Concomitant ring contraction cyclization strategy for the synthesis of novel 4-oxo-4,5-dihydro-pyrroloquinolines

Article abstract of DOI:10.1016/j.tetlet.2004.05.115

The synthesis of novel substituted pyrroloquinolinones is described by concomitant ring contraction cyclization form 2-(2-amino-5-nitro-phenyl)-[4H]-1, 3-thiazines, which were derived from N-substituted 5-nitro-anthranilonitrile. An easy access to novel 4-thiono-1,4-dihydro-1,3-quinazoline heterocycles is also mentioned.

Full text of DOI:10.1016/j.tetlet.2004.05.115

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5913–5916
Concomitant ring contraction cyclization strategy for the
synthesis of novel 4-oxo-4,5-dihydro-pyrroloquinolines
Gabriel Thia Manh,a Hicham Bakkali,a Lucie Maingot,a Muriel Pipelier,a Uday Joshi,a
a
Jean Paul Pradere, Stephane Sabelle, Remy Tuloup and Didier Dubreuil
b
b
a,
*
ꢀ
ꢁ
aLaboratoire de Synthꢀese Organique (UMR-CNRS 6513/FR-CNRS 2465), Facultꢁe des Sciences et des Techniques,
2 rue de la Houssiniꢀere, BP 92208, 44322 Nantes Cedex, France
bL’Orꢁeal, Centre de Recherche Avancꢁee, 1 avenue Eugꢀene Schueller, BP 22, 93601 Aulnay-sous-Bois Cedex, France
Received 24 February 2004; revised 24 May 2004; accepted 24 May 2004
Abstract—The synthesis of novel substituted pyrroloquinolinones is described by concomitant ring contraction cyclization form
2-(2-amino-5-nitro-phenyl)-[4H]-1,3-thiazines, which were derived from N-substituted 5-nitro-anthranilonitrile. An easy access to
novel 4-thiono-1,4-dihydro-1,3-quinazoline heterocycles is also mentioned.
Ó 2004 Elsevier Ltd. All rights reserved.
Synthesis of naturally occurring quinoline and hydro-
quinoline alkaloids and their analogues have gained a
lot of interest in the field of medicinal chemistry for their
broad spectrum therapeutic activity as antitumor,
receptor antagonist or agonist, antiarrhytmic, analgesic,
enzyme inhibition, antidepressant, antiulcer, antirheu-
matic, immunosuppressant, antiallergic, antimalarial,
and even antiviral. They are also used in agriculture as
pesticides, antioxidants, corrosion inhibitors, and even
in dyes as photoconductors and photosensitizers.1
alkaloid analogues.2 Quinolinone intermediates are also
of interest for the preparation of functionalized dihy-
droquinoline derivatives.1–4
Herein, we wish to report a short synthetic approach to
novel 4,5-dihydro-pyrrolo[3,2-c]quinolin-4-ones, which
offered multifunctional potential, by concomitant ring
contraction cyclization of 2-(2-aminoaryl)-[4H]-1,3-thi-
azine intermediates derived from N-thioacylamidine
precursors by [4+2] cycloaddition (Fig. 1).
3-, 4- or 3,4-Substituted-1,2-dihydroquinolin-2-one
skeletons, in particular, have received substantial
attention as they provide access to biologically potent
We first investigated a model reaction to achieve the
formation of 2-(2-amino-5-nitro-phenyl)-[4H]-1,3-thi-
azines 4 from 5-nitroanthranilonitrile 1 (Scheme 1). The
functionalisation sites
R'
R'
R"
HN
R'''
S
S
CO2Me
R'''
R'
C
N
N
NHR
ring contraction
NHR
O
N
R
R"
R"
arylaminothioacylamidine
Diels-Alder
3,4-pyrrolodihydroquinolin-2-one
arylaminothiazine
Figure 1.
Keywords: Hetero Diels–Alder reaction; Thiazines; Ring contraction; Pyrroloquinolinones.
* Corresponding author. Tel.: +33-2-51-12-54-14; fax: +33-2-51-12-54-02; e-mail: dubreuil@chimie.univ-nantes.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.115

5914
G. T. Manh et al. / Tetrahedron Letters 45 (2004) 5913–5916
NO2
NO2
NO2
NO2
H S g
2
(MeO) CMeNMe
2
2
S
+
S
C
N
Py, Et N,
3
r.t.
S
CH Cl r.t.
2
2,
C
CN
HN
N
Me
NMe2
NH2
NH2
NH2
NH2
1
Me
7 42%
6
40%
2
86 %
(MeO) CHNMe
2
2
CH Cl r.t.
2
2,
NO2
NO2
S
CO2Me
CO2Me
DMAD
S
1
+
S
CO2Me
CO2Me
CH Cl r.t.
r.t.
2
2,
C
N
H
NH2
N
NH2
4
NMe2
3
98 %
5
NMe2
NMe2
Scheme 1.
introduction of the diene moiety from nitroanthranilo-
nitrile 1 was first carried out by usual procedure described
for the preparation of N-thioacylamidine.5 Thus, the
sulfurization of nitrile group by treatment with gaseous
hydrogen sulfide in pyridine/triethylamine led to the thio-
amide 2 in 86% yield. The condensation of thio-amide 2
with N,N-dimethylformamide dimethyl acetal (1 equiv)
in dichloromethane gave the desired 2-(2-amino-5-nitro-
phenyl)thioacylamidine 3 in 98%.
attempted the preparation of the corresponding 4-
methyl heterodiene 6 from the thioamide 2. In the event,
when 2 was treated with N,N-dimethylacetamide
dimethyl acetal, in dichloromethane at room tempera-
ture, a 1:1 mixture of N-thioacylamidine 6 (40%) and
1,4-dihydro-6-nitro-4-thiono-1,3-quinazoline
7 (42%)
was isolated after the purification of the crude product
by column chromatography. The formation of the thi-
onoquinazoline 7, which could be easily optimized at
higher temperature (50 °C, 80%), is explained by the
attack of the aromatic amino group on the electrophilic
carbon bearing the dimethyl amino substituent.
Subsequent Diels–Alder reaction of the diene 3 with
dimethylacetylene dicarboxylate (1 equiv), in dichloro-
methane at room temperature, afforded the thiazine 4 in
low yield (40%) as the latter underwent a spontaneous
cycloreversion to generate the thioamide vinylog 5 and
nitroanthranilonitrile 1 at rt.
In order to evaluate the influence of the aminoaryl
group on the behavior of N-thioacylamidine, we exam-
ined the same reaction sequence with the N-protected
nitroanthranilonitrile precursors (Scheme 2).
Earlier reports in the literature indicate that the presence
of a methyl group at the 4-position of N-thioacylam-
idine retards the cycloreversion of thiazine heterocycles.6
To overcome the problem of cycloreversion, we
The preparation of the N-methyl and N-benzyl nitro-
anthranilonitrile 8a and 8b was then performed in good
yields (8a: 94% and 8b: 75%) by reaction of 2-fluoro-5-
NO2
NO2
NO2
NO2
RNH2/DMSO
r.t.
H2S g
(MeO)2CHNMe2
CH2Cl2, r.t.
S
S
Py, Et3N, r.t.
C
CN
CN
C
N
NH2
NHR
F
NHR
NHR
8a : R = Me 94%
8b : R = Bn 75%
9a : R = Me 95%
9b : R = Bn 90%
10a : R = Me 95%
10b : R = Bn 92%
NMe2
NMe2
CO2Me
NO2
NO2
HN
DMAD
t-BuOK
CO2Me
CO2Me
O2N
CH2Cl2, r.t.
S
THF, -5˚C
CO2Me
NMe2
O
N
NHR
N
R
HN
NHR
CO2Me
NMe2
11a : R = Me 89%
11b : R = Bn 98%
13a : R = Me 70%
13b : R = Bn 98%
12a : R = Me
12b : R = Bn
Scheme 2.

G. T. Manh et al. / Tetrahedron Letters 45 (2004) 5913–5916
5915
743–751, and references cited therein; (d) Cordi, A. A.;
Desos, P.; Ruano, E.; Al-Badri, H.; Fugier, C.; Chapman,
A. G.; Meldrum, B. S.; Thomas, J.-Y.; Roger, A.; Lestage,
P. Il Farmaco 2002, 57, 787–802; (e) Lange, J. H. M.;
Verveer, P. C.; Osnabrug, J. M.; Visser, G. M. Tetrahe-
dron Lett. 2001, 42, 1367–1369, and references cited
therein; (f) Bar, G.; Parsons, A. F.; Thomas, C. B. Chem.
Commun. 2001, 1350–1351; (g) Bar, G.; Parsons, A. F.;
Thomas, C. B. Tetrahedron 2001, 57, 4719–4728; (h) Patel,
M.; McHugh, R. J.; Cordova, B. C.; Klabe, R. M.;
Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. Bioorg.
Med. Chem. Lett. 2001, 11, 1943–1945; (i) Grudon, M. F.
In The Alkaloid: Quinoline Alkaloids Related to Anthra-
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705.
nitrobenzonitrile with primary amines such as methyl-
and benzylamine, respectively. Following the same
two-steps procedure, 8a–b were converted to the corre-
sponding N-thioacylamidines 10a–b (H2S, Py/Et3N,
then (MeO)2CHNMe2, CH2Cl2, rt 1 h) as shown in
Scheme 2.
In these cases, the condensation of N,N-dimethylform-
amide dimethyl acetal proceeded efficiently and the
desired 2-(2-alkylamino-5-nitro)phenylthioacylamidine
10a and 10b could be isolated in 90% and 82% overall
yield from nitrile 8, respectively. Diels–Alder reaction of
10a and 10b with dimethylacetylene dicarboxylate
(1 equiv), in dichloromethane at room temperature,
afforded the targeted 2-(2-alkylamino-5-nitro)phenyl-
thiazines 11a (89%) and 11b (98%), respectively.7
Treatment of the N-substituted aminophenylthiazines 11
by potassium tert-butoxide in THF was applied to ini-
tiate ring contraction of thiazines into pyrrole hetero-
cycles.8 The rearrangement of thiazines proceeded
smoothly to afford the biscarboxymethyl pyrroles 12a
and 12b, which on concomitant attack by aromatic
amino group on the methyl ester, afforded pyrrolo-
quinolinones 13a and 13b, in 70% and 98% yield,
respectively.9
€
€
3. Jaroch, S.; Holscher, P.; Rehwinkel, H.; Sulzle, D.;
Burton, G.; Hillmann, M.; McDonald, F. Bioorg. Med.
Chem. Lett. 2002, 12, 2561–2563.
4. Moon, M. W.; Morris, J. K.; Heier, R. F.; Chidester, C.
G.; Hoffmann, W. E.; Piercey, M. F.; Althaus, J. S.;
VonVoigtlander, P. F.; Evans, D. L.; Figur, L. M.; Lahti,
R. A. J. Med. Chem. 1992, 35, 1076–1092.
5. (a) Ane, A.; Prestat, G.; Thiam, M.; Josse, S.; Pipelier, M.;
ꢀ
Pradere, J. P.; Dubreuil, D. Nucleos. Nucleot. Nucl. Acid
2002, 21, 335–360, and references cited therein; (b) Prestat,
ꢀ
G.; Ane, A.; Dubreuil, D.; Pradere, J. P.; Lebreton, J.;
Evers, M.; Henin, Y. Nucleos. Nucleot. 2000, 19,
735.
6. Purseigle, F.; Dubreuil, D.; Goli, M.; Marchand, A.;
To summarize, we have designed a novel synthetic
pathway for the synthesis of pyrrolodihydroquinoli-
nones from aminophenylthiazine derivatives, which
were easily derived from the nitroanthranilonitrile pre-
cursors. The most important advantage of this strategy
lies in the fact that it is possible to introduce various
substituents at almost every step during the synthesis.
For example, substituted anthraniline derivatives or
various dienophiles could be used. In addition, the
presence of a nitro group would allow further derivati-
zation of the final 4,5-dihydro-[4H]-pyrrolo[3,2-c]quin-
olin-4-ones. We have also opened a new route to access
4-thiono-1,3-quinazoline derivatives, which are good
candidates for the synthesis of original alkaloid ana-
logues.10 The synthesis of pyrroloquinolinone and pyr-
roloquinoline based NCEs (New Chemical Entities) is
underway in order to study the structure activity rela-
tionship (SAR).
ꢀ
Toupet, L.; Pradere, J. P. Tetrahedron 1998, 54, 2545–
2562, and references cited therein.
7. Compound 11a: 1H NMR (300 MHz, CDCl3) d ppm: 2.38
(6H, s, NMe2); 3.05 (3H, d, J ¼ 5:1 Hz, Me); 3.87 (3H, s,
CO2Me); 3.90 (3H, s, CO2Me); 5.61 (1H, s, H-4); 6.71 (1H,
d, J ¼ 9:3 Hz,
H
arom); 8.20 (1H, dd, J ¼ 9:3 Hz,
J ¼ 2:2 Hz, Harom); 8.76 (1H, d, J ¼ 2:2 Hz, Harom); 9.74
(1H, br s, NH). Compound 11b: 1H NMR (300 MHz,
CDCl3) d ppm: 2.12 (6H, s, NMe2); 3.84 (3H, s, CO2Me);
3.88 (3H, s, CO2Me); 4.51 (2H, d, J ¼ 5:0 Hz, CH2); 5.40
(1H, s, H-4); 6.75 (1H, d, J ¼ 9:4 Hz, Harom); 7.26–
7.37 (5H, m, Ph); 8.17 (1H, dd, J ¼ 9:4 Hz, J ¼ 2:3 Hz,
H
arom); 8.81 (1H, d, J ¼ 2:3 Hz, Harom); 10.03 (br s, 1H,
NH).
8. (a) Abouelfida, A.; Pradere, J. P.; Jubault, M.; Tallec, A.
ꢀ
Can. J. Chem. 1992, 70, 14–18; (b) Manh, G. T.; Hazard,
ꢀ
R.; Tallec, A.; Pradere, J. P.; Dubreuil, D.; Thiam, M.;
Toupet, L. Electrochem. Acta 2002, 47, 2833–2841;
(c) Stanislav, R. Janssen Chim. Acta 1987, 5, 3–11.
9. 2-dimethylamino-5-methyl-8-nitro-4-oxo-4,5-dihydro-1H-
pyrrolo[3,2-c]quinoline-3-carboxylic acid methyl ester 13a:
1H NMR (300 MHz, DMSO-d6) d ppm: 2.98 (6H, s,
NMe2); 3.64 (3H, s, Me); 3.68 (3H, s, CO2Me); 7.67 (1H,
Acknowledgements
d, J ¼ 9:3 Hz,
H
arom); 8.18 (1H, dd, J ¼ 9:3 Hz,
J ¼ 2:2 Hz, Harom); 9.28 (1H, d, J ¼ 2:2 Hz, Harom); 11.72
(1H, br s, NH); 13C NMR (50.3 MHz, DMSO-d6) d ppm:
29.4 (Me); 41.5 (NMe2); 51.4 (CO2Me); 112.6, 115.9,
117.0, 126.9, 140.1, 141.2, 147.2 (Carom, Cpyrrol); 157.0
(CO); 166.0 (CO2Me); Elemental Anal. Calcd for
C16H16N4O5: C, 55.81; H, 4.68; N, 16.27. Found: C,
55.56; H, 4.35; N, 16.49. 5-Benzyl-2-dimethylamino-8-
nitro-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-3-car-
boxylic acid methyl ester 13b: 1H NMR (300 MHz,
DMSO-d6) d ppm: 3.00 (6H, s, NMe2); 3.75 (3H, s,
CO2Me); 5.57 (2H, br s, CH2); 7.11–7.30 (5H, m, Ph); 7.47
(1H, d, J ¼ 9:0 Hz, Harom); 8.05 (1H, dd, J ¼ 9:0 Hz,
J ¼ 2:5 Hz, Harom); 9.30 (1H, d, J ¼ 2:5 Hz, Harom); 11.80
(1H, br s, NH); 13C NMR (50.3 MHz, DMSO-d6) d ppm:
42.4 (NMe2); 45.74 (CH2); 52.4 (CO2Me); 95.0, 113.9,
ꢁ
We thank L’Oreal for financial support.
References and notes
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1996, 52, 15031–15070, and references cited therein.
€
€
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5916
G. T. Manh et al. / Tetrahedron Letters 45 (2004) 5913–5916
114.0, 117.2, 118.2, 121.8, 127.1, 127.9, 128.2, 129.5, 137.8,
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140.2, 142.2, 148.3 (Carom, Cpyrrole, and Cbenzyl); 158.0 (CO);
166.9 (CO2Me). Elemental Anal. Calcd for C22H20N4O5:
C, 62.85; H, 4.79; N, 13.33. Found: C, 62.72; H, 4.82; N,
12.98.
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