Benzo thiophenes nucleophilic substitution

The benzo[fc]thiophene sulfoxides, such as (142), generated from the parent benzo-thiophene on the H202-TFA-mediated oxidation, undergoes Michael-type nucleophilic addition of oxygen and sulfur nucleophiles in acidic media to produce 3-substituted benzo[fc]thiophenes (143). This method provides an easy two-step functionalization of 2-acylbenzo[fc]thiophene derivatives. ... 

Nucleophilic displacement of bromine in the readily available benzo[Z>]thiophene-l,l-dioxide 44 with phenols proceeds often in very good yields, as demonstrated by preparation of the molecule 45 <07TL2349>. It has also been found that 4-alkyl-2-nitrothiophenes participate in nucleophilic substitution reactions with secondary aliphatic amines in the presence of silver nitrate, rendering the corresponding 3-alkyl-2-amino-5-nitrothiophenes. In contrast, 2-nitrothiophene itself is ring-opened under such conditions <07JOC5771>. 

Some typical reactions of 1,1 -difluoroethene with nucleophiles are summarized in Scheme 2.18. Alkoxides [3], trialkylsilyl anion [4], ester enolates [5], and diphenylphosphinyl anion [6] attack the gem-difluorinated carbon of 5. However, it is noteworthy that nucleophilic substitution and proton abstraction are in some cases competitive, and thus s -butyl lithium abstracts the (3 -vinylic proton predominantly to generate vinyllithium. The lithium species can be trapped with an aldehyde, providing difluoroallyl alcohol, which is then hydrolyzed to a, (3-unsaturated carboxylic ester (11) [ 7 ] (Scheme 2.19). Some synthetically useful examples are shown in Schemes 2.20 and 2.21. Tetrathiafulvalene derivative (14) is prepared from difluorinated derivative (13) [8]. An elegant intramolecular version was demonstrated by Ichikawa, which provided a range of cyclized compounds (17), including dihydrofurans, thiophenes, pyrroles, and cyclopentenes, and also corresponding benzo derivatives (20) [2]. 

Bromobenzo [ ] thiophene 1,1-dioxide 117 and 3-bromo-2-phenylbenzo-[b]thiophene 1,1-dioxide 119 reacted with ammonia and primary and secondary amines to give the corresponding 3-aminobenzothiophene dioxides, 118 and 120, in good yields (Scheme 68) [17, 192-194]. 2-Benzoyl-3-chloro-benzo[ ]thiophene 1,1-dioxide 121 also reacted with a series of nitrogen nucleophiles to give substitution products 122 in good yields (Scheme 69) [195]. 

Bordwell et a/.354 358 have made an extensive study of the rearrangement reactions brought about by nucleophilic attack on a range of substituted halogenobenzo[b]thiophene-1,1-dioxides. 3-Chloromethyl- and 2-bromo-3-methylbenzo[b]thiophene-l,1-dioxide each give the same product with piperidine, the structure of which (Ref. 2, p. 358) has now been amended to 84 (R1 = R2 = H). With piperidine, 2-bromo-3-ethyl- and 2-ethyl-3-bromo-benzo[/>]thiophene-l,1-dioxides give amines 82a and 82b, respectively.354... 

Pyridazine-fused Systems.—Robba and co-workers have extended their earlier work on thienopyrazines to more heavily fused systems. From benzo[6]thiophen derivatives such as (575)—(577), the benzo[Z>]thieno-[2,3-reaction with hydra-zine. Compounds (579) and (580) could by standard methods be transformed to the chloro-derivatives, which easily undergo nucleophilic substitution, whereby different substituents were introduced at the pyridazinic... 

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. 

Pyrazole-, Thiazole>, and Imidazole>fused Thiophens.—Starting from (410) and carrying out nucleophilic substitution with thioglycolate followed by ring-closure, as described for (384) and (408), the thieno[2,3-d]pyrazole system (411) was synthesized. Their ionization constants have been determined and the transmission of the influence of the substituents R has been studied and found to be more feeble than in naphthalene d benzo[b]thiophen. From the cyano-derivative (412), thiophen-fused derivatives such as (413) and (414) have been synthesized. Electrophilic... 

Some theoretical aspects of thiophene reactivity and structure have also been discussed, for example the kinetics of proton transfer from 2,3-dihydrobenzo[6]thiophenc-2-onc <06JOC8203>, the configuration of imines derived from thiophenecarbaldehydes <06JOC7165>, and the relative stability of benzo[c]thiophene <06T12204>. The kinetics of nucleophilic aromatic substitution of some 2-substituted-5-nitrothiophenes in room temperature ionic liquids have also been investigated <06JOC5144>. 

The normal reactions of benzo[6]thiophene 1,1-dioxides have been reviewed (70AHC(11)177). Electrophilic substitution (nitration, bromination) takes place at position 6. 3-Halo derivatives undergo normal nucleophilic displacement reactions, but 2-bromobenzo[6]thiophene dioxide gives the 3-ethoxy derivative in ethanolic NaOH. The reaction of 3-methoxy derivatives with secondary amines can give rise either to enamines... 

The 2,3-double bond in benzo[6]thiophene-1,1-dioxides undergoes addition reactions with nucleophiles in a manner comparable to that of other a,/9-unsaturated sulfones no aromatic properties are detectable in this way for the thiophene ring.718-723 For example, thiophenol and p-thiocresol give the adducts (340 R = H or Me) in the presence of base.723 However, if the aryl mercaptan and the sulfone are heated together, a radical reaction occurs to give the corresponding 2-substituted compound.723 In contrast to the behavior of aryl mercap-... 

The chemical reactivity of simple heterocyclic aromatic compounds varies widely in electrophilic substitution reactions, thiophene is similar to benzene and pyridine is less reactive than benzene, while furan and pyrrole are susceptible to polymerization reactions conversely, pyridine is more readily susceptible than benzene to attack by nucleophilic reagents. These differences are to a considerable extent reflected in the susceptibility of these compounds and their benzo analogues to microbial degradation. In contrast to the almost universal dioxygenation reaction used for the bacterial degradation of aromatic hydrocarbons, two broad mechanisms operate for heterocyclic aromatic compounds ... 

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