Efficient synthesis of quinolo-oxepanes through [3+2] cycloaddition reaction of α,β-unsaturated ester with unstabilized azomethine ylides

Article abstract of DOI:10.14233/ajchem.2015.18915

New functionalized quinolo-oxepane were achieved by intramolecular 1,3-dipolar cycloaddition reaction of α,β-unsaturated ester with unstabilized azomethine ylides derived from various α-amino acids with high stereo selectivity and good yields. These deriv

Full text of DOI:10.14233/ajchem.2015.18915

Asian Journal of Chemistry; Vol. 27, No. 10 (2015), 3667-3670
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18915
Efficient Synthesis of Quinolo-oxepanes Through [3+2] Cycloaddition
Reaction of α,β-Unsaturated Ester with Unstabilized Azomethine Ylides
*
NAGARAJAN SARAVANAN , MARUTHAPILLAI ARTHANAREESWARI, PALANISAMY KAMARAJ and BITRAGUNTA SIVAKUMAR
Department of Chemistry, SRM University, Kattankulathur-603 203, India
*Corresponding author: E-mail: npss82@gmail.com
Received: 8 December 2014;
Accepted: 13 May 2015;
Published online: 22 June 2015;
AJC-17323
New functionalized quinolo-oxepane were achieved by intramolecular 1,3-dipolar cycloaddition reaction of α,β-unsaturated ester with
unstabilized azomethine ylides derived from various α-amino acids with high stereo selectivity and good yields. These derivatives were
synthesized via Wittig reaction under mild, neutral conditions in a short duration and consistently good yields. The structures of final
compounds were characterized by spectral analysis.
Keywords: Quinolines, 1,3-Dipolar cycloaddition, Azomethine ylides, Wittig reaction.
been the subject of synthetic studies. The oxepine natural
products are not only interest in terms of their biological
properties but are also intriguing from a biosynthetic viewpoint.
Cycloaddition reactions are one of the most important class
of reaction in synthetic organic chemistry. Within class, the
1,3-dipolar cycloaddition17 reaction has found extensive use
as a high-yielding and efficient, regio and stereo controlled
method for the synthesis of five membered heterocyclic
compounds18,19. Placing the ylide dipole and the alkene within
the same molecule provides direct access to bicyclic or poly-
cyclic product of considerable complexity. These cycloaddition
reactions were performed by reacting α-amino acids and
carbonyl compounds gave rise to in situ azomethine-ylide
formation which leads to form a five member nitrogen hetero-
cycles with regio and stereo control.
INTRODUCTION
Quinoline is a heterocyclic scaffold of paramount impor-
tance to human race. The utility of quinoline derivatives in the
areas of medicine, food, catalyst, dye, materials, refineries and
electronics is well established. As a result, the synthesis of
quinoline core and its derivatives have been an attractive goal
for the synthetic organic chemist. In the recent past there have
been several new developments in the chemistry associated
with quinolines. Quinoline nucleus occurs in several natural
compounds (cinchona alkaloids)1 and pharmacologically
active substances displaying a broad range of biological
activity. Quinoline has been found to possess antimicrobial2,
antituberculosis3, anti-bacterial4,5, antifungal6,7, cytotoxicity8,
antiviral9, antitumor10, antidepressant11 and analgesic12 activity.
Certain quinoline-based compounds also show effective
antihistamine13 activity. This broad spectrum of biological and
biochemical activities has been further facilitated by the
synthetic versatility of quinoline, which allows the generation
of a large number of structurally diverse derivatives. Quinoline
and its analogs have recently been examined for their modes
of function in the inhibition of tyrosine kinases14 and DNA
repair15. Some of the quinoline derivatives such as dutadrupine,
mepacrine and levofloxacin are in clinical use. In such sequence
of study it is observed that the activity of such nucleus may be
due to the presence of fused pyridine.
EXPERIMENTAL
Toluene was freshly distilled from sodium/benzophenone,
DMF from CaO and 1,2-dimethoxy ethane from NaH. All the
products were confirmed by their spectral data. 1H NMR and
13C spectra were recorded on a Bruker Biospin spectrometer
at 400 MHz; Mass spectra were recorded on Agilent mass
spectrometer. Flash column chromatography was performed
on Merck silica gel (230-400 mesh).
General procedure for the synthesis of substituted
quinoline carbaldehyde (1a-b): At 0 °C to a stirred solution
of POCl3 (39.6 g, 259 mmol) and anhydrous DMF (8 g, 111
mmol) was added acetanilide (5 g, 37 mmol). The mixture
was then heated to 65 °C and the progress of the reaction was
Examples of reduced oxepine-based natural products such
as brevetoxin-like polyether marine metabolites16 and dihydro-
oxepine epidithiodiketopiperazines are well known and have

3668 Saravanan et al.
Asian J. Chem.
monitored by TLC analysis. After 8 h the reaction mixture
was then cooled to room temperature and added cautiously
into ice-cold water. The solid precipitated was collected by
filtration to isolate the compound 1a as yellow solid.
TLC analysis. After 4 h, the reaction mixture was cooled to
ambient temperature and added cautiously into ice-cold water.
The contents were extracted with ethyl acetate washed with
water, dried over sodium sulphate and filtered. The filtrate was
concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography on
silica gel to the title compound 4a as white solid.
2-Chloroquinolin-3-carbaldehyde (1a): Yield 6.2 g (87
1
%), yellow solid. H NMR (400 MHz, CDCl3): δH 10.58 (s,
1H), 8.78 (s, 1H), 8.10 (m, 1H), 8.01 (m, 1H), 7.91 (m, 1H),
7.67 (m, 1H); LCMS: m/z 192.0 (M+).
Methyl (E)-3-[2-(2-formylphenoxy)quinolin-3-yl]acrylate
1
2-Chloro-6-methylquinolin-3-carbaldehyde (1b): Yield
1.0 g (77 %), off yellow solid. 1H NMR (400 MHz, CDCl3):
δH 10.55 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 8.0, 1H), 7.73 (m,
2H), 2.57 (s, 3H); LCMS: m/z 206.2 (M+).
General procedure for the synthesis of substituted
quinolyl α,β-unsaturated ester (2a-b): To a solution of com-
pound 1 (1 g, 5.2 mmol) in anhydrous 1,2-dimethoxyethane
was added methyl (triphenylphosphoranylidene)acetate (1.7
g, 5.2 mmol) and the mixture was heated to reflux for 8 h. The
reaction mixture was cooled to ambient temperature and
concentrated under reduced pressure. The solid thus obtained
was purified by flash column chromatography on silica gel to
yield the title compound 2 as white solid.
Methyl (E)-3-(2-chloroquinolin-3-yl)acrylate (2a):
Yield 1.0 g (77 %), white solid. 1H NMR (400 MHz, CDCl3):
δH 8.39 (s, 1H), 8.14 (d, J = 16.0, 1H), 8.03 (d, J = 8.4, 1H),
7.87 (d, J = 8.0, 1H), 7.78 (m, 1H), 7.61 (m, 1H), 6.58 (d, J =
16.0, 1H), 3.87 (s, 3H); LCMS: m/z 248.2 (M+).
Methyl (E)-3-(2-chloro-6-methylquinolin-3-yl)acrylate
(2b): Yield 0.89 g (75 %), white solid. 1H NMR (400 MHz,
CDCl3): δH 8.30 (s, 1H), 8.14 (d, J = 16.0, 1H), 7.92 (m, 1H),
7.60 (m, 2H), 6.57 (d, J = 16.0, 1H), 3.88 (s, 3H), 2.56 (s,
3H); LCMS: m/z 262.2 (M+).
(4a): Yield 0.54 g (67 %), white solid. H NMR (400 MHz,
CDCl3): δH 8.01 (s, 1H), 8.41 (s, 1H), 8.11 (d, J = 16.0, 1H),
8.04 (m, 1H), 7.69 (m, 1H), 7.55 (m, 2H), 7.42 (m, 2H), 7.25
(m, 3H), 6.84 (d, J = 16.0, 1H), 3.85 (s, 3H); LCMS: m/z
334.2 (M+).
Methyl (E)-3-[2-(2-formylphenoxy)-6-methylquinolin-
1
3-yl]acrylate (4b): Yield 0.92 g (76 %), off white solid. H
NMR (400 MHz, CDCl3): δH 10.2 (s, 1H), 8.30 (s, 1H), 8.11
(d, J = 16.0, 1H), 8.03 (m, 1H), 7.71 (m, 1H), 7.69 (m, 2H),
7.44 (m, 2H), 6.83 (d, J = 16.0, 1H), 3.87 (s, 3H), 2.50 (s,
3H); MS: m/z 348.2 (M+).
General procedure for the synthesis of quinolo-oxepane
derivatives (5a-d, 6a-b and 7a-b): A mixture of compound
4a (0.1 g, 0.3 mmol) and N-methyl glycine (0.05 g, 0.6 mmol)
in anhydrous xylene (3 mL) was heated to reflux and the
progress of the reaction was monitored by TLC analysis. The
reaction mass was then cooled to ambient temperature and
concentrated under reduced pressure. The crude product thus
obtained was purified by flash column chromatography on
silica gel to afford pure product 5a (Schemes I and II).
Methyl 3-methyl-2,3,3a,14b,tetrahydro-1H-benzo[6,7]-
pyrrolo[3’,2’:4,5]oxepino[2,3-b]quinoline-1-carboxylate
(5a): Viscous liquid, 1H NMR (400 MHz, CDCl3): δH 8.12 (s,
1H), 8.01 (m, 1H), 7.74 (m, 1H), 7.69 (m, 1H), 7.49 (m, 3H),
7.30 (m, 2H), 4.07 (d, J = 11.0, 1H), 3.87 (s, 3H), 3.74 (m,
2H), 3.25 (m, 1H), 2.89 (m, 1H), 2.30 (s, 3H); 13C NMR (400
MHz, CDCl3): δC 179.8, 172.3, 148.5, 144.2, 138.0, 135.2,
129.0, 127.4, 123.4 122.1 60.1 59.3, 52.1, 50.0, 42.4, 40.2;
LCMS: m/z 361.0 (M+).
General procedure for the synthesis of 2-substituted
quinolyl α,β-unsaturated ester (4a-b):At 0 °C, to a suspension
of sodium hydride (0.12 g, 4.8 mmol) in anhydrous DMF (5 mL)
were added salicylaldehyde (0.3 g, 2.4 mmol) and compound
2 (0.6 g, 2.4 mmol) in DMF solution. The mixture was heated
to 80 °C and the progress of the reaction was monitored by
O
COOMe
NH
CH
3
Ph P=CHCOOMe
3
POCl /DMF
3
O
N
Cl
N
Cl
R
R
R
2
1
R = H, 4-Me
2a-b
1a-b
MeOOC
1
R
OH
N
OH
H
COOMe
O
H
1
R
NH
O
O
N
O
3
N
O
R
R
5
NaH/DMF
4
5a-d
4a-b
Scheme-I

Vol. 27, No. 10 (2015)
Efficient Synthesis of Quinolo-oxepanes 3669
2H), 7.22 (m, 1H), 7.18 (m, 2H), 4.21 (m, 2H), 3.72 (s, 3H),
3.42 (m, 2H), 2.85 (m, 1H), 2.50 (s, 6H), 2.45 (m, 1H), 1.63
(m, 2H), 1.40 (m, 2H); LCMS: m/z 401.2 (M+).
MeOOC
H
N
N
H
COOH
COOMe
H
Methyl 1,2,3,4,5a,16b,17,17a-octahydrobenzo[6,7]-
indolizino[2’,3’4,5]oxepino[2,3-b]quinoline-17-carboxylate
(7a):Viscous liquid, 1H NMR (400 MHz, CDCl3): δH 7.91 (m,
2H), 7.58 (m, 1H), 7.49 (m, 3H), 7.28 (m, 1H), 7.13 (m, 2H),
4.20 (m, 1H), 3.90 (m, 1H), 3.68 (s, 3H), 3.01 (m, 1H), 2.90
(m, 1H), 2.34 (m, 2H), 1.56 (m, 2H), 1.46 (m, 4H); 13C NMR
(400 MHz, CDCl3): δC 179.8, 173.4, 160.5, 156.4, 144.2, 139.4,
135.8, 132.0, 129.7, 127.6, 125.9, 124.8, 123.4, 68.3, 66.2,
57.5, 51.8, 46.5, 29.7, 23.9, 21.4; LCMS: m/z 401.0 (M+).
Methyl 14-methyl-1,2,3,4,5a,16b,17,17a-octahydro-
benzo[6,7]indolizino[2’,3’4,5]oxepino[2,3-b]quinoline-17-
carboxylate (7b):Viscous liquid, 1H NMR (400 MHz, CDCl3):
δH 7.91 (m, 2H), 7.88 (d, J = 8.8, 1H), 7.45 (m, 3H), 7.26 (m,
2H), 7.19 (m, 2H), 4.15 (m, 1H), 3.89 (m, 2H), 3.74 (s, 3H),
3.01 (m, 1H), 2.80 (m, 1H), 2.45 (s, 6H), 2.40 (m, 1H), 2.12
(m, 1H), 1.50 (m, 2H), 1.20 (m, 2H); 13C NMR (400 MHz,
CDCl3): δC 179.3, 173.4, 160.5, 156.4, 144.2, 139.9, 135.8,
132.0, 129.7, 127.8, 125.9, 124.8, 123.4, 68.3, 66.2, 57.5, 51.8,
50.8, 46.5, 29.7, 24.8, 23.9, 21.4; LCMS: m/z 415.4 (M+).
N
O
O
N
O
R
R
6
4
6a-b
MeOOC
H
N
N
COOH
H
COOMe
O
H
N
O
N
O
R
R
7
4
7a-b
Scheme-II
Methyl 3-ethyl-2,3,3a,14b,tetrahydro-1H-benzo[6,7]-
pyrrolo[3’,2’:4,5]oxepino[2,3-b]quinoline-1-carboxylate
(5b): Viscous liquid, 1H NMR (400 MHz, CDCl3): δH 8.08 (s,
1H), 8.01 (m, 1H), 7.73 (m, 1H), 7.67 (m, 1H), 7.56 (m, 1H),
7.46 (m, 1H), 7.28 (m, 1H), 7.13 (m, 2H), 4.17 (d, J = 11.0,
1H), 3.82 (m, 1H), 3.66 (s, 3H), 3.48 (m, 2H), 2.75 (m, 1H),
2.45 (m, 1H), 2.33 (m, 1H), 1.09 (m, 3H);13C NMR (400 MHz,
CDCl3): δC 179.2, 163.3, 149.5, 144.3, 137.6, 133.3, 129.4,
127.5, 123.3, 122.2, 60.8, 57.6, 52.4, 49.7, 47.5, 40.4, 12.4;
LCMS: m/z 375.2 (M+).
Methyl 3,12-dimethyl-2,3,3a,14b,tetrahydro-1H-
benzo[6,7]pyrrolo[3’,2’:4,5]oxepino[2,3-b]quinoline-1-
carboxylate (5c): Gummy liquid, 1H NMR (400 MHz, CDCl3):
δH 8.01 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.52 (m, 2H), 7.44
(m, 4H), 4.01 (d, J = 11.0 Hz,1H), 3.86 (s, 3H), 3.75 (m, 2H),
3.25 (m, 1H), 2.85 (m, 1H), 2.52 (s, 6H); 13C NMR (400 MHz,
CDCl3): δC 176.3, 172.3, 149.3, 140.0, 136.4, 135.3, 128.3,
125.4, 122.0, 120.1, 103.3, 60.5, 58.6, 49.3, 42.3, 40.2; LCMS:
m/z 375.2 (M+).
Methyl 3-ethyl,12-methyl-2,3,3a,14b,tetrahydro-1H-
benzo[6,7]pyrrolo[3’,2’:4,5]oxepino[2,3-b]quinoline-1-
carboxylate (5d): Gummy solid, 1H NMR (400 MHz, CDCl3):
δH 7.99 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.53 (m, 1H), 7.46
(m, 2H), 7.27 (m, 1H), 7.16 (m, 2H), 4.20 (m, 2H), 3.74 (s,
3H), 3.45 (m, 2H), 2.85 (m 1H), 2.49 (s, 6H), 2.35 (m, 2H),
1.11 (t, J = 8.0 Hz, 3H); 13C NMR (400 MHz, CDCl3): δC
178.3, 173.2, 155.0, 149.6, 140.1, 135.3, 133.2, 128.4, 127.5,
123.2, 119.0, 104.3, 60.2, 58.5, 53.3, 47.2, 40.2, 14.4; LCMS:
m/z 389.2 (M+).
Methyl 2,3,4a,15b,16,16a-hexahydro-1H-benzo[6,7]-
pyrrolizino[2’,3’4,5]oxepino[2,3-b]quinoline-16-carboxylate
(6a): Gummy liquid, 1H NMR (400 MHz, CDCl3): δH 7.95 (s,
1H), 7.80 (m, 1H), 7.65 (m, 2H), 7.44 (m, 1H), 7.25 (m, 1H),
7.11 (m, 1H), 7.02 (m, 1H), 6.89 (m, 1H), 4.07 (d, J = 11.0,
1H), 3.88 (m, 1H), 3.72 (s, 3H), 2.88 (m, 1H), 2.70 (m, 1H),
2.35 (m, 2H), 1.60 (m, 2H), 1.45 (m, 2H); LCMS: m/z 387.2
(M+).
RESULTS AND DISCUSSION
In the course of our ongoing research the synthesis of
quinolo-oxepane were prepared through intramolecular 1,3-
diploar cycloaddition reaction with Wittig products. To our
best knowledge pyrrolidines and benzo-oxepanes which
are present in biologically active molecules have never been
combined with quinolines subunits. 2-Chloro 3-formyl quino-
lines were obtained by subjecting the suitable acetanilide
with Vilsmeier reagent (POCl3/DMF)20. Further the quinoline
skeleton was extended by Wittig reaction with phosphonium
ylides21 (Ph3P=CHCOOMe) in refluxing 1,2-dimethoxy ethane
gave the corresponding α,β-unsaturated ester (2) with high
stereoslectivity in good yields. Subsequent reaction of Wittig
product with salicylaldehyde in presence of NaH/DMF yields
compound 4.
With these activated alkenes we turned our attention to
the synthesis of cycloadducts22,23 through azomethine ylides
with various α-amino acids24,25. This reaction was conducted
in refluxing anhydrous xylene to afford quinolo-oxepane in
good yields. The yields of the reaction are tabulated in (Tables
1 and 2). The formation of the cyclo-adducts was confirmed
by spectral analysis.
Conclusion
The structures and the regiochemistry of the cycloadducts
5a-d, 6a, b and 7a, b were confirmed by spectroscopic data.
The reaction were found to be highly regioselective leading to
the formation of only one product in which ring junction
protons were found to be cis. In conclusion, this paper describes
the cycloaddition reactions of unstable azomethine ylides
generated in situ by the decarboxylative condensation of the
O-alkylated salicylaldehyde (4) with N-substituted glycine in
xylene to afford the novel quinolo-oxepane. This simple method
utilizes commercially available materials and is performed
under neutral conditions.
Methyl13-methyl-2,3,4a,15b,16,16a-hexahydro-1H-
benzo[6,7]pyrrolizino[2’,3’4,5]oxepino[2,3-b]quinoline-16-
carboxylate (6b): Gummy liquid, H NMR (400 MHz,
1
CDCl3): δH 7.98 (m, 1H), 7.90 (m, 1H), 7.55 (m, 1H), 7.42 (m,

3670 Saravanan et al.
Asian J. Chem.
TABLE-1
YIELDS OF QUINOLO-OXEPANE DERIVATIVES
ACKNOWLEDGEMENTS
The authors are thankful to the Head, Department of
Chemistry, SRM University for providing the laboratory
facilities.
Compd.
No.
Time
(min)
Yield
(%)
Product
MeOOC
CH3
N
H
H
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30
25
40
50
82
88
79
84
5a
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TABLE-2
YIELDS OF QUINOLO-OXEPANE DERIVATIVES
Compd.
No.
Time
(min)
Yield
(%)
Product
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N
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H
40
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N
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H
H
N
O
MeOOC
N
H
H
55
50
82
85
7a
7b
N
O
MeOOC
N
H
H
N
O