Azomethine group, alkylation

Nitrofuran antibacterials are synthetic compounds that are substitution products of the 5-nitrofuran nucleus, differing in the substituent at position 2. This substituent may be an azomethine group connected with other ring systems, or an alkyl, acyl, hydroxyalkyl, or carboxyl group, free or esterified. All these antibacterials are susceptible to photolysis, particularly by sunlight, and manipulations must be carried out under subdued light. 

R = Ph) is the most widely investigated of these compounds and serves as a suitable reference compound. Kalb and Bayer3 reported the methanol, ammonia, aniline, and sodium bisulfite adducts of this compound. The reactivity of the indolone increases when the electron density at the 2-position is reduced. In these cases (158 R = 4-nitrophenyl, 2-pyridyl, C02alkyl),49,61,62,91 the indolone adducts (175 Nu = OH, OEt) are stable and isolable the free indolones do not exist. The 2-alkylindolones (158 R = alkyl), in which the conjugation of the azomethine group is less extensive, are also very reactive. They too are only isolated as adducts (175 R = alkyl Nu = OH) with the exception of 158 (R = 1-Bu, Section IV,A,2). 

Aldehydes can be alkylated indirectly via the corresponding imines lithium dialkylamides readily deprotonate such imines at the position a to the azomethine group, and the carbanions formed can be alkylated with primary halides. This route to a-substituted aldehydes avoids the use of sodium borohydride, necessary in the dihydro-1,3-oxazine alternative. 

Most of these products are azo or anthraquinone types, often with a localised quaternary ammonium group isolated from the chromogen by a saturated alkyl chain, as in Cl Basic Red 18 (1.52). Such products often exhibit higher light fastness than the traditional delocalised types. Improved azomethine, methine and polymethine basic dyes of good light fastness are also available. In contrast to the more specialised traditional classes, the azo and methine dyes have contributed to the basic dye range across the entire spectrum of hues (see Table 1.6) and now account for a clear majority of all basic dyes listed in the Colour Index. 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Epoxidation also proceeds (Eq. 141) under mild conditions and with high stereoselectivity (95 5 erythro threo) despite the deactivating effect of the fluorine atom [361]. At a higher oxidation level, the Lausanne group described chemistry of a metallated azomethine derived from a,/Lunsaturated-a-fluoroaldehydes [362]. Highly flexible chemistry allowed alkylation at nitrogen, or at the (fluori-nated) -position, or at the -position (Fig. 8). 

The Pandey group has developed a silver fluoride-promoted desily lation of tertiary bis(silyl)amines as an interesting alternative method to access azomethine ylides (Scheme 2.10).18 Notably, this method allows the generation of nonstabilized azomethine ylides under essentially neutral conditions. The starting materials are prepared by a three-step process, sometimes coupled into a single operation. For example, Boc-protected pyrrolidine 36 can be sequentially deprotonated and silylated twice in a one-pot reaction (Scheme 2.10). Removal of the Boc group and alkylation of the free amine leads to bis(silyl)amine 37. When this compound is treated with 2 equiv of silver fluoride in the presence of phenyl vinyl sulfone, rapid formation of products 39 as single stereoisomers results. 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

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