Synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester and its isomer 1-oxo-2,9-dihydro-1H-β-carboline-4-carboxylic acid ethyl ester

Article abstract of DOI:10.1016/S0040-4020(02)01197-3

4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester was obtained when TosMIC was reacted with 3-methylene-oxindole acetic acid ethyl ester. An alternative synthesis to this pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions. A β-carboline, isomeric with the pyrroloquinolone, was synthesised utilizing a tosylimine.

Full text of DOI:10.1016/S0040-4020(02)01197-3

Tetrahedron 58 (2002) 9179–9185
Synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carboxylic acid ethyl ester and its isomer 1-oxo-2,9-dihydro-1H-b-
carboline-4-carboxylic acid ethyl ester
*
Jan Bergman and Stanley Rehn
¨ ¨
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute, and Sodertorn University College, Novum Research Park,
SE-141 57 Huddinge, Sweden
Received 18 July 2002; revised 29 August 2002; accepted 19 September 2002
Abstract—4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester was obtained when TosMIC was reacted with
3-methylene-oxindole acetic acid ethyl ester. An alternative synthesis to this pyrroloquinolone was performed via a reduction of a 2,3,4-
trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions. A b-carboline,
isomeric with the pyrroloquinolone, was synthesised utilizing a tosylimine. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
including cleavage of the oxindole moiety.8 Several
reactions of this type are known like the Bedford cleavage9
and the ready conversion of the O-acetate of isatine-3-oxime
to 2-isocyanatobenzonitrile and N, N0-bis (2-cyanophenyl)
urea10 as well as the conversion of 3,3,5,7-tetranitro-
oxindole to 3,5,7-trinitroindazole.11
Several spiro derivatives of oxindole, such as the alkaloid
horsfiline,1 1, and spirotryprostatin A,2 2, have pharmaco-
logically interesting properties such as cell cycle inhibition
at the G2/M phase. The ring systems of the horsfiline,
spiropyrrolidinyloxindole and the related pyrroloquinolones
3–5 (Fig. 1) have attained great interest and these tricyclic
structures form the core structure of a number of
biologically significant molecules. One recent well-
published example is martinelline 73 containing a [3,2-c]
fused pyrrole moiety. Jones et al.4 have synthesized [3,2-c]
3 and [3,4-c] 4 fused pyrroloquinolones by utilising an
intramolecular aryl radical cyclisation route. Nevertheless,
very few synthetic procedures leading to pyrrolo[2,3-
c]quinolones 5 have been reported, although this ring
system does occur as moieties in certain alkaloids.5 Very
recently Kafka et al. have reported the preparation of some
derivatives of 5, notably 6.6
2. Results and discussion
The product (74% yield) from the reaction between
oxindole 8a and TosMIC had the composition
C14H12N2O3. The 1H NMR contained, in addition to a
1,2-disubstituted benzene ring and an ethoxycarbonyl
group, three signals (two NH and a CH at 7.98 ppm).
With this information the pyrroloquinolone 14a (Scheme 1)
was proposed and the rationalization in Scheme 1 was
outlined. An initial Michael addition would lead to adduct
11, following the outlined pathway (a) in Scheme 1. After
loss of p-toluenesulfinate cyclisation would give compound
12. Cleavage of the oxindole moiety, promoted by the basic
conditions, results in compound 13, which recyclises to the
pyrroloquinolone 14. Using the corresponding methyl ester
8b, prepared in the same manner as the ethyl ester 8a, we
obtained the methyl ester pyrroloquinolone 14b in 52%
yield. When oxindole 8c12 was treated under the same
conditions as above, a related structure, 14c, was isolated in
79% yield. At the same time an alternative structure, namely
the b-carboline 15 can be discussed, which might be formed
via adduct 11, followed by ring closure and proton shift to
yield the hypothetical molecule 16, which might yield the
epoxide 17 via valence tautomerism (Scheme 1). The
We felt that the readily available (from isatin and triethyl
phosphonoacetate)7 compound 8a (Scheme 1) and
p-toluenesulfonylmethyl isocyanide (TosMIC) might give
rise to interesting heterocyclic spiro compounds. The ester
8a has been used for preparation of several spiro oxindoles,
such as 9 and 10 (Fig. 2). At the drawing board we
speculated that the spiro derivative 12 (Scheme 1) might be
obtained. However we also realized that the very structure
of 12 might render it sensitive to secondary reactions
Keywords: pyrroloquinolone; TosMIC; b-carboline; tosylimine.
*
Corresponding author. Tel.: þ46-8-608-9204; fax: þ46-8-608-1501;
e-mail: jabe@cnt.ki.se
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01197-3

9180
J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
Figure 1.
Scheme 1.

J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
9181
Figure 2.
Figure 3.
epoxide 17 opens and finally tautomerises to the b-carboline
15.
refluxed in DMF containing H4NOAc and a catalytic
amount of p-toluenesulfonic acid, lactonisation to the
reported17 indolopyrone 21a occurred. Whereas Mashelkar
and Usgaonkar reported a melting point of 808C, we found
that 21a decomposed at 2408C, which correlates better to
compound 21b, which melts at 2208C, reported by the same
authors.18 To avoid the acidity a dimethylvinylamino group
was introduced using N,N-dimethylformamide dimethyl
acetal, DMFDMA, but unfortunately this reagent also
simultaneously methylated19 the indole nitrogen to yield
22. From this reaction we also isolated the known
N-methylated diethylester 19b20 in 23% yield. When
compound 22 was refluxed in DMF with ammonium acetate
as a source of ammonia, the b-carboline 23 could be isolated
in 42% yield. To avoid methylation of the indole nitrogen a
new strategy was developed. Thus the tosyl imidate 2421
was now used as source of the C–N fragment, which after a
nucleophilic attack from the diethyl ester 19a had an effect
on the 2-carbethoxy unit that resulted in ring closure to the
desired previously unknown fused indolo pyridone 15 in a
modest yield (20%) (Scheme 2).
When the proton NMR spectrum of the b-carboline 15 was
compared with the proton NMR spectrum of the pyrrolo-
quinolone 14a it showed the same pattern. Nevertheless, it
differed to some extent, as the NH signals in the
pyrroloquinolone 14a were farther apart than in the
b-carboline 15. The hydrogen at position 9 in pyrrolo-
quinolone 14a and the corresponding hydrogen at position 5
in b-carboline 15 resonated at 9.23 and 8.83 ppm,
respectively. The higher value for 14a indicates that the
carbonyl oxygen is closer in space to this hydrogen than for
b-carboline 15, i.e. the pyrroloquinolone is more bent than
the b-carboline.
2.1. Synthesis of the b-carboline 15
b-Carbolines are ubiquitous in nature and several synthetic
strategies have been developed over the years, owing to the
wide range of biological activity that several b-carbolines
exhibit. The most common way of preparing b-carbolines is
the Pictet–Spengler type of reaction.13 To prepare the
hitherto unknown b-carboline 15 (its regioisomer 18, Fig. 3,
is known14) it was not possible to use the Pictet–
Spengler reaction, and therefore a new approach had to be
developed. A suitable starting point for compound 15 would
be the diethyl ester 19a, available by Fischer indolisation
according to Robinson.15 To insert the desired C–N
fragment we formylated according to Rozhkov.16 When
the required ring closure to the pyridone was tried with
ammonia, this only gave the enol 20 back (after acidic work
up), which probably was due to an initial deprotonation of
the enol (Scheme 2). However, when the enol 20 was
2.2. Alternative synthesis of the pyrroloquinolone 14a
To obtain the pyrroloquinolone 14a we disconnected the
amide bond. The synthon of this retrosynthetic step is a
2,3,4-trisubstituted pyrrole, where the 2 and 4-positions
consist of carbalkoxy groups and the 3-position of an
o-nitrophenyl moiety. Reacting TosMIC with o-nitrophenyl
cinnamic acid ethyl ester 2522 (Scheme 3), prepared via a
Horner–Wadsworth–Emmons reaction, yielded the 4-(o-
nitrophenyl)-3-carbethoxy pyrrole 26. To introduce the
second carbalkoxy group on the 3,4-disubstituted pyrrole 26
several acylation reagents such as trichloroacetyl chloride,23
Scheme 2. (a) NaH, ethylformate, Et2O; (b) NH4OAc, p-TosOH, DMF, reflux; (c) DMFDMA, DMF, heat; (d) NaH, 24, Et2O.

9182
J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
by ring opening and recyclization to eventually form the
ring-expanded product 14a.
3. Experimental
3.1. General
Scheme 3. (a) TosMIC, NaH, Et2O/DMSO.
NMR spectra were recorded in DMSO-d6 solutions, unless
otherwise stated, on a Bruker DPX 300 spectrometer,
operating at 300 MHz for 1H and 75 MHz for 13C, d values
were reported in ppm and J values in Herz. IR spectra were
recorded on a Perkin–Elmer 1600 FT-IR instrument.
Melting points were determined with a Buchi melting
point B-545 apparatus and are uncorrected. Elemental
analysis were performed by H. Kolbe Mikroanalytisches
Laboratorium, Mu¨lheim an der Ruhr, Germany.
oxalyl chloride24 and trifluoroacetic acid anhydride25 were
tested. Unfortunately none of these reagents were success-
ful. We therefore concluded that the o-nitrophenyl group
together with the carbethoxy group were too electron
withdrawing for acylations to be carried out. Therefore the
2-carboxy group have to be introduced in another way.
Using the modified method of the Barton–Zard reaction,26
that starts from the a,b-unsaturated sulfone 27, a 2,3,4-
trisubstituted pyrrole can be achieved. The required sulfone
27 was obtained by Knoevenagel condensation of o-nitro-
benzaldehyde with tosylacetonitrile.27 Treating the sulfone
27 with ethyl isocyanoacetate under basic conditions
yielded the trisubstituted pyrrole 28 in 72% yield (Scheme
4). Reduction of the nitro group and an intra molecular
amide formation completed the comparatively unusual ring
system of the desired pyrroloquinolone. Using sodium
dithionite in a refluxing ethanol/water mixture, however,
yielded 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carbonitrile 29 in a lower yield (39%). Changing the
conditions to iron in refluxing acetic acid, the yield of the
pyrroloquinolone 29 increased to 65%. Hydrolysis to the
ethyl ester was performed by refluxing the pyrroloquinolone
29 for 4 h in a 1:1 mixture of sulfuric acid and ethanol,
which yielded a grey solid, that did not show any nitrile
absorption in the IR spectrum. The proton NMR of the
crude product revealed a 4:1 mixture of the acid 30 and the
desired 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carboxylic acid ethyl ester 31, which proved to be identical
in all respects with the product 14a obtained by the simple
condensation of oxindole 8a and TosMIC. The total yield of
31 according to Scheme 4 was a mearge 11% as compared
with 74% when prepared directly from oxindole 8a and
TosMIC. Furthermore the b-carboline 15 could not be
detected in the reaction mixture. This independent synthesis
thus proves that the ester 8a when treated with TosMIC
undergoes a cycloaddition to the intermediate 12a, followed
3.1.1. 3-(Ethoxycarbonyl)methylene-1,3-dihydroindole-
2-one, 8a. The title compound was obtained in 85%
(0.1 mol scale) following the excellent procedure (Horner–
Wadsworth–Emmons) given by Franke.7 Various other
inferior procedures are given in the literature.28
3.2. General procedure for the addition of TosMIC to
compounds 8a–c
A solution of KOtBu (10 mmol) in THF (70 ml) was added
to a stirred solution of 8 (10 mmol) and TosMIC (10 mmol)
in THF (35 ml). The reaction was heated to reflux and the
colour changed from orange to brown and finally to black.
After 30 min the solid formed was collected, the THF
solution was poured out on ice/water and acidified with
AcOH. A brownish solid was collected by filtration. This
crude product was recrystallized from AcOH.
3.2.1. 4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carboxylic acid ethyl ester, 14a. KOtBu (1.12 g,
10 mmol) in THF (70 ml), 8a (2.17 g, 10 mmol) and
TosMIC (1.95 g, 10 mmol) in THF (35 ml). Yield 1.90 g
(74%) as a white solid, mp 310–3118C (dec); dH 1.33 (3H, t,
J¼7.1 Hz), 4.30 (2H, q, J¼7.1 Hz), 7.21 (1H, m), 7.36–
7.43 (2H, m), 7.98 (1H, d, J¼3.2 Hz), 9.23 (1H, d,
J¼8.2 Hz), 11.67 (1H, s), 12.98 (1H, s); dC 14.3 (q), 59.8
(t), 111.1 (s), 115.9 (d), 116.7 (s), 121.5 (d), 124.8 (s), 125.5
(s), 126.4 (d), 127.3 (d), 132.9 (d), 136.0 (s), 154.7 (s), 164.0
Scheme 4. (a) Ethyl isocyanoacetate, DBU, THF, 08C; (b) Fe, AcOH, reflux; (c) EtOH/conc. H2SO4 (1:1), reflux.

J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
9183
(s); IR (KBr) 3329, 2983, 1692, 1669, 1413, 1298, 1175,
1156, 1107, 748 cm21; Anal. calcd for C14H12N2O3: C,
65.62; H, 4.72; N, 10.93. Found: C, 65.74; H, 4.78; N, 10.88.
crude product was purified by flash chromatography and
yielded 2.64 g (87%) of 20. This material was used without
further purification in the next reaction. The NMR spectrum
showed the presence of two tautomers.
3.2.2. 4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carboxylic acid methyl ester, 14b. KOtBu (0.76 g,
6.8 mmol) in THF (20 ml), 8b (1.38 g, 6.8 mmol) and
TosMIC (1.33 g, 6.8 mmol) in THF (20 ml). Yield 0.85 g
(52%) as a brownish solid, mp. 3658C (dec); dH 3.83 (3H, s),
7.21 (1H, app. t, J¼7.5 Hz), 7.36–7.43 (2H, m), 7.99 (1H,
s), 9.22 (1H, d, J¼8.0 Hz), 11.67 (1H, s), 12.99 (1H, s); dC
51.4 (q), 110.7 (s), 116.0 (d), 116.7 (s), 121.6 (d), 124.8 (s),
125.6 (s), 126.4 (d), 127.3 (d), 133.0 (d), 136.1 (s), 135.7 (s),
164.5 (s); IR (KBr) 3213, 1694, 1672, 1466, 1414, 1299,
1154, 1106, 747 cm21; Anal. calcd for C13H10N2O3: C,
64.46; H, 4.16; N, 11.56. Found: C, 64.38; H, 4.12; N, 11.48.
3.2.6. 1-Oxo-1,9-dihydro-pyrano[3,4-b]indole-4-car-
boxylic acid ethyl ester, 21a. The ester 19 (1.0 g,
3 mmol) and H4NOAc (1.02 g, 17 mmol) and catalytic
amounts of TosOH (63 mg) were refluxed for 220 min in
DMF (25 ml). Addition of ice up to the double volume
quenched the reaction. A brown-red solid (0.23 g, 27%) was
collected, mp: 2408C (dec); dH 1.36 (3H, t, J¼7.1 Hz), 4.39
(2H, q, J¼7.1 Hz), 7.24 (1H, app. t, J¼8.4 Hz), 7.49 (1H,
app. t, J¼8.3 Hz), 7.58 (1H, d, J¼8.3 Hz), 7.84 (1H, s), 8.60
(1H, d, J¼8.4 Hz), 12.77 (1H, s); dC 14.1 (q), 61.1 (t), 110.6
(s), 112.9 (d), 119.5 (s), 120.8 (d), 121.0 (s), 121.1 (s), 125.3
(d), 127.7 (d), 140.2 (s), 149.9 (d), 155.5 (s), 164.1 (s); IR
(KBr) 3923, 3272, 1728, 1695, 1289, 1069, 757 cm21; Anal.
calcd for C14H11NO4: C, 65.37; H, 4.31; N, 5.44. Found: C,
65.22; H, 4.43; N, 5.43.
3.2.3. 1-Benzoyl-3,5-dihydro-pyrrolo[2,3-c]quinolin-4-
one, 14c. KOtBu (1.12 g, 10 mmol) in THF (100 ml), 8c
(2.49 g, 10 mmol) and TosMIC (1.95 g, 10 mmol) in THF
(35 ml). Yield 2.28 g (79%) as a light brown solid, mp 308–
3098C (dec); dH 7.18 (1H, app. t, J¼8.2 Hz), 7.37–7.46 (2H,
m), 7.52–7.57 (2H, m), 7.62–7.67 (2H, m), 7.82–7.85 (2H,
m), 8.83 (1H, d, J¼7.9 Hz), 11.75 (1H, s), 13.07 (1H, s); dC
116.0 (d), 116.8 (s), 119.5 (s), 121.4 (d), 125.2 (s), 126.0 (s),
126.1 (d), 127.4 (d), 128.4 (d), 129.2 (d), 132.0 (d), 135.0
(d), 136.2 (s), 140.0 (s), 154.8 (s), 190.9 (s); IR (KBr) 3356,
2873, 1663, 1630, 1407, 1296, 1112, 884 cm21; Anal. calcd
for C18H12N2O2: C, 74.99; H, 4.20; N, 9.72. Found: C,
74.92; H, 4.25; N, 9.78.
3.2.7. 3-(2-Dimethylamino-1-ethoxycarbonyl-vinyl)-1-
methyl-1H-indole-2-carboxylic ethyl ester, 22. A solution
of the diethyl ester 19a (3.2 g, 11 mmol) in DMFDMA
(7 ml, 52 mmol) was refluxed for 28 h. After quenching
with water (200 ml) the reaction mixture was extracted
with Et2O (4£50 ml) and the combined Et2O phase was
washed with water (3£30 ml) dried (MgSO4) and
evaporated to yield a brownish oil (3.72 g). Purification by
flash chromatography gave 0.8 g of 19b and 2.17 g (56%) of
the vinylamine 22 as a brownish solid. This material
was used without further purification in the next reaction.
The NMR spectrum showed the presence of two
tautomers.
3.2.4. 1-Oxo-2,9-dihydro-1H-b-carboline-4-carboxylic
ethyl ester, 15. A solution of diethyl ester 19a (2.00 g,
7 mmol) and sulfone amide 24 (3.30 g, 14 mmol) in THF
(30 ml) was added dropwise for 1 h to a cold (08C)
suspension of NaH 60% w/w (0.44 g, 18 mmol) in THF
(10 ml). The reaction was allowed to reach rt and quenched
after 22 h by adding approximately 10 g of ice. The mixture
was brought to 08C and treated with 50% AcOH (10 ml),
extracted with CHCl3 (3£50 ml), evaporated and triturated
with hot Et2O to yield a yellow solid (0.38 g, 20%). An
analytically pure sample was obtained by recrystallization
from AcOH, mp 307–3108C (dec); dH 1.36 (3H, t,
J¼7.1 Hz), 4.37 (2H, q, J¼7.1 Hz), 7.18 (1H, app. t,
J¼8.3 Hz), 7.43 (1H, app. t, J¼8.3 Hz), 7.56 (1H, d,
J¼8.3 Hz) 7.88 (1H, s), 8.78 (1H, d, J¼8.3 Hz), 12.00 (1H,
s), 12.28 (1H, s); dC 14.2 (q), 60.3 (t), 106.45 (s), 112.4 (d),
119.7 (d), 120.3 (s), 121. 4 (s), 125.6 (d), 126.4 (d), 127.8
(s), 131.7 (d), 139.5 (s), 155.6 (s), 165.1 (s); IR (KBr) 3462,
3222, 3152, 1684, 1655, 1291, 1103, 749 cm21; Anal. calcd
for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93. Found: C,
65.69; H, 4.70; N, 10.99.
3.2.8. 9-Methyl-1-oxo-2,9-dihydro-1H-b-carboline-4-
carboxylic ethyl ester, 23. The vinylamine 22 (0.7 g,
2 mmol), H4NOAc (0.81 g, 11 mmol) and catalytic amounts
of p-TosOH (20 mg) were refluxed in DMF (10 ml) for 7
days. Ice was then added until a solid appeared and the
mixture was the subsequently cooled to 08C whereupon a
light brownish solid was collected. The solid was then
washed with ice cold EtOH (5 ml) to yield 0.24 g of 23
(42%), mp 252–2548C; dH 1.35 (3H, t, J¼7.1 Hz), 4.24
(3H, s), 4.34 (2H, q, J¼7.1 Hz), 7.22 (1H, app. t, J¼8.3 Hz),
7.50 (1H, app. t, J¼8.4 Hz), 7.61 (1H, d, J¼8.4 Hz), 7.81
(1H, s), 8.79 (1H, d, J¼8.3 Hz), 11.98 (1H, s); dC 14.2 (q),
31.0 (q), 60.4 (t), 106.3 (s), 110.2 (d), 119.9 (d), 120.3 (s),
120.9 (s), 125.8 (d), 126.3 (s), 126.7 (d), 131.9 (d), 140.6 (s),
156.3 (s), 165.9 (s); IR (KBr) 2904, 2850, 1715, 1646, 1462,
1282, 1217, 1141. 1086, 747 cm21; Anal. calcd for
C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C,
66.64; H, 5.23; N, 10.28.
3.2.5. 3-(1-Ethoxycarbonyl-2-hydroxy-vinyl)1H-indole-
2-carboxylic ethyl ester, 20. A solution of ethyl formate
(11 ml, 137 mmol) and diethyl ester 19a (2.75 g, 10 mmol)
in ether (20 ml) was added dropwise to a suspension of 95%
w/w NaH (1.65 g, 66 mmol) over 10 min. After 3.5 h MeOH
(2 ml) was added and the reaction was cooled to 08C
whereupon 50% AcOH (10 ml) was added. The mixture was
extracted with Et2O (2£50 ml) and the combined organic
phases were washed with water (50 ml) and sat. aq.
NaHCO3 (50 ml), dried (MgSO4) and evaporated. The
3.2.9. 4-(2-Nitrophenyl)-1H-pyrrole-3-carboxylic acid
ethyl ester, 26. A solution of o-nitrophenyl cinnamic acid
ethyl ester 25 (1.01 g, 4.5 mmol) and TosMIC (1.06 g,
5.5 mmol) in Et2O (30 ml) and DMSO (10 ml) was added
dropwise during 40 min to a suspension of 60% w/w NaH
(0.50 g, 12.5 mmol) in Et2O (10 ml) at 08C. Stirring was
continued for 75 min and then the reaction was quenched by
adding ice followed by 1 M KOH (40 ml). The mixture was
extracted with CHCl3 (3£30 ml), dried (MgSO4) and

9184
J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
evaporated to yield a crude product that was recrystallized
from CHCl3/hexane to yield 0.46 g (39%) of 26 as a brown
solid, mp 161–1638C; dH 1.05 (3H, t, J¼7.1 Hz), 3.96 (2H,
q, J¼7.1 Hz), 6.95 (1H, t, J¼2.3 Hz), 7.38–7.55 (3H, m),
7.66 (1H, d, J¼7.5 Hz), 7.97 (1H, d, J¼8.1 Hz), 11.64 (1H,
s); dC; 13.9 (q), 58.8 (t), 112.5 (s), 119.4 (d), 120.8 (s), 123.8
(d), 125.2 (d), 127.7 (d), 130.4 (s), 132.6 (d), 133.0 (d),
149.1 (s), 163.7 (s); IR (KBr) 3290, 1674, 1527, 1355, 1322,
1165, 1138, 752 cm21; Anal. calcd for C13H12N2O4: C,
60.00; N, 10.76. Found: C, 59.88; N, 10.63.
3.2.13. 4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-
carboxylic acid ethyl ester, 31514a. The pyrroloquino-
lone 29 (0.22 g, 1 mmol) was refluxed in a 1:1 mixture of
ethanol (15 ml) and sulfuric acid (15 ml) for 3 h 40 min,
whereupon the reaction mixture was poured out on a water-
ice mixture (150 ml) and a grey solid was collected, which
was portioned between sat. aq. NaHCO3 (50 ml) and CHCl3
(50 ml). The organic phase was then evaporated to yield
compound 31; dH 1.34 (3H, q, J¼7.1 Hz), 4.30 (2H, q,
J¼7.1 Hz), 7.21 (1H, app. t, J¼8.3 Hz), 7.38 (1H, app. t,
J¼8.2 Hz), 7.44 (1H, d, J¼8.2 Hz), 7.97 (1H, d, J¼3.3 Hz),
9.22 (1H, d, J¼8.3 Hz), 11.70 (1H, s), 13.00 (1H, s); dC 14.3
(q), 59.8 (t), 111.0 (s), 116.0 (d), 116.7 (s), 121.5 (d), 124.7
(s), 125.5 (s), 126.4 (d), 127.2 (d), 133.0 (d), 136.1 (s), 154.7
(s), 164.0 (s).
3.2.10. 3-(2-Nitrophenyl)-2-(toluene-4-sulfonyl)-acrylo-
nitrile, 27. p-Nitrobenzaldehyde (3.04 g, 20 mmol) and
tosylacetonitrile (3.93 g, 20 mmol) were dissolved in
ethanol (60 ml) and piperidine (0.5 ml) was added. After
1.5 h of reflux the mixture was allowed to cool to 258C and
light brownish needles (4.36 g, 66%) were collected. After
partial concentration a second crop 0.37 g was obtained.
Total yield: 71%, mp 152–1538C (lit.,27 1498C); dH 2.46
(3H, s), 7.61 (2H, d, J¼8.1 Hz), 7.85–7.94 (6H, m), 9.02
(1H, s); dC 21.2 (q), 111.8 (s), 117.8 (s), 125.4 (d), 126.8 (s),
128.3 (d), 130.2 (d), 130.8 (d), 133.0 (d), 134.0 (s), 134.9
(d), 146.5 (s), 147.3 (s), 153.8 (d); IR (KBr) 3421, 1524,
References
1. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B.
J. Org. Chem. 1991, 56, 6527–6530.
2. (a) Edmondson, S. D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 1138–1140. (b) Sebahar, P. R.; Williams, R. M.
J. Am. Chem. Soc. 2000, 122, 5666–5667.
1342, 1155, 735, 674, 574 cm21
.
3.2.11. 4-Cyano-3-(2-nitro-phenyl)-1H-pyrrole-2-car-
boxylic acid methyl ester, 28. DBU (2.93 g, 19 mmol)
and ethyl isocyanoacetate (1.82 g, 16 mmol) were added
dropwise during 5 min to a cold, 08C, solution of tosyl
acrylonitrile 27 (5.26 g, 16 mmol) in dry THF (60 ml). The
reaction mixture was allowed to reach room temperature
during the night. After 20 h the reaction was quenched with
1 M HCl(aq) (50 ml) and extracted with CHCl3 (50 ml). The
water phase was extracted with CHCl3 (2£50 ml) and the
combined organic phases were washed with water
(2£50 ml) and brine (100 ml), dried (MgSO4) and evapor-
ated. The crude product was recrystallized from CHCl3 to
yield a light yellow solid (3.30 g, 72%), mp: 142–1438C; dH
0.98 (3H, t, J¼7.1 Hz), 4.02 (2H, q, J¼7.1 Hz), 7.53 (1H,
dd, J¼7.6, 1.4 Hz), 7.70 (1H, td, J¼7.6, 1.4 Hz), 7.81 (1H,
td, J¼7.6, 1.3 Hz), 7.98 (1H, s), 8.12 (1H, dd, J¼8.1,
1.2 Hz), 13.03 (1H, s); dC 13.8 (q), 60.8 (t), 95.2 (s), 115.0
(s), 119.9 (s), 124.3 (d), 127.0 (s), 128.3 (s), 129.7 (d), 130.6
(d), 132.7 (d), 133.2 (d), 149.0 (s), 159.1 (s); IR (KBr) 3259,
3. (a) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson,
P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417–6419.
(b) Mahmud, H.; Lovely, C. J.; Rasika Dias, H. V.
Tetrahedron 2001, 57, 4095–4105. (c) Ma, D.; Xia, C.;
Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189–2191. (d) Frank,
´
K. E.; Aube, J. J. Org. Chem. 2000, 65, 655–666.
4. (a) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294.
(b) Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41,
8951–8955. (c) Escolano, C.; Jones, K. Tetrahedron 2002, 58,
1453–1464.
5. Eiter, K.; Nagy, M. Monatsh. 1949, 80, 607–621.
´
ˇ
6. Klasek, A.; Kafka, S.; Polis, J.; Kosmrlj, J. Nineth Blue
Danube Symposium on Heterocyclic Chemistry, June 16–20,
2000.
7. Franke, A. Liebigs Ann. Chem. 1978, 717–725.
8. Bennett, G. B.; Mason, R. B.; Shapiro, M. J. J. Org. Chem.
1978, 43, 4383–4385.
9. Bedford, G. R.; Partridge, M. W. J. Chem. Soc. 1959,
1633–1634.
2232, 1683, 1526, 1354, 1279, 1188, 1138, 1013, 759 cm21
;
10. (a) Beckmann, E.; Bark, E. J. Prakt. Chem 1922, 105,
327–349. (b) Borsche, W.; Jacobs, W. Ber. Dtsch. Chem. Ges.
1914, 47, 354–363. (c) Borsche, W.; Sander, W. Ber. Dtsch.
Chem. Ges. 1914, 47, 2815–2826. (d) Borsche, W.;
Weußmann, H.; Fritzsche, A. Ber. Dtsch. Chem. Ges. 1924,
57, 1149–1152.
Anal. calcd for C14H11N3O4: C, 58.95; H, 3.89; N, 14.73.
Found: C, 58.86; H, 3.94; N, 14.70.
3.2.12. 4-Oxo-4,5-dihydro-3-H-pyrrolo[2,3-c]quinoline-
1-carbonitrile, 29. The pyrrole derivative 28 (0.27 g,
1 mmol) and iron (0.52 g, 10 mmol) were refluxed in
AcOH (15 ml). After 40 min the blackish refluxing mixture
was filtered and allowed to cool to room temperature,
whereupon a white solid (0.13 g, 65%) of 29 was
collected, mp 361–3658C (dec); dH 7.28 (1H, app. t,
J¼7.9 Hz), 7.43 (1H, app. t, J¼8.2 Hz), 7.48 (1H, d,
J¼8.2 Hz), 8.06 (1H, s), 8.26 (1H, d, J¼7.9 Hz), 11.30 (1H,
s), 12.89 (1H, s); dC 86.3 (s), 115.5 (s), 116.4 (d), 116.5 (s),
121.6 (d), 122.3 (d), 123.4 (s), 126.5 (s), 128.0 (d), 134.6
(d), 135.0 (s), 154.3 (s); IR (KBr) 3422 (NH), 2224 (CN),
1662 (CO), 1409, 1137, 767, 740 cm21; Anal. Calcd for
C12H7N3O: C, 68.89; H, 3.37; N, 20.09. Found: C, 68.75; H,
3.46; N, 19.88.
11. Bergman, J.; Bergman, S.; Brimert, T. Tetrahedron 1999, 55,
10447–10466.
12. Lindwall, H. G.; Maclennan, J. S. J. Am. Chem. Soc. 1932, 54,
4739–4744.
13. Love, B. E. Org. Prep. Proc. Int. 1996, 28, 1–64.
14. King, H.; Stiller, E. T. J. Chem. Soc. 1937, 466–473.
15. Robinson, J. R.; Good, N. E. Can. J. Chem. 1975, 35,
1578–1581.
16. Rozhkov, V. S.; Smushkevich, Y. I.; Suvorov, N. N.
J. Heterocycl. Chem. 1980, 45–48, Transl. from Khim. Get.
Soed. 1980, 55–58.
17. Mashelkar, U. C.; Usgaonkar, R. N. Chem. Ind. (London)
1978, 35–36.

J. Bergman, S. Rehn / Tetrahedron 58 (2002) 9179–9185
9185
18. Mashelkar, U. C.; Usgaonkar, R. N. Indian J. Chem. Sect. B
1978, 16B, 782–785.
ˇ
19. (a) Stanovinik, B.; Tisler, M.; Hribar, A.; Barlin, G. B.; Brown,
24. Treibs, A.; Kreuzer, F-H. Liebigs Ann. Chem. 1969, 721,
105–115.
¨ ¨
25. Bergman, J.; Renstrom, L.; Sjoberg, B. Tetrahedron 1980, 36,
D. J. Aust. J. Chem. 1981, 34, 1729–1738. (b) Middleton, R. W.;
Monney, H.; Parrick, J. Synthesis 1984, 740–743.
20. Gray, N. M.; Dappen, M. S.; Cheng, B. K.; Cordi, A. A.;
Biesterfeldt, J. P. J. Med. Chem. 1991, 34, 1283–1292.
21. Anglada, L.; Marquez, M.; Sacristan, A.; Ortiz, J. A. Eur.
J. Med. Chem. Chim. Ther. 1988, 23, 97–100.
2505–2512.
26. (a) Barton, D. H.; Kervagoret, J.; Zard, S. Z. Tetrahedron
1990, 46, 7587–7598. (b) Fumoto, Y.; Uno, H.; Murashima,
T.; Ono, N. Heterocycles 2001, 54, 705–720.
¨ ¨
27. Koppen-Kastrop, P.; Troger, J. J. Prakt. Chem. 1922, 104,
335–367.
22. Sinisterra, J. V.; Mouloungui, Z.; Dekmas, M.; Gaser, A.
Synthesis 1985, 1097–1100.
28. Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M.; Massera, C.
Eur. J. Org. Chem. 2001, 4607–4613, and references therein.
23. Harbuck, J. W.; Rapoport, H. J. Org. Chem. 1972, 37,
3618–3622.