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.     

General and regioselective synthesis of substituted pyrroles by metal-catalyzed or spontaneous cycloisomerization of (Z)-(2-en-4-ynyl)amines

A general and regioselective synthesis of substituted pyrroles 2 by cycloisomerization of readily available (Z)-(2-en-4-ynyl)amines 1 is reported. Spontaneous cycloisomerization leading to 2 occurred in the course of preparation of enynamines bearing a terminal triple bond or a triple bond substituted with a phenyl or a CH2OTHP group. When the triple bond was substituted with an alkyl or alkenyl group, enynamines were stable and could be converted into the corresponding pyrroles by metal catalysis. CuCl2 was found to be an excellent catalyst for cycloisomerization of substrates substituted at C-3, while PdX2 in conjunction with KX (X = Cl, I) turned out to be a superior catalyst for the reaction of enynamines unsubstituted at C-3.     

Copper- or phosphine-catalyzed reaction of alkynes with isocyanides. Regioselective synthesis of substituted pyrroles controlled by the catalyst

The copper-catalyzed reaction of isocyanides (CNCH2EWG1) 1 with electron-deficient alkynes (RC[triple bond]CEWG2) 2 gave the 2,4-di-EWG-substituted pyrroles 3 selectively, whereas the phosphine-catalyzed reaction of 1 with 2 afforded the 2,3-di-EWG-subsituted pyrroles 4. Accordingly, regioselective synthesis of substituted pyrroles has been achieved by merely choosing the catalyst.     

A novel access to bisformylated pyrroles via decarboxylation of N-aryl-γ-lactam-carboxylic acids under Vilsmeier reaction conditions

A simple methodology for the conversion of substituted N-aryl-γ-lactam 2/3-carboxylic acids to substituted N-aryl-diformylated pyrroles has been developed. Several γ-lactam 2/3-carboxylic acids were subjected to Vilsmeier reagent and substituted diformylated pyrroles are isolated in one-step process.     

A Two Step Synthesis of 1,2,3-Substituted Pyrroles

A method for preparing substituted pyrroles 3a-g in two steps from dihydrofurans 2a-b which were synthesized from α,α-diazocarbonyl derivatives 1a-b was developed. The relevance of this research work lies in the easiness of preparing the substituted dihydrofurans and transforming them into pyrroles under mild conditions.     

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.     

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).     

Synthesis of p-Aminophenyl Heteroaromatic Pyrroles

Three general methods for synthesis of heteroaromatic pyrroles were reported recently from our laboratory.¹ Application of these methods to the preparation of p-aminophenyl heteroaromtic pyrroles 3 will be discussed. Potential use of p-aminophenyl substituted heteroaromatic pyrroles 3 as electroluminescent materials is under current investigation.     

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.     

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.     

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.     

Facile synthesis of pyrroles via Rh(II)-catalyzed transannulation of 1-tosyl-1,2,3-triazoles with silyl or alkyl enol ethers

A novel Rh(II)-catalyzed transannulation of 1-tosyl-1,2,3-triazoles with silyl or alkyl enol ethers has been developed, which enables the facile synthesis of substituted pyrroles in a regiocontrollable manner. Moreover, the methodology could be extended to access 3-pyrrolin-2-one derivatives with silyl ketene acetals used as the reaction partner.     

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).     

Sequential aza-Baylis-Hillman/ring closing metathesis/aromatization as a novel route for the synthesis of substituted pyrroles

A new route to diverse 2-substituted-3-methoxycarbonyl pyrroles has been developed. Diverse SES protected alpha-methylene beta-aminoesters were obtained by a 3-component aza-Baylis-Hillman reaction. Diversity arose from the aryl aldehydes which can be used in this reaction. N-Alkylation with allyl bromide under mild conditions provided the corresponding dienes. These substituted dienes were cyclized by ring closing metathesis at room temperature or under microwave-activation with Grubbs-type II catalyst to yield SES-protected pyrroline intermediates. The final pyrroles were obtained by base-promoted dehydrodesulfinylation/aromatization. The scope of each of these reactions was explored.     

Conventional and Microwave-Assisted Facile One-Pot Synthesis of N-Substituted Pyrrole-2,3,4,5-tetracarboxylates Under Neat Conditions

Highly substituted pyrroles 3a,f were prepared conveniently in a reaction of (dimethyl- and diethyl-)acethylenedicarboxylates 1a–b with N-(methyl- and aryl-) hydroxylamines 2a–d in the presence of NaHCO₃ using both conventional heating and microwave irradiation. Excelent yields of the very pure products were isolated under solvent-free conditions both at classical as well as microwave heating.     

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.     

Reactions of substituted (1,3-butadiene-1,4-diyl)magnesium, 1,4-bis(bromomagnesio)butadienes and 1,4-dilithiobutadienes with ketones, aldehydes and PhNO to yield cyclopentadiene derivatives and N-Ph pyrroles by cyclodialkenylation

1,4-Dilithiobutadiene derivatives 1, 1,4-bis(bromomagnesio)butadiene derivatives 2 and metallacyclic (1,3-butadiene-1,4-diyl)magnesium reagents 3 were prepared and their reactions with ketones, aldehydes, and PhNO were investigated. Multiply substituted cyclopentadienes and N-Ph pyrroles were formed by unprecedented reaction conditions. The carbonyl group of aldehydes and ketones was deoxygenated during the reaction and behaved formally as a one-carbon unit; the N==O moiety of PhNO was cleaved to afford N-Ph pyrrole derivatives. Furthermore, different reactivities among these three types of reagents 1, 2 and 3 were revealed. The 1,4-dilithium reagents 1 readily reacted with both aldehydes and ketones; the 1,4-dimagnesium reagents 2 reacted with aldehydes, but not ketones; the metallacyclopentadiene reagents of magnesium 3 showed higher reactivity and did react with ketones.     

The highly enantioselective addition of indoles and pyrroles to isatins-derived N-Boc ketimines catalyzed by chiral phosphoric acids

The first asymmetric aza-Friedel-Crafts reaction of indoles and pyrroles with isatin-derived N-Boc ketimines catalyzed by chiral phosphoric acids is reported. In general, derivatives of substituted 3-amino-2-oxindoles were obtained with excellent enantioselectivities and high yields.     

Horner-Wadsworth-Emmons reagents as azomethine ylide analogues: pyrrole synthesis via (3 + 2) cycloaddition

Amido-substituted Horner-Wadsworth-Emmons reagents can serve as precursors to 1,3-dipoles for use in cycloaddition. These compounds are assembled in one pot via the TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites. The coupling of this synthesis with alkyne cycloaddition provides a three-component synthesis of pyrroles. The dipoles can be prepared with a diverse range of imines and acid chlorides, and (3 + 2) cycloaddition with unsymmetrical alkynes is highly regiospecific, providing a modular approach to form substituted pyrroles.     

Mono Halogen Substituted Calix[4]pyrroles: Fine-tuning the Anion Binding Properties of Calix[4]pyrrole

Abstract

Single halogen atom (i. e. I, Br, Cl and F) substituted calix[4]pyrroles, compounds 2, 3, 4 and 5, were synthesized. Studies of these systems reveal that replacement of a single β-pyrrolic hydrogen atom can increase the anion binding ability of calix[4]pyrroles for a variety of anions (e. g. Cl^?, Br^?, H₂PO₄ ^? and HSO^? ₄) relative to normal non-halogen substituted calix[4]pyrrole 1. In the case of chloride anion, the expected relative affinity sequence of 5 > 4 > 3 > 2 was observed. This was not found to be true for Br^?, H²PO^? ₄, and HSO^? ₄. Here, the chlorine substituted calix[4]pyrrole 4 was found to display a slightly higher affinity in the case of each anion than the fluorine-bearing derivative 5. This was rationalized in terms of intermolecular NH … F hydrogen bonding interactions being present in CD₂Cl₂ solutions of 5. Support for this latter conclusion came from concentration and temperature-dependent NMR spectroscopic studies.

A matched set of mono halogen substituted calix[4]pyrroles was used to study in detail, the extent to which halogen substituents may be used to fine-tune the anion binding properties of calix[4]pyrroles.