Tetra-substituted pyrroles

M. Calderelli, J. Habermann, S. V. Ley, Clean Five-Step Synthesis of an Array of 1,2,3,4-Tetra-substituted Pyrroles using Polymer-Supported Reagents , J. Chem. Soc, Perkin Trans. 11999,107-110. 

Scheme 2.70 Rapid construction of tetra-substituted pyrrole scaffolds using supported reagent methodology.

Caldarelh, M., Habermann, J. and Ley, S.V. (1999) Clean five-step synthesis of an array of 1,2,3,4-tetra-substituted pyrroles using pol3mier-supported reagents. Journal of the Chemical Society - Perkin Transactions 1, 107-110. 

Scheme 18.16 Library synthesis of tetra-substituted pyrroles.

Analogously to the precedent transition metal-catalyzed cycloisomerization of (Z)-pent-2-en-4-yn-l-ols like 113 into furan compounds (Scheme 8.45), Gabriele disclosed a general and a very convenient route leading to pyrroles 218 from nitrogen analogs of these reactive precursors (Scheme 8.81) [269]. Thus, di-, tri-, and tetra-substituted pyrroles 218 with different substitution patterns could be readily synthesized via the Cu(I)- or Cu(II)-catalyzed [270] cycloisomerization of (Z)-(2-en-4-ynyl)amines 217. The mechanism of this transformation is similar to that proposed for the transition metal-catalyzed synthesis of furans (Scheme 8.46). 

The Au(I)-catalyzed version of Gabriele s protocol for the synthesis of pyrroles was recently reported by Gagosz et td. (Scheme 8.82) [271]. It was demonstrated that N-tosyl-protected (Z)-(2-en-4-ynyl)amines 219 could undergo a facUe cydoisomeriza-tion into pyrroles 220 in the presence of cationic bis(trifluoromethanesulfonyl) imidate Au(I) complexes, very robust catalysts. Notably, tri- and tetra-substituted pyrroles 220 were synthesized in excellent yields and under very mild conditions within 5 min reaction time. 

Furthermore, N,N-disubstituted (2)-(2-en-4-ynyl)amines 221, possessing an allyl group, underwent the Au(I)-catalyzed cycloisomerization with a 1,3-allyl shift affording tri- and tetra-substituted pyrroles 222 (Scheme 8.83) [271]. This transformation allowed efHdent assembly of C2-homoallyl-substituted pyrroles bearing various... 

Later, Narasaka and coworkers reported that the scope of this transformation could be substantially improved with the use of Mn(III) catalysis [313]. These new reaction conditions allowed highly efficient employment of differently substituted simple non-activated alkyl-, aryl-, hetaryl- and even cydic vinyl azides 328 (Scheme 8.117). In addition, previously unreactive 1,3-diketones 33S could serve as feasible 1,3-dicarbonyl components in this formal [3 + 2] cycloaddition reaction, affording 2,3,5-tri-and 2,3,4,5-tetra-substituted pyrroles 336 in moderate to excellent yields... 

Ishii reported the Sm(III)-catalyzed route to various tri- and tetra-substituted pyrroles 347 employing 3 + 2 cydocondensation between imines 345 and ni-troalkenes 346. (Scheme 8.121) [315]. Theuseofaldimines andketemines with steric congestion at the imine functionality led to formation of the corresponding pyrrole products in diminished yields. According to the mechanistic proposal, the samarium... 

M. Lai, P. R. Bagdi, R. S. Basha, P. Saravanan, S. Patra, A. T. Khan, Tetrahedron Lett. 2012, 53, 4145 150. Synthesis of tetra-substituted pyrroles, a potential phosphodiesterase 4B inhibitor, through nickel(It) chloride hexahydrate catalyzed one-pot four-component reaction. 

Das et al. [29] developed a simple, efficient, cost-effective, and metal-free four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicaiboxyl-ates, and nitromethane for the synthesis of corresponding 1,2,3,4-tetra-substituted pyrroles 6 using molecular iodine as a catalyst (Scheme 10.4). 

Das B, Bhunia N, Lingaiah MA (2011) Simple and elficient metal-free synthesis of tetra-substituted pyrroles by iodine-catalyzed four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane. Synthesis 2011 3471-3474 Khan AT, Ghosh A, Khan MM (2012) One-pot four-component domino reaction for the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular iodine. Tetrahedron Lett 53 2622-2626... 

Milkiewicz and coworkers [16] prepared a series of novel tetra-substituted furo[3,2-b Ipyrroles from the methyl or ethyl 3-bromo-2-phcnyllliro 3,2-/ pyrrole-5-carboxylate 40, which was prepared from 3-bromo-2-phenylfuran-2-carbaldehyde 39. The compounds 40 were subjected to a Suzuki coupling with 4-chlorophenyl boronic acid to form 41, which was treated with a variety of alkylating agents to afford the corresponding esters 42. The esters were then saponified to acids 43 (Scheme 6). 

Mori has employed transmetallation, well documented in other organozirco-nium reactions [59], to form y-allylated a-silyl allyl amines (Eq. 19) [40,41] and substituted pyrroles (Eq. 20) [60] after the insertion of alkynes into the Zr-C bond of zirconaaziridines. The reaction sequence in Eq. 19 uses stoichiometric quantities of Zr, but catalytic amounts of Cu, and both the insertion and allylation steps proceed with high regioselectivity. Using an acyl halide instead of allyl chloride gives tetra- and pentasubstituted pyrroles, in a one-pot reaction (Eq. 20). 

Pyrrole reacts with aqueous formaldehyde and secondary amines in the presence of acetic acid to afford, in some cases, mixtures of products derived from attack at the 2- and 2,5-positions. The disubstitution products can be obtained in very high yields at about room temperature for example, a 92% yield of 2,5-bis(piperidylmethyl)pyrrole is obtained using this method. The same procedure apparently does not yield a Mannich base with l-methylpyrrole, but the use of aqueous formaldehyde and dimethylamine hydrochloride at 60 °C results in the formation of the 2-substitution product in 73% yield. Even highly substituted pyrroles react. Thus, ethyl 4,5-dimethylpyrrole-2-carboxylate and ethyl 2,5-dimethylpyrrole-3-carboxylate both undergo C-aminoalkylation at the unsubstituted position in 45 and 68% yields, respectively, with dimethylamine and formaldehyde in ethanolic solution. A number of tri- and tetra-substituted 2-methylpyrroles have been investigated with the exception of Knorr s pyrrole all gave side-chain substituted products with formaldehyde and a secondary amine in acetic acid. ... 

Mori has reported a route to tetra- and penta-substituted pyrroles by a sequence involving reaction of the iminosilaacyl complex 5 with an alkyne in the presence of LiEt3BH to afford an initial azazirconacyclopentene intermediate <97CL825>. Addition of acyl halides and CuCl leads to the pentasubstituted pyrrole 6 or the desilylated product 7 in this one-pot reaction. 

A number of 4-1-1 protocols for the synthesis of pyrrole cores featuring the Cu (I)primary amine derivatives as the key carbon-heteroatom bond forming reaction have been reported recently. Thus, Buchwald described an efficient Cu(I)-catalyzed synthesis of tri-, tetra-, and penta-substituted pyrroles 302 from 1,4-dihalo-l,3-dienes 300 and carbamates 281 (Scheme 8.107) [305]. This methodology displayed excellent functional group compatibility, providing good to... 

Beller reported a selective ruthenium-catalyzed synthesis of highly substituted pyrroles (e.g., 52). The sequence utihzes readily available starting materials benzylic ketone 49, amine 50 (ahphatic, aromatic, or ammonia), and vicinal diol 51.Tri-, tetra-, and pentasubstituted pyrroles can be easily prepared in moderate to high yields. A variety of aromatics, alkyl groups, and halogens are tolerated (13AG(I)597). 

Pyrrole des Typs I werden je nach Substitution am N-Atom tetra- oder dihydriert4 ... 

A novel aromatic substitution reaction with electron-deficient radicals, which avoids the use of stannanes, is promoted by the addition of tetra-n-butylammonium bromide [54]. Iodoacetonitrile and iodoacetic esters react with pyrroles and indoles in good to high yield upon photolysis in the presence of 2-methyloxirane and sodium thiosulphate (Scheme 6.34). 

---