Convenient synthesis of fluorazone derivatives by one-pot pyrrolation/cyclization of anthranilic acids

Article abstract of DOI:10.1016/j.tetlet.2011.08.139

A series of fused heterocyclic compounds based on a fluorazone structure has been prepared from anthranilic or ortho-aminoheteroaryl carboxylic acids by one-pot sequential pyrrolation/cyclization catalyzed by 4-chloropyridine hydrochloride, in generally good yield.

Full text of DOI:10.1016/j.tetlet.2011.08.139

Tetrahedron Letters 52 (2011) 5824–5826
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Convenient synthesis of fluorazone derivatives by one-pot
pyrrolation/cyclization of anthranilic acids
⇑
Francesca Aiello , Antonio Garofalo, Fedora Grande
Dipartimento di Scienze Farmaceutiche, Università della Calabria, Edif. Polifunzionale, Arcavacata di Rende 87036, Cosenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of fused heterocyclic compounds based on a fluorazone structure has been prepared from anthra-
nilic or ortho-aminoheteroaryl carboxylic acids by one-pot sequential pyrrolation/cyclization catalyzed
by 4-chloropyridine hydrochloride, in generally good yield.
Received 20 June 2011
Revised 3 August 2011
Accepted 24 August 2011
Available online 31 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
4-Chloropyridine hydrochloride
Clauson–Kaas pyrrolation
Ring closure reaction
Fused pyrrole derivatives
Introduction
in the case of amide intermediates.8 Only in a few instances steps
a (then c) and/or d can be bypassed. In fact, the pyrrolation of amino
Fluorazone (9H-pyrrolo[1,2-a]indol-9-one) and its analogues,
characterized by a benzo fused ring substituted or replaced for a
heterocycle 1 (Fig. 1), represent valuable intermediates in organic
synthesis. They have been extensively studied in relation to a variety
of biological activities showedby many oftheir functionalizedderiv-
atives including anticancer,1 psychostimulant,2 photosensitizing.3
A number of synthetic strategies have been therefore developed
for the preparation of (un)substituted-fluorazones and analogues to
be further elaborated into biologically active agents. Amongst the
numerous synthetic methods discovered, the most appealing ap-
pear those deriving from ortho-(1H-pyrrol-1-yl)aryl and heteroaryl
carboxylic acids, in turn obtained by pyrrolation of ortho-aminoaryl
(anthranilic) and ortho-aminoheteroaryl carboxylic acids, respec-
tively.4–6 However the complete synthetic elaboration of starting
aromatic ortho-aminoacids to the final ketones usually requires
too many reaction steps, which unavoidably results in time-
consuming processes, waste of materials as well as lowering of
overall yields. Typically, the reaction sequence implies: (a)
transformation of the aminoacid into the aminoester, often via an
intermediate isatoic anhydride;7 (b) pyrrolation on the amino
group under Clauson–Kaas conditions; (c) hydrolysis of the ester
group to reinstate the free carboxylic function or its transformation
into an amide; (d) activation of the carboxylic function to an acyl
chloride; (e) cyclization under different conditions; (f) hydrolysis
group with 2,5-dimethoxytetrahydrofuran (DMTHF) is now prefer-
entially carried out in 1,4-dioxane with 4-chloropyridine hydro-
chloride as the acid catalyst,8 without taking into account if the
carboxyl group was protected or not; whereas the classical reflux-
ing acetic acid conditions, which, according to our own experience,
generally require the carboxyl group protection to be effective. This
way, steps a and c of the above sequence can be avoided. Also, we
recently exploited a convenient procedure for the direct intramo-
lecular acylation of ortho-(1H-pyrrol-1-yl)aryl carboxylic acids by
the action of triphosgene, demonstrating that cyclization to ketones
could take place directly, under conditions requiring no preliminary
carboxylic activation (namely step d of the sequence).6
We herein investigated the possibility of converting anthranilic
acids 2a–h into fluorazones 1a–h, through a sequential one-pot
pyrrole formation/cyclization (Scheme 1), with the aim of discove-
ing straightforward alternative methods to reach compounds of
formula 1. Since both reactions were catalyzed by acids, we at-
tempted the transformation of anthranilic acid 2a by using DMTHF
and 4-chloropyridine hydrochloride as the acid catalyst, in a 1:1:2
ratio, in 1,4-dioxane at reflux, after different experimental tech-
niques. Fluorazone 1a was so obtained in variable yields, strictly
depending on reflux time and modalities of mixing the reagents.
The use of an excess of both reactants with respect to the amount
of the starting acid 2a did not seem to considerably influence the
reaction course. Thus, the best results were obtained by dissolving
4-chloropyridine hydrochloride in hot dioxane and then adding a
solution of anthranilic acid 2a and DMTHF in the same solvent. A
smooth conversion to fluorazone 1a was obtained through the
⇑
Corresponding author. Tel.: +39 0984493154; fax: +39 0984493298.
E-mail address: francesca.aiello@unical.it (F. Aiello).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.139

F. Aiello et al. / Tetrahedron Letters 52 (2011) 5824–5826
5825
O
Ar
N
1
Figure 1. Fluorazone derivative general structure.
O
2 eq. 4-chloropyridine.HCl
COOH
N
COOH
NH2
1 eq. DMTHF
Ar
Ar
Ar
1,4-dioxane, reflux, 24-36h
N
2a-ha
1a-h
3a-h
Scheme 1. One-pot pyrrolation/cyclization reaction. aSee Table 1.
Table 1
was then extended to analogous acids 2b–f variously substituted
on the phenyl ring, to give the corresponding substituted-ketones
1b–f in 40–90% yield (Table 1).9 Somewhat surprisingly, the con-
version of the unsubstituted acid 2a remained the least productive
in the series. The generality of this method was also confirmed by
the good results achieved by the synthesis of two hetero-isosteres
of fluorazone, namely, 5H-pyrido[3,2-b]pyrrolizin-5-one 1g and
4H-thieno[3,2-b]pyrrolizin-4-one 1h, which were obtained in 83%
and 44% yield, starting from 2-aminonicotinic acid 2g and 2-ami-
nothiophene-3-carboxylic acid 2h, respectively. It is worth noting
that 2-aminonicotinic acid 2g was reported to fail to react under
classical Clauson–Kaas conditions to give 2-(1H-pyrrol-1-yl)pyri-
dine-3-carboxylic acid 3g, unless previously transformed into an
ester.10
In conclusion, 4-chloropyridine hydrochloride proved to act as
the ideal catalyst for both pyrrolation on amino groups and intra-
molecular acylation of resulting pyrrole by a free carboxylic func-
tion, at the dioxane reflux temperature. This allows the
preparation of fluorazone based derivatives from ortho-aminoaryl
and heteroaryl carboxylic acids in generally good yield, after a sim-
ple work-up. A further advantage of the present procedure lies in
the easy availability of the starting aminoacids 2a–h, most of
which are commercial reagents.
Chemical structures, reaction time, yield and melting point of compounds 1a–h
O
Ar
N
Compd Ar
Reaction
time (h)
Yield
(%)
Mp (°C)
121–123 [lit.4a
119.5–121.5]
1a
36
24
24
23
89
36
Br
1b
176
Me
1c
[lit.6 110–111]
O
1d
36
24
34
75
[lit.6 124–125]
[lit.11 140–141]
Cl
References and notes
1e
1. (a) Grande, F.; Yamada, R.; Cao, X.; Aiello, F.; Garofalo, A.; Neamati, N. Expert
Opin. Invest. Drugs 2009, 18, 555–568; (b) Rochais, C.; Dallemagne, P.; Rault, S.
Anti-Cancer Agents Med. Chem. 2009, 9, 369–380; (c) Diana, P.; Stagno, A.;
Barraja, P.; Montalbano, A.; Carbone, A.; Parrino, B.; Cirrincione, G. Tetrahedron
2011, 67, 3374–3379.
2. Rault, S.; Lancelot, J. C.; Bouyazza, L.; Robba, M.; Quermonne, M. A.;
Nammathao, B.; Louchahi-Raoul, J.; Marcy, R. Eur. J. Med. Chem. 1991, 26,
939–946.
3. Bauer, R.; Heisler, G.; Konigstein, C. Spectrochim. Acta, Part A 1994, 50A, 57–67.
4. (a) Mazzola, V. J.; Bernady, K. F.; Franck, R. W. J. Org. Chem. 1967, 32, 486–489;
(b) Bailey, A. S.; Scott, P. W.; Vandrevala, M. H. J. Chem. Soc., Perkin Trans. 1
1980, 97–101.
5. (a) Rault, S.; Cugnon de Sévricourt, M.; Godard, A. M.; Robba, M. Tetrahedron
Lett. 1985, 26, 2305–2308; (b) Bouyazza, L.; Lancelot, J. C.; Rault, S.; Robba, M.;
Quermonne, M. A. J. Heterocycl. Chem. 1991, 28, 373–377.
180–181 [lit.11
179–180]
1f
24
24
24
62
83
44
Cl
1g
131 [lit.12 130]
[lit.13 123]
N
S
1h
6. Aiello, F.; Garofalo, A.; Grande, F. Tetrahedron Lett. 2010, 51, 6635–6636.
7. Bavetsias, V.; Skelton, L. A.; Yafai, F.; Mitchell, F.; Wilson, S. C.; Allan, B.;
Jackman, A. L. J. Med. Chem. 2002, 45, 3692–3702.
8. Lisowski, V.; Léonce, S.; Kraus-Berthier, L.; Sopkovà-de Oliveira Santos, J.;
Pierré, A.; Atassi, G.; Caignard, D. H.; Renard, P.; Rault, S. J. Med. Chem. 2004, 47,
1448–1464.
formation of intermediate 2-(1H-pyrrol-1-yl)benzoic acid 3a, as
confirmed by TLC and GC monitoring of the reaction. In some in-
stances, small aliquots of catalyst were added time to time in order
to drive the reaction to completion, although variable amounts of
intermediate 2-(1H-pyrrol-1-yl)benzoic acid 3a were recovered
even after prolonged reaction times. The yield, however, reached
only a 23%, after chromatographic purification. The procedure
9. Typical procedure for the pyrrolation/cyclization of ortho-aminoaryl carboxylic
acids. 7-Bromo-9H-pyrrolo[1,2-a]indol-9-one (1b). To
a hot solution of 4-
chloropyridine hydrochloride (42 mg, 0.280 mmol) in 1,4-dioxane (1 mL), was
added a solution of 5-bromo anthranilic acid (30 mg, 0.140 mmol) and 2,5-
dimethoxytetrahydrofuran (18.14
lL, 0.140 mmol) in 1,4-dioxane (600 lL).
The reaction was stirred at reflux for 24 h, then filtered on CeliteÒ. The residue

5826
F. Aiello et al. / Tetrahedron Letters 52 (2011) 5824–5826
obtained after evaporation of the solvent was dissolved in ethyl acetate (5 mL)
116.48, 114.73, 111.72. IR (KBr discs) 1690 cmÀ1. MS (EI) m/z 247 (M+). Anal.
Calcd for C11H6BrNO: C, 53.26; H, 2.44; N, 5.65; Br, 32.21. Found: C, 53.31; H,
2.28; N, 5.37; Br, 32.08. Mp: 176 °C.
and the resulting solution was washed with NaHCO3 saturated solution. The
solid obtained after drying and evaporation of the solvent was purified by silica
gel column chromatography (ethyl acetate/hexanes, 3/7 as eluent) to give pure
10. Cardinaud, I.; Gueiffier, A.; Debouzy, J.-C.; Milhavet, J.-C.; Chapat, J.-P.
Heterocycles 1993, 36, 2513–2522.
11. Kobayashi, K.; Himei, Y.; Fukamachi, S.; Tanmatsu, M.; Morikawa, O.; Konishi,
H. Tetrahedron 2007, 63, 4356–4359.
12. Ladurée, D.; Robba, M. Heterocycles 1984, 22, 303–305.
13. Rault, S.; Lancelot, J. C.; Effi, Y.; Robba, M. Heterocycles 1983, 20, 477–480.
compound 1b as
a yellow solid. The yield, after recrystallization from
cyclohexane, was 89% (31 mg). 1H NMR (CDCl3, 25 °C), d: 7.69 (d, 1H,
J = 1.8 Hz), 7.55 (dd, 1H, J = 8.1 and 1.9 Hz), 7.07 (d, 1H, J = 2.5 Hz), 7.01 (d,
1H, J = 8.1 Hz), 6.82 (d, 1H, J = 3.7 Hz), 6.34 (t, 1H, J = 2.7 Hz). 13C NMR (CDCl3,
25 °C), d: 177.90, 142.43, 136.40, 134.22, 131.88, 127.71, 119.82, 118.44,