Heterocyclic electron rich

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

Concerning nomenclature, fulvalene 2 and its related systems 1 and 3-6 are the parent structures of this class of heterocyclic cross-conjugated compounds. Both ring systems are numbered as shown in formula 9 (1,4,5,8-tetraazafulva-lene) beginning at the heteroatoms. Alternatively, as in the case of heptafulva-lene 10 (3,3 -diazaheptafulvalene), the numbers 1-7 and l -7 can be used.Tlie use of the name of the parent heterocycle connected by an olefinic double bond is often favored for the nomenclature of electron-rich olefines, for example, bis[3-(2,6-diisopropylphenyl)-4,5-dimethylthiazol-2-ylidene] for compound 51a (97LAR365). Similarly, azafulvalenes of type 11 and 12 can be re-... 

To complete this section, we note the cleavage of electron-rich DTDAFs by CH-acidic five-membered heterocycles of the oxazolidine, thiazolidine, and imidazolidine types (64BSF2857). 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles ... 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Hetero Diels-Alder reacdons using nitroalkenes followed by 1,3-dipolar cycloaddidons provide a nsefid strategy for the constnicdon of polycychc heterocycles, which are found in naturM products. Denmark has coined the term tandem [4t-2 /[3t-2 cycloaddidon of nitroalkenes for this type of reacdon. The tandem [4-i-2 /[3-i-2 cycloaddidon can be classified into font famihes as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respecdvely. " In generril, electron-rich alkenes are favored as dienophdes in [4-i-2 cycloaddidons, whereas electron-deficient alkenes are preferred as dipolarophdes in [3-i-2 cycloaddidons. 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). 

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]. 

Coupling reactions with diazonium salts to yield intensely colored azo derivatives have often been used for the detection of phenols, primary aromatic amines and electron-rich heterocyclics. 

In addition to bromides and iodides, the reaction has been successfully extended to chlorides,163 triflates,164 and nonafluorobutanesulfonates (nonaflates).165 These reaction conditions permit substitution in both electron-poor and electron-rich aryl systems by a variety of nitrogen nucleophiles, including alkyl or aryl amines and heterocycles. These reactions proceed via a catalytic cycle involving Pd(0) and Pd(II) intermediates. 

A different approach for the modification of the basic Malachite Green lactone structure has been the replacement of one 4-dimethylaminophenyl group by electron-rich heterocycles. The most thoroughly investigated heterocycle has been the 3-indolyl residue, which may be introduced by two different routes as shown in Scheme 7. 

Reaction of the indolylbenzoylbenzoic acid with electron-rich heterocycles other than indoles has also produced a number of novel color... 

Tables 15 and 16 show the absorption maxima of some metal complexes of benzothiazolyl-substituted formazans 230 and 231.283 The wavelengths are metal ion dependent, making formazans useful reagents for the identification of specific metal ions or the simultaneous determination of two ions. The wavelengths are much longer than those of the formazan anion (Table 14). The general trend for electron-rich substituents is toward a larger shift this is to be expected as it tends to enhance the aromatic character of the ring and increase the covalent character of the metal — nitrogen bond. The sharpness of the absorption band has been attributed to coordination to the heterocyclic nitrogen as in 232.57S...

Quinazolines containing an electron-rich carbocyclic ring have been associated with smooth muscle relaxant activity. The mechanism of action (phosphodiesterase inhibition, a- adrenergic blockade) and organ selectivity (bronchi, vascular smooth muscle) vary greatly with substitution on the heterocyclic ring. 

An interesting example of t 3 coordination of a boratabenzene to a transition metal has been observed for a Zr(IV)-boratanaphthalene complex (Scheme 20).35 Thus, treatment of the illustrated 1-boratanaphthalene with Cp+ZrCl3 furnishes an adduct in which the metal-carbon distance for the 3, 4, and 5 positions of the heterocycle (2.53-2.56 A) is significantly shorter than for the 2 and 6 positions (2.77-2.81 A). It is suggested that this distorted bonding mode is the consequence of the high electron demand of Zr(IV), which prefers coordination to the most electron-rich carbon atoms. ... 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

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. 

Electron-rich heterocyclic systems such as indolizines react readily with DEAZD (and PTAD) to give substitution products (Eq. 16).141 None of the formal [8 + 2] cycloaddition products (e.g., 89) are observed. This is in direct contrast to the reaction of indolizines with electrophilic acetylenes which gives high yields of cycloaddition products, presumably via a stepwise mechanism, in the presence of palladium on charcoal.142 This example of... 

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