Direct cyclization of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids into fused pyrrolizinones

Article abstract of DOI:10.1016/j.tetlet.2010.10.060

A series of fused heterocyclic compounds based on a pyrrolizinone structure have been prepared from ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids by intramolecular Friedel-Crafts acylation promoted by bis(trichloromethyl) carbonate, in generally good yield without using Lewis acid catalysts.

Full text of DOI:10.1016/j.tetlet.2010.10.060

Tetrahedron Letters 51 (2010) 6635–6636
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct cyclization of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic
acids into fused pyrrolizinones
⇑
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 pyrrolizinone structure have been prepared from
ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids by intramolecular Friedel–Crafts acylation
promoted by bis(trichloromethyl) carbonate, in generally good yield without using Lewis acid catalysts.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 September 2010
Revised 7 October 2010
Accepted 11 October 2010
Available online 20 October 2010
Keywords:
Fused pyrrole derivatives
Ring closure reactions
Friedel–Crafts acylation
Phosgene
Derivatives of fluorazone (9H-pyrrolo[1,2-a]indol-9-one) (1a)
and some of its isosteres, bearing the same 1H-pyrrolizin-1-one
framework 2 annelated to a heterocycle 3 (Fig. 1), show a broad
spectrum of biological activities including antidiabetic,1 psycho-
stimulant,2 antitubulin,3 photosensitizing,4 and hence are an
important class of nitrogen-containing heterocycles, and useful
intermediates in organic synthesis.5
yield. It is known that the intramolecular Friedel–Crafts acylation
of aromatic rings is of particular value in building up cyclic sys-
tems. This reaction generally requires two steps starting from car-
boxylic acids, namely the formation of the intermediate acyl
chloride and the subsequent cyclization catalyzed by a Lewis acid.
However, the use of the catalyst can be avoided when particularly
reactive substrates, such as heterocycles, are involved. Based on
our previous experience,13 we decided to attempt the intramolec-
ular cyclization of 2-(1H-pyrrol-1-yl)benzoic acid 4a to fluorazone
1a (Fig. 2) by use of an aprotic chlorinating reagent inert to the pyr-
role ring, but potentially capable of sufficiently activating enough
of the carboxylic function to be in situ nucleophilically attacked
Furthermore, we have recently found that some N0-heteroacyl-
9H-pyrrolo[1,2-a]indol-9-hydrazones, directly obtained from fluo-
razone 1a, show noticeable activity against a colon cancer cell
line.6 As a result, a number of synthetic strategies have been
developed for the preparation of (un)substituted-fluorazones and
analogs to be further elaborated into biologically active agents.
Among the numerous synthetic methods discovered for the
synthesis of basic fluorazone,7 those involving 2-(1H-pyrrol-1-
yl)benzoic acid as starting material appear as the most appealing,
offering the possibility to be in general extended to the conversion
of easily accessible ortho-(1H-pyrrol-1-yl)aryl carboxylic acids into
fused pyrrolizinones.8–12 All the existing methods suffered how-
ever from many drawbacks such as low yield, additional activation
of the carboxylic function before cyclization or sensitivity of the
pyrrole ring to the reagents employed. In order to avoid any inter-
mediate manipulation, which would limit the general utility of the
methods, we decided to reinvestigate the one-step Friedel–Crafts
cyclization of 2-(1H-pyrrol-1-yl)benzoic acid to find conditions
suitable to produce the cyclic ketone, and analogs thereof, in good
from the pyrrole
a
-carbon.
O
N
O
O
Het
N
N
1a
2
3
Figure 1. Reference structures.
O
COOH Friedel-Crafts
Ar
acylation
Ar
N
N
4a-ha
1a-h
⇑
Corresponding author. Tel.: +39 0984493154; fax: +39 0984493298.
E-mail addresses: francesca.aiello@unical.it (F. Aiello), garofalo@unical.it (A.
Garofalo), fedorag@gmail.com (F. Grande).
Figure 2. Cyclization reaction. aSee Table 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.060

6636
F. Aiello et al. / Tetrahedron Letters 51 (2010) 6635–6636
Table 1
isostere of fluorazone, by Friedel–Crafts intramolecular acylation.
Under our conditions, both these tricyclic compounds were
smoothly obtained from acid precursors 4g,h by action of triphos-
gene. Triphosgene thus proved to act as a selective and ideal re-
agent for uncatalyzed intramolecular acylation of pyrrole. The
value of the reagent in promoting such cyclization reactions has
to be attributed to its effectiveness in selectively chlorinating the
carboxylic group, giving rise to an intermediate prone to the direct
attack from the nucleophilic pyrrole, at the toluene reflux temper-
ature. The utility of the present procedure lies also in the easy
preparation of the starting materials 4a–h from corresponding
amino aryl or amino heteroaryl carboxylic acids, or esters thereof,
according to the method of Clauson–Kaas, which involves the
installation of the pyrrole ring through condensation of the amino
group with 2,5-dimethoxytetrahydrofuran, followed by alkaline
hydrolysis, in the case of esters.3,12
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.10a 119.5–
121.5]
1a
24
24
18
18
80
70
64
71
F
123
1b
[lit.12 124]
Me
111
1c
[lit.12 110–111]
O2N
200
1d
[lit.12 200–201]
References and notes
MeO
1e
1f
24
18
24
50
75
58
[lit.12 124–125]
192
1. Sugihara, H.; Matsumoto, N.; Hamuro, Y.; Kawamatsu, Y. Arzneimittel-Forsch.
1974, 24, 1560–1563.
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,
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3. Lisowsky, 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.
S
N
1g
[lit.16 112]
4. Bauer, R.; Heisler, G.; Konigstein, C. Spectrochim. Acta, Part A 1994, 50A, 57–67.
}
}
5. (a) Fogassy, K.; Kovács, K.; Keseru, G. M.; Toke, L.; Faigl, F. J. Chem. Soc., Perkin
Trans. 1 2001, 1039–1043; (b) Porretta, G. C.; Filacchioni, G.; Stefancich, G.;
Giuliano, R.; Artico, M. Il Farmaco 1978, 33, 263–270.
131
1h
24
77
[lit.17 130]
6. Grande, G.; Yamada, R.; Cao, X.; Aiello, F.; Garofalo, A.; Neamati, N. Expert Opin.
Investig. Drugs 2009, 18, 555–568.
7. See, for example: Kobayashi, K.; Himei, Y.; Fukamachi, S.; Tanmatsu, M.;
Morikawa, O.; Konishi, H. Tetrahedron 2007, 63, 4356–4359. and references
cited therein.
8. Rochais, C.; Dallemagne, P.; Rault, S. Anti-Cancer Agents Med. Chem. 2009, 9,
369–380.
9. Josey, A. D.; Jenner, E. L. J. Org. Chem. 1962, 27, 2466–2470.
10. (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.
11. (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.
12. Aiello, F.; Garofalo, A.; Grande, F. Tetrahedron 2010, 66, 274–277.
13. Fiorini, I.; Nacci, V.; Ciani, S. M.; Garofalo, A.; Campiani, G.; Savini, L.; Novellino,
E.; Greco, G.; Bernasconi, P.; Mennini, T. J. Med. Chem. 1994, 37, 1427–1438.
14. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 9, 894–895.
15. Typical procedure for cyclization of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl
carboxylic acids. 11H-Naphtho[2,3-b]pyrrolizin-11-one (1f). To a solution of 3-
(1H-pyrrol-1-yl)naphthalene-2-carboxylic acid (0.100 g, 0.42 mmol) in dry
toluene (1 mL) cooled to 0 °C, was added bis-(trichloromethyl)-carbonate
(0.125 mg, 0.42 mmol) in one portion. The mixture was heated to reflux for
18 h under argon. The solvent was evaporated and the residue obtained was
dissolved in ethyl acetate (5 mL). The organic solution was washed with water
(3 ꢀ 3 mL). The solid obtained after drying and evaporation of the solvent was
purified by silica gel column chromatography (diethyl ether/hexanes, 1:3 as
Among the common chlorinating agents, bis(trichloromethyl)
carbonate (triphosgene), a crystalline phosgene substitute,14 was
selected as the most suitable for our purposes. A smooth conver-
sion of 2-(1H-pyrrol-1-yl)benzoic acid 4a to fluorazone 1a was so
achieved with the use of an equimolar amount of bis(trichloro-
methyl) carbonate in toluene at reflux for 24 h (Table 1).
Under such conditions, no detectable quantities of pyrrole-chlo-
rinated side-products could be observed, while the final ketone 1a
was isolated in an 80% yield after a simple work-up and silica gel
column chromatography purification.
The procedure was then extended to analogous acids (4b–e)
variously substituted on the phenyl ring, to give the corresponding
substituted-ketones (1b–e) in 50–71% yield. To further explore the
generality of the method, we attempted the above conditions for
the cyclization of 3-(1H-pyrrol-1-yl)naphthalene-2-carboxylic acid
(4f), from which the hitherto unknown 11H-naphtho[2,3-b]pyrr-
olizin-11-one (1f) was obtained in a 75% yield.15 The effectiveness
of the method was so confirmed for the cyclization of ortho-(1H-
pyrrol-1-yl)aryl carboxylic acids. On the other hand, it is known
that classical Friedel–Crafts conditions are not effective for the
intramolecular acylation of ortho-(1H-pyrrol-1-yl)heteroaryl car-
boxylic acids. As an example, Rault et al.16 did not succeed to di-
rectly cyclize the 3-(1H-pyrrol-1-yl)thiophene-2-carboxylic acid
4g into 8H-thieno[2,3-b]pyrrolizin-8-one 1g, although they re-
ported the synthesis of this latter compound using the Vilsme-
ier–Haack fashion.3 Furthermore, Lauderée and Robba17 did not
manage to obtain 5H-pyrido[3,2-b]pyrrolizin-5-one 1h, a further
eluent) to give pure compound 1f as
a yellow solid. The yield, after
recrystallization from cyclohexane, was 0.69 g (75% yield). 1H NMR (CDCl3,
25 °C), d: 8.05 (s, 1H), 7.82 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.50 (t, 1H,
J = 6.9 Hz), 7.37 (m, 2H), 7.20 (m, 1H), 6.80 (m, 1H), 6.38 (m, 1H). 13C NMR
(CDCl3, 25 °C), d: 177.96, 135.39, 132.84, 131.18, 130.69, 130.47, 129.54,
129.18, 128.01, 126.08, 125.83, 119.06, 116.98, 112.97, 106.85. IR (KBr discs)
1884, 1643 cmꢁ1. MS (CI) m/z 220 (MH+). Anal. Calcd for C15H9NO: C, 81.18; H,
4.14; N, 6.39. Found: C, 81.11; H, 4.07; N, 6.55. Mp: 192 °C.
16. Rault, S.; Lancelot, J. C.; Effi, Y.; Robba, M. Heterocycles 1983, 20, 477–480.
17. Lauderée, D.; Robba, M. Heterocycles 1984, 22, 303–305.