Chloromethyl phenyl sulfone reaction

The reaction of 3-methoxy-1,2,4-triazine 1-oxide 20 with the carbanion generated from chloromethyl phenyl sulfone proceeds as the vicarious nucleophilic substitution (VNS) of hydrogen (Scheme 1, path B) via addition of the carbanion at position 5 of the heterocycle. Following base-induced elimination of HCl and protonation, 3-methoxy-5-phenylsulfonyl-1,2,4-triazine 4-oxides 65 result (88LA627). 

At the same time, the reaction of 1,2,4-triazine 4-oxides 55 with the anion of chloromethyl phenyl sulfone affords 5-(l-chloro-l-phenylmethyl)-l,2,4-triazines 66. In this case, autoaromatization of the a -adducts proceeds by the deoxygenative... 

Nitro-, 4-nitro-, 7-nitro-, 5,7-dinitro-, and 6,8-dinitroquinoline react with the carbanion of chloromethyl phenyl sulfone to give products of substitution of hydrogen at positions 4 3 8 6,8 and 5,7 respectively <96LA641>. The base-induced reaction of benzoyl chloride salts of quinoline iV-oxides with carbonitriles to give 2-quinolyldiacylamines as the main products has been reported <96TL(37)69>. 

Control of the regioselectivity of VNS is important. It is governed by three major factors the structure of the nitroarene the nature of the nucleophile, and the reaction conditions, especially solvent and base. The different effect of methoxy and hydroxy groups is interesting the reaction of l-methoxy-2,4-dinitrobenzene with chloromethyl phenyl sulfone proceeds in... 

Trifluoromethyl iodide is a poor substrate for SN2 reactions [28], The increased donativity of the methylene carbon as rendered by the fluorine atoms is reflected in its reluctance to enter a bonding relationship with a nucleophile. Similar reactivity patterns are known for chloromethyl phenyl sulfone [28] and chloromethyltrimethyl-silane. In these latter compounds the reactive center is directly linked to an acceptor group. 

In conclusion, all results obtained thus far on this reaction show that it is especially the 4-position in the 3-nitro-l,8-naphthyridines which is strongly favored toward the attack of the carbanion of chloromethyl phenyl sulfone. When position 4 is occupied by a substituent no reaction occurs. This behavior is in accordance with the behavior observed in reactions with liquid ammonia and liquid methylamine. 

When chloromethyl phenyl sulfone (130 Ar = phenyl) was subjected to the Darzens-type reaction with an aldehyde, a thermodynamically stable trans isomer (133) was produced exclusively (equation 32). This is in sharp contrast with the corresponding reaction of chloromethyl phenyl sulfoxide. Tavares proposed that the initial nucleophilic attack of the a-sulfonyl carbanion upon a carbonyl compound is rapidly reversible due to its stability, and that the product-determining step is the ring closure. Thermodynamic equilibrium between the two diastereomers of (132) allows predominant formation of the thermodynamically stable isomer (133) from the preferred transition state. ... 

Aral, S., Shioiri, T. Asymmetric Darzens reaction utilizing chloromethyl phenyl sulfone under phase-transfer catalyzed conditions. Tetrahedron 2002, 58,1407-1413. 

Later, Arai, and coworkers applied their PTC-mediated Darzens reaction conditions to the synthesis of optically active oc, 3-epoxysulfones [43], The reaction of the chloromethyl phenyl sulfone 102 with aromatic aldehydes under PTC conditions (101 (10mol%), KOH-toluene) at room temperature afforded the desired trans-epoxysulfones 103 in good yields and with moderate to good ee values (33-81%) (Scheme 8.35). On the other hand, aliphatic aldehydes gave the Darzens product as the racemates. The use of a Lewis acid additive (Sn(OTf)2) improved the selectivity, but only slightly (up to 32% ee). Under PTC conditions, chloromethylsulfone is transformed into the corresponding carbanion, which then reacts with the... 

The electrophilic phosphonylation of chloromethyl phenyl sulfone in the presence of n-BuLi (2 eq) proceeds smoothly at low temperature, probably via the sulfone dianion, to give diethyl 1-lithio-1-chloro-l-(phenylsulfonyl)methylphosphonate. This is treated in situ with aliphatic or aromatic aldehydes and ketones to obtain a-chloro-a,(3-unsaturated ketones by the Homer-Wadsworth-Emmons reaction in good overall yields (76—85%)... 

Another method to introduce a substituent into the 1,2,4-triazine system is vicarious nucleophilic substitution. Here, a carbanion with a leaving group at the carbanionic center reacts with a 1,2,4-triazine replacing protons in the 5-, 3- and 6-position with the carbanionic moiety. The reactivity of the various positions decreases in the order 5 > 3 > 6. This reactivity differs from that toward Grignard reagents. Thus, substitution of the 5-position occurs in the 1,2,4-triazine to afford 15 which undergoes elimination to 16 followed by protonation to yield 17 275,276 Carbanions of the following compounds were used in this reaction nitrones, chloromethyl phenyl sulfones, chloromethanesulfonamides and acetonitriles.274-378... 

Reactions of carbonyl compounds and imines. The salt 4 obtained from reaction of cinchonine with m-xylylene dibromide is shown to promote enantioselective transfer of the trifluoromethyl group from Me3SiCF3 to aryl ketones Also obtained from quinidine the salt containing a trifluorobenzyl group (5) promotes the condensation of chloromethyl phenyl sulfones with ArCFlO to give benzenesulfonyl epoxides ... 

However, under the conditions that favor dissociation of the adducts and disfavor p-elimination, namely, a higher temperature and absence of a strong base, the conventional S Ar of fluorine atom can be observed [13]. Interestingly, the reaction of wefa-dinitrobenzene with an excess of this carbanion gave the disubstitution product, whereas with equimolar amounts of reactants only monosubstitution proceeds. It is evident that the anion of 2,4-dinitrobenzyl phenyl sulfone is still sufficiently active electrophile to react with the carbanion of chloromethyl phenyl sulfone (Scheme 3) [14]. 

The effect of substituents on the rate of addition of carbanions to nitroarenes and the rate of p-elimination of HL from the o adducts have also been studied [8, 30, 31]. The former effect is an important parameter, because it is, in fact, a measure of influence of substituents on electrophilic activity of nitroaromatic rings. The effect of substituents on rate of the S Ar reactions of o- and p-halonitrobenzenes has been thoroughly studied [2, 32]. However, since the S Ar of halogen is a secondary process, the obtained data cannot be used as a real measure of electrophilicity of halonitroarenes. We have determined the effects of substituents and the ring structure on the rate of the VNS reactimi of nitroarenes with the carbanion of chloromethyl phenyl sulfone by using competitive experiments under the conditions, which assure a fast p-eUmination of HL from the o adducts [30, 31]. The values of VNS rates obtained under such conditions proved to correlate with those of the addition step. Selected values of the relative rate constants in relation to nitrobenzene as the standard are shown in Fig. 1. 

A variety of other azaaromatic compounds, pteridines [66], pyridazines [67] etc., enter the VNS reactions with the model carbanion of chloromethyl phenyl sulfone or other a-chlorocarbanions. In these reactions azine N-oxides are more active electrophiles than azines themselves. For instance, quinoline fails to enter the VNS reaction with the model carbanion, whereas quinoline N-oxide reacts rather smoothly [68]. Also 3-(chloromethylsulfonyl-amino)pyridine-N-oxide and its quinoline analogue are able to undergo intramolecular VNS reactions [61]. 

Introduction of arylsulfonylmethyl substituents into nitroheteroaromatic rings is of great practical value because these sulfones are versatile intermediates in organic synthesis. Nitrobenzyl aryl sulfones and their heterocyclic analogues can easily be transformed into the corresponding ethenyl derivatives by a simple alkylation with simultaneous elimination of arylsulfinate anion [125]. Diethyl methylenemalonate substituent can be introduced in the positimi 4- of 5-nitroimidazole via the VNS reaction of 5-nitroimidazole with the carbanion of chloromethyl phenyl sulfone [112, 124], followed by condensation of the obtained 4-(phenylsulfonyl)methyl derivative with diethyl bromomalonate or diethyl ketomalonate (Scheme 33) [126]. 

Both approaches described above have been used for the synthesis of indoles bearing the pentafluorosulfanyl group [36,37]. The reaction of meta- and para-nitro (pentafluorosulfanyl)benzene 25 with phenoxyacetonitrile (Scheme 15) under VNS conditions followed by hydrogenation gave rise to SFs-substituted indoles 26. At the same time, the reaction of nitro compounds 25 with chloromethyl phenyl sulfone and the subsequent reduction of the nitro group in substitution products led to amines 27 - precursors of 2-substituted indoles 28 (Scheme 15). 

The use of chloromethyl phenyl sulfone as a carbon nucleophile in the VNS reaction of 17 and 18 allowed one to obtain substitution products 27 and 28. In this case, the undesirable para-substituted regioisomer of 27 was formed in only 4% yield. Reduction of the nitro group in sulfones 27, 28 provided corresponding anilines 29 and 30, which gave good yields of imines 31, 32 with both electron-acceptor and electron-donor benzalde-hydes. Further cychzation under basic conditions provided access to 2-aryl substituted 5(6)-SF5-indoles 33 and 34 (Scheme 7). 

Products of VNS are generated and exist in the reaction mixtnres in the form of nitroben-zylic carbanions that are not electrophilic anymore thus, the reaction proceeds selectively as monosubstitution. Nevertheless, the carbanion of chloromethyl phenyl sulfone can react with m-dinitrobenzene to form products of mono- and disubstitution (Scheme 11.19). Obviously, the second nitro group in the nitrobenzyUc carbanion of the monosubstitution product imposes sufficient electrophilicity on the ring thus, this carbanion behaves as the electrophilic partner, a kind of Michael acceptor that is able to react with the carbanion of chloromethyl phenyl sulfone [34]. Of course, the reaction of this carbanion with dinitrobenzene is much faster than with the nitrobenzylic carbanion of the monosubstitution product, so the rates of monosubstitution and disubstitution differ substantially, and these reactions proceed with high selectivity. 

Since VNS can proceed under kinetic control, namely, initially formed a -adducts can be converted into the products faster than they dissociate, the reaction can serve as a proper tool for determination of electrophilic activities of nitroarenes. Effects of substituents on rates of S Ar was subject of thorough studies [43] however, the results, although useful in practice of synthesis, cannot be considered as a reliable measure of electrophilic activities of nitroarenes because S Ar of halogens is a slow secondary process preceded by a reversible formation of the o -adducts. On the other hand, the rate of VNS reaction under kinetic control reflects the rates of the initial nucleophilic addition of carbanions to nitroaromatic rings, thus can be used as measure of electrophilic activities of these compounds. Particularly convenient and reliable way to determine such effects is the competitive experiments in which two nitroarenes compete for the VNS reaction with carbanion of chloromethyl phenyl sulfone under conditions that assure faster (1-elimination of HCl from the o -adducts than their dissociation [42]. Relative rate constants of the addition of this carbanion to some nitroarenes in relation to nitrobenzene are given in Scheme 11.24. 

SCHEME 11.39 VNS versus aziridination of quinoxaline in the reaction with carbanion of chloromethyl phenyl sulfone [61]. 

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