Synthesis of pyrrolo[3,4-c]quinolines by 1,5-electrocyclisation of non-stabilised azomethine ylides

Article abstract of DOI:10.1016/j.tet.2005.06.032

A new route to the pyrrolo[3,4-c]quinoline ring system has been developed via the 1,5-dipolar electrocyclisation reactions of azomethine ylides derived from easily available 3-formylquinoline derivatives. The intermediacy of azomethine ylides was shown by the trapping of the proposed dipoles with N-phenylmaleimide.

Full text of DOI:10.1016/j.tet.2005.06.032

Tetrahedron 61 (2005) 8199–8205
Synthesis of pyrrolo[3,4-c]quinolines by 1,5-electrocyclisation of
non-stabilised azomethine ylides
a,
a
Miklos Nyerges, Aron Pinter, Andrea Viranyi, Gabor Blasko and Laszlo Toke
a
b
a
´
*
´
´
´
´
´
´
´ ˝
aResearch Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of Budapest,
H-1521 Budapest PO Box 91, Hungary
bEGIS Pharmaceuticals Ltd, H-1475 Budapest PO Box 100, Hungary
Received 27 April 2005; revised 24 May 2005; accepted 9 June 2005
Available online 5 July 2005
Abstract—A new route to the pyrrolo[3,4-c]quinoline ring system has been developed via the 1,5-dipolar electrocyclisation reactions of
azomethine ylides derived from easily available 3-formylquinoline derivatives. The intermediacy of azomethine ylides was shown by the
trapping of the proposed dipoles with N-phenylmaleimide.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The starting quinolines (1a–c) were prepared by the method
described by Meth-Cohn from the corresponding acetani-
lides by the treatment with the Vilsmeier reagent in a single
step.11 The non-stabilized azomethine ylides 2 were
generated from these aldehydes 1a–c using the decarboxyl-
ation method.12 The reaction of 2-chloro-3-formylquino-
lines 1a–c with sarcosine in refluxing xylene gave 2-methyl-
2,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]quinolin-4-ones 4a–c
in acceptable yields via the expected 1,5-electrocyclisation
reaction accompanied by hydrolysis of the chlorine function
under the applied reaction conditions in the presence of the
water formed in the first step (Scheme 1).
Quinolines and their derivatives are very important in
medicinal chemistry because of their wide occurrence in
natural products1 and drugs.2 Among the quinolines
2-chloro-3-formyl-quinolines occupy a prominent position
as they are key intermediates for further [b]-annelation of a
wide variety of rings and for various functional group
interconversions.3 The applications of these methodologies
have yielded beside the huge number of new quinoline
derivatives new synthetic approaches for alkaloids such as
camptothecin,4 luotonin A,5 22-hydroxyacuminatine6 or
nothapodytine7 (Fig. 1).
The intermediacy of azomethine ylides 2 was shown by
trapping the proposed dipoles with N-phenylmaleimide to
give the two isomeric cycloadducts 5 and 6 (endo–exo
ratioz1:1) in quantitative yield (Scheme 1).
In this paper, we describe8 the first [c]-annelation of this
type of quinoline by 1,5-electrocyclisation of azomethine
ylides.9 This conversion gives a direct route to the otherwise
hardly accessible pyrrolo[3,4-c]quinoline ring system.10
After the successful 1,5-electrocyclisation of non-stabilised
azomethine ylides, we studied the reactivity of the
analogous ester-stabilised system generated from the
corresponding Schiff-base 7 by thermal 1,2-prototropy.13
In contrast, in these cases, no 1,5-electrocyclisation was
observed, the 7 imine remained unchanged even after a
prolonged reaction time in refluxing xylene (Scheme 2).
This result is in good agreement with our earlier
observations on the reactivity of azomethine ylides in
electrocyclisation reactions.14
Figure 1.
We performed the next series of experiments with
conjugated azomethine ylides derived from 2-phenyl-3-
formylquinolines 10a–c. In these dipoles 11 there is a
Keywords: Azomethine ylide; Cycloaddition; Electrocyclisation; Pyrroles.
*
Corresponding author. Tel.: C36 14632213; fax: C36 14633648;
e-mail: mnyerges@mail.bme.hu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.032

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M. Nyerges et al. / Tetrahedron 61 (2005) 8199–8205
Scheme 1. (i) Sarcosine (2 equiv), xylene, 140 8C; (ii) N-phenylmaleimide (1 equiv).
possibility—besides the 1,5-electrocyclisation-of a 1,7-
electrocyclic ring closure onto the phenyl group.15 The
starting material was prepared in three simple steps from
the 2-chloro-3-formyl-quinolines including a palladium
catalysed Suzuki coupling with phenylboronic acid
(Scheme 2).
be explained by the delocalisation energy difference
between the lactam products 4 and compounds 14 having
a more extended conjugation.
The intermediacy of azomethine ylides 11 was again shown
by the trapping the dipole with N-phenylmaleimide to give
the two isomeric cycloadducts 15 and 16 (ratioz1:5) in
good yield. The stereochemistry of the major isomer (16)
was proved by NOE experiments (Scheme 4).
The reaction of the resultant quinolines 10a–c with
sarcosine in refluxing xylene, gave 2-methyl-4-phenyl-1H-
pyrrolo[3,4-c]quinolines 14a–c as products in moderate
yields (Scheme 3). The 1,5-electrocyclisations in these
cases were followed by full aromatisation to the tetrahydro-
1H pyrrolo[3,4-c]quinoline 13 ring system. This slightly
different result compared to the transformation 104, may
In conclusion, we have developed a new, one-step route
from simple starting materials to the challenging pyrrolo[3,
4-c]quinoline ring system via the 1,5-dipolar electrocyclisa-
tion reaction of non-stabilised azomethine ylides.
Scheme 2. (i) EtO2CCH2NH2$HCl, Et3N, CH2Cl2, rt; (ii) HOCH2CH2OH, PTSA, benzene, reflux; (iii) PhB(OH)2, Pd(OAc)2 (cat.), K2CO3, DME, H2O;
(iv) 5% HCl, THF, 80 8C.

M. Nyerges et al. / Tetrahedron 61 (2005) 8199–8205
8201
Scheme 3. (i) Sarcosine (2 equiv), xylene, 140 8C.
Scheme 4. (i) N-Phenylmaleimide (1 equiv), sarcosine (2 equiv), xylene, 140 8C.
2. Experimental
quinolin-4-one (4a). Pale yellow powder (0.45 g, 45%);
mp 145–6 8C; [Found: C, 72.0; H, 5.9; N, 14.0. C12H12N2O
requires C 71.98; H 6.04; N 13.99%]; 1H NMR (250 MHz,
DMSO-d6): 7.79 (s, 1H, H-3), 7.66 (d, 1H, JZ8.0 Hz, H-9),
7.54 (d, 1H, JZ8.0 Hz, H-6), 7.44 (t, 1H, JZ8.0 Hz, H-8),
7.14 (t, 1H, JZ8.0 Hz, H-7), 5.77 (broad s, 1H, NH), 5.17
(broad s, 1H, H-9b), 3.69 (t, 1H, JZ9.0 Hz, H-1), 3.30 (dd,
1H, JZ2.2, 9.0 Hz, H-1), 2.99 (s, 3H, NCH3); 13C NMR
(62.5 MHz, DMSO-d6): 160.4 (q), 148.5 (q), 130.8 (CH),
128.9 (q), 128.8 (CH), 128.0 (CH), 125.4 (CH), 123.6 (q),
121.3 (CH), 66.0 (CH), 59.8 (CH2), 31.2 (CH3); IR (KBr,
cmK1): 2944, 2868, 2790, 1651, 1581, 1541, 1507, 1446,
1408, 1359, 1308, 1286, 1252, 1150, 1106, 1071, 1038,
1002.
Melting points were determined on a Gallenkamp apparatus
and are uncorrected. Column chromatography was per-
formed using Merck Kieselgel 60 70–230 mesh, TLC on
aluminium sheets coated with Kieselgel 60 F254. Plates were
stained with anisaldehyde solution (100 ml glacial acetic
acid, 2 ml cc sulphuric acid and 1 ml anisaldehyde) and
heated at ca. 150 8C. IR spectra were measured on a
NICOLET FT-IR instrument. NMR spectra were obtained
on a Brucker 250 instrument. Chemical shifts are given
relative to dTMS. All solvents were purified according to
standard procedures and the quinolines 1a–c were prepared
by the method of Meth-Cohn et al.11
2.1. The 1,5-electrocyclisation reaction of azomethine
ylides 2. General procedure
2.1.2. 2-Methyl-8-methoxy-2,4,5,9b-tetrahydro-1H-pyr-
rolo[3,4-c]quinolin-4-one (4b). Pale yellow powder
(0.56 g, 53%); mp 157–8 8C; [Found: C, 67.6; H, 6.0; N,
12.1. C13H14N2O2 requires C 67.81; H 6.13; N 12.17%]; 1H
NMR (250 MHz, DMSO-d6): 7.75 (s, 1H, H-3), 7.48 (d, 1H,
JZ8.8 Hz, H-6), 7.17 (d, 1H, JZ2.4 Hz, H-9), 7.11 (dd, 1H,
JZ2.4, 8.8 Hz, H-7), 5.74 (broad s, 1H, NH), 5.16 (broad s,
1H, H-9b), 3.79 (s, 3H, OCH3), 3.65 (dd, 1H, JZ7.8,
10.5 Hz, H-1), 3.25 (dd, 1H, JZ4.0, 10.5 Hz, H-1), 2.95 (s,
3H, NCH3);13C NMR (62.5 MHz, DMSO-d6): 159.5 (q),
154.0 (q), 143.5 (q), 130.2 (CH), 129.1 (q), 126.5 (CH),
124.0 (q), 119.2 (CH), 108.1 (CH), 66.2 (CH), 60.0 (CH2),
The corresponding 2-chloro-quinoline-3-carbaldehyde 1a–c
(5.0 mmol), was dissolved in xylene (150 ml) and sarcosine
(1.34 g; 15.0 mmol) was added. The reaction mixture was
boiled for 4 h. After the reaction was completed all the
solvents were removed in vacuo and the residue was purified
by column chromatography (eluent: chloroform–methanol
8:1 vol/vol).
2.1.1. 2-Methyl-2,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]

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M. Nyerges et al. / Tetrahedron 61 (2005) 8199–8205
55.3 (CH3), 34.4 (CH3); IR (KBr, cmK1): 3160, 3062, 2994,
2939, 2831, 1648, 1618, 1582, 1500, 1453, 1430, 1404,
1336, 1292, 1235, 1204, 1166, 1097, 1062, 1038.
diastereomers); 1H NMR (250 0MHz, CDCl3): 8.21
0
1
1
(s, ⁄2H, 0Ar-4 H), 8.11 (s, ⁄2H, Ar-4 H), 7.55–7.25 (m, 8H,
Ar-50, 6 and 70H, Ph–H), 4.39 (d, 1⁄2H, JZ6.0 Hz, H-5), 4.09
(d, 1⁄2H, JZ8.5 Hz, H-5); 3.89 (t, 1⁄2H, JZ8.5 Hz, H-5a),
3.78–3.39 (m, 31⁄2H, H-2a, H-5a, H-3), 2.77 (s, 11⁄2H, CH3),
2.75 (s, 11⁄2H, CH3), 2.28 (s, 11⁄2H, NCH3), 2.22 (s, 11⁄2H,
NCH3); IR (KBr, cmK1): 2944, 2846, 1708, 1596, 1497,
1483, 1389, 1323, 1185, 1140, 1089, 1027, 941; HRMS:
Calcd: 387.1582 for C23H21N3O3; Found: 387.1588.
2.1.3. 2,6-Dimethyl-2,4,5,9b-tetrahydro-1H-pyrrolo[3,4-
c]quinolin-4-one (4c). Pale yellow powder (0.55 g, 52%);
mp 151 8C; [Found: C, 72.9; H, 6.4; N, 13.0. C13H14N2O
requires C 72.87; H 6.59; N 13.07%]; 1H NMR (250 MHz,
DMSO-d6): 7.77 (s, 1H, H-3), 7.49 (d, 1H, JZ7.5 Hz, H-9),
7.32 (d, 1H, JZ7.5 Hz, H-7), 7.04 (t, 1H, JZ7.5 Hz, H-8),
5.80 (broad s, 1H, NH), 5.09 (broad s, 1H, H-9b), 3.66 (dd,
1H, JZ7.7, 10.2 Hz, H-1), 3.29 (dd, 1H, JZ3.9, 10.2 Hz,
H-1), 3.01 (s, 3H, NCH3), 2.56 (s, 3H, CH3); 13C NMR
(62.5 MHz, DMSO-d6): 159.7 (q), 147.1 (q), 132.5 (q),
131.1 (CH), 129.1 (CH), 128.3 (q), 126.0 (CH), 123.1 (q),
120.8 (CH), 66.1 (CH), 59.8 (CH2), 31.1 (CH3), 17.8 (CH3);
IR (KBr, cmK1): 2942, 2860, 1653, 1583, 1543, 1511, 1442,
1361, 1318, 1256, 1151, 1111, 1071, 1032, 1012.
2.2.4. Ethyl-(2-chloroquinolin-3-yl)methyleneamino-
acetate (7). The 2-chlorquinoline-3-carbaldehyde 1a
(0.38 g; 2.0 mmol) was dissolved in dry dichloromethane
(40 ml). Ethyl glycinate hydrochloride (0.28 g; 2.0 mmol),
and triethylamine (0.29 ml, 0.2 g; 2.0 mmol) and approxi-
mately 2 g anhydrous magnesium sulfate was added. The
reaction mixture was stirred at room temperature overnight.
After filtration the reaction mixture was evaporated in
vacuo. The resulted solid was suspended in ether and filtered
again. The etheral solution was evaporated in vacuo to yield
the title product as a pale yellow solid (0.52 g, 94.0%); mp
121–2 8C; 1H NMR (250 MHz, CDCl3): 8.88 (s, 1H,
CH]N), 8.78 (s, 1H, H-4), 7.99 (d, 1H, JZ8.3 Hz, H-5),
7.87 (d, 1H, JZ8.3 Hz, H-6), 7.76 (t, 1H, JZ8.3 Hz, H-8),
7.56 (t, 1H, JZ8.3 Hz, H-7), 4.53 (s, 2H, NCH2), 4.29 (q,
2H, JZ7.8 Hz, OCH2), 1.33 (t, 2H, JZ7.8 Hz, CH3); 13C
NMR (62.5 MHz, CDCl3): 169.6 (q), 161.1 (CH), 148.4 (q),
137.8 (CH), 131.7 (CH), 130.7 (q), 128.7 (CH), 128.2 (CH),
127.5 (CH), 126.9 (q), 126.6 (q), 62.0 (CH2), 61.2 (CH2),
14.1 (CH3); IR (KBr, cmK1): 2981, 2877, 1743, 1646, 1596,
1488, 1373, 1268, 1187, 1087, 1029; HRMS: Calcd:
276.0665 for C14H13N2O2Cl; Found: 276.0660.
2.2. The 1,3-dipolar cycloaddition of azomethine ylides 2
to N-phenyl-maleimide. General procedure
The corresponding 2-chloro-quinoline-3-carbaldehyde 1a–c
(1.0 mmol), was dissolved in xylene (50 ml) and N-phenyl-
maleimide (0.17 g; 1 mmol), sarcosine (0.36 g; 4.0 mmol)
was added. The reaction mixture was boiled for 2 h. After
the reaction was completed all the solvents were removed in
vacuo and the residue was purified by column chromato-
graphy (eluent: hexanes–acetone 3:1 vol/vol).
2.2.1. 5-(2-Chloroquinolin-3-yl)-1,4-diaza-2,6-dioxo-4-
methyl-1-phenyl-bicyclo[3.3.0]octane (5a and 6a).
White powder (0.35 g, 95%); 1:1 mixture of two
diastereomers; 1H NMR (250 MHz, CDCl3): 8.27
(s, 1⁄2H, Ar-40H), 8.16 (s, 1⁄2H, Ar-40H), 8.03 (d0, 1⁄2H, JZ
8.2 Hz, Ar-50H), 7.830 (d, 1⁄2H, JZ8.2 Hz, Ar-5 H), 7.77–
2.3. Synthesis of 3-[1,3-dioxolane-2-yl]-2-chloroquino-
lines (8a–c). General procedure
0
0
1
The corresponding 2-chlorquinoline-3-carbaldehyde 1a–c
(60 mmol) was suspended in benzene (600 ml), and
ethylene glycol (4.5 ml, 5.0 g; 80.0 mmol) and p-toluene-
sulphonic acid (0.57 g; 3.0 mmol) was added. The reaction
mixture was refluxed for 4 h with the continous removal of
the formed water by the aid of a Dean–Stark trap. After the
reaction was completed saturated aq sodium hydrogen
carbonate solution (150 ml) was added. The organic layer
was separated, and washed with water (2!100 ml) and
brine (100 ml), dried over magnesium sulfate, and evapor-
ated under reduced pressure to give the title products.
7.27 (m, 8H, Ar-6 , 7 and 8 H, Ph–H), 4.37 (d, ⁄2H, JZ
6.0 Hz, H-5), 4.09 (d, 1⁄2H, JZ8.5 Hz, H-5), 3.90 (t, 1⁄2H, JZ
8.5 Hz, H-5a), 3.79–3.55 (m, 31⁄2H, H-2a, H-5a, H-3), 2.29
(s, 11⁄2H, NCH3), 2.23 (s, 11⁄2H, NCH3); IR (KBr, cmK1):
3060, 2972, 2940, 2836, 2780, 1708, 1619, 1591, 1560,
1496, 1456, 1388, 1320, 1188, 1172, 1158, 1043, 1010;
HRMS: Calcd: 373.1426 for C22H19N3O3; Found:
373.1434.
2.2.2. 5-(2-Chloro-6-methoxyquinolin-3-yl)-1,4-diaza-2,
6-dioxo-4-methyl-1-phenyl-bicyclo[3.3.0]octane (5b and
6b). White powder (0.40 g, 99%); 1:1 mixture of two
diastereomers; 1H NMR (250 MHz, CDCl3): 8.17
(s, 1⁄2H, Ar-40H), 8.08 (s, 1⁄2H, Ar-40H), 7.93 (d0, 1⁄2H, JZ
8.2 Hz, Ar-80H), 7.90 (d0, 1⁄2H, JZ8.2 Hz, Ar-8 H), 7.51–
7.26 (m, 5H, Ar-60 and 7 H, Ph–H), 7.17–6.95 (m, 3H, Ar-
50H and Ph–H), 4.35 (d, 1⁄2H, JZ6.0 Hz, H-5), 4.08 (d, 1⁄2H,
JZ8.5 Hz, H-5), 3.93 (s, 11⁄2H, OCH3), 3.91 (s, 11⁄2H,
OCH3), 3.87–3.41 (m, 4H, H-2a, H-5a, H-3), 2.24 (s, 3H,
NCH3); IR (KBr, cmK1): 2964, 2794, 1714, 1621, 1589,
1498, 1453, 1498, 1385, 1326, 1262, 1231, 1183, 1096,
1025; HRMS: Calcd: 403.1532 for C23H21N3O4; Found:
403.1534.
2.3.1. 3-(1,3-Dioxolane-2-yl)-2-chloroquinoline (8a). Pale
yellow solid (14.12 g, 100%); mp 59–60 8C; 1H NMR
(250 MHz, CDCl3): 8.58 (s, 1H, H-4), 8.26 (d, 1H, JZ
8.0 Hz, H-5), 7.58–7.41 (m, 2H, H-8 and H-6), 7.17 (t, 1H,
JZ8.0 Hz, H-7), 6.08 (s, 2H, CH), 4.13–4.06 (m, 4H,
OCH2CH2O); 13C NMR (62.5 MHz, CDCl3): 148.5 (q),
137.3 (CH), 131.4 (CH), 130.9 (q), 128.8 (CH), 128.0 (CH),
127.1 (CH), 126.5 (q), 126.2 (q), 100.2 (CH), 65.3 (2!
CH2); IR (KBr, cmK1): 2894, 1619, 1599, 1568, 1493, 1456,
1368, 1327, 1138, 1101, 1037; HRMS: Calcd: 235.0400 for
C12H10NO2Cl; Found: 235.0402.
2.2.3. 5-(2-Chloro-8-methylquinolin-3-yl)-1,4-diaza-2,6-
dioxo-4-methyl-1-phenyl-bicyclo[3.3.0]octane (5c and
6c). White powder (0.37 g, 95% 1:1 mixture of two
2.3.2. 3-(1,3-Dioxolane-2-yl)-2-chloro-6-methoxy-quino-
line (8b). Pale yellow solid (15.74 g, 98%); mp 79–80 8C;
1H NMR (250 MHz, DMSO-d6): 8.20 (s, 1H, H-4), 7.81 (d,

M. Nyerges et al. / Tetrahedron 61 (2005) 8199–8205
8203
1H, JZ9.2 Hz, H-8), 7.28 (dd, 1H, JZ2.8, 9.2 Hz, H-7),
6.97 (d, 1H, JZ2.8 Hz, H-5), 6.12 (s, 1H, CH), 4.11–4.08
(m, 2H, OCH2), 4.05–4.00 (m, 2H, OCH2), 3.81 (s, 3H,
OCH3); 13C NMR (62.5 MHz, DMSO-d6): 159.5 (q), 145.8
(q), 142.7 (q), 135.7 (CH), 129.0 (q), 128.9 (CH), 128.0 (q),
123.5 (CH), 106.3 (CH), 99.7 (CH), 65.0 (2!CH2), 55.5
(CH3); IR (KBr, cmK1): 3015, 2960, 2903, 1622, 1596,
1498, 1333, 1225, 1179, 1107, 1043, 1022. HRMS: Calcd:
265.0505 for C13H12NO3Cl; Found: 265.0501.
144.0 (q), 139.4 (q), 134.3 (CH), 130.4 (CH), 129.6 (2!
CH), 129.3 (q), 128.3 (CH), 128.0 (2!CH), 123.3 (CH),
115. 5 (q), 104.9 (CH), 100.8 (CH), 65.4 (2!CH2), 55.3
(OCH3); IR (KBr, cmK1): 3056, 2999, 2964, 2888, 2861,
1622, 1602, 1492, 1462, 1364, 1223, 1168, 1085, 1029;
HRMS: Calcd: 307.1208 for C19H17NO3; Found: 307.1212.
2.4.3. 3-(1,3-Dioxolane-2-yl)-8-methyl-2-phenylquinoline
(9c). White powder (5.79 g, 99%); mp 98–9 8C; H NMR
1
(250 MHz, CDCl3): 8.51 (s, 1H, H-4), 7.84 (d, 2H, JZ
7.8 Hz, Ph-20 and 60H), 7.69 (d, 1H, JZ8.1 Hz, H-9), 7.53–
7.35 (m, 6H, H-8, H-7 and Ph–H), 5.90 (s, 1H, CH), 4.16 (m,
2H, OCH2), 3.95 (m, 2H, OCH2), 2.81 (s, 3H, CH3); 13C
NMR (62.5 MHz, CDCl3): 157.3 (q), 147.0 (q), 139.8 (q),
137.3 (q), 135.7 (CH), 130.1 (CH), 130.0 (2!CH), 128.3
(q), 128.2 (CH), 127.9 (2!CH), 126.7 (q), 126.2 (CH),
125.8 (CH), 101.0 (CH), 65.5 (2!CH2), 17.8 (CH3); IR
(KBr, cmK1): 2953, 2892, 1615, 1599, 1568, 1481, 1463,
1365, 1170, 1084, 1072, 1062, 1009; HRMS: Calcd:
291.1259 for C19H17NO2; Found: 291.1265.
2.3.3. 3-(1,3-Dioxolane-2-yl)-2-chloro-8-methyl-quino-
line (8c). Pale yellow solid (14.80 g, 99%); mp 71–2 8C;
1H NMR (250 MHz, CDCl3): 8.31 (s, 1H, H-4), 7.61 (d, 1H,
JZ8.0 Hz, H-5), 7.51 (d, 1H, JZ8.0 Hz, H-7), 7.38 (t, 1H,
JZ8.2 Hz, H-6), 6.20 (s, 1H, CH), 4.09 (m, 4H, OCH2CH2O),
2.72 (s, 3H, CH3); 13C NMR (62.5 MHz, CDCl3): 146.9 (q),
136.8 (CH), 136.4 (q), 131.0 (CH), 129.1 (q), 128.5 (q),
127.7 (q), 126.8 (CH), 125.9 (CH), 100.5 (CH), 65.5 (2!
CH2), 17.8 (CH3); IR (KBr, cmK1): 2954, 2884, 1615, 1598,
1577, 1490, 1466, 1364, 1331, 1182, 1101, 1074, 1021;
HRMS: Calcd: 249.0556 for C13H12NO2Cl; Found:
249.0549.
2.5. Hydrolysis of ketal 9a–c—General procedure
2.4. Suzuki coupling. General procedure
The corresponding ketal 9a–c (20 mmol) was dissolved in
tetrahydofuran (300 ml), water (50 ml) and concentrated
hydrochloric acid (10 ml) was added. The reaction mixture
was refluxed for an hour under argon atmosphere. After the
reaction was completed saturated aq sodium hydrocarbonate
solution (150 ml) was added. The tetrahydrofurane was
removed in vacuo and the residue was extracted with ethyl
acetate (3!50 ml). The combined organic extracts were
washed with water (2!50 ml), brine (50 ml), dried over
magnesium sulfate, and evaporated under reduced pressure
to give the product.
The corresponding acetal (20 mmol) and phenylboronic
acid (2.93 g; 24.0 mmol) was dissolved in DME (75 ml)
under argon atmosphere. Potassiom carbonate (8.3 g;
60 mmol) dissolved in water (75 ml) was added followed
by palladium(II) acetate (49 mg; 0.2 mmol) and triphenyl
phosphine (0.21 g; 0.8 mmol). The reaction mixture was
refluxed for 1 h. After the reaction was completed it was
filtered through a pad of Celite and washed with ethyl
acetate. The organic layer was separated and the aqueous
phases was extracted with ethyl acetate (2!50 ml). The
combined organic extracts were washed with saturated aq
sodium hydrogen carbonate solution (50 ml), water (2!
50 ml) and brine (50 ml), dried over magnesium sulfate, and
evaporated under reduced pressure to give the crude
product, which was purified by flash vacuum chromato-
graphy (eluent: hexanes–ethyl acetate 3:1 vol/vol).
2.5.1. 2-Phenyl-quinoline-3-carbaldehyde (10a). White
powder (3.50 g, 100%); mp 105–6 8C; [Found: C, 82.5; H,
4.8; N, 6.0. C16H11NO requires C 82.38; H 4.75; N 6.00%];
1H NMR (250 MHz, CDCl3): 10.15 (s, 1H, CHO), 8.79 (s,
1H, H-4), 8.19 (d, 1H, JZ8.2 Hz, H-8), 7.96 (d, 1H, JZ
8.2 Hz, H-5); 7.83 (t, 1H, JZ8.2 Hz, H-7), 7.68 (m, 2H,
Ph–H), 7.52 (m, 4H, H-6 and Ph–H); 13C NMR (62.5 MHz,
CDCl3): 191.3 (CH), 160.1 (q), 149.4 (q), 138.0 (CH), 137.5
(q), 132.5 (CH), 130.1 (2!CH), 129.4 (CH), 129.3 (CH),
129.25 (CH), 128.6 (2!CH), 127.5 (q), 127.3 (CH), 126.2
(q); IR (KBr, cmK1): 2861, 1693, 1614, 1584, 1552, 1485,
1370, 1156, 1121, 1075, 1008.
2.4.1. 3-(1,3-Dioxolane-2-yl)-2-phenylquinoline (9a).
White powder (5.50 g, 99%); mp 88–90 8C; 1H NMR
(250 MHz, CDCl3): 8.58 (s, 1H, H-4), 8.21 (d, 1H, JZ
8.1 Hz, H-5), 7.87 (d, 1H, JZ8.1 Hz, H-8), 7.81–7.72 (m,
3H, H-6 and Ph–H), 7.54–7.41 (m, 4H, H-7 and Ph–H), 5.88
(s, 1H, CH), 4.18–4.07 (m, 2H, OCH2), 4.00–3.90 (m, 2H,
OCH2); 13C NMR (62.5 MHz, CDCl3): 158.8 (q), 147.7 (q),
139.1 (q), 135.5 (CH), 130.2 (CH), 129.5 (2!CH), 129.0
(CH), 128.4 (q), 128.3 (CH), 127.9 (2!CH), 127.7 (CH),
126.7 (q), 126.4 (CH), 100.7 (CH), 65.3 (2!CH2); IR (KBr,
cmK1): 3058, 2953, 2889, 1621, 1599, 1558, 1489, 1442,
1368, 1267, 1169, 1128, 1082, 1018; HRMS: Calcd:
277.1102 for C18H15NO2; Found: 277.1100.
2.5.2. 6-Methoxy-2-phenylquinoline-3-carbaldehyde
(10b). White powder (3.82 g, 97%); mp 125–6 8C;
[Found: C, 77.3; H, 4.8; N, 5.2. C17H13NO2 requires C
1
77.55; H 4.98; N 5.32%]; H NMR (250 MHz, CDCl3):
10.14 (s, 1H, CHO), 8.66 (s, 1H, H-4), 8.15 (d, 1H, JZ
8.3 Hz, H-8), 7.64 (m, 2H, Ph–H), 7.51 (m, 4H, H-7 and Ph–
H), 7.16 (d, 1H, JZ1.8 Hz, H-5), 3.93 (s, 3H, OCH3); 13C
NMR (62.5 MHz, CDCl3): 191.7 (CH), 158.3 (q), 158.0 (q),
145.9 (q), 137.8 (q), 136.4 (CH), 130.9 (CH), 130.3 (2!
CH), 129.4 (CH), 128.7 (2!CH), 127.7 (q), 127.4 (q), 125.8
(CH), 125.9 (CH), 55.6 (OCH3); IR (KBr, cmK1): 3452,
3057, 2955, 2855, 1686, 1618, 1585, 1563, 1492, 1446,
1416, 1367, 1349, 1226, 1169, 1130, 1027.
2.4.2. 3-(1,3-Dioxolane-2-yl)-6-methoxy-2-phenylquino-
line (9b). White powder (5.60 g, 91%); mp 102–3 8C; H
1
NMR (250 MHz, CDCl3): 8.42 (s, 1H, H-4), 8.04 (d, 1H,
JZ7.6 Hz, H-8), 7.75 (d, 2H, JZ7.5 Hz, Ph-20 and 60H),
7.41–7.28 (m, H-7 and Ph–H), 7.01 (s, 1H, H-5), 5.81 (s, 1H,
CH), 4.02 (m, 2H, OCH2), 3.82 (m, 2H, OCH2), 3.70 (s, 3H,
OCH3); 13C NMR (62.5 MHz, CDCl3): 157.7 (q), 156.5 (q),
2.5.3. 8-Methyl-2-phenylquinoline-3-carbaldehyde (10c).

8204
M. Nyerges et al. / Tetrahedron 61 (2005) 8199–8205
White powder (3.48 g, 94%); mp 109–11 8C; [Found: C,
82.7; H, 5.4; N, 5.7. C17H13NO requires C 82.57; H 5.30; N
5.66%]; 1H NMR (250 MHz, CDCl3): 10.16 (s, 1H, CHO),
8.71 (s, 1H, H-4), 7.76–7.40 (m, 8H, Ar-H), 2.81 (s, 3H,
CH3); 13C NMR (62.5 MHz, CDCl3): 191.7 (CH), 158.5 (q),
148.5 (q), 138.2 (CH), 137.7 (q), 132.4 (CH), 132.3 (q),
130.6 (2!CH), 129.2 (CH), 128.5 (2!CH), 128.4 (q),
127.2 (CH), 127.1 (CH), 126.1 (q), 17.8 (CH3); IR (KBr,
cmK1): 2861, 2844, 1692, 1611, 1580, 1555, 1485, 1371,
1152, 1119, 1075, 1011.
(KBr, cmK1): 3025, 2951, 1528, 1473, 1446, 1428, 1356,
1329, 1216, 1140, 1089, 1073, 1059, 1020; HRMS: Calcd:
272.1313 for C19H16N2; Found: 272.1313.
2.6.4. 5-(2-Phenyl-6-methoxy-quinolin-3-yl)-1,4-diaza-
2,6-dioxo-4-methyl-1-phenyl-bicyclo[3.3.0]octane (16).
2-(6-Methoxyphenyl)-quinoline-3-carbaldehyde
10b
(0.26 g; 1 mmol) was dissolved in xylene (50 ml) and
N-phenylmaleimide (0.17 g; 1.0 mmol) and sarcosine
(0.36 g; 4.0 mmol) was added. The reaction mixture was
refluxed for 1 h. On cooling the solvent was removed in
vacuo and the residue was purified by flash chromatography
(eluent: petroleum ether–acetone 3:1) to give the main
isomer as a crystalline product as a white powder (0.30 g,
65%); mp 172–3 08C; 1H NMR (250 MHz, DMSO-d6):
8.32 (s, 1H, Ar-4 H), 8.06 (d, 1H, JZ9 Hz, Ar-80H), 7.52–
7.37 (m, 9H, Ar-H, Ph–H), 7.10 (m, 3H, Ar-H, Ph–H), 3.93
(s, 3H, OCH3), 3.84 (d, 1H, JZ7.3 Hz, H-5), 3.65–3.50
(m, 4H, H-2a, H-3, H-5a), 2.07 (s, 3H, NMe); 13C NMR
(63 MHz, DMSO-d6): 176.2 (q), 175.5 (q), 158.4 (q), 157.9
(q), 143.4 (q), 139.9 (q), 134.7 (CH), 131.4 (q), 131.0 (q),
130.8 (CH), 129.8 (2!CH), 129.1 (2!CH), 128.6 (CH),
128.1 (2!CH), 127.9 (CH), 127.8 (q), 126.4 (2!CH),
123.1 (CH), 104.5 (CH), 68.0 (CH), 57.3 (CH2), 55.5 (CH3),
54.8 (CH), 44.2 (CH), 38.6 (CH3). HRMS: Calcd: 463.1895
for C29H25N3O3; Found: 463.1898.
2.6. 1,5-Electrocyclization reactions of azomethine ylides
11 generated from 2-phenyl-quinoline-3-carbaldehydes
10a–c. General procedure
The corresponding 2-phenyl-quinoline-3-carbaldehyde
10a–c (3.0 mmol) was dissolved in xylene (50 ml) and
sarcosine (0.54 g; 6.0 mmol) was added. The reaction
mixture was refluxed until the starting aldehyde completely
disappeared (judged by TLC). All the solvent was removed
in vacuo and the residue purified by flash chromatography
(eluent: petroleum ether–acetone 3:1) to give the crystalline
product.
2.6.1. 2-Methyl-4-phenyl-pyrrolo[3,4-c]quinoline (14a).
White powder (0.46 g, 59%); mp 182–3 8C; 1H NMR
(250 MHz, CDCl3): 8.10 (dd, 1H, JZ1.9, 7.9 Hz, H-9), 7.97
(dd, 2H, JZ2.0, 8.1 Hz, Ph-20 and 60H), 7.92 (dd, 1H, JZ
1.9, 7.9 Hz, H-6), 7.53–7.38 (m, 5H, H-7, H-8 and Ph–H),
7.27 (d, 1H, JZ1.8 Hz, H-3), 7.20 (d, 1H, JZ1.8 Hz, H-1),
3.77 (s, 3H, NCH3); 13C NMR (62.5 MHz, CDCl3): 155.6
(q), 142.8 (q), 140.3 (q), 129.7 (CH), 129.0 (CH), 128.5 (2!
CH), 128.4 (2!CH), 126.0 (CH), 125.8 (CH), 122.9 (q),
122.2 (CH), 121.9 (q), 117.6 (CH), 117.5 (q), 112.8 (CH),
37.4 (CH3); IR (KBr, cmK1): 3139, 2942, 1572, 1538, 1521,
1481, 1467, 1454, 1443, 1413, 1357, 1332, 1234, 1220,
1192, 1143, 1078, 1028; HRMS: Calcd: 258.1156 for
C18H14N2; Found: 258.1156.
Acknowledgements
This work was financially supported by the National Found
for Science and Research, Hungary (OTKA Project No. T
032221). M. N. thanks the Hungarian Academy of Sciences
´
for a Bolyai J. fellowship. A grant from the Jozsef Varga
Foundation provided to A. V. is gratefully appreciated.
References and notes
2.6.2. 8-Methoxy-2-methyl-4-phenyl-pyrrolo[3,4-c]qui-
noline (14b). White powder (0.43 g, 50%); mp 188 8C; H
1
NMR (250 MHz, CDCl3): 8.01 (d, 1H, JZ9.0 Hz, H-6),
7.96 (m, 2H, Ar-H), 7.49 (m, 3H, Ar-H), 7.30 (m, 2H, Ar-
H), 7.22 (d, 1H, JZ1.8 Hz, H-1), 7.09 (dd, 1H, JZ2.5,
9.0 Hz, H-7), 3.88 (s, 3H, OCH3), 3.83 (s, 3H, NCH3); 13C
NMR (62.5 MHz, CDCl3): 157.6 (q), 157.5 (q), 153.2 (q),
140.3 (q), 137.5 (q), 131.0 (CH), 128.8 (CH), 128.4 (2!
CH), 128.3 (2!CH), 122.9 (q), 122.7 (q), 117.4 (CH), 114.9
(CH), 112.8 (CH), 103.8 (CH), 55.4 (OCH3), 37.4 (NCH3);
IR (KBr, cmK1): 3142, 3058, 2933, 2832, 1706, 1616, 1531,
1485, 1474, 1452, 1434, 1369, 1250, 1210, 1165, 1141,
1104, 1030; HRMS: Calcd: 288.1262 for C19H16N2O;
Found: 288.1263.
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