Intramolecular 1,3-dipolar cycloaddition of azomethine ylides leading to pyrido[2,3-b]quinolines

Article abstract of DOI:10.1080/00397910802401142

A convenient six-step route to the previously unknown 1H-pyrrolo[2,3-f] benzo[b][1,8]naphthyridine ring system using an intramolecular 1,3-dipolar cycloaddition of nonstabilized azomethine ylides has been described.

Full text of DOI:10.1080/00397910802401142

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Intramolecular 1,3-Dipolar
Cycloaddition of Azomethine
Ylides Leading to Pyrido[2,3-
b]quinolines
Judit Tóth a , Barbara Somfai a , Gábor Blaskó b
,
András Dancsó b , László Töke a & Miklós Nyerges a
a Research Group of the Hungarian Academy
of Sciences, Department of Organic Chemical
Technology, Technical University of Budapest,
Budapest, Hungary
b EGIS Pharmaceuticals Ltd., Budapest, Hungary
Version of record first published: 01 Jun 2009
To cite this article: Judit Tóth, Barbara Somfai, Gábor Blaskó, András Dancsó,
László Töke & Miklós Nyerges (2009): Intramolecular 1,3-Dipolar Cycloaddition of
Azomethine Ylides Leading to Pyrido[2,3-b]quinolines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:13,
2258-2270
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Synthetic Communications1, 39: 2258–2270, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802401142
Intramolecular 1,3-Dipolar Cycloaddition
of Azomethine Ylides Leading to
Pyrido[2,3-b]quinolines
1
1
ꢀ
ꢀ
ꢀ 2 ꢀ 2
Judit Toth, Barbara Somfai, Gabor Blasko, Andras Dancso,
ꢀ
1
1
ꢀ
ꢀ
ꢀ
¨
Laszlo Toke, and Miklos Nyerges
1Research Group of the Hungarian Academy of Sciences, Department of Organic
Chemical Technology, Technical University of Budapest, Budapest, Hungary
2EGIS Pharmaceuticals Ltd., Budapest, Hungary
Abstract: A convenient six-step route to the previously unknown 1H-
pyrrolo[2,3-f]benzo[b][1,8]naphthyridine ring system using an intramolecular
1,3-dipolar cycloaddition of nonstabilized azomethine ylides has been described.
Keywords: Cycloadditions, heterocycles, tandem reactions, ylides
Quinolines and their derivatives are very important in medicinal chemistry
because of their wide occurrence in natural products[1] and drugs.[2] Among
the quinolines, 2-chloro-3-formyl-quinolines (1) occupy a prominent
position because they are intermediates for further [b]-annelation of a wide
variety of rings and for various functional group interconversions.[3] Beside
the large number of quinoline derivatives, the applications of these meth-
odologies have yielded new synthetic approaches for alkaloids such as camp-
tothecin,[4] luotonin A,[5] 22-hydroxyacuminatine,[6] or nothapodytine.[7]
Recently we have described[8] the first [c]-annelation of this type of
quinoline by 1,5-electrocyclization of azomethine ylides,[9] which gave a
direct route to the otherwise hardly accessible pyrrolo[3,4-c]quinoline
ring system (2) (Scheme 1).[10]
The 2-chloro-3-formylquinolines (1) remained popular starting
compounds for the synthesis of new heterocycles using intramolecular
Received June 12, 2008.
Address correspondence to Miklos Nyerges, Servier Research Institute of
ꢀ
Medicinal Chemistry, H-1031 Budapest, Zahony u. 7. Graphisoft Park, Hungary.
E-mail: miklos.nyerges@hu.netgrs.com
ꢀ
2258

Pyrido[2,3-b]quinolines
2259
Scheme 1. Synthetic annelations to 2-chloro-3-formylquinolines.
1,3-dipolar cycloadditions of various dipole types.[11] These results
prompted us to study the related reactions of azomethine ylides, which
gives direct access to the hitherto unknown hexahydro-1H-pyrrolo[2,3-
f]benzo[b][1,8]naphthyridin-4-ones.
RESULTS AND DISCUSSION
The starting quinolines (1a–c) were prepared by the method described by
Meth-Cohn and Narine from the corresponding acetanilides (3a–c) by
treatment with the Vilsmeier reagent in a very effective domino reaction
(Scheme 2).[12]
The quinoline ketals (4a–c) were reacted with excess of benzylamine
in the absence of any solvent at 180 ꢀC to give the expected 2-benzyla-
mino-quinolines, but at the same time the ketal was also replaced by a
Scheme 2. Reagents and conditions: i) POCl3, DMF, 80 ꢀC; and ii) HOCH2-
CH2OH, PTSA, benzene, reflux.

ꢀ
J. Toth et al.
2260
Scheme 3. Reagents and conditions: i) PhCH2NH2, 180 ꢀC; ii) 5% HCl, THF, rt;
and iii) PhCH2NH2, NaOBut, Pd(OAc)2, PPh3, toluene, 180 ꢀC.
benzylimino moiety. The direct reaction of the 3-formyl-quinolines
1a–c with benzylamine under the same conditions proceeded in much
lower yield.
The 3-(benzyliminomethyl)quinolines (6a-c) were easily hydrolized to
the corresponding aldehydes under mild conditions (Scheme 3). Alterna-
tively, in one example, the palladium-catalyzed coupling of benzylamine
to ketal-protected quinoline 5c was also investigated, followed by the
hydrolytic removal of the protecting group from 8, but the overall yield
was lower coupled with longer reaction times, so we decided to use the
route that applies the neat benzylamine.
The 2-aminoquinolines 7a–c were acylated with acryloyl chloride
in the presence of 4-(dimethylamino)pyridine (DMAP) in dimethyl
formamide solution at 80 ꢀC. The nonstabilized azomethine ylides 10
were generated from the aldehydes 9a–c in refluxing toluene using the
method of decarboxylative condensation with sarcosine.[13] The azo-
methine ylides intermediates reacted via the expected intramolecular
1,3-dipolar cycloaddition[14] to the acrylamide double bond to give the
tetracyclic hexahydro-1H-pyrrolo[2,3-f]benzo[b][1,8]naphthyridin-4-ones
11a–c as products, which were isolated in acceptable yields after column
chromatography (Scheme 4). The stereochemistry of the isolated cycload-
ducts (11) were proven by nuclear Overhauser effect (NOE) experiments.

Pyrido[2,3-b]quinolines
2261
=
Scheme 4. Reagents and conditions: i) CH2 CHCOCl, Et3N, DMF, DMAP,
80ꢀC; ii) CH3NHCH2COOH, toluene, 110ꢀC.
In summary, we have explored a convenient reaction sequence that
provides a useful route to the previously unknown 1H-pyrrolo[2,3-f]
benzo[b][1,8]naphthyridin ring system using an intramolecular 1,3-
dipolar cycloaddition of nonstabilized azomethine ylides.
EXPERIMENTAL
General
Melting points were determined on a Gallenkamp apparatus and are
uncorrected. Column chromatography was performed using Merck
Kieselgel 60, 70–230 mesh, and thin-layer chromatography (TLC) on
aluminium sheets coated with Kieselgel 60 F254. Plates were stained with
anisaldehyde solution (100 ml glacial acetic acid, 2 ml conc. sulfuric acid,
and 1 ml anisaldehyde) and heated at ca. 150 ꢀC. IR spectra were obtained
on a Bruker Vector 22 FT-IR instrument. NMR spectra were obtained
on Varian Inova 500, Bruker DRX-500, and Bruker 250 instruments.
Chemical shifts are given relative to dTMS. All solvents were purified
according to standard procedures.

ꢀ
J. Toth et al.
2262
Synthesis of N-Benzyl-3-[(benzylimino)methyl]quinolin-2-amines (6a–c)
General Procedure
The corresponding 3-[10,30-dioxolane-20-yl]-2-chloroquinoline (5a–c,
20 mmol) was suspended in benzylamine (10 ml), and the reaction mixture
was heated at 180 ꢀC for 1 h under an argon atmosphere. The excess of
benzylamine was removed with vacuum distillation, and the residue
was crystallized from ether to yield the yellow product.
Data for 6a–c
N-Benzyl-3-[(benzylimino)methyl]quinolin-2-amine (6a)
Yield: 6.46 g (92%); yellow crystals; mp. 123–124 ꢀC; 1H NMR
(500 MHz, CDCl3): 9.72 (1H, br s, NH), 8.46 (1H, s, H-4), 7.82 (1H, s,
=
CH N), 7.52 (6H, m, Ar-H), 7.33 (4H, m, Ar-H), 7.21 (4H, m, Ar-H),
4.84 (2H, d, J ¼ 5.5 Hz, NHCH2-), 4.77 (2H, s, NCH2); 13C NMR
(125 MHz, CDCl3): 163.0 (CH), 147.7 (q), 142.0 (CH), 140.0 (q), 139.6
(q), 134.7 (q), 129.7 (CH), 128.7 (2 ꢁ CH), 128.6 (2 ꢁ CH), 127.9
(2 ꢁ CH), 127.2 (2 ꢁ CH), 126.4 (CH), 126.1 (CH), 125.1 (CH), 121.1
(q), 121.5 (CH), 121.3 (CH), 118.1 (q), 64.8 (CH2), 44.7 (CH2); IR
(KBr, cmꢂ1): 3220, 3061, 3017, 2859, 1635, 1600, 1571, 1536, 1499,
1451, 1412, 1394, 1164, 1141, 1016. HRMS: calcd. 351.1735 for
C24H21N3; found 351.1734. H, 6.02; C, 82.02; N, 11.96.
N-Benzyl-3-[(benzylimino)methyl]-6-methoxyquinolin-2-amine (6b)
ꢀ
1
Yield: 7.31 g (96%); yellow crystals; mp 130 C; H NMR (500 MHz,
=
CDCl3): 9.56 (1H, br s, NH), 8.47 (1H, s, H-4), 7.81 (1H, s, CH N),
7.65 (1H, d, J ¼ 8.0 Hz, H-8), 7.42 (2H, d, J ¼ 7.5 Hz, Ph-H), 7.28 (9H,
m, Ar-H), 6.93 (d, 1H, J ¼ 2.5 Hz, H-5), 4.86 (2H, d, J ¼ 5.2 Hz,
NHCH2-), 4.78 (2H, s, NCH2), 3.85 (3H, s, CH3); 13C NMR (125 MHz,
CDCl3): 162.6 (CH), 154.5 (q), 154.1 (q), 141.7 (CH), 138.9 (q), 128.6 (q),
128.5 (2 ꢁ CH), 128.4 (q), 128.3 (2 ꢁ CH), 127.8 (2 ꢁ CH), 127.7
(2 ꢁ CH), 127.5 (CH), 127.0 (CH), 126.8 (CH), 122.9 (CH), 122.4 (q),
116.8 (q), 106.5 (CH), 65.0 (CH2), 55.5 (CH3), 45.0 (CH2); IR (KBr,
cmꢂ1): 3221, 3060, 3027, 2895, 2859, 1638, 1602, 1572, 1531, 1495,
1452, 1402, 1373, 1339, 1232, 1166, 1118, 1079, 1033. HRMS: calcd.
381.1841 for C25H23N3O; found: 381.1830. H, 6.08; C, 78.71; N, 11.02;
O, 4.19.

Pyrido[2,3-b]quinolines
2263
N-Benzyl-3-[(benzylimino)methyl]-8-methylquinolin-2-amine (6c)
ꢀ
1
Yield: 6.57 g (90%); yellow crystals; mp 118 C; H NMR (500 MHz,
CDCl3): 9.67 (1H, br t, J ¼ 5.4 Hz, NH), 8.47 (1H, s, H-4), 7.84 (1H, s,
=
CH N), 7.42 (4H, m, Ar-H), 7.26 (8H, m, Ar-H), 7.06 (1H, t, J ¼ 7.3 Hz,
H-6), 4.87 (2H, d, J ¼ 5.4 Hz, NHCH2-), 4.79 (2H, s, NCH2), 2.62 (3H, s,
CH3); 13C NMR (125 MHz, CDCl3): 162.8 (CH), 154.2 (q), 147.4 (q),
142.9 (CH), 140.2 (q), 139.1 (q), 134.1 (q), 131.1 (CH), 128.5 (2 ꢁ CH),
128.3 (2 ꢁ CH), 127.8 (2 ꢁ CH), 127.6 (2 ꢁ CH), 127.0 (CH), 126.6
(CH), 125.9 (CH), 121.9 (q), 121.3 (CH), 116.3 (q), 64.9 (CH2), 44.9
(CH2), 17.9 (CH3); IR (KBr, cmꢂ1): 3201, 3028, 2941, 2906, 2869,
1641, 1618, 1579, 1531, 1494, 1469, 1452, 1415, 1397, 1375, 1335, 1250,
1176, 1077, 1026. HRMS: calcd. 365.1891 for C25H23N3; found:
365.1901. H, 6.34; C, 82.16; N, 11.50.
Synthesis of 2-(Benzylamino)quinoline-3-carbaldehydes (7a–c)
General Procedure
The corresponding N-benzyl-3-[(benzylimino)methyl]quinolin-2-amine
(6, 10 mmol) was dissolved in tetrahydrofurane (50 ml), and 5% aqueous
hydrochloric acid (10 ml) was added. The reaction mixture was stirred at
room temperature for 2 h and then water (50 ml) and ether (50 ml) were
added. The organic phase was washed with water (2 ꢁ 50 ml) and brine
(50 ml), dried over MgSO4, and evaporated in vacuo. The residue was
crystallized from aqueous ethanol.
Data for 7a–c
2-(Benzylamino)quinoline-3-carbaldehyde (7a)
Yield: 1.44 g (55%); yellow crystals; mp 144 ꢀC; 1H NMR (300MHz,
DMSOd6): 10.05 (1H, s, CHO), 8.81 (1H, s, H-4), 8.72 (1H, br s, NH),
7.91 (1H, d, J¼ 7.8 Hz, H-5), 7.74 (1H, d, J ¼ 7.5 Hz, Ph-20 and 60H), 7.45
(4H, m, Ph-H and H-6 and H-7), 7.28 (1H, d, J ¼ 7.8 Hz, H-8), 4.89 (2H,
br s, CH2); 13C NMR (125 MHz, CDCl3): 194.2 (CH), 153.3 (q), 150.1
(q), 139.0 (q), 134.2 (q), 130.0 (CH), 128.8 (q), 128.6 (2 ꢁ CH), 127.9
(CH), 127.7 (2 ꢁ CH), 127.2 (CH), 123.3 (CH), 121.6 (CH), 117.6 (CH),
44.3 (CH2); IR (KBr, cmꢂ1): 3351, 2963, 2851, 1672, 1622, 1601, 1568,
1536, 1493, 1451, 1416, 1393, 1164, 1143, 1026. HRMS: calcd. 262.1106
for C17H14N2O; found: 262.1111. H, 5.38; C, 77.84; N, 10.68; O, 6.10.

ꢀ
J. Toth et al.
2264
2-(Benzylamino)-6-methoxyquinoline-3-carbaldehyde (7b)
ꢀ
1
Yield: 1.96 g (67%); yellow crystals; mp 153 C; H NMR (300 MHz,
CDCl3): 9.89 (1H, s, CHO), 8.20 (1H, br s, NH), 8.05 (1H, s, H-4),
7.59 (1H, d, J ¼ 8.0 Hz, H-8), 7.30 (6H, m, Ph-H and H-7), 6.91 (1H, s,
H-5), 4.83 (s, 2H, NCH2), 3.83 (3H, s, OMe); 13C NMR (125 MHz,
CDCl3): 192.9 (CH), 154.7 (q), 153.3 (q), 146.8 (CH), 139.3 (q), 128.3
(2 ꢁ CH), 127.9 (q), 127.8 (CH), 127.6 (2 ꢁ CH), 126.9 (CH), 125.7
(CH), 121.9 (q), 116.9 (q), 106.4 (CH), 55.3 (CH3), 44.4 (CH2); IR
(KBr, cmꢂ1): 3417, 3268, 2965, 2676, 1682, 1615, 1588, 1514, 1479,
1461, 1400, 1378, 1347, 1292, 1236, 1209, 1171, 1134, 1024. HRMS:
calcd. 292.1211 for C18H16N2O2; found: 292.1214. H, 5.52; C, 73.95; N,
9.58; O, 10.95.
2-(Benzylamino)-8-methylquinoline-3-carbaldehyde (7c)
Yield: 1.60 g (58%); yellow crystals; mp 139–140 ꢀC; 1H NMR (500 MHz,
CDCl3): 9.74 (1H, s, CHO), 8.32 (1H, t, J ¼ 5.5 Hz, NH), 7.88 (1H, s, H-
4), 7.38 (1H, t, J ¼ 7.1 Hz, Ph-40H), 7.36 (2H, t, J ¼ 7.1 Hz, Ph-20 and
60H), 7.22 (3H, m, H-5, Ph-30 and 50H), 7.14 (1H, d, J ¼ 8.0 Hz, H-7),
6.99 (1H, t, J ¼ 8.0 Hz, H-6), 7.00 (1H, t, J ¼ 7.7 Hz, H-6), 4.78 (2H, d,
J ¼ 5.5 Hz, CH2), 2.53 (3H, s, CH3); 13C NMR (125 MHz, CDCl3):
192.8 (CH), 153.1 (q), 149.4 (q), 148.2 (CH), 139.5 (q), 134.3 (q), 133.1
(CH), 128.2 (2 ꢁ CH), 127.7 (2 ꢁ CH), 126.8 (2 ꢁ CH), 121.9 (CH),
121.4 (q), 116.6 (q), 44.4 (CH2), 17.8 (CH3); IR (KBr, cmꢂ1): 3375,
3027, 2915, 1663, 1618, 1534, 1466, 1451, 1416, 1408, 1397, 1375, 1360,
1303, 1167, 1155, 1077. HRMS: calcd. 276.1262 for C18H16N2O; found:
276.1241. H, 5.84; C, 78.24; N, 10.14; O, 5.79.
N-Benzyl-3-(1,3-dioxolan-2-yl)-8-methylquinolin-2-amine (8)
3-[10,30-Dioxolane-20-yl]-8-methyl-2-chloroquinoline (4c, 2.50 g, 10 mmol)
was dissolved in dry toluene (50 ml) and benzylamine (1.18 g, 1.21 ml,
11 mmol); sodium tert-butoxide (0.96 g, 11 mmol) and triphenylpho-
sphine (0.39 g, 1.5 mmol) were added. The reaction was flushed with
argon and kept under an argon atmosphere. Then, palladium(II) acetate
(0.18 g, 0.8 mmol) was added, and the reaction mixture was heated under
reflux for 8 h. Palladium was filtered off using a pad of Celite1. The
remaining solution was washed with water (2 ꢁ 25 ml) and brine (25 ml),
dried over MgSO4, and evaporated in vacuo. The residue was purified by
column chromatography (eluent hexane–ethyl acetate 1:1) to yield the
title product (1.50 g, 47%).

Pyrido[2,3-b]quinolines
2265
1H NMR (500 MHz, CDCl3): 7.88 (1H, s, H-4), 7.37 (3H, m, Ar-H),
7.28 (4H, m, Ar-H), 7.23 (1H, t, J ¼ 7.2 Hz, H-5), 6.05 (1H, br s, NH),
5.81 (1H, s, CH), 4.82 (2H, d, J ¼ 5.5 Hz, NHC2), 3.95 (4H, m, OCH2-
CH2O), 2.61 (3H, s, CH3); 13C NMR (125 MHz, CDCl3): 153.2 (q),
146.6 (q), 140.3 (q), 135.0 (CH), 134.0 (q), 129.7 (CH), 128.4 (2 ꢁ CH),
127.7 (2 ꢁ CH), 126.7 (CH), 125.9 (CH), 122.3 (q), 121.7 (CH), 118.6
(q), 101.9 (CH), 64.7 (2 ꢁ CH2), 45.2 (CH2), 17.8 (CH2); IR (KBr,
cmꢂ1): 3442, 3061, 2980, 2891, 1628, 1598, 1571, 1526, 1491, 1412,
1368, 1330, 1262, 1208, 1179, 1136, 1100, 1037; HRMS: Calcd:
320.1524 for C20H20N2O2; found: 320.1544. H, 6.29; C, 74.98; N, 8.74;
O, 9.99.
2-(Benzylamino)-8-methylquinoline-3-carbaldehyde (7c)
Amine (8, 0.64 g, 2 mmol) was dissolved in tetrahydrofuran (10 ml), and
5% aqueous hydrochloric acid (2 ml) was added. The reaction mixture
was stirred at room temperature for 2 h, and then water (10 ml) and ether
(10 ml) were added. The organic phase was washed with water (2 ꢁ 10 ml)
and brine (10 ml), dried over MgSO4, and evaporated in vacuo. The resi-
due was purifed by flash chromatography (eluent hexane–ethyl acetate
1:1) to yield the title product (7c, 0.29 g, 52%).
Synthesis of Acrylamides (9a–c), General Procedure
The corresponding 2-(benzylamino)quinoline-3-carbaldehyde (7,
3.5 mmol) was dissolved in dry DMF (10 ml), and 4-dimethylaminopyri-
dine (10 mg) and triethylamine (0.38 g, 0.54 ml, 3.8 mmol) were added.
The resulting solution was heated to 80 ꢀC under an argon atmosphere,
and acryloyl chloride (0.34 g, 0.31 ml, 3.8 mmol) was added dropwise.
The reaction mixture was kept at 80 ꢀC for 15 h, then water (20 ml) and
ethyl acetate (25 ml) were added. The organic phase was washed by fur-
ther portions of water (3 ꢁ 10 ml) and brine (15 ml), dried over MgSO4,
and evaporated in vacuo. The residue was purified by column chromato-
graphy (eluent hexane–ethyl acetate 1:1) to yield the title products.
Data for 9a–c
N-Benzyl-N-(3-formylquinolin-2-yl)prop-2-enamide (9a)
1
Yield: 0.49 g (44%); pale yellow oil; H NMR (300 MHz, CDCl3): 8.67
(1H, s, CHO), 8.11 (1H, s, qui-H-4), 7.96 (1H, d, J ¼ 8.0 Hz, qui-H-8),

ꢀ
J. Toth et al.
2266
7.67 (1H, t, J ¼ 8.0 Hz, qui-H-7), 7.23 (8H, m, Bn-H, H-1, qui-H-5 and 6),
6.47 (1H, d, J ¼ 16.5 Hz, H-2), 5.83 (1H, br m, PhCH2), 5.36 (2H, br m,
H-2 and PhCH2); 13C NMR (125 MHz, CDCl3): 187.7 (CH), 172.0 (q),
161.1 (q), 152.8 (q), 140.1 (CH), 132.8 (q), 130.7 (CH2), 130.4 (CH),
129.3 (CH), 128.9 (2 ꢁ CH), 128.8 (2 ꢁ CH), 128.0 (CH), 127.7 (CH),
126.5 (CH), 124.1 (q), 122.2 (CH), 120.2 (q), 53.3 (CH2); IR (KBr,
cmꢂ1): 3063, 3031, 2927, 1698, 1618, 1586, 1536, 1495, 1408, 1191,
1080, 1029. HRMS: calcd. 316.1211 for C20H16N2O2; found: 316.1211.
H, 5.10; C, 75.93; N, 8.85; O, 10.11.
N-Benzyl-N-(3-formyl-6-methoxyquinolin-2-yl)prop-2-enamide (9b)
Yield: 0.63g (52%); pale yellow oil; 1H NMR (300 MHz, CDCl3): 9.42 (1H,
s, CHO), 8.47 (1H, s, qui-H-4), 7.94 (1H, d, J ¼ 7.5 Hz, qui-H-8), 7.46 (1H,
d, J ¼ 7.5 Hz, qui-H-7), 7.19 (1H, s, qui-H-5), 7.15 (6H, m, Bn-H and H-1),
6.36 (1H, d, J ¼ 17 Hz, H-2), 5.69 (2H, br m, H-2 and PhCH2), 5.47 (1H, br
s, PhCH2), 3.82 (3H, s, OMe); 13C NMR (125MHz, CDCl3): 187.9 (CH),
171.2 (q), 166.0 (q), 159.0 (q), 150.6 (q), 146.2 (q), 138.8 (CH), 132.7
(CH), 130.8 (CH), 129.8 (CH2), 129.9 (2ꢁ CH), 128.3 (2 ꢁ CH), 127.3 (q),
126.8 (CH), 126.7 (q), 126.5 (CH), 106.0 (CH), 55.7 (CH3), 52.2 (CH2);
IR (KBr, cmꢂ1): 3352, 2998, 2924, 2879, 1697, 1665, 1613, 1542, 1464,
1412, 1257, 1192, 1112, 1084, 1055, 1025. HRMS: calcd: 346.1317 for
C21H18N2O3; found: 346.1319. H, 5.24; C, 72.82; N, 8.09; O, 13.86.
N-Benzyl-N-(3-formyl-8-methylquinolin-2-yl)prop-2-enamide (9c)
1
Yield: 0.67 g (58%); pale yellow oil; H NMR (300 MHz, CDCl3): 8.65
(1H, s, CHO), 7.85 (1H, s, qui-H-4), 7.77 (2H, m, H-1 and qui-H-4),
7.51 (2H, m, H-5 and H-6), 7.28 (5H, m Bn-H), 6.47 (1H, d, J ¼ 16.6 Hz,
H-2), 5.60 (2H, br m, H-2 and PhCH2), 5.37 (1H, br s, PhCH2), 2.76 (3H,
s, Me); 13C NMR (125 MHz, CDCl3): 182.9 (CH), 165.2 (q), 164.0 (q),
145.6 (q), 143.6 (q), 142.0 (CH), 131.6 (q), 130.4 (CH), 128.9 (CH),
128.6 (2 ꢁ CH), 128.2 (CH2), 127.8 (2 ꢁ CH), 127.2 (CH), 126.8 (CH),
125.4 (CH), 122.5 (q), 121.2 (q), 52.3 (CH2), 17.5 (CH3); IR (KBr,
cmꢂ1): 3364, 3031, 2924, 2869, 1697, 1668, 1615, 1539, 1487, 1467,
1410, 1254, 1192, 1081, 1056, 1029. HRMS: calcd. 330.1368 for
C21H18N2O2; found: 330.1360. H, 5.49; C, 76.34; N, 8.48; O, 9.69.
Intramolecular 1,3-Dipolar Cycloaddition, General Procedure
The corresponding aldehyde (9, 1 mmol) was dissolved in toluene (25 ml),
and sarcosine (0.18 g, 2 mmol) was added. The reaction mixture was

Pyrido[2,3-b]quinolines
2267
refluxed for 6 h under an argon atmosphere. The water formed was
removed by the aid of a Dean–Stark trap. After completion of the reac-
tion, the reaction mixture was filtered through a pad of Celite1 and the
solvent was evaporated in vacuo. After column chromatography (eluent
hexane–ethyl acetate 1:1), the product was crystallized from ether.
Data for 11a–c
5-Benzyl-1-methyl-2,3,3a,4,5,11b-hexahydro-1H-pyrrolo[2,3-f]
benzo[b][1,8]naphthyridin-4-one (11a)
White powder (0.23 g, 66%), mp 194–195 ꢀC; 1H NMR (250 MHz,
CDCl3): 7.83 (1H, d, J ¼ 9.2 Hz, H-7), 7.81 (1H, s, H-11), 7.63 (1H, d,
J ¼ 9.2 Hz, H-10), 7.55 (1H, t, J ¼ 9.2 Hz, H-8), 7.45 (2H, d, J ¼ 7.6 Hz,
Bn-20 and 60H), 7.33 (1H, t, J ¼ 9.2 Hz, H-9), 7.12 (3H, m, Bn-CH),
5.49 (2H, s, PhCH2), 3.15 (2H, m, H-11b and H-3a), 3.01 (1H, m,
H-2), 2.70 (1H, m, H-2), 2.26 (2H, m, H-3), 2.14 (3H, s, NMe);
13C NMR (125 MHz, CDCl3): 169.5 (q, C-4), 148.7 (q, C-5a), 145.8 (q,
C-6a), 139.0 (q, Bn-10C), 138.5 (q, C-7), 129.7 (CH, C-11), 128.3 (2 ꢁ CH,
CH, Bn-CH), 127.9 (2 ꢁ CH, Bn-CH and H-9), 126.9 (CH, H-7), 126.5
(CH, H-8), 124.9 (CH, H-6), 120.2 (q, C-10a), 64.7 (CH, C-11b), 53.8
(CH2, Bn), 44.4 (CH2, C-2), 44.0 (CH, C-3a), 39.2 (NCH3), 25.6 (CH2,
C-3); IR (KBr, cmꢂ1): 3061, 3030, 2957, 2926, 2854, 1668, 1623, 1573,
1496, 1441, 1409, 1385, 1294, 1218, 1168, 1128, 1087, 1028. HRMS:
calcd. 343.1684 for C22H21N3O; found: 343.1672. H, 6.16; C, 76.94; N,
12.24; O, 4.66.
5-Benzyl-9-methoxy-1-methyl-2,3,3a,4,5,11b-hexahydro-1H-
pyrrolo[2,3-f]benzo[b][1,8]naphthyridin-4-one (11b)
White powder (0.27 g, 72%), mp 201–203 ꢀC; 1H NMR (300 MHz,
CDCl3): 7.79 (1H, s, H-11), 7.53 (2H, d, J ¼ 7.2 Hz, Bn-20 and 60H),
7.30 (dd, 1H, J 3.0 and 9.0 Hz, H-8), 7.29 (3H, m, Bn-H), 7.17 (1H,
d, J ¼ 9.0 Hz, H-7), 7.5 (1H, d, J ¼ 3.0 Hz, H-10), 5.54 (2H, s, PhCH2),
3.90 (3H, s, OMe), 3.22 (2H, m, H-11b and H-3a), 3.15 (1H, m, H-2),
2.78 (1H, m, H-2), 2.30 (2H, m, H-3), 2.24 (3H, s, NMe); 13C NMR
(125 MHz, CDCl3): 172.0 (q, C-4), 156.8 (q, C-9), 148.4 (q, C-5a),
142.3 (q, C-6a), 138.6 (q, Bn-10C), 136.7 (q, C-10a), 129.5 (CH. C-11),
128.5 (2 ꢁ CH, Bn-C), 128.0 (2 ꢁ CH, Bn-C), 126.6 (CH, Bn-40C),
125.6 (CH, C-7), 122.0 (CH, C-8), 118.3 (q, C-11a), 105.3 (CH, C-10),
65.0 (CH, C-11b), 55.5 (OCH3), 54.1 (CH2, Bn), 44.5 (CH2, C-2), 44.2
(CH, C-3a), 39.6 (NCH3), 25.8 (CH2, C-3); IR (KBr, cmꢂ1): 3056,

ꢀ
J. Toth et al.
2268
2925, 2834, 2808, 2771, 1666, 1609, 1504, 1458, 1436, 1398, 1374, 1262,
1232, 1214, 1201, 1163, 1100, 1078, 1029. HRMS: calcd. 373.1790 for
C23H23N3O2; found: 373.1792. H, 6.21; C, 73.97; N, 11.25; O, 8.57.
5-Benzyl-1,7-dimethyl-2,3,3a,4,5,11b-hexahydro-1H-pyrrolo[2,3-f]
benzo[b][1,8]naphthyridin-4-one (11c)
White powder (0.15 g, 41%), mp 194–195 ꢀC; 1H NMR (250 MHz,
CDCl3): 7.83 (1H, s, H-11), 7.45 (5H, m, Ar-H), 7.20 (3H, m, Ar-H),
5.60 (1H, d, J ¼ 14.2 Hz, PhCH2), 5.53 (1H, d, J ¼ 14.2 Hz, PhCH2),
3.19 (1H, d, J ¼ 5.6 Hz, H-11b), 3.09 (1H, m, H-3a), 3.74 (2H, m, H-2),
2.66 (3H, s, Ar-CH3), 2.28 (2H, m, H-3), 2.17 (3H, s, NCH3); 13C
NMR (125 MHz, CDCl3): 172.3 (q, C-4), 148.9 (q, C-5a), 145.3 (q, C-
6a), 138.5 (q, Bn-10C), 138.0 (CH, C-11), 136.1 (q, C-7), 130.0 (CH, C-
8), 128.1 (2 ꢁ CH, Bn-CH), 128.0 (2 ꢁ CH, Bn-CH), 126.6 (CH, Bn-
40C), 124.9 (CH, C-10), 124.7 (CH, C-9), 117.6 (q, C-10a), 64.8 (CH,
C-11b), 54.0 (CH2, Bn), 44.8 (CH2, C-2), 44.1 (CH, C-3a), 39.4
(NCH3), 25.7 (CH2, C-3), 18.1 (CH3); IR (KBr, cmꢂ1): 3027, 2938,
2835, 2778, 1666, 1622, 1497, 1476, 1449, 1433, 1411, 1381, 1362, 1337,
1289, 1237, 1221, 1160, 1104, 1077, 1035. HRMS: calcd. 357.1841 for
C23H23N3O; found: 357.1850. H, 6.49; C, 77.28; N, 11.76; O, 4.48.
ACKNOWLEDGMENTS
This work was financially supported by the National Fund for Science
and Research, Hungary (OTKA Project No. T 046196). A grant from
the EGIS Pharmaceuticals provided to J. T. is gratefully appreciated.
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