Synthesis of azanaphthoquinone annelated pyrroles

Article abstract of DOI:10.3987/COM-98-8401

The synthesis of azanaphthoquinone annelated pyrrole derivatives is described. The [c]-annelated derivative was synthesized by reaction of an azanaphthoquinone monoketal with tosylmethyl isocyanide. The synthesis of each of the two isomeric [b]-annelated pyrrole derivatives was realized by selective acylation reactions with pyrrole. Furthermore detailed NMR spectroscopic studies (¹H, ¹³C) are published.

Full text of DOI:10.3987/COM-98-8401

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 111 – 121, Received, 19th October, 1998
SYNTHESIS OF AZANAPHTHOQUINONE ANNELATED PYRROLES
Helmut Spreitzer*, Andrea Pichler, Wolfgang Holzer, Martin Kratzel, Rita Slanz,
Alexandra Koulouri, Petra Krenn, Rita Slanz, Ulrike Parrer, and Petra Szieber
Institute of Pharmaceutical Chemistry, University of Vienna, Pharmaziezentrum,
Althanstrasse 14, A-1090 Vienna, Austria
Abstract - The synthesis of azanaphthoquinone annelated pyrrole derivatives is
described. The [c]-annelated derivative was synthesized by reaction of an
azanaphthoquinone monoketal with tosylmethyl isocyanide. The synthesis of each
of the two isomeric [b]-annelated pyrrole derivatives was realized by selective
acylation reactions with pyrrole. Furthermore detailed NMR spectroscopic studies
(1H, 13C) are published.
INTRODUCTION
In continuation of our studies1 concerning the synthesis of pharmacologically active pyrrole and isoindole
derivatives we were interested in compounds (1), (2) and (3), which should serve as starting materials in
the projected syntheses of potentially cytostatic agents. Since quinones were unsuitable starting materials
in the reaction with tosylmethyl isocyanide for the synthesis of isoindoles, we envisaged the reaction with
an appropriate monoketal for the preparation of the [c]-annelated pyrrole (1).1
O
O
O
N
NH
N
N
N
N
H
H
O
O
O
1
2
3
An efficient synthesis of the new azanaphthoquinone monoketal (5/6) had to be worked out. The
synthesis to the [b]-annelated pyrroles (2) and (3) should be realized by two regioselectively controlled

sequential acylation reactions. Moreover, for all isomeric pyrrole derivatives unambiguous assignements
of signals in the 1H and 13C-NMR spectra are presented.
RESULTS AND DISCUSSION
a) Synthesis of [c]-annelated azanaphthoquinone pyrrole (1):
The reaction of α,β-unsaturated carbonyl compounds with tosylmethyl isocyanide represents a suitable
way for the straightforward synthesis of 3,4-substituted pyrroles.1-3 To make use of this reaction type we
were in need of monoketal (5) or (6). Unfortunately established oxidation methods of 5-isoquinolinol (or
its methyl ether) with Tl(III) nitrate4 or iodobenzene bis(trifluoroacetate)5 were unsuccessful. The reaction
of 4a and b, respectively, with iodobenzene diacetate afforded the dimethyl monoketal (5) only with poor
yields. Moreover the synthesis of 5 was accomanied by the formation of isomer (7).
O
OR
R'O
OR'
.
Tl(NO ) 3H O
3 3
or
2
or
N
N
N
PhI(OOCF )
3 2
R'O
OR'
O
6
4a R = H
5
4b R = CH
O
3
OCH3
OCH3
4a,b
5
+
N
PhI(OOCH )
3 2
7
OCH3
CH3O
H3OC
OCH3
+
1. TosMIC
H /H O
Anodic Oxidation
KOH, MeOH
2
6
1
+
N
N
2. H /H O
2
OCH3
OCH3
8
9
Another way to quinone monoketals can be realized by careful hydrolysis of an appropriate diketal.
Indeed diketal (9) could be made accessible in high yields by anodic oxidation6 of 5,8-dimethoxy-
isoquinoline (8)7. Subsequent selective hydrolization8 afforded nearly quantitatively dimethyl monoketal
(6). As previously described the reaction sequence with tosylmethyl isocyanide followed by hydrolysis of
the ketal finally led to the [c]-annelated azanaphthoquinone pyrrole (1).

b) Synthesis of [b]annelated azanaphthoquinone pyrroles (2) and (3):
Of critical importance in the synthesis of 2 and 3 was the regioselectivity of the acylation reaction of the
pyrrole nucleus. Snieckus’ tandem directed metalation reaction9 could not be exploited for the synthesis
of the title compounds because neither 2- nor 3-formylpyrrole (protected as benzyl derivatives)10,11 gave
any reaction with isonicotinic acid amide to furnish 2 or 3. Other methods to achieve regioselectivity
make use of 2-carboxylate substituted pyrroles.12 But these established methods have the disadvantage of
increasing the reaction steps. A convenient approach to realize regioselectivity of the acylation of pyrrole
seemed to attach a voluminous N-protecting group which allows acylation of pyrrole selectively in the C3-
position. After cleavage of this bulky protecting group subsequently selective intramolecular acylation
reaction at C2-position should finish the synthesis of the title compounds 2 and 3. For the synthesis of 2 as
starting materials pyridine-3,4-dicarboxylic acid anhydride (10) and N-triisopropylsilyl protected pyrrole
derivative (11)13 were selected.
O
O
O
+
N
2
N
N
N
R'
Si
OR
O
O
10
11
12
R = H, R' = Si(i-C H )
3 7 3
13 R = CH , R' = Si(i-C H )
14 R = CH , R' = H
15
3
3 7 3
3
3
R = CH , R' = O SPh
2
Indeed as a consequence of the bulky triisopropylsilyl protecting group acylation with 10 occurs as
expected selectively in the C3-position of the pyrrole nucleus, thus furnishing adduct (12) free of isomers.
After preparation of the corresponding methyl ester (13) with CH2N2 and deprotection with tetrabutyl
ammonium fluoride14 (TBAF; furnishing 14) the treatment with benzenesulfonyl chloride15 afforded N-
phenyl sulfonate (15). Whereas reaction with lithium diisopropyl amide (LDA) failed, the cyclization
with 2 equivalents of lithium hexamethyldisilazide (LiHMDS)16 was successful. The careful hydrolysis17
of the N-phenyl sulfonate with K2CO3 finally led to the title compound (2). An obvious straightforward
route using phenyl sulfonated pyrrole for the reaction with anhydride (10) was unsuccessful and furnished
only an inseparable mixture of acylated pyrrole derivatives. Moreover it should be emphasized that this
methodology has the great advantage that it could be exploited with a slight modification also for the
synthesis of isomer (3). Instead of anhydride (10) we used acid chloride (16)16 thus obtaining a shift of
reactivity from the C4-carboxylate (in 10) to the C3-positioned carboxylic acid chloride (in 16). As
expected the reaction of 16 with 11 furnished C-3 acylated pyrrole (17), which was converted to the title
compound (3) in analogy as described above.

O
O
O
O
N
OCH3
Cl
N
N
+
3
N
R
Si
OCH3
16
11
17
18
19
R = Si(i-C H )
R = H
3 7 3
R = O SPh
2
EXPERIMENTAL
Melting points were detected on a Reichert-Kofler hot-stage microscope and are uncorrected. The IR
spectra were recorded on a Perkin-Elmer FTIR 1605 spectrophotometer. MS spectra were obtained on a
Hewlett Packard 5890A/5970B-MSD instrument or on a Shimadzu QP 1000 spectrometer. All NMR
spectra were recorded on a Varian Unityplus 300 spectrometer (299.95 MHz for 1H, 75.43 MHz for 13C)
at 28oC. The solvent signal was used as an internal standard which was related to TMS with δ 7.26 ppm
(1H, CDCl3), δ 2.49 ppm (1H, DMSO-d6), δ 77.0 ppm(13C, CDCl3), δ 39.5 ppm (13C, DMSO-d6),). The
digital resolutions were 0.25 Hz/data point for the 1H-NMR spectra and 0.56 Hz/data point for the broad-
13
band decoupled C-NMR spectra. Spectral and structural assignments for all compounds investigated
were achieved by combined application of standard NMR techniques as described in ref.1 Anodic
oxidations were carried aout with a Elektro-Automatic Laboratory Power Supply (Typ 2326, Viersen,
Germany). For column chromatographic separations Merck silica gel 60, 70 - 230 mesh ASTM (Nr.
1.07734) or Aluminia B aluminium oxide (ICN Biomedicals, Nr. 2072) activity grade III were used. Thin
layer chromatography was performed on silica gel 60 F254 plates (Merck-Nr. 1.05554: 0.2 mm; Merck-
Nr. 1.07734: 2.0 mm, 20 x 20 cm) or aluminium oxide 60 F254 plates (Merck-Nr. 1.05550: 0.2 mm).
8,8-Dimethoxy-5,8-dihydro-5-isoquinolinone (5) and 6,6-Dimethoxy-5,6-dihydro-5-isoquinolinone (7)
To a solution of 0.5 g (3.7 mmol) of 5-hydroxyisoquinoline in 14 mL of dry MeOH at 0oC was added 1.5
g (4.6 mmol) of iodobenzene diacetate under Ar atmosphere. After stirring for 1 h at rt the mixture was
diluted with ethyl acetate and extracted with saturated aqueous NaHCO3 solution. The formed precipitate
was filtered off by suction. The filtrate was dried with anhydrous MgSO4 and carefully concentrated at
30oC. The residue was submitted to preparative TLC (silica gel, 2 mm, eluent: ethyl acetate/light
petroleum 1/1, 1% NEt3) affording a mixture of 5 and 7 (Rf = 0.42). Resolution of 5 and 7 was achieved
by TLC (silica gel, 0.2 mm, eluent: pentane/acetone 9/1, 1% NEt3, 6 developments) affording 26 mg
(4.6%) of 5 as semicrystallinic mass and 5 mg (1 %) of 7 as colorless oil. Compound (5): IR (KBr): cm-1

2939, 2836, 1683; MS: m/z (%) 205 (M++1, 2), 175 (16), 174 (100), 146 (23), 131 (10), 77 (15), 76 (19),
50 (30); 1H-NMR (CDCl3): δ (ppm) 3.29 (s, 6H, OMe), 6.61 (d, J = 10.6 Hz, 1H, H-6), 7.05 (d, J = 10.6
Hz, H-7), 7.83 (dd, J = 5.1 Hz and 0.9 Hz, 1H, H-4), 8.82 (d, J = 5.1 Hz, 1H, H-3), 8.82 (d, J = 0.9 Hz,
1H, H-1); 13C-NMR (CDCl3): δ (ppm) 51.2 (OMe), 94.1 (C-8), 118.3 (C-4, 1J = 167.8 Hz), 131.6 (C-6, 1J
1
1
= 167.1 Hz), 133.1 (C-8a), 136.4 (C-4a), 144.4 (C-7, J = 163.0 Hz), 149.8 (C-1, J = 183.0 Hz), 150.9
1
(C-3, J = 183.1 Hz), 183.0 (C-5). HRMS: Calcd for C9H11NO3: 205.07389. Found: 205.074+0.001.
Compound (7): IR (NaCl, liquid film): cm-1 2925, 2863, 1708; MS: m/z (%) 205 (M++1, 56), 177 (80),
175 (29), 174 (100), 146 (56), 132 (38), 118 (21), 76 (25); 1H-NMR (CDCl3): δ (ppm) 3.42 (s, 6H, OMe),
6.37 (d, J = 10.3 Hz, 1H, H-7), 6.77 (d, J = 10.3 Hz, H-8), 7.73 (dd, J = 4.9 Hz and 0.7 Hz, 1H, H-4), 8.59
(d, J = 0.7 Hz, 1H, H-1), 8.70 (d, J = 4.9 Hz, 1H, H-3); 13C-NMR (CDCl3): δ (ppm) 50.5 (OMe), 92.9 (C-
6), 119.4 (C-4), 126.8 (C-8), 129.3 (C-8a), 131.5 (C-7), 134.5 (C-4a), 148.9 (C-1), 150.8 (C-3), 193.0 (C-
5). HRMS: Calcd for C9H11NO3: 205.07389. Found: 205.074±0.001.
5,5,8,8-Tetramethoxy-5,8-dihydroisoquinolinone (9)
A solution of 5.0 g (26.5 mmol) of 5,8-dimethoxyisoquinoline (8)7 in 150 mL of 1 N methanolic
potassium hydroxide was electrolyzed for 2 h (monitored by TLC, silica gel, ethyl acetate/light petroleum
7/3) at rt in an undivided electrolysis cell with Pt-electrodes with a constant potential of 30 V. Afterwards
the solvent was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution
was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo furnishing 5.56 g (84%)
of 9. The crude product can be used for the next reaction step without further purification. For
spectroscopic purposes a small quantity of samples was purified by TLC (silica gel, ethyl acetate/light
petroleum 7/3, 1% NEt3) affording a yellowish oil. IR (NaCl, liquid film): cm-1 2942, 2832, 1733, 1597;
MS: m/z (%) 220 (100), 189 (49), 174 (41), 146 (22), 131 (9), 117 (5), 103 (8), 76 (7); 1H-NMR (CDCl3):
δ (ppm) 3.20 (s, 6H, C5-OMe), 3.23 (s, 6H, C8-OMe), 6.36 (A-part of an AB-system, J = 10.9 Hz, 1H,
H-6), 6.40 (B-part of an AB-system, J = 10.9 Hz, 1H, H-7), 7.53 (dd, J = 5.2 Hz and 0.8 Hz, 1H, H-4),
8.66 (d, J = 5.2 Hz, 1H, H-3), 8.91 (d, J = 0.8 Hz, 1H, H-1); 13C-NMR (CDCl3): δ (ppm) 50.9 (C8-OMe,
1J = 142.9 Hz), 51.0 (C5-OMe, 1J = 143.1 Hz), 94.1 (C-5), 94.5 (C-8), 120.1 (C-4), 131.2 (C-6, 1J = 163.2
Hz, 2J = 1.6 Hz), 131.3 (C-8a), 132.1 (C-7, 1J = 163.2 Hz, 2J = 1.6 Hz), 144.3 (C-4a), 149.1 (C-1), 149.7
(C-3). HRMS: Calcd for C12H14NO3 (M+-OCH3): 220.0974. Found: 220.0974±0.001. Anal. Calcd for
C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 61.87; H, 6.67; N, 5.33.
5,5-Dimethoxy-5,5-dihydro-8-isoquinolinone (6)
To a solution of 4.37 g (17.4 mmol) of diketal (9) in 155 mL of acetone were added 155 mL of 2%
aqueous acetic acid. After stirring for 45 min at 50oC the mixture was concentrated in vacuo and the

residue was dissolved in ether. The ethereal solution was washed with water and dried over anhydrous
MgSO4 and evaporated to afford 3.03 g (85%) of 6. The crude product can be used for the next reaction
step without further purification. For spectroscopic purposes a small sample was purified by TLC (silica
gel, ethyl acetate/light petroleum 7/3, 1% NEt3) furnishing a semicrystallinic mass. IR (NaCl, liquid film):
cm-1 2944, 2834, 1682, 1592; MS: m/z (%) 205 (M++1, 4), 174 (100), 146 (39), 131 (16), 117 (79; 103
(13), 76 (16), 50 (19); 1H-NMR (CDCl3): δ (ppm) 3.25 (s, 6H, OMe), 6.60 (d, J = 10.6 Hz, 1H, H-7), 7.01
(d, J = 10.6 Hz, 1H, H-6), 7.62 (dd, J = 5.2 Hz and 0.9 Hz, 1H, H-4), 8.87 (d, J = 5.2 Hz, 1H, H-3), 9.27
(d, J = 0.9 Hz, 1H, H-1); 13C-NMR (CDCl3): δ (ppm) 51.3 (OMe), 93.7 (C-5), 120.5 (C-4), 125.8 (C-8a),
132.4 (C-7), 143.4 (C-6), 147.4 (C-4a), 148.8 (C-1), 153.8 (C-3), 183.0 (C-8). HRMS: Calcd for
C11H11NO3: 205.07389. Found: 205.074±0.001. Anal. Calcd. for C11H11NO3.0.1H2O: C, 63.82; H, 5.45;
N, 6.77. Found: C, 63.60; H, 5.62; N, 6.41.
4,9-Dihydro-2H-pyrrolo[3,4-g]isoquinoline-4,9-dione (1)
Compound (6) (3.0 g, 14.7 mmol) and 2.88 g (14.7 mmol) of tosylmethyl isocyanide were dissolved in 18
mL of dry THF under Ar atmosphere. Under vigorous stirring 2.0 g (18.0 mmol) of potassium tert.-
butoxide in 18 mL of dry THF were added and the mixture was stirred for 18 h at rt. After addition of
water the mixture was exhaustively extracted with ethyl acetate. The combined organic extracts were
dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in 370 mL of acetone
and 46 mL of water. To this mixture 3.0 g (12 mmol) of pyridinium p-toluenesulfonate (PPTS) and 0.346
g (1.65 mmol) of pyridinum p-toluenesulfonic acid hydrate were added at rt. After stirring for 18 h the
mixture was diluted with 465 mL of ethyl acetate, washed with brine (465 mL), dried over anhydrous
MgSO4 and concentrated in vacuo. The solid residue (2.37 g) was rectified by column chromatography
→
(aluminium oxide, eluent: gradient ethyl acetate ethyl acetate/methanol 9/1) furnishing 0.963 g (33%)
of yellow crystals (mp undef. > 300oC decomp; ethyl acetate/methanol). IR (KBr): cm-1 3079, 2964,
1664, 1592; MS: m/z (%) 198 (M++1, 100), 170 (29), 142 (21), 115 (29), 87 (17), 77 (7), 66 (17), 50 (28);
1H-NMR (DMSO-d6): δ (ppm) 7.76 and 7.80 (AB-system, J = 1.6 Hz, each 1H, H-1 and H-3)18,7.92 (dd,
J = 4.9 Hz and 0.8 Hz, 1H, H-8), 9.01 (d, J = 4.9 Hz, 1H, H-7), 9.25 (d, J = 0.8 Hz, 1H, H-5), 12.70 (br s,
1H, NH); 13C-NMR (DMSO-d6): δ (ppm) 118.9 (C-8, 1J = 168.2 Hz, 2J = 8.9 Hz, 4J = 1.5 Hz), 121.3 (C-
3a and C-9a), 123.1 (1J = 192.4 Hz, 3J = 7.2 Hz) and 124.1 (1J = 192.4 Hz, 3J = 7.2 Hz) (C-1 and C-3),18
127.8 (C-4a), 140.6 (C-8a), 148.3 (C-5, 1J = 183.4 Hz, 3J = 11.4 Hz), 154.7 (C-7, 1J = 182.5 Hz, 2J = 3.2
3
Hz, J = 11.8 Hz), 178.4 (C-9), 179.0 (C-4). HRMS: Calcd for C11H6N2O2: 198.0429. Found:
198.043±0.001. Anal. Calcd for C11H6N2O2.0.3H2O: C, 64.90; H, 3.27; N, 13.76. Found: C, 64.91; H,
3.26; N, 13.58.

Methyl 4-[[1-(1,1,1-Triisopropylsilyl)-1H-3-pyrrolyl]carbonyl]nicotinate (13)
To a suspension of 17.6 g (132 mmol) of aluminium trichloride in 377 mL of dry CH2Cl2 was added
under Ar atmosphere 9.84 g (66 mmol) of pyridine-3,4-dicarboxylic acid anhydride (10). After stirring for
30 min at rt a solution of 4.1 g (18.3 mmol) of 1-(1,1,1-triisopropylsilyl)-1H-pyrrole in 75 mL of dry
CH2Cl2 was added dropwise and the stirring was continued for further 18 h at rt. Afterwards the mixture
was cooled to 0oC and hydrolyzed by addition of crushed ice. The resulting thick mass was diluted with
water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over
anhydrous MgSO4 and concentrated in vacuo thus affording 6.77 g (27%) of acid (12) of mp 163-165oC
(water). The crude acid was suspended in methanol and treated at rt by dropwise addition with an ethereal
solution of diazomethane. After complete reaction the mixture was evaporated to dryness. The residue
was dissolved in CH2Cl2 and extracted with water. After drying over anhydrous MgSO4 the organic
solvent was evaporated under diminished pressure. Yield 6.6 g (94 %). A sample was purified for
spectroscopic purposes by TLC (silica gel, ethyl acetate/light petroleum) thus obtaining colorless crystals
of mp 140-141oC (ethyl acetate/light petroleum). IR: cm-1 1723,1645, 1585. MS: m/z (%) 386 (M+, 3),
343 (11), 198 (100), 170 (17), 142 (52), 115 (36), 94 (27), 77 (34). 1H-NMR (CDCl3): δ (ppm) 1.07 (d, J
= 7.5 Hz, 18H, C-Me), 1.42 (septet, J = 7.5 Hz, 3H, CH of isopropyl), 3.69 (s, 3H, OMe), 6.61 (dd, J =
2.9 Hz and 1.5 Hz, 1H, pyrrole H-4), 6.76 (dd, J = 2.9 Hz and 2.1 Hz, 1H, pyrrole H-5), 7.07 (dd, J = 2.1
Hz and 1.5 Hz, 1H, pyrrole H-2), 7.37 (dd, J = 5.0 Hz and 0.7 Hz, 1H, pyridine H-5), 8.82 (d, J = 5.0 Hz,
13
pyridine H-6), 9.18 (d, J = 0.7 Hz, 1H, pyridine H-2); C-NMR (CDCl3): δ (ppm) 11.5 (CHMe2), 17.6
(CHMe2), 52.3 (OMe), 111.3 (pyrrole C-4), 121.6 (pyridine C-5), 124.2 (pyridine C-3), 126.2 (pyrrole C-
5), 127.1 (pyrrole C-3), 131.5 (pyrrole C-2), 149.7 (pyridine C-4), 151.2 (pyridine C-2), 153.0 (pyridine
C-6), 165.4 (COO), 189.0 (CO). HRMS: Calcd for C21H30N2O3Si: 386.2026. Found: 386.203±0.005.
Anal. Calcd for C21H30N2O3Si: C, 65.25; H, 7.82; N, 7.25. Found: C, 65.08; H, 7.64; N, 7.36.
Methyl 4-(1H-3-pyrrolylcarbonyl)nicotinate (14)
A solution of 6.6 g (17 mmol) of 13 in 125 mL dry acetonitrile was added under Ar atmosphere to 17 mL
(17 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF by drowise addition. After stirring
for 5 min the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous MgSO4
and concentrated in vacuo thus obtaining 7.19 g residue (containing a mixture of 14 and
triisopropylsilanol). Purification for spectroscopic purposes was carried out by TLC (silica gel, ethyl
acetate/light petroleum 6/4) affording colorless crystals of mp 151-152oC (ethyl acetate/light petroleum).
IR (KBr): cm-1 3252, 1729, 1633; MS: m/z (%) 231 (M++1, 1), 230 (M+, 9), 199 (3), 95 (6), 94 (100), 78
(2), 66(14), 61 (2); 1H-NMR (DMSO-d6): δ (ppm) 3.66 (s, 3H, OMe), 6.44 (m, 1H, pyrrole H-4), 6.89 (m,
1H, pyrrole H-5), 7.15 (m, 1H, pyrrole H-2), 7.47 (d, J = 4.9 Hz, 1H, pyridine H-5), 8.84 (d, J = 4.9 Hz,

1H, pyridine H-6), 9.03 (s, 1H, pyridine H-2), 11.62 (br s, 1H, NH); 13C-NMR (DMSO-d6): δ (ppm) 52.3
(OMe), 108.1 (pyrrole C-4), 120.7 (pyrrole C-5), 121.7 (pyridine C-5), 123.8 (pyrrole C-3), 123.9
(pyridine C-3), 126.5 (pyrrole C-2), 149.2 (pyridine C-4), 150.2 (pyridine C-2), 153.0 (pyridine C-6),
165.2 (COO), 187.8 (CO). HRMS: Calcd for C12H10N2O3: 230.06914. Found: 230.069±0.005. Anal.
Calcd for C12H10N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C, 62.35; H, 4.41; N, 11.96.
Methyl 4-[[1-phenylsulfonyl-1H-3-pyrrolyl]carbonyl]nicotinate (15)
To a vigorously stirred mixture of 7.19 g of the residue of the previously described reaction and 0.577 g
(1.7 mmol) of tetrabutyl ammoniumsulfate in 8.5 mL of 50% aqueous NaOH and 85 mL of CH2Cl2 was
added under Ar-atmosphere at rt a solution of 5.28 g (29.9 mmol) of benzenesulfonyl chloride in 8.5 mL
of CH2Cl2 by dropwise addition. After stirring for 30 min the mixture was diluted with CH2Cl2 and
washed with water. Drying over anhydrous MgSO4 and concentration in vacuo afforded crude 18 which
was purified by column chromatography (silica gel, ethyl acetate/light petroleum 6/4). Yield: 4.76 g (75
%) of colorless crystals of mp 128oC (ethyl acetate/light petroleum). IR (KBr): cm-1 3125, 1726, 1669, 1584,
1550, 1372, 1178, 1076; MS: m/z (%) 370 (M+, 8), 234 (32), 141 (16), 93 (10), 78 (12), 77 (100), 69 (19);
1H-NMR (DMSO-d6): δ (ppm) 3.57 (s, 3H, OMe), 6.70 (dd, J = 3.4 Hz and 1.6 Hz, 1H, pyrrole
H-4), 7.53 (m, 2H, pyrrole H-5, pyridine H-5), 7.66 (m, 2H, Ph H-3,5), 7.75 (m, 1H, pyrrole H-2), 7.80
m, 1H, Ph H-4), 8.06 (m, 2H, Ph H-2,6), 8.90 (d, J = 5.0 Hz, pyridine H-6), 9.09 (s, 1H, pyridine H-2);
13C-NMR (DMSO): δ (ppm) 52.5 (OMe), 112.3 (pyrrole C-4), 121.6 (pyridine C-5), 123.0 (pyrrole C-5),
123.3 (pyridine C-3), 127.0 (pyrrole C-2), 127.4 (Ph C-2,6), 127.9 (pyrrole C-3), 130.2 (Ph C-3,5), 135.4
(Ph C-4), 137.0 (Ph C-1), 147.9 (pyridine C-4) 150.6 (pyridine C-2), 153.7 (pyridine C-6), 164.8 (COO),
188.4 (CO). HRMS: Calcd for C18H14O5N2S: 370.0623. Found: 370.0635±0.005. Anal. Calcd for
C18H14O5N2S: C, 58.37; H, 3.81; N, 7.56. Found: C, 58.41; H, 3.73; N, 7.38.
4,9-Dihydro-1H-pyrrolo[3,2-g]isoquinoline-4,9-dione (2)
A solution of 4.76 g (12.9 mmol) of 14 in 400 mL dry. THF was added slowly at -76oC under Ar
atmosphere to 31.8 mL (31.8 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. After
the mixture was allowed to warm up to -40oC the reaction was completed at this temperature (DC
monitoring). The solvent was distilled off under diminished pressure and the residue was treated with
saturated NH4Cl solution and extracted with ethyl acetate. The combined organic extractes were dried
over anhydrous MgSO4 and concentrated in vacuo. The residue (3.99 g, 11.8 mmol) and 3.35 g (24.2
mmol) of potassium carbonate were dissolved in 90 mL methanol/water (2/1) and refluxed for 5 h.
Subsequently, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts
were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography

(silica gel, ethyl acetate) to afford 701 mg (27 %) of yellow crystals of mp 290oC (decomp.; ethyl
acetate). IR (KBr): cm-1 3034, 2921, 1657, 1558; MS: m/z (%) 199 (M++1, 13), 198 (M+, 100), 170 (62),
142 (49), 115 (32), 114 (15), 87 (16), 78 (12); 1H-NMR (DMSO-d6): δ (ppm) 6.71 (d, J = 2.7 Hz, 1H, H-
3), 7.39 (d, J = 2.7 Hz, 1H, H-2), 7.85 (d, J = 5.0 Hz, 1H, H-5), 9.00 (d, J = 5.0 Hz, 1H, H-6), 9.15 (s, 1H,
H-8), 13.07 (br s, 1H, NH); 13C-NMR (DMSO-d6): δ (ppm) 108.3 (C-3), 118.7 (C-5), 126.0 (C-8a), 126.9
(C-3a), 128.4 (C-2), 132.0 (C-9a), 139.2 (C-4a), 147.2 (C-8), 155.2 (C-6), 174.2 (C-9), 179.3 (C-4).
HRMS: Calcd for C11H6N2O2: 198.0429. Found: 198.0434±0.005. Anal. Calcd for C11H6N2O2.0.3H2O: C,
64.90; H, 3.27; N, 13.76. Found: C, 64.73; H, 3.33; N, 13.31.
Methyl 3-[[1-(1,1,1-Triisopropylsilyl)-1H-3-pyrrolyl]carbonyl]nicotate (17)
To a suspension of 6.0 g (45 mmol) of aluminium trichloride in 124 mL of dry CH2Cl2 was added under
Ar atmosphere a solution of 4.45 g (22.3 mmol) of methyl 3-chlorocarbonyl isonicotinate (16).16 After
stirring for 10 min at rt a solution of 2.52 g (11.3 mmol) of 1-(1,1,1-triisopropylsilyl)-1H-pyrrole in 30
mL of dry CH2Cl2 was added dropwise and the stirring was continued for further 18 h at rt. Afterwards
the mixture was cooled to 0oC and hydrolyzed by addition of crushed ice. After separation of the phases
the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water,
dried over anhydrous MgSO4 and concentrated in vacuo to afford 5.50 g (79 %) of crude 17 as dark
colored oil), which can be used for the next reaction step without any further purification. A sample was
purified for spectroscopic purposes by TLC (light petroleum/ethyl acetate 7/3) affording colorless crystals
of mp 72-73oC (ethyl acetate/light petroleum). IR (KBr): 1727, 1643, 1526; MS: m/z (%) 386 (M+, 7),
343 (26), 164 (48), 131 (23), 103 (38), 84 (38), 75 (100), 59 (56); 1H-NMR (CDCl3): δ (ppm) 1.05 (d, J =
7.4 Hz, 18H, CHMe2), 1.40 (septet, J = 7.4 Hz, 3H, CHMe2), 3.67 (s, 3H, OMe), 6.65 (dd, J = 2.9 Hz and
1.5 Hz, 1H, pyrrole H-4), 6.75 (dd, J = 2.9 Hz and 2.0 Hz, 1H, pyrrole H-5), 7.10 (dd, J = 2.0 Hz and 1.5
Hz, 1H, pyrrole H-2), 7.71 (dd, J = 5.0 Hz and 0.7 Hz, 1H, pyridine H-5), 8.80 (m, 2H, pyridine H-2,
pyridine H-6); 13C-NMR (CDCl3): δ (ppm) 11.4 (CHMe2), 17.5 (CHMe2), 52.5 (OMe), 111.4 (pyrrole C-
4), 122.6 (pyridine C-5), 126.1 (pyrrole C-5), 127.8 (pyrrole C-3), 131.5 (pyrrole C-2), 136.0 (pyridine C-
3), 137.4 (pyridine C-4), 149.1 (pyridine C-2), 151.1 (pyridine C-6), 166.0 (COO), 188.5 (CO). HRMS:
Calcd for C21H30N2O3Si:386.2026. Found: 386.202±0.005. Anal. Calcd for C21H30N2O3Si: C, 65.95; H,
7.82; N, 7.25. Found: C, 64.98; H, 7.56; N, 7.21.
Methyl 3-(1H-3-pyrrolylcarbonyl)nicotinate (18)
Compound (17) (5.50 g, 14.2 mmol) was converted to 18 in the same way as described for the synthesis
of 14 to afford 3.53 g residue (containing a mixture of 18 and triisopropylsilanol). A sample was purified
for spectroscopic purposes by TLC (ethyl acetate) affording colorless crystals of mp 105-108oC (ethyl

acetate). IR (KBr): cm-1 3147, 1732, 1635, 1586; MS: m/z (%) 230 (M+, 13), 199 (4), 95 (8), 94 (100), 86
(36), 84 (52), 69 (13), 66 (19); 1H-NMR (CDCl3): δ (ppm) 3.72 (s, 3H, OMe), 6.61 (m, 1H, pyrrole H-4),
6.78 (m, 1H, pyrrole H-5), 7.09 (m, 1H, pyrrole H-2), 7.74 (d, J = 5.0 Hz, 1H, pyridine H-5), 8.77 (s, 1H,
13
pyridine H-2), 8.80 (d, J = 5.0 Hz, 1H, pyridine H-6), 9.66 (br s, 1H, NH); C-NMR (CDCl3): δ (ppm)
52.8 (OMe), 109.3 (pyrrole C-4), 120.4 (pyrrole C-5), 122.9 (pyridine C-5), 125.4 (pyrrole C-3), 126.0
(pyrrole C-2), 136.1 (pyridine C-3), 137.3 (pyridine C-4), 148.8 (pyridine C-2), 151.1 (pyridine C-6),
165.9 (COO), 188.9 (CO). HRMS: Calcd for C12H10N2O3:230.0691. Found: 230.0701±0.005. Anal. Calcd
for C12H10N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C, 62.87; H, 4.67; N, 11.92.
Methyl 3-[[1-phenylsulfonyl-1H-3-pyrrolyl]carbonyl]nicotinate (19)
The crude residue of the previously described reaction was converted to the sulfonated product (19) in the
same way as described for the synthesis of compound (15). Purification by column chromatography
(silica gel, ethyl acetate/light petroleuem 2/1) afforded 0.90 g ( 17 %) of colorless crystals of mp 119-
120oC (ethyl acetate/light petroleum). IR (KBr): cm-1 3113, 1718, 1667, 1582; MS: m/z (%) 370 (M+, 9),
1
234 (22), 141 (16), 86 (67), 84 (100), 77 (78), 59 (34); H-NMR (CDCl3): δ (ppm) 3.58 (s, 3H, OMe),
6.67 (dd, J = 3.3 Hz and 1.5 Hz, 1H, pyrrole H-4), 7.14 (dd, J = 3.3 Hz and 2.3 Hz, 1H, pyrrole H-5), 7.36
(dd, J = 2.3 Hz and 1.5 Hz, 1H, pyrrole H-2), 7.50 (m, 2H, Ph H-3,5), 7.61 (m, 1H, Ph H-4), 7.72 (d, J =
5.0 Hz, 1H, pyridine H-5), 7.84 (m, 2H, Ph H-2,6), 8.68 (s, 1H, pyridine H-2), 8.81 (d, J = 5.0 Hz, 1H,
13
pyridine H-6); C-NMR (CDCl3) δ (ppm) 53.2 (OMe), 113.1 (pyrrole C-4), 122.6 (pyrrole C-5), 123.4
(pyridine C-5), 126.4 (pyrrole C-2), 127.6 (Ph C-2,6), 129.4 (pyrrole C-3), 130.2 (Ph C-3,5), 135.1 (Ph C-
4), 137.4 and 138.1 (Ph C-1, pyridine C-3, pyridine C-4),18 149.0 (pyridine C-2), 152.3 (pyridine C-6),
165.7 (COO), 188.6 (CO). HRMS: Calcd for C18H14O5N2S: 370.0623. Found: 370.0629±0.005. Anal.
Calcd for C18H14O5N2S: C, 58.37; H, 3.81; N, 7.56. Found: C, 58.62; H, 3.97; N, 7.45.
4,9-Dihydro-1H-pyrrolo[2,3-g]isoquinoline-4,9-dione (3)
Compound (19) (0.88 g, 2.4 mmol) was converted into pyrrole derivative (3) in the same way as
described for the synthesis of compound (2). Yield: 0.305 g ( 65 %) of yellow crystals of mp 250oC
(decomp., ethyl acetate). IR (KBr): 3035, 2762, 1660, 1590; MS: m/z (%) 198 (M+, 100), 197 (79; 183
(7), 170 (34), 142 (17), 115 (11); 1H-NMR (DMSO-d6): δ (ppm) 6.69 (d, J = 2.7 Hz, 1H, H-3), 7.42 (d, J
= 2.7 Hz, 1H, H-2), 7.85 (d, J = 4.9 Hz, 1H, H-8), 8.99 (d, J = 4.9 Hz, 1H, H-7), 9.13 (s, 1H, H-5), 13.09
(br s, 1H, NH); 13C-NMR (DMSO-d6): δ (ppm) 108.2 (C-3, 1J = 177.4 Hz, 2J = 8.5 Hz), 118.4 (C-8, 1J =
168.4 Hz, 2J = 9.1 Hz, 4J = 1.5 Hz), 126.2 (C-4a), 127.1 (C-3a), 129.0 (C-2, 1J = 189.4 Hz, 2J = 8.3 Hz),
131.9 (C-9a), 138.9 (C-8a), 147.4 (C-5, 1J = 183.5 Hz, 3J = 11.5 Hz), 155.1 (C-7, 1J = 183.0 Hz, 2J = 3.1

3
Hz, J = 11.8 Hz), 173.4 (C-9), 180.0 (C-4). HRMS: Calcd for C11H6N2O2:198.0429. Found: 198.0435
±0.005. Anal. Calcd for C11H6N2O2: C, 66.67; H, 3.05; N, 14.14. Found: C, 66.37; H, 3.29; N, 13.98.
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18. Assignments of the indicated resonances within one spectrum may be interchanged.