Electron-deficient heteroaromatics

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). 

In contrast to H shifts, C shifts cannot in general be used to distinguish between aromatic and heteroaromatic compounds on the one hand and alkenes on the other (Table 2.2). Cyclopropane carbon atoms stand out, however, by showing particularly small shifts in both the C and the H NMR spectra. By analogy with their proton resonances, the C chemical shifts of k electron-deficient heteroaromatics (pyridine type) are larger than those of k electron-rieh heteroaromatic rings (pyrrole type). 

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]. 

Alkali metal borohydrides are frequently used for the reduction of rc-electron-deficient heteroaromatic systems, but reduction of jt-electron-excessive arenes is generally possible only after protonation of the systems [e.g. 35-37]. The use of tetra-n-butylammonium borohydride under neutral conditions for the conversion of alkylindoles into indolines [38] is therefore somewhat unusual. Reduction of indoles by diborane under strongly alkaline conditions involves the initial interaction of the indolyl anion with the diborane to form an amino-borane which, under the basic conditions, reacts with a second molecule of diborane to produce the indoline [39]. The reaction of tetra-n-butylammonium borohydride with indoles could also proceed via the intermediate formation of diborane. 

The use of soluble amine bases failed to give products, whereas the heterogeneous conditions KOH/THF proved optimal in promoting aldoxime formation for a broad range of substrates. Optically active nitroalkanes including aromatic (both electron-rich and electron-deficient), heteroaromatic, branched and unbranched aliphatic substrates, as well as substrates that incorporate unprotected alcohol functionalities were successfully reduced. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

Nearly all combinations of common electron-excessive heteroaromatics have been achieved by modification of this procedure. However, this procedure has not been successful so far with electron-deficient heteroaromatics (76JOC2536). However, bis-Wittig heterocyclic reagents (75S765) have been condensed with a variety of dialdehydes to generate a series of annulenones (e.g. 47) and annulenes (78HCA2763, for a review see 77CRV513). 

Thus, photolytic treatment of O-acyl esters (2) with electron-deficient heteroaromatics salts prepared from the reaction of heteroaromatics with camphorsulfonic acid or trifluoroacetic acid, effectively produces the corresponding alkylated heteroaromatics. Details on the alkylation of heteroaromatics with O-acyl esters (2) are given in Chapter 5. 

The extremely electron-deficient heteroaromatic dications produced by quatemization of both ring nitrogen atoms of the naphthyridines very readily form pseudobases in aqueous solution. The data of Table I indicate that pKR+ values for N.AT-dimethylnaphthyridinium dications are 7-10 units lower than for the corresponding N-methylnaphthyridinium monocations. The N,N -bridged 1,10-phenanthrolinium dications 17 and 18 also have considerably lower pK values than the N-methyl-1,10-phenanthrol in ium... 

Carbon-carbon bond introduction in electron-deficient heteroaromatics 90UK1288. 

Inverse demand Diels-Alder cycloadditions of electron-rich nitriles with electron-deficient heteroaromatic dienes are also known. Typical examples of inter- and intra-moleculai instances of this process are shown in equations (29) and (30), respectively. 

As with the simple heterodienes, the electron-deficient heteroaromatic azadienes have proven ideally suited for 4Tt participation in LUMOdiene-controlled Diels-Alder reactions. In fact, it was Ae recognition of this electron-deficient nature of heteroaromatic azadienes that led to the proposed and demonstrated rate acceleration that may accompany the reversal of the electronic properties of the Diels-Alder diene-dienophile partners and subsequently led to the full investigation of the LUMOdiene-controlled Diels-Alder reaction. 

This logic type proved particularly difficult to emulate at the molecular scale until Credi et al. provided the breakthrough [48]. Following a mechanochemical line of attack (see Section 5.3.1), an electron-rich macrocycle 12 serves as a bead sliding on a string which is made from an electron-deficient heteroaromatic 13. The complex 12-13 is held together by charge transfer (CT) interactions. This same CT... 

Pyridine is a reasonably strong base and a good nucleophile. Although its dielectric constant is rather low (e = 12), many salts are soluble in pyridine and the solutions have good conductivity. In contradistinction to most bases, pyridine, which is a jr-electron-deficient heteroaromatic compound, is rather resistant toward oxidation. 

Hydrodimerization of activated alkenes is a well-established process. 7r-Electron-deficient heteroaromatic compounds activate a double bond similarly to a cyano or car-bethoxy group, and in accordance with that analogy vinylpyridines can be hydrodimer-ized. 4-Vinylpyridine [380] forms l,4-bis-(4-pyridyl)butane in 82% yield on electrolysis in a mildly alkaline solution containing methyltriethylammonium / -toluenesulfonate and some DMF. The mechanism is discussed in Chapter 21. 

The (6 5 6) systems discussed in this Section are combinations of fully conjugated Tu-electron excessive and Tu-electron-deficient heteroaromatic rings. They readily undergo electrophilic substitution reactions, which, as a rule, are highly regioselective. 

Diels-Alder reactions of electron deficient heteroaromatic dienes... 

The direct arylation of electron-deficient heteroaromatic A -oxides with aryl and alkenyl tosylates or mesylates was achieved by using a palladium catalyst (Scheme 6) [24]. 

As for direct amination of electron-deficient heteroaromatic A-oxides, the combination of liquid ammonia and potassium permanganate is known to be a very effective system for such type of C-H functionalizations. It has been reported that 6-phenyl-l,2,4-triazine-4-oxide can easily be aminated in liquid ammonia on treatment with potassium permanganate to give 5-amino-6-phenyl-l,2,4-triazine 4-oxide (Scheme 23) [49]. 

The chapter The SN -Amination of Aromatic Compounds , authored by Anna Gulevskaya and Alexander Pozharsky (Rostov-on-Don University, Russia), presents a comprehensive review on the direct Sn amination of electron-deficient heteroaromatic compounds. Recent advances in this area and many new aspects of the Sn amination are discussed, including new types of reagents, metal-free catalysts, solvents and the hydride ion acceptors. The review shows that the amination is rather promising synthetic alternative to both classic and transition metal-catalyzed amino-dehalogenation reactions. 

Oxadiazole is a stable electron deficient heteroaromatic compound. It is well known that 2,5-diphenyl-1,3,4-oxadiazole reacts with sodium to yield a radical anion which disproportionates to form a dianion (Scheme 2). 

Radical-based carbon-carbon bond formation with electron-deficient heteroaromatics. The reaction entails an intermolecular addition of a nucleophilic radical to protonated heteroaromatic nucleus. 

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