Green Synthesis of Pyrrole Derivatives

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Current Organic Synthesis, 2017, 14, 1-18 1 REVIEW ARTICLE

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 pyrroles (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

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 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: CH3COOH, H2O 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). When -R2 is other than hydrogen, reactions with organolithium and different gelatinous co-precipitates are formed with the reaction or organomagnesium compounds occur efficiently, and no effect of

4 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

Table 1. Comparison between the -nitrosoketone reduction process with Zn/CH3COOH and other alternative methods.

Yield Yield Pyrrole Classical Reduction Method-Purification Green Reduction-Purification Method (%) (%)

O NH

Zn, CH3COOH, 75°C, 1 h filtration, alkalinization, H2, Pd/C, 45 psig, 65-70°, 7 h filtration, alkaliniza- 53 77 O N salting out, extraction with CH2Cl2 tion, extraction CH2Cl2 N H O O O

Zn, CH3COOH, 120°C, 1 h filtration, alkaliniza- 93 Zn, Lactic acid, US, 40 KHz, 30 min, filtration 90 O tion, salting out, extraction CH2Cl2 N H O O O

Zn, CH3COOH, 120°C, 1 h filtration, alkaliniza- 75 Zn, Lactic acid, US, 40 KHz, 30 min, filtration 92 O tion, salting out, extraction CH2Cl2 N H O O O

Zn, CH3COOH, 120°C, 1 h filtration, alkaliniza- 48 Zn, Lactic acid, US, 40 KHz, 30 min, filtration 78 O tion, salting out, extraction CH2Cl2 N H O

O Zn, CH3COOH, 120°C, 1 h filtration, alkaliniza- 40 Zn, Lactic acid, US, 40 KHz, 30 min, filtration 75 tion, salting out, extraction CH2Cl2 O N H O O O

Zn, CH3COOH, 120°C, 1 h filtration, alkaliniza- 75 Zn, Lactic acid, US, 40 KHz, 30 min, filtration 90 O tion, salting out, extraction CH2Cl2 N H O

-R nature is observed. However, when -R2 = -H, the -R group is vents aggregation and passivation, which improves the reduction determinant; the yields are good when R = -CN (enamine nitriles), process of the metal dust. For this reason, the authors consider this but they decrease when R = -CO2Et (enamine esters) and are very synthesis route as a practical protocol for the industrial production low for R = -COR (enaminones). Following this methodology, pyr- of pyrrole derivatives. role derivatives can range from 10% yields for enaminones up to 92% for enamine nitrile derivatives. Replacement of the intermedi- 2.2. Paal-Knorr Method ary influences the way in which the cyclization leads to the forma- This synthetic method consists of a condensation process be- tion of pyrrole, which can be spontaneous using sodium ethoxide or tween the 1,4-dicarbonyl (11) compound and primary amines gen- silica as catalyst. All these difficulties make this process environ- erally catalyzed by a Bronsted acid, Bronsted base or Lewis acids. mentally less attractive than the original one, as it requires contami- The last condition can be used to obtain molecules with easily epi- nant solvents such as tetrahydrofuran, more complex reaction con- merizable functions in acid media; in this process, the carbonyl ditions (due to the use of organometallic compounds) and long compound provides four carbon atoms in the pyrrole structure, reaction times. while the amine provides the nitrogen atom [19]. However, the Wang et al. [22] conducted the synthesis of 18 pyrrole deriva- reaction is limited to amines without alkyl substituents in - tives by replacing the medium of acetic acid with lactic acid (see position, which is the case of cyclohexylamine [23]. The reaction Table 1) (Scheme 6), a weaker acid that is less volatile than acetic mechanism involves double amine condensation with the carbonyl acid with the advantage of being more easily recycled. Lactic acid compound and follows equivalent paths regardless of whether the shows good performance for the synthesis; as the products obtained reaction is catalyzed by a Bronsted acid or a Lewis acid (Scheme are less soluble than acetic acid, pyrrole yields increase and the 7). compound can be separated by simple filtration. The process also As shown, the Paal-Knorr reaction is a simpler reaction, but it is includes the use of ultrasound (frequency 40 kHz, power 500 W), more versatile than other pyrrole synthesis methods since the start- which increases the rate of reaction and avoids the use of high tem- ing reagents are stable and easy to achieve. For this reason, many peratures. Cavitation also facilitates the use of zinc because it pre- modifications and improvements have been carried out, ranging from

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 5

O O O NH 2 O N R + CH3OH R2 NH 2 R NH2 6 - 20 h R

(8) (9) Weinreb -vynilamide- enamine Weinreb -amide (N-methoxy-N-methyl-- R= CN, -CO2Et, (N-methoxy-N-methyl-- enaminocarboxamides) -COR aminocarboxamides) R1 R2 R O R1, THF R H -H2O N 1 NH 0.5 - 8 h R 1 - 5 h R2 (10) 1 R = H, CH3 , i-pr 28 examples R2= H, CH3, Ph, ethyl-1,3-dioxolano, 10 - 92% yields 1,3-dithianyl, 2-methyl-1,3-dithiane Scheme 5. 1 1 COR NaNO /lactic acid/0-5oC R OC NO 1,3-dicarbonyl 2 compound/Zn/lacticacid

R2 O O R2 MW 40KHz

R4 H N O O R2 COR3 R1= R2=OR Lactic acid R2=R4=CH O R1 3 R1OC NH 4 2 R O MW 40KHz R2 R3 18 examples 75-95% yields Scheme 6.

2 Lewis R Acid 2 1 3 R O R R Lewis Acid R NH 1 Lewis Acid 3 2 R O R3 O R4 O O HO O R4 1 R4 R1 O R3 Lewis Acid R R4 5 H N R NH 2 3 R5 R2 R R2

Lewis 2 3 2 Acid R R R H O R2 R3 R3 2 H Lewis Acid Lewis Acid 3 O HO R R1 R4 O O 1 R R1 1 H R4 NO N R N R4 R4 R5 NH R5 Lewis Acid R5 R5 R2 3 R2 R H 2 3 Lewis Acid H2O Lewis R R Acid O 1 R H R1 R4 N R4 N 5 R R5 R1= H, alkyl, aryll 2-3 R = H, alkyl, aryl, CO2-alkyl, CO2-aryl R4= H, alkyl, aryl 5 R = H, 1°, 2° or 3° alkyl, aryl, heteroaryl, NR2, NH2, OH, NH4OAC, (NH4)2CO3 Scheme 7.

6 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

O O O COOMe a)Et Zn/CH I /R COSEt or R CHO 2 2 2 2 2 R2 R1 OMe or followed by Et2Zn/R2CHO R1 O (12) b) PCC, CH2Cl2, SiO2 (13) COOMe O COOMe

R3 CH3COOH R2 + H2N R1 R2 R1 N O 5 eq. MW 150W, 120 - 150°C, 2-10 R min, open vessel 3

1 35 examples R =t-But, Et 65-88% yield R2= Aryl alkyl 3 R = Aryl, alkyl

Scheme 8.

R ZrCl4 + H2N N O U.S. (40kHz), 40°C, 7-180 min, solvent R free 30 examples 45-98% yields R= CH2=CHCH2, PhCH2, PhCH(CH3), X-Ph, naphthyl, 4-bromonaphthalen-1-yl, methyl-2-pyridinyl,5-methyl-2-pyridinyl X=o-CH3, m-CH3, p-CH3, 2,3-CH3, 2,4-CH3, p-t-Bu, 2,6-i-pr, o-CH3O, p-CH3, o-CH3CH2O, p-CH3CH2O, o-PhO, 2,4-Cl, 2,3-Cl, o-Br, p-Br, m-F3C, p-NO2, -2 4-CH3CH2O -NO2 Scheme 9.

R1 R1 R1 R1 NH2 O R NH2 2 1-10% citric acid N R N R N R or R R N NH + R1 2 Ball mill (zirconia ball, NH2 O 30 Hz),rt R2 R2 R2 R2

1 2 18 examples R= Aryl, Alkyl, R =R =Me 4 examples 4 examples 8-80% yields naphthyl. or 12-80% yields 6-78% yields R1=Me; R2=Ph Monopyrrole Bis(pyrrole) (15)

Scheme 10. the use of different types of Lewis acid catalysts and biodegradable Zhang et al. [27] reported the synthesis of 2,5-dimetyl- catalysts [24], through unusual solvents such as ionic liquids [25], substituted pyrroles (14) by ultrasound radiation from acetonylace- to the use of activation techniques such as microwave (MW) [26] tone, and alkyl or aromatic amines mediated by an inexpensive and ultrasound (US) [27]. Lewis acid (ZrCl4) to obtain high product yields in reaction times Among the new activation techniques, the most widely used is between 7 and 180 min. The procedure takes place in a solvent-free MW. This technique was used by Minetto et al. [28] for the synthe- medium, most products obtained are pure, and subsequent purifica- sis of different 1,4-diketones that were transformed into pyrroles, tion is not necessary (Scheme 9). furans and thiophenes by Paal-Knorr condensation. The reaction of By using a "green acid" of biological origin as catalyst, such as a -ketoester (12) with Et2Zn / CH2I2 gives 1,4-diketones (13) with citric acid, succinic acid, pyroglutamic acid, ascorbic acid, cam- different functionalities such as alkyl and aromatic functions in C1 phorsulfonic acid and oxalic acid, mechanical activation in ball mill and C4 positions, and ester functionality in C3 position. The pre- yields a variety of N-pyrroles [29]. The most important topic of this pared diketones are used in the Paal – Knorr reaction assisted by work is the low amount of catalyst used for the process (1%), citric microwave in acetic acid media, a biodegradable solvent that also acid being the most effective due its higher acidity. Pyrroles are functions as a catalyst (principles 1, 3, 5, 7 and 10 of Green Chem- obtained from acetonylacetone and 1-phenylpentane-1,4-dione, istry), to obtain the corresponding pyrrole derivatives. The best with moderate yields due to the great steric hindrance in the sub- results are obtained in an open container at 120-150 °C for a time strate, which causes a lower reactivity. The mild reaction conditions period from 2 to 10 min; depending on the nature of the substrates allow the synthesis of functionalized pyrroles with amine and alco- used (conventional synthesis can take more than 24 h), pyrrole hol groups, furthermore facilitating the synthesis of (bis)pyrroles yields may range from 65% to 88% (Scheme 8). (15) (Scheme 10).

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 7

Table 2. Common catalysts used in the Paal-Knorr reaction.

O NH2 Catalyst + N

Yield Catalyst Reaction Conditions t Ref. (%)

-Zr(KPO4)2 60°C, solvent-free 24 h 56 [30]

-Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 60°C, solvent-free 2 h 88 [30]

Sc(OTf)3 35°C, solvent-free 25 min 93 [32]

H3NSO3 rt, solvent-free 30 min 92 [33]

Molybdosulfuric acid 60 °C, solvent-free 40 min 96 [35]

3+ Fe -montmorillonite Rt, CH2Cl2 3 h 96 [36]

PEG-SO3H Rt, water 8 h 92 [41]

Bi(NO3)3•5H2O Rt, solvent-free or CH2Cl2 10 h 96 [42]

-cyclodextrin 60 °C, water 24 h 86 [44]

Several kinds of catalysts are used in the Paal-Knorr condensa- Jafari et al. [41] synthesized various pyrroles (16 examples) and tion (see Table 2), all them are different, including Lewis acids and (bis)pyrroles (3 examples) using PEG-SO3H as catalyst. The proc- Bronsted acids as diverse as -Zr (CH3PO3)1.2(O3PC6H4SO3H)0.8 ess is attractive because pyrroles are isolated in high yields (87%- and -Zr (KPO4)2 [30], Bi(NO3)3•5H2O [31], Sc(OTf)3 [32], 98%), it achieves a high degree of purity (first principle of Green H3NSO3 [33], CFCOOH [34] or molybdosulfuric acid [35], to Chemistry) and it is carried out in an aqueous medium. Recovery name only a few. However, many catalysts are expensive and com- involves only a filtration step (fifth and eighth principles of Green posed of transition metals and difficult to synthesize anions. In Chemistry), although reaction times range from 2 to 24 h. The cata- many cases, the catalyst synthesis involves significant energy waste lyst shows high substrate selectivity (Scheme 11). The conversion or complex processes for its production and purification. The fact of aliphatic amines is highly selective in comparison with that of that many of the heavy metal cations in the catalyst structure are in aromatic amines. A similar behavior occurs with substituted ani- toxic oxidation states and the anions are nonbiodegradable or ac- lines with carbonyl electron-withdrawing groups in comparison cumulative only adds to the problem, because these compounds with unsubstituted aniline. This shows the importance of the elec- cannot be reused easily and many of them are corrosive. tronic effects and nucleophilicity of the electron pair on nitrogen in Clays are safer and friendlier catalysts for this transformation. the Paal-Knorr reaction catalyzed by PEG-SO3H. In this case, the These catalysts derive from modified montmorillonites [36] with catalyst is easily recovered and can be reused up to four times with- metals of the first transition series through cation exchange. The out loss of activity. Fe3+-montmorillonite (see Table 2) is an inexpensive, noncorrosive This approach contrasts with the use of other catalysts in poly- and recyclable catalyst. The Paal-Knorr reaction using this catalyst mer base, as reported by Banik et al. [42] (polystyrene sulfonate). It is carried out under mild reaction conditions (room temperature) to can be considered more environmentally friendly because of shorter obtain high yields (69%-96% for alkyl and aryl amines with 2,5- reaction times for aromatic amines (comparison based on the prod- hexanedione) in short reaction times (1 to 6 h) and involves a sim- uct of unsubstituted aniline) under similar reaction conditions with ple purification step of the products, and the catalyst can be reused the advantage that PEG-SO3H is a biodegradable substance. three times without loss of its catalytic activity. Insoluble heteroge- Natural biopolymers such as xanthan are attractive solid sup- neous catalysts can be recovered by simple filtration or centrifuga- ports because they are eco-friendly products from renewable tion, in all kinds of solvents, as in the case of clays, acid resin Am- sources. Catalysts such as sulfuric acid supported on xanthan show berlite IR 120 [37], and tungstosulfuric acid [38], or by using a high yields in the Paal-Knorr synthesis and achieve a lower time magneto, as in the case of the magnetically modified sulfuric acid reduction compared to inorganic catalysts such as bismuth nitrate or (-Fe2O3-SiO2@OSO3H) [39], an inexpensive reusable catalyst of indium triflate, as in advanced activation techniques such as MW simple synthesis that can be used in solvent-free media with high [28]. Other harmless materials are also used directly as catalysts in efficiency in 2,5-dimethylsubstituted pyrrole and (bis)pyrrole de- the Paal-Knorr reaction under mild conditions using environmen- rivative synthesis. tally friendly solvents such as alcohols or water, as in the case of An important trend is the use of green catalysts that not only artificial sweeteners such as saccharin [43] and some sugar deriva- can be reused but are also biodegradable, some being obtained from tives such as -cyclodextrin [44], obtaining good results. biomass such as xanthan [40] or from synthetic polymeric struc- An alternative to the usual procedures consists of carrying out tures such as PEG [41]. the Paal-Knorr reaction with alternative solvents such as ionic liq- 8 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

NH O 2 PEG-SO H(1 mol-%) NH 3 2 + + N + N

O water, rt, 3h (1mmol) (1mmol) (1mmol) (92%) (8%) H O N PEG-SO3H(1 mol-%) + N NH2 O water, rt, 6h NH (100%)

(1mmol) (1.2 mmol)

O O O NH 2 NH2 PEG-SO3H(1 mol-%) N N + + + water, rt, 20h O

(1mmol) (1mmol) (1mmol) (96%) (4%) Scheme 11. O X H2O, non catalyst. 2 100 °C, 15 min R 3 1 + R R R1 R2 H2N N O R3 1 2 R =R =CH3 18 examples 3 R = Aryl, Alkyl 75-98% yields X= H, NH2, F, Cl, Br, alkyl, 2-ethylfuranyl, COOH, OR, 3-methylpyridinyl, etc.

Scheme 12.

O X Catalyst and solvent free, R2 RT or 100 °C, 15 min- 80 h + R3 1 R2 R1 R N H2N O R3

1 2 R =R =CH3, 44 examples R3= Alkyl, Aryl 32-100% yields X= H, NH2, F, Cl, Br, akyl, aryl, F3C,SH Scheme 13. uids [45], water [46], and under solvent and catalyst-free conditions Green Chemistry known as the atom economy principle. While the (Scheme 12). In the subsequent cases, although the process may reaction itself can be considered an environmentally compatible take a while longer for the reaction of some substrates, the proce- process because of the efficient yields and the aforementioned atom dure becomes simpler, more selective and environmentally friend- economy [48], there are many studies in which the reaction has lier due to the high atom economy, low energy consumption (it been experimentally modified to make it even more environmen- prevents conventional heating), and being a condensation reaction, tally friendly. The first step consists of developing a solvent-free the only by-product of the process is water, covering most of the reaction or replacing the commonly used solvents in the process principles of Green Chemistry [47]. Under this guideline, Cho et al. such as DMF, toluene, chloroform, acetonitrile, THF, etc. with less synthesized 47 different pyrroles from various diketones and polluting solvents such as methanol, ethanol or water. amines, obtaining quantitative yields for some of the pyrrole deriva- It corresponds to the formation of substituted pyrroles from - tives in times ranging from 15 min to 80 h of reaction (Scheme 13). ketoesters with -haloketones (16) in ammonia or primary amine media (Scheme 14). The reaction mechanism proceeds via enamine: 2.3. Hantzsch Pyrrole Reaction under heating the fast attack of amine on the -ketoester occurs; at The Hantzsch method is a clear example of a multicomponent this point, the enamine ester (3–aminocrotonate) formed is cyclized reaction [16] in which multiple reactions are combined in a single with the -haloketone to form the pyrrole. As one of the intermedi- synthetic operation that leads to the formation of a compound, in aries corresponds to 3-aminocrotonate, the reaction can be initiated this case pyrrole. It maximizes the inclusion of atoms in the reac- with this kind of compound. The regioselectivity of the derivative is tants in the final product, so it fully meets the second principle of completely dependent on the substituents in the starting reagents,

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 9

1 4 R2 R R R1 OR 3 4 + R + R X R3 O O NH2 O RO2C (16) R2

R1, R2, R3, R4=H, alkyl, aryl, R= alkyl, aryl X=Cl, Br, I, etc. Scheme 14. O O Rink NH2 N

O DCM, -15 °C, rt, 2.5 h O O Br R1 O O O NH 2 3 1 R R R NH2 N N

DMF, TMOF, rt, 2X24 h DMF, 2,6-di-tert-butyl-pyridine rt, 17 h

O O HN R3 H2N R3 20% TFA/DCM, 30 min 18 examples 91 -98% purity 2 N R N R2 R1 R1 1 R = PhCH2CH2 ,HOCH2CH2 , cyclopropyl, piperonyl, n-Bu, 2-furfuryl,yl, allyl, propargyl, tyraminyl, histaminyl, 2-(thiophen-2-yl)ethyl, 4-ethylmorpholine 2 R = X-Ph, [1,1'-biphenyl]-4-yl, 2,5-dimethoxyphenyl, CH3CH2, 3-(2,4- dichlorophenyl)isoxazol-5-ylm CO2H2CH3, naphtyl X=H, p-Cl, p-CN, p-F, 3,4-Cl, m-CH3O, m-NO2 3 R =H Scheme 15. and when the process is performed from aromatic amines, indoles the main attractions of this synthesis is the possibility of automation or carbazoles are available if cyclization occurs with - and the functionalization of the support for obtaining pyrrole at halocyclohexanones [49]. room temperature. This development is useful in combinatorial From a chemical point of view, the Hantzsch pyrrole synthesis synthesis in drug discovery due to the great biological activity that is a more versatile process in comparison with Paal-Knorr and pyrrole derivatives have. Knorr syntheses, because it no longer depends on achieving inac- Automation of the Hantzsch reaction was performed by Herath cessible intermediates such as symmetrical -aminoketones or et al. [53] with an approach to continuous flow chemistry [54]. The compounds such as 1, 3-diketones, and it does not form compounds process takes place in a microreactor containing pyrrole-3- with specific substitution such as 2,5-dialkypyrroles or N- carboxilic acids (17) and pyrrole-3-carboxilic highly substituted substituted pyrroles [50]. esters (18) with yields above 40%. The technique involves a 1 mL Trautwein et al. developed a method for the solid phase synthe- glass reactor with two injection points at which the preheated solu- sis of a pyrrole series using a Rink amide resin support [51]. The tions of the reactants in DMF are introduced, the reactor tempera- first step in the process is the conversion of the solid support to ture is maintained at 200°C, and the time in the reactor is no longer enamine, in order to continue the condensation of the enamine with than 8 min (Scheme 16). Yields are excellent but high-cost special the corresponding -bromoketone to finally get the pyrrole ring equipment is required; however, this process has the potential to (Scheme 15). During the process, the reaction time with the se- perform multistep reactions in a single step. The benefits of this lected -bromoketone is 3 h, yielding pyrrole species with purities method are the short reaction time and efficient production of a up to 98%. Under similar conditions, compounds with purities be- large number of compounds with high purity. It also remains con- tween 80% and 90% can be obtained when the -bromoketone is sistent with other principles of Green Chemistry, the first, which replaced with an aldehyde and a nitroalkane combination or a nitro- involves reducing by-products, and the eleventh, involving easy alkene [52]. However, one of the great difficulties of this method- online process monitoring for pollution prevention. ology is the highly polluting solvents used and the long reaction times needed in the Rink amide support functionalization and their Continuous processes are highly attractive and some of their respective enamine conversion. Despite these disadvantages, one of advantages were already mentioned. However, in chemical produc-

10 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

Scheme 16. O -CD

O O O N H N R , Water + + 2 R Br 60-70°C 12 examples R=H, X-Ph, PhCH2, m-CH3OPhCH2, m-BrPhCH2 79-89% yields X= H, p-CH3, p-F, p-CH3O, m,p-CH3O, p-Cl, p-n-Bu, 2,6-CH3CH2 Scheme 17. R NC R ONa CH COONH R1 3 4 EtO CN + Cl OHC R1 O H2O/CH3CH2OH, 80°C, 1h N OEt H

- - R, R1= H, CH3 , -(CH2)4 10 examples 38-66 yields Scheme 18. tion on a small scale, batch processes predominate due to techno- Cyclodextrin acts like a bowl forming an inclusion complex with logical, socioeconomic and human factors [55]. the 2-bromoacetophenone that reacts directly with the 2,4- This multicomponent reaction has been developed in different pentanedione before the amine. This reaction does not proceed via ways, in many of which the process involves the use of catalysts -enaminone, which explains why the reaction occurs with ary- that may be organic or inorganic and some of them, more environ- lamine, an unusual substrate for the Hantzsch reaction. mentally friendly than others [56]. In connection with the use of an The Hantzsch reaction has been generalized by Moss and environmentally friendly catalyst, Murthy et al. [57] developed the Nowak [58] to obtain different labile functionalities in the structure process using -cyclodextrin, a supramolecular catalyst; in this of the pyrrole derivatives, as in the case of substitution by reactive process various pyrrole derivatives are obtained in aqueous media. groups such as aldehyde and cyano groups in 2 and 3 positions. The yields of 1,5-diarylsubstituted pyrroles obtained are between This result was achieved by replacing the dicarbonyl compound 79% and 89% (Scheme 17), and the organic solvents are replaced with ketonitrile to form an enamine with ammonium acetate. The with water (fifth principle of Green Chemistry). The green and formed intermediates react with chloroacetaldehyde to give the biodegradable catalyst is highly effective (ninth principle of Green heterocyclic compound (Scheme 18). The process affords yields of Chemistry) under mild temperature conditions (60-70 °C) and can around 45% in one step at a temperature of 80°C, in aqueous media be reused more than once without considerable loss of activity. - and catalyst-free conditions. Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 11

R4 4 R R O NIS, p-TsOH 5 I 1 H2NR+ 5 R5 R HSVM (20 Hz), rt, 60 min O R4 O

CAN 5%, AgNO3 (1 eq.)

1 HSVM (20 Hz), rt, 60 min R = H, i-Bu, n-Bu, n-Hex, (CH3)2N, PhCH2, p-CH3Ph 2 R = CH3, n-Pr, CH3CH2 3 O R = CH3CH2O, CH3O, NH2 4 R3 R = H R4 20 examples R5= Ph, 2-naphthyl, 3-indolyl, 2-thopheyl, t-Bu, p-ClPh 65 -97% yields R2 R5 N R1 Scheme 19.

O O HN NH I O N

NH2 O NH

+ N F F O 1% Yb(Otf) EtOH 3, O 1% Yb(Otf)3, AgNO3 (1 eq.) O 40 °C, overnight HSVM (20Hz), 1h O O O O O O O

O O

O O N N

N F N F Hydrolisis 2M HCl, MeOH, rt, 3h

OH O

OH HO O

O O Atorvastatine lactone 1/2 Ca2+ 38% Scheme 20.

Despite the low yield in the process, the reaction is performed Mechanochemistry is another novel chemical activation tech- under catalyst-free conditions, achieving part of the concept of nique that allows pyrrole derivative synthesis. Mechanochemistry is sustainable chemistry. In the same way, Eftekhari-Sis et al. [59] an energy efficient alternative that reduces or avoids the use of reported an efficient method for the preparation of 5-aryl-4- solvents by using a high frequency grinding process with tiny beads hydroxy-2-methyl-1H-pyrrole-3-carboxylic acid esters from aryl- of an inert material to generate reactions (high-speed vibration mill- glyoxal hydrates with -dicarbonyl compounds in the presence of ing, HSVM). The grinding is achieved by the strong impact of inert ammonium acetate. The method involves the use of an ultrasound material balls that move with the reactants and catalysts in a con- system at room temperature (sixth principle of Green Chemistry) in tainer mill vibrating rapidly. Chemical reactions occur in places which the preparation times are reduced to 3-5 min from 30 – 60 where the balls collide, where the impact generates localized heat min in the conventional method. After completion of the reaction, and pressure points for short periods of time, thus the mechanical the solid product is isolated by simple filtration without purification energy is then used to generate chemical changes. Estevez et al. steps (first principle of Green Chemistry). [60] applied this technique, improving yields to obtain new pyrrole

12 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

R4 n I O R5 R3 O R4 n O O O R6 R2 5% CAN, CH3OH, R5 N rt, 30 min 3 R7 R2 R3 R R1 1 + R 1) NIS (2 eq.), 20% TSOH, 6 N R2 R H N H SVM (20 Hz), 60 - 120 min 2 1 7 (19) R 2) 5% CAN, AgNO3, R HSVM (20Hz), 60 min 16 examples n: 0-1 45 - 94% yields 1 R = m-Bu, CH3, n-Hex, PhCH2 2 E = n-Pr, CH3 3 R =CH3CH2O, NH2, CH3 4 R = H, CH3 5 R = H, CH3 6 R = H, CH3O 7 R = H, CH3

Scheme 21. derivatives with rare substitutions at position 5, such as phenyl, 2- 2.4. Other Common Reactions naphthyl, 3-indolyl and 2-thienyl, achieving excellent yields. 2.4.1. Other Multicomponent Reactions The reaction is simple at room temperature in a combination of a multicomponent and one-pot reaction, starting with the ketone Multicomponent reactions (MCRs) are convergent reactions, in and N-iodosuccinimide (NIS) in the presence of p-toluenesulfonic which three or more starting materials react to form a product, acid (pTsOH) to obtain -iodoketone. After 60 min of milling at 20 where basically all or most of the atoms contribute to the newly Hz, a mixture of the primary amine, a -dicarbonyl compound, 5% formed product. In an MCR, a product is assembled according to a ceric ammonium nitrate (CAN) and silver nitrate, in equivalent cascade of elementary chemical reactions. Thus, there is a network ratio to the starting ketone in the process, is added to the - of reaction equilibria, by which all reactions finally flow into an iodoketone formed (Scheme 19). The mixture is ground for 1 h irreversible step yielding the product. The challenge is to conduct under the same conditions, obtaining yields between 65% and 90%. an MCR in a way that the network of pre-equilibrated reactions The same authors [61] reported the same process for the synthe- channels into the main product and does not yield side products. sis of a molecule of pharmacological interest, atorvastatin, a phar- The result is clearly dependent on the reaction conditions: solvent, macological agent that is lipid-lowering (hypolipemiant). This work temperature, catalyst, concentration, the kind of starting material is the first report on the formation of the heterocyclic core of this and functional group. Such considerations are of particular impor- molecule. To carry out the process, CAN is replaced with another tance in connection with the design and discovery of novel MCRs catalyst because of its activity on the hydrolysis of acetals, ytter- [63]. bium triflate being the most suitable replacement. Using this methodology, atorvastatin was isolated with a yield of 38% (Scheme A convenient one-pot multicomponent reaction of aromatic al- 20). dehydes, 1, 3-dicarbonyl compounds, amine and nitromethane in the presence of 10 mol% ZnO nanoparticles for the synthesis of Menéndez group performed a comparative study for obtaining highly substituted pyrroles (Scheme 22), was described by Matloubi substituted pyrroles by classical reflux in an organic solvent and HSVM [62]. In this study, the reaction is optimized by comparing Moghaddam et al. [64]. The products are obtained with moderate to the behavior of different Lewis acids as catalysts, time and fre- good yields. This method offers several advantages, such as good quency of vibration milling, and the ratio -enaminone/- yields, a simple procedure, nonhazardous reaction conditions, and iodoketone, obtaining a regioselective and efficient process. By easily accessible substrates as starting material. using this methodology, a set of 35 polysubstituted pyrrole deriva- Another multicomponent reaction was developed by Viveka- tives with substituents in all positions of the pyrrole structure, in- nand [17]; the procedure follows a catalyst-free methodology in cluding the nitrogen atom, is achieved. Alkyl and aryl groups, with which a number of green solvents, such as ethanol, water, PEG- yields ranging between 32% and 97% in some alternative method- 200, glycerol and lactic acid, are tested for the sequential reaction ologies, have higher yields. Likewise, 16 examples of pyrrole fused systems (19), resulting from 4,5-dihydro-1H-benzo[g]indole, 1,4- that involves enamine formation, Michael addition and cyclization dihydroindeno[1,2-b]pyrrole, 4,5,6,7-tetrahydro-1H-indole and of primary amines, 1,3-dicarbonyl compounds and isatin-derived 1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole, can be obtained with compounds that afforded 3-(1H-pyrrol-3-yl)indolin-2-ones (20) efficiencies above 45% in all cases (Scheme 21). Although in some (Scheme 23). Using water, glycerol, PEG-200 and a solvent-free cases HSVM has lower yields, this technique has several advan- medium, they showed that the solvent-free conditions are better tages that make it environmentally friendly, including the solvent- regardless of the nature of the starting materials. The green solvents free medium (fifth principle of Green Chemistry), the combination are effective for alkyl and benzylamines, affording higher yields of two methodologies for reducing waste, i.e., a multicomponent compared to arylamines. In all cases, the products are isolated with reaction and mechanochemical activation (principles 1, 2, 6 of a high degree of purity, so purification by chromatography is not Green Chemistry) and finally, the use of an efficient catalyst (ninth necessary. principle of Green Chemistry).

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 13

R3 2 O O R

NH2 nano ZnO (10%-mol) 1 CHO NO2 H C R + R2 + H C + 3 H C 3 100 °C, solvent-free,15 h 3 N 3 R O R1 15 examples 1 R = PhCH2, p-X-Ph 37-82% yields X= p-CH3O, p-Br R2= X1-Ph, 2-furyl 1 X = H, p-Cl, p-CH3, p=NO2, m-NO2 3 R = CH3, CH3CH2O, CH3O Scheme 22. R4 3 R R5 Solvent-free or 3 O Glycerol or R O PEG-200 or 2 COR6 R 6 Water 2 4 COR R R 5 O + + R H2N 70 °C O N (20) N R1 R1 29 example 63-91% yields 1 R = H, PhCH2 2 R = H, CH3O, Br 3 R =2-thienyl, 2-naphtyl, CH3, X-Ph X= p-Cl, p-CH3, H 4 1 R = H, n-Bu, (CH2)2OH, (CH2)3OH, PhCH2, Ph, 1-naphthyl, X -Ph 1 X = p-Cl, o-CH3, m-CH3, p-CH3

Scheme 23.

CO R3 O CO R3 3 2 O 2 R O2C basic ionic liquids 1 H2N + R Cl + OH R1 aqueous media, 80°C R2 N R2 3 H CO2R 30 examples 1 83-96% yields R =p-X-Ph, CH3, n-Pr, t-Bu X = CH3, Cl, NO2 2 R = Ph, phCH2, CH3, n-Pr, t-Bu 3 R = CH3, CH3CH2 Scheme 24.

2.4.1.1. Pyrrole Derivatives from Activated Alkynes product affords between 75% and 94% yields, and the reaction times vary depending on the nature of the substrate. Aromatic Multicomponent reactions, such as the above-mentioned or the amines do not produce the desired products, just like the reaction well-known Hantzsch reaction, have attracted great interest in re- using bromopyruvate. The reusability of the catalyst was tested for cent years, especially those performed using activated alkynes bear- the formation of diethyl 1-ethyl-5-phenyl-1H-pyrrole-2,3-di- ing one or two carboxylate groups. A one-pot three-component carboxylate, which could be used up to three times without loss of synthesis was developed by Yavari et al. [65], using a basic ionic catalytic activity after being recovered by filtration, washed with liquid as catalyst in aqueous medium (Scheme 24). The process is ethyl acetate and dried at room temperature for 24 h before each faster compared to catalysts such as sodium hydroxide and although catalytic cycle. it gives lower yields, the catalyst can be reused without significant Reaction media such as PEG-400 [67] have been used with loss of activity. good results for the same reaction, since it is a recyclable, biode- Another simple, fast and efficient methodology involving a gradable and inexpensive solvent. Although a structural variety three-component reaction was developed by Sabbaghan et al. [66], similar to the one achieved using NR-ZnO solvent-free medium is yielding polysubstituted pyrroles from amines, 2-bromoaceto- obtained, the reaction time increases to 10 h at a temperature of phenone and dialkyl acetylenedicarboxylates under solvent-free 60 °C. However, all the reactions are very clean, and the yields for conditions, and ZnO nanostructures as catalyst (Scheme 25). Inter- pyrrole derivatives are high. The use of 2-bromoacetophenones estingly, the catalyst used is much cheaper than ionic liquids. The bearing electron-withdrawing substituents (-Br, -NO2) in -para

14 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

CO2R1

2 CO2R O O CO R Br 2 1 NH2 1 H3CH2COC Br N R + + ò NR-ZnO 15 -mol% R 2 3 O Solvent free, 70 °C, 45 - 60 min R2 CO2R R 10 examples 75-94% yields 1 R =CH3(CH2)5, CH3CH2, PhCH2, p-Cl-PhCH2, p-CH3-PhCH2, Ph, p-CCH3O-Ph 2 R = CH3, CH3CH2 3 R = H, CH3O, Cl Scheme 25. O NH2 CO R2 CO R2 2 OH 2 NC NH NC C N 1 2 O + R + + 2 OH CO2R Ethanol reflux, 30 min 3 3 R N CO R2 R 2 R1

37 examples 1 64-93% yields R = p-X-Ph, m-X-Ph, o-X-Ph, CH3(CH2)3 X= p-F, p-Cl, p-Br, p-CH3, p-CH3, p-(CH3)2CH, p-CH3CH2O, p-NO2, m-Cl, m-CH3, m-OH, o-CH3CH2 2 R = CH2CH3, CH3 3 R = Ph, thiophen-2-yl, 4-CH3OC6H4, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4 Scheme 26.

R Water, MW, 150°C, 30 min H N MeO 2 + O OMe N R 18 examples 1 81-99% yields R= 2-pyridyl, 2-pyrazin, Ph-X, O2S-Ph-X , O2S-naphthyl X= H, p-Cl, m-Cl, p-OCH3, p-NO2, p-NO2, p-CH3, m-CH3, o-CH3 1 X = H, p-Cl, p-CH3, p-OCH3, p-NO2, o-CH3, p-Br Scheme 27. position, amines with electron-donating groups (-Me, -OMe) and dimethoxytetrahydrofuran and various anilines and sulfonamides. electron-withdrawing groups (-F) in -para position gave the desired The standard literature indicates good yields for these compounds products in high yields. using P2O5, a corrosive and extremely hygroscopic compound, and Not only three-component reactions have been developed for dry toluene as solvent, in times ranging from 45 min to 22 h, which pyrrole derivative synthesis, Feng et al. [68] performed a four- results in a complex matrix that requires a complicated series of component synthesis using a mixture (1:1:1:1) of monohydrate purification steps [70]. In contrast with this report, in which the arylglyoxal, aniline, dialkyl but-2-ynedioate or alkyl acetoacetate, synthesis of these compounds is induced by MW and develops from and malononitrile in ethanol without catalyst (Scheme 26). Follow- different types of anilines and sulfonamides, these two compounds ing this procedure, highly substituted pyrroles are obtained in excel- are easier to handle and with less risk of toxicity (Scheme 27), reac- lent yields within 30 min with a low environmental impact as a tion times decrease to 30 min, obtaining quantitative yields for green solvent is used in a reaction with high atom efficiency. some species (see Table 3). Furthermore, the study describes that the process depends on the pKa of the nucleophile used, so no acid 2.4.2. Clauson-Kaas Reaction catalysts are used. The Clauson-Kass reaction is a process of pyrrole synthesis A similar procedure using MW was developed by Miles et al. based on the condensation between an aromatic or aliphatic primary [71], promoting the reactions of less nucleophilic amines using amine with 2,5-dimethoxytetrahydrofuran in the presence of an acid acetic acid as reaction media, and the same catalyst reduced the catalyst. Generally, the acid catalysts used for the process are acetic reaction times to 10 min with high yields. It is noteworthy that de- acid, phosphorous pentoxide, and 4-chloropyridinium chloride. The spite the difficulties of using acetic acid as solvent, such as its vola- reaction easily converts nitrogen of an amino group into a pyrrole tility, it is a green and biodegradable solvent that comes from re- group whenever there is not an acid labile group [19]. newable sources. An interesting variation in the process was the release of the MW system and the use of catalysts and solvent-free Wilson et al., in a catalyst-free medium and using water as sol- conditions developed by Ramesh et al. [72] to synthesize N- vent (principles 1, 3, 5, 7, 8 and 10 of Green Chemistry), were able substituted pyrroles from aromatic amines. Again, as in the reac- to obtain N-aryl and N-arylsulfonylpyrroles [69] from 2,5- tions listed above, the main drawback is the increased reaction time.

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 15

Table 3. A comparison of experimental conditions for obtaining N-aryl and N-arylsulfonylpyrroles.

Yield Yield Pyrrole Reaction Conditions – Purification Methodology Reaction Condition – Purification Methodology (%) (%)

P O , dry toluene, 125°C, 45 min. Evaporation, flash N 2 5 87 Water, MW, 150°C, 30 min, filtration 90 chromatography

CuI, n-Bu4NBr, NaOH, toluene, reflux, 22 h. N CH3 88 Water, MW, 150°C, 30 min, filtration 98 Extraction, flash chromatography

P O , dry toluene, 125°C, 45 min, evaporation flash N Cl 2 5 79 Water, MW, 150°C, 30 min, filtration 93 chromatography

CuI, n-Bu NBr, NaOH, toluene, reflux, 22 h. N O 4 84 Water, MW, 150°C, 30 min, filtration 99 Extraction, flash chromatography

CuI, N-hydroxymaleimide, CH3ONa, DMSO, 110°C, 40 N NO2 45 Water, MW, 150°C, 30 min, filtration 97 h. Extraction, flash chromatography O Montmorillonite K-10, 3 min MW. Filtration, flash N S 93 Water, MW, 150°C, 30 min, filtration 99 chromatography O

O P2O5, dry toluene, 125°C, 20 min. Evaporation, flash N S CH3 100 Water, MW, 150°C, 30 min, filtration 89 chromatography O

O P O , dry toluene, 125°C, 20 min. Evaporation, flash N S Cl 2 5 85 Water, MW, 150°C, 30 min, filtration 92 chromatography O

O Montmorillonite K-10, 3 min MW. Filtration, flash N S O 95 Water, MW, 150°C, 30 min, filtration 95 chromatography O

O TfOH, CH2Cl2, rt, 2 h. Extraction, flash N S NO2 86 Water, MW, 150°C, 30 min, filtration 98 chromatography O

NH2 O R1 HO * R3 3 * N 1 2 + Cl R 3 N R R R3 N R2 R * H * 1 R1 R2 O R R2 15 examples Classical method 72 - 95% yields (4-6 h) MW method 68 - 88% yields (4-6 min) 1 R =(CH3)2CH, CH3, CH3OOCCH2, CH2CH2SCH3, Ph, CH2OH Enantiomeric excess >98% 2 R = COOCH3, COOCH2CH3, CH(OH)Ph, CH2OH, CH3, CH2Ph 3 R = H, CH3, CH2CH3, CH(CH3)2, Cyclohexyl Scheme 28.

However, for deactivated anilines such as p-fluoro, p-chloro, p- logically active compounds, Demir et al. [75] developed a method bromo and p-nitroaniline, the reaction times are similar to that ob- for condensation synthesis from chiral amines, -amino alcohols, tained with the unsubstituted aniline. In 2013, a series of pyrroles and esters of -aminoacids with chloroenones (Scheme 28). The derived from chiral amines was obtained by this reaction in a sol- process results in yields above 60% without racemization of the vent-free medium using an acidic ionic liquid, 1-hexyl-3- products in mild reaction conditions (triethylamine reflux). Twelve methylimidazolium hydrogen sulfate ([hmim][HSO4]), as catalyst compounds were obtained with enantiomeric excesses 98% in that, despite being a synthetic product, is considered a safe and reaction times from 4 to 6 h. The same working group developed a environmentally friendly reagent [73]. Compared to acetic acid, procedure using MW (500 W), conducting the reaction in solid [hmim][BF4] and [hmim][H2PO4], this compound increases by 30% phase with silica gel as support and triethylamine as catalyst [76]. the yield of the model reaction carried out between (S)- Thus, the reaction time was reduced to 4–6 min, with the advan- phenylethylamine and 2,5-dimethoxytetrahydrofuran [74]. The tages of good yields without racemization of the products and mild process concludes with the use of MW (90 W), so that the processes reaction conditions, avoiding toxic solvents and dangerous reagents. are carried out for 4–25 min. However, the reusability of the catalyst is not mentioned. 2.4.4. Pyrroles from Oximes and Carbide Calcium carbide is a major source of acetylene, an important 2.4.3. Pyrrole Derivatives from -aminoacids raw material for the synthesis of various compounds via many reaction routes, such as carbonylation, dimerization, vinylation, ethiny- Because homochiral pyrroles derived from amine and amino ac- lation and oligomerization [77]. The oxime vinylation reaction al- ids are important starting reagents for the synthesis of various bio- lows obtaining 2-arylpyrroles, which are synthons for the synthesis

16 Current Organic Synthesis, 2017, Vol. 14, No. 0 Zúñiga et al.

Classical method H H R=H, -CO2Me N N 1)Halogenation or NH-protection Ar

2)[M] coupling reaction/Ph-X R O N HO N H H /Base or R Ar H CO2Me /Au(I) Ar

R= 1-naphthyl, Py, Ph, X-Ph Kaewchangwat method X= p-CH3, p-CH3O, p-Cl, p-(CH3)2N, p-(n-BO) OH O N R NH 2)CaC2, KOH 1)NH2.HCl, NaHCO3 DMSO/60 °C, 4h 18-crown-6,100 °C, 15h R R 10 example 38-88% Scheme 29. R1 R3 R4 2 HN R NO2

2 + R N 3 R CH3OH, 120°C, 14-35 h 1 R4 O R 26 examples 1 R = Aryl, PhCH2, cyclohexyl 54-92% yields 2 R =H, CH3 R3= Aryl, furanyl 4 R = COCH3, COCH2CH3, CH3 Scheme 30.

R3 R1 R3 O O I2 + H N 2 HSVM, 30 Hz, 20 min NO2 R N R2 1 R = H, NO2, CN, OMe 18 examples 2 R = Ph, n-Bu, PhCh2, Cyclohexyl 75-94% yields 3 R = CH3, OEt Scheme 31. of BODIPY dyes. Kaewchangwat’s group [78] developed a one-pot been reported. However, this procedure is not environmentally simple procedure starting from acetophenones and hydroxylamine friendly due to the use of halogenated compounds [79]. Michael for obtaining oximes that are converted into 2-arylpyrroles by reac- addition and cyclization of enaminones or enaminoesters to ni- tion with CaC2 in a similar reaction to that of Trofimov process, but troolefins is a straightforward approach to the construction of the avoiding the use of heavy metals as catalysts (Scheme 29). The pyrrole rings according to the principles of Green Chemistry process uses DMSO as reaction solvent for the hydrolysis of CaC2 (Scheme 30). Guan et al. [80] improved the synthetic method and to generate acetylene in situ. The reaction is performed in basic developed an efficient, practical and environmentally friendly medium using potassium hydroxide and 18-crown-6 as catalyst, method for the synthesis of polysubstituted pyrroles. Under opti- with process yields ranging from 38% to 88% at 100 °C. The mized reaction conditions, they studied the effect of substrates, method developed uses inexpensive starting materials (ketoximes), starting from the reaction of 1- (2-nitroprop-1-enyl) benzene, sev- avoids handling acetylene gas and heavy metals, and the general eral enaminoesters and methyl-3-(phenylamino) but-2-enoate with steps of the process are significantly shortened. Therefore, it can be several nitroolefins. This process has a high tolerance to a wide considered a convenient, safe, environmentally friendly, green and variety of functional groups. Nitroolefins with methyl, methoxy, sustainable process. Moreover, it can be easily applied in large amino, fluoro and chloro groups in the aromatic ring produce the scale manufacturing in chemical industries and for routine labora- corresponding pyrroles in good yields. In general, the electron-rich tory synthesis. nitroolefins are more reactive than electron-deficient ones. Elec- tron-rich enaminoesters show increased reactivity and give higher 2.4.5. Pyrroles from Nitroolefins yields than electron-deficient ones; however, reactions are insensi- The metal-free synthesis of substituted pyrroles by domino re- tive to steric hindrance of the substituents on aromatic rings. The action with cyclic enaminones and halogenated nitroolefins has reaction was improved by Gao’s group [81] by applying HSVM

Green Synthesis of Pyrrole Derivatives Current Organic Synthesis, 2017, Vol. 14, No. 0 17 using molecular iodine as catalyst in a solvent-free medium. The [16] Wang, S.F.; Guo, C.L.; Cui, K.K.; Zhu, Y.T.; Ding, J.X.; Zou, X.Y.; Li, optimized methodology is performed at 30 Hz, reducing the reac- Y.H., Lactid acid as an invaluable Green solvent for ultrasound-assisted scal- able synthesis of pyrrole derivatives, Ultrason. Sonochem., 2015, 26, 81-86. tion time to 20 min, the polysubstituted pyrroles reaching between [17] Vivekanand, T.; Vinoth, P.; Agieshkumar, B.; Sampath, N.;Sudalai, 78% and 94% yields (Scheme 31). A.;Menéndez, J.C.;Sridharan, V., Highly efficient regioselective synthesis of pyrroles via a tandem enamine formation – Michael addition- cyclization se- quence under catalyst- and solvent-free conditions, Green Chem., 2015, 17, CONCLUSION 3415-3423. The main challenge of Green Chemistry is to gradually elimi- [18] Wang, Z. 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