Pyrroles electrophilic cyclization

Intramolecular electrophilic cyclization of methyl selenoate gives only a 12% yield of benzo[/]pyrrolo[2,l- ][l,3]thiazepin-9(10H)-one 285, while cyclization of an acetate derivative under a variety of the conditions failed (Scheme 61 (1998JMC3763)). An alternate route from pyrrole ketones 286 by oxidation and TFAA induced cyclization proved to be advantageous providing a 40% yield of 285. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

In the first step, the fairly acidic proton on CIO of the red biladiene-ac salt 6 is abstracted and, even in solution in polar solvents, the salts are converted into the corresponding yellow bilatriene-u/ic salts 7. With a base such as piperidine, the salts 7 form the green bilatriene-a/>e free base. For further reaction to the porphyrin it is important that the salts 7 are oxidized to the bilatriene enamines 8 which cyclize via the electrophilic carbon of the terminal pyrrole ring by the loss of the leaving group X to 9. Porphin (10) is finally obtained by the loss of... 

An approach to isobacteriochlorins1 ln-e makes use of Pd(II) or metal-free bilatrienes 1 as starting materials. Cyclization of the corresponding bilatriene derivatives is induced by base in the presence of palladium(II) or zinc(II) which exercise a template effect. Zinc can be readily removed from the cyclized macrotetracycles by acid whereas palladium forms very stable complexes which cannot be demetalated. Prior to the cyclization reaction, an enamine is formed by elimination of hydrogen cyanide from the 1-position. The nucleophilic enamine then attacks the electrophilic 19-position with loss of the leaving group present at the terminal pyrrole ring. 

Electronic factors also influenced the outcomes of these cyclization reactions cyclization of pyrrole 84 to bicyclic amine 85 is catalyzed by the sterically open complex 79a. In this reaction, initial insertion into the Y - H bond occurred in a Markovnikov fashion at the more hindered olefin (Scheme 19) [48]. The authors proposed that the Lewis basic aromatic ring stabilizes the electrophilic catalyst during the hydrometallation step, overriding steric factors. In the case of pyrroles and indenes, the less Lewis basic nitrogen contained in the aromatic systems allowed for the cyclization of 1,1-disubstituted alkenes. 

The foregoing examples show that the nucleophilic attack to nitroarenes at the o>T/ o-position followed by cyclization is a general method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion derived from ethyl isocyanoacetate as the reactive anion for the preparation of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyrimidines depending on the structure of nitroarenes (Eqs. 9.56 and 9.57).89 The synthesis of pyrroles is discussed in detail in Chapter 10. 

Two sequential lithiations and treatments with different bifunctional electrophiles make possible one-pot syntheses of relatively complex molecules. Thus, in the [1+2+2] annulation depicted in Scheme 69, alkylation of 1-benzylbenzotriazole 399 with 2-bromoacetaldehyde diethyl acetal to give intermediate 426 is followed by alkylation with W-benzylideneaniline to produce derivative 427. Following treatment with formic acid causes cyclization to ethoxypyrrolidine 428 that subsequently eliminates ethanol and benzotriazole to give pyrrole 429 <1997JHC1379>. 

In a similar fashion, hydroformylation of N-allyl-pyrrols leads to 5,6-dihydroindolizines via a one-pot hydroformylation/cyclization/dehydration process (Scheme 27) [81,82]. The cyclization step represents an intramolecular electrophilic aromatic substitution in a-position of the pyrrole ring. This procedure was expanded to various substrates bearing substituents in the al-lyl and in the pyrrole unit. 

Intramolecular electrophilic reactions of substituted pyrrole-2-carboxylic acids or their amides lead to benzo[d]pyrrolo[l,2-a]azepinones. Acid 70 in this fashion undergoes Fiiedel-Crafts cyclization to furnish fused azepine 71 in good yield (Equation (6) (2000JOC2479)). 

The oldest methods for synthesis involve the condensation-cyclization of trifluor-omethyl or fluoroalkyl pyrroles in the presence of a metal salt. These reactions afford tetrakis(fluoroalkyl) porphyrins. The electrophilic trifluoromethylation of porphyrins is selective and leads to /I-CF3 and meso-CVT, porphyrins. While condensation of meio-trifluoromethyl-dipyrromethane with an aldehyde in acidic medium is rather difficult, it proceeds with better yields and permits a selective introduction of trifluoromethyl groups in meso The Ruppert reagent (CF3TMS) has been used to... 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

Another pyrrole cyclization involves nucleophilic addition of amines to electrophilic 1,3-dienes, e.g. 2,3-diphenylsulfonyl-1,3-butadiene and 2-acetyl-3-phenylsulfonyl-1,3-butadiene (88TL3041, 9ism). 

Although it is more usual to obtain the halogenoacyl derivatives of pyrrole and indole by direct acylation (see Section 3.05.1.2.6), it is possible to carry out electrophilic halogena-tion of acylindoles <79HC(25-3)357). 3,4-Diacetyl-l,2,5-trimethylpyrrole has also been reported to react with phenyltrimethylammonium tribromide to give the 3,4-bis(bromoacetyl) derivative, which cyclizes in the presence of a zinc-copper catalyst to yield 4,5,6,7-tetrahydro-l,2,3-trimethyl-4,7-dioxoisoindole (74CC1034). 

The prototype reactions for synthesis of pyrrole, indole and carbazole by processes involving electrophilic nitrogen are outlined in Scheme 3 with a nitrene as the electrophilic form of nitrogen. This conceptual scheme must be generalized to include nitrenoids and nitrene equivalents to accomodate the range of cyclizations which can proceed by this mechanism. In practice, this mechanistic pattern is rare for pyrroles, known but only of moderate utility for indoles, and among the most efficient methods for the synthesis of carbazoles. 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

The intermediates which are assumed to be involved in the Knorr cyclization can also be prepared by addition of a-amino ketones to electrophilic alkynes (equation 77). This methodology has found use primarily with dimethyl acetylenedicarboxylate to form pyrrole-2,3-dicarboxylate esters (equation 77), but methyl propiolate is also reactive (68T1567,69T527, 64JA107, 62JOC3346). 

The cyclization steps are facilitated by the ready susceptibility of the pyrrole ring to electrophilic attack. Step-wise approaches such as these give much better yields than attempts at cyclizative annelation of pyrroles with potentially bifunctional reagents. For example, the cyclizative condensation of pyrrole with 2,5-hexanedione, which gives 4,7-dimethylindole (equation 138), is plagued with by-product formation to the extent that the indole is obtained in only 28% yield (68AJC2053). 

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

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