Heterocycles electron-deficient

No simple electrophilic substitution, for example nitrosation, nitration, sulfonation or halogenation of a C—H bond, has so far been recorded in the pteridine series. The strong 7T-electron deficiency of this nitrogen heterocycle opposes such electrophilic attack, which would require a high-energy transition state of low stability. 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

The above examples illustrate reactions at an electron-deficient carbon atom. Other 1,1-bielectrophiles allow the direct introduction of a heteroatom into the resultant heterocycle. The most widely applicable and versatile methods for the synthesis of 1,2,5-thiadiazoles and 1,2,5-selenadiazole rely on this approach. 

A versatile method for the synthesis of a variety of five-membered heterocycles and their ring-fused analogs involves the reaction of a neutral 47r-electron-3-atom system with a 27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity exerting only a moderate influence on the reaction, indicates that the cycloaddition proceeds via a concerted mechanism 63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in general terms by the expression in Scheme 8. 

The participation of a single double bond of a heterocycle is found in additions of small and large rings azirines (Section 5.04.3.3) and thietes (Section 5.14.3.11) furnish examples. Azepines and nonaromatic heteronins react in this mode, especially with electron deficient dienes (Scheme 16 Section 5.16.3.8.1). 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

The structural principles and reaction chemistry of B-8 compounds have recently been reviewed. This includes not only electron-precise 4-, 5- and 6-membered heterocycles of the types described above, but also electron-deficient polyhedral clusters based on closo-. 

An interesting intermediate 30 was proposed to result from the sequential addition of pyridine to tetrachlorocyclopropene (31). Compound 30 represents an alkyl nitrogen ylide with two 1-chloroalkyl pyridinium moieties in the same molecule. Pyridines with electron-withdrawing groups and heterocycles with an electron-deficient nitrogen, for example, pyridine-3-carbaldehyde or quinoline, react with 31 to yield the corresponding mono-substituted products 32a and 32b (83JOC2629) (Scheme 8). 

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. 

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. 

Other electron-deficient heterocyclic systems have also been investigated as electron-transporting materials. In particular, devices employing poly(phenyl qui-noxaline) 43 as an ECHB layer have shown improvements in device efficiency when used in conjunction with an emissive PPV layer [75]. 

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]. 

Recently, Li et al. have reported an efficient 1,3-dipolar cycloaddition of azides with electron-deficient alkynes without any catalysts at room temperature in water.128 The reaction has been applied successfully to the coupling of an azido-DNA molecule with electron-deficient alkynes for the formation of [l,2,3]-triazole heterocycle (Eq. 4.66). 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

As sulfones are known to be readily displaced from electron deficient nitrogen-containing heterocycles, Bessard noted significant rate enhancements as well as improved yields in the displacement of the chloride on pyrimidine 49 by alcohols, through the use of sodium methylsulfinate as a catalyst <00T4739>. The production of trialkoxypyrimidines 51 as potential herbicides, presumably formed from the displacement of methysulfinate from intermediate 50 by the various alcohols, required a less than a stoichiometric amount of sodium methylsulfinate (typically 0.10-0.25 equivalents). 

The 2-thiobenzopyrylium salt 86 behaves as an electron-deficient diene undergoing [4++2] polar cycloadditions with electron-rich alkenes to give the benzo-fused bicyclo[2.2.2]thia-heterocycles 87 (Scheme 59) <00TL2161>. 

Pyridine is a jt-electron-deficient heterocycle. Due to the electronegativity of the nitrogen atom, the a and y positions bear a partial positive charge, making the C(2), C(4), and C(6) positions prone to nucleophilic attacks. A similar trend occurs in the context of palladium chemistry. The a and y positions of halopyridines are more susceptible to the oxidative addition to Pd(0) relative to simple carbocyclic aryl halides. Even a- and y-chloropyridines are viable electrophilic substrates for Pd-catalyzed reactions under standard conditions. 

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