Pyridines electron-poor

An alternative drivirg force could involve a donor - acceptor interaction. The electron-poor pyridine ring that is coordinated to the copper cation can act as electron acceptor with respect to the aromatic ring of the -amino acid. The fact that donating substituents on the amino acid increase the efficiency... 

The fluorination of quinoline was performed in a microstructured reactor operated in the annular-flow regime, which contained one microchannel with two consecutive feeds for gas and liquid [311,312]. The role of the solvent was large. The reaction was totally unselective in acetonitrile and gave only tarlike products. With formic acid, a mixture of mono- and polyfluorinated products besides tar was formed. No tar formation was observed with concentrated sulfuric acid as solvent at 0-5 °C. In this way, a high selectivity of about 91% at medium conversion was achieved. Substitution was effective only in the electron-rich benzenoid core and not in the electron-poor pyridine-type core. The reactivity at the various positions in the quinoline molecule is 5 > 8 > 6 and thus driven by the vicinity to the heteroatom nitrogen that corresponds to the electrophilic reactivity known from proton/deuterium exchange studies in strong acid media. 

Even the electron-poor pyridine and quinoline systems carrying donor substituents (238), (239), and (241) undergo (4-1-2) cycloadditions at 130°C and extended reaction times (12-14 hours) (Scheme 44) <93AP(326)427> to yield pyridopyridazines (237) as well as the pyridazinoquinoline (242) the latter results from the reaction of the electron-rich 1,2-naphthalene double bond. 

In contrast to electrophiles, nucleophiles prefer reaction at the electron-poor pyridine nucleus. These reactions are quite analogous to those with pyridine. 

The azanaphthalenes (benzopyridines) quinoline and isoquinoline contain an electron-poor pyridine ring, susceptible to nucleophilic attack, and an electron-rich benzene ring that enters into electrophilic aromatic substitution reactions, usually at the positions closest to the heterocyclic unit. 

Pyridine is the prototypic electron-poor 6-membered ring heterocycle conceptually obtained by replacing one of the CH units of benzene with nitrogen (Figure 8.1.1). The aromaticity originally found in the benzene framework is maintained in... 

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

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. 

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

Moderate to good enantioselectivities were obtained for nearly all examples, but the products from 83a-c could be recrystallized to higher enantiomeric purity. Addition of iodine was critical for catalysis as was the use of a ligand with electron-poor para-fluorophenyl groups on the phosphorous atom. Substitution at the 3 position of the pyridine ring was described as being difficult for both the quinolines and pyridine systems. The resulting hydrazine derivatives could be easily converted to piperdines by reduction with Raney nickel or under Birch conditions. 

The pyridine nucleotides NAD and NADP always function in unbound form. The oxidized forms contain an aromatic nicotinamide ring in which the positive charge is delocalized. The right-hand example of the two resonance structures shown contains an electron-poor, positively charged C atom at the para position to nitrogen. If a hydride ion is added at this point (see above), the reduced forms NADH or NADPH arise. No radical intermediate steps occur. Because a proton is released at the same time, the reduced pyridine nucleotide coenzymes are correctly expressed as NAD(P)H+HT... 

The oxidation of substituted pyridines to iV-oxides was reported by Sharpless and coworkers to proceed with yields between 78 and 99% (Scheme 154). A variety of substituents like electron donor as well as acceptor groups and alkenyl substituents are tolerated. In 1998, Sharpless and coworkers reported an alternative method for the preparation of pyridine-A-oxides in which the MTO/H2O2 catalyst could be replaced by cheaper inorganic rhenium derivatives (ReOs, Re207, HOReOs) in the presence of bis(trimethylsilyl) peroxide (equation 73). Yields of the prepared A-oxides after simple workup (filtration and bulb to bulb distillation) ranged from 70-98%. Molecular sieves slowed down the reaction while small amounts of water (0-15%) were essential for the reaction. Both electron-poor or electron-rich pyridines give high yields of their A-oxides and while para-... 

The pioneer work on this subject using simple 1-azadienes is due to Ghosez et al. (82TL3261 85JHC69) they succeeded in reacting 1-azadienes as 47r-electron components in Diels-Alder cycloadditions. Thus, l-dimethylamino-3-methyl-l-azabuta-l,3-diene (a,/3-unsaturated hydrazone) 54 did undergo [4 + 2] cycloaddition to typical electron-poor dienophiles, e.g., methyl acrylate, dimethyl fumarate, acrylonitrile, maleic anhydride, and naphthoquinone, producing pyridine derivatives 55-57 (Scheme 14). 

X - and especially X -phosphorins are electron-rich aromatic compounds, comparable with aniline, whereas pyridine and pyridinium ions are electron-poor and are comparable to nitrobenzene. Many chemical properties can be easily understood once this fact is taken into account. 

Other reactions of electron-poor aza-heterocycles that are suspected to involve a SET mechanism include 1-lithiodithiane with pyridine (73CL1307) and 1,8-naphthyridine (78ZC382), and LDA with pyridine (82JOC599). 

In the case of the electron poor alkenes, results were more varied. Under all conditions examined, reactions with methyl vinyl ketone, acrylonitrile, methacrylonitrile and 4-vinyl pyridine afforded products with IR spectra equivalent to those obtained without the addition of the alkene (side reaction). In the cases of vinyl bromide and chloromethyl styrene, unreacted PCTFE was recovered unchanged. It is speculated that electron transfer to the alkene proceeded in each case. While the product of vinyl bromide reduction was not observed, perhaps because of volatility, one could isolate poly(chloromethylstyrene) in the latter case. 

Support-bound pyridines and partially saturated pyridines can be valuable synthetic intermediates, enabling various types of chemical transformation. Piperidinones can be prepared on cross-linked polystyrene by the addition of organometallic reagents to tetrahydropyridinones (Entry 10, Table 15.23). 1,2-Dihydropyridines are electron-rich dienes that can undergo Diels-Alder reaction with electron-poor dienophiles. Diels-Alder cycloaddition of support-bound 1,2-dihydropyridines has been used to prepare nitrogen-containing polycyclic systems (Entry 12, Table 15.23). 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

Figure 10.2 illustrates selected examples of these epoxide products. Aromatic and heteroaromatic aldehydes proved to be excellent substrates, regardless of steric or electronic effects, with the exception of pyridine carboxaldehydes. Yields of aliphatic and a,/ -unsaturated aldehydes were more varied, though the enantio-selectivities were always excellent. The scope of tosylhydrazone salts that could be reacted with benzaldehyde was also tested (Fig. 10.3) [29]. Electron-rich aromatic tosylhydrazones gave epoxides in excellent selectivity and good yield, except for the mesitaldehyde-derived hydrazone. Heteroaromatic, electron-poor aromatic and a,/ -unsaturated-derived hydrazones gave more varied results, and some substrates were not compatible with the catalytic conditions described. The use of stoichiometric amounts of preformed sulfonium salt derived from 4 has been shown to be suitable for a wider range of substrates, including those that are incompatible with the catalytic cycle, and the sulfide can be recovered quantitatively afterwards [31]. Overall, the demonstrated scope of this in situ protocol is wider than that of the alkylation/deprotonation protocol, and the extensive substrate...

More recently, Chiu and coworkers have developed a Ni complex containing a tetradentate pyridine/NHC ligand (complex 18, Eq. 22) which catalyzes the Suzuki reaction at catalyst loadings between 1 and 3 mol% [56]. Aryl iodides, bromides, and chlorides with both electron-rich and -poor aryl rings were compatible. However, electronically poor or electronically neutral aryl bromides performed much better than did electron-rich aryl bromides. It was also found that the use of 2 equivalents of PPh3 was crucial to achieving high yields with aryl chlorides. 

Photocycloaddition reactions of alkyl and aryl 2-thioxo-3//-benzoxazole-3-carboxylates 142 to alkenes afforded stable isolable spirocyclic aminothietanes 143 <02HCA2383> similar reactions with both electron-poor and electron-rich alkenes were also performed on 2-methyloxazolo[5,4-h]pyridine <02EJO4211>. 

In general, the rate of the reaction of arylation of phenols by aryllead triacetate increases with the electron density of the phenolic substrate. When pyridine is used as a base, no reaction takes place with electron-poor phenols, such as 2,6-dichlorophenol or 2,6-dichloro-4-nitrophenol.45 45a However, the reaction of the sodium salt of perfluorophenol 43 with phenyllead triacetate under more forcing conditions led to a range of products the product of >rtfe -arylation, the 6-aryl-2,4-cyclohexadienone 44 together with minor amounts of the product of / zra-arylation 45 and the unsymmetrical diaryl ether 46 (Equation (43)).69... 

An alternative one-step polar cyclization procedure involves the condensation of n nucleophiles with amides to efficiently produce highly substituted pyridines <07JA10096>. As shown below, acetylenes 5 or enol ethers 6 react with electron-poor and electron-rich N-vinyl and A-aryl amides 7 that are activated with triflic anhydride in the presence of 2-chloropyridine. This novel method employs mild reaction conditions and provides rapid access to highly substituted pyridines 8 with good regiocontrol. 

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