Synthesis of 3- and 5-amino-5-(3)-(pyrrol-2-yl)isoxazoles

5-Amino-3-(pyrrol-2-yl)isoxazoles were selectively prepared by the reaction of 2-(2,2-dicyano-1-ethylthioethenyl)pyrroles with hydroxylamine in methanol. Under analogous conditions, 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl) pyrroles with hydroxylamine gave 5-aminoisoxazoles and their structural isomers, 3-aminoisoxazoles (3-5% yield). The latter were selectively prepared by reacting 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles with hydroxylamine in the presence of aqueous NaOH and from the products of intramolecular cyclization of 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles, 1-ethylthio-3-iminopyrrolizines and hydroxylamine.     

Synthesis and Properties of 2-Alkyl-1-(2-aminoethyl)pyrroles

3-Chloropropenyl alkyl ketones or 2-methoxy-3-chloropropyl alkyl ketones in reaction withethylenediamine furnish previously unknown 2-alkyl-1-(2-aminoethyl) pyrroles. Their reaction with 2'2'-dichlorodiethyl ether gave rise to 2-alkyl-1-(2-morpholinoethyl)pyrroles, with anhydrides ofdicarboxylic acids the corresponding amidoacids and imides of dicarboxylic acids were obtained.     

Palladium and copper cocatalyzed tandem N-H/C-H Bond functionalization: synthesis of CF3-containing indolo- and pyrrolo[2,1-a]isoquinolines

A palladium- and copper-catalyzed tandem N-H/C-H bond functionalization reaction of ortho-(2-chlorovinyl)bromobenzenes with indoles and pyrroles has been developed. A variety of CF(3)-containing indolo- and pyrrolo[2,1-a]isoquinolines were prepared in moderate to good yields via the cyclization of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)benzenes with indoles and pyrroles.     

1,4-Disubstituted and 1,4,5-Trisubstituted 2-[(Benzotriazol-1-yl)methyl]pyrroles as Versatile Synthetic Intermediates

The CH(2)Bt substituent, unlike previously used CH(2)X substituents, enables (i) the synthetic elaboration of pyrroles with unsubstituted ring positions and (ii) electrophilic as well as nucleophilic substitutions to give pyrroles of type pyrrolyl-2-CHENu. Thus, 1,4-disubstituted (7) and 1,4,5-trisubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles (15) were easily prepared from the reaction of 5-(benzotriazol-1-yl)-1,2-epoxy-3-pentynes 4 or 14 with primary amines in i-PrOH. The 2-(benzotriazol-1-yl)methyl side chains of compounds 7 and 15 were elaborated by nucleophilic substitution and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety to afford a variety of 1,2,4-trisubstituted (6, 8-9, 11-13) and 1,2,4,5-tetrasubstituted pyrroles (18, 20-22).     

Substituent-Dependent Divergent Synthesis of 2-(3-Amino-2,4-dicyanophenyl)pyrroles,Pyrrolyldienols and 3-Amino-1-acylethylidene-2-cyanopyrrolizines via Reaction of Acylethynylpyrroles with Malononitrile

An efficient method for the synthesis of pharmaceutically and high-tech prospective 2-(3-amino-2,4-dicyanophenyl)pyrroles (in up to 88% yield) via the reaction of easily available substituted acylethynylpyrroles with malononitrile has been developed. The reaction proceeds in the KOH/MeCN system at 0 °C for 2 h. In the case of 2-acylethynylpyrroles without substituents in the pyrrole ring, the reaction changes direction: instead of the target 2-(3-amino-2,4-dicyanophenyl)pyrroles, the unexpected formation of pyrrolyldienols and products of their intramolecular cyclization, 3-amino-1-acylethylidene-2-cyanopyrrolizines, is observed.     

Pyrroles from ketoximes and acetylene

2-(2-Furyl)pyrroles and 1-vinyl-2-(2-furyl)pyrroles were obtained in up to 80% yields in the reaction of ketoximes of the furan series with acetylene in MOH—dimethyl sulfoxide (M = Li, K) Superbase media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1058–1061, August, 1981.     

Chemo- and regioselectivity in the reactions of polyfunctional pyrroles

The chemo- and regioselectivity of the reduction, oxidation and Wittig reaction of polyfunctional pyrroles, containing a variety of reactive centres was investigated. The reaction of 3,5-dichloropyrrole-2,4-dicarboxaldehydes with potassium permanganate leads to regioselective oxidation of the 2-formyl group, while the Wittig reaction with 1 equiv of a triphenylphosphorane produced the 2-alkenyl substituted pyrroles.     

Formal [4+2] Reaction between 1,3‐Diynes and Pyrroles: Gold(I)‐Catalyzed Indole Synthesis by Double Hydroarylation

Indole synthesis by a gold(I)‐catalyzed intermolecular formal [4+2] reaction between 1,3‐diynes and pyrroles has been developed. This reaction involves the hydroarylation of 1,3‐diynes with pyrroles followed by an intramolecular hydroarylation to give the 4,7‐disubstituted indoles. This reaction can also be applied to the synthesis of carbazoles when indoles are used as the nucleophiles instead of pyrroles.     

Copper-catalyzed tandem reactions of 1-(2-iodoary)-2-yn-1-ones with isocyanides for the synthesis of 4-oxo-indeno[1,2-b]pyrroles

A novel copper-catalyzed tandem reaction of 1-(2-iodoaryl)-2-yn-1-ones with isocyanides is described. The reaction is through a formal [3 + 2] cycloaddition/coupling tandem process and leads to efficient formation of 4-oxo-indeno[1,2-b]pyrroles.     

Synthesis of polysubstituted N-H pyrroles from vinyl azides and 1,3-dicarbonyl compounds

Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from alpha-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting from the same vinyl azides.     

Reaction of chromone-3-carboxaldehydes with TOSMIC: synthesis of 4-(2-hydroxybenzoyl)pyrroles

Chromone-3-carboxaldehydes 1 react with tosylmethylisocyanide (TOSMIC) in the presence of DBU in THF at room temperature to furnish, after in situ deformylation, good yields of 2-tosyl-4-(2-hydroxybenzoyl)pyrroles 2. When the same reaction is performed with potassium carbonate in methanol under reflux pyrroles 2 are again isolated, but in lower yields. Finally, from the reaction of 1a in the presence of a stronger base (NaOH) only a small amount of the 3-substituted derivative 3a along with polymeric material is isolated.     

Efficient and Mild Protocol for the Synthesis of 4(3)-Substituted 3(4)-Nitro-1H-pyrroles and 3-Substituted 4-Methyl-2-tosyl-1 H-pyrroles from Nitroolefins and Tosylmethyl Isocyanide in Ionic Liquids

A mild and convenient method for the synthesis of 4(3)‐substituted 3(4)‐nitro‐1H‐pyrroles and 3‐substituted 4‐methyl‐2‐tosyl‐1H‐pyrroles from nitroolefins and tosylmethyl isocyanide (TosMIC) in ionic liquid 1‐butyl‐3‐methylimidazolium bromide ([bmIm]Br) was developed. The reactions were performed at room temperature with KOH as base with good yields in a short time (about 2 h). Some tough conditions, such as absolutely anhydrous organic solvents, low temperature, hazardous and expensive strong base or organic base, were not needed. The yields of 4(3)‐substituted 3(4)‐nitro‐1H‐pyrroles were moderate, but excellent yields were achieved for the preparation of 3‐substituted 4‐methyl‐2‐tosyl‐1H‐pyrroles. This strategy was quite general and it worked in a broad range of nitroolefins with aromatic, aliphatic or heterocyclic substituents. The recovered ionic liquid could be reused as solvent for several times without significant decrease of reaction yields.     

One-step synthesis of 3,5-disubstituted-2-pyridylpyrroles from the condensation of 1,3-diones and 2-(aminomethyl)pyridine

3,5-Disubstituted- and 3,4,5-trisubstituted-2-(2-pyridyl)pyrroles may be synthesized efficiently from the novel condensation of 2-(aminomethyl)pyridine and 1,3-diones. The cyclization reaction was found to proceed through the intermediacy of a (2-pyridyl)methylimine. A marked dependence of the regioselectivity in the reaction of unsymmetrical diones on the presence of additional aminomethylpyridine suggests that two pathways to the product pyrroles are available.     

The versatile role of norbornene in C-H functionalization processes: concise synthesis of tetracyclic fused pyrroles via a threefold domino reaction

The synthesis of novel tetracyclic fused pyrroles from 1-(2-iodophenyl)-1H-pyrrole and various bromoalkyl-aryl alkynes via a palladium(0)-catalyzed and norbornene-mediated threefold domino reaction is reported. PdCl₂ and tri-2-furylphosphine (TFP) in the presence of norbornene and Cs₂CO₃ in CH₃CN at 90 °C gave a variety of tetracyclic fused pyrroles in usually high yields. In the described reaction sequence two of the three carbon-carbon bonds are formed by functionalization of an unactivated aryl C-H bond.     

Rhodium(III)-catalyzed arene and alkene C-H bond functionalization leading to indoles and pyrroles

Recently, the rhodium(III)-complex [Cp*RhCl(2)](2) 1 has provided exciting opportunities for the efficient synthesis of aromatic heterocycles based on a rhodium-catalyzed C-H bond functionalization event. In the present report, the use of complexes 1 and its dicationic analogue [Cp*Rh(MeCN)(3)][SbF(6)](2) 2 have been employed in the formation of indoles via the oxidative annulation of acetanilides with internal alkynes. The optimized reaction conditions allow for molecular oxygen to be used as the terminal oxidant in this process, and the reaction may be carried out under mild temperatures (60 °C). These conditions have resulted in an expanded compatibility of the reaction to include a range of new internal alkynes bearing synthetically useful functional groups in moderate to excellent yields. The applicability of the method is exemplified in an efficient synthesis of paullone 3, a tetracyclic indole derivative with established biological activity. A mechanistic investigation of the reaction, employing deuterium labeling experiments and kinetic analysis, has provided insight into issues of reactivity for both coupling partners as well as aided in the development of conditions for improved regioselectivity with respect to meta-substituted acetanilides. This reaction class has also been extended to include the synthesis of pyrroles. Catalyst 2 efficiently couples substituted enamides with internal alkynes at room temperature to form trisubstituted pyrroles in good to excellent yields. The high functional group compatibility of this reaction enables the elaboration of the pyrrole products into a variety of differentially substituted pyrroles.     

Heterocyclic alpha-alkylidene cyclopentenones obtained via a Pauson-Khand reaction of amino acid derived allenynes. A scope and limitation study directed toward the preparation of a tricyclic pyrrole library

The synthesis of a novel class of tricyclic pyrroles has been accomplished by using a Pauson-Khand/Stetter/Paal-Knorr reaction sequence. Full details of the Pauson-Khand reaction of amino acid tethered allenynes 4a-e and 9a-d are disclosed. The study of this reaction led to the discovery of an unprecedented substituent effect on the diastereoselectivity of the Mo(CO)6 mediated allenic Pauson-Khand reaction. It was found that amino acid tethered allenynes with aromatic side chains afford alpha-alkylidene cyclopentenones with the opposite diastereoselectivity compared to those with aliphatic side chains. This effect has been attributed to complexation of the metal mediator to the aromatic ring in the substrate. Furthermore, an isomerization of one of the diastereomers of the alpha-alkylidene cyclopentenones was encountered, leading to eventual decomposition. The stable diastereomers were found to react well in the Stetter reaction leading to 1,4-diketones that were converted to pyrroles. The observation that the first generation of 2-alkyl-substituted pyrroles was unstable led to a second generation of 2-carboxamide pyrroles with sufficient stability for biological tests which are in progress.     

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).     

Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and Acetylenes

The formal cycloaddition of α‐metallated methyl isocyanides 1 onto the triple bond of electron‐deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3 . The scope and limitations of this reaction (24 examples, 25–97 % yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu^I‐mediated synthesis of 2,3‐disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5–88 %yield).     

Rh-catalyzed transannulation of N-tosyl-1,2,3-triazoles with terminal alkynes

The first transannulation of 1,2,3-triazoles with terminal alkynes into pyrroles is reported. The reaction proceeds in the presence of a Rh(2)(oct)(4)/AgOCOCF(3) binary catalyst system providing a straightforward approach to 1,2,4-trisubstituted pyrroles in good to excellent yields.     

Reactions of heterocumulenes with organometallic reagents: XVII. One-pot synthesis of alkoxy and (alkylsulfanyl)-substituted pyrroles and 2,3-dihydropyridines from aliphatic isothiocyanates and lithiated alkoxyallenes

A fundamentally new approach was developed to designing pyrrole and dihydropyridine rings from available allenes and isothiocyanates involving a single preparative stage. Applying the reaction of lithiated alkoxyallenes with aliphatic isothiocyanates we have synthesized previously unknown 1-alkyl(cycloalkyl) pyrroles and 2,3-dihydropyridines with rare alkoxy- and alkylsulfanyl substituents. It was proved that the five- and six-membered azaheterocycles formed as a result of competing reactions of direct intramolecular cyclization of S-alkylated adducts of lithiated alkoxyallenes with isothiocyanates (1-aza-1,3,4-trienes) into pyrroles and of [1,5]-sigmatropic rearrangement into conjugated 2-aza-1,3,5-trienes with subsequent closure into dihydropyridine ring (through 6π-electrocyclization).