Synthesis of some complex pyrano[2,3-b]- and pyrido[2,3-b]quinolines from simple acetanilides via intramolecular domino hetero Diels-Alder reactions of 1-oxa-1,3-butadienes in aqueous medium

Article abstract of DOI:10.1016/j.tet.2009.06.036

Some complex pyrano[2,3-b]- and pyrido[2,3-b]quinolines were synthesized from simple acetanilides via intramolecular domino hetero Diels-Alder reactions of 1-oxa-1,3-butadienes using water as solvent.

Full text of DOI:10.1016/j.tet.2009.06.036

Tetrahedron 65 (2009) 7099–7104
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Synthesis of some complex pyrano[2,3-b]- and pyrido[2,3-b]quinolines from
simple acetanilides via intramolecular domino hetero Diels–Alder reactions
of 1-oxa-1,3-butadienes in aqueous medium
*
Biswajita Baruah, Pulak J. Bhuyan
Medicinal Chemistry Division, North East Institute of Science & Technology, Jorhat 785006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Some complex pyrano[2,3-b]- and pyrido[2,3-b]quinolines were synthesized from simple acetanilides via
intramolecular domino hetero Diels–Alder reactions of 1-oxa-1,3-butadienes using water as solvent.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 February 2009
Received in revised form 10 June 2009
Accepted 11 June 2009
Available online 17 June 2009
1. Introduction
research in recent years. Diels–Alder reactions involve cyclic elec-
tron shifts and ring closure where the number of
s-bonds increase
The importance of quinoline and its annelated derivatives is well
recognized by synthetic and biological chemists. Compounds pos-
sessing this ring system have wide applications as drugs and
pharmaceuticals.1 Pyrano- and pyridoquinolines are two important
classes of compounds that constitute the basic frameworks of
a number of alkaloids of biological significance, for example,
geibalasine, ribalinine, flindersine, etc. (Fig. 1).2 Therefore, consid-
erable efforts have been directed towards the preparation and
synthetic manipulation of these molecules. As a result, a number of
compounds have been obtained with diverse biological activities.3
The development of resource and eco-friendly process in terms
of sustainable chemistry has become a focal point in chemical
at the expense of -bonds without the loss of any fragment and yet
p
result in the formation of the desired cyclic compound. In the
present world of green chemistry, such chemical processes with
high atom economy have received a growing interest from the
scientific community. Hetero Diels–Alder reactions are becoming
a mainstay of heterocyclic and natural product synthesis.4 Espe-
cially efficient are those cycloaddition where the heterodienes are
formed in situ (domino hetero Diels–Alder).5 Among these re-
actions, the domino oxa-1,3-butadiene Diels–Alder reaction is
highly useful method for the synthesis of dihydropyrans.6
The use of environmentally benign solvents like water repre-
sents very powerful green chemical technology procedures from
both the economical and synthetic point of view.7 They not only
reduce the burden of organic solvent disposal, but also enhance the
rate of many organic reactions.
OMe
O
OH
OH
As part of our continued interest on quinolines8 and synthesis of
diverse heterocyclic compounds9 of biological significance, we re-
port here the synthesis of some novel complex pyrano[2,3-b]- and
pyrido[2,3-b]quinolines from simple acetanilides via intra-
molecular domino hetero Diels–Alder reactions involving 1-oxa-
1,3-butadienes in aqueous medium (Scheme 1).
N
O
N
O
Me
ribalinine
geibalansine
O
O
N
N
N
H
O
Me
2. Results and discussion
(CH2)3N(Me)2
antidepressant agent
flindersine
Acetanilides 1 were chosen as the parent molecules in our re-
action strategy (Scheme 1). The 2-chloro-3-formyl quinolines 2
were prepared from 1 by our own method.8a Thus acetanilide 1a
(R¼H) on treatment with the Vilsmeier reagent (DMF–POCl3) gave
2-chloro-3-formyl quinoline 2a in excellent yield (80%). The re-
action of 2a with prenyl alcohol in presence of sodium hydroxide
(50% aqueous solution) under phase transfer catalytic condition was
(synthetic origin)
Figure 1.
* Corresponding author. Tel.: þ91 0376 2370121.
E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.036

7100
B. Baruah, P.J. Bhuyan / Tetrahedron 65 (2009) 7099–7104
CHO
Cl
CHO
O
R
R
R
i
ii
N
N
NHCOCH3
3a R=H
O
2a R=H
2b R=Me
1a R=H
3b R=Me
1b R=Me
H3C
O
O
N
CH3
O
H3C
N
N
O
4b
O
N
H
CHO
O
R
O
O
iii
O
N
O
O
CH3
N
R
H3C
O
HN
N
N
NH
O
O
Ha
3a R=H
O
Ha
R
3b R=Me
R
O
Hb
5a R=H
Hb
N
H3C
CH3
O
5b R=Me
N
N
N
7a R=H
7b R=Me
8a R=H
8b R=Me
O
Ha
R
Scheme 2.
Hb
O
N
6a R=H
6b R=Me
Scheme 1. (i) DMF–POCl3, 80 ꢀC, (ii) prenyl alcohol/TBAB/NaOH, (iii) N,N-dimethyl
barbituric acid (4a).
O
O
O
O
Ha
found to be the most suitable method to introduce the dienophile in
compound 2a and to prepare 3a. Following the Tietze protocol of
domino Knoevenagel hetero Diels–Alder reaction, 3a was reacted
with N,N-dimethylbarbituric acid (4a) in presence of piperidine at
room temperature using water as solvent. The intermediate Knoe-
venagel adduct 5a was observed by TLC control and appearance of
the yellow colour within 15 min. It was not isolated and allowed to
cyclise at room temperature which after 3 h stirring gave the cis
fused pentacyclic pyrano[2,3-b]quinoline derivative 6a with high
yield 80% and diastereoselectivity (>99%). The structure of the
compound was ascertained from the spectroscopic data. 1H NMR
R
CHO
O
R
Hb
9
N
N
O
3a R=H
3b R=Me
10a R=H
10b R=Me
H3C
Ph
O
N
N
N
N
H3C
Ha
Ph
CHO
R
R
O
Hb
spectra showed the absence of the prenylic protons at
d
4.16 (d, 2H),
3.30
11
N
O
N
O
5.27 (t, 1H) and the presence of two another N-Me protons at
d
and 3.36 as singlets. The cis-fusion at the ring junction of 6a is
strongly supported by the coupling constant of 4.77 Hz between the
two hydrogens Ha and Hb in the 1H NMR spectrum. Similarly com-
pound 6b was synthesized and characterized (Table 1).
12a R=H
3a R=H
12b R=Me
3b R=Me
Scheme 3.
pyrazolin-5-one 11 to generate the oxabutadiene systemwhich after
cyclisation resulted the products 10 and 12 respectively (Scheme 3,
Table 1).
Aldehydes X obtained from the reaction of 2 with allyl alcohol
instead of prenyl alcohol were found to react with N,N-dimethyl
barbituric acid 4a to afford the Knoevenagel adduct which could
not be transformed to the hetero Diels–Alder adduct Y even on
heating at 200 ꢀC for 48 h (Scheme 4).
Table 1
Synthesis of pyrano[2,3-b]quinolines 6, 7, 8, 10 and 12
Product
R
Time (h)
Yield (%)
Mp (ꢀC)
6a
6b
7a
7b
8a
8b
10a
10b
12a
12b
H
Me
H
Me
H
Me
H
Me
H
Me
3
3
80
76
45
45
30
25
75
70
80
74
274–276
287–288
312–314
320–322
310–312
316–318
274–276
288–290
197–199
210–212
4.5
4.5
4.5
4.5
3
3
4
4
O
H3C
O
CH3
O
N
N
O
H3C
O
CH3
O
N
N
CHO
O
4a
When the reaction was studied by utilizing N-methyl barbituric
acid 4b with compound 3 two regioisomeric cycloadducts 7 & 8 were
formed (Scheme 2). Obviously it is because of the two possible
oxabutadiene sites of the Knoevenagel condensed product formed
from the reaction of unsymmetrical barbituric acid 4b with 3a. Thus
the reaction of 3awith 4b gave the two isomers 7a and 8a in a ratio of
3:2 and in 75% yield. The structures of the compounds were ascer-
tained from the spectroscopic data and elemental analysis. The
compound 7a showed a broad singlet at
whereas 8a showed the presence of the NH proton at
compound 7b and 8b were synthesized and characterized (Table 1).
The reaction was then extended by utilizing other cyclic dicar-
bonyl compounds viz.1,3-indanedione 9 and 3-methyl-1-phenyl-2-
N
O
N
X
Y
Scheme 4.
In order to synthesize the pyrido[2,3-b]quinoline derivatives,
the dienophile site was prepared from 2 by treatment with N-allyl
methyl amine in presence of K2CO3 under refluxing condition in
DMF for 4 h (Scheme 5). Thus the reaction of 2a with N-allyl methyl
amine in presence of K2CO3 afforded the compound 13a. The
compound 13a on treatment with N,N-dimethylbarbituric acid 4a
in prsence of piperidine as catalyst and water as solvent at room
temperature afforded the hetero Diels–Alder cycloadduct, 15a in
d
8.90 for the NH proton
4.89. Similarly
d

B. Baruah, P.J. Bhuyan / Tetrahedron 65 (2009) 7099–7104
7101
5 h and in 70% yield. The formation of the orange-red intermediate
14a was observed in TLC plate in 15 min. It could not be isolated
which cyclised at room temperature after 5 h stirring to the cis-
fused pentacyclic pyrido[2,3-b]quinoline derivative 15a giving high
yield (70%). The structure of the compound was determined from
the spectroscopic data. 1H NMR spectra showed the absence of the
The reaction was then studied by condensing pyrazolone 11 with
13a which afforded exclusively the cis-adduct 18a in good yield
(Scheme 7). Similarly compound 18b was synthesized by utilizing
13b with 11. The structures of the compounds were determined
from the spectroscopic data and elemental analysis (Table 2).
allylic protons at
presence of two N-Me protons at
d
5.98 (m, 1H), 5.32 (d, 2H), 3.53 (d, 2H) and the
3.31 and 3.35 as singlets. The cis-
H3C
Ph
N
d
N N
(i)
N
Ph
fusion at the ring junction of 15a was confirmed from the coupling
CHO
R
O
O
H3C
constant of 4.53 Hz between Ha and Hb in the 1H NMR spectrum.
R
11
N
N
CH3
N
N
CH3
13a R=H
R
iii
R
CHO
Cl
ii
i
13b R=Me
Ph
O
N
N
N
NHCOCH3
H3C
(i) Pyrazolone (11)
Piperidine
2a R=H
1a R=H
1b R=Me
R
2b R=Me
water, 6 h
O
N
N
N
CH3
O
H3C
N
N
R
CHO
CH3
18a R=H
18b R=Me
O
N
CH3
N
R
Scheme 7.
13a R=H
N
13b R=Me
Table 2
Synthesis of pyrido[2,3-b]quinolines 15, 16, 17 and 18
CH3
14 R=H
14 R=Me
O
H3C
O
CH3
N
N
Product
R
Time (h)
Yield (%)
Mp (ꢀC)
O
15a
15b
16a
16b
17a
17b
18a
18b
H
5
5
6
6
6
6
6
6
70
65
42
39
28
26
55
52
167–168
187–189
267–269
297–299
265–266
294–296
155–157
170–172
Ha
R
Me
H
Me
H
Me
H
Me
Hb
N
N
CH3
15a R=H
15b R=Me
Scheme 5. (i) DMF–POCl3, 80 ꢀC. (ii) N-allyl methyl amine, K2CO3, DMF, (iii) N,N-dimethyl
barbituric acid (4a).
As in the earlier case when N-methyl barbituric acid 4b was
reacted with 13a two products 16a and 17a were formed in the ratio
3:2 (Scheme 6). The two products could be separated by column
chromatography giving a combined yield of 70%. The structures of
the compounds were determined from the spectroscopic data. The
1H NMR spectra of the compounds showed the cis-fusion at the ring
junction for both the isomer 16a and 17a. The 1H NMR spectra of
However, we failed in the reaction to replace the chloro group of
2a by simple N-phenyl allyl-amine in the presence of base, e.g.,
Na2CO3, NaHCO3 even at elevated temperature.
In conclusion we have reported the synthesis of some complex
pyrano[2,3-b]- and pyrido[2,3-b]quinolines from simple acetanilides
and via intramolecular domino hetero Diels–Alder reactions in-
volving 1-oxa-1,3-butadienes. The reactions were performed in
aqueous medium and products were isolated simply by filtration
almost in the pure form.
16a showed a broad singlet at
d 8.83 for NH proton whereas 17a
showed a broad singlet at
d
4.90 for the NH proton.
3. Experimental
3.1. General
CHO
R
N
+
N
CH3
13a R= H
13b R=Me
N- Me Barbituric acid (4b),
Piperidine, water, rt, 6 h
All reagents and solvents were of reagent grade and were used
without drying. The IR spectra were recorded on Perkin–Elmer
system-2000 FTIR spectrometer. 1H NMR and 13C NMR spectra were
recorded on Bruker Avance-DPX 300 MHz and 75 MHz FT NMR in
CDCl3 using TMS as an internal standard. LRMS were recorded in
Bruker Daltonics ESQUIRE 3000 LC ESI ion trap mass spectrometer.
Elemental analyses were performed on Perkin–Elmer-2400 spec-
trometer at the Analytical Chemistry Division, NEIST, Jorhat. Ana-
lytical TLC and column chromatography were performed using
E. Merck aluminum-backed silica gel plates coated with silica gel
O
O
H3C
N
NH
CH3
HN
N
O
O
O
O
R
R
R
N
N
CH3
N
N
CH3
O
N
O
H3C
O
CH3
O
N
NH
O
HN
N
G
and E. Merck silica gel (100–200 mesh); Melting points
(uncorrected) were determined on a Buchi B-540 apparatus.
O
Ha
Ha
R
Hb
Hb
3.2. General procedure for the synthesis of 2-chloro-3-
formylquinolines 2
N
N
N
CH3
CH3
16a R=H
16b R=Me
17a R=H
17b R=Me
POCl3 (9 mL, 98.28 mmol) was added dropwise from a droping
funnel to DMF (2.7 mL, 34.65 mmol) taken in a round bottom flask
Scheme 6.

7102
B. Baruah, P.J. Bhuyan / Tetrahedron 65 (2009) 7099–7104
keeping the temperature at 0–5 ꢀC. The mixture was allowed to stir
for about 5 min. Acetanilide 1a (1.4 g, 10.37 mmol) was then added
to the reaction mixture and heated the resulting solution for 8 h
(75–80 ꢀC). The reaction mixture was cooled to room temperature
and then poured into crushed ice under stirring condition. A pale
yellow compound appeared at once. The precipitate thus appeared
was filtered and washed with water and dried. The crude com-
pound was then recrystallised from ethylacetate. 2a. Yield 1.59 g
(80%), mp 148–149 ꢀC. Similarly compound 2b was synthesized. 2b.
Yield 1.71 g (82%), mp 124–125 ꢀC.
C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C, 67.22; H, 5.83; N,
10.73.
7a: Brown solid. Yield¼164 mg (45%); mp¼312–314 ꢀC; Rf
(EtOAc) 0.18. IR (KBr): 3415.8, 3010.9, 2954.0, 1702.5, 1656.2,
755.6 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.57 (s, 6H, OCMe2), 2.94–
3.10 (m, 1H, Hb), 3.33 (s, 3H, NMe), 3.84 (d, J¼4.9 Hz, 1H, Ha), 4.12 (d,
J¼4.8 Hz, 2H, OCH2), 7.12–7.96 (m, 5H, Ar), 8.90 (s, 1H, NH). 13C NMR
(75 MHz, CDCl3):
d 27.85, 28.23, 29.32, 32.92, 54.40, 85.11, 117.10,
126.29, 127.16, 127.81, 130.75, 137.99, 145.41, 149.86, 153.68, 154.44,
161.20, 166.10, 166.45. ESI-MS m/z (%): 366.3 (MþH)þ (100). Anal.
Calcd for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C, 65.81; H,
5.19; N, 11.45.
3.3. General procedure for the synthesis of 2-prenyloxy-3-
formylquinolines 3
7b: Brownish white solid. Yield¼169 mg (45%); mp¼320–
322 ꢀC; Rf (EtOAc) 0.20. IR (KBr): 3418.0, 3012.2, 2955.7, 1702.6,
1657.4, 756.8 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 1.56 (s, 6H,
In a round bottom flask containing 10 mL of 50% aqueous NaOH
solution was added prenyl alcohol (0.6 mL, 10 mmol) and catalytic
amount of tetrabutyl amonium bromide. To this added a solution of
2-chloro-3-formyl quinoline 2a (1.53 g, 8 mmol) in dichloro-
methane (10 mL) and allowed to stirred the reaction mixture for
5 h. The organic layer was separated and washed 2–3 times with
water. The solvent was evaporated and the crude product thus
formed was separated by means of column chromatography (5%
EtOAc/hexane). The structure of the compound was determined
OCMe2), 2.35 (s, 3H, Me), 2.96–3.10 (m, 1H, Hb), 3.34 (s, 3H, NMe),
3.89 (d, J¼4.5 Hz,1H, Ha), 4.15 (d, J¼4.3 Hz, 2H, OCH2), 7.02–7.82 (m,
4H, Ar), 8.91 (s, 1H, NH). 13C NMR (75 MHz, CDCl3):
d 20.86, 27.80,
28.39, 29.37, 32.96, 54.91, 86.01, 117.70, 126.21, 127.10, 127.42,
130.51, 138.05, 145.33, 149.69, 153.78, 154.40, 161.87, 166.27, 166.49.
ESI-MS m/z (%): 380.4 (MþH)þ (100). Anal. Calcd for C21H21N3O4: C,
66.48; H, 5.58; N, 11.07. Found: C, 66.54; H, 5.51; N, 11.10.
8a: Dark brown solid. Yield¼110 mg (30%); mp¼310–312 ꢀC; Rf
(EtOAc) 0.16. IR (KBr): 3442.0, 3015.1, 2954.8, 1702.5, 1624.8,
from the spectroscopic data. 1H NMR (300 MHz, CDCl3):
d 1.71 (s,
758.1 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.56 (s, 6H, OCMe2), 2.96–
3H), 1.75 (s, 3H), 4.16 (d, J¼4.7 Hz, 2H), 5.27 (t, J¼4.6 Hz, 1H), 7.27–
8.76 (m, 5H), 10.56 (s, 1H). 3a. Yield 1.01 g (52%), mp 65 ꢀC. Similarly
compound 3b was synthesized and characterized. 3b. Yield 1.05 g
(50%), mp 62 ꢀC.
3.08 (m, 1H, Hb), 3.37 (s, 3H, NMe), 3.90 (d, J¼4.0 Hz,1H, Ha), 4.14 (d,
J¼4.1 Hz, 2H, OCH2), 4.89 (s, 1H, NH), 7.01–8.11 (m, 5H, Ar). 13C NMR
(75 MHz, CDCl3):
d 27.92, 28.81, 29.54, 32.86, 54.33, 84.80, 116.89,
126.43, 127.429, 127.91, 130.74, 138.01, 145.42, 149.95, 153.49,
154.23, 161.21, 166.11, 166.57. ESI-MS m/z (%): 366.1 (MþH)þ (100).
Anal. Calcd for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C,
65.77; H, 5.16; N, 11.57.
3.4. Experimental procedure for the synthesis of pyrano[2,3-
b]quinolines
8b: Dark brown solid. Yield¼95 mg (25%); mp¼317–319 ꢀC; Rf
(EtOAc) 0.17. IR (KBr): 3444.6, 3014.9, 2956.7, 1704.3, 1627.3,
To an aqueous solution of 2-prenyloxy-3-formylquinolines 3
(1 mmol) in a 100 mL round bottom flask added 1 mmol of active
methylene compound 4/9/11 and 1 drop of piperidine and then
allowed to stir at room temperature. The reaction mixture becomes
yellow within 15 min which shows the formation of the Knoeve-
nagel condensed product. Stiring was continued for 3–4.5 h. The
product 6/10/12 appeared as yellowish/brownish/white compound
in the reaction mixture. The compound was filtered and recrys-
tallised (20% EtOH/CHCl3). Yields 70–80%. In the reaction of 3 with
4b two products were formed. The solid product obtained in this
reaction was filtered and separated by column chromatography
(EtOAc). The structure of the compounds were confirmed as
regioisomers 7 & 8 from the spectroscopic data.
758.9 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.56 (s, 6H, OCMe2), 2.33
(s, 3H, Me), 2.94–3.06 (m, 1H, Hb), 3.37 (s, 3H, NMe), 3.90 (d,
J¼4.1 Hz, 1H, Ha), 4.16 (d, J¼4.2 Hz, 2H, OCH2), 4.89 (s, 1H, NH),
7.09–8.05 (m, 4H, Ar). 13C NMR (75 MHz, CDCl3):
d 21.10, 27.34,
28.45, 29.67, 32.88, 54.75, 84.09, 116.62, 126.49, 127.42, 127.89,
130.44, 138.47, 145.33, 149.90, 153.88, 154.27, 161.11, 166.06, 166.73.
ESI-MS m/z (%): 380.4 (MþH)þ (100). Anal. Calcd for C21H21N3O4: C,
66.48; H, 5.58; N, 11.07. Found: C, 66.43; H, 5.63; N, 11.11.
10a: Yellowish brown solid. Yield¼277 mg (75%); mp¼274–
276 ꢀC; Rf (EtOAc) 0.15. IR (KBr): 2922.6, 1708.5, 1655.1, 771.6 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d 1.57 (s, 6H, OCMe2), 2.83–3.11 (m, 1H,
Hb), 3.70 (d, J¼4.7 Hz, 1H, Ha), 4.15 (d, J¼4.8 Hz, 2H, OCH2), 7.27 (s,
1H, Ar), 7.37 (d, J¼7.2 Hz, 1H, Ar), 7.41–7.50 (m, 1H, Ar), 7.52 (d,
J¼6.9 Hz, 1H, Ar), 7.65 (t, J¼7.3 Hz, 1H, Ar), 7.76 (d, J¼7.2 Hz, 1H, Ar),
7.84 (d, J¼7.1 Hz, 1H, Ar), 7.96 (d, J¼8.0 Hz, 1H, Ar), 8.04 (s, 1H, Ar).
6a: Light yellow solid. Yield¼300 mg (80%); mp¼274–276 ꢀC; Rf
(90% EtOAc/pet. ether) 0.21. IR (KBr): 3014.3, 2958.4, 1704.1, 1655.7,
756.9 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.56 (s, 6H, OCMe2), 2.83–
3.11 (m, 1H, Hb), 3.30 (s, 3H, NMe), 3.36 (s, 3H, NMe), 3.70 (d,
J¼4.7 Hz,1H, Ha), 4.15 (d, J¼4.8 Hz, 2H, OCH2), 7.48–7.57 (m, 1H, Ar),
7.67–7.79 (m, 2H, Ar), 7.96–8.10 (m, 1H, Ar), 8.17 (s, 1H, Ar). 13C NMR
13C NMR (75 MHz, CDCl3):
d 25.87, 30.12, 34.52, 58.01, 79.95, 105.82,
118.97, 121.64, 122.92, 123.07, 126.95, 127.79, 130.31, 130.60, 132.54,
135.37, 135.69, 138.86, 141.20, 144.90, 155.14, 169.98, 180.61. ESI-MS
m/z (%): 370.4 (MþH)þ (100). Anal. Calcd for C24H19NO3: C, 78.03; H,
5.18; N, 3.79. Found: C, 78.12; H, 5.01; N, 3.73.
(75 MHz, CDCl3):
d 27.87, 28.27, 28.54, 29.37, 33.56, 54.61, 85.88,
116.38, 126.55, 127.14, 127.77, 130.91, 138.03, 145.23, 150.14, 153.62,
154.43, 161.58, 166.11, 166.50. ESI-MS m/z (%): 380.1 (MþH)þ (100).
Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58; N, 11.07. Found: C,
66.36; H, 5.64; N, 11.10.
10b: Crimson white solid. Yield¼268 mg (70%); mp¼274–
276 ꢀC; Rf (EtOAc) 0.12. IR (KBr): 2924.0, 1709.1, 1655.4, 772.1 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d 1.57 (s, 6H, OCMe2), 2.45 (s, 3H, Me),
6b: Yellowish white solid. Yield¼298 mg (76%); mp¼274–
2.84–3.12 (m, 1H, Hb), 3.72 (d, J¼4.2 Hz, 1H, Ha), 4.14 (d, J¼4.7 Hz,
2H, OCH2), 7.35 (d, J¼7.3 Hz, 1H, Ar), 7.42 (s, 1H, Ar), 7.54 (d,
J¼7.9 Hz, 1H, Ar), 7.67 (t, J¼7.8 Hz, 1H, Ar), 7.78 (d, J¼7.4 Hz, 1H, Ar),
7.85 (d, J¼7.2 Hz, 1H, Ar), 7.98 (d, J¼7.7 Hz, 1H, Ar), 8.05 (s, 1H, Ar).
276 ꢀC; Rf (90% EtOAc/pet. ether) 0.20. IR (KBr): 3014.3, 2958.4,
1704.1, 1655.7, 756.9 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.56 (s, 6H,
OCMe2), 2.34 (s, 3H, Me), 2.86–3.14 (m, 1H, Hb), 3.31 (s, 3H, NMe),
3.36 (s, 3H, NMe), 3.80 (d, J¼4.9 Hz, 1H, Ha), 4.13 (d, J¼4.2 Hz, 2H,
13C NMR (75 MHz, CDCl3):
d 20.92, 25.81, 30.43, 34.76, 58.21, 79.81,
OCH2), 7.39–7.98 (m, 4H, Ar). 13C (75 MHz, CDCl3):
d
21.98, 27.64,
105.77, 118.68, 121.40, 123.09, 123.12, 127.10, 127.89, 130.42, 130.62,
132.64, 135.51, 135.86, 138.59, 141.31, 145.21, 155.23, 169.84, 180.44.
ESI-MS m/z (%): 384.3 (MþH)þ (100). Anal. Calcd for C25H21NO3: C,
78.31; H, 5.52; N, 3.65. Found: C, 78.27; H, 5.56; N, 3.60.
28.31, 28.22, 29.42, 33.48, 54.75, 86.00, 116.12, 126.30, 127.41,
127.79, 131.01, 138.11, 145.17, 150.20, 153.49, 154.41, 161.50, 166.14,
166.39. ESI-MS m/z (%): 394.2 (MþH)þ (100). Anal. Calcd for

B. Baruah, P.J. Bhuyan / Tetrahedron 65 (2009) 7099–7104
7103
12a: Dirty white solid. Yield¼318 mg (80%); mp¼197–199 ꢀC; Rf
2.71–2.91 (m, 1H, Hb), 2.96 (s, 3H, NMe), 3.28 (s, 3H, NMe), 3.33 (s,
3H, NMe), 3.47 (d, J¼1.8 Hz, 2H, NCH2), 3.96 (d, J¼4.2 Hz, 1H, Ha),
4.10 (d, J¼4.7 Hz, 2H, OCH2), 7.24–7.84 (m, 4H, Ar). 13C NMR
(EtOAc) 0.72. IR (KBr): 3065.2, 2953.6, 1595.9, 1513.2, 772.2 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d 1.56 (s, 6H, OCMe2), 2.64 (s, 3H,
NCMe), 3.02–3.23 (m, 1H, Hb), 4.11 (d, J¼4.4 Hz, 2H, OCH2), 4.29 (d,
(75 MHz, CDCl3): d 22.27, 27.46, 28.15, 29.31, 32.41, 39.52, 44.14,
J¼4.9 Hz, 1H, Ha), 7.13–8.06 (m, 10H, Ar). 13C NMR (75 MHz, CDCl3):
51.08, 115.64, 125.41, 127.39, 129.62, 130.71, 137.90, 145.81, 150.49,
153.70, 155.02, 160.41, 166.15, 166.48. ESI-MS m/z (%): 379.3
(MþH)þ (100). Anal. Calcd for C21H22N4O3: C, 66.65; H, 5.86; N,
14.80. Found: C, 66.71; H, 5.92; N, 14.71.
16a: Pinkish white colour solid. Yield¼147 mg (42%); mp¼267–
269 ꢀC; Rf (70% EtOAc/pet. ether) 0.25. IR (KBr): 3414.3, 3011.2,
2955.8,1704.7,1654.7, 756.4 cmꢁ1. 1H NMR (300 MHz, CDCl3), 2.89–
2.92 (m, 1H, Hb), 3.09 (s, 3H, NMe), 3.31 (s, 3H, NMe), 3.71 (d,
J¼4.4 Hz, 2H, NCH2), 3.92 (d, J¼4.9 Hz,1H, Ha), 4.06 (d, J¼4.6 Hz, 2H,
OCH2), 7.17 (s, 1H, Ar), 7.27 (t, J¼7.2 Hz, 1H, Ar), 7.52 (t, J¼7.5 Hz, 1H,
Ar), 7.65 (s, 1H, Ar), 7.75 (s, 1H, Ar), 8.83 (s, 1H, NH). 13C NMR
d
14.51, 27.22, 33.41, 54.65, 86.11, 102.20, 121.31, 125.49, 126.10,
127.48, 127.79, 128.43, 129.53, 130.96, 137.65, 139.81, 146.12, 148.22,
153.47, 166.70. ESI-MS m/z (%): 398.7 (MþH)þ (100). Anal. Calcd for
C25H23N3O2: C, 75.55; H, 5.83; N, 10.57. Found: C, 75.47; H, 6.90; N,
10.61.
12b: Light brown solid. Yield¼329 mg (80%); mp¼210–212 ꢀC;
Rf (EtOAc) 0.65. IR (KBr): 3064.8, 2954.1, 1593.4, 1510.4, 773.5. 1H
NMR (300 MHz, CDCl3): d 1.56 (s, 6H, OCMe2), 2.35 (s, 3H, Me), 2.65
(s, 3H, NCMe), 3.04–3.25 (m, 1H, Hb), 4.12 (d, J¼4.9 Hz, 2H, OCH2),
4.30 (d, J¼4.5 Hz, 1H, Ha), 7.26–8.13 (m, 9H, Ar). 13C NMR (75 MHz,
CDCl3):
d
13.96, 21.12, 27.21, 33.44, 54.66, 86.85, 102.11, 121.39,
(75 MHz, CDCl3): d 27.36, 28.29, 32.42, 35.21, 43.98, 53.92, 116.11,
125.40, 126.80, 127.62, 127.91, 128.54, 129.28, 130.40, 137.10, 139.17,
146.78, 148.64, 153.66, 166.31. ESI-MS m/z (%): 412.9 (MþH)þ (100).
Anal. Calcd for C26H25N3O2: C, 75.89; H, 6.12; N, 10.21. Found: C,
75.80; H, 6.22; N, 10.27.
125.26, 127.43, 129.52, 130.68, 137.59, 145.49, 150.14, 153.61, 154.93,
160.43, 166.18, 166.48. ESI-MS m/z (%): 351.4 (MþH)þ (100). Anal.
Calcd for C19H18N4O3: C, 65.13; H, 5.18; N, 15.99. Found: C, 65.21; H,
5.10; N, 15.92.
16b: Brownish white colour solid. Yield¼142 mg (39%);
3.5. Typical experimental procedure for the synthesis of 13
mp¼297–299 ꢀC; Rf (70% EtOAc/pet. ether) 0.23. IR (KBr): 3431.2,
3014.7, 2957.1, 1702.3, 1657.0, 756.9 cmꢁ1 1H NMR (300 MHz,
.
In a simple experimental procedure, equimolar amounts of 2-
chloro-3-formyl quinoline 2a (2 mmol) and N-allyl methyl amine
(2 mmol) were taken in a round bottom flask containing 5 mL of
DMF. 2 mmol of K2CO3 was added to the reaction mixture and
refluxed for 4 h. The reaction mixture was cooled to room tem-
perature and poured into crushed ice under continuous stirring. It
was then extracted with dichloromethane, dried with anhydrous
Na2SO4, evaporated under reduced pressure and purified by pre-
parative TLC (5% EtOAc/hexane) to furnish 13a (176 mg, 60%). The
structure of the compound was determined from the spectroscopic
CDCl3): d 2.36 (s, 3H, Me), 2.89–2.92 (m, 1H, Hb), 3.04 (s, 3H, NMe),
3.33 (s, 3H, NMe), 3.69 (d, J¼4.2 Hz, 2H, NCH2), 3.91 (d, J¼4.9 Hz,1H,
Ha), 4.04 (d, J¼4.7 Hz, 2H, OCH2), 7.14–7.64 (m, 4H, Ar), 8.83 (s, 1H,
NH). 13C NMR (75 MHz, CDCl3):
d 21.91, 27.33, 28.32, 33.02, 35.31,
43.77, 53.81, 116.21, 126.16, 127.51, 129.44, 131.08, 137.69, 145.17,
150.10, 153.67, 154.97, 160.19, 166.22, 166.49. ESI-MS m/z (%): 365.7
(MþH)þ (100). Anal. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N,
15.37. Found: C, 65.85; H, 5.61; N, 15.41.
17a: Dark brown colour solid. Yield¼98 mg (28%); mp¼265–
266 ꢀC; Rf (70% EtOAc/pet. ether) 0.22. IR (KBr): 3441.9, 2954.0,
data. 1H NMR (300 MHz, CDCl3):
d
3.10 (s, 3H), 3.53 (d, J¼4.4 Hz,
1702.1, 1625.9, 759.2 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.75–2.87
2H), 5.32 (d, J¼4.0 Hz, 2H), 5.98–6.07 (m, 1H), 7.20–8.47 (m, 5H),
(m,1H, Hb), 3.12 (s, 3H, NMe), 3.32 (s, 3H, NMe), 3.70 (d, J¼4.1 Hz, 2H,
NCH2), 3.94 (d, J¼4.4 Hz, 1H, Ha), 4.02 (d, J¼5.9 Hz, 2H, OCH2), 4.90
(s, 1H, NH), 7.16–7.26 (m, 2H, Ar), 7.54 (t, J¼7.7 Hz, 1H, Ar), 7.66 (d,
10.54 (s, 1H).
3.6. Experimental procedure for the synthesis of pyrido[2,3-
b]quinolines
J¼7.7 Hz, 1H, Ar), 7.74 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d 27.35,
28.30, 32.40, 35.18, 43.97, 54.01, 116.20, 125.14, 127.40, 129.55,
130.54,137.62,145.30,150.32,153.66,154.99,160.80,166.25, 166.55.
ESI-MS m/z (%): 351.2 (MþH)þ (100). Anal. Calcd for C19H18N4O3: C,
65.13; H, 5.18; N, 15.99. Found: C, 65.21; H, 5.09; N, 15.92.
To an aqueous solution of 2-prenyloxy-3-formylquinolines 13
(1 mmol) added 1 mmol of active methylene compound 4/11 and 1
drop of piperidine and then allowed to stir at room temperature.
The reaction mixture becomes orange-red within 15 min which
shows the formation of the Knoevenagel condensed product. Stir-
ring was continued for 5–6 h. The product 15/18 appeared as yel-
lowish white compound in the reaction mixture. The compound
was filtered and recrystallised (20% EtOH/CHCl3). Yields 50–70%.
In the reaction of 13 with 4b two products were formed. The
products were separated by column chromatography (70% EtOAc/
pet. ether). The structures of the compounds were confirmed as
regioisomers 16 and 17 from the spectroscopic data.
17b: Brown colour solid. Yield¼95 mg (26%); mp¼294–296 ꢀC;
Rf (70% EtOAc/pet. ether) 0.21. IR (KBr): 3440.5, 2953.2, 1704.0,
1627.3, 758.1 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 2.37 (s, 3H, Me),
2.78–2.91 (m, 1H, Hb), 3.02 (s, 3H, NMe), 3.31 (s, 3H, NMe), 3.68 (d,
J¼4.1 Hz, 2H, NCH2), 3.84 (d, J¼4.4 Hz, 1H, Ha), 4.0 (d, J¼5.9 Hz, 2H,
OCH2), 4.92 (s, 1H, NH), 7.28 (d, J¼7.6 Hz, 1H, Ar), 7.54 (t, J¼7.7 Hz,
1H, Ar), 7.66 (s, 1H, Ar), 7.74 (d, J¼7.5 Hz, 1H, Ar). 13C NMR (75 MHz,
CDCl3):
d 22.01, 27.33, 28.39, 32.42, 35.49, 43.08, 54.21, 116.14,
125.22, 127.50, 129.35, 131.01, 137.82, 145.10, 150.33, 153.48, 155.06,
161.10, 166.21, 166.32. ESI-MS m/z (%): 365.3 (MþH)þ (100). Anal.
Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.37. Found: C, 65.82; H,
5.47; N, 15.45.
15a: Brownish white colour solid; Yield¼255 mg (70%);
mp¼167–168 ꢀC; Rf (70% EtOAc/pet. ether) 0.30. IR (KBr): 3011.2,
2955.8, 1704.5, 1654.7, 756.4 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
18a: Brown solid. Yield¼210 mg (55%); mp¼155–157 ꢀC; Rf (70%
EtOAc/pet. ether) 0.35. IR (KBr): 3066.2, 2924.0, 1596.6, 1519.1,
d
2.70–2.90 (m, 1H, Hb), 2.95 (s, 3H, NMe), 3.31 (s, 3H, NMe), 3.35 (s,
3H, NMe), 3.48 (d, J¼1.5 Hz, 2H, NCH2), 3.92 (d, J¼4.5 Hz, 1H, Ha),
754.1 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.65 (s, 3H, NCMe), 2.95 (s,
4.11 (d, J¼4.9 Hz, 2H, OCH2), 7.26–7.89 (m, 5H, Ar). 13C NMR
3H, NMe), 3.23–3.45 (m, 1H, Hb), 3.70 (d, J¼4.4 Hz, 2H, NCH2), 4.11
(d, J¼4.3 Hz, 2H, OCH2), 4.36 (d, J¼4.1 Hz, 1H, Ha), 7.09 (d, J¼7.3 Hz,
1H, Ar), 7.18–7.42 (m, 4H, Ar), 7.52 (d, J¼7.7 Hz, 1H, Ar), 7.63 (s, 1H,
Ar), 7.66 (d, J¼7.6 Hz, 1H, Ar), 7.82 (d, J¼8.4, 1H, Ar), 7.95 (s, 1H, Ar).
(75 MHz, CDCl3):
d 27.68, 28.25, 29.17, 32.45, 39.41, 44.22, 51.03,
115.29, 125.45, 127.31, 129.81, 130.52, 137.92, 145.69, 150.25, 153.71,
154.89, 160.21, 166.05, 166.28. ESI-MS m/z (%): 365.1 (MþH)þ (100).
Anal. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.37. Found: C,
65.84; H, 5.62; N, 15.40.
13C NMR (75 MHz, CDCl3):
d 13.49, 26.23, 31.48, 38.14, 44.42, 54.92,
96.61, 121.30, 125.21, 125.42, 127.40, 127.76, 128.33, 129.45, 130.93,
137.40, 139.03, 145.89, 148.01, 153.26, 166.47. ESI-MS m/z (%): 383.4
(MþH)þ (100). Anal. Calcd for C24H22N4O: C, 75.37; H, 5.80; N,
14.65. Found: C, 75.43; H, 5.74; N, 14.69.
15b: Brown colour solid: Yield¼245 mg (65%); mp¼187–189 ꢀC;
Rf (70% EtOAc/pet. ether) 0.27. IR (KBr): 3010.6, 2952.6, 1702.7,
1659.2, 755.8 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.39 (s, 3H, Me),

7104
B. Baruah, P.J. Bhuyan / Tetrahedron 65 (2009) 7099–7104
18b: Dark brown solid. Yield¼206 mg (52%); mp¼170–172 ꢀC; Rf
Benerjee, S.; Raha, M.; Kundu, A. P.; Basu, A.; Ghose, M.; Roy, K.; Bandyopadhyay,
S. Bioorg. Med. Chem. 2002, 10, 1687; (d) Bringmann, G.; Reichert, Y.; Kane, V.
Tetrahedron 2004, 60, 3539; (e) Kournetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M.
M. Curr. Org. Chem. 2005, 9, 141.
(70% EtOAc/pet. ether) 0.30. IR (KBr) 3064.9, 2926.7, 1589.6, 1525.0,
755.7 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.34 (s, 3H, Me), 2.65 (s,
2. (a) Corral, R. A.; Orazi, O. O. Tetrahedron Lett. 1967, 7, 583; (b) Sekar, M.; Prasad,
K. J. R. J. Nat. Prod. 1998, 61, 294; (c) Puricelli, L.; Innocenti, G.; Delle Monache, G.;
Caniato, R.; Filippini, R.; Cappelletti, E. M. Nat. Prod. Lett. 2002, 16, 95; (d) Marco,
J. L.; Carreiras, M. C. Mini-Rev. Med. Chem. 2003, 3, 518.
3. (a) Pozzo, J. L.; Samat, A.; Guglielmetti, R.; Dubest, R.; Aubard, J. Helv. Chim. Acta
1999, 80, 725; (b) Ghorab, M. M.; Adbel-Hamide, S. G.; Farrag, H. A. Acta Pol.
Pharm. 2001, 58, 175; (c) Wang, Y. G.; Lin, X.-F.; Cui, S.-U. Synlett 2004, 1175; (d)
Bowman, R. M.; Grundon, M. F.; James, K. J. J. Chem. Soc., Perkin Trans. 1 1973,
1055; (e) Morel, A. F.; Larghi, E. L. Tetrahedron: Asymmetry 2004, 15, 9; (f) Sekar,
M.; Prasad, K. J. R. J. Chem. Technol. Biotechnol. 1998, 72, 50; (g) Coscia, A. T.;
Dickerman, S. C. J. Am. Chem. Soc. 1959, 81, 3098.
4. (a) For leading references, see: Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, NY,1986; Vol. 4, p 1; (b)
Foder, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Wiley: New York, NY,1985; Vol. 3, p 1; (c) Boger, D.; Weinreb, S. M. Hetero
Diels–Alder Methodology in Organic Synthesis; Academic: San Diego, CA, 1987;
Chapter 2, p 34; (d) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57, 6099.
5. Tietze, L. F.; Racklemann, N. Pure Appl. Chem. 2004, 76, 1967.
3H, NCMe), 2.95 (s, 3H, NMe), 3.24–3.45 (m, 1H, Hb), 3.71 (d,
J¼4.6 Hz, 2H, NCH2), 4.09 (d, J¼4.9 Hz, 2H, OCH2), 4.34 (d, J¼4.2 Hz,
1H, Ha), 7.09 (d, J¼7.3 Hz, 1H, Ar), 7.15–7.41 (m, 4H, Ar), 7.60 (s, 1H,
Ar), 7.69 (t, J¼7.7 Hz, 1H, Ar), 7.82 (d, J¼7.4 Hz, 1H, Ar), 7.95 (s, 1H,
Ar). 13C NMR (75 MHz, CDCl3):
d 13.42, 21.97, 26.25, 31.48, 38.17,
44.34, 54.95, 96.60, 121.55, 125.32, 125.55, 127.38, 127.71, 128.40,
129.47, 130.94, 137.44, 139.01, 145.84, 148.11, 153.17, 166.48. ESI-MS
m/z (%): 397.5 (MþH)þ (100). Anal. Calcd for C25H24N4O: C, 75.73; H,
6.10; N, 14.13. Found: C, 75.79; H, 6.15; N, 14.02.
Acknowledgements
We thank the DST, New Delhi, for financial support. B.B. thanks
the CSIR (India) for the award of Senior Research Fellowship and
Director, NEIST, Jorhat for providing the facilities to performthework.
6. Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651.
7. (a) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John Wiley and Sons:
New York, NY, 1997; p. 1; (b) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751.
8. (a) Devi, I.; Baruah, B.; Bhuyan, P. J. Synlett 2006, 2593; (b) Kalita, P. K.; Baruah,
B.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 7779; (c) Baruah, B.; Deb, M. L.;
Bhuyan, P. J. Synlett 2007, 873.
References and notes
9. (a) Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2009, 50, 243; (b) Deb, M. L.;
Bhuyan, P. J. Synlett 2008, 325; (c) Deb, M. L.; Bhuyan, P. J. Synthesis 2008, 2891;
(d) Deb, M. L.; Baruah, B.; Bhuyan, P. J. Synthesis 2007, 286; (e) Deb, M. L.;
Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 6453.
1. (a) Elderfield, R. C. In Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley:
London, 1960; Vol. 4, Chapter 1, p 1; (b) Wright, C. W.; Addae-Kyereme, J.; Breen,
A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek, Y.; Kendrick, H.; Phillips, R. M.;
Pollet, P. L. J. Med. Chem. 2001, 44, 3187; (c) Sahu, N. P.; Pal, C.; Mandal, N. B.;