The Hantzsch Pyrrole Synthesis: Non-Conventional Variations and Applications of a Neglected Classical Reaction

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Syn thesis M. Leonardi et al. Short Review

The Hantzsch Pyrrole Synthesis: Non-conventional Variations and Applications of a Neglected Classical Reaction

Marco Leonardi R2 R3 Verónica Estévez Microwave Flow Mercedes Villacampa O O Conventional Photochemical R4 COR3 J. Carlos Menéndez* 0000-0002-0560-8416 O X 5 R R5 R2 Unidad de Química Orgánica y Farmacéutica, Departamento de Química en N R4 Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, Solid phase Sonochemical R1 Plaza de Ramón y Cajal sn, 28040 Madrid, Spain NH2 Hantzsch pyrrole Mechanochemical synthesis [email protected] R1

Received: 10.09.2018 pyrroles are also known, exhibiting properties such as anti- Accepted after revision: 18.10.2018 mycobacterial5 and antimalarial6 activities, inhibition of Published online: 03.12.2018 7 8 DOI: 10.1055/s-0037-1610320; Art ID: ss-2018-z0610-sr HIV virus fusion, and hepatoprotection, among many oth- ers. Some of these compounds have reached the pharma- Abstract Pyrrole is one of the most important one-ring heterocycles ceutical market, including the anti-inflammatory drugs because of its widespread presence in natural products and unnatural zomepirac and tolmetin, the antihypercholesterolemic bioactive compounds and drugs in clinical use. The preparation of pyr- 9 roles by reaction between primary amines, β-dicarbonyl compounds, agent atorvastatin, and the anticancer drug sunitinib (Fig- and α-halo ketones, known as the Hantzsch pyrrole synthesis, is re- viewed here for the first time. In spite of its age and its named reaction HO OH HO OH OH status, this method has received little attention in the literature. Recent work involving the use of non-conventional conditions has rejuvenated HO OH N this classical reaction and this is emphasized in this review. Some appli- N cations of the Hantzsch reaction in target-oriented synthesis are also OMe discussed. N N 1 Introduction O 2 The Conventional Hantzsch Pyrrole Synthesis N 3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions 4 Applications of the Hantzsch Pyrrole Synthesis OH Halitulin Me 5 Conclusions Lamellarin R Cl H N R1 Key words pyrrole, green chemistry, solid-phase synthesis, R Cl O sonochemistry, flow synthesis, photoredox catalysis, mechanochemical HO OH N O synthesis CO2H Cl

N This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O Me X Cl 1 Introduction R = H, R1 = Me Tolmetin Marinopyrrole A (X = H) R = Me, R1 = Cl Zomepirac Marinopyrrole B (X = Br) Pyrrole can be considered as one of the most important simple heterocycles. It is present in a variety of natural O O NEt2 NH products including two pigments essential for life, namely H3C NH heme and chlorophyll. It can also be found in a large num- CH3 N ber of bioactive secondary metabolites, many of which are CH F CH N 3 3 of a marine origin1–3 and include the lamellarins, halitulin, F H O and the marinopyrroles, which have attracted much recent OH N attention because of their high activity against methicillin- H Sunitinib OH resistant bacteria.4 A large number of bioactive non-natural CO2H Atorvastatin Figure 1 Some important pyrrole derivatives

Syn thesis M. Leonardi et al. Short Review

ure 1). Furthermore, pyrroles are also very important in materials science10 and they are also valuable building blocks for the synthesis of alkaloids and unnatural heterocycles.11 Pyrrole derivatives can be assembled by many ap- proaches, including the traditional Knorr, Paal–Knorr, and Hantzsch reactions.12 Nevertheless, the synthesis of highly substituted and functionalized pyrroles remains challeng- (from left to right) ing because it very often poses problems of regioselectivity. Marco Leonardi was born in Terni (Italy), and studied Pharmaceutical An additional complication comes from the need for mild Chemistry and Technology at Università degli Studi di Perugia in Italy. reaction conditions owing to the low chemical stability of He enlisted in the Department of Organic and Medicinal Chemistry, many pyrroles. School of Pharmacy with an Erasmus grant in 2012 to carry out the ex- perimental work for his graduation thesis. He is currently in the late stages of his Ph.D. thesis project, supervised by Drs Villacampa and Menéndez. This project is focused on the synthesis of pyrrole-based di- 2 The Conventional Hantzsch Pyrrole Syn- versity-oriented libraries using mechanochemical multicomponent re- thesis actions and their application to the identification of new bioactive compounds. Verónica Estévez Closas was born in Madrid and studied Pharmacy at Among the classical methods for pyrrole synthesis, the Universidad Complutense, Madrid (UCM). She joined the Department Hantzsch reaction is the less developed one. Indeed, in view of Organic and Medicinal Chemistry, School of Pharmacy, UCM, and re- of its named reaction status, it is surprising to realize how ceived her Ph.D. in 2013. Her thesis work, supervised by Dr. M. Villaca- scant attention it has received. Thus, Hantzsch’s 1890 origi- mpa and Prof. J.C. Menéndez, was focused on new multicomponent 13 reactions for the synthesis of pyrroles and their application to the nal note describes the synthesis of a single pyrrole deriva- preparation of bioactive compounds. Afterward, she joined, as a post- tive (Scheme 1). In a paper published in 1970, Roomi and doctoral researcher, the group of Prof. R. Orru, Synthetic and Bio-Or- MacDonald stated that they had only been able to find in ganic Chemistry group, in Vrije Universiteit Amsterdam. She worked in the chemical literature eight additional examples published the European Lead Factory (ELF) project, a novel European platform for in the intervening 80-year period. Furthermore, these reac- innovative drug discovery. Her main research interests have focused on the development of multicomponent reactions for their application in tions proceeded in yields below 45% and allowed very little the early phases of the drug discovery process. structural variation, which was limited to alkyl substituents Mercedes Villacampa was born in Madrid and studied Pharmacy and at C-4 and C-5. Optics at UCM. During her Ph.D. thesis, she worked on the synthesis of By tweaking the reaction conditions, the Roomi and natural product based serotonin analogues. After spending her post- MacDonald study extended slightly the scope of the doctoral studies with Professor Nicholas Bodor (University of Florida, Gainesville), she obtained a position of Professor Titular at the Organic Hantzsch reaction and allowed the preparation of com- and Medicinal Chemistry Department, UCM. She has also carried out pounds with substituents different from methyl at C-2 and postdoctoral work at the laboratory of Professor Kendall N. Houk (Uni- esters other than ethyl at C-3. However, yields remained be- versity of California at Los Angeles, UCLA). Her research fields include low 50% and the preparation of N-substituted pyrroles was computational chemistry and the development of new synthetic meth- 14 odologies, including multicomponent reactions, for their employment still not possible. More recent examples of the Hantzsch to the preparation of heterocycles to find new biological activities. pyrrole synthesis under traditional conditions still suffer José Carlos Menéndez was born in Madrid and studied Pharmacy from many limitations in scope.15 (UCM) and Chemistry (UNED). Following a Ph.D. in Pharmacy (supervisor: Dr. M. M. Söllhuber) and a postdoctoral stay at the Department of Chemistry at Imperial College, London (supervisor: Prof. Steven V. Ley),

in 1989 he joined the Department of Organic and Medicinal Chemistry This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. at the School of Pharmacy (Universidad Complutense, Madrid), where he is presently a Full Professor. He has been a visiting Professor at the Universities of Marseille (2007) and Bologna (2014) and in 2017 he was elected as a Full Member of the Spanish Royal Academy of Pharmacy. He has varied research interests in synthetic and medicinal chemistry, including the development of new multicomponent and domino reactions for diversity-oriented synthesis and the design, synthesis and study of new multi-target compounds for the diagnosis and treatment of neurodegenerative diseases and as chemotherapeutic agents (anti- tubercular, antileishmanial, anticancer). This work has been document- Scheme 1 The first reported example of the Hantzsch pyrrole synthesis ed in about 250 research papers, reviews, and chapters and 11 patents. He has also co-authored several Medicinal Chemistry textbooks. Depending on the nature of the α-halo carbonyl sub- strate, the reaction can furnish 5-substituted/4,5-disubstituted pyrroles (starting from α-halo ketones) or 4-substi-

Syn thesis M. Leonardi et al. Short Review tuted derivatives (starting from α-halo aldehydes). Some presence of LDA afforded the C-alkylation product 3. Its re- representative pyrrole derivatives prepared by the action with a variety of organometallic nucleophiles includ- Hantzsch method are summarized in Figure 2. ing Grignard reagents, organolithium derivatives, and DIBAL-H, gave initially the N-deprotonated intermediates 4. 5-Substituted or 4,5-disubstituted pyrroles Their reaction with the nucleophile proceeded in fully che- R2 CO Et X R2 CO-Z 2 moselective fashion in favor of the Weinreb amide and gave NH2 intermediates 5, which finally cyclized in situ to furnish the R R1 Me R1 O O Me N H 2,3-dihydropyrrolizines 6 (Scheme 3). This method allowed Examples: a broad scope in the substituent coming from the organo- CO2Et H3C COMe metallic reagent (R1 = H, alkyl, ethenyl, ethynyl, aryl, or 16 Me masked function). F3C N Me N H 60% (ref. 15a) CO2H Z Me 33% (ref. 15b) N N OMe H 4-Substituted pyrroles LDA, THF O Z = CN, CO2Me, CO2Et R CO2Et –78 to 0 °C X R CO-Z 1 NH2 OMe Me N Z H O R O Me N N H H Br Me 3 R1M Example: O 2 CO Et 2 Me N OMe Me Me Z O N 1 R1M H 48% (ref. 15c) N 2 H2O H O N Z 1 Figure 2 Some representative pyrroles prepared by the Hantzsch reaction R M 5 4

The yields obtained in these conventional Hantzsch pyr- – H2O role syntheses are moderate and rarely surpass 60%. Com- Z 6 13 examples pounds arising from competing side reactions have rarely 1 N R 40–99% yield been isolated, although in some literature examples, involv- (64% average) ing the use of α-chlorocarbonyl starting materials, the Scheme 3 Hantzsch synthesis of fused pyrroles involving β-keto Wein- Hantzsch reaction has been found to compete with a Feist– reb amides as the dicarbonyl component Benary furan synthesis, with no incorporation of the amine component into the product (Scheme 2, see also Scheme 26 below)). We will finally mention that Pal and co-workers have described a variation of the Hantzsch pyrrole synthesis in- CO2Et volving a change in the regioselectivity of the reaction, al- Hantzsch though the method seems mostly restricted to 1,3-dike- R Me CO Et N R O 2 H tones and aromatic amines. Thus, the reaction between an- ilines, a 1,3-diketone, and phenacyl bromide in the Cl O Me R CO2Et Feist- presence of Yb(OTf)3 as a Lewis acid catalyst leads to 4-sub- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. NH3 Benary stituted pyrroles (Scheme 4).17 O Me

Scheme 2 Competing Hantzsch and Feist–Benary reactions Ar-NH2 Ph COMe Br COMe Yb(OTf)3 MeCN, 80–85 °C + Me A variation of the Hantzsch pyrrole synthesis using β- Ph O O Me N keto Weinreb amides as the dicarbonyl component has also Ar been developed. By exploiting the reactivity of the Weinreb Scheme 4 Hantzsch pyrrole synthesis in the presence of Yb(OTf)3 amide function, this method allows the presence of a very broad variety of ketone substituents at the C-3 position of Although the mechanism of the Hantzsch pyrrole syn- the pyrrole products. Thus, the reaction between ethyl pyr- thesis has not been studied in detail, it is commonly accept- rolidin-2-ylideneacetate and related substrates bearing al- ed that it starts by the formation of an enaminone or enam- ternative electron-withdrawing substituents Z (compounds ino ester 7 by reaction of the primary amine with the dicar- 1) and N-methoxy-N-methyl-α-bromoacetamide (2) in the bonyl compound. This intermediate then reacts with the α-

Syn thesis M. Leonardi et al. Short Review halo carbonyl component, leading to the C-alkylated inter- Abdel-Mohsen and co-workers, in 2015, applied the mediate 8, which furnishes the final product 9 by cyclocon- same method to the synthesis of 5-(N-substituted pyrrol-2- densation with loss of a molecule of water (Scheme 5). yl)-8-hydroxyquinolines 10, with potential biological interest (Scheme 7).19 The method was later extended in 2016 to O the synthesis of tetrahydroindoles by use of cyclic 1,3-dike- COR3 O 3 R NH tones as starting materials, although in this case the solvent 2 X + 1 R5 20 R 2 was ethanol. R2 O – H2O R NH R4 R1 7 O O Me O Me 4 Me Me 4 3 R R COR DABCO (10 mol%) R5 COR3 N O Cl H2O, 60 °C R 5 2 R R – H O O N 2 HN R2 1 NH2 R R1 N 9 8 R N HO OH Scheme 5 Commonly accepted mechanism for the Hantzsch pyrrole 10 synthesis 14 examples 65–93% yield (75% average) Scheme 7 DABCO-promoted synthesis of pyrroles bearing a 5-(8-hy- The Yb(OTf)3-associated change in regioselectivity men- tioned above can be ascribed to an increased reactivity of droxyquinolin-5-yl) substituent the carbonyl with respect to the alkyl halide due to efficient coordination of its oxygen atom with this potent Lewis acid. A mechanistic proposal is summarized in Scheme 8 for To summarize, Hantzsch reactions performed in solu- the case of the 5-(N-substituted pyrrol-2-yl)-8-hydroxy- tion under conventional conditions often give modest quinolines 10, and involves the initial reaction of the start- yields and do not show a broad substituent scope. These ing 5-(chloroacetyl)quinoline derivative with the organo- limitations explain the limited use of this classical method catalyst to give the highly electrophilic intermediate 11. Its and have stimulated in recent years the development of a reaction with enaminone 12, formed from the primary number of non-conventional variations of the reaction.

3 Hantzsch Pyrrole Synthesis under Non- Cl O conventional Conditions O Me

O NH2 3.1 Hantzsch Pyrrole Synthesis in Green Solvents N R Me and in the Absence of Solvent OH

– H2O DABCO R In 2012, Meshram and co-workers developed an or- R O HN N O HN ganocatalytic approach to the Hantzsch pyrrole synthesis, Me N Me using 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst and Me Me O O 12 water as the reaction medium (Scheme 6).18 The authors Cl – DABCO

examined mainly the structural variation of the primary – HCl This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. amine component, and proved that a variety of alkyl or aryl N N substituents were tolerated, and also three different OH 13 OH phenacyl bromides, but the only β-dicarbonyl component 11 DABCO that they studied was pentane-2,4-dione. – (DABCO)H Me Me O O Me O O Me O NH Me 2 N O DABCO R (DABCO)H Me R2 H O, 60 °C 2 – DABCO N Me Me O Br N R R1 – H2O N R2 25 examples N OH 80–92% yield OH (85% average) 10

R1 Scheme 8 Mechanism proposed to explain the DABCO organocatalysis in the Hantzsch pyrrole synthesis Scheme 6 Hantzsch pyrrole synthesis in water, promoted by DABCO

Syn thesis M. Leonardi et al. Short Review amine and pentane-2,4-dione, gives 13, cyclocondensation (Scheme 10).22 A previous experiment by Nageswar and co- of which is aided by deprotonation of the enamine nitrogen workers had shown that the Hantzsch reaction fails in PEG- by DABCO. 400/water in the absence of catalysts at 120 °C.21 Nageswar and co-workers have performed some examples of the Hantzsch pyrrole synthesis by using water as sol- R1 O Me vent and with the aid of β-cyclodextrin as a supramolecular NH2 catalyst. In this particular case, the authors examined only O R2 Alum the structural variation of the primary amine component Me O Br PEG 400/H2O O O 21 (3:2) (Scheme 9). 70 °C, 4–6 h O N Me 2 O R O O O Me Me O 16 16 examples Me Me 1.β-CD/H O 15 2 1 83–91% yield RNH Me R H H 2 2. 60–70 °C (87% average) O N O O + O Br R Al3 O O 14 Br O 12 examples O 78–89% yield O (84% average) O O Me Scheme 9 Cyclodextrin-promoted Hantzsch pyrrole synthesis in water O O O R1 Me HN O The formation of a phenacyl bromide–cyclodextrin R1 complex was proved by NMR experiments that suggested O O O the mode of inclusion shown in Figure 3, as shown by the O n upfield shift of the H-3 and H-5 protons at the broader rim 17 of the cyclodextrin. This mode of complexation is compati- Scheme 10 Hantzsch pyrrole synthesis promoted by alum in PEG-water ble with a subsequent alkylation of the dicarbonyl component to yield a 1,4-dicarbonyl intermediate that would then furnish the pyrrole by a Paal–Knorr reaction, as suggested Zhao and co-workers discovered that irradiation at 500 by the authors (structure A), but also with the usual W of α-bromoacetophenones, ethyl acetoacetate, and pri- Hantzsch mechanism involving the alkylation of an enami- mary amines in a pressurized microwave vial afforded 5- none (structure B). arylpyrroles 18 in good yields, without the need for any solvent or catalyst (Scheme 11). In terms of scope, the reaction R tolerated well the presence of electron-withdrawing or HO Me HN Me electron-releasing groups in the α-bromoacetophenone O O Br component and the use of alkyl-, aryl-, and (hetero)arylme- Br H H O O thylamines. Modifications of the β-dicarbonyl component Me O Me O were not investigated.23

O O O OEt Me OEt MW, 500 W, R2 solvent-free

NH2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. A B O Me R3 N Br R1 Figure 3 Complexation of phenacyl bromide by β-cyclodextrin R3 18 1 R 18 examples R2 77–88% yield Das and co-workers have performed a three-component (82% average) Hantzsch synthesis from primary amines, pentane-2,4-di- Scheme 11 Microwave-assisted, solvent- and catalyst-free Hantzsch one, and 3-(bromoacetyl)coumarin derivatives 15 in a mix- synthesis of pyrroles ture of water and polyethylene glycol (PEG-400) in the presence of Alum (AlK(SO4)2·12H2O), an ecofriendly catalyst that requires an aqueous medium. The reaction leads to the When starting from a pre-formed enaminone, micro- synthesis of pyrrole derivatives 16 containing the pharma- wave irradiation proved unnecessary. Thus, Yavari and co- cological important coumarin moiety. The role of polyeth- workers found that by simply stirring compounds 19 and α- ylene glycol is to provide a micellar environment, and the bromo ketones 20 under solvent-free conditions at room Al3+ in alum acts as a Lewis acid, as shown in structure 17 temperature, they could isolate the corresponding 5-substituted pyrroles 21 in good to excellent yields (Scheme 12).24

Syn thesis M. Leonardi et al. Short Review

R2 O O R2 O H-C(OEt)3 NH O neat 2 N DMF N + H H O rt, 3 h R1 Br Me rt, 2 x 24 h R3 O Me Me NH Me NH 3 N 20 R 22 R1 1 R1 R 23 4 19 21 R Br 12 examples 2,6-di-tert-butylpyridine 65–94% yield DMF, rt, 17 h (82% average) R5 O

Scheme 12 Solvent-free synthesis of 5-substituted pyrroles O O 4 4 R NH2 20% TFA R N CH2Cl2, 30 min, rt H 3.2 Hantzsch Pyrrole Synthesis under Solid-Phase R5 Me R5 Me Conditions N N R1 R1 24 Jung and co-workers reported, in 1998, a solid-support- Scheme 14 Solid-phase synthesis of pyrrole-3-carboxamide derivatives ed three-component Hantzsch reaction, involving the use of an acetoacetylated Rink resin 22. This material was pre- sound for 1.5 hours (Scheme 16). It was observed that parti- pared by treatment of commercial polystyrene Rink amide cles with a smaller crystallite size were obtained in the ion- resin with a variety of acetoacetylating reagents such as ic liquid than in water. It is relevant for the mechanism of diketene at –15 °C to room temperature, 2,2,6-trimethyl- the reaction to note that the ZnO-NPs thus obtained have 1,3-dioxin-4-one at 110 °C, or N-hydroxysuccinimidyl ace- both Lewis acid sites (Zn2+) and Lewis basic sites (O2–). toacetate at room temperature (Scheme 13). As shown in These catalysts were re-used up to three times, with no sig- Scheme 14, the Rink resin thus modified was first treated nificant loss in yield. with primary amines, presumably to afford the corresponding β-enaminoamides 23. This step was followed by reac- R2 R2 Br O O tion with α-halo carbonyl compounds to give pyrroles 24, NP-ZnO (15 mol%) which were finally liberated from the solid support by acid O solvent-free, )))) R3 R3 Me 1 N hydrolysis. Due to the structure of the resin-contained di- Me O NH2-R R1 carbonyl component, the method was restricted to the 13 examples preparation of pyrrole-3-carboxamide derivatives, which 87–95% yield (91% average) were isolated in excellent purities, but unfortunately the authors failed to report the reaction yields.25 Scheme 15 Ultrasound-promoted Hantzsch pyrrole synthesis in the presence of ZnO nanoparticles

O O O Br Me NN O , nHex nHex ))) H C Me O Zn(OAc) 2 Me O O 2 [HHIM]Br 1.5 h + Zn(OH) –2 NP-ZnO NH2 4 or NaOH water-free O N Me Rink resin H O O 22 ZnO nanoparticles N Lewis Lewis O Me basic site acid site O Scheme 13 Synthesis of an acetoacetylated Rink resin Scheme 16 Synthesis and schematic structure of the ZnO nanoparticles This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

3.3 Sonochemical Hantzsch Pyrrole Synthesis The reaction was proposed to follow the usual Hantzsch mechanism, with the Zn2+ sites acting as Lewis acids inter- Shahvelayati and co-workers described an efficient acting with the carbonyls in the 1,3-dicarbonyl compound Hantzsch pyrrole synthesis performed in the absence of sol- and the α-bromo ketone and thus facilitating the formation vents, under irradiation with an ultrasonic cleaner with a of the intermediate enamino ester and its alkylation to give frequency of 60 kHz and an intensity of 285 W, and cata- 25. On the other hand, the O2– sites may deprotonate the lyzed by ZnO nanoparticles (Scheme 15).26 The catalyst was NH in intermediate 25 and thus facilitate the final cyclocon- prepared by treatment of zinc acetate with sodium hydrox- densation step, with concomitant assistance by coordina- ide in an ionic liquid, followed by irradiation with ultra- tion of its carbonyl with a Lewis acidic site (Scheme 17).

Syn thesis M. Leonardi et al. Short Review

1 R1 R NH2 HN O O O O O O 2 Br 2 Me R 5 Me R – H2O H3C OtBu R Br DMF DMF 1 3 R -NH2 R 0.5 M 0.5 M O 200 °C – HBr 8 min DIPEA DIPEA 1 Me R 1.0 equiv 0.5 equiv H O N O N O O R2 2 R1 Me R OtBu OH O O 5 5 3 R CH3 R CH3 R R3 N N 25 R1 R1 4 examples 14 examples 76–82% yield 40–65% yield R2 (79% average) (56% average) R2 O EDC, HOBt O 3 DIPEA, R NH2 HO R3 Me O R3 Me – H2O N R3 N N R1 H R1 R5 Scheme 17 The role of ZnO nanoparticles in catalyzing the Hantzsch N CH3 pyrrole synthesis R1 5 examples 30–53% yield 3.4 Hantzsch Pyrrole Synthesis under Flow Condi- (39% average) tions Scheme 18 Hantzsch pyrrole synthesis under continuous flow conditions

As summarized in Scheme 18, Cosford and Herath described a one-pot synthesis of pyrrole-3-carboxylic acid de- O 3 5 ν R R Br h (blue LED) rivatives based on the Hantzsch reaction that involves the 4 R Ir(ppy)3, DMSO continuous flow of tert-butyl acetoacetate, primary amines, 1 5 (Et3N), rt, 2 h 2 4 R R R N R NH and α-bromo ketones at 200 °C during 8 minutes. R1 R3 The generation of HBr during the alkylation step was R2 21 examples exploited to achieve the in situ hydrolysis of the tert-butyl 31–99% yield (76% average) ester groups. The subsequent coupling of the carboxylic substituent to diverse amines was also described and gave Scheme 19 Photochemical Hantzsch pyrrole synthesis pyrrole-3-carboxamide derivatives, including two cannabi- noid receptor subtype 1 (CB1) inverse agonists.27 If desired, the pyrrole derivatives could be isolated in ester form by O R5 R3 R5 adding one equivalent of base to trap HBr. 4 Et N R H 3 4 2 N – H O R N R R1 R3 2 1 3.5 Hantzsch Pyrrole Synthesis under Photoredox R This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R2 30 Catalysis Ir(ppy)3 O R5 hn R4 H Wu and co-workers developed a photochemical version N R1 R3 of the Hantzsch pyrrole synthesis when they discovered Ir(ppy) * 3 Ir(ppy)3 R2 that the irradiation with visible light (λ = 450 nm) of a 29 DMSO solution of enaminones and α-bromo ketones at room temperature, in the presence of a catalytic amount of O O R1 Br R5 NH Ir(ppy) as a photosensitizer, afforded 2,5-diaryl-substitut- 4 4 3 R R R3 28 2 ed pyrroles in good to excellent yields (Scheme 19). Fur- R5 27 R 28 thermore, an increase in yield to quantitative levels was 26 achieved by addition of triethylamine to the reaction medi- Scheme 20 Proposed mechanism for the photoredox-promoted um. Hantzsch synthesis

Syn thesis M. Leonardi et al. Short Review

The mechanism proposed to explain this transforma- vent-free method afforded considerably higher yields of tion is summarized in Scheme 20. Irradiation of the photo- pyrroles than previous versions of the Hantzsch reaction, in sensitizer leads to its excited form Ir(ppy)3*, which, follow- spite of comprising an additional step, and was far broader ing single electron-transfer oxidation by the starting α-bro- in scope (Scheme 21).30,31 + mo ketone 26, is transformed into Ir(ppy)3 . The reduced 26, The generality of the mechanochemical method was upon debromination, generates radical 27, which adds to proved by its application to the preparation of fused pyrrole the enaminone 28 to furnish another radical, 29. This spe- systems derived from the indole 34, homoindole 35, ben- + cies transfers one electron to Ir(ppy)3 , closing the catalytic zo[g]indole 36, and indeno[1,2-b]pyrrole 37 frameworks, cycle, and affords imine 30, which finally furnishes the final which had not been previously possible using the Hantzsch pyrrole products by intramolecular cyclocondensation with reaction, from β-dicarbonyl compounds 31, primary loss of a molecule of water. amines 32, and cyclic ketones 33 (Scheme 22). Again, the mechanochemical method proved to have considerable ad- 3.6 Hantzsch Pyrrole Synthesis under Mechano- vantages in terms of yield over a similar solution-phase chemical Conditions protocol.31

O Due to our interest in the use of cerium(IV) ammonium R5 R5 n 29 3 nitrate (CAN) as a Lewis acid catalyst, we investigated the R NH2 + + or R1 O Hantzsch reaction in ethanol between β-dicarbonyl com- O R2 O R 32 n pounds, primary amines, and α-iodo ketones in the pres- 33a, n = 1,2 31 33b, n = 0,1 ence of CAN and silver nitrate, which was necessary in or- 1. CAN (5 mol%) der to prevent reductive dehalogenation of the starting α- 2. NIS, TsOH, HSVM (20 Hz), rt, 1 h iodo ketones by the HI liberated in the alkylation step. In 3. Add 31 and 32, then 2013, we discovered that the reaction could be also per- AgNO3, HSVM (20 Hz), rt, 1 h formed in a solvent-free fashion, under high-speed vibra- O O 3 tion milling conditions (HSVM) in a mixer mill working at R3 R R5 R5 20 Hz with the use of a single zirconium oxide ball 20 mm n Me or R2 in diameter. Furthermore, the mechanochemical version of N N n the Hantzsch pyrrole synthesis could be telescoped with R1 R R1 the synthesis of the starting α-iodo ketone from the corre- 34 (n = 1), 35 (n = 2) 36 (n = 0), 37 (n = 1) sponding ketone and N-iodosuccinimide (NIS). This sol- 5 examples 16 examples 40–97% yield 41–94% yield (57% average) (79% average) O R4 Scheme 22 Mechanochemical synthesis of fused pyrrole derivatives 3 R NH2 + 5 R1 R O 2 NIS, O R Bearing in mind the importance of symmetrical com- TsOH (10 mol%) CAN HSVM (20 Hz) (5 mol%) pounds formed by two identical pharmacophores connect- 60 min O ed by a spacer chain in the drug discovery field, we studied the pseudo-five-component reactions between diamines, R4 I 3 R α-iodo ketones (prepared in situ from aryl ketones, 2 equiv) HN R2 R5 O and β-dicarbonyl compounds (2 equiv). We found that the R1

mechanochemical method allowed the efficient construc- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

AgNO3, HSVM tion of two pyrrole systems at the ends of a central chain in (20 Hz), 60 min a single synthetic operation, furnishing compounds 38 O (Scheme 23). One example of the construction of three pyr- R4 3 R role rings was also achieved.32 In the same context, we also studied the Hantzsch reac- R5 R2 N tions of some symmetrical aromatic compounds containing R1 35 examples two acetyl groups and successfully employed them as sub- 32–97% yield strates for pseudo-five-component reactions leading to ad- (70% average) ditional symmetrical systems 39 capped by two pyrrole Scheme 21 Hantzsch pyrrole synthesis under high-speed vibration milling rings (Scheme 24).31

Syn thesis M. Leonardi et al. Short Review

33 O synthesis of pemetrexed starts from 2,6-diaminopyrimi-

CH3 din-4(3H)-one 40 and an α-bromoaldehyde 41, which is the R3 2 2 + H2N NH2 R5 O suitable kind of reaction partner to obtain a β-substituted O R2 NIS, TsOH (10 mol%) pyrrole moiety. The Hantzsch reaction was achieved by ex- CAN HSVM (20 Hz) posure of these starting materials to sodium acetate and af- (5 mol%) 60 min forded compound 42 after saponification of the ester group. R3 R2 I A final conjugation with diethyl glutamate and a second sa- O HN 2 ponification afforded pemetrexed disodium 43 (Scheme 25). NH O R5 O Pemetrexed regioisomeric structures bearing the side

R2 R3 chain at the position adjacent to the pyrrole nitrogen (e.g., compound 46) are also accessible by Hantzsch chemistry, replacing the α-halo aldehyde by an α-halo ketone deriva- CAN (5 mol%) tive. In this case, two starting materials were assayed, cor- AgNO3, HSVM 34 35 (20 Hz), 60 min responding to X = Cl and X = Br. In the first case, a 1:1 mixture of products was obtained, corresponding to a furan R3 R2 R5 derivative 44 arising from a competing Feist–Benary reac- O N N tion, and the desired pyrrole derivative 45. On the other O R4 hand, when X = Br the reaction showed full selectivity in fa- R5 R2 R3 vor of the Hantzsch product (Scheme 26). 38 15 examples The anti-inflammatory agent 48, an analogue of zome- 45–68% yield pirac, was synthesized from diethyl 3-oxopentanedioate, (61% average) methylamine, and α-chloroacetone.36 It is interesting to NH2 H2N NH2 = H2N 1–11 note that in this case the Hantzsch reaction gave the unex- NH2 pected 4-substituted regioisomer. This result was ascribed Me H N NH2 2 N Si 3 to the fact that, upon mixing diethyl acetonedicarboxylate H Me Me O and methylamine, a precipitate was formed that was identi- N 3 NH2 Si Me fied as a salt of the enolate anion. Thus, the authors pro- H2N N H2N 3 posed that the reaction follows the mechanism summa- 3 rized in Scheme 27, involving the reaction of this anion Scheme 23 Pseudo-five-component double Hantzsch pyrrole synthe- with the carbonyl group of α-chloroacetone, followed by an ses from diamines alkylation-cyclocondensation reaction sequence with methylamine to give pyrrole derivative 47. Further functional group manipulation furnished the target compound 48. 4 Applications of the Hantzsch Pyrrole Syn- The Hantzsch pyrrole synthesis has been applied to the thesis synthesis of radiolabeled pyrroles. Since pyrrole-2,3,5-tricarboxylic acid is a metabolite of melatonin, a radiolabeled The anticancer drug pemetrexed (LY231514, Alimta®) version of this compound was deemed to be useful as a bio- and related compounds provide a good example of the ap- marker to monitor the effectiveness of drug candidates plication of the Hantzsch reaction to the synthesis of com- against hyperpigmentation. In this context, the synthesis of 13 15 plex heterocyclic systems containing a pyrrole fragment. A [ C4, N]pyrrole-2,3,5-tricarboxylic acid 50 was carried out This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

O O

Me Me

O NIS (2 equiv), TsOH (20 mol%) HSVM, 1–2 h, 20 Hz 3 O O NH2 R 22 R3 R3 R1 O O O Me I I Me N Me CAN (10 mol%), AgNO3 (2 equiv) N HSVM (20 Hz), 60 min R1 R1 39 4 examples 84–94% yield (88% average) =

Scheme 24 Pseudo-five-component double Hantzsch pyrrole syntheses from diacetylated aromatic starting materials

Syn thesis M. Leonardi et al. Short Review

O CO H O O 2 OMe 1. NaOAc 2 HN 2. NaOH HN + OHC N H2N N NH2 H2N N Br 41 H 40 42 COOEt

H2N COOEt NMM, CDMT

O O CO2Na CO2Et O O 2 N 2 N H NaOH H HN HN CO Na H N N N 2 H N N N CO2Et 2 H 2 H 43 Pemetrexed (LY231514, AlimtaTM) Scheme 25 Synthesis of the anticancer drug pemetrexed based on a Hantzsch pyrrole synthesis

NH2 COOMe N NH2 3 Feist-Benary (a) N H2N N O H O H2N N O DMF 44 rt O NaO2C HN OR O N H2N N NH2 NH H 2 CO2Na NH2 N Hantzsch (b) 3 N X 3 H N N N 2 H 3 H N N N O 2 H CO2Me 45 X = Cl, (a):(b) = 1:1 46 X = Br, only (b) Scheme 26 Synthesis of a homologue of the pemetrexed C-2 regioisomer using a route that had as the key step the Hantzsch pyrrole O OEt O OEt 13 15 synthesis from [1,2,3,4- C4]ethyl acetoacetate, NH4OH, 37 O O and chloroacetaldehyde. The pyrrole derivative 49 thus Me NH2 NH Me obtained had all the radiolabels in place and was trans- O O 3 formed into 50 by additional functional group manipula- OEt OEt tion (Scheme 28). Precipitates Atorvastatin is the best-known member of the statins, O Cl the main group of cholesterol-lowering drugs. This drug Me This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. was marketed in 1997 as its calcium salt under the trade ® O OEt name Lipitor and spent almost a decade at the top of the Me COOEt Me NH2 O list of largest-selling branded pharmaceuticals, being thus COOEt regarded as the best-selling drug in history. N O Cl Thus, atorvastatin can be arguably regarded as the most Me 47 OEt Me important unnatural pyrrole derivative ever made. This compound has received much attention from synthetic chemists, and the target of all this work is normally the Me atorvastatin lactone, which is readily transformed into the COOH 38 drug molecule by hydrolysis followed by salt formation. In N the literature, the construction of the atorvastatin pyrrole Cl Me core is normally based on the Paal–Knorr pyrrole synthesis 48 or 1,3-dipolar cycloadditions. We noticed that our mecha- Scheme 27 Synthesis of a 4-methylpyrrole derivative by an anomalous Hantzsch reaction and its proposed mechanistic explanation

Syn thesis M. Leonardi et al. Short Review

O O tion, which is susceptible to hydrolysis by CAN. After some

CO Et optimization work, we discovered that ytterbium triflate * 2

H3C * * OEt

* * H O * * # 2 was a suitable catalyst for the desired process, although the O NH4OH # (34%) N CH3 reaction was slow at room temperature. The enaminoamide Cl H H 49a = 12C, 14N 53 thus obtained was transformed into pyrrole 55 upon 49b = 13C, 15N treatment with α-iodo ketone 54 under mechanochemical

* = 12,13 C 5 steps Hantzsch reaction. Treatment with acid led to the deprotec- # = 14,15 N tion of the terminal tert-butyl ester, with concomitant cy- *

CO2H

* clization of the resulting hydroxy acid to give atorvastatin

* * 39 # lactone 56 (Scheme 29). HO2C N CO2H H We will finally discuss one example of the application of 50 Hantzsch pyrroles as starting materials for the synthesis of (12% overall) more complex heterocycles. The generation of diversity- Scheme 28 Synthesis of a radiolabeled pyrrole derivative by a oriented libraries by combination of a multicomponent re- Hantzsch reaction action with a complexity-generating event is known as the build-couple-pair strategy and was initially proposed by nochemical pyrrole synthesis was well suited to achieve a Schreiber and Nielsen as a new strategy for the exploration very short, convergent route to the atorvastatin lactone, al- of chemical space in search for bioactive compounds.40 The though we acknowledged the fact that the target is a penta- mildness of the mechanochemical Hantzsch reaction al- substituted pyrrole with a branched substituent at C-2 and lowed its compatibility with the presence in the starting an amide group at C-3 would bring our method to its limits. materials of functional groups (e.g., acetals) that are In the event, the reaction between β-ketoamide 51 and the amenable to a subsequent cyclization reaction. Thus, when commercially available amine 52, corresponding to the the mechanochemical Hantzsch reaction was performed atorvastatine side chain, was problematic and it did not starting from 2-aminoacetaldehyde dimethyl acetal 57, β- take place at all, under our usual CAN catalysis. In view of dicarbonyl compounds, and acyclic and cyclic α-iodo ke- the success of initial model reactions starting from 51, this tones, the corresponding pyrroles and fused pyrroles 58 result was attributed to the presence of the acetal protec- were obtained uneventfully.

Me O H Ph Ph N NH Ph I Ph N Me Ph H O O O Me O 51 Me N HN F Me + NH Yb(OTf) (1 mol%), EtOH F 2 3 Me 40 °C, overnight 54

Yb(OTf)3 (1 mol%) O O AgNO3 (1 equiv) Me O Me HSVM (20 Hz, 60 min) O Me O Me O Me Me O O O O Me O O Me

Me Me This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Me Me Me Me (55 40% from 51 and 52) Me 52 53 2 M HCl MeOH, rt, 3 h

O Ph O Ph NH Ph Ph N Me H N Me F Me N Ca2+ F Me

OH O OH HO O O O 2 56 (atorvastatin lactone) Calcium atorvastatin (94%) Scheme 29 Synthesis of atorvastatin based on the mechanochemical Hantzsch pyrrole synthesis

Syn thesis M. Leonardi et al. Short Review

I O NIS, TsOH (10 mol%) O HSVM (20 Hz) 60 min Build O R3

Couple R2 O O N AgNO3, HSVM CAN (20 Hz), 60 min OMe R3 R3 (5 mol%) 58 + 21 examples OMe O R2 NH HN R2 2 65–88% yield MeO MeO (75% average) TMSOTf (15 mol%) OMe OMe Pair CH2Cl2, rt, 10 min 57 O R3

R2 N

59 21 examples 65–90% yield (80% average) Scheme 30 Synthesis of complex polyheterocyclic frameworks from a Hantzsch pyrrole

We then discovered that their treatment with catalytic (2) For reviews of specific families of pyrrole alkaloids, see: amounts of trimethylsilyl triflate allowed very mild and ef- (a) Fürstner, A. Angew. Chem. Int. Ed. 2003, 42, 3582. (b) Bailly, ficient Pommeranz–Fritzsch-type cyclizations that gave C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363. (c) Fan, H.; polycyclic compounds 59, corresponding to six different Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264. 41 (d) Forte, B.; Malgesini, B.; Piutti, C.; Quartieri, F.; Scolaro, A.; frameworks, in high yields (Scheme 30). Papeo, G. Mar. Drugs 2009, 7, 705. (e) Al-Mourabit, A.; Zancanella, M. A.; Tilvi, S.; Romo, D. Nat. Prod. Rep. 2011, 28, 1229. 5 Conclusions (3) For the biosynthesis of pyrrole natural products, see: Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. The Hantzsch pyrrole synthesis, one of the classical 2006, 23, 517. (4) (a) Hughes, C. C.; Prieto-Davo, A.; Jensen, P. R.; Fenical, W. Org. methods for the construction of simple heterocycles, has Lett. 2008, 10, 629. (b) Li, R. Med. Res. Rev. 2016, 36, 169. been long neglected in spite of its named reaction status. In (5) (a) Biava, M.; Porretta, G. C.; Manetti, V. Mini-Rev. Med. Chem. recent years, the use of a number of non-conventional ap- 2007, 7, 65. (b) Biava, M.; Porretta, G. C.; Poce, G.; Supino, S.; proaches has improved its outcome and broadened its Sleiter, G. Curr. Org. Chem. 2009, 13, 1092. (c) Biava, M.; scope. We hope that this review will stimulate the use of Porretta, G. C.; Poce, G.; Battilocchio, C.; Alfonso, S.; de Logu, A.; this important reaction by the synthetic community. Manetti, F.; Botta, M. ChemMedChem 2011, 4, 593. (6) Kunfermann, A.; Witschel, M.; Illarionov, B.; Martin, R.; Rottmann, M.; Höffken, H. W.; Seet, M.; Eisenreich, W.; Knölker, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Funding Information H.-J.; Fischer, M.; Bacher, A.; Groll, M.; Diederich, F. Angew. Chem. Int. Ed. 2014, 53, 1. Financial support of our research from MINECO (grant CTQ2015- (7) Teixeira, C.; Barbault, F.; Rebehmed, J.; Liu, K.; Xie, L.; Lu, H.; 68380-R) and CAM (B2017/BMD-3813) is gratefully acknowledged.MinEisdcteoreion o Cmoym ía petitivid(Cad TQ2015-68380-R)ConEsedjeeuría c acióJun v,Deneytup doC rteo,mu- Jiang, S.; Fan, B.; Maurel, F. Bioorg. Med. Chem. 2008, 16, 3039. nidad de Madrid (B2017/BMD-3813) (8) Chin, Y. W.; Lim, S. W.; Kim, S.-H.; Shin, D.-Y.; Suh, Y.-G.; Kim, Y.-B.; Kim, Y. C.; Kim, J. Bioorg. Med. Chem. Lett. 2003, 13, 79. (9) For a review of the discovery and development of atorvastatin, References see: Roth, B. D. Prog. Med. Chem. 2002, 40, 1. (10) For selected reviews of the role of pyrrole derivatives in materi- (1) For general reviews of antitumor natural pyrrole derivatives, als science, see: (a) Higgins, S. J. Chem. Soc. Rev. 1997, 26, 247. see: (a) Dembitsky, V. M.; Gloriozova, T. A.; Poroikov, V. V. Mini- (b) Maeda, H. Eur. J. Org. Chem. 2007, 5313. (c) Loudet, A.; Rev. Med. Chem. 2005, 5, 319. (b) Gupton, J. T. Top. Heterocycl. Burgess, K. Chem. Rev. 2007, 107, 4981. (d) Berlin, A.; Vercelli, B.; Chem. 2006, 2, 53. Zotti, G. Polym. Rev. 2008, 48, 493.

Syn thesis M. Leonardi et al. Short Review

(11) For reviews of the use of pyrroles as synthetic building blocks, (23) Kan, W.; Jing, T.; Zhang, X.-H.; Zheng, Y.-J.; Chen, L.; Zhao, B. see: (a) Donohe, T. J.; Thomas, R. E. Chem. Rec. 2007, 7, 180. Heterocycles 2015, 91, 2367. (b) Mal, D.; Shome, B.; Dinda, B. K. In Heterocycles in Natural (24) Yavari, I.; Ghazvini, M.; Azad, L.; Sanaeishoar, T. Chin. Chem. Lett. Product Synthesis; Majumdar, K. C.; Chattopadhyay, S. K., Ed.; 2011, 22, 1219. Wiley-VCH: Weinheim, 2011, Chap. 6. (25) Trautwein, A. W.; Süssmuth, R. D.; Jung, G. Bioorg. Med. Chem. (12) For reviews of the synthesis of pyrroles, see: (a) Black, D. ST. C. Lett. 1998, 8, 2381. Science of Synthesis 2001, 9, 444. (b) Ferreira, V. F.; de Souza, M. (26) Shahvelayati, A. S.; Sabbaghan, M.; Banihashem, S. Monatsh. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Chem. 2017, 148, 1123. Proced. Int. 2001, 33, 411. (c) Joshi, S. D.; More, U. A.; Kulkarni, (27) Herath, A.; Cosford, N. D. P. Org. Lett. 2010, 12, 5182. V. H.; Aminabhavi, T. M. Curr. Org. Chem. 2013, 17, 2279. (28) Lei, T.; Liu, W.-Q.; Li, J.; Huang, M.-Y.; Yang, B.; Meng, Q. Y.; (d) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. Chen, B.; Tung, C.-H.; Wu, L.-Z. Org. Lett. 2016, 18, 2479. 2010, 39, 4402. (e) Estévez, V.; Villacampa, M.; Menéndez, J. C. (29) Sridharan, V.; Menéndez, J. C. Chem. Rev. 2010, 110, 3805. Chem. Soc. Rev. 2014, 43, 4633. (f) Gulevich, A. V.; Dudnik, A. S.; (30) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Commun. Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084; see also 2013, 49, 591. references 29 and 30. (31) Estévez, V.; Sridharan, V.; Sabaté, S.; Villacampa, M.; Menéndez, (13) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. J. C. Asian J. Org. Chem. 2016, 5, 652. (14) Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689. (32) Leonardi, M.; Villacampa, M.; Menéndez, J. C. Beilstein J. Org. (15) For representative examples, see: (a) Kameswaran, V.; Jiang, B. Chem. 2017, 13, 1957. Synthesis 1997, 530. (b) Biev, A. T.; Nankov, A. N.; Prodanova, P. (33) Qi, H.; Wen, J.; Li, L.; Bai, R.; Chen, L.; Wang, D. J. Heterocycl. P. Dokl. Bulg. Akad. Nauk. 2000, 53, 29. (c) Matiychuk, V. S.; Chem. 2015, 52, 1565. Martyak, R. L.; Obushak, N. D.; Ostapiuk, Y. V.; Pidlypnyi, N. I. (34) Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein, F.; Kisliuk, R. L. Chem. Heterocycl. Compd. 2004, 40, 1218. J. Med. Chem. 2004, 47, 6893. (16) Calvo, L.; González-Ortega, A.; Sañudo, M. C. Synthesis 2002, (35) Deng, Y.; Wang, Y.; Cherian, C.; Hou, Z.; Buck, S. A.; Matherly, L. 2450. H.; Gangjee, A. J. Med. Chem. 2008, 51, 5052. (17) Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Meda, C. L. (36) Carson, J. R.; Wong, S. J. Med. Chem. 1973, 16, 172. T.; Kandale, A.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Parsa, (37) Skaddan, M. B. J. Labelled Compd. Radiopharm. 2010, 53, 73. K. V. L.; Kumar, K. S.; Pal, M. RSC Adv. 2012, 2, 9142. (38) (a) Jie-Jack, L.; Douglas, S. J.; Drago, R. S.; Bruce, D. R. Contempo- (18) Meshram, H. M.; Bangade, V. M.; Reddy, B. C.; Kumar, G. S.; rary Drug Synthesis, Chap. 9,; Wiley-Interscience: Hoboken, Thakur, P. B. Int. J. Org. Chem. 2012, 2, 159; 2004. (b) Casar, Z. Curr. Org. Chem. 2010, 14, 816. (c) Harrington, https://www.scirp.org/journal/ijoc/. P. J. Pharmaceutical Process Chemistry for Synthesis: Rethinking (19) Abdel-Mohsen, S. A.; El-Ossaily, Y. A. Heterocycl. Commun. 2015, the Routes to Scale-up; Wiley: Hoboken, 2011, Chap. 9,. 21, 207. (39) Estévez, V.; Villacampa, M.; Menéndez, J. C. Org. Chem. Front. (20) Abdel-Mohsen, S. A.; El-Emary, T. ARKIVOC 2016, (iv), 184. 2014, 1, 458. (21) Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar, Y. (40) Nielsen, T. E.; Schreiber, S. L. Angew. Chem. Int. Ed. 2008, 47, 48. V. D. Helv. Chim. Acta 2009, 92, 2118. (41) Leonardi, M.; Villacampa, M.; Menéndez, J. C. J. Org. Chem. 2017, (22) Pal, G.; Paul, S.; Das, A. R. Synthesis 2013, 45, 1191. 82, 2570. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.