3-substituted Pyrroles Research Articles

Unusual Regio- and Chemoselectivity in Oxidation of Pyrroles and Indoles Enabled by a Thianthrenium Salt Intermediate.

A dearomative oxidation of pyrroles to Δ3-pyrrol-2-ones is described, which employs a sulfoxide as oxidant, in conjunction with a carboxylic acid anhydride and a Brønsted acid additive. 3-substituted pyrroles undergo regioselective oxidation to give the product isomer in which oxygen has been introduced at the more hindered position. Regioselectivity is rationalized by a proposed mechanism that proceeds by initial thianthrenium introduction at the less-hindered pyrrole α-position, followed by distal attack of an oxygen nucleophile and subsequent elimination of thianthrene. The same reaction conditions are also able to effect a chemoselective oxidation of indoles to indolin-3-ones and additionally of indolin-3-ones to 2-hydroxyindolin-3-ones. Here again, the regio- and chemoselectivities are rationalized through the intermediacy of a thianthrenium salt.

Enantioselective synthesis of hetero-triarylmethanes by chiral phosphoric acid-catalyzed 1,4-addition of 3-substituted indoles with azadienes

An efficient catalytic enantioselective 1,4-addition reaction of 3-substituted indoles, pyrroles and furans with substitution of azadienes by a chrial phosphoric acid was developed. A large variety of C2 substituted triarylmethanes derivatives were achieved in moderate to good yields (up to 98%) with generally excellent enantioselectivities (up to 99% ee).

ChemInform Abstract: Sulfonyl Azoles in the Synthesis of 3‐Functionalized Azole Derivatives

AbstractReview: [111 refs.

Sulfonyl Azoles in the Synthesis of 3-Functionalized Azole Derivatives.

Sulfonyl indoles, as well as related azolyl derivatives, have been recently introduced in synthesis as stable precursors of reactive indolenine intermediates. This personal account reports on the discovery of sulfonyl azoles and their practical utilization in many synthetic processes for the preparation of functionalized 3-substituted indoles, indazoles, and pyrroles. The indolenine intermediates obtained by treatment of sulfonyl azoles with Brønsted bases or Lewis acids can be considered as vinylogous imino derivatives that can be made to react with different nucleophilic reagents. These include organometallic reagents, reducing agents, stabilized carbanions, and heteronucleophiles. The controlled and mild conditions for the generation of indolenines from sulfonyl azoles make these substrates particularly useful in asymmetric synthesis, exploiting organo- or metal-catalyzed processes. Although less exploited, sulfonyl indoles can also be involved in photochemical processes for the preparation of polycyclic derivatives.

Highly Efficient Aluminum Trichloride Catalyzed Michael Addition of Indoles and Pyrroles to Maleimides

A highly efficient synthetic strategy for Michael addition of indoles and pyrroles to maleimides has been developed using the Lewis acids zinc chloride or aluminum trichloride as the catalyst. The reactions generated 3-substituted indoles and 2-substituted pyrroles in high yields with excellent regioselectivity in the presence of a catalytic amount of zinc chloride or aluminum trichloride under mild reaction conditions. The method is simple, efficient, and practical.

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.

1,2‐Migration of the Thio Group in Allenyl Sulfides: Efficient Synthesis of 3‐Thio‐Substituted Furans and Pyrroles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 2- and 3-Substituted N-Methylpyrroles

A reliable method of synthesis of 3-bromo-N-methylpyrrole by the use of N-bromosuccinimide and a catalytic amount of PBr3 is reported. The method described opens a facile route to a variety of 3-substituted pyrroles, which are otherwise difficult to access. In addition, conditions under which pure 2-bromo-N-methylpyrrole can be obtained have been established.

Elucidation of the mechanism of pyrrole formation during thermal degradation of 13C-labeled l-serines

Pyrolysis of [13C-1], [13C-2] and [13C-3]-labelled l-serines generated mono-substituted methyl and ethyl derivatives of pyrroles and pyrazines among other compounds. Analyses of label incorporation into the pyrroles have indicated their formation through aldol condensation of acetaldehyde with different α-aminocarbonyl compounds followed by cyclization and loss of water (Knorr pyrrole synthesis). Comparison of the label incorporation patterns of the α-aminocarbonyls involved in the formation of methyl and ethyl-substituted pyrroles with that of similarly substituted pyrazines, revealed their common origin. In addition, α-aminocarbonyls involved in the formation of 2- and 3-substituted pyrroles had identical label distribution patterns, indicating their formation through the same carbonyl precursors. Furthermore, the major pathway (55%) leading to the formation of the α-aminocarbonyl precursors of methyl-substituted pyrroles involved aldol addition of formaldehyde to glycolaldehyde, whereas the only pathway leading to the formation of the α-aminocarbonyl precursors of ethyl-substituted pyrroles involved the interaction of alanine — formed in situ — with glycolaldehyde.

The synthesis of a number of 3-alkyl and 3-carboxy substituted pyrroles; their chemical polymerisation onto poly(vinylidene fluoride) membranes, and their use as gas sensitive resistors

A number of synthetic pathways to 1-phenylsulphonyl and 1-tosylsulphonyl pyrrole have been reviewed and repeated. Two novel methods of producing this pre-cursor to 3-substituted poly(pyrroles) have been developed utilising crown ether phase transfer reagents or the aprotic solvent dimethylsulphoxide (DMSO). The most effective method of producing 1-phenylsulphonyl pyrrole was via the reaction of 1-phenyl or p-toluene sulphonamide and 2,5 diethoxytetrahydrofuran (the Clauson–Kaas method). The method was facile and yielded 81% of a highly pure product. 1-Phenylsulphonyl and 1-tosylsulphonyl pyrrole were utilised as pre-cursors, in the synthesis of a range of 3-substituted pyrroles via Friedel–Crafts acylation reactions. Subsequent de-protection followed by reduction yielded the 3-alkyl substituted pyrrole monomers, whilst, a thallium transposition via the Willgerdot–Kindler reaction yielded the 3-carboxy derivatives which were then deprotected to give the 3-carboxy pyrrole monomers or esterified to yield the 3-substituted ester analogues. The 3-substituted pyrrole monomers were then polymerised chemically onto poly(vinylidene fluoride) membranes to yield conducting polymer films. The resulting 3-substituted polymer films were tested for their gas sensitivity towards a number of classes of volatile organic compounds (VOCs). The 3-substituted polymers were found to exhibit enhanced sensitivity and differing selectivities to the test vapours when compared to poly(pyrrole) alone. The selectivity of the resulting sensors to certain organic vapours could be controlled by altering the substituents on the pyrrole ring, for instance where alkyl chains were added the responses of the resulting sensors to non-polar vapours such as hexane were enhanced. The addition of longer alkyl chains to the pyrrole ring resulted in a progressive enhancement in the sensitivity to non-polar vapours whilst the sensitivity to polar compounds remained constant or was reduced.

Post-column photochemical reaction detection in liquid chromatography based on photosensitized generation of singlet molecular oxygen: Study of reaction parameters and application to the determination of polychlorinated biphenyls

The parameters effecting the sensitivity and selectivity of a photochemical reaction detection scheme based on the reaction of 3-substituted pyrroles with singlet molecular oxygen (1O2) in HPLC are reported. Polychlorinated biphenyls (PCBs) were chosen as model compounds for the detection scheme. Following separation by reverse-phase chromatography, PCBs are excited by a Hg pen-ray lamp in a crocheted PTFE photochemical reactor. PCBs that are efficient1O2-sensitizers promote ground state O2 (3Σ-3) to an excited state (1Σg+ or1Δg) which rapidly oxidizes 3-substituted pyrroles which are added to the mobile phase. Detection is based on the loss of pyrrole. The reaction is catalytic in nature since one analyte molecule may absorb light many times, producing large amounts of1O2. Detection limits for 4,4′-dichlorobiphenyl and Aroclors 1242, 1248 and 1254 were improved by 1–2 orders of magnitude over optimized UV-absorbance detection. Configuration of the photochemical reactor and judicious choice of the wavelength used to follow the loss of pyrrole were determined to be the most important factors in terms of sensitivity of the detection scheme. Comparison of three reagents (i.e. 3-substituted-pyrroles) used for trapping1O2 demonstrates the effect of substitution on sensitivity and to some extent selectivity of PCB determination.

Polymerization of Monolayers of 3-Substituted Pyrroles

Derivatives of 3-substituted pyrroles were spread at the air−water interface. Stable films could be obtained for pyrroles with side chains containing more than 10 carbons. 3-Hexadecanoylpyrrole could not be polymerized as a monolayer whereas the alkyl derivatives could be polymerized successfully without having additional monomer in the subphase. The monolayers could be transferred onto hydrophobic substrates with transfer ratios close to unity. The polymers formed were soluble in chloroform and tetrahydrofuran. Molecular-weight averages obtained by gel permeation chromatography ranged from 3500 to 6000 when polymerized on ammonium peroxydisulfate and 5000 to 15000 when polymerized on ferric chloride subphase solutions. 1H NMR indicates that the polymerization is highly regular, leading to a constitutionally ordered 2,5-poly(3-alkylpyrrole).

Photooxidation of 3-Substituted Pyrroles: A Postcolumn Reaction Detection System for Singlet Molecular Oxygen in HPLC

A postcolumn photochemical reaction detection scheme, based on the reaction of 3-substituted pyrroles with singlet molecular oxygen ((1)O(2)), has been developed. The method is selective and sensitive for the determination of a class of organic compounds called (1)O(2)-sensitizers and is readily coupled to HPLC. Following separation by HPLC, analytes ((1)O(2)-sensitizers) are excited by a Hg pen-ray lamp. Analytes that are efficient (1)O(2)-sensitizers promote ground-state O(2) ((3)Σ(g)(-)) to an excited state ((1)Σ(g)(+) or (1)Δ(g)), which reacts rapidly with tert-butyl-3,4,5-trimethylpyrrolecarboxylate (BTMPC) or N-benzyl-3-methoxypyrrole-2-tert-carboxylate (BMPC), which is added to the mobile phase. Detection is based on the loss of pyrrole (BTMPC or BMPC). The reaction is catalytic in nature since one analyte molecule may absorb light many times, producing large amounts of (1)O(2). Detection limits for several (1)O(2)-sensitizers were improved by 1-2 orders of magnitude over optimized UV-absorbance detection. This paper discusses the optimization of the reaction conditions for this photochemical reaction detection scheme and its application to the detection of PCBs, nitrogen heterocycles, nitro and chloro aromatics, and other substituted aromatic compounds.

The Birch reduction of 3-substituted pyrroles

Abstract The Birch reduction of electron-deficient 3-substituted pyrroles is described. Use of a reductive alkylation procedure involving sodium metal in liquid ammonia gave good yields of 4-alkyl-2-pyrrolines. The identity of these products was proven by an X-ray structure of a crystalline derivative. Moreover, the pyrroles used in this study could be readily prepared by reaction of TOSMIC with acrylic amides and esters and, once the reduction was complete, the ester activating group could be easily removed to yield the corresponding N-protected β-proline derivatives.

Synthesis, phase behaviour and polymerisation of mesogenic materials based on 3-substituted pyrroles

Synthetic routes which lead to the formation of 3-substituted pyrroles with mesogenic units are described. Two particular compounds have been prepared: 3-{6-[4-(4-methoxyphenylazo)phenoxy]hexyl}pyrrole and 3-[6-(4′-cyanobiphenyl-4-yloxy)hexyl]pyrrole. Both exhibit monotropic liquid crystalline phases, and for the latter compound the stability of the mesophase observed could be increased by incorporation of a small amount of a commercially available liquid crystal. Electrochemical investigations show that the azobenzene based material is a poor candidate for the formation of polypyrrole derivatives, because of the ease with which competing oxidative processes occur. The cyanobiphenyl derivative, in contrast, has been polymerised electrochemically to form electrically conducting polymer films; these films reveal an electrochromic effect by virtue of reversible doping. It has also proved possible to polymerise this material chemically to give a polymeric material which is soluble in a variety of solvents. A further procedure involved oxidation with bromine vapour to polymerise the material in an aligned state; the yields of such polymers, however, are poor, and considerably lower than those obtained for materials prepared in the isotropic melt.

A new synthesis of monosubstituted succinaldehydes and 3-substituted pyrroles from acetonitriles. Formal synthesis of 2,3-dihydro-7-methyl-2H-pyrrolizidin-1-one (Danaidone), a semiochemical of danaid butterflies

A convenient and versatile synthesis of monosubstituted succinaldehydes and 3-substituted pyrroles from acetonitriles was devised. The methodology was applied to the preparation of 9 , the penultimate intermediate in the Meinwald and Meinwald synthesis of Danaidone. 12

Synthesis and 1,3-dipolar cycloaddition reaction of homoadamantane-incorporated nitrones and rearrangement of the cycloadducts to homoadamantane-fused pyrroles

The bridging nitrones 7, 8 incorporated in a homoadamantane ring system were obtained by oxidation of 4-azahomoadamantane 5, 6 with SeO 2/H 2O 2. The 1,3-dipolar cycloaddition reaction of these nitrones with the electron-deficient alkynes proceeded regiospecifically at 0 °C-r. t. to give 4-substituted isoxazolines. The reaction with phenylacetylene required forced conditions, where 5-substituted isoxazoline 9d was obtained from 7 using the dipolarophile as a solvent, and rearranged pyrrole 12d was formed directly from 8 at a higher reaction temperature. The resulted cycloadducts from ketonitrone 8 were further converted to homoadamantane-fused pyrroles. In this case, 2-substituted and 3-substituted pyrroles 12a and 12e were obtained respectively from the same starting material via the different mechanism. The former arose via an acylaziridine route by thermolysis and the latter via an enamine route in protic solvents.

Vinyl Polymers Bearing a Pyrrole Ring. II. 5,10,15,20-Tetraphenylporphyrins with a Substituent-Bearing Vinyl Group at the Pyrrole Residue and Their Zinc Complexes

Abstract 5,10,15,20-Tetraphenylporphyrins (Por) with a styrenic double bond-bearing substituent attached at the pyrrole residue with an amide or ester spacer were synthesized starting with 3-substituted pyrroles. Free radical copolymerization of ZnPor, prepared from Por, with 1-vinyl-2-pyrrolidone gave more favorable results than did Por.

Electrochemical glucose sensors on permselective non-conducting substituted pyrrole polymers

Our aim has been to construct biosensors which can be produced in large numbers for commerical use with high stability and selectivity. Thin-film technology is able to provide the high purity and reproducibility required of the electrode surface and the high spatial resolution of the electrode structure. A four-electrode electrochemical cell with an outer diameter of 2.5 mm possessing two identical working electrodes is produced by using glass sheets or Upilex foils as electrode carriers. These sheets, coated with thin titanium layers acting as an adhesion layer, are covered with platinum to form an electro-chemical electrode. After structuring, the conducting lines are isolated by silicon nitride or polyimide. To coat the platinum electrodes with polymeric layers new strategies in the synthesis of 1- and 3-substituted pyrroles have been developed to obtain 1-(carboxyalkyl) pyrroles, 2-(1-pyrrolo)-acetylglycine, 1-alkylpyrroles, 1-(4-carboxybenzyl)-pyrrole, 1-(4-nitrophenyl) pyrrole, 4-(3-pyrrolo)-4-ketobutyric acid and 3-((keto 4-nitrophenyl) methyl) pyrrole as monomers. New types of polymer-coated electrodes are prepared and characterized further by electrochemical oxidation and polymerization of these monomers in organic solvents. To couple enzymes and to activate terminal carboxy and nitro groups of the polymer, water-soluble carbodiimides and chloranil are found to give the best results. The activated electrodes are reacted immediately with glucose oxidase and the glucose sensors thus obtained are stored at 4 °C. Electrodes covered by substituted polypyrrole layers having no redox activity show two fundamental advantages: a significant increase of response per unit area due to the porous polymer and permeation control for interfering electroactive substances by the polymeric layer, resulting in a distinct increase in selectivity.

A convenient method of synthesis of 1,3-disubstituted pyrroles

A method has been proposed for the detosylation of 3-substituted pyrroles by potassium in tetrahydrofuran with a simultaneous activation of the 1-position for the subsequent alkylation or acylation of the pyrrolepotassium derivative.