The Hantzsch Pyrrole Synthesis: Non-conventional ......2 The Conventional Hantzsch Pyrrole Syn-thesis Among the classical methods for pyrrole synthesis, the Hantzsch reaction is the

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M. Leonardi et al. Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2019, 51, 816–828short reviewen

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The Hantzsch Pyrrole Synthesis: Non-conventional Variations and Applications of a Neglected Classical ReactionMarco Leonardi Verónica Estévez Mercedes Villacampa J. Carlos Menéndez* 0000-0002-0560-8416

Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, Plaza de Ramón y Cajal sn, 28040 Madrid, [email protected]

Conventional

Microwave

Photochemical

Solid phase

Mechanochemical

Flow

Sonochemical

O

R2

O

R3

NH2

R1

R5

O

R4

XR2

COR3

N

R1

R5

R4

Hantzsch pyrrole synthesis

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Received: 10.09.2018Accepted after revision: 18.10.2018Published online: 03.12.2018DOI: 10.1055/s-0037-1610320; Art ID: ss-2018-z0610-sr

Abstract Pyrrole is one of the most important one-ring heterocyclesbecause of its widespread presence in natural products and unnaturalbioactive compounds and drugs in clinical use. The preparation of pyr-roles by reaction between primary amines, β-dicarbonyl compounds,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 reactionstatus, this method has received little attention in the literature. Recentwork involving the use of non-conventional conditions has rejuvenatedthis classical reaction and this is emphasized in this review. Some appli-cations of the Hantzsch reaction in target-oriented synthesis are alsodiscussed.1 Introduction2 The Conventional Hantzsch Pyrrole Synthesis3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions4 Applications of the Hantzsch Pyrrole Synthesis5 Conclusions

Key words pyrrole, green chemistry, solid-phase synthesis,sonochemistry, flow synthesis, photoredox catalysis, mechanochemicalsynthesis

1 Introduction

Pyrrole can be considered as one of the most importantsimple heterocycles. It is present in a variety of naturalproducts including two pigments essential for life, namelyheme and chlorophyll. It can also be found in a large num-ber of bioactive secondary metabolites, many of which areof a marine origin1–3 and include the lamellarins, halitulin,and the marinopyrroles, which have attracted much recentattention because of their high activity against methicillin-resistant bacteria.4 A large number of bioactive non-natural

pyrroles are also known, exhibiting properties such as anti-mycobacterial5 and antimalarial6 activities, inhibition ofHIV virus fusion,7 and hepatoprotection,8 among many oth-ers. Some of these compounds have reached the pharma-ceutical market, including the anti-inflammatory drugszomepirac and tolmetin, the antihypercholesterolemicagent atorvastatin,9 and the anticancer drug sunitinib (Fig-

Figure 1 Some important pyrrole derivatives

N Cl

ClX

OHO

NCl

Cl

OOH

Marinopyrrole A (X = H)Marinopyrrole B (X = Br)

H

N

HO OH

OH

O

OMe

Lamellarin R

N

HO

OH

N

OHOH

NHO

N

MeHalitulin

NH

H3C

CH3

NH

O

NH

F

O

NEt2

Sunitinib

N

Me

CO2H

O

R1

R

R = H, R1 = Me TolmetinR = Me, R1 = Cl Zomepirac

N

CO2H

CH3

CH3

NH

O

F

OH

OH

Atorvastatin

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 816–828

http://orcid.org/0000-0002-0560-8416

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ure 1). Furthermore, pyrroles are also very important inmaterials science10 and they are also valuable buildingblocks for the synthesis of alkaloids and unnatural hetero-cycles.11

Pyrrole derivatives can be assembled by many ap-proaches, including the traditional Knorr, Paal–Knorr, andHantzsch reactions.12 Nevertheless, the synthesis of highlysubstituted and functionalized pyrroles remains challeng-ing because it very often poses problems of regioselectivity.An additional complication comes from the need for mildreaction conditions owing to the low chemical stability ofmany pyrroles.

2 The Conventional Hantzsch Pyrrole Syn-thesis

Among the classical methods for pyrrole synthesis, theHantzsch reaction is the less developed one. Indeed, in viewof its named reaction status, it is surprising to realize howscant attention it has received. Thus, Hantzsch’s 1890 origi-nal note13 describes the synthesis of a single pyrrole deriva-tive (Scheme 1). In a paper published in 1970, Roomi andMacDonald stated that they had only been able to find inthe chemical literature eight additional examples publishedin the intervening 80-year period. Furthermore, these reac-tions proceeded in yields below 45% and allowed very littlestructural variation, which was limited to alkyl substituentsat C-4 and C-5.

By tweaking the reaction conditions, the Roomi andMacDonald study extended slightly the scope of theHantzsch reaction and allowed the preparation of com-pounds with substituents different from methyl at C-2 andesters other than ethyl at C-3. However, yields remained be-low 50% and the preparation of N-substituted pyrroles wasstill not possible.14 More recent examples of the Hantzschpyrrole synthesis under traditional conditions still sufferfrom many limitations in scope.15

Scheme 1 The first reported example of the Hantzsch pyrrole synthesis

Depending on the nature of the α-halo carbonyl sub-strate, the reaction can furnish 5-substituted/4,5-disubsti-tuted pyrroles (starting from α-halo ketones) or 4-substi-

(from left to right)

Marco Leonardi was born in Terni (Italy), and studied Pharmaceutical Chemistry and Technology at Università degli Studi di Perugia in Italy. He enlisted in the Department of Organic and Medicinal Chemistry, 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-versity-oriented libraries using mechanochemical multicomponent re-actions and their application to the identification of new bioactive compounds.Verónica Estévez Closas was born in Madrid and studied Pharmacy at Universidad Complutense, Madrid (UCM). She joined the Department of Organic and Medicinal Chemistry, School of Pharmacy, UCM, and re-ceived her Ph.D. in 2013. Her thesis work, supervised by Dr. M. Villaca-mpa and Prof. J.C. Menéndez, was focused on new multicomponent reactions for the synthesis of pyrroles and their application to the preparation of bioactive compounds. Afterward, she joined, as a post-doctoral researcher, the group of Prof. R. Orru, Synthetic and Bio-Or-ganic Chemistry group, in Vrije Universiteit Amsterdam. She worked in the European Lead Factory (ELF) project, a novel European platform for innovative drug discovery. Her main research interests have focused on the development of multicomponent reactions for their application in the early phases of the drug discovery process. Mercedes Villacampa was born in Madrid and studied Pharmacy and Optics at UCM. During her Ph.D. thesis, she worked on the synthesis of natural product based serotonin analogues. After spending her post-doctoral studies with Professor Nicholas Bodor (University of Florida, Gainesville), she obtained a position of Professor Titular at the Organic and Medicinal Chemistry Department, UCM. She has also carried out postdoctoral work at the laboratory of Professor Kendall N. Houk (Uni-versity of California at Los Angeles, UCLA). Her research fields include computational chemistry and the development of new synthetic meth-odologies, including multicomponent reactions, for their employment to the preparation of heterocycles to find new biological activities.José Carlos Menéndez was born in Madrid and studied Pharmacy (UCM) and Chemistry (UNED). Following a Ph.D. in Pharmacy (supervi-sor: 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 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 reac-tions 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-ed in about 250 research papers, reviews, and chapters and 11 patents. He has also co-authored several Medicinal Chemistry textbooks.


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tuted derivatives (starting from α-halo aldehydes). Somerepresentative pyrrole derivatives prepared by theHantzsch method are summarized in Figure 2.

Figure 2 Some representative pyrroles prepared by the Hantzsch reaction

The yields obtained in these conventional Hantzsch pyr-role syntheses are moderate and rarely surpass 60%. Com-pounds arising from competing side reactions have rarelybeen isolated, although in some literature examples, involv-ing the use of α-chlorocarbonyl starting materials, theHantzsch reaction has been found to compete with a Feist–Benary furan synthesis, with no incorporation of the aminecomponent into the product (Scheme 2, see also Scheme 26below)).

Scheme 2 Competing Hantzsch and Feist–Benary reactions

A variation of the Hantzsch pyrrole synthesis using β-keto Weinreb amides as the dicarbonyl component has alsobeen developed. By exploiting the reactivity of the Weinrebamide function, this method allows the presence of a verybroad variety of ketone substituents at the C-3 position ofthe pyrrole products. Thus, the reaction between ethyl pyr-rolidin-2-ylideneacetate and related substrates bearing al-ternative electron-withdrawing substituents Z (compounds1) and N-methoxy-N-methyl-α-bromoacetamide (2) in the

presence of LDA afforded the C-alkylation product 3. Its re-action with a variety of organometallic nucleophiles includ-ing Grignard reagents, organolithium derivatives, andDIBAL-H, gave initially the N-deprotonated intermediates 4.Their reaction with the nucleophile proceeded in fully che-moselective fashion in favor of the Weinreb amide and gaveintermediates 5, which finally cyclized in situ to furnish the2,3-dihydropyrrolizines 6 (Scheme 3). This method alloweda broad scope in the substituent coming from the organo-metallic reagent (R1 = H, alkyl, ethenyl, ethynyl, aryl, ormasked function).16

Scheme 3 Hantzsch synthesis of fused pyrroles involving β-keto Wein-reb amides as the dicarbonyl component

We will finally mention that Pal and co-workers havedescribed a variation of the Hantzsch pyrrole synthesis in-volving a change in the regioselectivity of the reaction, al-though the method seems mostly restricted to 1,3-dike-tones and aromatic amines. Thus, the reaction between an-ilines, a 1,3-diketone, and phenacyl bromide in thepresence of Yb(OTf)3 as a Lewis acid catalyst leads to 4-sub-stituted pyrroles (Scheme 4).17

Scheme 4 Hantzsch pyrrole synthesis in the presence of Yb(OTf)3

Although the mechanism of the Hantzsch pyrrole syn-thesis has not been studied in detail, it is commonly accept-ed that it starts by the formation of an enaminone or enam-ino ester 7 by reaction of the primary amine with the dicar-bonyl compound. This intermediate then reacts with the α-

NH

Me

CO2Et

R1Me

CO-Z

OR1 O

XNH2

R

NH

Me

CO2Et

Me

48% (ref. 15c)

NH

MeF3C

CO2Et

60% (ref. 15a)

N Me

COMe

CO2H

H3C

33% (ref. 15b)

Examples:

NH

Me

CO2Et

Me

CO-Z

OH O

XNH2

R

RR

Example:

5-Substituted or 4,5-disubstituted pyrroles

4-Substituted pyrroles

R2 R2

NH

Me

CO2Et

R

O Me

CO2EtRMe

CO2Et

O

R O

Cl

NH3

Feist-Benary

Hantzsch

NH

Z

Br

O

N

OMe

Me

Z = CN, CO2Me, CO2Et LDA, THF–78 to 0 °C

NH

Z

N

O

Me

OMe

NH

Z

R1O

– H2O

N

Z

R113 examples40–99% yield(64% average)

N Z

N

O

Me

OMe

M

R1M

1 R1M 2 H2O

1

2

3

45

6

N Me

COMe

O Me

COMe

OPh

+

Br Yb(OTf)3MeCN, 80–85 °C

Ph

Ar

Ar-NH2


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halo carbonyl component, leading to the C-alkylated inter-mediate 8, which furnishes the final product 9 by cyclocon-densation with loss of a molecule of water (Scheme 5).

Scheme 5 Commonly accepted mechanism for the Hantzsch pyrrole synthesis

The Yb(OTf)3-associated change in regioselectivity men-tioned above can be ascribed to an increased reactivity ofthe carbonyl with respect to the alkyl halide due to efficientcoordination of its oxygen atom with this potent Lewis acid.

To summarize, Hantzsch reactions performed in solu-tion under conventional conditions often give modestyields and do not show a broad substituent scope. Theselimitations explain the limited use of this classical methodand have stimulated in recent years the development of anumber of non-conventional variations of the reaction.

3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions

3.1 Hantzsch Pyrrole Synthesis in Green Solvents and in the Absence of Solvent

In 2012, Meshram and co-workers developed an or-ganocatalytic approach to the Hantzsch pyrrole synthesis,using 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst andwater as the reaction medium (Scheme 6).18 The authorsexamined mainly the structural variation of the primaryamine component, and proved that a variety of alkyl or arylsubstituents were tolerated, and also three differentphenacyl bromides, but the only β-dicarbonyl componentthat they studied was pentane-2,4-dione.

Scheme 6 Hantzsch pyrrole synthesis in water, promoted by DABCO

Abdel-Mohsen and co-workers, in 2015, applied thesame method to the synthesis of 5-(N-substituted pyrrol-2-yl)-8-hydroxyquinolines 10, with potential biological inter-est (Scheme 7).19 The method was later extended in 2016 tothe synthesis of tetrahydroindoles by use of cyclic 1,3-dike-tones as starting materials, although in this case the solventwas ethanol.20

Scheme 7 DABCO-promoted synthesis of pyrroles bearing a 5-(8-hy-droxyquinolin-5-yl) substituent

A mechanistic proposal is summarized in Scheme 8 forthe case of the 5-(N-substituted pyrrol-2-yl)-8-hydroxy-quinolines 10, and involves the initial reaction of the start-ing 5-(chloroacetyl)quinoline derivative with the organo-catalyst to give the highly electrophilic intermediate 11. Itsreaction with enaminone 12, formed from the primary

R2

COR3

NH

R1

OR2

O

R3NH2

R1+– H2O

7

R5

O

R4

X

R2

COR3

N

R1

R5

R4

R2

COR3

HN

R1

R5

O

R4

– H2O

89

BrOMe

O

MeO

R2

NH2

H2O, 60 °C

R2

N Me

Me

O

25 examples80–92% yield (85% average)

R1

R1

DABCO

ClO

Me

O

Me

O

R

NH2

DABCO (10 mol%)H2O, 60 °C RN

Me

Me

O

1014 examples65–93% yield (75% average)

N

HO OH

N

Scheme 8 Mechanism proposed to explain the DABCO organocatalysis in the Hantzsch pyrrole synthesis

Me

O

MeO

R

NH2

– H2O

Me

O

Me

HNR

Cl

O

N

OH

O

N

OH

NN

Cl

O

N

OH

Me

O

Me

HNR

– (DABCO)H

O

N

OH

Me

O

MeN

R

RN

Me

Me

O

OH

N

– DABCO– HCl

– H2O

10

13

12

11

DABCO

DABCO

(DABCO)H– DABCO


820


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amine and pentane-2,4-dione, gives 13, cyclocondensationof which is aided by deprotonation of the enamine nitrogenby DABCO.

Nageswar and co-workers have performed some exam-ples of the Hantzsch pyrrole synthesis by using water as sol-vent and with the aid of β-cyclodextrin as a supramolecularcatalyst. In this particular case, the authors examined onlythe structural variation of the primary amine component(Scheme 9).21

Scheme 9 Cyclodextrin-promoted Hantzsch pyrrole synthesis in water

The formation of a phenacyl bromide–cyclodextrincomplex was proved by NMR experiments that suggestedthe mode of inclusion shown in Figure 3, as shown by theupfield shift of the H-3 and H-5 protons at the broader rimof the cyclodextrin. This mode of complexation is compati-ble with a subsequent alkylation of the dicarbonyl compo-nent to yield a 1,4-dicarbonyl intermediate that would thenfurnish the pyrrole by a Paal–Knorr reaction, as suggestedby the authors (structure A), but also with the usualHantzsch mechanism involving the alkylation of an enami-none (structure B).

Figure 3 Complexation of phenacyl bromide by β-cyclodextrin

Das and co-workers have performed a three-componentHantzsch synthesis from primary amines, pentane-2,4-di-one, and 3-(bromoacetyl)coumarin derivatives 15 in a mix-ture of water and polyethylene glycol (PEG-400) in thepresence of Alum (AlK(SO4)2·12H2O), an ecofriendly catalystthat requires an aqueous medium. The reaction leads to thesynthesis of pyrrole derivatives 16 containing the pharma-cological important coumarin moiety. The role of polyeth-ylene glycol is to provide a micellar environment, and theAl3+ in alum acts as a Lewis acid, as shown in structure 17

(Scheme 10).22 A previous experiment by Nageswar and co-workers had shown that the Hantzsch reaction fails in PEG-400/water in the absence of catalysts at 120 °C.21

Scheme 10 Hantzsch pyrrole synthesis promoted by alum in PEG-water

Zhao and co-workers discovered that irradiation at 500W of α-bromoacetophenones, ethyl acetoacetate, and pri-mary amines in a pressurized microwave vial afforded 5-arylpyrroles 18 in good yields, without the need for any sol-vent or catalyst (Scheme 11). In terms of scope, the reactiontolerated well the presence of electron-withdrawing orelectron-releasing groups in the α-bromoacetophenonecomponent and the use of alkyl-, aryl-, and (hetero)arylme-thylamines. Modifications of the β-dicarbonyl componentwere not investigated.23

Scheme 11 Microwave-assisted, solvent- and catalyst-free Hantzsch synthesis of pyrroles

When starting from a pre-formed enaminone, micro-wave irradiation proved unnecessary. Thus, Yavari and co-workers found that by simply stirring compounds 19 and α-bromo ketones 20 under solvent-free conditions at roomtemperature, they could isolate the corresponding 5-substi-tuted pyrroles 21 in good to excellent yields (Scheme 12).24

Me

O O

Me

RNH2

1.β-CD/H2O2. 60–70 °C

N

R

Me

MeO

1412 examples78–89% yield(84% average)

Br

O

O

Br

O

HO

Me

HO Me

A

O

Br

O

HO

Me

HN Me

B

R

16 16 examples83–91% yield(87% average)

O

O

O

OO

O

O

OO

O

OO

O

O

Al3+

HH

MeO

Me

R1

HN

OO

Br O

R1

R2N

Me

Me

O

R1

O

O

O

BrO

O

Me

O

MeO

R2

NH2

Alum

PEG 400/H2O (3:2)

70 °C, 4–6 h

R1

n

15

17

NH2 O

BrR3

Me

O O

OEt

R2

R118


MW, 500 W, solvent-free

N

R3

Me

OEt

O

R2

R1


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Scheme 12 Solvent-free synthesis of 5-substituted pyrroles

3.2 Hantzsch Pyrrole Synthesis under Solid-Phase Conditions

Jung and co-workers reported, in 1998, a solid-support-ed three-component Hantzsch reaction, involving the use ofan acetoacetylated Rink resin 22. This material was pre-pared by treatment of commercial polystyrene Rink amideresin with a variety of acetoacetylating reagents such asdiketene at –15 °C to room temperature, 2,2,6-trimethyl-1,3-dioxin-4-one at 110 °C, or N-hydroxysuccinimidyl ace-toacetate at room temperature (Scheme 13). As shown inScheme 14, the Rink resin thus modified was first treatedwith primary amines, presumably to afford the correspond-ing β-enaminoamides 23. This step was followed by reac-tion with α-halo carbonyl compounds to give pyrroles 24,which were finally liberated from the solid support by acidhydrolysis. Due to the structure of the resin-contained di-carbonyl component, the method was restricted to thepreparation of pyrrole-3-carboxamide derivatives, whichwere isolated in excellent purities, but unfortunately theauthors failed to report the reaction yields.25

Scheme 13 Synthesis of an acetoacetylated Rink resin

3.3 Sonochemical Hantzsch Pyrrole Synthesis

Shahvelayati and co-workers described an efficientHantzsch pyrrole synthesis performed in the absence of sol-vents, under irradiation with an ultrasonic cleaner with afrequency of 60 kHz and an intensity of 285 W, and cata-lyzed by ZnO nanoparticles (Scheme 15).26 The catalyst wasprepared by treatment of zinc acetate with sodium hydrox-ide in an ionic liquid, followed by irradiation with ultra-

sound for 1.5 hours (Scheme 16). It was observed that parti-cles with a smaller crystallite size were obtained in the ion-ic liquid than in water. It is relevant for the mechanism ofthe reaction to note that the ZnO-NPs thus obtained haveboth Lewis acid sites (Zn2+) and Lewis basic sites (O2–).These catalysts were re-used up to three times, with no sig-nificant loss in yield.

Scheme 15 Ultrasound-promoted Hantzsch pyrrole synthesis in the presence of ZnO nanoparticles

The reaction was proposed to follow the usual Hantzschmechanism, with the Zn2+ sites acting as Lewis acids inter-acting with the carbonyls in the 1,3-dicarbonyl compoundand the α-bromo ketone and thus facilitating the formationof the intermediate enamino ester and its alkylation to give25. On the other hand, the O2– sites may deprotonate theNH in intermediate 25 and thus facilitate the final cyclocon-densation step, with concomitant assistance by coordina-tion of its carbonyl with a Lewis acidic site (Scheme 17).

Br

neatrt, 3 h

O

R3

R2

O

NHMe NMe

OR2

R3

R1


R1

19

20

NH2

Rink resinNH

O

Me

O

OH2C

O

O

O

Me

Me

Me

O

,

or

NO

O

Me

OO

O

22

Scheme 14 Solid-phase synthesis of pyrrole-3-carboxamide derivatives

O Me

O

NH

NH2

R1+

H-C(OEt)3DMF

NHMe

O

NH

R1

rt, 2 x 24 h

R4

OR5

Br2,6-di-tert-butylpyridine

DMF, rt, 17 h

N MeR5

R4 N

O

H20% TFA

CH2Cl2, 30 min, rt

N MeR5

R4 NH2

O

R1R1

2223

24

BrNP-ZnO (15 mol%)solvent-free, ))))

O

R3

R2

O

Me N Me

O

R2

R3

R1


NH2-R1O

Scheme 16 Synthesis and schematic structure of the ZnO nanoparticles

Zn(OAc)2+

NaOH

N NnHexnHexBr

Lewis acid site

Lewis basic site

ZnO nanoparticles

[HHIM]Br

water-freeZn(OH)4

–2

)))

1.5 hNP-ZnO


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Scheme 17 The role of ZnO nanoparticles in catalyzing the Hantzsch pyrrole synthesis

3.4 Hantzsch Pyrrole Synthesis under Flow Condi-tions

As summarized in Scheme 18, Cosford and Herath de-scribed a one-pot synthesis of pyrrole-3-carboxylic acid de-rivatives based on the Hantzsch reaction that involves thecontinuous flow of tert-butyl acetoacetate, primary amines,and α-bromo ketones at 200 °C during 8 minutes.

The generation of HBr during the alkylation step wasexploited to achieve the in situ hydrolysis of the tert-butylester groups. The subsequent coupling of the carboxylicsubstituent to diverse amines was also described and gavepyrrole-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 byadding one equivalent of base to trap HBr.

3.5 Hantzsch Pyrrole Synthesis under Photoredox Catalysis

Wu and co-workers developed a photochemical versionof the Hantzsch pyrrole synthesis when they discoveredthat the irradiation with visible light (λ = 450 nm) of aDMSO solution of enaminones and α-bromo ketones atroom temperature, in the presence of a catalytic amount ofIr(ppy)3 as a photosensitizer, afforded 2,5-diaryl-substitut-ed pyrroles in good to excellent yields (Scheme 19).28 Fur-thermore, an increase in yield to quantitative levels wasachieved by addition of triethylamine to the reaction medi-um.

R1-NH2

R2

O

Me

O

Me

HNR1

O

R2

Br

OR3

– HBr

Me

NR1

O

R2

O

R3

N Me

O

R2

R3

R1

HO

– H2O

Me

N

R1

O

R2

O

R3

H

– H2O N Me

O

R2

R3

R1

25

Scheme 18 Hantzsch pyrrole synthesis under continuous flow conditions

N CH3R5

R1

O

OtBu

N CH3R5

R1

O

OH

200 °C 8 min

DIPEA1.0 equiv

DIPEA0.5 equiv

H3C OtBu

O O

R5Br

O

R1 NH2

DMF0.5 M

DMF0.5 M



N

O

N

CH3

R1

R5

R3


EDC, HOBt DIPEA, R3NH2

H

Scheme 19 Photochemical Hantzsch pyrrole synthesis

R2

NH

R3

R1

R4

O

Br

R5

hν (blue LED)Ir(ppy)3, DMSO (Et3N), rt, 2 h

N

R3

R2

R5

R4

R1


Scheme 20 Proposed mechanism for the photoredox-promoted Hantzsch synthesis

Ir(ppy)3

hn

Ir(ppy)3* Ir(ppy)3

R4

O

Br

R5

R2

HN

R3R1

R4

OR2

NR3R1

R4

O

HN

R3

R2

R5

R4

R1

R4

O

R5

R2

NH

R3

R1

R5

R5Et3N

– H2O

2627

28

29

30


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The mechanism proposed to explain this transforma-tion is summarized in Scheme 20. Irradiation of the photo-sensitizer leads to its excited form Ir(ppy)3*, which, follow-ing single electron-transfer oxidation by the starting α-bro-mo ketone 26, is transformed into Ir(ppy)3

+. The reduced 26,upon debromination, generates radical 27, which adds tothe enaminone 28 to furnish another radical, 29. This spe-cies transfers one electron to Ir(ppy)3

+, closing the catalyticcycle, and affords imine 30, which finally furnishes the finalpyrrole products by intramolecular cyclocondensation withloss of a molecule of water.

3.6 Hantzsch Pyrrole Synthesis under Mechano-chemical Conditions

Due to our interest in the use of cerium(IV) ammoniumnitrate (CAN) as a Lewis acid catalyst,29 we investigated theHantzsch reaction in ethanol between β-dicarbonyl com-pounds, primary amines, and α-iodo ketones in the pres-ence of CAN and silver nitrate, which was necessary in or-der to prevent reductive dehalogenation of the starting α-iodo ketones by the HI liberated in the alkylation step. In2013, we discovered that the reaction could be also per-formed in a solvent-free fashion, under high-speed vibra-tion milling conditions (HSVM) in a mixer mill working at20 Hz with the use of a single zirconium oxide ball 20 mmin diameter. Furthermore, the mechanochemical version ofthe Hantzsch pyrrole synthesis could be telescoped withthe synthesis of the starting α-iodo ketone from the corre-sponding ketone and N-iodosuccinimide (NIS). This sol-

vent-free method afforded considerably higher yields ofpyrroles than previous versions of the Hantzsch reaction, inspite of comprising an additional step, and was far broaderin scope (Scheme 21).30,31

The generality of the mechanochemical method wasproved by its application to the preparation of fused pyrrolesystems derived from the indole 34, homoindole 35, ben-zo[g]indole 36, and indeno[1,2-b]pyrrole 37 frameworks,which had not been previously possible using the Hantzschreaction, from β-dicarbonyl compounds 31, primaryamines 32, and cyclic ketones 33 (Scheme 22). Again, themechanochemical method proved to have considerable ad-vantages in terms of yield over a similar solution-phaseprotocol.31

Scheme 22 Mechanochemical synthesis of fused pyrrole derivatives

Bearing in mind the importance of symmetrical com-pounds formed by two identical pharmacophores connect-ed by a spacer chain in the drug discovery field, we studiedthe pseudo-five-component reactions between diamines,α-iodo ketones (prepared in situ from aryl ketones, 2 equiv)and β-dicarbonyl compounds (2 equiv). We found that themechanochemical method allowed the efficient construc-tion of two pyrrole systems at the ends of a central chain ina single synthetic operation, furnishing compounds 38(Scheme 23). One example of the construction of three pyr-role rings was also achieved.32

In the same context, we also studied the Hantzsch reac-tions of some symmetrical aromatic compounds containingtwo acetyl groups and successfully employed them as sub-strates for pseudo-five-component reactions leading to ad-ditional symmetrical systems 39 capped by two pyrrolerings (Scheme 24).31Scheme 21 Hantzsch pyrrole synthesis under high-speed vibration milling

R5 ONIS,

TsOH (10 mol%) HSVM (20 Hz)

60 min

R4

R5 O

R4 I

O R2

O

R3 NH2

R1

HN R2

O

R3

R1

+

CAN (5 mol%)

AgNO3, HSVM (20 Hz), 60 min

N R2

R1

O

R3

R5

R4


N

R1

R2

O

R5

R3

n

n

R5

O

nN

R1

Me

O

R5

R3

33a, n = 1,2

36 (n = 0), 37 (n = 1)16 examples41–94% yield(79% average)

34 (n = 1), 35 (n = 2)5 examples

40–97% yield(57% average)

1. CAN (5 mol%)2. NIS, TsOH, HSVM (20 Hz), rt, 1 h3. Add 31 and 32, then AgNO3, HSVM (20 Hz), rt, 1 h

O R2

O

R3NH2

R1+ or

or

+

R

nR5

O

33b, n = 0,1

R

31

32


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4 Applications of the Hantzsch Pyrrole Syn-thesis

The anticancer drug pemetrexed (LY231514, Alimta®)and related compounds provide a good example of the ap-plication of the Hantzsch reaction to the synthesis of com-plex heterocyclic systems containing a pyrrole fragment. A

synthesis of pemetrexed33 starts from 2,6-diaminopyrimi-din-4(3H)-one 40 and an α-bromoaldehyde 41, which is thesuitable kind of reaction partner to obtain a β-substitutedpyrrole moiety. The Hantzsch reaction was achieved by ex-posure of these starting materials to sodium acetate and af-forded compound 42 after saponification of the ester group.A final conjugation with diethyl glutamate and a second sa-ponification afforded pemetrexed disodium 43 (Scheme 25).

Pemetrexed regioisomeric structures bearing the sidechain 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-tive. In this case, two starting materials were assayed, cor-responding to X = Cl34 and X = Br.35 In the first case, a 1:1mixture of products was obtained, corresponding to a furanderivative 44 arising from a competing Feist–Benary reac-tion, and the desired pyrrole derivative 45. On the otherhand, when X = Br the reaction showed full selectivity in fa-vor of the Hantzsch product (Scheme 26).

The anti-inflammatory agent 48, an analogue of zome-pirac, was synthesized from diethyl 3-oxopentanedioate,methylamine, and α-chloroacetone.36 It is interesting tonote that in this case the Hantzsch reaction gave the unex-pected 4-substituted regioisomer. This result was ascribedto the fact that, upon mixing diethyl acetonedicarboxylateand methylamine, a precipitate was formed that was identi-fied as a salt of the enolate anion. Thus, the authors pro-posed that the reaction follows the mechanism summa-rized in Scheme 27, involving the reaction of this anionwith the carbonyl group of α-chloroacetone, followed by analkylation-cyclocondensation reaction sequence with me-thylamine to give pyrrole derivative 47. Further functionalgroup manipulation furnished the target compound 48.

The Hantzsch pyrrole synthesis has been applied to thesynthesis of radiolabeled pyrroles. Since pyrrole-2,3,5-tri-carboxylic acid is a metabolite of melatonin, a radiolabeledversion of this compound was deemed to be useful as a bio-marker to monitor the effectiveness of drug candidatesagainst hyperpigmentation. In this context, the synthesis of[13C4,15N]pyrrole-2,3,5-tricarboxylic acid 50 was carried out

Scheme 23 Pseudo-five-component double Hantzsch pyrrole synthe-ses from diamines

O R2

O

R3

+2

CAN (5 mol%)

HN

R2

O

R3

NH

R2

O

R3

CH3

O2

R5

O

I

2R5

NIS, TsOH (10 mol%) HSVM (20 Hz)

60 min

CAN (5 mol%) AgNO3, HSVM (20 Hz), 60 min

N

R2

O

R3

N

R2

O

R3R5

R5

R4


H2NNH2

1–11

NH2H2NNH

NH2H2N

NH2

NH2N

N

NH2

Si

OSi

H2N

Me

Me

Me

Me

=

3

3

3

3

NH2H2N

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

=

N Me

O

R3

R1

O

Me

NIS (2 equiv), TsOH (20 mol%) HSVM, 1–2 h, 20 Hz

CAN (10 mol%), AgNO3 (2 equiv) HSVM (20 Hz), 60 min

NH2

Me

O

R3

R1

NMe

R1

O

R3

OOO

I I

O

Me

394 examples

84–94% yield (88% average)

2 2


825


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using a route that had as the key step the Hantzsch pyrrolesynthesis from [1,2,3,4-13C4]ethyl acetoacetate, 15NH4OH,and chloroacetaldehyde.37 The pyrrole derivative 49 thusobtained had all the radiolabels in place and was trans-formed into 50 by additional functional group manipula-tion (Scheme 28).

Atorvastatin is the best-known member of the statins,the main group of cholesterol-lowering drugs. This drugwas marketed in 1997 as its calcium salt under the tradename Lipitor® and spent almost a decade at the top of thelist of largest-selling branded pharmaceuticals, being thusregarded as the best-selling drug in history.

Thus, atorvastatin can be arguably regarded as the mostimportant unnatural pyrrole derivative ever made. Thiscompound has received much attention from syntheticchemists, and the target of all this work is normally theatorvastatin lactone, which is readily transformed into thedrug molecule by hydrolysis followed by salt formation.38 Inthe literature, the construction of the atorvastatin pyrrolecore is normally based on the Paal–Knorr pyrrole synthesisor 1,3-dipolar cycloadditions. We noticed that our mecha-

Scheme 25 Synthesis of the anticancer drug pemetrexed based on a Hantzsch pyrrole synthesis

HN

N

O

NHH2N

CO2H

HN

N

O

NHH2N

NH

OCO2Na

CO2Na

43 Pemetrexed (LY231514, AlimtaTM)

2

2

N

HN

NH2

O

H2N

+

Br

OHC

O

OMe

NMM, CDMT

H2N COOEt

COOEt

HN

N

O

NHH2N

NH

OCO2Et

CO2Et

2NaOH

4041 42

1. NaOAc2. NaOH

Scheme 26 Synthesis of a homologue of the pemetrexed C-2 regioisomer

N

HN

NH2

O

H2N

CO2MeO

N

N

NH2

OH2N

COOMe

3X

N

NH

NH2

OH2N

46

3Feist-Benary (a)

Hantzsch (b)

DMF rt

45X = Cl, (a):(b) = 1:1

X = Br, only (b)

N

NH2N NH

NH2

O

OR

3

NH

NaO2C

CO2Na

N

NH2N NH

NH2

O

3

44

Scheme 27 Synthesis of a 4-methylpyrrole derivative by an anomalous Hantzsch reaction and its proposed mechanistic explanation

NH2MeO

O OEt

O

OEt

O

O OEt

O

OEt

NH3 Me

Precipitates

Me

O

Cl

O

O OEt

O

OEt Me

Cl

NH2Me

N

Me COOEt

COOEt

Me

N

Me

COOH

MeCl

47

48


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nochemical pyrrole synthesis was well suited to achieve avery short, convergent route to the atorvastatin lactone, al-though we acknowledged the fact that the target is a penta-substituted pyrrole with a branched substituent at C-2 andan amide group at C-3 would bring our method to its limits.In the event, the reaction between β-ketoamide 51 and thecommercially available amine 52, corresponding to theatorvastatine side chain, was problematic and it did nottake place at all, under our usual CAN catalysis. In view ofthe success of initial model reactions starting from 51, thisresult was attributed to the presence of the acetal protec-

tion, which is susceptible to hydrolysis by CAN. After someoptimization work, we discovered that ytterbium triflatewas a suitable catalyst for the desired process, although thereaction was slow at room temperature. The enaminoamide53 thus obtained was transformed into pyrrole 55 upontreatment with α-iodo ketone 54 under mechanochemicalHantzsch reaction. Treatment with acid led to the deprotec-tion of the terminal tert-butyl ester, with concomitant cy-clization of the resulting hydroxy acid to give atorvastatinlactone 56 (Scheme 29).39

We will finally discuss one example of the application ofHantzsch pyrroles as starting materials for the synthesis ofmore complex heterocycles. The generation of diversity-oriented libraries by combination of a multicomponent re-action with a complexity-generating event is known as thebuild-couple-pair strategy and was initially proposed bySchreiber and Nielsen as a new strategy for the explorationof chemical space in search for bioactive compounds.40 Themildness of the mechanochemical Hantzsch reaction al-lowed its compatibility with the presence in the startingmaterials of functional groups (e.g., acetals) that areamenable to a subsequent cyclization reaction. Thus, whenthe mechanochemical Hantzsch reaction was performedstarting from 2-aminoacetaldehyde dimethyl acetal 57, β-dicarbonyl compounds, and acyclic and cyclic α-iodo ke-tones, the corresponding pyrroles and fused pyrroles 58were obtained uneventfully.

Scheme 28 Synthesis of a radiolabeled pyrrole derivative by a Hantzsch reaction

H3C OEt

O

**

**

* = 12,13 C

# = 14,15 N

NH4OH#

H

O

Cl

H2O

NH

CH3

CO2Et

***

49a = 12C, 14N49b = 13C, 15N

*

5 steps

50(12% overall)

(34%)#

NH

CO2H

CO2H

***

*

#HO2C

O

Scheme 29 Synthesis of atorvastatin based on the mechanochemical Hantzsch pyrrole synthesis

O O

HN

Me

Me

Ph

O O

O

O

NH2

MeMe

Me

Me

Me

Yb(OTf)3 (1 mol%), EtOH40 °C, overnight

O

NH

Me

Me

Ph

O O

O

O

HN

MeMe

Me

Me

Me

52

Yb(OTf)3 (1 mol%) AgNO3 (1 equiv)

HSVM (20 Hz, 60 min)

N

Ph

O

NH

Ph

Me

Me

O O

O

O

F

Me

Me

MeMeMe

(55 40% from 51 and 52)

56 (atorvastatin lactone) (94%)

N

Ph

O

NH

Ph

Me

MeF

O

HO O

O

Ph

F

I

2 M HCl MeOH, rt, 3 h

+

N

Ph

O

NHPh

Me

MeF

OH

OH

OO 2

Ca2+

Calcium atorvastatin

51

53

54


827


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We then discovered that their treatment with catalyticamounts of trimethylsilyl triflate allowed very mild and ef-ficient Pommeranz–Fritzsch-type cyclizations that gavepolycyclic compounds 59, corresponding to six differentframeworks, in high yields (Scheme 30).41

5 Conclusions

The Hantzsch pyrrole synthesis, one of the classicalmethods for the construction of simple heterocycles, hasbeen long neglected in spite of its named reaction status. Inrecent years, the use of a number of non-conventional ap-proaches has improved its outcome and broadened itsscope. We hope that this review will stimulate the use ofthis important reaction by the synthetic community.

Funding Information

Financial support of our research from MINECO (grant CTQ2015-68380-R) and CAM (B2017/BMD-3813) is gratefully acknowledged.Ministerio de Economía y Competitividad ( CTQ2015-68380-R)Consejería de Educación, Juventud y Deporte, Comu-nidad de Madrid (B2017/BMD-3813)

References

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Scheme 30 Synthesis of complex polyheterocyclic frameworks from a Hantzsch pyrrole

NIS, TsOH (10 mol%)

HSVM (20 Hz) 60 min

O R2

O

R3 CAN (5 mol%)

+

AgNO3, HSVM (20 Hz), 60 min

MeO

OMe

NH2 HN R2

O

R3

OMe

MeO

OO

I

N

O

R3

R2

OMe

OMe

Build

Couple


N

O

R3

R2

TMSOTf (15 mol%) CH2Cl2, rt, 10 minPair


57


828


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dis

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pro

hibi

ted.

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