Layered zirconium phosphate and phosphonate as heterogeneous catalyst in the preparation of pyrroles

Article abstract of DOI:10.1016/S0040-4039(03)00810-4

Pyrroles may be prepared by condensation of alkyl and aryl amines and 1,4-diketones (Paal-Knorr reaction) under potassium exchanged layered Zirconium phosphate and zirconium sulfophenyl phosphonate catalyst in solvent free conditions.

Full text of DOI:10.1016/S0040-4039(03)00810-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3923–3925
Layered zirconium phosphate and phosphonate as heterogeneous
catalyst in the preparation of pyrroles
Massimo Curini,a,* Francesca Montanari,a Ornelio Rosati,a Eduardo Lioyb and Roberto Margaritab
aDipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Via del Liceo 1, Universita` degli Studi,
06123 Perugia, Italy
bBristol Myers Squibb Srl, Via del Murillo Km 2.8, 04010 Sermoneta (LT), Italy
Received 3 March 2003; revised 24 March 2003; accepted 27 March 2003
Abstract—Pyrroles may be prepared by condensation of alkyl and aryl amines and 1,4-diketones (Paal–Knorr reaction) under
potassium exchanged layered Zirconium phosphate and zirconium sulfophenyl phosphonate catalyst in solvent free conditions.
© 2003 Elsevier Science Ltd. All rights reserved.
It is well established that many acidic and basic solids
can act as catalysts or promoters in liquid-phase
organic synthesis.1 Surface mediated solid-phase reac-
tion are of growing interest due to their ease of set-up,
mild conditions, rapid reaction, selectivity, increased
yields, high purity of products and low cost, compared
with their homogeneous counterpart.2
acid-base interaction, can decrease the amines availabil-
ity.
The reaction takes from 30 min to 24 h and after a
simple
work-up
affords
N-substituted
2,5-
dimethylpyrroles (Scheme 1).
As shown in Table 1, several aliphatic and aromatic
amines gave the corresponding N-substituted pyrroles
in good to excellent yield. It is important to note that
the steric hindrance effect (entry 3, 6) of some amines
decreases the reaction yield and in the case of
adamantylamine (entry 12) we did not observe any
reaction.
Based on our previous experience in the use of potas-
sium exchanged layered zirconium phosphate3 [a-
Zr(KPO4)2, surface area=15.5 m2/g, 11<pKa<11.84] as
basic catalyst and zirconium sulfophenyl phosphonate
[a-Zr(O3PCH3)1.2(O3PC6H4SO3H)0.8, surface area=24
m2/g, −5.6<pKa<−8.4]5 as acid catalyst in organic syn-
thesis, we found that these catalysts were an excellent
promoter for the preparation of pyrroles by condensa-
tion of alkyl and aryl amines and 1,4-diketones.
The acid or basic catalysts do not present any differ-
ence about the time and the yield of the reaction when
aliphatic amines are used. Otherwise the a-
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 is more efficient than
a-Zr(KPO4)2 in the reactions of 2,5-hexanedione with
less basic aromatic amines, because it is possible an
activation of 2,5-hexandione, by the acid catalyst, via
oxygen protonation.
Although various methods are known for the synthesis
of pyrroles by Paal–Knorr condensation6 only a little
attention has been paid to the use of basic or acid solids
for this purpose.7
The condensation reaction was carried out by adding
the acid (or basic) catalyst (in the proper % ratio) to a
stirred mixture of 2,5-hexanedione (1 mmol) and amine
(2 mmol) at room temperature.8 The use of 2 equiv. of
amine affords a valuable increase of the reactions
yields, especially in the case of a-Zr(CH3PO3)1.2
-
(O3PC6H4SO3H)0.8 where absorption effect, due to
* Corresponding author. Tel.: +39-075-5855106; fax: +39-075-
5855116; e-mail: curmax@unipg.it
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00810-4

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M. Curini et al. / Tetrahedron Letters 44 (2003) 3923–3925
Table 1. Pyrroles derivatives produced via Scheme 1
Entry
R
a-Zr(KPO4)2
Yield (%)b
a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8
Time (h)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
n-Propyl
n-Butyl
sec-Butyl
iso-Butyl
1
1
5
2
2
24
24
24
24
24
24
24
85
95
72
78
81
48
79
65
56a
1
1
5
2
2
24
2
20
2
20
20
24
87
99
76
79
89
Benzyl
Cyclohexyl
p-Methoxyphenyl
o-Hydroxyphenyl
Phenyl
p-Nitrophenyl
2-Pyridinyl
Adamantyl
52
91
94
9
88a
68a
47a
a
10
11
12
–
–
a
a
a
–
–
a The reaction was carried out at 60°C.
b Isolated yields.
The reported procedure clearly demonstrates that lay-
ered zirconium phosphate and phosphonate are both
good catalysts for the preparation of N-alkyl-2,5-
dimethylpyrroles, while the acid catalyst is preferable
for the preparation of N-aryl-2,5-dimethylpyrroles.
5. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Nocchetti, M. Tetrahedron Lett. 2002, 43, 2709–2711 and
references cited therein.
6. Cooney, J. V.; McEwen, W. E. J. Org. Chem. 1981, 46,
2570–2573.
7. (a) Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis
1986, 409–411; (b) Sreekumar, R.; Padmakumar, R.
Synth. Commun. 1998, 28, 1661–1665; (c) Samajdar, S.;
Becker, F. F.; Banik, B. K. Heterocycles 2001, 55, 1019–
1022.
8. General procedure: To a mixture of amine (2 mmol) and
2,5-hexanedione (1 mmol), under stirring and at room
temperature (or 60°C, see Table 1), catalyst (12% molar
The important features of our method are: mild reac-
tion conditions, simple work-up and recyclable nature
of the catalysts employed9 whose preparation does not
require any particular skill.10,11 Furthermore, the lower
quantity of a-Zr(KPO4)2 (12% molar) or a-
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 (6% molar) required
in this procedure respect to solid catalysts (e.g. Al2O3,
zeolites, montmorillonites) used in analogous methods
reported in literature, make ours catalysts highly
efficient.
for
a-Zr(KPO4)2
or
6%
molar
for
a-
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8
)
was added. After
appropriate time the reaction was diluted with
dichloromethane, filtered on buckner and washed with a
5% HCl solution to remove the amine excess. The organic
solution was evaporated under vacuum affording the
pyrrol derivative with good purity.
Studies for the application of our method to the synthe-
sis of several heterocyclic compounds are under investi-
gation in our laboratory.
Analytical data for selected compounds:
2,5-Dimethyl-1-butyl-1H-pyrrole: (pale yellow oil); 1H
NMR (CDCl3, 200 MHz) l 0.95 (t, J=7 Hz, CH3, 3H),
1.36 (m, CH2, 2H), 1.58 (m, CH2, 2H), 2.19 (s, CH3, 6H),
3.69 (t, J=8.3 Hz, CH2, 2H), 5.78 (s, pyrrolics, 2H);
GC/MS (m/z) (M+) 151, 136, 122, 108, 94. Anal. calcd
for C10H17N: C, 79.41; H, 11.33; N, 9.26. Found: C,
79.38; H, 11.37; N, 9.25.
Acknowledgements
The project is supported by Bristol Myers Squibb,
Sermoneta (Latina), Italy. We thank Professor
Umberto Costantino for helpful discussion.
1-Benzyl-2,5-dimethyl-1H-pyrrole: (white solid, mp 42–
1
44°C); H NMR (CDCl3, 200 MHz) l 2.14 (s, CH3, 6H),
5.03 (s, CH2, 2H), 5.87 (s, pyrrolics, 2H), 6.89 (m, PhH,
2H), 7.29 (m, PhH, 3H); GC/MS (m/z) (M+) 187, 170,
129, 107, 91. Anal. calcd for C13H15N: C, 84.28; H, 8.16;
N, 7.56. Found: C, 84.33; H, 8.15; N, 7.52.
References
1. (a) Hattori, H. Chem. Rev. 1995, 95, 537–558; (b) Corma,
A. Chem. Rev. 1995, 95, 559–614.
2. Kabalka, G. W.; Pagni, R. M. Tetrahedron 1997, 53,
7999–8065.
1-(4-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole: (pale yel-
1
low solid, mp 59–60°C); H NMR (CDCl3, 200 MHz) l
2.03 (s, CH3, 6H), 3.85 (s, OCH3, 3H), 5.88 (s, pyrrolics,
2H), 6.96 (m, PhH, 2H), 7.14 (m, PhH, 2H); GC/MS
(m/z) (M+) 201, 186, 171, 159, 145, 129. Anal. calcd for
C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.56;
H, 7.55; N, 6.94.
3. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Tsadjout, A. Synth. Commun. 2002, 32, 355–362 and
references cited therein.
4. The pKa was estimated by means of the indicator
method: Benesi, H. A. J. Am. Chem. Soc. 1956, 78, 5490.

M. Curini et al. / Tetrahedron Letters 44 (2003) 3923–3925
3925
2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyridine: (colourless oil);
1H NMR (CDCl3, 200 MHz) l 2.13 (s, CH3, 2H), 5.89 (s,
pyrrolics, 2H), 7.25 (m, PhH, 2H), 7.81 (m, PhH, 1H),
8.61 (m, PhH, 1H); GC/MS (m/z) (M+) 172, 157, 145,
130, 94. Anal. calcd for C11H12N2: C, 76.71; H, 7.02; N,
16.27. Found: C, 77.67; H, 7.05; N, 16.25.
following yields: 54, 57, 53% (a-Zr(KPO4)2) and 85, 84,
82 (a-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8).
10. For the preparation of a-Zr(KPO4)2, see: Alberti,
G.; Torracca, E. J. Inorg. Nucl. Chem. 1968, 30, 317–
318.
11. For the preparation of a-Zr(CH3PO3)1.2(O3PC6H4-
SO3H)0.8, see: Alberti, G.; Casciola, M.; Costantino, U.;
Peraio, A.; Montoneri, E. Solid State Ionics 1992, 50,
315–322.
9. The catalysts can be reused several times after washing
with dichloromethane and drying at 120°C for 12 h. The
reaction (entry 9) has been repeated three times with the