Convenient synthesis of substituted pyrroles via a cerium (IV) ammonium nitrate (CAN)-catalyzed Paal–Knorr reaction

1 Introduction

The pyrrole nucleus is, perhaps, the most important heterocycle abundantly found in bioactive natural molecules such as porphyrins and alkaloids (Katrizky, 2004; Sundberg, 1996). Pyrrole ring is also present in various drugs including many anti-inflammatants, immunosuppressants, COX-2 inhibitors, analgesic, antitubercular agents (Zhou and Giannakakou, 2005; Li et al., 1999; Doherty, 2004; Gribble, 1996; Biava et al., 2010) as well as the highly successful cholesterol-lowering drug atorvastatin (Lipitor, Fig 1), (Sawant and Maier, 2010). Additionally, pyrrole with 1,2,5-trisubstitution pattern exhibits remarkable biological properties as illustrated by the anti-inflammatory agents amtolmetin and tolmetin (Fig. 1), (Shue et al., 2004; Bertaccini and Coruzzi, 1998). As a result of their pharmaceutical significance, a number of methods have been developed for the preparation of substituted pyrroles. These include the Hantzsch reaction (Hantsch, 1890), conjugate addition reaction (Dieter and Yu, 2000), reductive coupling (Furstner et al., 1995), aza-Wittig reaction (Katrizky et al., 1994), and other multistep operations (Periasamy et al., 1999).

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Figure 1

Some pyrrole-containing drugs.

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However, the classical Paal–Knorr reaction, in which a 1,4 diketone is condensed with an amine, continues to be the most attractive method for the synthesis of pyrroles (Wang et al., 2004; Banik et al., 2005; Danks, 1999; Chen et al., 2006; Aghapoor et al., 2012). Despite its popularity, the Paal–Knorr reaction suffers from limitations such as drastic reaction conditions, high cost, poor yields, tedious workup and longer reaction time. Therefore, the development of milder and non-hazardous methods for pyrrole synthesis continues to be a very important area of investigation.

2 Results and discussion

In continuation of our ongoing investigations on the development of useful synthetic protocols suitable for applications in the field of combinatorial chemistry and chemistry-driven drug discovery (Kamal et al., 2007a,b, 2009, 2010) we undertook a study directed at developing cerium based catalysts for promoting the Paal–Knorr reaction under mild conditions. The results obtained in this study are presented in the following sections.

Cerium salts are inexpensive, soluble in many organic solvents, stable under aerobic condition and are less toxic. The most important cerium based reagent in organic synthesis is indubitably cerium (IV) ammonium nitrate (CAN), the usefulness of which was amply demonstrated by a wide array of synthetic transformations developed by Nair and Deepthi (2007).

The cerium salts selected for the study were cerium (III) chloride, cerium (IV) sulfate and CAN. They were screened as catalysts in the reaction between aniline 1 and hexane-2,5-dione 2 in methanol at room temperature and CAN emerged as a superior catalyst in terms of yields, catalyst loading and reaction time (Table 1).

In an attempt to find the optimum reaction conditions and to improve the overall efficiency of this CAN catalyzed Paal Knorr reaction, we examined the effect of the concentration of catalyst and the solvent used. It was observed that at a concentration of 5 mol percent, CAN provides the best results with 96% of pyrrole formation in 15 min. However, the decrease in concentration of CAN from 5% to 2.5% resulted in lower yields (Entry 7–8, Table 1). Additionally, the reaction was carried out in different organic solvents and a direct correlation between solubility of CAN (and polarity) and yield was observed (Toulene < CH₂Cl₂ < CH₃CN < EtOH < MeOH). The yields of product in different solvents are in a fashion as Toluene (yield: 35%) < CH₂Cl₂ (yield: 45%) < CH₃CN (yield: 75%) < EtOH (yield: 90%) < MeOH (yield: 96%)). Moreover, the reaction was also performed in the most polar solvent water, and the experimental yield after purification was 25%.

The optimized reaction conditions were then applied for the synthesis of a sortiment of 2,5-dimethyl pyrroles by the reaction of 2 with a series of aliphatic, heterocyclic and benzylic amines (Table 2). The addition of catalytic amount of CAN (5 mol%) typically resulted in the completion of the reaction within 10–20 min at ambient temperature. It is noteworthy that this protocol for the synthesis of pyrroles from polycyclic aromatic aniline (Table 2, Entry g) and heterocyclic amines (Table 2, Entry j, l, and r). Other notable pyrrole derivatives that were accessible by this method include N-phthalimido pyrrole 3i and the bis-pyrrole 3k. The use of nearly equimolar amounts of substrates in this protocol is advantageous when compared to the conventional methods that use excess of amine in order to promote the condensation (Curuni et al., 2003). Moreover, as no strong acid is used, the present method does not require neutralization after completion of the reaction. Finally, the method was scaled up to generate multigram quantities of pyrroles without any significant loss in yields.

Table 2 Synthesis of 1,3,5-substituted pyrroles from primary amines (1a–r) and diketone 2a using catalytic amount of CAN.

Entry	Substrate (1a-r)	Product (3a-r)	Time (min)	Yield (%)a
a			15	95
b			15	88
c			15	84
d			15	93
e			16	92
f			17	75
g			16	94
h	Ph–H2C–NH2		15	92
i			15	93
j			18	75
kb	NH2(CH2)NH2		18	88
l			17	85
m			15	88
n			16	89
o			15	88
p			18	84
q			15	85
r			18	83

a Isolated yield after column chromatography.

b Two equivalents of diketone 2a used.

Diaryl pyrroles constitute an important and privileged structural motif in the context of medicinal chemistry applications (Biava et al., 2010). In order to access these valuable pyrrole derivatives, substituted aryl diketones were employed in the CAN-catalyzed condensations (Table 3). Pleasingly, the reactions afforded a number of diaryl pyrroles in excellent yields under the optimal reaction conditions (Table 3).

Table 3 CAN-catalyzed synthesis of diaryl pyrrole from anilines and aryl diketones.

Entry	Amine	Diketone	Product	Time (min)	Yield (%)a
s				15	92
t				15	93
u				16	95
v				18	90
w				15	88

a Isolated yield after column chromatography.

Nair has reported that CAN effectively catalyzes the hydrolysis of acetals²¹ and this property was exploited in a one-pot synthesis of N-substituted pyrrole (1a) from 2,5-dimethoxytetrahydrofuran (2g) and primary amines. It is presumable that CAN initially deprotects the acetal functionality and subsequently promotes the Paal–Knorr reaction (Scheme 2). (See Scheme 1).

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Scheme 2

B.

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Scheme 1

A.

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3 Conclusion

In summary, the present CAN-catalyzed protocol provides a mild, efficient and practical variant of the Paal–Knorr pyrrole synthesis. Excellent yields of variously substituted pyrroles are obtained under ambient reaction conditions. Continued investigations to generate libraries of substituted pyrrole derivatives for applications in the field of chemistry-driven drug discovery are currently underway and the results will be reported in due course.

4 Experimental