Access to pyrrole-based heterocyclic compounds via addition of pyrrole to C=C and C=N bonds

Introduction

Pyrrole is an important chemical motif in organic chemistry and its derivatives are widely used in the synthesis of pharmaceuticals, agrochemicals, dyes, photographic chemicals, perfumes and other organic compounds [1–3]. Pyrrole-based organic structures, tetrapyrrolic heme and chlorophyll, have significant importance in the metabolism of living organisms and named as “pigments of life”. Additionally, pyrrolic compounds are main constituents of many heterocyclic compounds such as indolizidines [4], pyrrolizines [5], porphyrins [6] and expanded porphyrins [7]. Due to this importance of pyrrole derivatives, functionalization of pyrrole compounds and their chemistry are ongoing research areas in organic synthesis.

One of the major approaches for the functionalization of pyrroles is the Friedel-Crafts alkylation by using suitable Lewis acid catalysts. The main problem with this method is the oligomerization of pyrrole in the reaction medium due to its sensitivity to acidic environments. Recently, a variety of catalysts such as indium chloride [8], copper bromide [9] and zirconium [10] under mild reaction conditions have been applied to overcome this problem. Studies in this area are currently focused on the investigation of eco-friendly, reusable new catalysts with high selectivity, high stability and low toxicity. As part of these studies, metal triflates have been shown to be efficient, water stable and reusable catalysts in promoting regioselective and stereoselective alkylation of pyrrole compounds [11, 12].

Over the past ten years we have been working on the development of new synthetic methods for the synthesis of pyrrole-based heterocyclic compounds including pyrrolizines and porphyrins. The first step in these studies is the addition of pyrrole to C=C or C=N bonds in the presence of metal triflates. These reactions supply important intermediates for the preparation of [5-5] nitrogen containing bicyclic heterocycles and macrocyclic aromatic porphyrins. In this paper, we review our results on the synthesis of pyrrole-based heterocyclic systems starting from the addition of pyrroles to C=C and C=N bonds in the presence of metal triflate catalysts (Scheme 1).

Scheme 1

Synthesis of pyrrole-based heteroaromatics.

Addition of pyrrole to C=C bonds

Bridgehead nitrogen heterocycles have been playing an important role in medicinal chemistry since they are used as key templates in the development of important therapeutic agents [13]. Among these heterocycles, pyrrolizine derivatives have been identified as analgesic, anti-inflammatory agents, aromatase and tumor inhibitors [14]. Although pyrrolizines can be isolated from nature, synthetically they can be accessible through the cyclization of N-alkyl and C-alkylpyrrole derivatives [15, 16]. Different approaches have been used to synthesize pyrrolizines such as base-catalyzed condensation [17], flash vacuum pyrolysis [18–20], intramolecular cyclization of C-alkylpyrrole derivatives in the presence of Na₂CO₃ [21], intramolecular Wittig reaction of N-substituted phosphorus ylides [22, 23], and boron tribromide [16].

Pyrroles bearing different functional groups are important precursors in the synthesis of bicyclic heterocycles. These precursors could be obtained by addition of pyrrole to α,β-unsaturated compounds containing electron-withdrawing groups at the α-position, such as alkoxycarbonyl, carbonyl, cyano, sulfinyl, sulfonyl or phosphoryl groups which are valuable Michael acceptors [24].

We have chosen ester, cyano, ketone and phosphonate functionalized active methylene compounds for the synthesis of Michael acceptors [25–30]. These acceptors could easily be obtained by the Knoevenagel condensation of active methylene compounds and aldehydes. Addition of pyrrole to these Michael acceptors requires a catalyst. Therefore we searched different types of catalysts such as Lewis acids, protic acids and clays in these reactions and among the tested catalysts, metal triflates showed the highest efficiency.

We first studied the addition of pyrrole or homochiral pyrroles 1 to α-oxo-β,γ-unsaturated esters 2 and 4 (Scheme 2) [25, 27] and tested the activities of different metal triflates for both reactions. While Y(OTf)₃ was the most efficient catalyst for the synthesis of alkylated homochiral pyrroles 3 (50–84 % yield), Cu(OTf)₂ gave the highest yield for 5 in the addition of pyrrole to α-oxo-β,γ-unsaturated esters 4 (45–83 % yield).

Scheme 2

Addition of pyrroles to α-oxo-β,γ-unsaturated esters.

In other studies, 2-benzylidenemalonates 6a, methyl 2-cyano-3-phenylacrylates 6b and 2-benzylidenemalononitriles 6c were used as Michael acceptors for addition reactions [26, 28, 29]. The best results were obtained in the presence of Gd(OTf)₃ for 2-benzylidenemalonates and with Cu(OTf)₂ for methyl 2-cyano-3-phenylacrylates and 2-benzylidenemalononitriles (Scheme 3).

Scheme 3

Addition reactions of pyrrole to different Michael acceptors.

The success of metal triflate-catalyzed addition reactions to different Michael acceptors directed our work towards the synthesis of heterocyclic organophosphorus compounds that exhibit a wide range of bioactivities such as Edg receptor antagonistic, bone-resorption inhibitory, antibiotic, antibacterial and antifungal properties [31–35]. For the synthesis of these structures, addition reaction of pyrrole to vinylphosphonates in the presence of Sc(OTf)₃ was employed for the first time (Table 1, entry 5) [30].

Table 1

Selected examples of the addition reactions of pyrrole to α,β-unsaturated compounds.

Entry	R1	R2	Yield %	Cat	Product	Ref
1	CO2CH3	CO2CH3	80	Gd(OTf)3	7	[26]
2	H	COCO2CH3	83	Cu(OTf)2	8	[27]
3	CN	CO2CH3	90	Cu(OTf)2	9	[28]
4	CN	CN	65	Cu(OTf)2	10	[29]
5	CO2CH3	PO(OCH3)2	98	Sc(OTf)3	11	[30]

Some selected examples of addition reactions of pyrrole are given in Table 1. All alkylated pyrrole derivatives 7–11 were obtained regioselectively with high yields. The experimental results showed that different metal triflates should be tested for each Michael acceptor in order to obtain the best result.

The obtained Michael adducts are very convenient structures to access [5-5] membered ring system of pyrrolizines (Scheme 4). On the basis of this concept, we continued to the synthesis of novel pyrrolizines through the intramolecular cyclization of C-alkylated pyrroles. Reaction of dimethyl 2-(phenyl(1H-pyrrol-2-yl)methyl)malonate (7) with NaH in THF at 0 °C yielded methyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolizine-2-carboxylate (12). Derivatives of dimethyl 2-(phenyl(1H-pyrrol-2-yl)methyl)malonate gave the corresponding methyl 3-oxo-2,3-dihydro-1H-pyrolizine derivatives in 65–78 % yield by intramolecular cyclization reactions [26].

Scheme 4

Intramolecular cyclization of C-alkylated pyrroles.

Intramolecular cyclization reaction of methyl 3-phenyl-2-cyano-3-(1H-pyrrol-2-yl)propanoate (9) in THF at 50 °C gave the 3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolizine-2-carbonitrile (13) in 63 % yield. Further reactions of the derivatives of methyl 3-aryl-2-cyano-3(1H-pyrrol-2-yl)propanoates with NaH in the optimized conditions formed the corresponding pyrrolizines in 43–89 % yields in trans configuration [29]. Additionally, the synthesized methyl 2-(dimethoxyphosphoryl)-3-phenyl-3-(1H-pyrrol-2-yl)propanoate (11) and its substituted phenyl derivatives were very convenient starting materials for the synthesis of 14 and its derivatives. Their intramolecular cyclization reactions in THF at rt gave the novel phosphoryl pyrrolizines in 44–99 % yield [30]. Configurations of the synthesized phosphoryl pyrrolizines were assigned as trans according to their vicinal coupling constants that were ranging between 4.0 and 4.4 Hz. Cyclization products, methyl 3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolizine-2-carboxylates 12 and phosphoryl pyrrolizines 14, were obtained as single diastereomers and 3-oxo-1-phenyl-2,3-dihydro-1H-pyrrolizine-2-carbonitriles 13 were obtained with high diastereoselectivity.

Unlike other alkylated pyrrole derivatives, methyl 2-oxo-4-phenyl-4-(1H-pyrrol-2-yl)butanoate (8) gave the cyclization product only by heating without using any reagent [27]. All derivatives of methyl 2-oxo-4-phenyl-4-(1H-pyrrol-2-yl)butanoate (5a) were transformed to methyl 3-hydroxy-1-phenyl-2,3-dihydro-1H-pyrrolizine-3-carboxylates (15a-h) quantitatively by intramolecular self-cyclization reaction between pyrrole nitrogen and keto group (Scheme 5).

Scheme 5

Intramolecular self-cyclization of C-alkylated pyrroles.

Addition of pyrrole to C=N bonds

Even though the addition of pyrrole to C=C bond offers a wide range of alkylated pyrroles, addition of pyrrole to C=N bonds that allows to access many macro heterocyclic compounds is still a challenge in terms of synthetic approach. We investigated the synthesis of aminoalkylated pyrrole derivatives from the addition of pyrrole to N-tosyl imines with the aim to access porphyrin macrocycles and their substructures [36]. The classical method for pyrrole alkylation with C=N bonds is the Mannich reaction [37, 38]. The reactions of pyrroles with imines in the presence of Lewis acid or protic acid catalysts are known methods to synthesize aminoalkylated pyrrole derivatives [39, 40]. In the light of our previous studies on metal triflate-catalyzed reactions, we searched the addition of pyrrole to N-tosyl imines 16 (Scheme 6). In this context, we optimized the reaction conditions and alkylated products 17 were obtained in 44–80 % yields with 10 mol % of Cu(OTf)₂ at 0 °C [36].

Scheme 6

Addition reaction of pyrrole to N-tosyl imines.

When the same reaction was carried out with 2 equivalents of pyrrole at room temperature, meso-substituted dipyrromethane products 18 were obtained as side products in 15–20 % yields (Scheme 7).

Scheme 7

Synthesis of meso-substituted dipyrromethanes.

After the successful addition of pyrrole to N-tosyl imines, along with obtaining dipyrromethane as a promising side product, we turned our attention to the synthesis of meso-substituted dipyrromethanes as main products by in situ addition of a second pyrrole to pyrrolesulfonamide structure [41].

meso-Substituted and β-substituted dipyrromethane derivatives are important starting materials of many macro heterocyclic aromatic compounds including porphyrins [42, 43], expanded porphyrins [44] and corroles [45]. In order to synthesize these important synthons, various metal triflates, reactant ratio and temperature were screened. Two different metal triflates, Gd(OTf)₃ and Cu(OTf)₂, gave the product with comparable yields. At the optimum conditions, 40 equivalents of pyrrole was used both as solvent and reactant. While dipyrromethanes with electron donating substituents formed in high yields at room temperature (Table 2, entries 1–5), dipyrromethanes with electron withdrawing substituents could be obtained at 100 °C (Table 2, entries 6–10). Optimized reaction conditions for all meso-substituted dipyrromethane products are summarized in Table 2 [41].

Table 2

Optimized conditions for the synthesis of meso-substituted dipyrromethanes.

Entry	R	Catalyst	Temperature	Yield (%)
1	C6H5-	Gd(OTf)3	rt	69
2	4-CH3O-C6H4-	Cu(OTf)2	rt	85
3	2-CH3O-C6H4-	Gd(OTf)3	rt	71
4	4-CH3-C6H4-	Gd(OTf)3	rt	83
5	2-OH-C6H4-	Gd(OTf)3	rt	90
6	4-NO2-C6H4-	Gd(OTf)3	100 °C	79
7	4-CF3- C6H4-	Cu(OTf)2	100 °C	85
8	4-F-C6H4-	Gd(OTf)3	100 °C	70
9	4-Cl-C6H4-	Gd(OTf)3	100 °C	71
10	4-Br-C6H4-	Gd(OTf)3/Cu(OTf)2	100 °C	74

The success in the synthesis of dipyrromethanes with high yields encouraged us to investigate the use of these important building blocks in the synthesis of meso-substituted porphyrins. The main approach in the literature for the porphyrin synthesis is the reaction of pyrrole or dipyrromethane with aldehydes in the presence of various Lewis or protic acids [46, 47]. Development of alternative synthetic methods to aldehyde condensation affording porphyrin products with high yield is a challenge of porphyrin chemistry. Some of these methods are self condensation reactions of aminomethyl substituted pyrroles (I) [48] or condensation of pyrrole with bis(aminomethyl)dipyrromethanes (II) [49] and bis(aminomethyl)pyrroles (III) [50].

Although the synthesis of these starting materials appears to be simple with Mannich reaction, the method only allows the synthesis of A₂- and AB-type porphyrin products. In order to contribute the use of aminoalkylated pyrrole derivatives in porphyrin chemistry, we studied the reaction of dipyrromethanes with N-tosyl imines in the presence of catalytic amounts of metal triflates. Porphyrins were obtained by a two-step reaction consisting in situ formation of porphyrinogens 19 and its oxidation with DDQ. All parameters were optimized (10 mM of reactants, 10 mol % Cu(OTf)₂, DCM and 1.5 h reaction time) by considering the sensitivity of porphyrins to reaction conditions. In the optimized reaction conditions, A₄-type meso-substituted porphyrins 20 were isolated in 13–45 % yields comparable to those reported previously (Scheme 8) [51].

Scheme 8

Synthesis of meso-substituted porphyrins.

This new method was also applied in the synthesis of trans-A₂B₂-porphyrins 21 by condensation of 5-phenyldipyrromethane with different N-tosyl imines and desired products were obtained in the range of 18–30 % yields (Scheme 9). The scrambling level of the products was detected by MALDI-TOF analysis and only trace amounts of scrambled porphyrins were observed [51].

Scheme 9

Synthesized trans-A₂B₂-porphyrins.

To gain insight into the mechanism of this reaction, mono and bissulfonamidealkyldipyrromethanes were subjected to condensation reactions. While the condensation of bisalkylated dipyrromethane 23 furnished the porphyrin (18 %), self condensation of sulfonamidealkyldipyrromethane 22 led to high yield (42 %) of porphyrin (Scheme 10). Therefore, sulfonamidealkyldipyrromethane structure was determined as the main intermediate in the formation of meso-substituted porphyrins [51].

Scheme 10

Synthesis of porphyrins from mono and bissulfonamidealkyldipyrromethanes.

After the development of a new method for the synthesis of meso-substituted porphyrins under mild reaction conditions with low scrambling level, the use of N-tosyl imines in pyrrole chemistry was broadened to the synthesis of triheteroarylmethanes which have diverse applications in the areas of non-linear optics, conducting polymers and food industry [52].

Initially, all reaction parameters were optimized using a model reaction. Cu(OTf)₂ and Montmorillonite K-10 clay were found to be the most suitable environment-friendly catalysts for the reaction of aryl substituted N-tosyl imines with excess amount of heteroaromatic compounds. Triheteroarylmethanes 24 including different aromatic groups (pyrrole, furan, thiophene and indole) were synthesized in moderate to high yields in the presence of recoverable, non-toxic and environmentally benign catalysts under mild reaction conditions (Scheme 11) [53].

Scheme 11

Synthesis of triheteroarylmethanes.

Conclusion

The metal triflate-catalyzed addition reaction of pyrrole to C=C and C=N bonds outlined in this paper furnishes the synthesis of [5-5] bicyclic heteroaromatics and macrocyclic structures. C-C bond formation by addition of pyrrole to Michael acceptors or N-tosyl imines is performed under mild reaction conditions. The synthesis of C-alkylated pyrrole derivatives provides a straightforward approach to pyrrolizines. The addition reaction of pyrrole to N-tosyl imines is very productive to access pyrrole sulfonamides, meso-substituted dipyrromethanes, and triheteroarylmethanes. This new metal triflate-catalyzed approach also allows to obtain A₄- and trans-A₂B₂-meso-substituted porphyrins.