀ1. H NMR: d 8.03e8.00 (m, 1H), 7.98e7.85 (m,
Yellow solid (227 mg, 45%). Mp¼114e116 ꢁC. IR (KBr)
1H), 7.58e7.53 (m, 2H), 7.34e7.20 (m, 3H), 6.79 (d,
J¼9.9 Hz, 2H), 6.19 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.69
(s, 1H), 5.34 (d, J¼4.2 Hz, 1H), 4.12 (q, J¼4.8 Hz, 2H),
3.96 (s, 3H), 3.36 (s, 3H), 1.12 (t, 3H). 13C NMR: d 165.2,
164.3, 164.1, 149.0, 147.6, 141.3, 129.9, 129.7, 125.3,
123.0, 116.2, 115.7, 99.0, 95.5, 78.5, 72.3, 69.1, 69.0, 54.4,
54.2, 53.8, 52.6, 51.4, 15.0. HRMS (EI) m/z calcd for
C27H23BrN2O6, 550.0739; found, 550.0734.
nmax: 3030, 2232, 1748, 1698, 1621, 1307, 1210, 998 cmꢀ1
.
1H NMR: d 7.88e7.84 (m, 2H), 7.83e7.74 (m, 2H), 7.11e
7.04 (m, 3H), 6.81 (d, J¼9.0 Hz, 2H), 5.97 (dd, J1¼4.2 Hz,
J2¼9.6 Hz, 1H), 5.71 (s, 1H), 5.29 (d, J¼4.2 Hz, 1H), 4.13
(q, J¼4.8 Hz, 2H), 3.86 (s, 3H), 3.53 (s, 3H), 1.12 (t, 3H).
13C NMR: d 166.5, 165.2, 163.4, 144.9, 144.6, 143.3, 136.1,
129.8, 128.7, 127.5, 120.9, 119.0, 117.9, 114.3, 111.6,
107.1, 96.2, 70.3, 66.8, 54.7, 54.5, 53.1, 52.3, 50.8, 14.3.
HRMS (EI) m/z calcd for C27H23ClN2O6, 506.1245; found,
506.1248.
1
Key H NMR values for the minor isomer, 13e: 6.23 (dd,
J1¼4.2 Hz, J2¼9.8 Hz, 0.26H), 5.71 (s, 0.25H), 5.30 (d,
J¼4.2 Hz, 0.24H), 3.94 (s, 0.75H), 3.33 (s, 0.75H).
1
Key H NMR values for the minor isomer, 13b: 5.92 (dd,
J1¼4.2 Hz, J2¼9.6 Hz, 0.25H), 5.70 (s, 0.24H), 5.31 (d,
4.2.6. 4-Ethyl 1,2-dimethyl 4-cyano-3-(naphthalen-2-yl)-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-
tricarboxylate, 12f
J¼4.2 Hz, 0.24H), 3.85 (s, 0.75H), 3.52 (s, 0.75H).
4.2.3. 4-Ethyl 1,2-dimethyl 4-cyano-3-(4-(trifluoromethyl)-
phenyl)-4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-
tricarboxylate, 12c
Yellow solid (271 mg, 52%). Mp¼136e138 ꢁC. IR (KBr)
nmax: 3016, 2236, 1742, 1722, 1643, 1289, 1224, 1108,
1
1086 cmꢀ1. H NMR: d 8.18e8.16 (m, 1H), 7.87e7.80 (m,
Yellow solid (243 mg, 45%). Mp¼132e134 ꢁC. IR (KBr)
1H), 7.58e7.50 (m, 2H), 7.46e7.41 (m, 3H), 7.02e6.90 (m,
3H), 6.76 (d, J¼9.9 Hz, 2H), 6.13 (dd, J1¼4.2 Hz,
nmax: 3022, 2235, 1740, 1700, 1623, 1302, 1216, 1109 cmꢀ1
.

V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
3573
J2¼9.7 Hz, 1H), 5.66 (s, 1H), 5.18 (d, J¼4.2 Hz, 1H), 4.11 (q,
4.3.1. Dimethyl 3-(4-chlorophenyl)-4,4-dicyano-4,4a-dihydro-
J¼4.8 Hz, 2H), 3.98 (s, 3H), 3.37 (s, 3H), 1.11 (t, 3H). 13C
NMR: d 166.8, 166.3, 165.5, 149.0, 147.6, 141.3, 129.9,
127.8, 125.3, 125.2, 125.0, 123.0, 116.2, 113.7, 109.2, 95.5,
77.5, 59.4, 54.8, 54.3, 53.4, 51.2, 45.7, 14.7. HRMS (EI) m/z
calcd for C31H26N2O6, 522.1791; found, 522.1796.
3H-pyrido[1,2-a]quinoline-1,2-dicarboxylate, 17a
Yellow solid (275 mg, 60%). Mp¼128e130 ꢁC. IR (KBr)
nmax: 3031, 2933, 2235, 1744, 1712, 1667, 1646, 1528,
.
1435, 1357 cmꢀ1
1H NMR: d 7.53 (d, J¼7.5 Hz, 2H),
7.44e7.32 (m, 3H), 7.30e7.21 (m, 2H), 6.69e6.63 (m, 1H),
6.00 (dd, J1¼4.2 Hz, J2¼9.0 Hz, 1H), 5.93 (d, J¼4.5 Hz,
1H), 4.62 (s, 1H), 4.55 (d, J¼4.2 Hz, 1H), 3.84 (s, 3H), 3.52
(s, 3H). 13C NMR: d 164.5, 164.1, 145.3, 134.6, 129.0,
125.6, 125.4, 125.2, 114.7, 112.9, 111.7, 110.2, 109.3,
104.7, 66.7, 53.4, 52.1, 51.2. HRMS (EI) m/z calcd for
C25H18ClN3O4, 459.0986; found, 459.0982.
1
Key H NMR values for the minor isomer, 13f: 6.20 (dd,
J1¼4.2 Hz, J2¼9.7 Hz, 0.23H), 5.62 (s, 0.25H), 5.22 (d,
J¼4.2 Hz, 0.24H), 3.97 (s, 0.75H), 3.31 (s, 0.74H).
4.2.7. 4-Ethyl 1,2-dimethyl 4-cyano-3-phenyl-4,4a-dihydro-
3H-pyrido[1,2-a]quinoline-1,2,4-tricarboxylate, 12g
Pale yellow solid (184 mg, 39%). Mp¼112e114 ꢁC. IR
1
Key H NMR values for the minor isomer, 18a: 6.14 (dd,
J1¼4.2 Hz, J2¼9.0 Hz, 0.21H), 5.88 (d, J¼4.5 Hz, 0.20H),
(KBr) nmax: 2997, 2237, 1746, 1722, 1640, 1312, 1132 cmꢀ1
.
1H NMR: d 7.34e7.25 (m, 2H), 7.31e7.21 (m, 2H), 7.19e
7.16 (m, 1H), 7.12e7.09 (m, 1H), 7.05e6.96 (m, 2H), 6.82
(d, J¼9.9 Hz, 2H), 5.97 (dd, J1¼4.2 Hz, J2¼9.0 Hz, 1H), 4.62
(s, 1H), 4.52 (d, J¼4.2 Hz, 1H), 4.09 (q, J¼4.8 Hz, 2H), 3.82
(s, 3H), 3.58 (s, 3H), 1.12 (t, 3H). 13C NMR: d 165.5, 165.2,
164.8, 159.0, 141.4, 136.8, 135.1, 130.7, 129.9, 129.5, 125.9,
125.4, 124.2, 118.9, 118.1, 115.9, 113.6, 112.6, 111.2, 96.2,
54.6, 53.0, 51.2, 45.6, 15.2. HRMS (EI) m/z calcd for
C27H24N2O6, 472.1634; found, 472.1629.
4.61 (s, 0.22H), 3.83 (s, 0.60H), 3.51 (s, 0.61H).
4.3.2. Dimethyl4,4-dicyano-3-(4-fluorophenyl)-4,4a-dihydro-
3H-pyrido[1,2-a]quinoline-1,2-dicarboxylate, 17b
Yellow solid (257 mg, 58%). Mp¼138e140 ꢁC. IR (KBr)
nmax: 3110, 2965, 2232, 1747, 1716, 1667, 1640, 1532, 1444,
1
1361 cmꢀ1. H NMR: d 7.56 (d, J¼7.4 Hz, 3H), 7.39e7.31
(m, 2H), 7.28e6.65 (m, 2H), 6.69e6.59 (m, 1H), 6.07 (dd,
J1¼4.4 Hz, J2¼9.0 Hz, 1H), 5.98 (d, J¼4.5 Hz, 1H), 4.60 (s,
1H), 4.52 (d, J¼4.2 Hz, 1H), 3.83 (s, 3H), 3.53 (s, 3H). 13C
NMR: d 165.7, 165.3, 147.7, 134.4, 128.4, 125.6, 125.4, 123.2,
116.7, 112.6, 111.2, 110.0, 88.7, 63.7, 53.5, 53.1, 52.4. HRMS
(EI) m/z calcd for C25H18FN3O4; 443.1281; found, 443.1286.
1
Key H NMR values for the minor isomer, 13g: 6.02 (dd,
J1¼4.2 Hz, J2¼9.0 Hz, 0.25H), 4.60 (s, 0.24H), 4.55 (d,
J¼4.2 Hz, 0.25H), 3.80 (s, 0.75H), 3.56 (s, 0.75H).
1
4.2.8. 4-Ethyl 1,2-dimethyl 4-cyano-3-(4-methoxyphenyl)-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2,4-tricarboxyl-
ate, 12h
Key H NMR values for the minor isomer, 18b: 6.0 (dd,
J1¼4.4 Hz, J2¼9.0 Hz, 0.20H), 5.95 (d, J¼4.5 Hz, 0.22H),
4.64 (s, 0.20H), 3.82 (s, 0.60H), 3.52 (s, 0.60H).
Yellow solid (176 mg, 35%). Mp¼132e134 ꢁC. IR (KBr)
1
nmax: 3011, 2235, 1749, 1736, 1644, 1316, 1128 cmꢀ1. H
4.3.3. Dimethyl 4,4-dicyano-3-(4-(trifluoromethyl)phenyl)-
4,4a-dihydro-3H-pyrido[1,2-a]quinoline-1,2-dicarboxylate,
17c
NMR: d 7.52e7.45 (m, 2H), 7.04e6.91 (m, 3H), 6.60e6.56
(m, 2H), 6.42 (d, J¼9.9 Hz, 2H), 5.97 (dd, J1¼4.2 Hz,
J2¼9.0 Hz, 1H), 4.66 (s, 1H), 4.55 (d, J¼4.2 Hz, 1H), 4.12
(q, J¼4.8 Hz, 2H), 3.84 (s, 3H), 3.65 (s, 3H), 3.60 (s, 3H),
1.11 (t, 3H). 13C NMR: d 165.2, 164.9, 163.7, 141.4, 136.8,
135.1, 130.7, 129.9, 129.5, 128.2, 124.4, 124.2, 118.9,
117.1, 113.6, 112.6, 111.2, 96.2, 77.4, 77.0, 76.5, 56.0, 53.2,
52.4. HRMS (EI) m/z calcd for C28H26N2O7, 502.1740; found,
502.1746.
Yellow solid (281 mg, 57%). Mp¼140e142 ꢁC. IR (KBr)
nmax: 3032, 2975, 2229, 1734, 1658, 1603, 1579, 1428,
1
1334 cmꢀ1. H NMR: d 8.06e8.01 (m, 2H), 7.72e7.69 (m,
3H), 7.58e7.52 (m, 2H), 6.65e6.60 (m, 1H), 6.21 (dd,
J1¼4.2 Hz, J2¼9.2 Hz, 1H), 5.92 (d, J¼4.2 Hz, 1H), 4.63 (s,
1H), 4.50 (d, J¼4.2 Hz, 1H), 3.82 (s, 3H), 3.59 (s, 3H). 13C
NMR: d 165.6, 164.6, 144.2, 142.3, 132.5, 131.3, 130.5,
130.2, 128.8, 127.3, 125.3, 122.6, 116.7, 112.0, 111.7, 109.7,
105.5, 57.7, 53.3, 51.6, 47.4. HRMS (EI) m/z calcd for
C26H18F3N3O4, 493.1249; found, 493.1244.
1
Key H NMR values for the minor isomer, 13h: 6.11 (dd,
J1¼4.2 Hz, J2¼9.0 Hz, 0.26H), 4.59 (s, 0.25H), 4.50 (d,
J¼4.2 Hz, 0.23H), 3.81 (s, 0.75H), 3.62 (s, 0.76H).
1
Key H NMR values for the minor isomer, 18c: 6.30 (dd,
J1¼4.2 Hz, J2¼92 Hz, 0.25H), 5.96 (d, J¼4.5 Hz, 0.24H),
4.3. Experimental procedure for the synthesis of
pyridoquinoline derivatives by the reaction of quinoline,
DMAD, and arylidenemalononitriles
4.68 (s, 0.24H), 3.83 (s, 0.75H), 3.60 (s, 0.75H).
4.3.4. Dimethyl 3-(4-bromophenyl)-4,4-dicyano-4,4a-dihydro-
3H-pyrido[1,2-a]quinoline-1,2-dicarboxylate, 17d
A solution of quinoline (0.53 mmol), DMAD (0.53 mmol),
and arylidenemalononitrile (0.44 mmol) in dry toluene (3 mL)
was stirred at 110 ꢁC in a sealed tube for 12 h. The solvent was
removed under vacuum and the residue was subjected to chro-
matography on a silica gel (100e200 mesh) column using
hexaneeethyl acetate (85:15) solvent mixtures to afford a dia-
stereomeric mixture of the pyridoquinolines (the ratio was
Yellow solid (287 mg, 57%). Mp¼154e156 ꢁC. IR (KBr)
nmax: 2955, 2239, 1742, 1715, 1607, 1546, 1435, 1236 cmꢀ1
.
1H NMR: d 7.48 (d, J¼7.2 Hz, 2H), 7.41e7.38 (m, 3H),7.30e
7.18 (m, 2H), 6.67e6.55 (m, 1H), 6.12 (dd, J1¼4.5 Hz,
J2¼9.1 Hz, 1H), 5.87 (d, J¼4.5 Hz, 1H), 4.62 (s, 1H), 4.52 (d,
J¼4.2 Hz, 1H), 3.83 (s, 3H), 3.54 (s, 3H). 13C NMR: d 164.5,
164.2, 133.8, 130.6, 129.3, 128.8, 128.5, 126.1, 125.3, 125.0,
1
determined from H NMR).

3574
V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
122.7, 113.3, 112.8, 111.1, 109.8, 65.6, 62.8, 52.1, 51.6. HRMS
(EI) m/z calcd for C25H18BrN3O4, 503.0481; found, 503.0485.
3018, 3012, 2432, 2399, 1732, 1726, 1521, 1496, 1477,
1423, 1232 cmꢀ1 1H NMR: d 7.37e7.22 (m, 3H), 7.08e
.
1
Key H NMR values for the minor isomer, 18d: 6.09 (dd,
7.02 (m, 3H), 6.84e6.81 (m, 1H), 6.78e6.65 (m, 1H), 6.63
(d, J¼4.2 Hz, 1H), 5.60 (dd, J1¼5.7 Hz, J2¼9.9 Hz, 1H),
5.49e5.44 (m, 1H), 5.38e5.22 (m, 2H), 4.44e4.37 (m, 1H),
4.25e4.18 (m, 1H), 3.92 (s, 3H), 3.61 (s, 3H). 13C NMR:
d 172.8, 165.2, 163.6, 144.7, 138.0, 137.4, 131.6, 128.9,
128.6, 127.4, 127.0, 126.3, 125.5, 121.9, 121.8, 120.4,
119.9, 118.2, 113.5, 104.6, 102.7, 79.2, 53.5, 53.3, 51.7.
HRMS (EI) m/z calcd for C26H21BrN2O6, 536.0583; found,
536.0580.
J1¼4.5 Hz, J2¼9.1 Hz, 0.21H), 5.92 (d, J¼4.5 Hz, 0.20H),
4.66 (s, 0.22H), 3.80 (s, 0.60H), 3.50 (s, 0.60H).
4.3.5. Dimethyl 4,4-dicyano-3-(4-nitrophenyl)-4,4a-dihydro-
3H-pyrido[1,2-a]quinoline-1,2-dicarboxylate, 17e
Yellow solid (268 mg, 57%). Mp¼148e150 ꢁC. IR (KBr)
nmax: 3054, 2235, 1724, 1612, 1603, 1596, 1426, 1329,
1
1265 cmꢀ1. H NMR: d 7.59e7.53 (m, 2H), 7.49e7.42 (m,
1
3H), 7.36e7.29 (m, 2H), 6.66e6.59 (m, 1H), 6.32 (dd,
J1¼4.2 Hz, J2¼9.0 Hz, 1H), 5.88 (d, J¼4.2 Hz, 1H), 4.71 (s,
1H), 4.54 (d, J¼4.2 Hz, 1H), 3.85 (s, 3H), 3.63 (s, 3H). 13C
NMR: d 166.4, 165.6, 149.8, 131.6, 131.4, 129.7, 127.4,
127.2, 125.5, 125.2, 123.5, 122.7, 112.9, 112.6, 110.1, 109.5,
69.4, 53.5, 52.1, 51.4, 47.7, 38.5. HRMS (EI) m/z calcd for
C25H18N4O6, 470.1226; found, 470.1222.
Key H NMR values for the minor isomer, 21a: 6.61 (d,
J¼4.2 Hz, 0.25H), 5.68 (dd, J1¼5.6 Hz, J2¼9.9 Hz, 0.23H),
3.91 (s, 0.75H), 3.60 (s, 0.75H).
4.4.2. Dimethyl 10-allyl-20-oxo-4aH-spiro[[1,3]oxazino-
[3,2-a]quinoline, 3-30-indoline]-1,2-dicarboxylate, 20b
Orange crystalline solid (256 mg, 56%). Mp¼154e156 ꢁC.
IR (KBr) nmax: 3685, 3010, 2989, 2369, 1739, 1686, 1532,
1
Key H NMR values for the minor isomer, 18e: 6.39 (dd,
J1¼4.2 Hz, J2¼9.0 Hz, 0.16H), 5.93 (d, J¼4.2 Hz, 0.17H),
1
1455, 1221 cmꢀ1. H NMR: d 7.36e7.22 (m, 4H), 7.08e7.0
4.69 (s, 0.14H), 3.86 (s, 0.5H), 3.64 (s, 0.5H).
(m, 3H), 6.85e6.83 (m, 1H), 6.68e6.66 (m, 1H), 6.20 (d,
J¼4.2 Hz, 1H), 5.99 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.89e
5.82 (m, 1H), 5.40e5.24 (m, 2H), 4.41e4.32 (m, 1H), 4.23e
4.19 (m, 1H), 3.90 (s, 3H), 3.63 (s, 3H). 13C NMR: d 164.7,
164.2, 163.9, 144.7, 138.0, 131.6, 128.9, 128.6, 127.4, 127.0,
126.3, 125.5, 121.9, 120.4, 119.9, 118.2, 116.6, 113.5, 102.7,
80.1, 53.5, 53.0, 52.9. HRMS (EI) m/z calcd for C26H22N2O6,
458.1478; found, 458.1473.
4.3.6. Dimethyl 4,4-dicyano-3-p-tolyl-4,4a-dihydro-3H-
pyrido[1,2-a]quinoline-1,2-dicarboxylate, 17f
Yellow solid (162 mg, 37%). Mp¼116e118 ꢁC. IR (KBr)
nmax: 3041, 2219, 1739, 1703, 1609, 1582, 1533, 1461, 1335,
1
1277, 1184 cmꢀ1. H NMR: d 7.51 (d, J¼4.4 Hz, 2H), 7.46e
7.40 (m, 3H), 7.32e7.27 (m, 2H), 6.58e6.47 (m, 1H), 6.59
(dd, J1¼4.1 Hz, J2¼9.2 Hz, 1H), 5.85 (d, J¼4.2 Hz, 1H), 4.88
(s, 1H), 4.60 (d, J¼4.2 Hz, 1H), 3.99 (s, 3H), 3.72 (s, 3H),
2.34 (s, 3H). 13C NMR: d 165.0, 164.7, 140.9, 139.5, 139.2,
128.7, 128.5, 125.0, 124.7, 119.8, 115.6, 112.5, 111.8, 109.8,
109.6, 69.6, 53.4, 51.3, 47.2, 37.6, 22.4. HRMS (EI) m/z calcd
for C26H21N3O4, 439.1532; found, 439.1538.
1
Key H NMR values for the minor isomer, 21b: 6.16 (d,
J¼4.2 Hz, 0.26H), 6.02 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 0.24H),
3.88 (s, 0.75H), 3.61 (s, 0.75H).
4.4.3. Dimethyl 50-bromo-10-methyl-20-oxo-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline, 3-30-indoline]-1,2-
dicarboxylate, 20c
1
Key H NMR values for the minor isomer, 18f: 6.61 (dd,
J1¼4.1 Hz, J2¼9.2 Hz, 0.46H), 5.88 (d, J¼4.2 Hz, 0.48H),
Orange solid (265 mg, 52%). Mp¼136e138 ꢁC. IR (KBr)
4.91 (s, 0.5H), 3.97 (s, 1.5H), 3.71 (s, 1.5H).
nmax: 3016, 2544, 2367, 1740, 1678, 1556, 1511, 1375 cmꢀ1
.
1H NMR: d 7.27e7.19 (m, 3H), 7.05e7.6.99 (m, 2H),
6.94e6.91 (m, 1H), 6.81e6.77 (m, 2H), 6.13 (d, J¼4.3 Hz,
1H), 5.95 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 3.82 (s, 3H),
3.75 (s, 3H), 3.42 (s, 3H). 13C NMR: d 165.0, 164.5, 163.3,
144.8, 138.2, 131.6, 128.9, 128.7, 127.0, 126.3, 126.0,
121.9, 120.8, 120.4, 119.9, 117.3, 114.7, 104.5, 95.7, 80.2,
53.3, 51.9, 31.4. HRMS (EI) m/z calcd for C24H19BrN2O6,
510.0426; found, 510.0422.
4.4. Experimental procedure for the synthesis of
oxazinoquinoline derivatives by the reaction of quinoline,
DMAD, and N-alkylated isatins
N-Substituted isatin (0.44 mmol), quinoline (0.53 mmol),
and DMAD (0.53 mmol) were taken in a sealed tube in dry
toluene (3 mL), and the mixture was heated at 110 ꢁC for
12 h. The solvent was distilled off under reduced pressure on
a rotary evaporator and the residue was subjected to column
chromatography on silica gel (100e200 mesh) column using
90:10 hexaneeethyl acetate as eluent to afford a diastereomeric
mixture of oxazinoquinoline derivatives. The data of the major
isomer is given in each case.
1
Key H NMR values for the minor isomer, 21c: 6.21 (d,
J¼4.3 Hz, 0.25H), 5.98 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 0.24H),
3.80 (s, 0.76H), 3.74 (s, 0.75H).
4.4.4. Dimethyl 50-bromo-20-oxo-10-(prop-2-ynyl)-4aH-
spiro[[1,3]oxazino[3,2-a]quinoline, 3-30-indoline]-1,2-
dicarboxylate, 20d
4.4.1. Dimethyl 10-allyl-50-bromo-20-oxo-4aH-spiro[[1,3]-
oxazino[3,2-a]quinoline, 3-30-indoline]-1,2-dicarboxylate,
20a
Orange solid (267 mg, 50%). Mp¼152e154 ꢁC. IR (KBr)
1
nmax: 3012, 2536, 1744, 1680, 1548, 1501, 1299 cmꢀ1. H
NMR: d 7.29e7.20 (m, 3H), 7.07e6.98 (m, 2H), 6.25 (d,
J¼4.2 Hz, 2H), 5.95 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 4.64e
4.62 (m, 1H), 4.35 (dd, J1¼3.4 Hz, J2¼7.6 Hz, 1H), 4.89 (s,
Orange crystalline solid (306 mg, 57%). Mp¼164e166 ꢁC
(recrystallized from CH2Cl2ehexane). IR (KBr) nmax: 3680,

V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
3575
2H), 3.90 (s, 3H), 3.58 (s, 3H), 2.30 (s, 1H). 13C NMR:
4.5.1. Dimethyl 30,50-di-tert-butyl-60-oxo-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline-3,10-cyclohexa[2,4]diene]-
1,2-dicarboxylate, 23a
d 165.8, 164.2, 163.3, 145.0, 143.4, 138.4, 130.1, 129.8,
128.7, 127.9, 122.7, 121.7, 118.9, 118.5, 114.3, 102.8, 96.2,
80.6, 78.3, 77.4, 73.4, 53.2, 52.2, 29.2. HRMS (EI) m/z calcd
for C26H19BrN2O6, 534.0426; found, 534.0420.
Yellow solid (260 mg, 53%). Mp¼166e168 ꢁC. IR (KBr)
nmax: 2949, 1755, 1748, 1738, 1535, 1441, 1254 cmꢀ1. H
1
1
Key H NMR values for the minor isomer, 21d: 6.23 (d,
J¼4.2 Hz, 0.22H), 5.97 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 0.24H),
NMR: d 7.66e7.60 (m, 2H), 6.98e6.95 (m, 1H), 6.88e6.80
(m, 2H), 6.05 (s, 1H), 5.91 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H),
5.42 (d, J¼4.2 Hz, 1H), 5.32 (s, 1H), 3.86 (s, 3H), 3.60 (s,
3H), 1.20 (s, 9H), 1.16 (s, 9H). 13C NMR: d 196.6, 164.9,
164.4, 148.7, 142.2, 136.8, 132.6, 125.5, 125.3, 122.3, 119.4,
115.1, 110.8, 78.4, 53.4, 51.2, 35.5, 28.7, 28.6. HRMS (EI)
m/z calcd for C29H33NO6, 491.2308; found, 491.2311.
3.89 (s, 0.75H), 3.56 (s, 0.75H).
4.4.5. Dimethyl 20-oxo-10-(prop-2-ynyl)-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline, 3-30-indoline]-1,2-
dicarboxylate, 20e
Orange solid (476 mg, 58%). Mp¼158e160 ꢁC. IR (KBr)
4.5.2. Dimethyl 20,40-di-tert-butyl-60-oxo-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline-3,10-cyclohexa[2,4]diene]-
1,2-dicarboxylate, 24a
nmax: 3292, 3102, 2113, 1748, 1740, 1649, 1566, 1242 cmꢀ1
.
1H NMR: d 7.69e7.65 (m, 2H), 7.38e7.32 (m, 4H), 6.69 (d,
J¼9.9 Hz, 1H), 6.22 (d, J¼4.2 Hz, 1H), 5.88 (dd,
J1¼4.2 Hz, J2¼9.6 Hz, 1H), 4.56e4.55 (m, 1H), 4.35 (dd,
J1¼3.6 Hz, J2¼7.4 Hz, 1H), 4.54 (s, 2H), 3.88 (s, 3H), 3.60
(s, 3H), 2.32 (s, 1H). 13C NMR: d 164.8, 163.3, 161.5,
144.8, 144.3, 138.2, 132.5, 129.6, 128.1, 127.8, 127.2,
120.7, 119.7, 118.9, 118.3, 112.0, 102.3, 80.8, 73.4, 72.5,
53.4, 52.5, 30.8. HRMS (EI) m/z calcd for C26H20N2O6,
456.1321; found, 456.1326.
Yellow viscous liquid (64 mg, 13%). IR (KBr) nmax: 2952,
1
1757, 1749, 1742, 1533, 1443, 1256, 998 cmꢀ1. H NMR:
d 7.52e7.49 (m, 2H), 7.25 (s, 1H), 7.0e6.98 (m, 1H), 6.94e
6.91 (m, 2H), 5.93 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.46 (d,
J¼4.2 Hz, 1H), 5.37 (s, 1H), 3.88 (s, 3H), 3.63 (s, 3H), 1.22
(s, 9H), 1.19 (s, 9H). 13C NMR: d 192.6, 165.5, 164.6, 148.4,
140.8, 138.4, 137.3, 128.6, 128.3, 126.1, 121.7, 119.6, 114.3,
111.8, 86.3, 79.4, 53.6, 51.3, 35.8, 35.5, 29.0, 28.8. HRMS
(EI) m/z calcd for C29H33NO6, 491.2308; found, 491.2312.
1
Key H NMR values for the minor isomer, 21e: 6.17 (d,
J¼4.2 Hz, 0.21H), 5.85 (dd, J1¼4.2 Hz, J2¼9.6 Hz, 0.21H),
3.89 (s, 0.6H), 3.61 (s, 0.6H).
4.5.3. Dimethyl 100-oxo-4aH,100H-spiro[[1,3]oxazino-
[3,2-a]quinoline-3,90-phenanthrene]-1,2-dicarboxylate, 23b
Yellow solid (263 mg, 55%). Mp¼188e190 ꢁC. IR (KBr)
4.4.6. Dimethyl 50-bromo-10-ethyl-20-oxo-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline, 3-30-indoline]-1,2-
dicarboxylate, 20f
nmax: 2955, 1748, 1712, 1688, 1578, 1443, 1220 cmꢀ1. H
1
NMR: d 8.25e8.23 (m, 2H), 7.98e7.96 (m, 2H), 7.79e7.77
(m, 1H), 7.55e7.52 (m, 2H), 7.39e7.28 (m, 3H), 7.02e6.98
(m, 2H), 6.93e6.86 (m, 1H), 6.75 (d, J¼5.2 Hz, 1H), 6.50 (dd,
J1¼4.4 Hz, J2¼10.2 Hz, 1H), 3.86 (s, 3H), 3.65 (s, 3H). 13C
NMR: d 191.8, 165.8, 165.2, 148.7, 142.3, 137.6, 136.2, 132.3,
130.9, 128.5, 128.1, 125.6, 124.4, 124.2, 124.0, 121.2, 118.7,
116.6, 114.5, 113.7, 111.2, 90.8, 81.1, 53.3, 51.8. HRMS (EI)
m/z calcd for C29H21NO6, 479.1369; found, 479.1366.
Orange solid (254 mg, 57%). Mp¼148e150 ꢁC. IR (KBr)
1
nmax: 2988, 1744, 1740, 1677, 1593, 1566, 1155 cmꢀ1. H
NMR: d 7.27e7.19 (m, 3H), 7.05e7.00 (m, 3H), 6.99e6.92
(m, 3H), 6.80e6.77 (m, 1H), 6.13 (d, J¼4.3 Hz, 1H), 5.97
(dd, J1¼4.3 Hz, J2¼9.8 Hz, 1H), 3.86e3.79 (m, 1H), 3.68
(s, 3H), 3.57 (s, 3H), 1.29 (t, J¼7.2 Hz, 3H). 13C NMR:
d 165.4, 164.4, 163.7, 144.3, 137.8, 128.6, 127.4, 126.5,
125.5, 122.9, 121.8, 118.9, 118.2, 113.7, 112.4, 96.9, 80.6,
52.9, 51.6, 40.8, 14.0. HRMS (EI) m/z calcd for
C25H22N2O6, 446.1478; found, 446.1482.
4.5.4. Dimethyl 20-oxo-20H,4aH-spiro[[1,3]oxazino[3,2-a]-
quinoline-3,10-acenaphthylene]-1,2-dicarboxylate, 23c
Yellow solid (262 mg, 58%). Mp¼162e164 ꢁC. IR (KBr)
1
Key H NMR values for the minor isomer, 21f: 6.19 (d,
J¼4.3 Hz, 0.23H), 5.99 (dd, J1¼4.3 Hz, J2¼9.8 Hz, 0.20H),
nmax: 2962, 1744, 1709, 1700, 1588, 1433, 1230 cmꢀ1. H
1
3.66 (s, 0.6H), 3.53 (s, 0.6H).
NMR: d 8.07e8.04 (m, 2H), 7.98e7.96 (m, 2H), 7.77e7.73
(m, 2H), 7.64e7.55 (m, 2H), 7.02e6.98 (m, 2H), 6.75e6.73
(d, J¼7.8 Hz, 1H), 6.50e6.48 (m, 1H), 6.26 (dd, J1¼4.8 Hz,
J2¼9.8 Hz, 1H), 3.86 (s, 3H), 3.65 (s, 3H). 13C NMR:
d 194.4, 165.0, 164.6, 145.1, 142.6, 137.7, 136.2, 132.1,
128.2, 128.0, 125.6, 125.3, 124.2, 124.1, 121.2, 118.7,
116.3, 114.7, 113.7, 111.2, 101.1, 81.6, 53.0, 51.5. HRMS
(EI) m/z calcd for C27H19NO6, 453.1212; found, 453.1217.
4.5. Experimental procedure for the synthesis of
oxazinoquinoline derivatives by the reaction of quinoline,
DMAD, and 1,2-benzoquinones
1,2-Benzoquinone (0.44 mmol), quinoline (0.53 mmol),
and DMAD (0.53 mmol) were taken in a sealed tube in dry
toluene (3 mL) and the mixture was heated at 110 ꢁC for
10e12 h. The solvent was removed under reduced pressure
on a rotary evaporator. The residue on chromatographic sepa-
ration on a silica gel (100e200 mesh) column using 90:10
hexaneeethyl acetate as eluent afforded a regioisomeric mix-
ture of oxazinoquinoline derivatives.
4.5.5. Dimethyl 30-tert-butyl-60-oxo-4aH-spiro-
[[1,3]oxazino[3,2-a]quinoline-3,10-cyclohexa[2,4]diene]-
1,2-dicarboxylate, 23d
Yellow solid (213 mg, 47%). Mp¼112e114 ꢁC. IR (KBr)
nmax: 2953, 1741, 1705, 1688, 1590, 1522, 1154 cmꢀ1
.

3576
V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
1H NMR: d 7.56e7.51 (m, 2H), 7.41e7.38 (m, 1H), 7.33 (d,
J¼9 Hz, 1H), 7.04e6.98 (m, 1H), 6.92e6.88 (m, 1H), 6.28
(d, J¼9.1 Hz, 1H), 5.84 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H),
5.66 (s, 1H), 5.48 (d, J¼4.4 Hz, 1H), 3.86 (s, 3H), 3.65 (s,
3H), 1.06 (s, 9H). 13C NMR: d 191.2, 165.1, 164.1, 150.1,
138.6, 137.6, 137.2, 134.4, 128.6, 128.3, 127.8, 122.7,
122.2, 121.2, 114.5, 112.9, 112.7, 111.2, 87.1, 79.4, 53.0,
51.5, 31.9, 27.0. HRMS (EI) m/z calcd for C25H25NO6,
435.1682; found, 435.1687.
NMR: d 7.54e7.52 (m, 2H), 7.30e7.12 (m, 21H), 6.88e
6.79 (m, 2H), 6.76e6.73 (m, 1H), 5.93 (dd, J1¼4.2 Hz,
J2¼9.8 Hz, 1H), 5.46 (d, J¼4.2 Hz, 1H), 5.26 (s, 1H), 4.82
(s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.64 (s, 3H). 13C NMR:
d 193.0, 164.8, 163.3, 156.3, 142.3, 141.4, 138.3, 137.1,
131.3, 128.7, 128.5, 128.2, 128.1, 126.5, 126.2, 126.0,
124.5, 124.4, 124.1, 121.5, 118.8, 114.4, 112.0, 92.4, 80.6,
59.3, 54.3, 53.5, 53.2, 51.3. HRMS (EI) m/z calcd for
C48H39NO7, 741.2727; found, 741.2722.
4.5.6. Dimethyl 40-tert-butyl-60-oxo-4aH-spiro[[1,3]ox-
azino[3,2-a]quinoline-3,10-cyclohexa[2,4]diene]-
1,2-dicarboxylate, 24d
4.5.10. Dimethyl 30,50-dibenzhydryl-20-methoxy-60-oxo-4aH-
spiro[[1,3]oxazino[3,2-a]quinoline-3,10-cyclo-
hexa[2,4]diene]-1,2-dicarboxylate, 24f
Yellow solid (148 mg, 20%). Mp¼182e184 ꢁC. IR (KBr)
Yellow viscous liquid (100 mg, 23%). IR (film) nmax: 2955,
1743, 1712, 1672, 1599, 1565, 1287 cmꢀ1. 1H NMR: d 7.50e
7.47 (m, 2H), 7.41e7.38 (m, 1H), 7.04e6.98 (m, 1H), 6.76 (d,
J¼5 Hz, 1H), 6.68 (d, J¼7.9 Hz, 1H), 6.21 (d, J¼8 Hz, 1H),
6.05 (s, 1H), 5.96 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.09 (d,
J¼4.4 Hz, 1H), 3.85 (s, 3H), 3.66 (s, 3H), 1.04 (s, 9H). 13C
NMR: d 190.6, 165.3, 164.4, 145.3, 138.8, 136.5, 136.0,
128.7, 122.6, 121.8, 120.0, 113.3, 112.9, 86.5, 79.6, 54.2,
51.2, 35.3, 27.4. HRMS (EI) m/z calcd for C25H25NO6,
435.1682; found, 435.1686.
nmax: 2952, 1744, 1710, 1672, 1504, 1436, 1255, 1148 cmꢀ1
.
1H NMR: d 7.26e7.18 (m, 23H), 6.92e6.84 (m, 2H), 6.72e
6.70 (m, 1H), 5.88 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.42 (d,
J¼4.2 Hz, 1H), 5.23 (s, 1H), 4.88 (s, 1H), 3.84 (s, 3H), 3.80
(s, 3H), 3.66 (s, 3H). 13C NMR: d 193.4, 164.6, 163.2,
155.7, 142.5, 142.1, 137.3, 128.6, 128.4, 128.0, 126.2,
126.1, 125.5, 124.7, 124.2, 122.2, 116.8, 93.3, 80.3, 58.9,
54.4, 53.6, 52.9, 50.7. HRMS (EI) m/z calcd for C48H39NO7,
741.2727; found, 741.2723.
4.5.7. Dimethyl 20,40-di-tert-butyl-50-methoxy-60-oxo-4aH-
spiro[[1,3]oxazino[3,2-a]quinoline-3,10-cyclo-
Acknowledgements
hexa[2,4]diene]-1,2-dicarboxylate, 23e
D.S. thanks the CSIR, Govt. of India, New Delhi for
Research Fellowship. Thanks are also due to Ms. Saumini
Mathew for recording NMR data and Ms. S. Viji for mass
spectral analysis.
Yellow viscous liquid (224 mg, 43%). IR (film) nmax: 2954,
1748, 1708, 1666, 1600, 1567, 1432 cmꢀ1. 1H NMR: d 7.52e
7.49 (m, 2H), 7.25 (s, 1H), 6.98e6.86 (m, 2H), 6.94e6.91 (m,
2H), 5.93 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 5.83 (m, 1H), 5.46
(d, J¼4.2 Hz, 1H), 5.37 (s, 1H), 3.88 (s, 3H), 3.63 (s, 3H), 1.22
(s, 9H), 1.19 (s, 9H). 13C NMR: d 192.1, 165.2, 164.1, 154.3,
150.4, 138.7, 137.3, 128.9, 128.6, 127.2, 123.3, 121.6, 119.5,
114.6, 113.2, 87.0, 79.5, 60.7, 53.6, 51.6, 35.3, 31.4, 31.2,
30.7. HRMS (EI) m/z calcd for C30H35NO7, 521.2414; found,
521.2420.
References and notes
1. Diels, O.; Alder, K. Liebigs Ann. Chem. 1932, 498, 16e49.
2. (a) Acheson, R. M.; Woollard, J. J. Chem. Soc., Perkin Trans. 1 1975,
438e445; (b) Acheson, R. M.; Taylor, G. A. Proc. Chem. Soc. 1959,
186e187; (c) Acheson, R. M.; Taylor, G. A. J. Chem. Soc. 1960,
1691e1701; (d) Acheson, R. M.; Gagan, J. M. F.; Taylor, G. A.
J. Chem. Soc. 1963, 1903e1906.
4.5.8. Dimethyl 30,50-di-tert-butyl-20-methoxy-60-oxo-4aH-
spiro[[1,3]oxazino[3,2-a]quinoline-3,10-cyclo-
3. Huisgen, R. Topics in Heterocyclic Chemistry; Castle, R., Ed.; John Wiley
and Sons: New York, NY, 1969; Chapter 8, p 223; (b) Huisgen, R. Z.
Chem. 1968, 8, 290e298.
hexa[2,4]diene]-1,2-dicarboxylate, 24e
Yellow viscous liquid (115 mg, 22%). IR (film) nmax: 2955,
1746, 1711, 1664, 1602, 1566, 1428 cmꢀ1. 1H NMR: d 7.52e
7.47 (m, 2H), 7.44 (s, 1H), 7.02e6.98 (m, 2H), 6.92e6.88 (m,
2H), 6.74 (dd, J1¼4.2 Hz, J2¼9.8 Hz, 1H), 6.01e5.94 (m,
2H), 4.17 (s, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 1.13 (s, 9H),
0.99 (s, 9H). 13C NMR: d 191.3, 165.5, 163.8, 138.0, 137.3,
137.2, 134.3, 133.1, 128.5, 128.3, 128.1, 126.3, 121.5,
119.2, 114.7, 109.7, 92.8, 78.8, 59.7, 53.3, 51.5, 31.4, 31.3,
29.2, 29.1. HRMS (EI) m/z calcd for C30H35NO7, 521.2414;
found, 521.2419.
4. (a) Winterfeldt, E.; Naumann, A. Chem. Ber. 1965, 98, 3537e3545; (b)
Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1967, 6, 423e434.
5. Acheson, R. M.; Plunkett, A. O. J. Chem. Soc. 1964, 2676e2683.
6. Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem. Ber. 1967, 100,
1094e1106.
7. (a) Nair, V.; Nair, J. S.; Vinod, A. U. Synthesis 2000, 1713e1718; (b) Nair,
V.; Deepthi, A.; Beneesh, P. B.; Eringathodi, S. Synthesis 2006, 1443e
1446.
8. Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar, V.; Bindu, S. Org. Lett.
2004, 6, 767e769.
9. Nair, V.; Deepthi, A.; Manoj, P.; Bindu, S.; Sreekumar, V.; Beneesh, P. B.;
Mohan, R.; Suresh, E. J. Org. Chem. 2006, 71, 2313e2319.
10. (a) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2001, 3, 3495e
3497; (b) Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett. 2002, 4,
2807; (c) Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.;
Gonnade, R. C. Org. Lett. 2002, 4, 3575e3577; (d) Nair, V.; Sreekanth,
A. R.; Biju, A. T.; Rath, N. P. Tetrahedron Lett. 2003, 44, 729e732; (e)
Nair, V.; Devi, B. R.; Varma, R. L. Tetrahedron Lett. 2005, 46, 5333e
5335.
4.5.9. Dimethyl 20,40-dibenzhydryl-50-methoxy-60-oxo-4aH-
spiro[[1,3]oxazino[3,2-a]quinoline-3,10-cyclo-
hexa[2,4]diene]-1,2-dicarboxylate, 23f
Yellow solid (296 mg, 40%). Mp¼176e178 ꢁC. IR (KBr)
1
nmax: 2948, 1742, 1708, 1668, 1499, 1434, 1254 cmꢀ1. H

V. Nair et al. / Tetrahedron 64 (2008) 3567e3577
3577
11. Nair, V.; Bindu, S.; Sreekumar, V. Org. Lett. 2003, 5, 665e667.
12. (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899e907; (b)
Nair, V.; Menon, R. S.; Sreekanth, A.; Abhilash, N.; Biju, A. T. Acc.
Chem. Res. 2006, 39, 520e530.
14. (a) Benameur, L.; Bouaziz, Z.; Nebois, P.; Bartoli, M. H.; Boitard, M.;
Fillion, H. Chem. Pharm. Bull. 1996, 44, 605; (b) Chevalier, J.; Atifi,
S.; Eyraud, A.; Mahamoud, A.; Barbe, J.; Pages, J.-M. J. Med. Chem.
2001, 44, 4023.
15. The crystal structures of compounds 12a and 20a have been deposited at
the Cambridge Crystallographic Data Centre and allocated the reference
numbers CCDC 662517 and 662518, respectively.
13. Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron Lett. 2007, 48, 3667e
3670.