Virtual libraries of tetrapyrrole macrocycles. Combinatorics, isomers, product distributions, and data mining

A software program (PorphyrinViLiGe) has been developed to enumerate the type and relative amounts of substituted tetrapyrrole macrocycles in a virtual library formed by one of four different classes of reactions. The classes include (1) 4-fold reaction of n disubstituted heterocycles (e.g., pyrroles or diiminoisoindolines) to form β-substituted porphyrins, β-substituted tetraazaporphyrins, or α- or β-substituted phthalocyanines; (2) combination of m aminoketones and n diones to form m × n pyrroles, which upon 4-fold reaction give β-substituted porphyrins; (3) derivatization of an 8-point tetrapyrrole scaffold with n reagents, and (4) 4-fold reaction of n aldehydes and pyrrole to form meso-substituted porphyrins. The program accommodates variable ratios of reactants, reversible or irreversible reaction (reaction classes 1 and 2), and degenerate modes of formation. Po?lya's theorem (for enumeration of cyclic entities) has also been implemented and provides validation for reaction classes 3 and 4. The output includes the number and identity of distinct reaction-accessible substituent combinations, the number and identity of isomers thereof, and the theoretical mass spectrum. Provisions for data mining enable assessment of the number of products having a chosen pattern of substituents. Examples include derivatization of an octa-substituted phthalocyanine with eight reagents to afford a library of 2,099,728 members (yet only 6435 distinct substituent combinations) and reversible reaction of six distinct disubstituted pyrroles to afford 2649 members (yet only 126 distinct substituent combinations). In general, libraries of substituted tetrapyrrole macrocycles occupy a synthetically accessible region of chemical space that is rich in isomers (>99% or 95% for the two examples, respectively).     

Preparation of twelve 1-methyl-2-formyl-5-substituted pyrroles and their hydrazones

Preparation of twelve 1-methyl-2-formyl-5-substituted pyrroles (2a-1), with five of them as new compounds, is described. Their derivatives, i.e., 1-methyl-2-formyl-5-substituted pyrrole phenyl hydrazones (3a-1) and 1-methyl-2-formyl-5-substituted pyrrole (4-nitrophenyl) hydrazones (4a-1) are all new compounds. They have also been prepared and further identified.     

Addition/oxidative rearrangement of 3-furfurals and 3-furyl imines: new approaches to substituted furans and pyrroles

Furans and pyrroles are important synthons in chemical synthesis and are commonly found in natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare 2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of organolithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields. Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of 3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl 3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in Honda's synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions, 2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.     

Singlet oxygen reactions of 3-methoxy-2-pyrrole carboxylic acid tert-butyl esters. A route to 5-substituted pyrrole precursors of prodigiosin and analogs

Reaction of the tert-butyl ester of 3-methoxy-2-pyrrole carboxylic acid with singlet oxygen yields a peroxidic intermediate which undergoes coupling with a range of nucleophiles to yield 5-substituted pyrroles. Among these products are α,α′-bipyrroles which serve as precursors of prodigiosin, including A-ring substituted analogues.     

Highly regioselective radical alkylation of 3-substituted pyrroles

It is reported that the intermolecular oxidative radical substitution on 3-substituted pyrroles gives the 2,3-disubstituted pyrroles in a highly regioselective manner. This behavior is explained on the basis of the relative stabilities of the intermediate radicals formed in the process. The methodology reported herein represents a direct entry into 2,3-disubstituted pyrroles, which might be used to construct more complex molecules.     

Dual-parameter Correlation Analysis of the Redox Potential Data of 1-Methyl-2-formyl-5-substituted Pyrroles and their Hydrazones

It has been suggested about forty years ago that the transition states of polarographic potential-determining steps possess free radical character1. However, the dual-parameter correlation analysis [eqn. (1)] have never been successfully applied to the redox potentials until our recent report on five series of aromatic compounds shows that polarographic processes are affected by the polar effect as well as the spin-delocalization effect2. The purpose of this paper is to study the correlation…     

A qualitative molecular orbital picture of 2-substituted carbonyl derivatives of furan and pyrrole

The conformational preferences for some 2-substituted furans and pyrroles have been studied by MINDO/3 and a qualitative model including solvent effects is proposed.     

Sulfenylation of some pyrroles and indoles

Methylsulfenylation of 1-substituted pyrroles and indoles was observed using 1-(methylthio)morpholine and an acid catalyst or with methylsulfenyl chloride and excess pyridine. 1-Substituents which are activating or weakly deactivating towards electrophilic substitution such as alkyl, 2-cyanoethyl, dimethylamino, trialkylsilyl, 2-chloroethyl and 2-phenylsulfonylethyl were used. The 2-chloroethyl and 2-phenylsulfonylethyl groups which can be removed with a strong base can be used to obtain 1H-methylthiopyrroles and indoles. 1-Phenylsulfonyl and 1-acetyl substituents are too strongly deactivating for these sulfenylations to be successful. Mono and disubstituted pyrroles and monosubstituted indoles can be isolated from these reactions, however, because the methylthio group is activating towards electrophilic substitution the main advantage of these reactions is the synthesis of tri and tetrasubstituted pyrroles and disubstituted indoles. 1-Methyl-2,3,4,5-tetra-methylthiopyrrole and 1-methyl-2,3-dimethylthioindole are oxidized to the corresponding 3,4-disulfoxide and 3-sulfoxide and with excess oxidizing agent to the tetrasulfone and disulfone, respectively.     

Gold(I)-catalyzed rearrangement of 3-silyloxy-1,5-enynes: an efficient synthesis of benzo[b]thiophenes, dibenzothiophenes, dibenzofurans, and indole derivatives

With the IPr ligand (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) on gold(I) excellent yields in the benzanellation of 2-substituted thiophenes, benzothiophenes, pyrroles, benzofurans, and indoles were achieved. The 1-siloxybut-3-ynyl side chains, incorporated in the anellation, are easily accessible by the addition of a propargyl metal reagent to a formyl group and silylation of the alcohol. This conveniently allows an anellation at the position of the formyl group under mild conditions. All reactions involve a 2,3-shift of the side chain in the anellation step and thus, provide an easy access to specific substitution patterns. Only in the case of 2-substituted indoles with their highly nucleophilic 3-position a direct hydroarylation without shift is observed. On the other hand, 3-substituted indoles give the same products as 2-substituted indoles. Then, a 3,2-shift in the indole ring system has to be involved.     

Synthesis of indoloand pyrroloquinazolones

2-Quinazolone reacts with various π-surplus systems (indoles and pyrroles) to give 3,4-dihydro-4-substituted 2-quinazolones. These compounds are capable of oxidation to 4-substituted 2-quinazolones. o-Carbamidobenzylideneurea gives identical products in these reactions.     

Reduction of α - substituted succinonitriles with diisobutylaluminum hydride: a facile method for the synthesis of 3-substituted pyrroles

Treatment of four representative α - substituted succinonitriles (2) with diisobutylaluminum hydride, followed by hydrolysis of each reaction mixture with aqueous sodium dihydrogen phosphate, afforded 3-substituted pyrroles (4) in approximately 50% yield.     

Synthetic transformations of higher terpenoids: XIV. Synthesis of pyrrololabdanoids from lambertianic acid

Treatment of lambertianic acid methyl ester with lead tetraacetate gave terpenoid 2,5-diacetoxydihydrofuran which reacted with primary amines to yield 3-terpenyl-substituted pyrrol-2(5H)-ones; the reaction with hydrazine led to the corresponding pyridazine derivative. The obtained furanoterpenoids underwent oxidative methoxylation by the action of N-chlorobenzenesulfonamide or N-bromosuccinimide in methanol. 2,5-Dimethoxydihydrofurans thus formed were smoothly converted into 3-substituted furan-2(5H)-one in acid medium. Hydrogenation of 2,5-dimethoxydihydrofurans, followed by treatment with amines, gave 1,3-disubstituted pyrroles.     

Synthesis of 1,2,3,5-substituted pyrroles from α-bromoacetophenones and 2-nitroethene-1,1-diamines

The simple synthesis of 1,2,3,5-substituted pyrroles from α-bromoacetophenones and 2-nitroethene-1,1-diamines in the presence of K₂CO₃ in DMF at 120 °C is described. A range of fused and non-fused polysubstituted pyrroles were prepared in high yields with short reaction times.     

3-Lithiopyrroles by Halogen-Metal Interchange of 3-Bromo-1-(triissopropylsilyl)pyrroles. Synthesis of Verucarin E and Other 3-Substituted Pyrroles. Preliminary Communication

3-Lithio-1-(trimethylsilyl)pyrrole ( 7 , Schem 2), obtained by halogen-metal interchange from the 3-bromo compound 2 , reacted with various electrophilic reagents to provide products, which on fluoride ion desilylation, gave 3-substituted pyrroles in good overall yields. One such pyrrole 13 (Schem 3), was converted into 2-formyl-3-octadeclpyrrole ( 14 ), reputed to be a metabolite of the marine sponge Oscarella lobularis. 3,4-Dibromo-1-(triisopropylsityl)pyrrole ( 5 ) was efficiently transformed, by a process involving two consecutive bromine-lithium exchange reactions (Scheme 4), into the antibiotic verrucarin E 17.     

Commercially available simple ionic liquids-promoted dehydrative carbon–carbon bond-forming reaction of diarylmethanols and triarylmethanols with pyrroles,thiophene, furan and indoles

Two commercially available simple ionic liquids, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate and 1-ethyl-2,3-dimethylimidazolium trifluoromethansulfonate, effectively promote the solvent-free dehydrative carbon–carbon (C–C) bond-forming reaction of a variety of diarylmethanols and triarylmethanols with π-rich heteroaromatics, such as pyrroles, indole, furan, and thiophene without ring-opening and polymerization to give the corresponding not only 2-substituted pyrroles, furan, and thiophene but also 3-substituted indoles in good to excellent yields with moderate to excellent regioselectivities. These dehydrative C–C bond formation reactions of alcohols offer several advantages, such as the use of stoichiometric amounts of π-rich heteroaromatics and ionic liquids, water is the only by-product, there is no need for either organic solvents or expensive metal or strong Brønsted acid catalysts in the reaction, and the diversity of diarylmethylation and triarylmethylation.     

A Theoretical Study on the Tautomerism of C-Carboxylic and Methoxycarbonyl Substituted Azoles

DFT calculations (B3LYP/6-31+G^**) have been carried out on 106 tautomers and conformers of NH-azoles bearing CO₂H and CO₂CH₃ groups. The following azoles systems have been studied: 2-substituted pyrroles, 2-substituted indoles, 2-substituted imidazoles, 2-substituted benzimidazoles, 4(5)-substituted imidazoles, 3(5)-substituted pyrazoles, 3-substituted indazoles (1H and 2H), 3,4(5)-substituted-1,2,3(5)-triazoles, 2,3(5)-substituted-1,2(3),4-triazoles, 4(5)-1,2,3,4(5)-tetrazoles. In the case of pyrazole, 3,5-disubstituted derivatives have also been computed, including four dimers.Dedicated to our friend Professor Vladimir I. Minkin on his 70th anniversary.     

Regioselective preparation of 2-substituted 3,4-diaryl pyrroles: a concise total synthesis of ningalin B

Methylisocyanoacetate undergoes a 2 + 3 cycloaddition with alpha,beta-unsaturated nitriles to provide a regioselective synthesis of 2-substituted 3,4-diaryl pyrroles. The ease of preparation of alpha,beta-unsaturated nitriles allows the rapid synthesis of pyrroles with varied substituents. Using this method, a key intermediate (1) for the synthesis of the marine natural products lukianol A, lamellarin O, and lamellarin Q was prepared in two steps. A total synthesis of ningalin B (11) was also accomplished utilizing this methodology.     

Catalytic asymmetric Friedel-Crafts/protonation of nitroalkenes and N-heteroaromatics

The catalytic asymmetric Friedel-Crafts/protonation of indoles and pyrroles with α-substituted nitroalkenes to give the corresponding adducts in a highly anti-selective manner was achieved by an imidazoline-aminophenol (L2)-Cu complex. The anti-adducts could be successfully transformed to biochemically important α-substituted β-heteroarylalkylamines.     

Ruthenium-catalysed conversion of 1,4-alkynediols into pyrroles

Various 1,2,5-substituted pyrroles have been synthesised from 1,4-alkynediols using a ruthenium catalysed isomerisation to give the corresponding 1,4-dicarbonyl compounds, which undergo in situ cyclisation to pyrroles in the presence of amine.     

Synthesis of 2-substituted endo-hymenialdisine derivatives

The first synthesis of 2-substituted endo-hymenialdisine derivatives 1-4 is described started with 2-substituted pyrroles and 5-substituted pyrrolo-2-carboxylic acids.