Oxidation

The Oxidation of Pyrrole

James K. Howard,[a] Kieran J. Rihak,[b] Alex C. Bissember,[b] and Jason A. Smith*[b]

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Abstract: The dearomatization of heterocycles has beena powerful means for producing functional molecules in syn-thesis. In the case of pyrroles, reductive methods (such asthe Birch reduction) have been most widely exploited, whileoxidative methods are generally dismissed as too difficult orunpredictable to be useful. However, since the early twenti-eth century considerable research has been carried out onthe controlled oxidation of pyrroles to give highly function-

alized products, using a variety of oxidants. This review pres-ents a summary of all work up until the present day in thearea of pyrrole oxidation, looking at the use of peroxide, sin-glet oxygen, hypervalent iodine reagents, a range or organicand inorganic oxidants, and electrochemical approaches. Italso offers some perspective on the potential future role ofpyrrole oxidation in synthesis.

1. Introduction

The dearomatization of carbo- and heterocyclic ring systems isa powerful tool that has wide synthetic utility. This transforma-tion can be achieved by various methods including enzymatic,photochemical, radical, transition metal-mediated, reductive,oxidative, or electrochemical approaches. A number of reviewsconcerned with the dearomatization of carbocycles have beenwritten, and a few have focused on heterocycles.[1] Conceptual-ly, heterocyclic dearomatization can be a more powerful toolin synthetic chemistry owing to the inherent reactivity of thecyclic system. This can be exemplified by the ability of pyrrole,the fundamental nitrogen-containing five-membered aromaticheterocycle, to undergo substitution followed by partial reduc-tion to pyrrolines or catalytic hydrogenation to provide pyrroli-dines. Certainly, this strategy has been used in the constructionof many advanced intermediates towards natural product totalsynthesis.

In contrast to the reductive dearomatization of pyrroles, farless attention has focused on the oxidative dearomatization ofpyrrolic systems. The oxidation of pyrrole has the potential toyield 3-pyrrolin-2-ones, however, due to the reactive nature ofthis molecule it often undergoes decomposition or uncontrol-led polymerization under oxidative and acidic conditions. Thepresent review will focus on the oxidation of pyrrole and pyr-role-containing systems towards 3-pyrrolin-2-ones and relatedpyrrole systems, and has been categorized according to theoxidizing agent used.[2]

2. Oxidation of Pyrrole with Peroxides

2.1. Hydrogen Peroxide Oxidations

Research into the oxidation of pyrroles with peroxide oxidantshas almost exclusively featured the use of hydrogen peroxidewith the earliest attempts carried out by Angeli and co-workers

and Pieroni and co-workers during the 1920s. Although theirexperiments on pyrrole, using hydrogen peroxide in aceticacid, did not provide conclusive results of reaction productsthey suggested that hydroxypyrroles and 2-pyrrolyl-pyrroleswere among those formed.[3] However, work by Fischer andco-workers during the 1930s and 1940s established that oxidiz-ing pyrrole with hydrogen peroxide in pyridine yielded onemajor product, proposed to be a 2-hydroxypyrrole.[4] This wasfurther supported by an investigation by Huni and co-work-ers.[5] Interestingly, it was not until nearly twenty years laterthat any complete and correct structural assignments of prod-ucts were made.

Indeed, Nuclear Magnetic Resonance (NMR) analysis of pyr-rolones and alkoxypyrroles by Plieninger and co-workers[6] ledAtkinson et al. to attempt the oxidation of pyrroles under simi-lar reaction conditions to those employed by Fisher.[7] In thisway, it was observed that for a range of 3,4-dialkyl and 2,3,4-trialkyl pyrroles, the major products were the corresponding 3-pyrrolin-2-ones (2 and 5, Scheme 1). They also obtained malei-mide 3 as a by-product.[8]

Bocchi and co-workers revisited Angeli and Pieroni’s initialwork to comprehensively investigate the oxidation of pyrrolein acetic acid (Scheme 2).[9] It was found that pyrrole 6 is initial-ly oxidized to a mixture of pyrrolinones 7 and 8, where 7 canfurther react with pyrrole under acidic conditions. When the re-action was carried out in water, 7 and 8 were the sole productsin a combined yield of 30 %.

Further work by Bocchi investigated the oxidation of N-methylpyrrole, and various monomethyl- and dimethyl-substi-tuted pyrroles with hydrogen peroxide in water and ethanol/

[a] Dr. J. K. HowardSchool of ChemistryUniversity of LeedsWoodhouse Lane, Leeds, LS2 9JT (UK)

[b] K. J. Rihak, Dr. A. C. Bissember, Dr. J. A. SmithSchool of Physical Sciences—ChemistryUniversity of TasmaniaHobart, Tasmania 7001 (Australia)E-mail : Jason.Smith@utas.edu.au Scheme 1. Atkinson’s oxidations of pyrroles with hydrogen peroxide.

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ether mixtures.[10] These gave similar pyrrolinone products tothose previously observed, in yields of 22–53 %.

Since the 1970s a number of research groups have appliedBocchi’s and Atkinson’s methods to an assortment of pyrrolescaffolds, generally giving comparable yields.[11] Lightner andco-workers were able to oxidize 3,4-dimethylpyrrole in pyri-dine/methanol to efficiently prepare 3,4-dimethyl-3-pyrrolin-2-one in a 95 % yield.[12] Kancharla and Reynolds used hydrogenperoxide and barium carbonate in water, which gave a 60 %yield of 3-ethyl-3-pyrrolin-2-one from the oxidation of 3-ethyl-pyrrole.[13]

More recently Pichon-Santander and Scott undertook studiesemploying 2-formylpyrrole substrates in a Baeyer–Villiger ap-proach (Scheme 3).[14] In this case, depending on the presenceand position of an electron-withdrawing group on the parentpyrrole, the major product was found to be either the 3- or 4-pyrrolin-2-one, (11 or 12). Yields ranged from approximately78–95 % and 37-39 % for those substrates giving 3-pyrrolin-2-ones and 4-pyrrolin-2-ones, respectively. In addition, the oxida-tion of a range of 2-formyldipyrromethanes was investigated(13, Scheme 4). They found that if the 2-positions of both pyr-roles were substituted, and the amount of hydrogen peroxide

was not in great excess, only ring A was oxidized. The productswere obtained in good yields.

Pelkey’s group have made use of hydrogen peroxide in thesynthesis of a range of 3,4-dialkyl and 3,4-diarylpyrrolinones.[15]

Various pyrrole-containing Weinreb amides 15 were synthe-

James Kenneth Howard obtained his Bachelorof Science (Hons) in 2010 at the University ofTasmania. He carried out his PhD studiesunder the joint supervision of Dr. Jason Smith,Dr. Christopher Hyland, and Dr. Alex Bissem-ber. His project was devoted to the develop-ment of new methodologies in organic syn-thesis with two main focuses : the oxidativedearomatization of pyrroles, and the straindriven rearrangement of cyclopropenes. In2015 he moved to the University of Leeds toundertake post-doctoral research under theguidance of Professor Adam Nelson, focusingon biocatalytic pathways for the productionof fluorinated building blocks for synthesis.

Kieran Josef Rihak was born in Hobart, Tas-mania and completed his BSc (Hons) at theUniversity of Tasmania. He is currently under-taking a PhD at the University of Tasmaniaunder the supervision of Jason Smith andAlex Bissember, investigating synthetic appli-cations for the controlled oxidation of pyr-roles.

Alex Christopher Bissember is a graduate ofthe Australian National University where heobtained both his BSc(Hons) and PhD degrees,the latter obtained under the supervision ofProfessor Martin G. Banwell in 2010. He com-pleted his postdoctoral research with Profes-sor Gregory C. Fu at the Massachusetts Insti-tute of Technology and the California Instituteof Technology. In 2013, he joined the facultyin the School of Physical Sciences—Chemistryat the University of Tasmania where his re-search activities focus on transition metal cat-alysis and establishing new strategies forcomplex molecule synthesis.

Jason Alfred Smith is a graduate of the Flin-ders University of South Australia where heobtained both his BSc (Hons) and PhD de-grees, the latter under the supervision of Pro-fessor Rolf Prager. He has carried out post-doctoral research at The Texas A& M Universi-ty (with Professor Sir Derek H. R. Barton) andat The Australian National University (withProfessor Martin G Banwell). In 2001 hejoined the faculty in the School of Chemistryat The University of Tasmania where his re-search activities focus on synthetic methodol-ogies and their application to the synthesis ofbiologically active and/or structurally complexmolecules and natural products isolation.

Scheme 2. Bocchi’s oxidation of pyrrole with hydrogen peroxide in aceticacid.

Scheme 3. Baeyer–Villiger oxidation of 2-formylpyrroles.

Scheme 4. Baeyer–Villiger oxidation of 2-formyldipyrromethanes.

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sized by Barton–Zard pyrrole cyclocondensations of substitut-ed nitroalkenes and activated isocyanides. These were then re-duced to the corresponding 2-formylpyrroles 16 and oxidizedby a Baeyer–Villiger reaction to yield 3-pyrrolin-2-ones 17 asthe sole products (Scheme 5).

2.2. Oxidation of Pyrrole with Benzoyl Peroxide

Benzoyl peroxide has also been employed for the oxidation ofpyrroles. Aiura and Kanaoka reported the reaction of variousN-substituted pyrroles with this peroxide to give mixtures ofboth 2-benzoyloxy and 2,5-dibenzoyloxy-substituted productsin combined yields of 28–57 % (Scheme 6).[16] Treatment of pyr-

role itself gave uncontrollable polymerization to pyrrole black.In addition to their above-mentioned studies employing hy-

drogen peroxide, Bonnet and co-workers investigated oxida-tions of tetraphenyl-substituted pyrroles with benzoyl perox-ide.[17] For 2,5-diphenylpyrrole, 2,3,5- and 1,2,5-triphenylpyrrole,the primary products were the pyrrole with a benzoyloxy sub-stituent in the 3- or 4-position, isolated in yields of 31–78 %.For 2,3,4,5-tetraphenylpyrrole, the major product was reportedas 2-benzoyloxy-2,3,4,5-tetraphenyl-2H-pyrrole (22), isolated in53 % yield (Scheme 7). It was proposed that these reactions donot proceed by attack of a benzoyloxyl radical but ratherthrough attack on molecular benzoyl peroxide.

3. Oxidation of Pyrrole with Singlet Oxygen

3.1. Reactions with Photochemically-Generated SingletOxygen (1O2)

Oxidation of pyrrole through a singlet oxygen-mediated path-way is arguably one of the most common and well-establishedmethods for the oxidation of pyrrole reported in the literature.This oxidation pathway requires pyrrole to react with singletoxygen, which is commonly generated in situ using a dye sen-sitizer. There have been reports detailing the autoxidation ofpyrrole (that being the oxidation with molecular oxygen with-out a sensitizer, which limits the likelihood of oxidationthrough a singlet oxygen pathway), including the oxidation ofpyrrole with molecular oxygen reported by Ciamician andSilber in 1912.[18] However, this review will focus exclusively onthe oxidation of pyrrole with singlet oxygen as this generallyprovides much more controlled oxidation.

A comprehensive review in 1974 by David Lightner detailedthe conception and progress of the use of dye-sensitized sin-glet oxygen to oxidize pyrrole moieties. As such, this sectionwill focus on those advances that have been made since thattime.[19]

In 1975, Lightner and Pak published a detailed investigationinto the oxidation of various tert-butyl-substituted pyrroleswith singlet oxygen.[20] As with previous oxidations of pyrrolewith singlet oxygen, various product mixtures were observed,with pyrrolinones and maleimides being the major compoundsobtained (Scheme 8). This study also illustrated the significant

differences in singlet oxygen performance and product distri-bution depending upon solvent choices. Experiments involvingthree regioisomeric tert-butyl-substituted pyrroles, found negli-gible differences in reaction rates between each of the isomersin a number of solvents. However, in comparing the reactionrates across solvents, it was observed that the rate of reactionin acetone is an order of magnitude slower than in methanol,despite the lifetime of singlet oxygen being longer in acetonethan in methanol.[21] This slower reaction rate in acetone resultsin lower yields as well as more complex reaction mixtures,which includes cleavage of the ring. Lightner and co-workerscarried out mechanistic studies using low temperature 1H NMR

Scheme 5. Baeyer–Villiger oxidation of 2-formylpyrroles with hydrogen per-oxide, from Weinreb amide precursors.

Scheme 6. Oxidation of N-substituted pyrroles with benzoyl peroxide.

Scheme 7. Benzoyl peroxide oxidation of 2,3,4,5-tetraphenylpyrrole.

Scheme 8. An example of Lightner’s varying oxidations in methanol andacetone.

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spectroscopy and 18O incorporation experiments.[22] From theseexperiments they concluded that while competing [2+2]-cyclo-addition reaction across C2 and C3 was possible, it was morelikely that reactions in acetone were proceeding through rear-rangement of the endo-peroxide formed in the [4+2] process.However, the nature of the products isolated from acetone ex-periments, such as 27, strongly suggests a competing [2+2] re-action.

During the 1990s there was renewed interest in the singletoxygen reaction with pyrrole containing molecules, driven bythe research focus of the groups of Boger and Wasserman. In1991, Boger and Baldino showed excellent conversion of twopyrrole-2-carboxylic acids 28 and 29 to their respective 3-pyr-rolin-2-ones 30 and 31 (Table 1).[23] After a solvent screen for

optimal conditions they were able to provide 3-pyrrolin-2-one30 and 31 from the pyrrole-2-carboxylic acids 28 and 29 in83 % and 92 % yields, respectively. The regiochemistry of theproduct was defined from the oxidative decarboxylation mech-anism. Notably, the optimized results for each pyrrole were ob-tained in different solvent systems, using Rose Bengal as thesensitizer. Furthermore, Boger and Baldino were the first toreport a cleaner conversion by using a filtered light source(uranium yellow glass filter, >330 nm).

Shortly after Boger and Baldino’s experiments, Wassermanand co-workers used singlet oxygen in combination with tert-butylpyrrole-2-carboxylates (Scheme 9).[24] Focusing on the 3-methoxypyrrole 33, different product distributions were ob-tained when the reaction was performed under different con-ditions. By using methylene blue as the sensitizer in methanolthey were able to produce 3-pyrrolin-2-one 34 in a 45 % yieldas a product of the addition of singlet oxygen across C2 andC5 of the pyrrole. The amide 35 and epoxide 36 were pro-duced in 35 % and 10 % yields, respectively, and were likely

a result of the addition of singlet oxygen across C2�C3. An80 % yield of 3-pyrrolin-2-one 34 was obtained in the presenceof pyridine. Furthermore, in applying the same reaction condi-tions to the equivalent 3-hydroxypyrrole, it was observed thatsinglet oxygen adds across the C2�C3 bond of the pyrrole ex-clusively.

In 1993, the groups of Boger and Wasserman came togetherto publish a total synthesis of d,l- and meso-forms of the natu-ral product isochrysohermidin (37, Scheme 10).[25] Consistent

with Wasserman’s report in 1991,[24] when the bipyrrole 38 wassubjected to the photochemically-derived singlet oxygen oxi-dation, addition at the C2�C3 bond of the pyrrole took place,resulting in a 30 % yield of amide 39. Interestingly, when thebipyrrole 40 (with carboxylic acid functionality present at theC2-position) was subjected to the conditions, a mixture of thetwo isomeric 3-pyrrolin-2-one-based natural product analogues(d,l- and meso-37) were observed in a combined 70 % yield.This change in reaction profile was again due to the advanta-geous decarboxylation rearrangement of the intermediateendo-peroxides.

Table 1. Boger and Baldino’s conditions for the controlled oxidation ofpyrroles 28 and 29.

Pyrrole Solvent t [h] Result

28 MeOH 5 30(20 %), 32 (12 %)MeOH 1 30 (35 %), 32 (32 %)MeOH/H2O (2:1) 1 30 (37 %), 32 (26 %)iPrOH/H2O (2:1) 1 30 (79 %)iPrOH/H2O (3:1) 1 30 (83 %)MeCN/H2O (3:1) 1 30 (62 %)

29 MeCN/H2O (3:1) 1 31 (92 %)iPrOH/H2O (3:1) 1 31 (80 %)

Scheme 9. Wasserman’s singlet oxygen oxidation with 3-methoxypyrrole 33.

Scheme 10. The total synthesis of d,l- and meso-forms of the natural productisochrysohermidin

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Wasserman and co-workers further explored the oxidation ofpyrroles with singlet oxygen by trapping the intermediate gen-erated from N-unsubstituted pyrroles upon exposure to thephotochemical conditions (Scheme 11).[26] They showed thatupon reacting with singlet oxygen, pyrrole 41 coupled toa second pyrrolic unit to produce bipyrrole 42, via peroxide 43and pyrrole 44.26a Further expanding on this, they went on tocouple the activated intermediate to other nucleophiles togenerate a suite of substituted pyrrolic analogues.[26b,c]

In 2002, Demir and co-workers subjected chiral 2-methylpyr-role-derivatives (45) to standard photochemically-derived sin-glet oxygen conditions with tetraphenylporphyrin as the sensi-tizer (Scheme 12).[27] While expecting to produce 5-hydroxyl-5-

methyl-2-pyrrol-3-ones, they observed that the major productof the oxidation was a 5-methylene derivative (46). They ap-plied the oxidation across a range of chiral pyrroles, resultingin the respective chiral 5-methylene-2-pyrrol-3-one in moder-ate-to-good yields (58–70 %).

In 2004, Demir subsequently illustrated that the oxidation ofpyrroles 47 that feature pendant chiral N-substituents contain-ing terminal alcohols led to the formation of bicyclic 2-pyrro-lin-3-ones 48 through intramolecular cyclization at the 2-posi-tion of the ring (Scheme 13).[28] Moderate yields of mixed ste-reoisomeric 2-pyrrolin-3-ones 48 were obtained by this pro-cess, with some bias toward one enantiomer in each case. Thestereoselectivity, while minor, was attributed to the hindered

internal rotation of the N-substituents as was supported bya computational study.[29]

Alberti and co-workers investigated the reaction of singletoxygen with ethanolamine-derived pyrroles featuring methylsubstituents at the 2- and/or 5-positions on the ring.[30] In theircomprehensive mechanistic study, the product diversity of thesinglet oxygen oxidation was assessed, examining the effectsof a variety of sensitizers and solvents. It was observed that,under all conditions, bicyclic compounds (such as 50) were theminor products. A difference was observed in reaction mixtureproduct profiles between protic and aprotic solvents, and themost striking difference occurred in experiments using 2,5-di-methylpyrrole 49. When the oxidation of pyrrole 49 was un-dertaken in aprotic solvents a range of pyrrolidinone-derivedproducts 50–52 and aldehyde 53 were observed to form(Scheme 14). However, in protic solvents it was noted that pyr-role 49 does not undergo cycloaddition with singlet oxygenand instead the methyl substituents at 2- and 5-positions areoxidized, resulting in ethers 54 and 55.

3.2. Reactions with Chemically Generated Singlet Oxygen

For the oxidation of pyrrolic species, the chemical generationof singlet oxygen has not received as much attention as the

Scheme 11. Oxidative coupling of pyrrole and a range of nucleophiles.

Scheme 12. Oxidation of chiral 2-methylpyrroles.

Scheme 13. Demir’s oxidative conditions when applied to chiral 2-methylpyrroles containing terminal alcohol susbstituents.

Scheme 14. Alberti’s oxidation of ethanolamine derived pyrroles.

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photosensitized-generation of singlet oxygen. However, Was-serman and co-workers have made some interesting observa-tions.[24, 30] In the attempted transformation of bipyrrole 38 tod,l- and meso-isochrysohermidin, the bipyrrole 38 (without thecarboxylic acid functionality found in bipyrrole 40) was sub-jected to singlet oxygen generated by the decomposition oftriphenylphosphine–ozone complex.[24] Remarkably, this result-ed in the desired mixture of isochrysohermidins (37) in a 42 %yield, rather than amide 39. Furthermore, using triphenylphos-phite–ozone complex as the source of singlet oxygen, theyfound that they could selectively oxidize a single ring of a bi-pyrrole in 42 % yield. As a follow up to this initial study, Was-serman and co-workers used dilute ozone to generate thesame mixture of isochrysohermidins (37), thus suggesting thatit was the decomposition of ozone generating singlet oxygenin the previous report. They applied this method to the pyrrole56 to generate 3-pyrrolin-2-one 57 in a 25 % yield(Scheme 15).[30]

4. Oxidation of Pyrrole with Organic Oxidants

There have been a number of cases where pyrroles have beensuccessfully oxidized with organic oxidants. Inomata and co-workers reported an oxidation of some tert-butyl-3,4-dialkyl-1H-pyrrole-2-carboxylates employing 3,4,5,6-tetrachloro-1,2-benzoquinone (o-chloranil). In this way, 3-pyrrolin-2-ones wereprepared in yields of 61–82 % (Scheme 16).[32]

Interestingly, further work by the Inomata group using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), provided ratherdifferent results. In this case the pyrrole core was not oxidized,with oxidation instead occurring at the a-position of the alkylsubstituent at the 4-position of the pyrrole. This gave 4-(1 ace-toxyalkyl)pyrroles when the reaction was carried out in thepresence of acetic acid and 4-acylpyrroles in the presence ofmethanol.[33] Also, when glycols were used instead of methanolor acetic acid, pyrroles with hydroxyalkyl esters at the 4-posi-tion were identified.[34]

There are also examples of meta-chloroperoxybenzoic acid(m-CPBA) being used as an oxidant. Awruch and Frydman re-ported oxidizing 2,4-dimethyl-3-ethylpyrrole (kryptopyrrole,60), with two equivalents of m-CPBA in diethyl ether at 10 8Cfor 45 min (Scheme 17). A mixture of products was isolatedfrom this reaction, including 4- and 3-pyrrolin-2-ones 61 and62 in yields of 37 % and 9.5 %, respectively. An acyclic species(63) and trace quantities of a dipyrrolinone were also ob-served.[35]

Battersby and co-workers also used m-CPBA, in a Baeyer–Vil-liger approach, to oxidize a tetra-substituted 2-formylpyrrolespecies (64) to a pyrrolinone (65, Scheme 18). This approachgave pyrrolinone 65 in a 60 % yield.[36]

5. Hypervalent Iodine Oxidation of Pyrrole

The oxidative dearomatization of pyrrole with hypervalentiodine has not been reported as widely as the aforementionedmethods. However, there have been some very interesting ob-servations within the recent literature.

In 2011, Alp and co-workers reported a controlled oxidationof the electron-deficient N-tosylpyrrole (66) with phenyliodinebis(trifluoroacetate) (PIFA, Scheme 19).[37] It was reported thatupon reaction with a single equivalent of the hypervalentiodine, quantitative conversion is achieved, producing a mixtureof 1-tosyl-3-pyrrolin-2-one (67) in an 81 % yield and 5-hydroxy-1-tosyl-3-pyrrolin-2-one (68) in a 19 % yield. When the oxida-tion was performed with two equivalents of the hypervalentiodine, conversion to only 5-hydroxy-1-tosyl-3-pyrrolin-2-one(68) occurred, in 93 % yield.

Research performed within the Suna group demonstratedthe use of phenyliodine diacetate (PIDA) with Pd(OAc)2 inacetic acid to selectively mono-acetoxylate a range of electron-rich and electron-deficient pyrroles in good-to-excellent yields(such as 69, Scheme 20).[38] The intermediate iodonium pyrroles

Scheme 15. Wasserman and colleagues’ use of ozone in oxidation.

Scheme 16. Oxidation of pyrroles with o-chloranil.

Scheme 17. Awruch and Frydman’s use of m-CPBA.

Scheme 18. Battersby’s use of m-CPBA.

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were isolated before subjection to Pd-catalyzed rearrangementat room temperature to generate the acetoxy pyrroles. Further-more, they were able to perform this two-step reaction in one-pot. Upon heating the reaction to 100 8C, it was observed thatsome substrates returned 3-pyrrolin-2-ones and maleimides

The Smith group demonstrated the use of the hypervalentiodine reagent Dess–Martin periodinane (DMP) for the con-trolled oxidation of various electron-rich pyrroles to 3-pyrrolin-2-ones.[39] The pyrrolinones that were produced from the oxi-dation with DMP incorporated the oxidant as part of the prod-uct. A range of electron-rich pyrroles were oxidized to theiranalogous pyrrolinones in good-to-excellent yields, with pyr-role itself giving a 56 % yield (Scheme 21).

Furthermore, interesting chemoselectivity was observed inthis approach. By subjecting the alcohol-containing pyrrole 74to the reaction conditions, it was observed that the pyrrolemoiety was more reactive than the alcohol. The oxidation of 2-alkyl substituted pyrroles, generating the alkylidene derivativesafter elimination of the hydroxyl of the less stable intermediatehemiaminal, was also demonstrated (Scheme 22).

Kita and co-workers have developed the use of PIFA anda Lewis acid additive in the oxidative coupling of pyrroles togive bipyrroles, rather than oxidative dearomatization. UsingPIFA and TMSBr, a range of substituted pyrroles were coupledto give the corresponding bipyrroles in yields of up to 78 %(Scheme 23).[40]

Kita and co-workers have also applied this method to theoxidative cyanation of pyrroles using PIFA with BF3

.OEt2 andTMSCN,[41] explored recyclable hypervalent iodine reagentswith adamantane cores for coupling reactions,[42] and the cou-pling of pyrroles with azoles.[43] In the latter case, PIDA was theoxidant used. While these oxidative couplings were carried outusing hypervalent iodine oxidants, there are also instanceswhere FeCl3 is used for oxidative coupling of pyrroles.[44]

6. Electrochemical Oxidations of Pyrrole

There have been investigations into the anodic oxidation ofpyrroles. This process is irreversible and typically results in thedeposition of pyrrole black and other polymeric materials, de-pending on the substitution of the pyrrole.[45] However, thereare a few examples in the literature where non-polymericproducts were isolated and characterized. Weinberg andBrown reported the anodic oxidation of N-methylpyrrole (80)in methanol in 1966, which gave 2,2,5,5-tetramethoxy-N-methyl-3-pyrroline (81, Scheme 24) as the major product ina yield of 57 %. This result was in contrast to that obtainedwhen oxidizing furans under the same conditions, where 2,5-dimethoxydihydrofurans were reported as the major prod-ucts.[46]

Tedjar and co-workers reported the electrochemical oxida-tion of alkyl and ester-substituted N-methyl or N-unsubstituted

Scheme 19. Alp and co-workers oxidation of N-tosylpyrrole with PIFA.

Scheme 20. Acetoxylation of pyrroles with PIDA and Pd(OAc)2, demonstratedby Suna and co-workers.

Scheme 21. Controlled pyrrole oxidation with Dess–Martin periodinane.

Scheme 22. Combined oxidation/elimination to give alkylidene derivatives.

Scheme 23. Oxidative coupling with PIFA to give bipyrroles.

Scheme 24. Anodic oxidation of N-methylpyrrole.

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pyrroles in methanol. N-Methylpyrrole was observed to give2,2-5,5-tetramethoxy-N-methyl-3-pyrroline in anhydrous metha-nol. However, 5,5-dimethoxy-1-methyl-3-pyrrolin-2-one wasproduced when the reaction took place in solution with 5 %water. Under the anhydrous oxidation conditions, using 2,5-di-methylpyrrole resulted in conversion of the methyl substitu-ents to methyl ethers (2-methoxymethyl-5-methylpyrrole in43 % yield, and 2,5-dimethoxymethylpyrrole in 12 % yield).[47]

Fuchigami and co-workers have reported isolating pyrroli-none products from the anodic fluorination of N-methyl andN-tosylpyrroles. Products varied depending on the supportingelectrolyte and pyrrole used, from 2,5-difluoropyrrolines, 2-fluo-ropyrroles, and 5,5-difluoro-3-pyrrolin-2-ones. The pyrrolinonewas observed in the highest yield (54 %) for 2-cyano-N-methyl-pyrrole (82) in a supporting electrolyte of Et3N-5HF(Scheme 25).[48]

7. Miscellaneous Methods for the Oxidation ofPyrrole

Treibs and Bader produced a pyrrolinone species on treatmentof 2,4-dimethyl-3-carbethoxypyrrole-5-sulfonic acid (85) withbromine in an aqueous solution. This reaction initially gave 2-tribromomethyl-2-hydroxy-4-methyl-3-bromopyrrolin-5-one(86) in a 50 % yield, yet decomposed to give 3-bromo-4-meth-ylmaleimide (87) in water at reflux (Scheme 26).[49]

Procopiou and Highcock reported the surprising oxidationof the brominated pyrrole 88 with 2,2’-azobis(2-methylpropio-nitrile) (AIBN), to give the 3-pyrrolin-2-one derivative 89(Scheme 27). This transformation was carried out in air and thepyrrolinone was isolated in a yield of 42 %.[50]

The first example of the use of lead tetraacetate to oxidizepyrrolic species was carried out by Bonnet and co-workers in1987.[51] This involved the treatment of dipyrrole diacid 90 togive dipyrrolinone species 91 in a yield of 13 % (Scheme 28).

Yamamoto and co-workers&&reference added, ok?&&[52]

reported the oxidation of a pyrrole through the generation ofthe 2-tri-n-butylstannane derivative 90 and subsequent treat-ment with lead tetraacetate (Scheme 28). Treating the trialkyl-

tin-substituted pyrrole with lead tetraacetate gave the 3-pyrro-lin-2-one 93 in a 20 % yield (Scheme 29).[46]

Lead tetraacetate has also been used by the Inomata groupto directly oxidize a selection of 2-tert-butylester-5-iodo-pyr-roles with a variety of alkyl and aryl substituents in the 3- and4-positions (Scheme 30). The reaction afforded the correspond-

ing pyrrolinones in excellent to quantitative yields.[53] This wasfurther applied to their synthesis of phycocyanobilin deriva-tives.[54]

Liermann and Opatz observed the oxidation of a pyrrolicspecies with lead tetraacetate, to give a pyrrolinone product,in the course of their synthesis of Lamellarins U and G.[55] Theiraim was to initially hydrolyze an ester at the 2-position of 96and then use lead tetraacetate to promote an oxidative cycliza-tion reaction, as had been reported by Steglich and co-workersfor Lamellarin syntheses.[56] However, in this case the oxidationof the pyrrole core dominated, despite the similarity of thesubstrate in the two reactions (Scheme 31).

Scheme 25. Anodic fluorination leading to oxidation.

Scheme 26. Treatment of a pyrrole-5-sulfonic acid with bromine and subse-quent decomposition to a maleimide.

Scheme 27. Oxidation with catalytic AIBN.

Scheme 28. Oxidation using lead tetraacetate.

Scheme 29. Oxidation of a 2-tri-n-butylstannane pyrrole with lead tetraace-tate.

Scheme 30. Inomata and co-workers oxidation with lead tetraacetate.

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Inomata and co-workers carried out investigations into thetwo step oxidation of 2-tosyl-substituted pyrroles by bromina-tion followed by hydrolysis with aqueous trifluoroacetic acid(TFA), as part of their syntheses of linear tetrapyrrole chromo-phores.[57] They developed methods for the regioselective oxi-dation of a range of 2-tosyl-5-bromopyrroles to the corre-sponding pyrrolinones (Scheme 32). It was also observed thatthe tosyl group could rearrange from the 2-position to the 5-position of the ring prior to oxidation taking place, with thetransformation being favored when the 3-substituent was steri-cally bulky.[58]

The same group also found that treating the pyrrole with m-CPBA and NaI enhanced the yield for pyrroles where the 3-po-sition was occupied by a pendant S-tolyl group. It was postu-lated that the reaction proceeded through sulfoxide genera-tion and intramolecular nucleophilic attack of the sulfoxideonto the pyrrole (Scheme 33).[59]

Inomata and co-workers investigated using dimethyl sulfox-ide (DMSO) as an external nucleophile, which allowed for

a wider range of substrates to be oxidized to give similar pyr-rolinone products. They report that oxidation occurs usingDMSO in TFA, with the addition of only a catalytic amount ofiodine and two equivalents of zinc, rather than requiring largeexcesses of sodium iodide (Scheme 34).[60] This method hasbeen exploited in a number of the group’s synthetic proj-ects.[61]

Lightner and co-workers used TFA/H2O to oxidize 3,4-dialkyl-5-bromo-2-tosylpyrroles, in the synthesis of lipophilic bilirubinand fluorescent cholephilic dipyrrinones.[62] They also made use

of the isomerization of tosyl groups as described byInomata and co-workers. Banwell and co-workers oxi-dized the bicyclic pyrrole derivative 104 by treating itwith bromine in acetic acid (Scheme 35).[63] This gavethe tricyclic 3-pyrrolin-2-one 105 in a 65 % yield,which was used to confirm the stereochemistry at C8in 105 by X-ray crystallography.

Lindel and Troegel reported the oxidation of 2-

acylpyrroles as part of their investigation into fluorinating suchspecies with Selectfluor (106, Scheme 36) under microwaveconditions.[64] They observed that when an excess of Select-fluor was used, the pyrrole was not fluorinated but was actual-ly oxidized, thus giving 3-pyrrolin-2-one products in yields of25–32 %.

Couturier et al. developed a total synthesis of 5-chloroarme-niaspirole A as part of their studies into the antibacterial activi-ties of related armeniaspiroles analogues (Scheme 37).[65] To-

Scheme 31. Liermann and Opatz’ oxidation with lead tetraacetate.

Scheme 32. Oxidation of 2-tosyl substituted pyrroles with trifluoroaceticacid.

Scheme 33. Oxidation of 2-tosyl substituted pyrroles with m-CPBA

Scheme 34. Inomata and co-workers use of DMSO with zinc and catalyticiodine.

Scheme 35. Banwell and co-workers intramolecular cyclization/oxidation of65.

Scheme 36. Oxidation under microwave conditions with a fluorinatingagent.

Scheme 37. Synthesis of an armeniaspirole analogue by Couturier et al.

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wards this target, pyrrole 109 was treated with N-chlorosucci-nimide in acetic acid and triethylamine, with the phenol groupof the aryl substituent adding into C5 to yield a spirocycle.

Kim and co-workers reported isolating 3-pyrrolin-2-one prod-ucts while attempting to synthesize pyrrole-2-phosphonatesfrom pyrroles, through the treatment with dialkyl phospho-nates and manganese or silver salts as oxidants. They opti-mized conditions for the formation of these pyrrolinones,using AgNO3 and K2S2O8, in a dimethylformamide (DMF)/H2Omixture heated for 2 h, and applied it to the oxidation of five2,4-diphenylpyrroles with varying N-substituents(Scheme 38).[66]

As part of their investigations into electron paramagneticresonance (EPR) spectroscopy, Kao et al. reported an interest-ing account of pyrrole oxidation. N-Hydroxy-2,5-di(tert-butyl)-3-ethoxycarbonylpyrrole (113) was treated with nickel peroxidein benzene, both in air and under an atmosphere of nitrogen(Scheme 39). In both cases three products were obtained: radi-

cal 114 a, pyrrolinone oxide 114 b, and diradical 115. Althoughno yields were reported, the major product obtained from re-action in air was 114 a, while the major product was 115 whenthe reaction was performed under nitrogen. On standing in air,it was observed that 114 a converted to 114 b.[67]

Further to this nickel peroxide work, Kao et al. attempted tosynthesize other nitroxides suitable for EPR imaging, andfound a new pyrrole oxidation pathway with Oxone instead.Their original intention was to simply oxidize the 3-formyl sub-stituent of pyrrole 116 to the corresponding ethyl ester. How-

ever, after carrying out the oxidation in ethanol they foundthat they instead produced 117 (Scheme 40). Suspecting thatthis resulted from a Baeyer–Villiger-type oxidation, they repeat-ed the reaction in DMF to avoid using a protic solvent, whichcould act as a nucleophile. Under these conditions, the onlytransformation was that of the formyl group to a formate ester(118). This was then hydrolyzed under anhydrous conditions toyield the hydroxypyrrole 119, but further transformation to117 was not observed. This led to the conclusion that in thepresence of Oxone, the formate ester and/or the hydroxypyr-role 119 react further to give the pyrrolinone system of 117.[68]

Reynolds and co-workers have developed an oxidationmethod in their synthesis of 23-hydroxyundecylprodiginones,using tetrapropylammonium perruthenate/N-methylmorpho-line-N-oxide (TPAP/NMO) on a range of substituted pyrroles.[69]

Pyrroles with no N-substituent and 2-alkyl substituents gavethe corresponding pyrrolin-2-ones with an unsaturated C5 po-sition, in yields of 32–39 % (Scheme 41). Pyrroles with methyl,

Boc, and tosyl N-substituents did not react, and when an alco-hol group was present it was oxidized preferentially.

Martin and co-workers developed a tandem C�H functionali-zation and C�O bond formation method using aryl iodide cata-lysts, which displayed interesting site selectivities when usedwith biphenyl substrates depending on the catalyst and addi-tives used. They applied this to the synthesis of tricyclic pyrroli-done 123 and pyrrolinone 124, observing that changing thearyl iodide in this case reversed the selectivity for pyrrolinone

Scheme 38. Kim and co-workers oxidation with AgNO3 and K2S2O8.

Scheme 39. Kao and co-workers use of NiO2 under inert and oxygenatedconditions.

Scheme 40. Oxone mediated oxidation.

Scheme 41. Appication of a TPAP/NMO oxidation strategy.

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and pyrrolidone products (Scheme 42).[70] Depending on thecatalyst used, the selectivity for 123 or 124 could be reversed,with overall yields of nearly 70 % achieved.

X. Conclusion and Perspective

Historically, the oxidation of pyrroles has been perceived as un-predictable, too difficult or low yielding to be syntheticallyuseful. However, the work covered in this review illustratesthat if substrates and oxidants are appropriately matched,good yields of synthetically useful intermediates can be ob-tained. As such, it is reasonable to conclude that the oxidationof pyrroles will find further applications in organic synthesis inthe future.

Keywords: oxidation · peroxides · pyrrole · pyrrolidinone ·singlet oxygen

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Manuscript received: June 24, 2015

Accepted Article published: August 21, 2015

Final Article published: && &&, 0000

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FOCUS REVIEW

Oxidation

James K. Howard, Kieran J. Rihak,Alex C. Bissember, Jason A. Smith*

&& –&&

The Oxidation of Pyrrole

Py in the Sky : The oxidation of pyrrolescan yield give highly functionalizedproducts. This review presents a summa-ry of all work up until the present dayin the area of pyrrole oxidation bya range of oxidants.

A focus review on the #oxidation of #pyrrole by Smith et al. SPACE RESERVED FOR IMAGE AND LINK

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Dr. James K. HowardKieran J. RihakDr. Alex C. BissemberDr. Jason A. Smith

Chem. Asian J. 2015, 00, 0 – 0 www.chemasianj.org � 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim15

These are not the final page numbers! ��

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