n-acylpyrroles: more than amides - stuba.skszolcsanyi/education/files/chemia... · 2012. 9. 6. ·...

MICROREVIEW

DOI: 10.1002/ejoc.201101470

N-Acylpyrroles: More Than Amides

Anna M. Goldys[a] and Christopher S. P. McErlean*[a]

Keywords: Nitrogen heterocycles / Amides / Acylation / Protecting groups

This microreview highlights the synthetically versatile N-acylpyrrole functional group. The preparation, electronicproperties and unique reactivity of these amide systems arehighlighted. Capable of functioning as acid, ester, amide, al-dehyde and ketone equivalents, of serving as acylating

1. Introduction

Amides that form stable tetrahedral intermediates uponreaction with organometallic reagents are highly versatilefunctional groups. In particular, N-methoxy-N-methylamides (Weinreb amides, 1, Scheme 1)[1,2] have been widelyused as precursors to ketones or aldehydes. Addition of anorganometallic species to a Weinreb amide gives a tetrahe-dral intermediate of type 2 that is stabilised by a coordina-tion network involving the alkoxide, the N-methoxy groupand the metal counterion. Hydrolysis of the complex re-leases the desired aldehyde or ketone. Their ease of forma-tion, reliable reactivities and relative cost-effectiveness haveensured that Weinreb amides are used in both academic andindustrial settings.[2,3] Despite their popularity, the Weinreb

[a] School of Chemistry, The University of Sydney,2006 Sydney, NSW, AustraliaFax: +61-2-9351-3329E-mail: [email protected]

Anna Goldys is from Warsaw, Poland and conducted her secondary education in Sydney, Australia. In 2010 she completeda Bachelor of Science degree with first class honours at the University of Sydney under the supervision of Dr C. S. P.McErlean, graduating with a University Medal. She has been the recipient of the Frank E. Dixon Undergraduate Prize,a University of Sydney Honours Scholarship and the Agnes Campbell Honours Prize. She is currently a ClarendonScholar undertaking studies toward a D.Phil. at the University of Oxford.

Chris McErlean was born in Northern Ireland in 1975 and grew up in Australia. In 1997 he graduated with a first classhonours degree from the University of Queensland. He was awarded his PhD from the same institution in 2002 under thesupervision of Prof. W. Kitching. After postdoctoral studies in the laboratories of Prof. J. S. Clark at the University ofNottingham, he joined the group of Prof. C. J. Moody at the University of Exeter and the University of Nottingham. In2007 he returned to Australia to take up a Lectureship in Organic Chemistry at the University of Sydney. His researchinterests include reaction development for total synthesis and sustainable catalysis.

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agents, of enhancing the reactivities of α,β-unsaturated sys-tems and of undergoing a wide range of other reactions, thismicroreview shows N-acylpyrroles to be more than justamides.

amides have several limitations, including decreased reactiv-ity of the carbonyl unit, side reactions of the amine unitand instability of the protonated tetrahedral intermediate(a putative hemi-aminal). This microreview highlights thesynthesis and transformations of alternative amide unitsthat also form stable tetrahedral intermediates: 1-acyl-1H-pyrroles (4), commonly called N-acylpyrroles, possess all ofthe advantages of the Weinreb amides but display height-

Scheme 1. Amides that form tetrahedral intermediates.

A. M. Goldys, C. S. P. McErleanMICROREVIEWened reactivity and increased synthetic potential. In ad-dition to their application as precursors to aldehydes andketones (Scheme 1), N-acylpyrroles can also function asprecursors to acids, esters and amides. Unlike in the case ofWeinreb amides, protonation of N-acylpyrrole-derived tet-rahedral intermediates such as 5 gives stable pyrrolic carb-inols 6 that can be generated as single stereoisomers if nec-essary and can be used to direct subsequent transforma-tions. These features make N-acylpyrroles a useful alterna-tive to the more commonly employed Weinreb amides.

2. Preparation of N-Acylpyrroles

Although the preparation of N-acylpyrroles has a longhistory, the installation of this functional group in complex-molecule settings may be viewed as the chief obstacle to itswidespread adoption. A number of different strategies toaccess N-acylpyrroles have been developed. Classical routesinclude the addition of pyrrole anion [typically N-lithio-pyrrole (8, Scheme 2), obtained by treatment of pyrrolewith n-butyllithium] to acid chlorides[4–8] and the Paal–Knorr (or the related Clauson–Kaas) pyrrole synthesis.[9–12]

Both aromatic and aliphatic N-acylpyrroles have been pre-pared by these economical and operationally simple meth-ods in single-step fashion and in good yields.

Scheme 2. Classical routes to N-acylpyrroles.

However, these traditional methods are not withoutlimitations. The strongly basic conditions associated withthe use of N-lithiopyrrole might not be compatible with allsubstrates and the addition of N-metallated pyrroles tocarbonyl compounds sometimes results in substitution atthe 2-position of the pyrrole ring.[8] Although Evans andco-workers utilised this approach with considerable suc-cess,[5] Shibasaki and co-workers have highlighted the pro-pensity of N-metallated pyrroles to undergo rearrangementto give 2-substituted pyrroles.[13] Similarly, the Paal–Knorrand Clauson–Kaas pyrrole syntheses both require pro-longed heating under acidic conditions, which might be in-compatible with substrates containing acid-sensitive groups.

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To circumvent these limitations, synthetic routes to N-acylpyrroles that avoid both strongly basic and stronglyacidic reaction conditions have been developed. For thesynthesis of aryl-derived N-acylpyrroles, D’Silva and co-worker reported DMAP-catalysed additions of pyrrole toaryl acid chlorides (Scheme 3).[14] Several procedures cata-lysed or mediated by transition or rare-earth metals havealso been reported. Examples include niobium- andyttrium-catalysed additions of pyrrole to aldehydes,[15] ad-ditions of pyrrole to ketenes catalysed by FeII-cyclo-pentadienyl complex to give chiral 1-aryl-N-acylpyrrole de-rivatives[16] and the Mo(CO)6-mediated carbamoylation ofaryl halides.[17]

Scheme 3. Example of DMAP-catalysed N-acylpyrrole synthesis.

A widely utilised approach to N-acylpyrrole derivativesinvolves the addition of aryl or alkyl nucleophiles to 1,1�-carbonyldipyrrole (15, Scheme 4). The resulting pyrroliccarbinol can be treated with a catalytic amount of base toeliminate one molecule of pyrrole and generate the corre-sponding N-acylpyrrole. The use of 1,1�-carbonyldipyrroleto form N-acylpyrroles was first reported by Becker and co-worker in 1974[18] and has recently been highlighted by thegroups of Evans[4] and Shibasaki.[13] α,β-Unsaturated N-acylpyrroles are the most challenging substrates to generateand the 1,1�-carbonyldipyrrole methodology has been usedto deliver these compounds in high yields. When vinyl nu-cleophiles are employed (Scheme 4) the elimination of pyr-role occurs spontaneously during the reaction workup in a

Scheme 4. N-Acylpyrrole synthesis using 15.


manner analogous to that seen with the correspondingWeinreb amides.

Shibasaki and co-workers have developed an alternative,mild preparation of α,β-unsaturated N-acylpyrroles thatalso employs 1,1�-carbonyldipyrrole (Scheme 5).[13,19] Ad-dition of methylene-triphenylphosphorane to 1,1�-carbonyl-dipyrrole, followed by the spontaneous elimination ofpyrrole, gives compound 20. Wittig olefination with appro-priate aldehydes gives the corresponding α,β-unsaturated N-acylpyrroles 21. Although this is a two-step procedure, themild reaction conditions and uniformly excellent yields ob-tained make it a useful route for accessing α,β-unsaturatedN-acylpyrroles. Subsequently, Shibasaki and co-workers re-ported that the corresponding Horner–Wadsworth–Emmons reaction with use of 22 gave the desired α,β-unsat-urated N-acylpyrroles with improved E/Z selectivity.[20]

Scheme 5. Shibasaki and co-worker’s preparation of α,β-unsatu-rated N-acylpyrroles.

A less frequently used alternative to 1,1�-carbonyldi-pyrrole is N-carboxypyrrolic anhydride. This compound isproduced by the addition of N-lithiated pyrrole onto solidcarbon dioxide to give N-pyrrolecarboxylic acid, followedby formation of the anhydride by use of 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide.[21] N-Carboxypyrrolicanhydride is analogous to 1,1�-carbonyldipyrrole in thattreatment with a nucleophile results in the formation of thecorresponding N-acylpyrrole.

Other methods for preparing N-acylpyrroles include theoxidation of the corresponding aliphatic amides 23(Scheme 6) with manganese dioxide,[22,23] DDQ[23,24] orN,N-di-tert-butyldiaziridinone/CuI.[25] A number of pyrrolesyntheses other than the Paal–Knorr or Clauson–Kaas pro-cedures have also been used to generate N-acylpyrroles, in-cluding the CuI-catalysed double N-alkenylation of amides24 (Scheme 7),[26] the three component InCl3-catalysed cou-pling of propargylic alcohols, 1,3-diketones and amides,[27]

the Zav’yalov pyrrole synthesis[28] and the cross-metathesisof allylamines and crotonaldehyde.[29] A unique approachto the synthesis of N-acylpyrroles that has been investigatedby Zakrzewski is the transfer of pyrrole from a rheniumcomplex to acyl chlorides.[30]

Scheme 6. Oxidation of aliphatic amides.

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Scheme 7. Copper-catalysed double N-alkenylation.

It is evident that a large number of synthetic methodolo-gies for accessing the N-acylpyrrole unit now exist. Classicalapproaches that utilise strongly basic or strongly acidic re-action conditions are no longer mandatory. Protocols forthe installation of this useful functional group onto eventhe most challenging substrates are available.

3. Properties and Reactivity of N-Acylpyrroles

The useful reactivity of the N-acylpyrrole functionalgroup is due to the unique nature of the pyrrolic amide.Because the pyrrole lone pair is delocalised in the aromaticsystem, it is less available to interact with the carbonyl unitthan the lone pair of a non-aromatic nitrogen. This makesthe carbonyl unit of an N-acylpyrrole electronically moresimilar to a ketone than to a conventional amide.

This electronic characteristic is evident in spectroscopicfeatures such as the 17O NMR chemical shift of the N-acyl-pyrrole oxygen, which indicates that the carbonyl oxygenis deshielded relative to typical amides (Table 1).[31,32] As aconsequence of the nitrogen lone pair being less availableto contribute to the amide character of the N-acylpyrroleunit, the rotational barrier of the C–N bond of the N-acyl-pyrrole is lowered relative to those in aliphatic amides. In-deed, the barriers to rotation of pyrrolic amides have beenshown to be about 33 kJ mol–1 lower than for N,N-dimeth-ylformamide.[33,34] DFT calculations of the LUMO energiesfor N-acylpyrroles also support this description of pyrrolicamides, with N-acylpyrroles having LUMOs approximately0.5 eV lower than a typical amide (morpholinyl amide). Infact, the N-acylpyrrole LUMO is closer in energy to that ofa phenyl or methyl ketone (Table 2).[13] Additionally, NMRstudies have shown that the aromaticity of pyrrole is notsignificantly affected by a variety of different N-substitu-ents, corroborating the view that the nitrogen lone pairs in

Table 1. 17O NMR shift of selected carbonyl units.

R1 R2 17O NMR [ppm][a]

Pyrrol-1-yl Me 4073H-Pyrrolizin-3-one 386[b]

N(Me)2 Me 324NH2 Me 286Me Me 572

NCS Ph 460.4[b]

[a] Data taken from ref.[31] [b] Data taken from ref.[32]

A. M. Goldys, C. S. P. McErleanMICROREVIEWN-acylpyrroles do not significantly contribute to amide sta-bilisation.[35] The ketone-like reactivity of N-acylpyrroles isaptly illustrated by their facile reduction with lithium andsodium borohydride. Conventional amides are unreactivetowards such mild reductants.[4]

Table 2. LUMO energy of selected carbonyl units.

R LUMO energy[a] [eV]

3-Phenylimidazol-2-yl –2.37Ph –2.09

Pyrrol-1-yl –2.06Oxazolidinon-2-yl –2.05

Me –1.88OMe –1.72

Morpholin-1-yl –1.56

[a] Data taken from ref.[13]

Mechanistic and kinetic studies of N-acylpyrrole hydrol-ysis under both basic and acidic conditions have been con-ducted.[36–39] N-Acylpyrroles 4 were found to hydrolysemore rapidly than acetanilides,[36] which is consistent withthe heightened reactivity of the carbonyl unit resulting froma lack of n�π* stabilisation of the amide bond. The exis-tence of stable pyrrolic carbinol intermediates of type 6(Scheme 8) was first hinted at in a study of the base-cata-lysed hydrolysis of N-acylpyrroles, as was the base-catalysedelimination of pyrrole from a pyrrolic carbinol to form acarbonyl compound.[36] Donohue and co-workers foundthat the hydrolysis of N-acetylpyrrole was largely secondorder in hydroxide ions at low hydroxide concentrations,but first order at high hydroxide concentrations. From thatresult the authors deduced that the hydrolysis mechanisminvolved nucleophilic attack of hydroxide to give an inter-mediate that was decomposed by a second equivalent ofhydroxide. They suggested the now generally acceptedmechanism for base-catalysed elimination of pyrrole fromstable tetrahedral intermediates depicted in Scheme 8.

Scheme 8. Generation of pyrrolic carbinols and subsequent elimi-nation.

Nucleophilic addition to N-acylpyrroles 4 gives stable,isolable, tetrahedral pyrrolic carbinols 6. The stability ofpyrrolic carbinols is also a consequence of the aromaticityof pyrrole, because the weakly basic nitrogen is unlikely tobecome protonated and undergo elimination. The crystalstructure of a pyrrolic carbinol with methyl and phenyl sub-stituents was obtained by Evans and co-workers and re-vealed a C–N bond length of 1.478 Å, which was longerthan previously reported C–N bonds, as well as a shorterthan average C–O bond (1.411 Å in comparison with anaverage of 1.432 Å for a Csp3–OH bond).[4] These observa-


tions were attributed to hyperconjugation between the oxy-gen lone pairs and the C–N σ* orbital.

Pyrrolic carbinols 6 have been found to be stable underweakly acidic (PPTS in H2O/THF) and weakly basic (tri-ethylamine/pyridine) conditions for up to 10 hours at roomtemperature.[4] However, upon treatment with a catalyticamount of strong base[4] or heating,[40] pyrrole is eliminatedto give the corresponding carbonyl compound 27(Scheme 8). The stabilities of pyrrolic carbinols have alsobeen found to be dependent both on the appended substitu-ents, with greater steric bulk resulting in a faster rate ofelimination of pyrrole, and on the counterion (if the hy-droxy group is deprotonated by use of an organometallicreagent), with Mg2+ salts being the most stable, followed byLi+ and then Na+.[4]

The stabilities of pryrrolic carbinols allow these interme-diates to undergo a number of synthetic operations beforethe carbonyl unit is unmasked. In addition to their height-ened reactivities, this feature makes N-acylpyrrole unit su-perior to Weinreb amides in terms of synthetic utility.

4. Synthetic Applications of N-Acylpyrroles

The synthetic utility of N-acylpyrroles has seen them de-ployed in a number of roles in synthesis. N-Acylpyrroleshave served as activated acid equivalents in acylation reac-tions with subsequent transformation into other functionalgroups. They have been used as enolisable substrates inaldol-type chemistry and as ester equivalents with enhancedreactivity in conjugate additions to α,β-unsaturated sys-tems. N-Acylpyrroles have been used as masked aldehydes,and finally, the pyrrole rings of N-acylpyrroles have beenutilised to provide ready access to heterocyclic compounds.

4.1. N-Acylpyrroles as Acylating Agents

Almost 30 years ago, Chan and co-workers reported thestraightforward transformations of N-acylpyrroles into avariety of carbonyl compounds such as aldehydes, estersand primary and secondary amides through treatment withborohydride, alkoxide and amines, respectively (Scheme 9).The formation of pyrrolic carbinols and tertiary alcohols

Scheme 9. Transformations of N-acylpyrroles reported by Chanand co-workers.


(through initial formation of a ketone and subsequent nu-cleophilic attack) was also reported.[11] Another early ac-count of the use of N-acylpyrroles as acylating agents wasreported by Brandänge and co-worker in the formation ofβ-keto esters (Scheme 10).[41] In that work, the nucleophilicaddition of a lithium ester enolate to N-acetylpyrrole (34)generated pyrrolic carbinol 35, which was simply heated toeliminate pyrrole and give the β-keto ester 36. A subsequentpublication by Brandänge and co-workers describes the for-mation of ketones by treatment of N-acylpyrroles with anorganolithium nucleophile to form the pyrrolic carbinol,followed by heating with anhydrous potassium carbon-ate.[23] Brandänge and co-workers also demonstrated theuse of N-acylpyrrole 38 as an electrophile in an intramo-lecular Reformatsky reaction, which gave a yield superiorto that obtained with the analogous ester substrate 37(Scheme 11).

Scheme 10. Monoacylation of N-acylpyrroles.

Scheme 11. Intramolecular Reformatsky reactions of N-acyl-pyrroles.

Evans and co-workers’ 2002 publication on pyrroliccarbinols describes the formation of ketones and aldehydesthrough the treatment of N-acylpyrroles with organo-lithium, Grignard or borohydride reagents, followed by eli-mination of pyrrole.[4] Complementarily to previous re-ports, Evans and co-workers showed that treatment with acatalytic amount of DBU at 0 °C is sufficient to effect theelimination of pyrrole from pyrrolic carbinols.

Thanks to their ability to form stable tetrahedral inter-mediates in a manner analogous to Weinreb amides, N-acyl-pyrroles are useful acylating agents when double addition


of the nucleophile to the carbonyl group needs to be avo-ided. Because of the high electrophilicities of N-acyl-pyrroles, the addition of organometallic nucleophiles cantake place at –78 °C, resulting in the formation of a stablepyrrolic carbinol. This prevents subsequent nucleophilic ad-dition. Treatment with catalytic DBU, or in some cases sim-ple heating, results in the decomposition of the pyrroliccarbinol and formation of the desired carbonyl compound.This reactivity has been illustrated by Silvonek and co-workers’ synthesis of the fluorescent dyes prodan and acryl-odan.[42]

4.2. Conjugate Additions to α,β-Unsaturated N-Acylpyrroles

The most extensively studied application of N-acyl-pyrroles is the use of α,β-unsaturated N-acylpyrroles asMichael acceptors in asymmetric conjugate additions ofvarious nucleophiles, with the earliest reports of such trans-formations appearing in publications by the groups of Shib-asaki[19] and Arai.[43] Indeed, much of the development ofsynthetic applications of α,β-unsaturated N-acylpyrroles isattributable to Shibasaki’s group, who have used these sub-strates in their development of asymmetric reactions cata-lysed by rare earth complexes and application of linkedBINOL ligands in asymmetric catalysis.[44] α,β-UnsaturatedN-acylpyrroles are valuable as Michael acceptors for metal-catalysed asymmetric conjugate additions because of theirmonodentate coordination mode, which allows for the useof chiral catalysts developed for asymmetric conjugate ad-ditions to α,β-unsaturated ketones with compounds thatpossess ester-equivalent functional groups. Furthermore,the high electrophilicities of α,β-unsaturated N-acylpyrrolesrelative to α,β-unsaturated esters or other ester equivalentsmakes them attractive substrates for conjugate additions.The resulting pyrrolic amide-containing product can easilyundergo a variety of transformations into, for example,ketones, aldehydes, esters or alcohols. Such conjugate ad-dition reactions typically involve a metal complex contain-ing a chiral ligand, which, as a Lewis acid, activates thecarbonyl group and/or activates and delivers the nucleo-phile. As highlighted in Scheme 12, this method has beensuccessfully applied to asymmetric conjugate additions ofhydroperoxides (to give 44),[19,45] amines (to give 43),[20,46]

phosphites (to give 47),[47] phosphane oxides (to give 48),[48]

malonates (to give 41, 49),[49,50] dimethylsulfoxonium meth-ylide (to give 46),[51] arylboronic acids[52] and cyanide (togive 45).[53–55]

Another notable application of α,β-unsaturated N-acyl-pyrroles is their use in the enantioselective conjugate cyan-ation/protonation reaction developed by Shibasaki and co-workers (Scheme 13).[54–56] The α,β-unsaturated N-acyl-pyrroles 50 were treated with a polynuclear gadoliniumcomplex containing the Brønsted acid ligand 51. Conjugateaddition of cyanide anion to the substrates gave gadoliniumenolate intermediates, which was followed by the enantio-selective delivery of a proton from the ligand. The resultingchiral α-substituted carbonyl compounds 52 are produced

A. M. Goldys, C. S. P. McErleanMICROREVIEW

Scheme 12. Enantioselective transformations of α,β-unsaturated N-acylpyrroles.

in excellent yields and with good enantiomeric excesses,which can be readily improved by recrystallization becausethe N-acylpyrrole products are crystalline solids. The pres-ence of the N-acylpyrrole functional group also allows forthe facile conversion of the products of this reaction intothe synthetically useful compounds such as 53 and 54.

Scheme 13. Enantioselective conjugate cyanation/protonation.

Other conjugate additions developed for α,β-unsaturatedN-acylpyrroles include a palladium-catalysed conjugateallylation,[57] and a Sc(OTf)3-catalysed conjugate additionof 2-methylquinoline.[58]

As well as in these metal-based protocols, α,β-unsatu-rated N-acylpyrroles have also been employed as electro-philes in organocatalysed reactions. Organocatalytic asym-metric conjugate additions of nitroalkanes[59] and 1,3-di-carbonyl nucleophiles[60] onto N-acylpyrroles have been re-ported to proceed in good yields. The heightened electro-philicities of N-acylpyrrole units have seen α,β-unsaturatedN-acylpyrroles used as enabling groups to facilitate the gen-eration of 1,4-dicarbonyl products through Stetter reac-tions.[61] Notably, both intramolecular and intermolecular


variants of the reaction were equally facile when an N-acyl-pyrrole Michael acceptor was employed (Scheme 14).

Scheme 14. N-Acylpyrrole-enabled Stetter reactions.

Finally, α,β-unsaturated N-acylpyrroles are compatiblewith the growing field of “on-water” catalysis. In contrastwith low-molecular-weight acrylates, the aqueous insolubil-ity of N-acrolyl-2,5-dimethylpyrrole (58, Scheme 15) hasseen this acceptor unit employed for “on-water” catalysedconjugate additions of anilines and thiophenols,[46] a meth-odology subsequently utilised in the synthesis of the phar-maceutical agent (�)-thiazesim.[62]

Scheme 15. On-water conjugate additions of anilines.

4.3. N-Acylpyrrole-Derived Enols and Silyl Enol Ethers

Thanks to their ketone-like reactivity, N-acylpyrroles canfunction as ester or amide enolate equivalents. N-Acyl-pyrrole-derived silyl enol ethers are particularly useful forthese purposes, due to their high nucleophilicities.[63] Silylenol ethers formed from N-acylpyrroles have been used asnucleophiles in Mukaiyama aldol[64] and Mukaiyama–


Scheme 16. Transformations of N-acylpyrrole-derived silyl enol ethers.

Michael reactions (Scheme 16).[63,65,66] The silyl enol ethersare easily obtained by treatment of the pyrrolic amides withsodium hexamethyldisilazide in THF in the presence ofDMPU, followed by quenching with chlorotrimethylsil-ane.[5] This gives high yields of (Z)-configured silyl enolethers 61 (�98:2 Z/E ratios).[5] The application of these rea-gents in Mukaiyama aldol reactions has been studied byNelson and co-workers.[64] Silyl enol ethers derived from N-acylpyrroles (in comparison with those derived from thioes-ters and ketones) gave the highest yields of all-syn aldolproducts 63 and possessed the greatest reactivities in p-ni-trophenoxide-catalysed additions to chiral α-substituted al-dehydes.[64]

Evans and co-workers developed additions of the N-acyl-pyrrole-derived silyl enol ethers 61 to the α,β-unsaturatedimide derivatives 64,[63,66] mediated by a chiral CuII com-plex (Scheme 16), which gave anti-configured Michael ad-ducts 65 with excellent enantiomeric excesses. (It is gen-erally known that ketone-derived E-configured silyl enolethers give rise to the syn-configured adducts, but this hasnot yet been demonstrated with N-acylpyrrole-derived silylenol ethers.[67]) Although reported as Mukiayama–Michaeladditions the mechanism has not been elucidated, and thesereaction might proceed through a hetero-Diels–Aldermechanism, analogous to the Diels–Alder aminations ofsilyl enol ethers (including N-acylpyrrole-derived silyl enolethers) previously investigated by Evans and co-workers.[5]

Asymmetric, organocatalytic Mukaiyama–Michael ad-ditions of N-acylpyrrole-derived silyl enol ethers were devel-oped by MacMillan and co-workers. Like the Evans meth-odology, they also gave the anti-configured Michael adducts67 (Scheme 16).[65]

N-Acylpyrrole-derived metal enolates may also be usedas synthetically useful intermediates. Noting the similaritybetween aromatic ketones and N-acylpyrroles, Shibasakiand co-workers were able to extend their previously estab-lished methodology for the catalytic asymmetric Mannichreactions between β-hydroxy ketones[68] and N-(2-hy-droxyacetyl)pyrrole (69, Scheme 17).[69] Treatment of 69with indium(III) isopropoxide and the linked BINOL cata-lyst 70 led to the formation of the corresponding indiumenolate, which underwent stereoselective addition to a rangeof imines 68, forming β-amino-α-hydroxy N-acetylpyrroles


71. Shibasaki and co-workers also demonstrated the syn-thetic utility of the N-acylpyrrole-containing products byconverting them into esters, amides and pyrrolic carbinols(which were further subjected to base-catalysed eliminationor used as substrates for Horner–Wadsworth–Emmons ole-finations).

Scheme 17. Indium enolate from an N-acylpyrrole.

Recently, Wang and co-workers[70] utilised the readily en-olisable N-acylpyrrole 73 (Scheme 18) in a one-pot enantio-selective Mannich/Horner–Wadsworth–Emmons cascade togive the Baylis–Hillman-type product 75.

Scheme 18. Mannich/Horner–Wadsworth–Emmons cascade.

4.4. Pyrrolic Carbinols as Aldehyde Protecting andStereodirecting Groups

The mild reductions of N-acylpyrroles to give stablepyrrolic carbinols open an avenue for synthetic applicationthat is not available to the corresponding Weinreb amides.Pyrrolic carbinols have been employed as temporary pro-tecting and/or stereodirecting groups, which can sub-

A. M. Goldys, C. S. P. McErleanMICROREVIEW

Scheme 19. N-Acylpyrrole-derived carbinols as temporary protecting and stereodirecting groups.

sequently be converted into the corresponding aldehyde oracid derivatives. This useful synthetic strategy was first ex-plicitly described by Evans and co-workers[4] and has sub-sequently been used to great effect by Dixon and co-workers.[71] Pyrrolic carbinols have been accessed by the ad-dition of lithiated pyrrole to aldehydes.[72] Ligand-mediatedenantioselective addition of lithiated pyrrole to aldehydeshas also been reported, but gave the products with onlymodest levels of enantioselectivity.[40,73] In the course ofthose studies the utility of chiral pyrrolic carbinols as di-recting groups in the reduction of nearby carbonyl groupswas demonstrated.[40] The culmination of this work was thetotal synthesis of the natural product tarchonanthuslactone(Scheme 19), in which N-acylpyrrole 76 was subjected toan asymmetric reduction and the resulting chiral pyrroliccarbinol 77 was used as a directing group for the borohyd-ride reduction of two neighbouring carbonyl units.[71] Con-veniently, the basic conditions of the subsequent Horner–Wadsworth–Emmons reaction effected the elimination ofpyrrole and the generation of the aldehyde in situ, allowingfor a cascade deprotection/olefination reaction sequencefrom 79 to give 80. This effective sequence illustrates theutility of the N-acylpyrrole functional group because it canreadily be reduced to the chiral carbinol, which is then re-moved in a single step to create a new functional group.

4.5. N-Acylpyrrole Reactions Involving the Pyrrole Ring

Although the carbonyl unit of an N-acylpyrrole presum-ably attenuates the well-known nucleophilicity of the pyr-role ring to some degree, some N-acylpyrroles remain reac-tive enough to engage in nucleophilic additions. This allowsfor the rapid generation of complex N-acylpyrrole-contain-ing structures. Examples of this mode of reactivity(Scheme 20) include the formation of pyrrolo[2,1-b][1,3]-

Scheme 21. N-Acylpyrrole-derived carbinols as temporary protecting and stereodirecting groups.


benzothiazin-9-ones 82[74] and medium-sized N,S-heterocy-cles 84[75] by intramolecular nucleophilic attack of N-acyl-pyrroles onto electrophilic sulfur atoms, acid-catalysed con-jugate additions of N-acylpyrroles to α,β-unsaturatedketones[76] and 2-perfluoroalkylation of N-acylpyrroles inthe presence of a ruthenium complex.[77]

Scheme 20. Selected reactions of nucleophilic N-acylpyrroles.

Electrophilic aromatic substitution is not the only reac-tion pathway available for functionalising the pyrrole ringof an N-acylpyrrole – radical-based reactions are also pos-sible. An impressive example of this is MacMillan’s reportof the organocatalysed SOMO α-arylation of aldehydes(Scheme 21).[78] Enamine formation with an 4-imidazol-idinone, followed by two single-electron oxidations by[Fe(phen)3]·(PF6)3, effects the stereoselective α-arylation ofthe aldehyde 85 through a radical mechanism. Another ex-ample is the intramolecular addition of malonyl radicals atthe 2-positions in N-acylpyrroles, mediated by the photore-dox catalyst tris(2,2�-bipyridyl)ruthenium dichloride, re-ported by Tucker and co-workers.[79]

A complementary method of incorporating N-acyl-pyrroles into more complex structures involves the use ofmetal-catalysed couplings. Nucleophilic attack of N-acetyl-pyrrole (34, Scheme 22) onto Hg2+ [as mercury(II) chloride]


allows for the selective 2-mercuration of the pyrrole ring,forming (N-acetyl-2-pyrrolyl)mercury(II) chloride (89),which benefits from additional stabilisation by the coordi-nating carbonyl group (Scheme 22). Treatment with iodidegives bis(N-acetyl-2-pyrrolyl)mercury (90), which can un-dergo subsequent transmetallation with other transitionmetals in preparation for cross-coupling reactions.[80]

Scheme 22. Organomercury-based N-acylpyrroles.

Itahara reported that the treatment of N-benzoyl- or N-(2,6-chlorobenzoyl)pyrrole with Pd(OAc)2 resulted in 2-pal-ladation, followed by intramolecular arylation at the 2-posi-tion.[81] In a similar vein, Colbry and co-workers used ametal-catalysed coupling of N-acylpyrrole 91 (Scheme 23)as the key step in their synthesis of the antibacterial naturalproduct 6,8-dihydroxy-7-propyl-9H-pyrrolo[1,2-b][1,3]benz-oxazin-9-one.[82]

Scheme 23. Palladium-catalysed intramolecular cyclisation of an N-acylpyrrole.

Heating N-acylpyrrole 91 with Pd(OAc)2 resulted in pal-ladation at the 2-position of the pyrrole ring, followed byan intramolecular cyclisation to give the heterocycle 92.Coupling between the pyrrolic 2-position and sp3-hybrid-ised carbon atoms is also possible. Liégault and Fagnoureported PdII-catalysed intramolecular coupling betweenthe pyrrolic 2-position of aliphatic N-acylpyrrole 93 and thecarbons of the aliphatic chain (Scheme 24).[83]

Scheme 24. Palladium-catalysed intramolecular CH insertion in anN-acylpyrrole.

Substituted N-acylpyrroles have also been reported toundergo metal-catalysed reactions. Knochel and co-workerreported palladium(II)-catalysed couplings of aryl and vinylbromides with 2,5-dimethyl-N-acylpyrroles, leading to theformation of fused, pyrrole-containing bicyclic compounds96 and 98 (Scheme 25).[84] This method has been demon-strated for a variety of N-substituted 2,5-dimethylpyrrolesas well as for N-acylpyrroles.


Scheme 25. Palladium-catalysed intramolecular CH insertion insubstituted N-acylpyrroles.

4.6. Diels–Alder Reactions of N-Acylpyrroles

The bulk of the work described in this microreview hasutilised the aromatic nature of the pyrrole ring to sequesterthe nitrogen lone pair and reduce the amide character ofthe N-acylpyrrole. Conversely, one may also consider thatsome degree of amide character would reduce the aromatic-ity of the pyrrole ring. Thanks to this electronic pertur-bation, N-acylpyrroles exhibit more diene-like characterthan the corresponding unsubstituted pyrroles.[85] Conse-quently, N-acylpyrroles have been used as substrates forDiels–Alder [4+2] cycloadditions, although this is not a fac-ile process. Early reports involved Diels–Alder reactions be-tween N-acylpyrroles and electron-deficient alkynes[86–88]

(the reactions do not proceed with electron-rich alkynes)such as dimethyl acetylenedicarboxylate (99) to give aza-bicyclo[2.2.1]heptadienes 100 (Scheme 26). At the elevatedreaction temperatures used for these cycloadditions, the bi-cyclic products underwent retro-Diels–Alder reactions togive the 3,4-disubstituted pyrrole 101 in low yield.[87] Unac-tivated alkenes generally do not participate in Diels–Alderreactions with N-acylpyrroles at ambient pressure,[86,89] butat high pressure more reactive dienophiles such as N-phen-ylmaleimide do react.[90]

Scheme 26. Diels–Alder cycloaddition involving an N-acylpyrrole.

A complicating factor in N-acylpyrrole cycloadditions isthe possibility of competing Michael additions involvingthe nucleophilic pyrrole ring to give 2-substituted N-acyl-pyrroles.[87] Inverse-electron-demand Diels–Alder reactionsinvolving N-acylpyrroles had previously been reported,[91,92]

but these required very forcing reaction conditions. Re-cently, though, inverse-electron-demand Diels–Alder cyclo-additions that proceed at 0 °C or ambient temperature havebeen reported. Reactions between the N-acylpyrrole 102(Scheme 27) and masked o-benzoquinones 103 gave the de-

A. M. Goldys, C. S. P. McErleanMICROREVIEWsired cycloadducts 104 in good yields.[93] However, in viewof the forcing conditions previously required to effect theseinverse-electron-demand Diels–Alder reactions, it is notclear whether or not these reactions do in fact proceedthrough a stepwise conjugate addition mechanism.

Scheme 27. A possible Diels–Alder cycloaddition of an N-acyl-pyrrole.

α,β-Unsaturated N-acylpyrroles have also been used asdienophiles in Diels–Alder reactions (Scheme 28). Arai andco-workers synthesised the optically active α,β-unsaturated2-tolylsulfinyl-N-acylpyrroles 105, which participated inDiels–Alder reactions with cyclopentadiene (106) in thepresence of AlCl3 or Yb(OTf)3 catalysts.[94] The resultingcycloadducts 107 were formed with high diastereoselectivityand the 2-(tolylsulfinyl)pyrrole chiral auxiliary 109 could berecovered by methanolysis of the N-acylpyrrole moiety.

Scheme 28. Diels–Alder cycloaddition involving an α,β-unsaturatedN-acylpyrrole.

Figure 1. N-Acylpyrrole-containing natural products.


5. Miscellaneous

5.1. Occurrence in Natural Products

Despite the ubiquity of pyrrole-containing natural prod-ucts,[95] only a few examples of naturally occurring com-pounds containing the N-acylpyrrole functional group havebeen reported (Figure 1). Compounds 110–112, each con-taining a N-(2,3-dihydrocinnamoyl)pyrrole subunit, for ex-ample, have been isolated from plants in the Piper ge-nus.[96,97] Compounds 113 and 117 were isolated from thefungus Penicillium brevicompactum and were used as leadcompounds for the development of pyrrole-containing fun-gicides and insecticides.[98] The marine environment is a richsource of alkaloids, including pyrrole-based natural prod-ucts such as N-acylpyrroles 114 and 115,[99] isolated fromthe sponge Dendrilla nigra, which are structurally similar tothe lamerallins, in particular lamerallins O and R.[95] Ofthese compounds, 115 was found to inhibit the activationof hypoxia-inducible factor-1 (HIF-1) in a human breasttumour cell-based assay with an IC50 of 1.9 μm. HIF-1 isconsidered to be an important molecular target for anti-tumour drugs. The C16-unsaturated alkamides 118–121 andthe cyclised compound 116 were isolated from the root ex-tract of the flowering plant Achillea ageratifolia. The sim-plest structure of this class of natural products – N-acetyl-pyrrole (34) – is also found as a component of the aromasof roast foods such as meat and coffee.[100]

5.2. Medicinal Chemistry Applications

As amides with heightened reactivity that also functionas ester and ketone precursors, N-acylpyrroles have foundapplication in medicinal chemistry studies (Figure 2).Rekka and co-worker, for instance, evaluated a series ofbenzoylpyrroleacetic acids, including N-benzoyl-3-pyrroleacetic acid 123, intended to mimic the structure ofglycine-based non-steroidal anti-inflammatory drugs, forthe treatment of diabetes-related complications by targetingthe enzyme aldose reductase.[101] Another study investigated


the ability of α,β-unsaturated N-acylpyrrolyl peptides 122to inhibit a threonine protease by acting as Michael ac-ceptors for threonine.[102] Several of these peptides provedto be effective inhibitors, as well as displaying good phar-macokinetic properties and cell membrane permeabilities.In addition, this study demonstrated the compatibility ofthe α,β-unsaturated N-acylpyrrole unit with a Fmoc solid-phase peptide synthesis strategy.

Figure 2. N-Acylpyrroles with medicinal properties.

In some cases, the heightened reactivities of N-acyl-pyrroles have rendered them unsuitable for biological appli-cations. Dong and co-workers studied pyrrole-based inhibi-tors of mitogen-activated kinase in relation to cancer treat-ment.[103] However, it was found that the N-acetylpyrrolecompounds 124 and 125, despite displaying excellent activi-ties in an enzyme assay, performed poorly in a cellular assaydue to the instability of the N-acetylpyrrole units. In fact,deacetylation of the pyrroles was observed over the courseof the assay.

6. Conclusions

The quest to combine increased reactivity with syntheticversatility has led to the emergence of the N-acylpyrrolefunctional group as an acid, ester, amide, aldehyde andketone equivalent. A large number of protocols are avail-able for the preparation of N-acylpyrroles, which, thanksto the aromaticity of pyrrole, possess unique reactivity. N-Acylpyrroles function as acylating agents, they enhance thereactivity of α,β-unsaturated systems, they form enolatesand silyl enol ethers and they undergo metal-catalysedtransformations and Diels–Alder-type chemistry on thepyrrole ring. Unlike the corresponding Weinreb amides,protonation of the tetrahedral intermediate arising from nu-cleophilic addition onto an N-acylpyrrole results in a stablepyrrolic carbinol that can be generated as a single stereoiso-mer and that can function as aldehyde protecting group andstereodirecting group.

Given their ease of preparation, unique reactivity andwide-ranging chemistry, we anticipate that N-acylpyrroleswill find increasing application in synthetic settings.


Acknowledgments

C. S. P. M thanks the Selby Scientific Foundation for a Selby Re-search Award and A. M. G. gratefully acknowledges receipt of anAustralian Postgraduate Award.

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Received: October 10, 2011Published Online: December 20, 2011

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