Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H) -one via palladium-catalyzed intramolecular arylation

Article abstract of DOI:10.1016/j.tet.2004.05.067

The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c] pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.

Full text of DOI:10.1016/j.tet.2004.05.067

Tetrahedron 60 (2004) 6079–6083
Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]-
quinolin-4(5H)-one via palladium-catalyzed
intramolecular arylation
a
Bruno Delest,a Jean-Yves Tisserand,a Jean-Michel Robert,a Marie-Renee Nourrisson,
,
*
´
Patricia Pinson,a Muriel Duflos,a Guillaume Le Baut,a Pierre Renardb and Bruno Pfeifferb
a
´
´
Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, 1 rue Gaston Veil, BP 53508, 44035 Nantes Cedex 01, France
´
Laboratoires SERVIER, 1 rue Carle Hebert, 92415 Courbevoie Cedex, France
b
Received 10 February 2004; revised 17 May 2004; accepted 24 May 2004
Abstract—The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by
a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded
the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule
imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.
q 2004 Published by Elsevier Ltd.
1. Introduction
Heterocycles with a plane structure have attracted con-
siderable interest in pharmaceutical research due to their
therapeutic potentialities; in the field of anticancer agents,
several drugs have been designed because their structure
allowed DNA intercalation and/or interaction with topo-
isomerases.1,2 Such molecules display a wide range of
chemical structure but among them we can distinguish
several compounds with a plane arc-shaped structure like
ellipticine3 and intoplicine,4 which are long-known topo-
isomerase II inhibitors (Fig. 1). Due to multidrug-resistance
phenomena, the search for new active structures is still a
challenge. Interestingly, amiloride (Fig. 1), a drug used as
diuretic, acts also as a topoisomerase II inhibitor.6 This
activity has been strongly correlated with the ability of the
molecule to adopt a plane arc-shaped conformation. A
similar structure has been observed in other cytotoxic
compounds like grossularines,7,8 but unfortunately, the
authors did not investigate their action against topo-
isomerases (Fig. 1). Therefore, we were interested in the
synthesis of a new tetracyclic structure inspired from
ellipticine, amiloride and grossularines: imidazo[4,5-c]-
pyrrolo[3,2-g] quinolinone (Fig. 2).
Figure 1. Topoisomerase-II inhibitors.
Keywords: Amide coupling; DCP/DMF complex; Palladium-catalyzed
intramolecular arylation; 8,9-Dihydroimidazo[4,5-c]pyrrolo[3,2-g]-
quinolin-4(5H)-one.
*
Corresponding author. Tel.: þ33-2-40-41-28-64; fax: þ33-2-40-41-28-
76; e-mail address: jmrobert@sante.univ-nantes.fr
Figure 2. Imidazo[4,5-c]pyrrolo[3,2-g]quinolines.
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.05.067

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B. Delest et al. / Tetrahedron 60 (2004) 6079–6083
Scheme 1. Retrosynthetic pathways for 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one synthesis.
Scheme 2. (i) KNO3, H2SO4; (ii) tBuCOCl, Et3N, DCE, 0 8C, 4 h; (iii) H2, Raney Ni, THF, rt, 24 h.
In this communication, we wish to report the first synthesis
of this new tetracyclic structure.
imidazole in analogy with O’Connell’s method7 (Scheme
3). 4,5-Dicyanoimidazole was alkylated with benzyl
chloride in the presence of sodium hydride in N,N-
dimethylformamide to afford compound 5 in 81% yield.
Nitrile functions of 5 were then hydrolyzed into diacid 6
with 94% yield. Compound 6 can then be selectively
decarboxylated at the 5-position to 1-benzylimidazole-4-
carboxylic acid 8 by refluxing for 4 h in N,N-dimethyl-
acetamide at 165 8C in 80% yield, whereas decarboxylation
occurred at the 4-position when heated in acetic anhydride
at 100 8C to give 7 in almost quantitative yield.
2. Results and discussion
A convergent synthesis has been selected for the preparation
of such molecules, the key-steps of this pathway being the
coupling of an aminoindoline derivative with a protected
imidazole-4-carboxylic acid, and a palladium-catalyzed
cyclization on the amide (Scheme 1).
First, the synthesis of the indoline moiety4 was performed
by nitration of indoline according to Teventev et al.5 in
concentrated sulphuric acid affording 6-nitroindoline 1 in a
95% yield (Scheme 2). The intracyclic nitrogen atom of the
pyrroline ring was then protected by a pivaloyl group, using
pivaloyl chloride and triethylamine in 1,2-dichloroethane,
providing 6-nitro-1-pivaloylindoline 2 in a 95% yield.
Reduction of the nitro group by catalytic hydrogenation
using Raney nickel as catalyst, led to 6-amino-1-pivaloyl-
indoline 3 in a quantitative yield. Bromination of compound
3, with bromine in acetic acid, afforded 6-amino-5-bromo-
1-pivaloylindoline 4 as the sole product in 91% yield.
Coupling of the indoline moiety with the imidazole residue
was achieved using a complex of phenyl dichlorophosphate
and N,N-dimethylformamide. This complex was first
described by Cramer and Winter in 1961 as an efficient
phosphorylation agent,9 and was used by Garcia et al. to
activate acids as mixed anhydrides of carboxylic and
phosphoric acids in the synthesis of esters.10 We have
been able to couple sterically hindered aromatic amines
with strongly deactivated carboxylic acids in stoichiometric
amounts at room temperature with good yields thanks to this
complex.11 This complex revealed to be non expensive and
easy to prepare. In addition, its use afforded amide 9 from
amine 4 and acid 7 in 77% yield (Scheme 4). Amidic
nitrogen in compound 9 was then methylated to afford
compound 10 in 59% yield. Compound 11 with the desired
The synthesis of the imidazole moiety has been achieved
starting from the commercially available 4,5-dicyano-
Scheme 3. (i) NaH, DMF, PhCH2Cl; (ii) NaOH 10 M; (iii) Ac2O, 100 8C; (iv) DMA, 165 8C.

B. Delest et al. / Tetrahedron 60 (2004) 6079–6083
6081
Scheme 4. (i) DCP, DMF, pyridine, CH2Cl2, rt, 2 h; (ii) NaH, MeI, DMF; (iii) Pd(OAc)2 (cat.), PPh3 (cat.), K2CO3, DMA, 170 8C.
tetracyclic structure was obtained, via palladium-catalyzed
intramolecular cyclization, in 28% yield with a catalytic
system consisting of palladium acetate and triphenylphos-
phine when heating at 170 8C in N,N-dimethylacetamide in
the presence of potassium carbonate.
(200 mL), extracted with dichloromethane (200 mL),
washed with water (100 mL), dried over sodium sulfate,
filtered and evaporated. The residue was purified by column
chromatography over silicagel eluting with dichloro-
methane to give 2 (5.56 g, 95%). Mp 138 8C. IR (KBr,
1
cm21): 1646, 1519, 1347. H NMR (CDCl3, 250 MHz) d
1.38 (s, 9H), 3.24 (t, 2H, 3JHH¼8.1 Hz), 4.35 (t, 2H, 3JHH
¼
3
3
3. Summary
8.1 Hz), 7.28 (d, 1H, JHH¼8.2 Hz), 7.88 (dd, 1H, JHH
¼
4
4
8.2 Hz, JHH¼2.1 Hz), 9.04 (d, 1H, JHH¼2.1 Hz). 13C
NMR (CDCl3, 250 MHz) d 27.6, 29.2, 40.3, 49.9, 113.2,
119.1, 124.1, 138.1, 145.7, 147.7, 177.1. MS (þESI): m/z:
249 [MHþ].
We reported the synthesis of imidazo[4,5-c]pyrrolo[3,2-g]-
quinolin-4(5H)-ones by a convergent pathway. Key step
involved amide coupling with a DCP/DMF complex, non
expensive and easy-to-prepare reagent which revealed
efficient, and Heck-type arylation. The scope of use of this
coupling agent is currently under way and will be soon
reported elsewhere. This novel tetracyclic structure may
prove to be of great interest in different therapeutic areas,
especially as anticancer agent.
4.1.3. 6-Amino-N-pivaloylindoline (3). A solution of 2
(2.01 g, 8.10 mmol) in THF (50 mL) was placed in a Parr
apparatus for hydrogenation. Raney nickel (1 g) rinsed with
ethanol and THF was added. The suspension was stirred
overnight under 150 psi of hydrogen at room temperature
and then filtered over celite, rinsed with THF, dried over
calcium chloride, filtered and evaporated to give 3 (1.77 g,
99%). Mp 126–127 8C. IR (KBr, cm21): 3433, 3390, 1630,
4. Experimental
4.1. General
1
1332, 1201. H NMR (CDCl3, 250 MHz) d 1.37 (s, 9H),
3
3.03 (t, 2H, JHH¼7.9 Hz), 3.61 (large s, 2H), 4.21 (t, 2H,
3
4
3JHH¼7.9 Hz), 6.37 (dd, 1H, JHH¼7.9 Hz, JHH¼2.1 Hz),
6.95 (d, 1H, 3JHH¼7.9 Hz), 7.73 (d, 1H, 4JHH¼2.1 Hz). 13
C
4.1.1. 6-Nitroindoline (1). A solution of potassium nitrate
(7.17 g, 70.9 mmol) was added at 0 8C to a solution of
indoline (6 g, 50.2 mmol) in concentrated sulfuric acid
(40 mL). After stirring 75 min at room temperature, the
solution was poured into ice–water (400 mL) and pH was
brought to 4 with 10 N sodium hydroxide. Basification
was pursued until precipitation stopped. The solution was
extracted with dichloromethane (300 mL), washed with
water (200 mL), dried over sodium sulfate, filtered,
evaporated to give 1 (7.88 g, 95%). The solid was
recrystallized from diethyl ether/hexane. Mp 67–68 8C.
NMR (CDCl3, 250 MHz) d 27.5, 28.4, 40.2, 50.0, 105.2,
110.1, 120.5, 124.3, 145.6, 145.9, 176.6. MS (þESI): m/z:
219 [MHþ].
4.1.4. 6-Amino-5-bromo-N-pivaloylindoline (4). To a
solution of 3 (5 g, 22.9 mmol) in acetic acid (277 mL),
bromine (1.41 mL, 27.5 mmol) was added drop-by-drop.
After stirring 1 h at room temperature, the solution was
poured into water (250 mL), extracted with dichloro-
methane (150 mL), dried over sodium sulfate, filtered and
evaporated. The crude mixture was purified by column
chromatography over silicagel eluting with dichloro-
methane and then with a 97/3 mixture of dichloromethane
and ethanol to give 4 (6.19 g, 91%). Mp 163–164 8C. IR
1
(lit.5 67 8C, ligroin) IR (KBr, cm21): 3415, 1511. H NMR
(CDCl3, 250 MHz) d 3.10 (t, 2H, 3JHH¼8.4 Hz), 3.68 (t, 2H,
3
3JHH¼8.4 Hz), 3.92 (s, 1H); 7.13 (d, 1H, JHH¼7.9 Hz),
4
3
7.35 (d, 1H, JHH¼2.1 Hz), 7.54 (dd, 1H, JHH¼7.9 Hz,
4JHH¼2.1 Hz). 13C NMR (CDCl3, 250 MHz) d 29.9, 48.0,
102.8, 114.1, 124.2, 136.9, 148.2, 152.5. MS (þESI): m/z:
165 [MHþ].
1
(KBr, cm21): 3455, 3342, 1627, 648. H NMR (CDCl3,
250 MHz) d 1.37 (s, 9H), 3.04 (td, 2H, 3JHH¼8.1 Hz, 4JHH
¼
0.9 Hz), 4.00 (large s, 2H), 4.21 (t, 2H, 3JHH¼8.1 Hz), 7.19
(large s, 1H), 7.84 (s, 1H). 13C NMR (CDCl3, 250 MHz) d
27.6, 28.2, 40.2, 50.0, 102.7, 106.1, 122.0, 127.3, 143.1,
145.0, 176.6. MS (þESI): m/z: 297, 299 [MHþ].
4.1.2. 6-Nitro-N-pivaloylindoline (2). Triethylamine
(8.2 mL, 59 mmol) was added to a solution of 1 (3.86 g,
23.5 mmol) in 1,2-dichloroethane. Pivaloyl chloride
(4.4 mL, 36 mmol) was added at 0 8C. After stirring 4 h at
30 8C, the solution was poured into 0.3 M chlorhydric acid
4.1.5. N-Benzyl-4,5-dicyanoimidazole (5). To a solution
of 4,5-dicyanoimidazole (8.90 g, 75.4 mmol) in DMF

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B. Delest et al. / Tetrahedron 60 (2004) 6079–6083
(100 mL), a 60% suspension in mineral oil of sodium
hydride (3.62 g, 90.4 mmol) was added under a nitrogen
atmosphere at 0 8C. The solution was stirred at room
temperature until gas evolution stopped. Benzyl chloride
(10.4 mL, 90.4 mmol) was then added at 0 8C and the
solution was stirred 12 h at room temperature, evaporated to
dryness, solubilized in dichloromethane (200 mL), washed
with water (3£200 mL), dried over sodium sulfate, filtered
and evaporated to afford 5 (12.7 g, 81%). Mp 124–125 8C.
1H NMR (CDCl3, 250 MHz) d 5.28 (s, 2H), 7.68 (s, 1H),
7.27–7.47 (m, 5H). 13C NMR (CDCl3, 250 MHz) d 50.6,
111.8, 112.3, 108.4, 121.9, 127.8, 128.6, 129.0, 134.4,
143.5. MS (þESI): m/z: 209 [MHþ].
3JHH¼8.1 Hz), 5.16 (s, 2H), 7.18–7.22 (m, 2H), 7.33–7.42
4
4
(m, 4H), 7.52 (d, 1H, JHH¼1.2 Hz), 7.63 (d, 1H, JHH
¼
1.2 Hz), 9.22 (s, 1H), 9.31 (s, 1H). 13C NMR (CDCl3,
250 MHz) d 27.6, 28.5, 40.1, 49.9, 51.3, 107.6, 112.4, 122.9,
127.1, 127.5, 127.9, 128.4, 129.0, 134.6, 135.1, 136.8,
137.5, 144.7, 159.8, 176.1. MS (þESI): m/z: 481, 483
[MHþ].
4.1.10. N-(5-Bromo-1-pivaloylindolin-6-yl)-N-methyl-
(1-benzylimidazol-4-yl)carboxamide (10). A 60% suspen-
sion in mineral oil of sodium hydride (0.099 g, 2.5 mmol)
was added at 0 8C to a solution of 9 (0.79 g, 1.64 mmol) in
DMF (20 mL) under nitrogen atmosphere. The reaction
mixture was then stirred at room temperature until gas
evolution stopped. Methyl iodide (0.123 mL, 1.97 mmol)
was then added at 0 8C. The mixture was stirred 12 h at
room temperature, evaporated to dryness, solubilized in
dichloromethane (30 mL), washed with water (3£20 mL),
dried over sodium sulfate, filtered and evaporated to afford
10 (0.482 g, 59%). Mp 98–100 8C. 1H NMR (CDCl3,
250 MHz) d 1.35 (s, 9H), 3.13 (m, 2H), 3.32 (s, 3H), 4.25
(m, 2H), 4.95–4.97 (m, 2H), 6.78–6.82 (m, 1H), 7.00–7.05
(m, 2H), 7.20–7.45 (m, 5H), 8.21 (s, 1H). MS (þESI): m/z:
495, 497 [MHþ].
4.1.6. N-Benzylimidazole-4,5-dicarboxylic acid (6). Com-
pound 5 (19.3 g, 92.7 mmol) was refluxed in a 6 M sodium
hydroxide solution (250 mL, 1.5 mol) during 2 h. The hot
solution was filtered and washed with a solution of 3 M
chlorhydric acid (1.1 L). The filtrate was cooled and filtered
to get 6 (21.5 g, 94%). Mp 217–218 8C. 1H NMR (DMSO-
d6, 250 MHz) d 5.83 (s, 2H), 7.32–7.43 (m, 5H), 9.36 (s,
1H). 13C NMR (DMSO-d6, 250 MHz) d 50.9, 125.9, 128.0,
128.6, 135.8, 137.1, 138.5, 158.8, 159.5. MS (þESI): m/z:
247 [MHþ].
4.1.7. N-Benzylimidazole-4-carboxylic acid (7). Carb-
oxylic acid 6 (1.00 g, 4.06 mmol) was placed in acetic
anhydride (30 mL) and heated at 100 8C during 25 min. The
solution was evaporated. The residue was suspended in
ethanol, filtered and recrystallized in ethanol to afford 7
(0.81 g, 99%). Mp 254–255 8C. 1H NMR (DMSO-d6,
250 MHz) d 5.58 (s, 2H), 7.17–7.40 (m, 5H), 7.67 (d, 1H,
4.1.11. 1-Benzyl-5-methyl-7-pivaloyl-8,9-dihydroimi-
dazo[4,5-c]pyrrolo[3,2-g]quinolin-4-(5H)one (11). Under
an nitrogen atmosphere, palladium acetate (17.2 mg,
0.08 mmol), potassium carbonate (0.212 g, 1.53 mmol),
triphenylphosphine (40.2 mg, 0.15 mmol) were added to
a solution of 10 (0.38 g, 0.77 mmol) in 15 mL of
N,N-dimethylacetamide. After 3 freeze/pump/thaw cycles,
the mixture was stirred at 170 8C during 24 h. It was then
evaporated to dryness under reduced pressure. Dichloro-
methane (150 mL) was added, the organic phase was
washed with 0.5 M sodium hydroxide (100 mL) and with
a saturated solution of sodium chloride (50 mL), dried over
sodium sulfate, filtered and evaporated. The residue was
purified by column chromatography over silicagel eluting
with a 90:10 mixture of dichloromethane and ethanol to give
11 (0.088 g, 28%). Mp .300 8C. IR (KBr, cm21): 1640,
4
4JHH¼0.9 Hz), 8.13 (d, 1H, JHH¼0.9 Hz), 12.9 (large s,
1H). 13C NMR (DMSO-d6, 250 MHz) d 48.7, 126.9, 128.0,
128.8, 137.0, 137.7, 143.0, 161.0. MS (þESI): m/z: 203
[MHþ].
4.1.8. N-Benzylimidazole-5-carboxylic acid (8). Com-
pound 6 (1.00 g, 4.06 mmol) was placed in N,N-dimethyl-
acetamide (15 mL) and heated at 165 8C during 4 h. The
solution was evaporated. The residue was recrystallized in
ethanol to afford 8 (0.66 g, 80%). Mp 221–222 8C. 1H NMR
(DMSO-d6, 250 MHz) d 5.28 (s, 2H), 7.34–7.44 (m, 5H),
7.93 (d, 1H, 4JHH¼1.2 Hz), 7.96 (d, 1H, 4JHH¼1.2 Hz), 12.2
(large s, 1H). 13C NMR (DMSO-d6, 250 MHz) d 49.8,
125.9, 127.7, 127.9, 128.7, 133.4, 137.1, 138.5, 163.5. MS
(þESI): m/z: 203 [MHþ].
1
1665. H NMR (CDCl3, 250 MHz) d 1.40 (s, 9H), 3.08 (t,
2H, 3JHH¼8.0 Hz), 3.84 (s, 3H), 4.29 (t, 2H, 3JHH¼8.0 Hz),
5.65 (s, 2H), 7.08–7.15 (m, 2H), 7.30–7.40 (m, 3H), 7.42
(s, 1H), 7.76 (s, 1H), 8.54 (s, 1H). 13C NMR (CDCl3,
250 MHz) d 27.6, 28.4, 30.2, 40.5, 50.1, 50.9, 105.5, 108.7,
116.6, 125.4, 126.2, 128.4, 129.3, 131.8, 132.6, 134.8,
138.3, 142.4, 145.3, 158.2, 177.3. MS (þESI): m/z: 415
[MHþ].
4.1.9. N-(5-Bromo-1-pivaloylindolin-6-yl)-(1-benzylimi-
dazol-4-yl)carboxamide (9). To DMF (0.29 mL,
3.76 mmol),
phenyl
dichlorophosphate
(0.37 mL,
2.47 mmol) was added at 0 8C and stirred for 5 min. Then
dichloromethane (15 mL) and 7 (0.4 g, 1.98 mmol) were
added. Solution was stirred for 10 min and pyridine
(0.64 mL, 7.9 mmol) was added. Solution was stirred for
10 min and 4 (0.705 g, 2.37 mmol) was added. After stirring
4 h at room temperature, the mixture was poured into water
(30 mL), extracted with dichloromethane (3£50 mL),
evaporated and purified by column chromatography over
silica eluting with a 95:5 mixture of dichloromethane and
ethanol to give 9 (0.735 g, 77%). Mp 203–204 8C. IR (KBr,
cm21): 3352, 1684, 1642, 656. 1H NMR (CDCl3, 250 MHz)
Acknowledgements
`
A grant from the Ministere de l’E’Education Nationale, de
la Recherche et de la Technologie is acknowledged for this
work. We thank Servier laboratories for financial support.
References and notes
3
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