Thiophene electron-rich

The replacement of two CH groups in benzene by a neutral NR, O or S introduces into the new ring an electron-donating heteroatom. This electron-donor character is accentuated in the pyrrole anion where N is introduced. Thus the five-membered rings with one heteroatom are electron rich (rr-excessive), and the chemistry of pyrrole, furan and thiophene is dominated by this effect and is again considered together as a whole in Part 3. 

Small shift values for CH or CHr protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally Sh = 2.5 - 3.2), alkene CH (generally 4, = 4.5-6) and aro-matic/heteroaromatic CH (Sh = 6 - 9.5), and also between rr-electron-rich (pyrrole, fiiran, thiophene, 4/ = d - 7) and Tt-electron-deficient heteroaromatic compounds (pyridine, Sh= 7.5 - 9.5). 

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

In 2001 the first microwave-enhanced Sonogashira protocol including examples of heteroaromatic skeleta appeared. Trimethylsilylacetylene could be efficiently introduced on electron-rich and electron-deficient heteroaromatics as exemplified by thiophene and pyridine, respectively (Scheme 49) [68]. 

The site of dihydroxylation in heterocycles depends on the nature of the heteroaromatic system (Scheme 9.31) usually, electron-rich heterocycles like thiophene are readily biooxidized but give conformationally labile products, vhich may undergo concomitant sulfoxidation [241]. Electron deficient systems are not accepted only pyridone derivatives give corresponding cis-diols [242]. Such a differentiated behavior is also observed for benzo-fused compounds biotransformation of benzo[b] thiophene gives dihydroxylation at the heterocyclic core as major product, while quinoline and other electron-poor systems are oxidized at the homoaromatic core, predominantly [243,244]. 

Electron-rich aromatic compounds such as durene, p-dimethoxybenzene, mesitylene, anisole, thiophene, and fluorene can be benzoylated or acetylated by the corresponding Af-acylimidazole in trifluoroacetic acid to give the corresponding benzophenone or acetophenone derivative in good yield (Method A). As the actual acylating agent, a mixed anhydride of trifluoroacetic acid and benzoic acid has been proposed 1973... 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many rt-electron-rich heteroaryls including furan, thiophene, benzo[ ]furan and benzo[6] thiophene [42, 43]. In reactions of chloropyrazines with furan, thiophene and pyrrole, disubstituted heterocycles were also isolated albeit in low yields. 

Although excellent yields of the unsaturated amides and urethans could be obtained, hydrolysis of the urethans gave poor yields of the aldehyde. The application of the Curtius degradation resulted in excellent yields of the various intermediates and a fair yield of the aldehyde. It appears that the presence of the heterocyclic moiety renders these aldehydes less stable than the corresponding aldehydes in the benzene series. Possibly the electron rich thiophene ring bestows a higher reactivity on the hydrogen atoms of the methylene carbon. 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

R = OAc). Besides benzene, electron-rich arenes as well as thiophenes were successfully benzylated. 

The electron-rich thiophene ring system can be annelated by intramolecular Friedel-Crafts acylation reactions to give fused thiophenes <99IJC648, 99JMC2774>. The synthesis of a thiophene isostere of ninhydrin involved an intramolecular Friedel-Crafts acylation <99SL1450>. Specifically, treatment of thiophene 86 with thionyl chloride followed by aluminum chloride gave annelated thiophene 87. The synthesis of isothianinhydrin 88 was then accomplished in six steps from 87. 

The term charge tranter refers to a succession of interactions between two molecules, ranging from very weak donor-acceptor dipolar interactions to interactions that result in the formation of an ion pair, depending on the extent of electron delocalization. Charge transfer (CT) complexes are formed between electron-rich donor molecules and electron-deficient acceptors. Typically, donor molecules are p-electron-rich heterocycles (e.g., furan, pyrrole, thiophene), aromatics with electron-donating substiments, or compounds... 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Such [2 + 2] cycloadditions have also been observed when the alkyne is electron-rich and the benzo[6 ]thiophene electron-poor. Thus 3-nitrobenzo[6]thiophene reacts with ynamines to form the cycloadduct (285) the addition is regioselective and the product shows no tendency to isomerize to the corresponding benzothiepin (74TL2503). 

Several alternatives are open to the reactive nitrene species residing adjacent to the nucleus. The singlet nitrene can attack a suitable proximate, electron-rich centre or it may insert in the thiophene double bond to form an azirine which can subsequently undergo further transformations. A third alternative is for the singlet to cross over to the triplet state and then undergo the reactions characteristic of this biradical species. 

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