Dihydropyrroles from pyrroles

Coupled intermolecular hydroaminations and intramolecular cycUzations give pyrroles resulting from isomerization of the initially formed exomethylene dihydropyrrole derivatives (Eq. 4.85) [137]. 

Methoxyethyltosylamide also participates in the [3 -I- 2] addition reaction with 102, although it does not give any of the expected dihydropyrrole derivative 104. Instead, the major product was found to be pyrrole 105, which presumably results through ready elimination of methanol from the putative intermediate 104. Thus, this addition holds promise for the synthesis of 2-substituted tosylpyrroles (Scheme 29). In addition to 105, a minor product 106 (12%) is also formed in this reaction. 

The relative importance of through-bond (hyperconjugative) and through-space (homoconjugative) interactions between the heteroatom and the double bond in 2,5-dihydro-furan, -thiophene and -pyrrole has been the subject of a CNDO/S study (76ZN(A)215). This analysis concluded that the proportion of through-space interaction increased from 19% in the dihydrofuran and 20% for dihydrothiophene to 83% for the dihydropyrrole (cf. Section 2.3.3.9). 

Despite the isolation of O-vinyloximes from the products of reaction of ketoximes with acetylene, and the demonstration of their conversion to pyrroles by superbase KOH/DMSO (see Section IV.A), the suggested (81MI4) intermediate stages of this rearrangement long remained unproved. The intermediate 4//-2-hydroxy-2,3-dihydropyrroles (94) (Scheme 45) were first isolated by Trofimov et al. (83KGS276). 

The corresponding 2-hydroxy-2,3-dihydropyrrole (94a), the product of rearrangement of the O-vinyloxime 93a (see Section IV.B), is converted to the 3//-pyrrole 97 under the conditions of the reaction with acetylene (85KGS1573), and this provides more evidence for the O-vinyloxime route to pyrroles from ketoximes and acetylene. 

Toxicity has been demonstrated in analogues of pyrrolizidine alkaloids with a pyrrole or dihydropyrrole ring. The vascular changes in the lungs of rats after intravenous injection of pyrrole carbamates have been reported.60 The distribution of radioactivity in rats given tritium-labelled synthanecine A (16) bis-N-ethyl-carbamate and bis-hydroxymethyl-l-methylpyrrole has been studied.61 Biliary excretion is important for the disposal of pyrrolic metabolites from retrorsine and synthanecine A bis-N-ethylcarbamate, but not for the parent compounds.62... 

Dihydropyrroles, e.g., 214, are formed on the reduction of pyrroles and simple alkylpyrroles with zinc and acid. These are derived from the corresponding -protonated species. 

The synthesis of )-A -BOC-2-hydroxymethyl-2,5-dihydropyrrole )-923 with ee up to 98% was achieved by its irreversible acetylation catalyzed by Pseudomonas fluorescens lipase (Scheme 179) <1998TA403>. Precursor ( )-922 for compound 923 can be easily prepared from commercially available pyrrole-2-carboxylic acid 921 by Birch reduction, followed by esterification and reduction according to literature procedure <1996JOC7664>. 

In the presence of triethylamine, enaminones 11 are synthesized in high yields from the corresponding amino ester or amino nitrite hydrochlorides and vinylogous esters 10, Scheme 4 (89TL6173, 92S533). The products are precursors for trifluoromethyl-substituted pyrroles and dihydropyrroles (Section V,C). 

Using the above-mentioned hydrazone intermediates, derived from attack of nucleophilic species bearing carbonyl, cyano or carboxylate functions in a-position, many widely functionalized 1-aminopyrroles have been obtained (i.e. 3-substituted-l-aminopyrroles, l-amino-2,3-dihydropyrrol-2-ols, 1,2-diaminopyrroles, pyrrolo(2,3-6]pyrroles, 1-amino-l//-pyrrol-2(3/J)-ones, and 3-unsubstituted-l-aminopyrroles). The reaction pathway indicates an intramolecular interaction between the >C=N-NH- nitrogen atom and one of the above-mentioned functional groups followed by an appropriate molecular rearrangement and/or elimination, leading to the heterocyclization process. Scheme 1 shows the type of new pyrroles synthesized in our laboratory. 

Azomethine ylides can also be generated from a-cyano- or a-phenylthiomethylamines <85JOC4006, 86CB813). Silver fluoride promotes the elimination. The adducts from alkynes are 2,5-dihydropyrroles which can be oxidized to pyrroles by ddq (Scheme 82). 

This group also found that azlactones react with vinyl phosphosphonium salts to give A -unsubstituted pyrroles 224 (Table 4.15). Further support for the regio-chemistry comes from the reaction of 2-carboxyvinyltriphenylphosphonium bromide 225 with munchnones 149 to give the pyrroles shown (Fig. 4.80). With azlactone 226, the dihydropyrrole 227 is isolated. 

Chiral intermediates for the synthesis of (-)-anisomycin (1) and (+)-anisomycin (anti-1) (153), (R)-2-(p-methoxyphenyl)methyl-2,5-dihydro-pyrrole (142) and its (S)-isomer (+)-187, have been efficiently synthesized from D-tyrosine and L-tyrosine, respectively (Scheme 20) [28]. D-tyrosine was converted to 0-methyl D-tyrosine methyl ester (182) [72-75] which was treated with di-tert-butyl dicarbonate to protect the amino group. Subsequent reduction of the ester group with sodium borohydride in the presence of lithium chloride furnished the alcohol 183. Swern oxidation of 183 followed by chain extension with the anion derived from bis(2,2,2-trifluoroethyl)(ethoxycarbonylmethyl)-phosphonate afforded (Z)-Q ,/0-unsaturated ester (184), which was used immediately without purification to avoid or minimize any possible racemization of the chiral center. Reduction of the ester group of 184 with diisobutylaluminium hydride afforded the alcohol 185 which after mesylation followed by intramolecular cyclization gave the desired 2,5-dihydropyrrole derivative 186. Removal of the tert-butyloxycarbonyl group was achieved by treatment with trifuoroacetic acid to give (-)-142 in 62% overall yield from 182. The (S)-2,5-dihydropyrrole (-l-)-187 was also prepared in the same manner starting from L-tyrosine. Since (-l-)-187 had been transformed into (-l-)-anisomycin (anti-1) (153), (-)-142 could also be transformed to the (-)-anisomycin (1) [26,66]. 

Syntheses from Non-Carbohydrate Sources. The Birch reduction of an iV-protected 2-carboxymethyl substituted pyrrole and subsequent quench with an appropriate electrophile e.g. methyl 2,3,4-tri-0-benzyl-6-deoxy-6-iodo-a-D-glucopyranoside) affords a simple route to N-protected 2,2-disubstituted dihydropyrroles 81. These can be further elaborated into the corresponding 4-sub-stituted imino-ribitols 82 in good overall yield by a simple strategy of reduction, acetylation, syn-dihydroxylation and deprotection. ... 

The introduction of an allyl group on the N-substituent of an aza-MBH adduct affords compounds that could be used as suitable starting materials for RCM reactions to construct pyrrole skeletons. Kim s group, " Adolfsson s group and Lamaty s group have each reported the RCM towards the synthesis of 2,5-dihydropyrrole skeletons from MBH adducts (Scheme 4.140). The RCM of adducts 451 by use of the commercially available second-generation... 

The reaction of azomethine ylide formed from the aziridine 77a with trifluoro-methylaryl acetylenes gave a mixture of dihydropyrroles 109 and 110, which formed a 1 3 mixture of pyrroles 111 and 112 by oxidation with DDQ [49]. 

Intramolecular nitrogen attack in propargylated enaminones allows silver-catalyzed access to functionalized pyrroles. This Ag-promoted hydroamination can also be used to obtain A bridgehead pyrroles. Silver nitrate-mediated cyclization of allenylamines, available from Uthiated alkoxy allenes and imines or through reaction of l-(lV-carbamoyl)-alkylcuprates with propargyl substrates, provides access to 2,5-dihydropyrrole derivatives. Iminoallenes can be used for the synthesis of substituted p)moles in moderate yields in the presence of potassium carbonate. ... 

Indium(III) chloride catalyzes the microwave-assisted reaction of a-azidochalcones 34 with 1,3-dicarbonyl compounds 35 in water to form polysubstituted pyrroles 36 (Scheme 11) [42]. The reaction has been explained through the formation of an azirine interm iate. Addition of enols from 1,3-dicarbonyl compounds on azirines forms aziridines, which undergo ring opening to form a,(5-unsaturated amines. The amines cyclize via dihydropyrroles to form pyrroles. 

The first evidence that the reaction could be stopped successfully at the stage of formation of the intermediate 47/-2-hydroxy-2,3-dihydropyrroles has appeared in the work [322]. These exotic pyrrole derivatives are prepared from oximes of isopropyl- and iso-butylphenylketones (Scheme 1.146). 

Trofimov, B.A., S.E. Korostova, A.I. Mikhaleva et al. 1983. 4/f-2-Oxy-2,3-dihydropyrroles as intermediates in the formation of pyrroles from ketoximes and acetylene in the system KOH-DMSO. Khim Geterocicl 2 276. 

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