An efficient synthesis of N-substituted pyrroles catalyzed by MgI₂ etherate

Introduction

Pyrroles are important heterocyclic compounds displaying remarkable pharmacological properties such as antibacterial, antiviral, anti-inflammatory, antitumoral and antioxidant activities (Fürstner et al., 1998; Jacobi et al., 2000; Fürstner, 2003). Furthermore, pyrroles are also considered to be important building blocks in many naturally occurring compounds such as heme, chlorophyll and vitamin B₁₂ (Santo et al., 1998; Ragno et al., 2000; Hoffmann and Lindel, 2003; Bellina and Rossi, 2006). In view of their important significance, preparation of pyrroles has attracted considerable attention of chemists in recent years. Many methodologies have been developed for the construction of the pyrrole moiety regarded as skeleton (Fang et al., 2012; Heugebaert et al., 2012). Among them, the Paal-Knorr synthesis remains the most useful preparative method for generating pyrroles (Aghapoor et al., 2012; Balme, 2012; Rahmatpour, 2012).

Recently, many methods for the synthesis of pyrroles, such as Paal-Knorr cyclization of primary amines and 1,4-diketones, have been developed in the presence of various Lewis acid catalysts, such as Ti(OⁱPr)₄ (Yu and Quesne, 1995), ZrOCl₂·8H₂O (Rahmatpour, 2011), Sc(OTf)₃ (Chen et al., 2006), Bi(NO₃)₃·5H₂O (Banik et al., 2004), UO₂(NO₃)₂·6H₂O (Satyanarayana and Sivakumar, 2011), BiCl₃/SiO₂ (Aghapoor et al., 2012), InCl₃ (Shanthi and Perumal, 2009) and FeCl₃ (Azizi et al., 2009). Some of the synthetic protocols suffer from disadvantages, such as the use of stoichiometric and even excess amounts of catalyst, harsh reaction conditions, prolonged reaction time, expensive reagents and low yield of the products. From the above viewpoints, the development of less expensive, environmentally benign and easily handled promoters for the synthesis of N-substituted pyrroles by Paal-Knorr condensation under neutral, mild and convenient condition is still highly desirable.

MgI₂ etherate is easily preparative, inexpensive and easier to be handled than other metal halides such as Ti(OⁱPr)₄, InCl₃ and Sc(OTf)₃. To the best of our knowledge, there is no report of the use of MgI₂ etherate as a mild catalyst for the Paal-Knorr reaction. In the continuation of our research field, herein, we will wish to report a simple and efficient procedure for the Paal-Knorr pyrrole condensation of primary amines with 2,5-hexadione catalyzed by MgI₂ etherate under mild reaction conditions in good to excellent yields (Scheme 1).

Scheme 1

MgI₂ etherate catalyzed Paal-Knorr condensation.

Results and discussion

We initiated our studies by carrying out the Paal-Knorr condensation of aniline with 2,5-hexadione in the presence of 3 mol% of MgI₂ etherate (1.0 m in Et₂O/benzene 1:2) in CH₂Cl₂ at room temperature. After stirring for 2.0 h, the desired 2,5-dimethyl-N-phenyl pyrrole (2a) was afforded in 93% yield. In order to evaluate the generality of this process, a variety of diversified examples illustrating the present method for the synthesis of 2,5-dimethyl-N-substituted pyrroles (2b–2o) were studied. The results are listed in Table 1. The reaction of 2,5-hexadione with a series of aromatic substituted primary amines bearing either electron-donating (Table 1, entries 2–5) or electron-withdrawing (Table 1, entries 6–9) groups on the aromatic ring was carried out as catalyzed by 3 mol% of MgI₂ etherate under mild conditions. As shown in Table 1, the reaction proceeded smoothly in Dichloromethane (DCM) at reflux and provided a single product without any side products in good to excellent yields. Furthermore, the substitution group on the phenyl ring could affect the yield and reaction rate in the Paal-Knorr reaction. We have observed the reactivity of anilines bearing an electron-donating group (i.e., -OMe, -OEt) reacted much faster than aniline-bearing electron-withdrawing group (i.e. -Cl, -F, -NO₂) and provided the corresponding products in excellent yields. The Paal-Knorr condensation of 2,6-diisopropylaniline with 2,5-hexadione also gave a good yield although it has a more sterically hindered effect (Table 1, entry 5). Furthermore, we have examined the Paal-Knorr reaction of aliphatic amines with 2,5-hexadione (Table 1, entries 10 and 11). Also, the corresponding products were obtained with excellent yields. Unfortunately, no reaction of tert-butylamine with 2,5-hexadione was observed under the same conditions, due to its higher steric hindrance. Under further observation, it is observed that the reaction of chiral amine such as (R)-(+)-1-(1-naphthyl)ethylamine 1l with 2,5-hexadione provided the optically pyrrole derivative without racemization. Moreover, we examined the reactivity of heterocyclic amines with 2,5-hexadione in the presence of MgI₂ etherate. Thus, using 3 mol% of MgI₂ etherate the Paal-Knorr reaction of heterocyclic amine such as 2-aminopyridine (1m) affords 2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (2m) in 92% yield (Table 1, entry 13). Therefore, heterocyclic amines exhibited analogous behavior to that of aromatic amines and aliphatic amines. Interestingly, the condensation of (R)-2-amino-2-phenylacetamide, which has two amino groups, exclusively gave (R)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-2-phenylacetamide (2n) with the retention of absolute configuration.

Table 1

Paal-Knorr condensation of 2,5-hexadione catalyzed by MgI₂ etherate^a.

Entry	Amine	t (h)	Productb	Yield (%)c
1	C6H5NH2	2	2a	93
2	3-MeOC6H4NH2	4	2b	80
3	3,4-(MeO)2C6H3NH2	2	2c	95
4	4-EtOC6H4NH2	2	2d	92
5	2,6-(iPr)2C6H3NH2	8	2e	76
6	2-FC6H4NH2	6	2f	74
7	3,5-F2C6H3NH2	4	2g	73
8	3-ClC6H4NH2	2	2h	86
9	4-NO2C6H4NH2	10	2i	78
10	4-CH3OC6H4CH2NH2	2	2j	90
11	4-ClC6H4(CH2)2NH2	2	2k	97
12		2	2l	78
13		2	2m	92
14		8	2n	70

^aThe reaction was carried out by the condensation of 2,5-hexadione (6 mmol) with primary amine (5 mmol) catalyzed by 3 mol% of MgI₂ etherate.

^bAll products were identified by their ¹H NMR spectra.

^cYields of products isolated by column chromatography.

The reaction using MgI₂ etherate as a catalyst has shown an important feature, that is, the ability to tolerate various amines including aliphatic, aromatic and heterocyclic amines. To extend the scope of MgI₂ etherate-catalyzed Paal-Knorr condensation for the synthesis of N-substituted pyrrole derivatives, other substituted diketones such as 1,4-diphenylbutane-1,4-dione and 1-phenylpentane-1,4-dione were investigated. Unfortunately, no reaction of 1,4-diphenylbutane-1,4-dione with p-methoxyaniline occurred. The condensation of 1-phenylpentane-1,4-dione with p-methoxyaniline or p-methoxybenzyl amine resulted in good yields (Scheme 2).

Scheme 2

Paal-Knorr condensation with 1-phenylpentane-1,4-dione catalyzed by MgI₂ etherate.

The high coordinating ability of magnesium (II) towards oxygen atoms of the carbonyl moiety is presumably responsible for the effective activation of ketonic carbonyl. To examine the halide anion effect, halogen analogs of MgI₂ etherate, MgCl₂ etherate and MgBr₂ etherate were compared under parallel reaction conditions (3 mol% of catalyst) in the Paal-Knorr condensation of aniline with 2,5-hexadione. MgCl₂ etherate and MgBr₂ etherate are less effective in terms of substrate conversion yield and provide the moderate yields. Apparently, the unique reactivity of MgI₂ etherate is attributed to the dissociative character of iodide counterion and a more Lewis acidic cationic [MgI]⁺ species.

In conclusion, we have demonstrated the unique reactivity of MgI₂ etherate in the Paal-Knorr reaction for the synthesis of N-substituted pyrroles. Compared to previously reported methodologies, the present protocol features simple operation, mild condition and good to excellent yield. Exploitation of this protocol for generation of novel multicyclic structures is actively pursued in our lab.

Experimental section