Send Orders for Reprints to [email protected] Current Organic Synthesis, 2017, 14, 1-18 1 REVIEW ARTICLE Green Synthesis of Pyrrole Derivatives Omar Miguel Portilla Zúñigaa, Ángel Gabriel Sathicqa, José Jobanny Martínez Zambranob and Gustavo Pablo Romanellia,c,* aCentro de Investigación y Desarrollo en Ciencias Aplicadas “Dr. Jorge J. Ronco” (CINDECA-CCT-CONICET), Universidad Nacional de La Plata, La Plata, Argentina; bEscuela de Química, Universidad Pedagógica y Tecnológica de Colombia, 15000 Tunja, Colombia; cCISAV. Cátedra de Química Orgánica, Facultad de Ciencias Agrarias y Forestales, Universidad Nacional de La Plata. Calles 60 y 119 s/n, B1904AAN La Plata, Argentina Abstract: Pyrroles are organic cyclic compounds with an extensive and fascinating chemistry. These compounds A R T I C L E H I S T O R Y have a wide structural variety and are an important basis in technological development as they can be used as Received: May 29, 2016 drugs, dyes, catalysts, pesticides, etc. Therefore, the production of these heterocyclic compounds by efficient Revised: October 26, 2016 clean methodologies is a great achievement in contemporary chemistry. In this paper, we show recent green pro- Accepted: November 15, 2016 cedures in the synthesis of pyrrole derivatives, such as Hantzsch, Knorr and Paal-Knorr syntheses, as well as new DOI: eco-friendly synthetic procedures with high efficiency and low environmental impact. 10.2174/1570179414666161206124 318 Keywords: Pyrrole, green synthesis, heterocyclic compounds, Hantzsch synthesis, Knorr synthesis, Paal-Knorr synthesis. lation and Wittig reactions [15]. However, these processes have 1. INTRODUCTION disadvantages such as the long reaction time, the use of toxic and The pyrrole core (1) is widely distributed in nature as the main volatile solvents, low yields, complex purification methods, and the structure of important molecules such as porphyrins and porphyrin need of high temperature for the occurrence of some reactions [16]. analogues: hemoglobin, chlorophylls, vitamin B12, cytochromes, Due to the diverse applications of pyrroles, there is a constant chlorine, bacteriochlorine, etc. [1] It is also a structural part of dif- search for environmentally compatible processes for their prepara- ferent secondary metabolites that have been used in therapeutic tion following the principles of Green Chemistry, i.e., cleaner, effi- drugs [2]. cient and safe processes. Within this framework, a wide variety of The pyrrole derivatives and analogues have interesting biologi- catalysts and sustainable methodologies have been developed, such cal activities, such as virus inhibition and specialized inhibition of as the use of microwave and ultrasound activation techniques [17], HIV virus [3], hepatoprotective, antimycotic, antibacterial [4], cho- and the replacement of conventional solvents with green solvents lesterol-lowering [5], antipsychotic, antihypertensive, anticarcino- such as ethanol, water and ionic liquids or processes performed gen, antimalarial and anticonvulsant activity [6]. These compounds under solvent-free conditions [18]. This paper reports the latest have an important role in other areas of technological advancement, results in pyrrole synthesis that aims to make the common reactions being used in sensor development, semiconductor synthesis [7], more eco-friendly for the preparation of these heterocyclic com- catalysts [8], corrosion inhibitors [9], preservatives [10], lumines- pounds using green methodologies. cence chemistry [11], and spectrochemical analysis [12]. Pyrrole has an aromatic structure with five members, including 2. SYNTHETHIC METHODS a nitrogen atom. Compared with other heterocyclic compounds 2.1. Knorr Pyrrole Synthesis such as pyridine, where the hydrogen atom is not bonded to nitro- This synthetic method involves the condensation of aminoke- gen, the pyrrole is a weakest base because the lone pair in the nitro- tone (2) and an -carbonyl compound (3), typically with active gen contributes to the aromaticity in the structure. methylene groups such as a -ketoester. The reaction proceeds with Pyrroles are unstable toward mineral acids and are protonated a heat treatment under acidic conditions to obtain tetra- and N-H in the 2-position. The resulting cation polymerizes easily produce substituted pyrroles (4) usually using acetic acid as solvent (Scheme pyrrole resins. The common reactions in pyrroles are electrophilic 2). substitutions in 2, 5-position [1]. Due to the fact that -amino ketones have a tendency to self- Pyrroles are obtained by three classical condensation methods: condense, it is preferred to generate them in situ from the corre- Hantzsch reaction [13], Knorr and Paal-Knorr reactions [14]. Other sponding nitrosoketones. The formation of the -nitrosoketone can pyrrole synthesis methods include multicomponent, addition, anne- be easily developed using HNO2 on a carbonyl compound, and subsequently, in the presence of a reducing agent (generally Zn dust), the -aminoketone (2) is produced. The N-substituted pyr- roles (5) can be synthesized from secondary -amino ketones and *Address correspondence to this author at the Centro de Investigación y Desarrollo en Ciencias Aplicadas “Dr. Jorge J. Ronco” (CINDECA-CCT-CONICET), Universidad when unsymmetrical ketones are used regioselectively, the larger Nacional de La Plata, Calle 47 N 257, B1900AJK. La Plata, Argentina; substituent is located in the C4 ring. The reaction mechanism in- E-mail: [email protected] volves the condensation of amine with the -carbonyl compound to 1570-1794/17 $58.00+.00 © 2017 Bentham Science Publishers 2 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al. H Br N HO COOH N Pyrrole core OH N H2N O N N HO N H H N HN N F O O H2N Cl N H NH Br Atrovastatin konbu´acidin A Br (Synthetic hypolipemiant) (Cyclin-dependent kinase 4 inhibitor isolated from Hymeniacidon sp.) O Cl H EtO2S N N N H O N 2-(1-ethylpyrrolidin-2-yl)-5-(5-(ethylsulfonyl)-2- O methoxyphenyl)-1H-pyrrole CO H 2 CO H (Synthetic antipsychotic) 2 Tolmetin Zomepirac H N O2N Cl N Cl O CO2H Pyrrolnitrin Ketorolac (Natural antifungal and antibiotic) (Synthetic analgesic and anti-inflammatory compounds) N N N Mg 2+ N N Fe N N N O HOOC CO2CH3 Chlorophyll-a Heme COOH O C20H34O (Biological supramolecular pyrrole derivatives) Scheme 1. R2 R3 R2 O acid or base/ O reducing agent + R R R R1 3 1 N 4 R4 solvent, heat HN R R (2) (3) (4) R= H, aryl, alkyl; R2=alkyl, CO2R; R2= alkyl, aryl; R3= electron-withdrawing group (EWG)= COR, CO2R, CN SO2R; R4=H, alkyl, aryl, CO2R; reducing agent: Zn/AcOH, NaS O , Pd(C)/H , solvent; AcOH, H O 2 4 2 2 Scheme 2. Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 3 R 2 R2 reducing R R HNO 1 2 O 2 O agent R 1 R1 solvent H2N O NO (5) (2) R R R R R 3 1 2 O H O R 1 2 R O R +H 3 3 2 + -H O R3 NH O 2 R4 H2N O H2O R4 R4 -H R4 N R1 -aminoketone imine (6) H R O R 3 2 R3 R2 O R3 HO R3 R tautomerization R 2 2 -H2O R N R R N R 4 1 4 1 R4 R H N R1 4 +H -H N R1 imine (6) enamine (7) R3 R3 R2 -H R2 R4 +H R4 N R1 N R1 1 H R = H, aryl, CO2R R2=Alkl, aryl 3 (1) R = electron-withdrawing group (EWG); COR, CO2R, CN, SO2R 4 R =H, alkyl, aryl, CO2R Reducing agent: Zn/CH3COOH, Na2S2O4, Pd(C)/H2 Solvent: CH COOH, H O 3 2 Scheme 3. H N Et N t-BuOMe, rt 2 Et2N + O O O NH2 O t-BuO O H , Pd/C, 45 psig, 65 - 70 °C= 77% 2 HN HN Zn, CH3COOH, 65 °C = 53% NEt2 Scheme 4. form the corresponding imine (6), and then a tautomeric equilib- products. These drawbacks are added to the environmental prob- rium produces an enamine (7) that can be cyclized via nucleophilic lems involved in the treatment of nonstoichiometric zinc salts. The attack on the carbonyl group in the intermediate. Finally, dehydra- disposal of the waste is an important condition to scale the process tion and tautomerization generate the pyrrole core (Scheme 3) [19]. (first principle of Green Chemistry). By using 10 wt% Pd/C, the Despite the efficiency in the reaction, the reduction process re- yield increases to 24% (Scheme 4), achieving a more efficient sults in an environmental problem when it is carried out on a large methodology and a cleaner catalyst (see Table 1) (ninth principle of scale; for this reason, the reduction with zinc dust is substituted by Green Chemistry). hydrogenation processes [19]. A clear example of this was given by Another way to make this process more environmentally Manley et al. [20] using 10% wt Pd/C, a reusable and cleaner cata- friendly is by avoiding reductions, which is achieved with the use lyst to include the hydrogenation in the formation of the pyrrole of fewer carbonyl reactive compounds than -aminoketones. Under ring instead of the reduction process with Zn/H+ to obtain - this concept, Alberola et al. introduced the use of Weinreb - aminoketones. The palladium catalyst is more expensive, but it is aminoamides (8) [21] to obtain N-methoxy-N-methyl-- recovered by filtration and can be reused because the pH changes enaminocarboxamides (9). The reaction of these compounds with due to the extraction of products generated from the acid medium organometallic derivatives of lithium, magnesium, and aluminum do not affect its activity or composition producing contaminants, generates intermediates and after cyclizing, it produces polysubsti- facilitating the separation of the products and a simple workup. In tuted pyrrole derivatives (10). The efficiency in the preparation of contrast, by alkalizing the reaction medium to precipitate the or- these intermediates depends on the substituents -R2 and -R (Scheme ganic compound when the reducing agent is Zn, the metal dissolves 5).