Cine-substitution products

In general, heterocyclic nitro compounds undergo cine substitution reactions more readily than nitrobenzenes. For example, the reaction of 5-acyl- or 5-alkoxycarbonyl-2-nitrofurans with the anion of nitroalkanes gives cine substitution products in excellent yields (Eq. 5.66).104... 

When a,p-unsamrated sulfones are employed as substrates for the rhodium-catalyzed 1,4-addition of aryltitanium reagents, they provide cine-substitution products instead of regular 1,4-addition products [Eq. (3.16)]. This new process... 

An exhaustive study has been made on the 3,4-dinitrothiophene system <78JCS(Pl)li40>. This gives rise to a plethora of interesting products, depending on the 2,5-substituents and on the nucleophile used. In the reaction of 3,4-dinitrothiophene with thiophenoxide in methanol, the major compound isolated was the cine substituted product (421) based on the intermediates isolated, the mechanism shown in Scheme 138 has been put forward. 

JOC4257). In the reaction of monobromo compounds (486) and (487) with piperidine, the major products are normal ones with 3-bromobenzo[6]thiophene (487) a small amount of the cine substituted product (489) is formed (Scheme 166). 2,3-Dibromobenzo[f>]thio-phene (488) initially gives the 2-piperidino-3-bromo derivative (490) at 106 °C, which is debrominated to (489) at 180 °C. This result suggests that the small amount of (489) from (487) might arise through a transbromination-debromination sequence (73JOC1365). 

Triarylphosphines were prepared by the reaction between lithium diphenylphosphide in THF and m-and p-iodotoluene (or the corresponding bromo compounds), 4-bromobiphenyl and p-dibromobenzene in yields of 70-80% (isolated after oxidation, as the phosphine oxides).143 The absence of cine substitution products is a synthetic advantage and would have been taken as a prima facie indication that the displacements are examples of the 5rn1 reaction, had the mechanism been recognized at the time. Operation of the radical ion mechanism in DMSO, or liquid ammonia, in which marginally improved yields are obtained, was confirmed by Swartz and Bunnett,48 but no extension to the scope of the reaction was made. Rossi and coworkers have developed a procedure for one-pot preparation of triarylphosphines starting from elemental phosphorus (Scheme 6).146 As an example of the synthesis of a symmetrical tri-arylphosphine, triphenylphosphine (isolated as its oxide) was obtained in 75% yield, with iodobenzene as the aryl halide (ArX in Scheme 6, steps i-iii only). Unsymmetrical phosphines result from the full sequence of reactions in Scheme 6, and p-anisyldiphenylphosphine (isolated as its oxide) was produced in 55% yield, based on the phosphorus used, when chlorobenzene (ArX) and p-methoxyanisole (AiOC) were used. 

The kinetics and mechanism of the reactions of trialkyl phosphites with mucochloric acid (dichloroaldehydoacrylic acid) have been studied.6 Cine-substitution products are formed in reactions of 2,5- and 2,6-dichloro-l,4-benzoquinone with pyrrolidine.7... 

The kinetics and mechanism of the reactions of trialkyl phosphites with mucochloric acid (dichloroaldehydoacrylic acid) have been studied. Cine-substitution products are formed in reactions of 2,5- and 2,6-dichloro-l,4-benzoquinone with pyrrohdineJ The reaction of vinyl fluoride with CN has been studied by the DFT B3YLP/6-31- -G(d) method. This nucleophilic substitution is mainly a n attack with a barrier height of 14.8kcalmol , which is 17.91 kcalmoC more favovuable than the a attack. 

When fran5-)8-[fluoro(dimethyl)silyl]styrene was allowed to react with iodobenzene, a small amount of 1,1-diphenylethene (cine substitution product) was produced in addition to the expected tra/ii -stilbene (ipso substitution product) [Eq.(12)]. 

Under the same conditions, o -[fluoro(dimethyl)silyl]styrene gave a 75 25 mixture of ipso and cine substitution products. Formation of the ipso substitution product was favored with the substrate having an electron-withdrawing group, whereas an electron-donating group gave preferential cine substitution [Eq.(l3)] [10]. 

For halogenated pyrimidines, dehydrohalogenation competes with elimination of the hydride ion, as shown for 5-bromopyrimidine (173) in Scheme 64 (82JHC1285). Other examples are the amination of 4-tert-butyl-5-chloropyrimidine (174) and 2,4-di-fert-butyl-5-chloropyrimidine (175) with potassium amide in liquid ammonia (78RTC288). Some cine-substitution products (176 and 177) were also obtained (Scheme 65). From isotopic labeling studies, it was determined that the Sn(ANRORC) mechanism was not involved. 

The reaction of cyanide with a protected 5-bromouridine is instructive under mild conditions a cine-substituted product is obtained via a Michael addition followed by p-elimination of bromide, but at higher temperatures, conversion of the 6- into the 5-cyano-isomer is observed, i.e. the product of apparent, direct displacement of bromide is obtained. The higher-temperature product arises via an isomerisation involving another Michael addition, then elimination of the 6-cyano group. 

Substitution at the carbon that was attached to the leaving group is called direct substitution. Substitution at the adjacent carbon is called cine substitution (cine comes from kinesis, which is Greek for movement ). In the following reaction, o-toluidine is the direct-substitution product m-toluidine is the cine-substitution product. 

The second possibility requires an alternative to the elimination-addition mechanism to account for the formation of the cine-substitution product. Several such reactions are known, the von Richter reaction [equation (16)] being the oldest and most thoroughly studied. Since the accepted mechanism of this reaction specifically requires the presence of a nitro group, it has been suggested that if nitro groups are absent cine-substitution may be taken as good evidence of an aryne mechanism. While this statement may be valid for simple benzenoid compounds it does not necessarily hold for highly substituted or heterocyclic aromatics. 

Another nonaryne pathway to cine-substitution products is the abnormal addition-elimination (AEa) mechanism [equation (18)] in which the nucleophile adds ortho to the leaving group which is subsequently eliminated. An essentially similar mechanism was suggested and rejected for the amina-tion of halobenzenes, since the observed 1 1 ratios of normal to cine-substitution products from both chloro- and iodobenzene-l- C would require the highly unlikely, fortuitous combination of normal (AEn) [equation (19)] and abnormal (AEa) [equation (18)] substitution for two different halobenzenes. Understandably, it was concluded that the elimination-addition (EA) ... 

Either of the halobenzofurazans 600 or 601 reacts with thiomethoxide ion to give both the 4- (602a) and the 5-thiomethoxy (603a) compounds but not in identical ratios. Although an elimination-addition mechanism via the aryne 604 was considered for at least part of this reaction it was rejected based on the low basicity of mercaptide ion and on the lack of deuterium incorporation from solvent in the normal-substitution products. An AEa mechanism (Section II.2.A.e) was proposed instead to account for the cine-substitution products and seems to be consistent with the available data. ... 

One example of a cine-substitution which in principle could involve a hetarynium species recently has been reported in the pyrazole series. Reaction of the dinitropyrazole 636 with secondary amines leads to the cine-substitution product 637. Although an elimination-addition process via the hetarynium species 638 was considered, an AEa mechanism (Section II.2.A.e) involving 639 and 640 was preferred and adequately accounts for all the observations. 

Nucleophilic Substitution, Metallation, and Halogen-Metal Exchange.—Direct nucleophilic displacement of the 7-chloro-group of 7-chloro-3-methyl-benzo[b]thiophen has been achieved. 3-Bromobenzo[b]thiophen was reduced to the 3-deuterio-derivative by the reaction with sodium borodeuteride and palladium chloride. Meisenheimer complexes were formed in the reaction of methoxide ion with 2-methoxy-3-nitro- and 3-methoxy-2-nitrobenzo[b]thiophen. Rate and equilibrium data were determined in methanol at 25 C. On treatment of 2-bromobenzo[b]thiophen with potassium amide in liquid ammonia, bromine migration to the adjacent carbon atom was observed. Considerable evidence for the occurrence of an intermolecular transbromination was obtained. The reaction of 3-bromo-benzo[b]thiophen with piperidine has been reinvestigated and found to give primarily the normal, but also some of the cine-substitution product, which is the only product obtained in the reaction of 2-bromobenzo[b]thiophen. Possible mechanisms for some of these reacticms are suggested. 

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