Pyrroles alkenylation

Scheme 7.55 The protective group at nitrogen as a regiochemical switch in intramolecular pyrrole alkenylations.

A protecting group strategy was employed by Gaunt and co-workers to control the regioselectivity of oxidative palladium(ll)-catalyzed pyrrole alkenylation (Scheme 10.3). When pyrrole was substituted with a Boc group (10), its natural reactivity... 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Photolysis of (Z)-3-phenyl-2-(2-phenylvinyl)-2//-azirine (1) in benzene solution yields 1-phenyl-3//-2-benzazepine (2) in excellent yield.39 However, the stereochemistry of the alkenyl side chain and the solvent used are important in determining the outcome of the reaction. For example, the E-isomer of the 2//-azirine 1 on photolysis in benzene solution yields 2,3-diphenyl-pyrrole as the major product (85 %) the pyrrole is also obtained on heating the Z- or E-isomer in benzene solution. In contrast, irradiation of the Z-isomer in methanol yields only acyclic products. 

Fischer alkenylcarbene complexes undergo cyclopentannulation to alkenyl AT,AT-dimethylhydrazones (1-amino-1-azadienes) to furnish [3C+2S] substituted cyclopentenes in a regio- and diastereoselective way along with minor amounts of [4S+1C] pyrrole derivatives. Enantiopure carbene complexes derived from (-)-8-(2-naphthyl)menthol afford mixtures of trans,trans-cycloipentenes and ds,ds-cyclopentenes with excellent face selectivity [75]. The mechanism proposed for the formation of these cyclopentene derivatives is outlined in Scheme 28. The process is initiated by nucleophilic 1,2-attack of the carbon... 

The Cacchi group [85] developed a Pd-catalyzed domino process between o-alky-nyltrifluoroacetanilides as 6-157 and aryl or alkenyl halides, which leads to substituted pyrroles within an indole system. This scheme was successfully applied to the preparation of indolo[2,3-a]carbazoles as 6-158 using N-benzyl-3,4-dibro-momaleimide (Scheme 6/1.42). The indolocarbazole is found in several bioactive natural products as arcyriaflavin A and the cytotoxic rebeccamycin. 

Nitrodienes19 and nitrotrienes20 can be used in Leusen-pyrrole synthesis to give 3-alkenyl-4-nitropyrroles or 2-alkenyl-3-alkadienyl-4-nitropyrroles, as shown in Eqs. 10.15 and 10.16, respectively. 

A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of IV-substitution with bulky groups directing to C-3. The oxidative alkenylation of (V-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the (V-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

A similar reaction of pyrroles 20 with acrylates provides the C-2 substituted a-alkenyl derivatives 21 in 24-91% yield [29]. The 2,6-dichlorobenzoyl protecting group is noteworthy as it prevents cyclization of the phenyl group onto the pyrrole ring (vide infra). 

Alkenyl and alkynyl Fischer carbene complexes reacted with pyrrole imine 108 to give, through a 1,2- and 1,3-metal migration, respectively, indolizine derivatives at a different level of unsaturation (Scheme 29) <1999JA3065>. 

Regioselective fluorodestannylation of alkenyl and heteroaryl molecules to give 34 can be achieved under mild conditions with cesium fluoroxysulfate, while x-fluoro ketones, e.g. 35, are formed when the tin group is attached to the benzylic position.42 The pyrrole ring in indole derivatives is also successfully fluorinated using this method, e.g. formation of 36.42-45... 

Pyrroles can be a-alkenylated by acetylenedicarboxylic ester, as discussed in Section 3.3.1.8.1. 

Catalytic reduction of the C-alkenyl and -alkynyl substituents over palladium or Raney nickel can be effected without concomitant hydrogenation of the heterocyclic system to give the corresponding alkyl-pyrroles and -indoles (72HC(25-2)65, B-77MI30504). 

The one-stage transformation of 3-butenyl-l-methyl ketoxime (63) to 2-methyl-3-(2-propenyl-l)pyrrole (64) and 2-methyl-3-(l-propenyl-l)-l-vinylpyrrole (65) (Scheme 34) (82TL5063) is typical and demonstrates two essential features of this version of the reaction the reaction either can be stopped selectively at the stage of pyrrole ring formation without vi-nylation onto the N—H bond and prototropic isomerization of the alkenyl, or it can form an N-vinylpyrrole in which the double bond of the alkenyl is shifted into conjugation with the pyrrole ring. 

The nonvinylated pyrrole 64 with nonisomerized alkenyl radicals can be obtained at the reaction temperature not exceeding 100°C by heating no more than 1 hr with a slight excess of acetylene under 3-7 atm. The synthesis of this pyrrole can also be performed under atmospheric pressure by passing acetylene through the reaction mixture upon stirring. In... 

Representatives of Alkenyl and Cyclopropyl Pyrroles Derived from Alkenyl and Cyclopropyl Ketoximes... 

RC=CKWG) yields 2,4-di-EWG-substituted pyrroles in the presence of copper catalyst but 2,3-di-EWG-substituted pyrroles in the presence of a phosphine catalyst.74 The 3 + 2-cycloaddition of diazoalkanes to (6 )-3-p-tolylsulfinylfuran-2(5//)-one produces diastereoisomeric pyrazolines in almost quantitative yield and with des >98%. (g) The sulfinyl group is responsible for the complete control of the n-facial selectivity in all these reactions.75 The Rh(II)-catalysed intramolecular 1,3-dipolar cycloaddition reaction of diazoamides (57) with alkenyl and heteroaromatic n -bonds yields pen-tacyclic compounds (59), via the ylide (58), in good to excellent yields and in a (g) stereocontrolled manner (Scheme 15).76... 

In CHEC-II(1996), several applications of dihydro-2//-l,2,3-diazaphospholes, generated in situ from a ketone hydrazone and PC13, as useful intermediates for the synthesis of indoles, pyrroles, pyrrolylacetates, and 1,2-di-hydro-2-alkenyl-37/-pyrazol-3-ones are listed <1996CHEC-II(4)771>. 

Photocycloisomerization of Boc-protected 5-alkenyl-2,5-dihydro-l H-pyrrol-2-ones. Helvetica Chimica Acta, 86, 515-521. 

Pyrroles can be -alkenylated by reaction with acetylenedicarboxylic ester, for example, to give an /Z mixture (1 3.3) of alkenes 110 (Scheme 48) <2006JOC7793>. 

A process that can be regarded as a vinylogous Vilsmeier reaction, is a further means to access alkenylated pyrroles, e.g., Scheme 50 <1996M77>. 

The reactions of 1-vinyl- (R = H) and Tprop-2-enyl- (R = Me) substituted tetrahydroindoles 690 with tetracyano-ethylene in equimolar amounts in DMSO afforded 3-tricyanovinyl-substituted derivatives 691 as the only products (Equation 166) <2001ARK37>. Hence, the iV-alkenyl substituent in the pyrroles does not react with tetracyanoethy-lene according to the [2-1-2] cycloaddition mechanism typical of other 1-vinyl-substituted heterocyclic compounds. 

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