Aryl-substituted pyrroles

The Paal-Knorr cyclization was employed to produce highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads. Therefore, l,4-diketone-2,3-diester was assembled from an Sn2 displacement of ethyl 2-bromoacetoacetate with the anion of the ketoester. Condensation with an aniline then provided a library of fully substituted pyrroles. 

Lautens and Hulcoop developed a Pd-catalyzed annula-tion of 3-aryl substituted pyrroles to yield indoles, following retro-Diels-Alder loss of cyclopentadiene (Scheme 2, equations 1 and 2) [4]. Miura, Satoh, and coworkers found that indoles were formed from Af-methylpyrrole-2 carboxylic acid and alkynes as catalyzed by palladium (equation 3) [5, 6]. The indoles themselves undergo this oxidative coupling with alkynes to form octa-substituted carbazoles, e.g.4[6]. 

Modification of the initial route also allowed the preparation of 2-aryl-substituted pyrroles. The aryl pyrrole motif occurs in various natural products such as in the broad-spectrum antibiotic pyrrolonihin and in the insecticide dioxapyrrolomycin. Therefore, new routes to these structural types are always important. For example, immobilized reagents and scavengers may conveniently be used to prepare a hbrary of 3-aryl-substituted pyrroles as shown in Scheme 6.6. 

SCHEME 6.6 Preparation of a library of 3-aryl-substituted pyrroles. 

Pyrroles are very sensitive to the action of singlet oxygen ( O2). Wasserman (1970) has observed a novel type of oxidation in the case of aryl-substituted pyrroles exemplified by the photooxidation of 2,3,4,5-tetraphenylpyrrole in methanol. There is special interest in the reactions of imidazoles with O2 since it has been shown that photooxi-dative inactivation of certain enzymes involves destruction of histidine residues, and more specifically oxidation of the imidazole ring (Wasserman and Lenz). These heterocyclic system behave in many respects like furans and pyrroles, but are more prone to cleavage through reactions resembling the oxidation of enamines by 02 (Wasserman et al. 1968). 

In 1999, Mederski s group [93] at Merck preclinic2il pharmaceutical research published an account on the application of this method for the synthesis of Af-aryl-substituted pyrrole- and indole-2-carboxylic esters. These intermediates were important for the synthesis of factor Xa antagonists. 

The aerobic dehydrogenative annulation of 2-aryl-substituted pyrroles and indoles for a variety of alkynes, using the system ruthenium(Il) catalyst with oxidant Cu(0Ac)2.H20, was then reported. The reaction was now performed under ambient air as the ideal sacrificial oxidant, thus only 10 mol% of Cu (0Ac)2.H20 could be used for efficient transformations of indoles [(Eq. 89)] [178]. This method could also be applied to synthesize pyrrolo[2,l-a]isoquinolines from 2-arylpyrroles with dialkyl-, diaryl-, or alkylarylacetylenes with an excellent regioselectivity. The competition experiments showed that an electron-deficient alkyne favours this reaction and that the more acidic C-H bond activation is favoured [(Eq. 89)] [178]. 

Interestingly, it was found that the indole core could be successfully extended to pyrrole-derived systems. For example, A/-aryl-substituted pyrrole 229 smoothly reacted with n-butyl acrylate 227a affording the corresponding cyclized product in 60 % yield (Scheme 3.71). 

The reaction allows not only diverse 2- and 2,3-substituted pyrroles but also their N-vinyl derivatives to be synthesized. Naturally, yields of the products depend on the structure of initial reactants and the reaction conditions, but in the case of simple ketoximes, they are quite constant and range 70%-95% under optimal conditions. Apart from alkyl- and aryl-substituted pyrroles, other hitherto hardly available or even unknown pyrroles became accessible. 

One pot reaction for the synthesis of aryl substituted pyrrole derivatives from but-2-ene-l,4-diones and but-2-yne-l,4-diones via Pd/C-catalyzed hydrogenation of the carbon-carbon double bond/triple bond followed by amination-cyclization has been studied by Rao et al. (2004). 

The synthesis will therefore normally produce a 2,4-substituted pyrrole, with in addition an ester group or an acyl group at the 3-position, if a keto ster or a diketone respectively has been employed, and an ester group or an alkyl (aryl) group at the 5-position, according to the nature of the amino-ketone. 

There are examples of preferential arylation of Af-substituted pyrroles, thiophenes and furans in the 2-position. A preparatively useful reaction of this type is the o-nitrophenylation of thiophene (Scheme 40). A phase transfer catalytic technique has been recommended for this reaction (77TL1871). 

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). 

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. 

These workers have also used 3-iodopyrrole 103 to prepare the corresponding tin derivative 104 for Stille couplings to furnish 3-arylpyrroles 105 [78], These pyrrole derivatives are important for the synthesis of (i-aryl-substituted porphyrins for studies of heme catabolism. Also synthesized in this study were compounds 106 and 107 [78]. 

Although the heteroaryl Heck reactions of chloropyrazines with pyrrole itself were low-yielding for both mono- and bis-arylation products, better yields were obtained for N-phenylsulfonylpyrrole. Bulkier alkyl substituents on the pyrazine ring promoted the formation of C(3)-substituted pyrroles. The C(3)-substituted pyrrole 64 was the major product (62%) for the coupling of 1 and Al-phenylsulfonylpyrrole, while C(2)-substituted pyrrole 63- was a minor product (15%). 

Metten B, Kostermans M, Van Baelen G, Smet M, Dehaen W (2006) Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles. Tetrahedron 62 6018-6028... 

Benzo[4,5]furo[3,2- ]pyrrole 86 and benzo[4,5]thieno[3,2- ]pyrrole 87 were used for the synthesis of new constrained aryl-substituted 4,4-difluoro-4-bora-3a,4a-diaza-r-indacene (BODIPY) dyes 86 and 89 <2000JOC2900>. Their fluorescence characteristics were investigated and compared with the unconstrained systems published by Burghart and co-workers (Scheme 8) <199881276, 1999JOC7813>. 

Certain polyaryl-substituted pyrroles can be prepared by condensation of a benzoin and a benzyl aryl ketone with ammonium acetate (equation 128) (38JOC361, 71ZOR1264). The details of the mechanism are not known but one assumes enamines are involved and that the carbonyl and hydroxymethylene oxidation level of the benzoin are probably interconvertible via an enediol or related substance. A possible formulation is given in Scheme 15. 

The lithium derivatives of 1-substituted pyrroles and indoles provide another general route of access to 2-acyl pyrroles and indoles. The ketones can be obtained directly by reaction with aryl nitriles or acid halides but, at least for 1-benzenesulfonylindole, a two-step procedure involving reaction with an aldehyde followed by oxidation of the carbinol to the ketone is frequently more convenient (equation 179) (73JOC3324, 75JOC2613). This method is probably the most general route to 2-acylindoles, although many have also been prepared by direct Fischer cyclization (see Section 3.06.3.4.2). 

Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2//-pyrroles with moderate to good yields.68 The Pt(II)-or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3-dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4C104-Taniaphos with nearly complete exo- selectivity and enantioselec-tivities up to 85% ee.10 The 3 + 2-cycloaddition of benzol/>]thiophene 1,1-dioxide... 

Ravikanth and coworkers have synthesized (S-pyrrole-substituted 21,23-dithiaporphyrins by refluxing 21,23-dithiaporphyrin with NBS in chloroform. (5-Aryl-substituted thiaporphyrin 238 (Scheme 94) has been obtained by condensing 3,4-disubstituted pyrroles 237 with thiophene diol 222 (X=S) under mild acid conditions (00CL480). 

M., Artico, M., Corelli, F., Forte, M., Caporuscio, F., Angiolella, L., Palamara, A.T. Antifungal agents. 11. N-substituted derivatives of l-[(aryl)[4-aryl-lH-pyrrol-... 

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