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Selective Synthesis of b-Alkylpyrroles

Teruhisa Tsuchimoto*[a]

� 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 4064 – 40754064

DOI: 10.1002/chem.201002248

Introduction

Pyrroles, in which two electrons on a nitrogen atom andfour p-electrons from each of four carbon atoms contributeto an aromatic sextet, constitute an important class of nitro-gen-containing heterocyclic arenes.[1] The five-memberedring system is now well recognized as “electron-rich”, whichis also referred to as “p-excessive”, due to delocalization ofthe two electrons from the nitrogen atom to other carbonmembers.[1c] In particular relation to these properties, elec-trophilic aromatic substitution (SEAr) reaction of pyrroleshas a long-standing history in synthetic organic chemistry, interms of introduction of various functional groups onto thepyrrole ring.[2] As a distinct tendency, the SEAr reactionoccurs predominantly at an a-carbon atom, the position ad-jacent to the nitrogen atom, because attack of an electro-phile to the a-position leads to a more stable cation inter-mediate having three resonance forms, while reaction at a b-carbon atom gives a less stable cation with only two reso-nance forms (Scheme 1, electrophile=El+).[2] Due to suchelectronic characteristics of pyrroles, regioselective function-alization at the b-position is still a challenging research issuein the field of organic chemistry.

Pyrroles having simple and functionalized alkyl chains atthe b-position are important frameworks found in naturalproducts[3] as well as functional organic materials[4] includ-ing, for instance, conducting polymers and gas-sensitivemembranes. b-Alkylpyrroles are crucial also as building

blocks for construction of porphyrins.[5] Developing a usefulsynthetic strategy for b-alkylpyrroles is thus of outstandingimportance in a variety of aspects. Intra- and intermolecularring-closing reactions are obvious candidates for the synthe-sis of b-alkylpyrroles,[5d, 6] but, because of the sufficient aro-maticity and p-excessive nature of pyrroles, direct installa-tion of alkyl groups onto pyrroles by way of SEAr processseems to be more straightforward to access b-alkylpyrroles.However, as described in the previous paragraph, the prefer-ential a-nucleophilicity of pyrroles actually makes the b-al-kylation considerably difficult. In fact, a vast amount of re-search has thus far been devoted to exclusive or selective a-alkylation of pyrroles, in which various organic moleculessuch as alkenes,[7] alcohols,[8] allylic acetates,[9] ketones,[10]

imines,[11] epoxides,[12] aziridines[12] and diazo compounds[13]

have been the alkylating agents of choices. Under such sit-uation, how do you alkylate pyrroles at the b-position regio-selectively? In order to offer clear and valuable guidance tothe query, this Concept article will focus on providing anoverview with respect to “selective synthesis of b-alkylpyr-roles from pyrroles” mainly through the SEAr route,

[14]

wherein our recent achievements will be also presented.

Use of Pyrroles with an Electron-WithdrawingGroup at the a-Position

In the Friedel–Crafts reaction proceeding through SEAr pro-cess, it is well-known that electron-withdrawing groups(EWGs) such as carbonyl and cyano substituents on a ben-zene ring act as meta-directing groups for incoming electro-philes (Scheme 2).[15] The regiochemical nature concerningthe meta-orientation extends also to pyrroles,[16] while, strict-ly, the terms ortho/meta/para cannot be applied to such five-membered situation. Thus, the strategic “trick” in this sec-tion is obstruction of electrophilic attack to the a-position,by controlling the electronic nature of the pyrrole ring withthe aid of the EWG attached on the a-carbon (Scheme 2).

With respect to the SEAr reaction of pyrroles 1, Rinkesreported the first example as nitration with HNO3 alreadyin 1934, while its b-regioselectivity is moderate.[17] After 30years since the pioneering study, Anderson and Hopkinsfirst applied the strategy to Lewis acid-promoted b-alkyla-tion using 2-propyl chloride as an alkylating agent.[18] The

Abstract: b-Alkylpyrroles are key structural motifsfound in many natural products and biologically activecompounds as well as functional organic materials. Forthis reason, synthetic chemists continue to be interestedin construction of the framework of b-alkylpyrroles.Due to sufficient aromaticity and p-excessive nature ofpyrroles, a straightforward approach to b-alkylpyrrolesshould be electrophilic aromatic substitution (SEAr)toward the pyrrole ring. However, since a primary nu-cleophilic site of pyrroles is an a-position, some “trick”is required to direct incoming alkyl electrophiles towarda b-position. This Concept article focuses on presentingprevious efforts that have been devoted to the synthesisof b-alkylpyrroles, mainly through the SEAr route.

Keywords: alkylation · electrophilic aromaticsubstitution · heterocycles · pyrroles · regioselectivity

[a] Prof. Dr. T. TsuchimotoDepartment of Applied Chemistry, School of Science and TechnologyMeiji University, 1-1-1 Higashimita, Tama-kuKawasaki 214-8571 (Japan)Fax: (+81) 44-934-7228E-mail : [email protected]

Scheme 1. A general mechanistic scheme on SEAr reaction of pyrroles.

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CONCEPT

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outline of the strategy is illustrated in Scheme 3. Althoughthe key process is the second stage (1 to 2), two furthersteps for the introduction and removal of the EWG are, inpractice, necessary to obtain desired b-alkylpyrroles 3.[19]

The representative results for the b-2-propylation of 1 arecollected in Table 1.

The EWG on the pyrrole a-position certainly overridesthe intrinsic pyrrole regiochemistry, and hence the substitu-tion selectively takes place at the C4. However, both the b-selectivity and yield depend on not only the EWG but alsothe Lewis acid. As Table 1 indicates, 1 having CHO appearsto be the most reactive (entries 1 and 2) and is converted ex-clusively to 4-(prop-2-yl)pyrrole 4. In contrast, the use ofthe acetyl and ester derivatives results in the lower b-selec-

tivities and, in addition, contamination with disubstitutedpyrroles 6 (entries 3–5). For the formation of 5, rearrange-ment of the iPr group from the C4 to the C5 rather thandirect alkylation at the C5 is proposed to be suitable, on thebasis of some experimental observations.

Anderson and co-workers also reported tert-butylation of1 under essentially the identical conditions as above(Table 2).[20] Due to much more facile rearrangement of thetBu group, prudent choices of both the EWG and Lewisacid are required for high b-selectivity, which is thus at-tained in the use of 1 with the CN group and of GaCl3 as aLewis acid (entry 4). No di-tert-butylation occurs here in anycases.

Now, actually, it is unnecessary to pre-synthesize pyrroles1 (EWG=CHO, COMe, CO2Me, CN) that have appearedin this section, because they are available as commercialsources, in contrast to the 1960s and early 70s. Accordingly,total efficiency of the method relies on facility of removingthe EWG.[21] In most cases, decarboxylation of the carboxylgroup is adopted as a final step (Scheme 4). When EWGsare CO2Me and CN, they are removable readily in one-pot,by the hydrolysis–decarboxylation sequences.[20b] Removalof CHO from a pyrrole ring is achieved in two steps, which

Scheme 2. Preferred reaction sites of arenes and pyrroles with EWGs inSEAr process.

Table 1. Lewis acid-mediated b-2-propylation of pyrroles 1.[a]

Entry EWG Lewis acid t [h] Yield [%] of 4–6 4/5/6

1 CHO AlCl3 2 83 >99:

are oxidation of the CHO to CO2H and then decarboxyla-tion.[22]

The b-directing effect of the EWG can be utilized also forsynthesis of b-n-alkylpyrroles, though no direct alkylation ofpyrrole rings is involved. As Scheme 5 indicates, the method

disclosed by Anderson and co-workers consists of the fol-lowing three steps:[20b, 23] 1) the introduction of the thioestergroup onto the pyrrole a-carbon, 2) the regioselective b-acy-lation of 9 via SEAr reaction, and 3) the synthesis of b-n-al-kylpyrroles 11 by the combination of the Wolff–Kishner re-duction of the carbonyl moiety and the removal of the thio-ester group by the hydrolysis and decarboxylation. The acy-lation of 9 giving 10 a–c seems to proceed in a complete b-regioselective manner (Scheme 6).

Use of Pyrroles with an Arylsulfonyl Group on theNitrogen Atom

In reaction with more than a stoichiometric amount ofAlCl3, arylsulfonyl (As) groups such as phenylsulfonyl (Ps)and tosyl (Ts) ones on the pyrrole nitrogen atom affect todirect incoming electrophiles to the b-position. The strategicfocus in this section is to prevent attack of electrophiles to

the pyrrole a-carbon, with the assistance of the As group at-tached on the nitrogen atom. The methodology can be di-vided mainly into two categories (Scheme 7). One of them isLewis acid-mediated direct b-alkylation of N-As-pyrrole 12(strategy A), and the other, which constitutes the majorityin this section, starts with the b-acylation of 12 promotedalso by Lewis acids (strategy B).

Acylation and/or nitration of N-Ps–pyrrole (12 a), dis-closed independently by Anderson�s and Rokach�s groups in1981, are the first examples utilizing the b-directing effect ofthe As group.[24] In almost all the reactions, remarkable b-se-lectivities are recorded. Two years later, Anderson and col-leagues again first demonstrated direct alkylation of 12 a(strategy A), but only the tert-butylation proceeds in a regio-selective manner (Scheme 8, 12 a to 13 a).[25] Treatment of13 a with KOH in aqueous MeOH then gives b-tert-butylpyr-role (14 a). In contrast to the tert-butylation, other alkylationwith 2-propyl chloride or ethyl bromide results in muchlower b-selectivity and yield of the product. Thus, the majorinconvenience of the strategy A is that an alkyl group to beinstalled successfully to the b-position of 12 must be bulkyin size.

Kakushima and co-workers have reported the synthesis ofb-alkylpyrrole 14 b as the first performance of the strategyB, which, in detail, includes the following four steps: 1) theAlCl3-mediated b-selective acetylation, 2) the transforma-tion mediated by thallium nitrate,[26] 3) the hydrolysis of theester part, and 4) the removal of the Ps group (Scheme 9).[27]

The last two steps, both of which use bases, can be combinedinto a single operation (see, step b in Scheme 10). In con-trast to the b-selective acylation observed in the first step,alteration of AlCl3 into BF3·OEt2 drastically changes the ori-entation, thus leading to a-selective acylation.[27,28] A proper

Scheme 5. A schematic route for synthesis of b-n-alkylpyrroles 11a–c.

Scheme 6. AlCl3-promoted regioselective b-acylation of 9.

Scheme 7. Schematic outline for synthesis of b-alkylpyrroles 14 with pyr-roles 12 as starting substrates.

Scheme 8. Synthesis of b-alkylpyrrole 14 a based on strategy A.


CONCEPTSelective Synthesis of b-Alkylpyrroles

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choice of a Lewis acid is thus highly important for the strat-egy B to obtain b-acylpyrroles 15 selectively. The strategy iseffective, especially for the synthesis of b-alkylpyrroles 14 c–f bearing carboxyl, hydroxy and ester groups (Scheme 10).[29]

Havinga and co-workers have reported a different ap-proach of the strategy B by means of more simple reactionsequences, which are the reduction of the carbonyl (theClemmensen reduction in this case) following the b-acyla-tion, and then the final desulfonylation, whereas the methodincludes the transformation of Cl to SO3Na. Unfortunately,details of the reaction conditions of as well as yield of theeach step are not specified (Scheme 11).[30]

After the publication of the Havinga�s report, R�he andco-workers refined the method by replacing toxic and acidicZn–Hg/HCl with NaAlH2(OCH2CH2OCH3)2 (Red-Al), andthus synthesized several b-alkylpyrroles 14 h with differentlengths of alkyl chains, while the reduction of the carbonyland the desulfonylation are performed in the reverse order,compared to the original Havinga�s method (Scheme 12).[31]

Due to the reliability of the strategy reported by Havinga�sand R�he�s groups, it has so far been utilized widely for pre-paring monomers directed towards poly(b-alkylpyrrole)sthat are significant as conducting polymers, gas sensitive re-sistors, DNA sensors, and wool coating textiles.[4g,32] In otherreports, reducing systems other than Red-Al and Zn–Hg/HCl are often selected.[33]

Although a reasonable explanation why N-As–pyrroles 12react with acylating agents selectively at the b-positionshould remain to be discussed further, its possible interpre-tation has recently been provided by Huffman and co-work-ers.[34] In the AlCl3-mediated acylation of N-Ts–pyrrole(12 b), they describe that high b-selectivities are ascribed tohigher reactivity of in situ formed b-pyrrolyl–aluminum s-complex b-16 than that of a-16 (Scheme 13). The formationof a-16 and b-16 can be confirmed by D2O quenching of thereaction mixture, resulting in the incorporation of the Datom at the C2 and C3. They propose that the lower reactiv-ity of a-16 may be attributed to the following two aspects:

Scheme 9. Synthesis of b-alkylpyrrole 14b based on strategy B, includingthallium-mediated transformation.

Scheme 10. Synthesis of b-alkylpyrroles 14c–f based on strategy B, in-cluding thallium-mediated transformation (step a). Step a: Tl ACHTUNGTRENNUNG(NO3)3,Montmorillonite K-10, HC ACHTUNGTRENNUNG(OMe)3 in MeOH, RT. Step b: 1) NaOH inMeOH/H2O, reflux; 2) H3O

+ . Step c: R’OH, dicyclohexylcarbodiimide(DCC), 4-(dimethylamino)pyridine (DMAP) in CH2Cl2, 20 8C. Step d: 1)BH3·SMe2 in THF, 20 8C; 2) NaOH in MeOH/H2O, reflux. Step e:R’’CO2H, DCC, DMAP in CH2Cl2, 20 8C.

Scheme 11. Synthesis of b-alkylpyrrole 14g based on strategy B, includingsequences of reduction of a carbonyl group and desulfonylation.

Scheme 12. Synthesis of b-alkylpyrroles 14 h based on strategy B, includ-ing sequences of desulfonylation and reduction of carbonyl groups.

Scheme 13. Possible reaction mechanisms including formation of pyrrol-yl–aluminum s-complexes 16.

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1) a more sterically encumbered C2 in a-16 compared withthe C3 in b-16, and 2) the formation of much more stable a-16’ with a less nucleophilic C2, responsible for the coordina-tion of the oxygen atom to the aluminum center.

Use of Pyrroles with a Bulky Group on theNitrogen Atom

A bulky group on a pyrrole nitrogen atom has a pronouncedsteric b-directing effect in SEAr reaction. A key “trick” inthis section is thus to interfere with access of electrophilesto pyrrole a-positions, on the basis of steric shielding fromthe bulky substituent. For this purpose, tBu,[35] triphenyl-methyl and triisopropylsilyl (TIPS) groups have been usedas bulky substituents.[14] Among them, the TIPS group islikely to be the most practical in terms of b-selectivity[36] aswell as easy removability.[37] In fact, there have been somereports on direct b-alkylation of N-TIPS–pyrrole (17)[38] viathe SEAr process (Scheme 14).

[39] However, treatment of 17with more simple alkyl electrophiles has no precedent.

N-TIPS–b-bromopyrrole (20), derived selectively from theSEAr-based bromination of 17 with N-bromosuccinimide(NBS), serves as a source of N-TIPS–b-alkylpyrroles 22,thus resulting from the bromine–lithium exchange followedby trapping of in situ formed pyrrolyl–lithium 21 with alkylhalides or aldehydes, while this idea includes no direct SEAralkylation of pyrroles (Scheme 15).[40,41] The b-bromopyrrole(20) engages also in the palladium-catalyzed coupling withalkyl Grignard reagents to provide 23 (Scheme 16).[42] More-over, 20 is a key substrate for synthesis of C-nucleosides,[43]

and a ketorolac analogue as a potential non-steroidal, anti-inflammatory drug.[44] In a similar manner as 20, N-TIPS–b,b’-dibromopyrrole, which can be readily prepared by treat-ing 17 with 2 molar equivalents of NBS,[40b,45] is reportedly auseful platform for b,b’-dialkylpyrroles.[42b, 45]

Use of N-Metal–Pyrrole and Pyrrole–MetalComplexes

N-Metal–pyrrole species often undergo attack of electro-philes at the b-position. As the first example on this topic,in 1969, Castro and co-workers have reported that N-MgCl–pyrrole (24) in THF reacts with ethylene oxide to give 2-(pyrrol-3-yl)ethanol (25) exclusively, albeit in a low yield(Scheme 17).[46] As shown also in Scheme 17, N-ZnBr–pyr-role (26)[47] and N-ReCl2 ACHTUNGTRENNUNG(PMe2Ph)3–pyrrole (27)[48] partici-pate in this category, though the b-selectivities with respectto the zinc-mediated reactionare moderate. As speculated inthe research with 24, THF onthe Mg in complex 28 maycreate an effective steric shieldaround the a-carbon (see struc-ture to the left). This consider-ation may apply to the zinccase performed in THF. In thecase of 27, bulkiness of the [ReCl2 ACHTUNGTRENNUNG(PMe2Ph)3] part may ar-range such a steric environment. The b-selectivities observedin the three reactions may therefore be ascribed, at least inpart, to the steric hindrance induced by the metal–ligand or–solvent moiety.

By Harman and co-workers, b-selective alkylation of h2-pyrrole–osmium(II) complex 29 has been achieved upontreatment with a range of alkylating agents (Scheme 18).[49]

The complex (29) is readily prepared from [OsIII-ACHTUNGTRENNUNG(NH3)5OTf]ACHTUNGTRENNUNG(OTf)2 (Tf =SO2CF3) and N-methylpyrrole inthe presence of magnesium metal. The h2 coordination dis-rupts delocalization of p electrons in the pyrrole ligand,thereby inducing enamine character to the pyrrole.[50] Thisaspect, which is thus the “trick” in this system, effectively af-fects the b-alkylation toward the pyrrole ring. Alkylatingagents include aldehydes, ketones, Michael acceptors, acetals

Scheme 14. Examples on direct b-alkylation of N-TIPS–pyrrole (17).Ac= COMe. Boc=CO2tBu.

Scheme 15. Synthesis of N-TIPS–b-alkylpyrroles 22.

Scheme 16. Palladium-catalyzed synthesis of N-TIPS–b-alkylpyrroles 23.dppf =1,1-bis(diphenylphosphino)ferrocene.



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and alkyl triflates. When these alkylating agents are used,3H-pyrrolium species 30–35 are quite stable, and moderateexternal bases such as amines must be used to achieve re-ar-omatization (e.g., 35 to 37). Due to the stability of these3H-pyrrolium systems, these reactions are negative to suchundesired reactions as multiple alkylation and polymeri-zation. In the use of a hard electrophile like methyl triflate,the alkylation at the nitrogen atom is competitive with theb-alkylation (35 vs 36). The b-alkylated pyrrole can be re-moved from the osmium metal simply by heating.[49b] Withthis chemistry, selective b-alkylation of an osmium–nitrogen-unsubstituted pyrrole complex is difficult since the alkyla-tion is most likely to occur at the nitrogen atom. An asym-metric variant with the same strategy has been reported alsoby the Harman�s group.[51]

Use of Simple Pyrroles: Indium-CatalyzedReductive Alkylation with Alkynes or Carbonyl

Compounds as Alkyl Group Suppliers

Recently, we have established a conceptually new strategyto introduce diverse alkyl groups onto pyrroles with perfectb-selectivity. Under indium catalysis, the strategy can be per-formed readily by a simple mixing of N-substituted pyrroles39, Et3SiH and either alkynes 38

[52] or carbonyl compounds(see below).[53] The alkyne-based reaction, which has beendeveloped prior to the reaction of carbonyl compounds, isthe first example of catalytic b-alkylation of pyrroles in asingle step. At first, we present the details of the alkyne-based reaction. The origin of the “trick” for the reaction isin our own previous research, which is the indium-catalyzeddouble addition of 39 to 38.[54] Our original idea proposed asthe working hypothesis is shown in Scheme 19. The impor-tant aspect is that b,b’-adducts 41 are formed selectivelyover other two isomers, that is, a,b’-adducts 40 and a,a’-ad-ducts in the double addition reaction.[55] This interesting andunusual selectivity is responsible for the thermodynamic sta-bility of 41, whose steric repulsion between the two pyrrolylgroups is the least among the three isomers, as shown at thebottom in Scheme 19. During the course of the mechanisticstudies on the isomerization between 40 and 41, we envis-aged that in situ trapping of cationic intermediate 42 with ahydride reagent would allow to develop an innovative one-step strategy for synthesizing b-alkylpyrroles 43.

Scheme 17. Examples of b-selective alkylation with N-metal–pyrrole spe-cies. Tf=SO2CF3.

Scheme 18. Synthesis of osmium complex 29 and its reaction with alkylat-ing agents. a) PhCHO, TBSOTf, MeCN, RT, 5 min; b) EtCOEt, TBSOTf,MeCN, RT, 0.5 min; c) CH2 =CHZ, TBSOTf, MeCN, RT, 5 min, andthen H2O; d) PhCH ACHTUNGTRENNUNG(OMe)2, TBSOTf, MeCN, RT, 5 min; e) MeOTf,DME, RT; f) PrNH2. [Os]= [Os

II ACHTUNGTRENNUNG(NH3)5] ACHTUNGTRENNUNG(OTf)2. TBS = tert-butyldime-thylsilyl. DMA =N,N-dimethylacetamide. DME =1,2-dimethoxyethane.

Scheme 19. Working hypothesis for b-alkylation of N-substituted pyrrolesunder indium catalysis, and relative stability of dipyrrolylalkanes. [In]=indium ACHTUNGTRENNUNG(III) salt.


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The results acquired by applying our concept are summar-ized in Scheme 20. The b-alkylation can be performed byeither method A or B, depending on the structure of R1 and

R2. Method A is the simple procedure allowing the simulta-neous treatment of 38, 39 and Et3SiH with the indium cata-lyst. In method B, 38 and 39 are pretreated with the catalystbefore the reduction with Et3SiH. With these two proce-dures, regiospecific b-alkylation by various combinations ofsubstrates is feasible. The internal alkyne, 4-octyne, is alsoavailable, albeit requiring higher loadings of the pyrrole andindium catalyst at the higher temperature, compared to thestandard conditions (Scheme 21). It is definitely worthnoting that all of the reactions proceed with perfect b-selec-tivity.

The one-step strategy does not work well for pyrrole(R2 =H in 39). However, a two-step strategy is reliable inthis situation. Thus, the first step is the b-alkylation of N-benzylpyrrole 39 a by method A or B. With the desired alkylgroup in place, the benzyl group is removed with a low-valent titanium reagent, giving nitrogen-unsubstituted b-al-kylpyrroles 44 (Scheme 22).

Besides the hydride nucleophile, 2-methylfuran andMe3SiCN can be used as carbon nucleophiles [Nu(C)] forextension of a carbon�carbon bond, where method B usingIn ACHTUNGTRENNUNG(OTf)3 as a catalyst is effective.[56] The representative re-sults are collected in Scheme 23. Although a-alkylpyrroles

46 are slightly co-produced in the reaction of N-methylpyr-role with 2-methylfuran, the selectivity can be improved en-tirely by replacing N-methylpyrrole with pyrroles bearingthe bulkier substituent (R2 =Bn, tBu, Ph) on the nitrogenatom. Scheme 23 shows only the benzyl case. The syntheticreaction of the furylpyrrolylalkane can be regarded as sub-strate-selective double addition in which each one moleculeof a pyrrole and a furan adds to an alkyne. This is the firstexample of the assembly of alkynes and two different heter-ocyclic arenes.

In spite of the outstanding simplicity of the alkyne-basedb-alkylation, the scope of alkynes 38 is restricted mainly toterminal alkynes, the terminal carbon of which is inevitablyincorporated just as the methyl group into product 43. Wetherefore envisioned that replacing 38 with carbonyl com-pounds 47 would drastically extend the diversity of alkylgroups installable onto 39, giving 48 (Scheme 24).[53] More-over, it was expected that the use of 47, which is cheaper ingeneral than 38, would make the process highly attractiveand practical.

The procedures, method A and B, employed for the pre-ceding research are applicable also to this case, simply by al-tering 38 to 47, and the results are summarized inScheme 25. As well as the simple alkyl chain, the cyclicstructure that is inaccessible from alkynes can be treatedwith ease. A range of functional groups, sulfide, ester, alken-yl, boryl, cyano and alkoxy, are compatible with the strategy.One of the major highlights herein is to ensure the access to

Scheme 20. Indium-catalyzed reductive b-alkylation of N-substituted pyr-roles with alkynes and Et3SiH. 38 (0.500 mmol), 39 (1.50 mmol formethod A or 2.00 mmol for method B), Et3SiH (0.750 mmol), InX3(0.125–0.150 mmol, 25–30 mol %), 1,4-dioxane (1.0 mL). See ref. [52] andits Supporting Information for further details. PI=phthalimidoyl. Bn=benzyl. Nf =SO2C4F9.

Scheme 21. Indium-catalyzed reductive b-alkylation of N-methylpyrrolewith 4-octyne. 4-Octyne (0.500 mmol), N-methylpyrrole (7.50 mmol),Et3SiH (0.750 mmol), InACHTUNGTRENNUNG(ONf)3 (0.175 mmol), H2O (50.0 mmol).

Scheme 22. Synthesis of nitrogen-unsubstituted b-alkylpyrroles 44. a)TiCl3 (2.0 equiv), Li (13 equiv), I2 (1.0 equiv), THF, RT, 16 h.

Scheme 23. Indium-catalyzed synthesis of b-alkylpyrroles 45 incorporat-ing carbon nucleophiles [Nu(C)= 2-methylfuran, Me3SiCN]. 38(0.250 mmol), 39 (1.00 mmol), Nu(C) (0.750 or 1.00 mmol), In ACHTUNGTRENNUNG(OTf)3(62.5 mmol), 1,4-dioxane (0.7 or 2.0 mL). See ref. [56] and its SupportingInformation for further details.



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the primary alkyl group that is impossible to handle in thealkyne variant. The carbon nucleophiles such as Me3SiCN,2,3-dimethylthiophene and 4-vinylanisole also participatewell in this reaction (Scheme 26). Using these nucleophilesenables installation of the tertiary alkyl unit onto the b-posi-tion of 39. Worthy of note is that regioselectivities on pyr-role rings are perfectly controlled in all the cases.

Nitrogen-unsubstituted b-alkylpyrroles 50 are easily acces-sible also in this case, by employing the same procedure pre-sented in Scheme 27. As can be seen from Schemes 25–27,the special emphasis in this research is that the indium-cata-lyzed b-alkylation combined with the de-benzylation canoffer all six variations consisting of nitrogen-substituted and-unsubstituted b-alkylpyrroles 48–50 with primary, secon-dary and tertiary alkyl groups.

Despite that a,b’-dipyrrolylalkanes 51, which possibly leadto a-alkylpyrroles 55 by the elimination of the b-pyrrolylring, exist in the reaction mixture before the trapping withnucleophiles,[52–56] a natural question is why no 55 is formed

in this strategy. On the basis of experimental results, we canprovide the most plausible interpretation for the question.In both the methods with alkynes and carbonyl compounds,the first step surely affords an isomeric mixture of dipyrroly-lalkanes, among which b,b’-isomers 52 predominate. Afterthis stage, the exclusive generation of b-alkylpyrroles 56 isascribed to two synergistic effects as shown in Scheme 28,

Scheme 24. Indium-catalyzed reductive b-alkylation of N-substituted pyr-roles: Alkynes versus carbonyl compounds as sources of alkyl groups.

Scheme 25. Indium-catalyzed reductive b-alkylation of N-substituted pyr-roles with carbonyl compounds and Et3SiH. 47 (0.30 mmol), 39 (0.90–1.2 mmol), Et3SiH (0.45 mmol), InX3 (30–75 mmol, 10–25 mol %), 1,4-di-oxane (0.50 mL). See ref. [53] and its Supporting Information for furtherdetails. [B] =B(pinacolate). Cumyl=2-phenylisopropyl.

Scheme 26. Indium-catalyzed synthesis of b-alkylpyrroles 49 incorporat-ing carbon nucleophiles [Nu(C)=Me3SiCN, 2,3-dimethylthiophene, 4-vi-nylanisole]. 47 (0.250 mmol), 39 (1.00 mmol), Nu(C) (0.375 or0.750 mmol), In ACHTUNGTRENNUNG(NTf2)3 (37.5–50.0 mmol), 1,4-dioxane (0.25 mL).Scheme 27. Synthesis of nitrogen-unsubstituted b-alkylpyrroles 50. a)TiCl3 (2.0 equiv), Li (13 equiv), I2 (1.0 equiv), THF, RT, 16 h.

Scheme 28. Possible routes from 51 and 52 to products 55 and 56. [In]=indium ACHTUNGTRENNUNG(III) salt. Nu=nucleophile.


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where the possible routes from 51 and 52 are depicted. Thefirst significant effect is the dominant formation of 54 beingmuch more stable than alternative cationic species 53, whichhave 1,3-allylic-type strain between R2 and R3. The secondis higher leaving ability of the a-pyrrolyl group to the b-pyr-rolyl group. Since 52 with two b-pyrrolyl groups inevitablyleads to only 56, the above two effects play crucial roles es-pecially in the process of the transformation of 51. The plau-sible reaction mechanism is thus provided in Scheme 29.

The indium ACHTUNGTRENNUNG(III) salt {[In]} first assembles alkynes 38 or car-bonyl compounds 47 and pyrroles 39 into dipyrrolylalkanes57, one pyrrolyl group in which coordinates to the [In] andthen eliminates to give cationic species 54 exclusively, viathe C ACHTUNGTRENNUNG(sp3)�C ACHTUNGTRENNUNG(pyrrolyl) bond cleavage. The trapping of 54with nucleophiles (Nu) leads to final products 56.

Summary and Outlook

In summary, it was found that the strategies on b-alkylationof pyrroles via the SEAr process can be classified into fivemajor categories. In each strategy, the unique “trick” oper-ates nicely to direct electrophiles toward the b-site of pyr-roles. Prior to disclosing our new system in 2009, the meth-odology starting with the b-acylation of N-As–pyrrolesseems to have been the primary contributor to offer b-alkyl-pyrroles, probably due to its reliability of providing thetarget structure and moderate scope of substrates. However,requiring the multi-step as well as the stoichiometricamount of promoters has remained issues to be improved.In contrast to such classical approaches including others, wehave achieved, for the first time, the catalytic synthesis of b-alkylpyrroles in a single step with the aid of an indium salt.This conceptually novel strategy includes the following sali-ent features: 1) broad scope of substrates, 2) remarkablefunctional group compatibility, and 3) perfect b-selectivities.With carbonyl compounds as alkyl group suppliers, all varia-tions, that is, primary, secondary and tertiary alkyl units canbe installed in place onto the pyrrole ring. Although the de-benzylation and de-cumylation guide us to nitrogen-unsub-stituted b-alkylpyrroles, at present, their direct synthesiswith high yields and b-selectivities unfortunately appears to

be beyond the scope of our strategy. Accordingly, elegantcatalytic one-step synthesis of nitrogen-unsubstituted b-al-kylpyrroles from pyrrole remains a challenge for the future.

Finally, I hope that this Concept article will help stimulatethe relevant research in this field so that innovative findingswith practicality and simplicity are made in the comingyears.

Acknowledgements

Our research described herein was supported in part by a Grant-in-Aidfor Scientific Research (No. 21750107) from the Ministry of Education,Culture, Sports, Science and Technology, Japan. Partial financial supportfor our research from Nissan Chemical Industries, L.T.D. is gratefully ac-knowledged. We also acknowledge Shin-Etsu Chemical and MitsubishiMaterials for their generous support of our research.

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Scheme 29. A plausible reaction route. [In]= indium ACHTUNGTRENNUNG(III) salt. Nu =nucle-ophile. In the use of 38 as starting substrates, R3 in the intermediate andproduct is Me. [a] In the use of 47 as starting substrates, H2O is formed.



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[55] For example, upon treatment of 1-octyne and N-methylpyrrole withIn ACHTUNGTRENNUNG(OTf)3 (10 mol %), a 85:15 mixture of the corresponding b,b’- anda,b’-adducts is produced. No a,a’-isomer is thus formed. Use of pyr-roles with bulkier substituents on the nitrogen atom leads to higherselectivity of 41. For further details, see reference [54].

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Published online: March 14, 2011


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