Ether-substituted pyrroles

Pyrrole is soluble in alcohol, benzene, and diethyl ether, but is only sparingly soluble in water and in aqueous alkaUes. It dissolves with decomposition in dilute acids. Pyrroles with substituents in the -position are usually less soluble in polar solvents than the corresponding a-substituted pyrroles. Pyrroles that have no substituent on nitrogen readily lose a proton to form the resonance-stabilized pyrrolyl anion, and alkaU metals react with it in hquid ammonia to form salts. However, pyrrole pK = ca 17.5) is a weaker acid than methanol (11). The acidity of the pyrrole hydrogen is gready increased by electron-withdrawing groups, eg, the pK of 2,5-dinitropyrrole [32602-96-3] is 3.6 (12,13). 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

A process which has proved valuable in synthesis is the addition of singlet oxygen to A-alkyl- and especially A-acylpyrroles producing 2,3-dioxa-7-azabicyclo[2.2.1]-heptanes which react with nucleophiles, such as silyl enol ethers, mediated by tin(II) chloride, generating 2-substituted pyrroles which can be used, as shown, for the synthesis of indoles. 

This section covers cyclizations to the pyrrole nucleus catalyzed by other metals (Ti, Mn, Ru, Pd, Pt, Zn, In). Dembinski and co-workers used zinc(II) chloride as ligand-free catalyst for the microwave-assisted cyclization of homopropargyl azides 26 to afford substituted pyrroles 27 (Scheme 8) [62]. A similar methodology for the synthesis of 2,4,5-trisubstituted pyrroles was described by Driver et al. employing substituted 1-azidobuta-l,3-dienes in a cyclization reaction using catalytic amounts of zinc(ll) iodide [63]. A three-component zinc-catalyzed one-pot cyclization of aromatic and aliphatic propargylic acetates, silyl enol ethers, and primary amines to substituted pyrroles has been described by Zhan et al. The reaction sequence includes propargylation of the silyl enol ether, amination, 5-exo-(7ig-cyclization, and isomerization [64]. Hiroya and co-workers have shown... 

Bromination of Aromatic Compounds. Phenols, anilines, and other electron-rich aromatic corrqiounds can be monobromi-nated using NBS in DMF with higher yields and higher levels of para selectivity than with Br2 iV-TrimethyIsilylanilines and aromatic ethers are also selectively brominated by NBS in CHCI3 or ecu. A-Substituted pyrroles are brominated with NBS in THF to afford 2-bromopyrroles (1 equiv) or 2,5-dibromopyrroles (2 equiv) with high selectivity, whereas bromination with Br2 affords the thermodynamically more stable 3-bromopyrroles. The use of NBS in DMF also achieves the controlled bromination of imidazole and nitroimidazole. Thiophenes are also selectively brominated in the 2-position using NBS in acetic acid-chloroform. ... 

A rhodium-catalyzed transannulation of tosyl-triazoles 9 with silyl or alkyl enol ethers 10 was developed that allows for the synthesis of substituted pyrroles 11 with regiocontrol.The addition ofTsOH promotes the final dehydration step to afford pyrroles with different functionality. The method can also be adjusted to allow for the synthesis of 3-pyrrolin-2-ones by using silyl ketene acetals as one of the coupling partners (14TL6455). 

A recent report from Kirsch s group illustrated that vinyl propargyl ethers 36, as surrogates of skipped allenyl ketones 37, could be employed in a very efficient synthesis of densely substituted pyrroles 29S via the Ag/Au(I)-catalyzed... 

Functionalization of pyrrole with ether groups has been studied less, probably because of the difficulties often encountered in the synthesis of substituted pyrroles. 3,4-Dimethoxypyrrole (46) has been prepared [249] electropolymerization has given a highly conducting polymer (120 S cm" ), but its electrochemical behavior is not significantly different from that of polypyrrole. 

A mixture of amine (1 5 mmol), 1,4-dicarbonyl compound (2 6 mmol), and sulfamic acid (25 mg, 5 mol%) was stirred at room temperature under solvent-free conditions for specified period (30-90 min for varying entries). After completion of the reaction, as indicated by thin-layer chromatography (TLC), the reaction mixture was diluted with diethyl ether and filtered to recover the catalyst. The ether layer was washed with brine, dried (MgS04), and coti-centrated in vacuo. The residue was purified by silica-gel column chromatography (20% ethyl acetate in hexane) to afford the desired substituted pyrrole (3) in excellent yield (81-93%). The recovered catalyst was washed with diethyl ether and activated at 70 "C prior to reuse it could be reused for the next reaction without losing any significant activity as tested for at least three times. All the products were characterized by H NMR, HRMS and analytical data. 

For example, reaction with aromatic aldehydes gives a-alkynyl amino alcohols, which can be trapped as their silyl ethers. Base-catalyzed isomerization to an allenic isomer followed by hydrolysis and concomitant cyclization affords 2-substituted pyrroles (eq 16). ... 

For preparative purposes the Gattermann reaction is much more useful. It was first usedS5 to prepare ethyl 2-formyl-3,5-dimethyl- and ethyl 3-formyl-2,5-dimethyl-pyrrole-4-carboxylate, by means of hydrogen cyanide and hydrogen chloride in ether. Later applications sometimes involved minor changes such as the use of chloroform as solvent, or of Adams modification of the reaction . Formylation generally occurs at an a-position, but if none is open there is usually no difficulty in jS-substitution. Pyrrole-2-aldehyde cannot be made this way, for it reacts further to form dyestuffs, but several 1-alkylpyrroles have been satisfactorily formylated . The initial... 

Perfluorinated heterocycHc compounds are of interest due to their synthetic uses and bioactivity. Bouillon and coworkers transformed fluori-nated fiirans into substituted pyrroles and 3-pyrrolin-2-ones (2004S711). 2-Perfluoroalkyl furans were treated with benzylamine in ether at room temperature for 16 h to provide a mixture of N-benzyl-3-pyrrohn-2-one diastereomers. 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

The high reactivity of pyrroles to electrophiles is similar to that of arylamines and is a reflection of the mesomeric release of electrons from nitrogen to ring carbons. Reactions with electrophilic reagents may result in addition rather than substitution. Thus furan reacts with acetyl nitrate to give a 2,5-adduct (33) and in a similar fashion an adduct (34) is obtained from the reaction of ethyl vinyl ether with hydrogen bromide. 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104], In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(tntIuoromethyl)benzyne were shown to react in moderate yields with A7-(trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

In attempting to extend the method to other activated aromatics, it was found that pyrroles give mixtures of 2- and 3-substituted products, and that naphthol ethers and benzo[6]thiophene fail to react. 

Ferreira developed a novel method for the preparation of masked 1,4-dicarbonyl derivatives for utilization in the Paal-Knorr synthesis of pyrroles <00SC3215>. In this process, the reaction between diazocompound 3 and n-butyl vinyl ether using dirhodium tetraacetate as catalyst provides dihydrofurans 4 which are easily converted into substituted... 

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