Microwave-Assisted Paal-Knorr Reaction. A Rapid Approach to Substituted Pyrroles and Furans

Article abstract of DOI:10.1021/ol0362820

(Equation presented) An array of tetrasubstituted pyrroles (and trisubstituted furans) was obtained using a simple three-step procedure. Functional homologation of a β-ketoester with an aldehyde followed by oxidation gave a series of differently substitut

Full text of DOI:10.1021/ol0362820

ORGANIC
LETTERS
2004
Vol. 6, No. 3
389-392
Microwave-Assisted Paal−Knorr
Reaction. A Rapid Approach to
Substituted Pyrroles and Furans
Giacomo Minetto, Luca F. Raveglia,† and Maurizio Taddei*
Dipartimento Farmaco Chimico Tecnologico, UniVersita` degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy, and NiKem Research srl, Via Zambeletti 25 20021
Baranzate di Bollate, Milano, Italy
taddei.m@unisi.it
Received November 22, 2003
ABSTRACT
An array of tetrasubstituted pyrroles (and trisubstituted furans) was obtained using a simple three-step procedure. Functional homologation
of a â-ketoester with an aldehyde followed by oxidation gave a series of differently substituted 1,4-dicarbonyl compounds that can be rapidly
cyclized with the Paal−Knorr procedure carried out under microwave irradiation.
Pyrrole is one of the most prominent heterocycles, having
been known for more than 150 years,1 and it is the structural
skeleton of several natural products, synthetic pharmaceu-
ticals, and electrically conducting materials.2
Within these large classes of relevant products, tetrasub-
stituted pyrroles are extremely important, displaying anti-
bacterial, antiviral, anticonvulsant, and antioxidant activities
and inhibiting cytokine-mediated diseases.3
One of the most common approaches to pyrrole synthesis
is the Paal-Knorr reaction in which 1,4-dicarbonyl com-
pounds are converted to pyrrole via acid-mediated dehydra-
tive cyclization in the presence of a primary amine.4 In this
reaction, the 1,4-dicarbonyl compound provides the four
carbons of the pyrrole with the possible substituents, whereas
the amine provides the nitrogen with its substituent. The main
limitations to intensive use of this reaction are the strong
reaction conditions required for cyclization (use of boiling
acetic acid for extended times) and the low availability of
(3) Kaiser, D. G.; Glenn, E. M. J. Pharm. Sci. 1972, 61, 1908. Daisone,
G.; Maggio, B.; Schillaci, D. Pharmazie 1990, 45, 441. Almerico, A. M.;
Diana, P.; Barraja, P.; Dattolo, G.; Mingoia, F.; Putzolu, M.; Perra, G.;
Milia, C.; Musiu, C.; Marongiu, M. E. Il Farmaco 1997, 52, 667. Lehuede,
J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J. M.
Eur. J. Med. Chem. 1999, 34, 991. Chong, P. H.; Bachenheimer, B. S.
Drugs 2000, 11, 351. Pinna, G. A.; Loriga, G.; Murineddu, G.; Grella, G.;
Mura, M.; Vargiu, L.; Murgioni, C.; La Colla, P. Chem. Pharm. Bull. 2001,
49, 1406. Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F.
Tetrahedron Lett. 2003, 44, 4443.
(4) Some recent applications of the Paal-Knorr synthesis: Dong, Y.;
Naranjan, N.; Ablaza, S. L.; Yu, S.-X.; Bolvig, S.; Forsyth, D. A.; Le
Quesne, P. W. J. Org. Chem. 1999, 64, 2657. Haubmann, C.; Huebner, H.;
Gmeiner, P. Bioorg. Med. Chem. Lett 1999, 9, 3143. Robertson, J.; Hatley,
R. J. D.; Watkin, D. J. J. Chem. Soc., Perkin. Trans. 1 2000, 3389. Wurtz,
N. R.; Turner, J. M.; Baird, E. E.; Dervan, P. B. Org. Lett, 2001, 3, 1201.
Ballini, R.; Bosica, G.; Fiorini, G.; Giarlo, G. Synthesis 2001, 2003. Braun,
R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297. Arrowsmith, J.;
Jennings, S. A.; Clark, A. S.; Stevens, M. F. G. J. Med. Chem. 2002, 45,
5458. For other syntheses of pyrroles, see: Bartolo, G.; Salerno, G.; Fazio,
A. J. Org. Chem. 2003, 68, 7853 and references therein.
† NiKem Research srl.
(1) The name pyrrole comes from πυFFïσ and ꢀλRιïν (red oil): Runge,
R. Ann. Physik. 1834, 31, 67. See also: Bayer, A; Emmerlung. H. Chem.
Ber. 1870, 3, 517.
(2) Gossauer, A. Die Chemie der Pyrrole; Springer-Verlag: Berlin, 1974.
Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F., Eds.; Pergamon Press: Oxford, 1996; Vol.
2, p 207. Fu¨rstner, A. Synlett 1999, 1523. Higgins, S. Chem. Soc. ReV.
1997, 26, 247.
10.1021/ol0362820 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/03/2004

nonsymmetrically substituted 1,4-dicarbonyl compounds. The
classical approach to this class of products is the condensation
of enolates with phenacyl bromides,5 thus limiting the
preparation to pyrroles with aryl substituents. Alternative
approaches need several steps of reactions with chromato-
graphic separations to obtain the intermediates for cyclization.
Consequently, there is still room for improvement to the
synthesis, particularly with regard to rapid access of pyrroles
starting from commercially available intermediates.
a simplification of the mixture. After removing the Cr salts
originating from the PCC, we observed the exclusive
formation of compound 4 that was isolated as a crude product
suitable for use in the next steps.
This synthetic sequence was found to have general
application for the substrates described in Table 1 where the
Table 1. 1,4-Dicarbonyl Compounds Prepared as Reported in
Scheme 2
Scheme 1
R1
R2
product
yield (%)
t-Bu
t-Bu
Et
Et
Et
Ph
4
5
6
7
8
9
90
86
91
90
91
92
CH2-CH2-Ph
Ph
CH2Ph
C3H7
p-Cl-C6H4
As part of a program assessing the application of micro-
wave chemistry in parallel synthesis of biologically relevant
products,6 we considered the possibility of preparing polysub-
stituted pyrroles via the Paal-Knorr reaction. The synthesis
of pyrrole by microwave (MW)-assisted dehydrogenation of
pyrrolidines with MnO2 and by reaction of 2,4-hexandione
with amines neat or in montmorillonite in a microwave cavity
has been previously reported.7 Before approaching a sys-
tematic study of the Paal-Knorr cyclization, we took into
account the preparation of differentially substituted 1,4-
diketones. In this respect, we found the functional homolo-
gation of a â-ketoester with an aldehyde recently reported
by Zercher and co-workers to be very attractive.8 Following
this report, we reacted methyl 4,4-dimethyl-3-oxopentanoate
1 with Et2Zn, CH2I2, and benzaldehyde, obtaining product 2
as a mixture of diasteroisomers. In this reaction, hemiacetal
3 was also formed as evidenced by chromatographic and 1H
NMR analysis (Scheme 2). Instead of trying to separate and
Et
yields of the 1,4-dicarbonyl compounds 4-9 obtained with
this reaction are reported. To speed up the procedure, the
mixture obtained after the addition of the aldehyde was
quenched with silica gel. After the mixture was stirred for
an additional 30 min and filtering under vacuum, the solvent
was evaporated and the crude product obtained was directly
submitted to PCC oxidation. Again, after a complete oxida-
tion, filtration on a short path of silica provided pure 1,4-
dicarbonyl compounds without any hydrolytic workup.9
The first step of the reaction was extremely sensitive to
the presence of acid that could quench the intermediate anion
generated by rearrangement of the oxycyclopropyl derivative
(produced by reaction of the â-keto ester in the enolic form).8
The presence of traces of water generated the ketoester 2b
and even when an aldehyde having a NHCbz group was used,
the main reaction product was the same ester. Only when
the reaction mixture was stirred for more than 2 h did we
observe the formation of the methoxy derivative 2c as
previously reported by Zercher.8 It is obvious that in this
case we had to purify the product by flash chromatography.
The main byproduct observed in the first step was the
unreacted aldehyde that was probably transformed in the next
step into acid, separable in the short-path chromatography.
Regarding the second step, we observed higher yields using
PCC freshly prepared10 instead of using commercially
available samples. The oxidation took 12-24 h, and in some
Scheme 2a
a Conditions: (a) Et2Zn, CH2I2 followed by PhCHO, SiO2. (b)
PCC, CH2Cl2, SiO2.
(6) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M.; Taddei, M.
J. Comb. Chem. 2003, 5, 465. Lampariello, L. R.; Piras, D.; Rodriquez,
M.; Taddei, M. J. Org. Chem. 2003, 68, 7893.
(7) (a) Oussaid, B.; Garrigues, B.; Soufiaoui, M. Can. J. Chem. 1994,
72, 2483. (b) Ruault, P.; Pilard, J. F.; Touaux, B.; Texier-Boullet, F.;
Hamelin, J. Synlett 1994, 935. (c) Danks, T. N. Tetrahedron Lett. 1999,
40, 3957.
(8) Lai, S.; Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Taples, R. J. Org.
Lett. 2001, 3, 4169.
isolate the components of the mixture, we carried out the
oxidation of the crude reaction with PCC in CH2Cl2 at room
temperature. Inspection on the TLC of the reaction showed
(9) This procedure was carried out in our laboratory using a parallel
synthesizer such as Syncore from Buchi.
(10) Corey, E. J.; Suggs, J. W. Tetrahedron Lett, 1975, 2647.
(5) See for example: Pinna, G. A.; Curzu, M. M.; Sechi, M.; Chelucci,
G.; Maciocco, E. Il Farmaco 1999, 54, 542.
390
Org. Lett., Vol. 6, No. 3, 2004

Scheme 3a
Scheme 4
a Conditions: (a) EtOH, HCl, MW, 3 min. (b) NaOH, EtOH/
H2O reflux, 6 h.
cases, additional amounts of PCC were needed to induce a
complete conversion of the starting material into the desired
1,4-diketones. Attempts to speed up the reaction by heating
(traditional and microwave) gave lower yields of the
products. Also, the use of other oxidant (PDC, MnO2,
TEMPO in the presence of different co-oxidants) gave
unsatisfactory results.
a Conditions: (a) NaOH, EtOH/H2O, reflux, 10 min. (b) Toluene,
reflux, 12 h. (c) DIBAL-H, toluene 0 °C, 2 h. (d) MePPh3Br, BuLi,
THF 2 h, 66% overall yield.
First attempts to cyclize compound 4 were carried out in
acidic conditions.11 Heating a solution of ketone 4 in EtOH/
H2O in the presence of catalytic amounts of HCl in a sealed
tube inserted into a microwave cavity generated the furan
10 in 3 min at 140 °C and a maximum internal pressure of
120 psi.12 After the mixture was cooled, the furan was
extracted with diethyl ether and isolated in 95% yields and
in good purity (GC-mass and NMR analysis).13 The carboxyl
group could be removed by saponification followed by
decarboxylation with NaOH in boiling EtOH/H2O. Starting
from ketoesters 5 and 9 we obtained furans 12 and 13
(Scheme 3) in very good yields. This procedure allowed the
preparation of these furans in two simple steps with chro-
matography separation required in the last step exclusively
for an analytical sample.
It is worth noting that, when the reaction was conducted
under traditional heating, good yield of pyrrole 14 was not
obtained after 12 h of heating at 110 °C (external oil bath
150°). After this period, the starting material was still present
in the reaction medium that had begun to become very dark
with formation of less than 15% of the desired product.
Microwave-assisted Paal-Knorr cyclization was carried
out on different 1,4-diketoesters in the presence of different
amines and always gave the expected pyrroles 14-22 in good
yields (see Table 2). After aqueous alkaline workup, the
Table 2. 1,2,3,5-Tetrasubstituted Pyrroles Prepared as
Reported in Scheme 3
For the preparation of the pyrrole, we explored different
conditions. Microwave heating of the ketone 4 in the
presence of benzylamine used as a solvent (as described in
the literature)7c did not produce the expected pyrrole.
Analogously, when different amounts of acids were used to
catalyze the reaction, furan 10 was the main product of the
cyclization. Pyrrole 14 was effectively obtained by heating
a solution of ketone 4 in the presence of benzylamine in
acetic acid in a sealed tube in a microwave cavity heated to
180 °C for 3 min (maximum internal pressure ) 120 psi).
Exactly the same result was obtained by heating an open
round-bottomed flask equipped with a reflux condenser under
microwave irradiation (internal temperature 150°) for 5 min.14
(11) Knorr, L. Chem. Ber. 1884, 17, 1635.
(12) All the experiments under microwave irradiation were carried out
using a Discover System from CEM.
(13) For a microwave-mediated transformation of a 1,4-diketones into
furan, see: Rao, H. S. P.; Jothilingam, S. J. Org. Chem. 2003, 68, 5392.
(14) Although the boiling temperature of acetic acid is about 118 °C,
this was the internal temperature recorded by the Discover System during
the experiments. Using the open flask method, we could prepare pyrrole
14 in a 2.5 g scale
products were extracted with ethyl acetate and purified by
column chromatography. When neutral amines were used,
Org. Lett., Vol. 6, No. 3, 2004
391

we observed also the formation of different amounts of the
corresponding acetamides. These kinds of byproducts were
not present using amines with an additional basic center, as
in the case of the preparation of compound 22 in Table 2.
Saponification of 14 with NaOH gave acid 15a, which could
be decarboxylated in boiling toluene to give 15b.
Alternatively, reduction with DIBAL-H of 14 gave alde-
hyde 16, which was submitted to Wittig reaction conditions
to give product 17.
In conclusion, we have described a new rapid and versatile
approach to trisubstituted furans and tetrasubstitued pyrroles
in few highly efficient steps starting from commercially
available â-ketoesters. Additional work is in progress in order
to obtain different kinds of heterocycles using the same
strategy.
Acknowledgment. The work was financially supported
by MIUR (Rome) as a project within PRIN-2002 and by
the University of Siena as a PAR project 2002.
Supporting Information Available: Experimental gen-
eral procedure and spectra of compounds 14-22. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0362820
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Org. Lett., Vol. 6, No. 3, 2004