SRN1 Substitution Processes

The lack of reactivity of 3-halo substituents under non-radical nucleophilic substitution conditions allows differential functionalization of pyri-dines by 3-umpolung and 2-nucIeophilic substitution processes. Thus, treatment of 2-fluoro-3-iodopyridine (189) with oxygen or amine nucleophiles affords products 191 which, upon subjection of SRN1 reactions with carbon, phosphorus, and sulfur systems, give 2,3-difunctionalized pyri-dines 192 (Scheme 56) (88JOC2740). 

Substituent effects in reaction 1 have received little attention because of the lack of suitable methods of generating specific free radicals under basic conditions. One general process involving reaction 1 is the SRN1 substitution... 

There is a limited number of examples of preparations involving the reaction of stannyl-alkali metal compounds with a substituted heteroarene, for example, Equations (58)-(60).88,197,198 Some of these reactions (e g Equation (58)) occur only with photoirradiation, showing that they involve SRN1 processes, but others may be straightforward nucleophilic heteroaromatic substitutions. 

There are not many successful examples of arylation of carbanions by nucleophilic aromatic substitution. A major limitation is the fact that aromatic nitro compounds often react with carbanions by electron-transfer processes.111 However, such substitution can be carried out under the conditions of the SRN1 reaction (see Section 11.4). 

Unactivated aryl halides also undergo nucleophilic displacement via electron transfer in the initial step the so-called SRN1 mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the Srn process often competes with the addition-elimination pathway. The SRN reactions are radical chain processes, and are usually photochemically promoted. For example, ketone (895) is formed by the SRN1 pathway from 2-chloroquinoxaline (894) (82JOC1036). 

Intramolecular nucleophilic substitution by the anions of o-haloanilides is another viable oxindole synthesis. This is a special example of the category Ic process described in Section 3.06.2.3. The reaction is photo-stimulated and the mechanism is believed to be of the electron-transfer type SRN1 rather than a classical addition-elimination mechanism. The reaction is effective when R = H if 2 equivalents of the base are used to generate the dianion (equation 202) (80JA3646). 

The most important recent development in this area has been the use of various single-electron reductants to initiate the free radical chain process. Such reduc-tants have been most commonly metals or anionic species, and such processes have been used either to initiate addition processes or substitution (SRN1) processes... 

For the chemist practicing polysubstituted aromatic and heteroaromatic synthesis, methods steeped in classical electrophilic (1, Scheme 1) [1] and nucleophilic substitution [2] and SRN1 (2) [3] reactions have been joined and, not infrequently super-ceded, by vicarious substitution (3) [4] and by DoM (4) [5] processes. The Murai ortho CH activation (5) [6] is a recently evolving and potential competitive method to the DoM tactic. The 60 years since its discovery by Wittig and Gilman, and 40 years since its systematic study by the school of Hauser, the DoM reaction has advanced by the contributions of Christensen, Beak, Meyers, and many other... 

The SRN1 process has proven to be a versatile mechanism for replacing a suitable leaving group by a nucleophile at the ipso position. This reaction affords substitution in nonactivated aromatic (ArX) compounds, with an extensive variety of nucleophiles ( u ) derived from carbon, nitrogen, and oxygen to form new C—C bonds, and from tin, phosphorus, arsenic, antimony, sulfur, selenium, and tellurium to afford new C-heteroatom bonds. 

The addition of a nucleophile to a radical to form the radical anion of the substitution product constitutes the main feature of a SRN1 process, although the chain can be short or even nonexistent (reaction 2). For a photoinduced reaction, a quantum yield higher than 1 can be taken as evidence of a chain reaction, although a global quantum yield below 1 cannot be used as a criterion against a chain reaction [9,10]. 

Aryl amide anions are bidentate nucleophiles allowing C—C bond formation and the synthesis ofaminobiaryls. PhNH- gives low yields of substitution with Arl under irradiation, whereas 2-naphthylamide ions react by a photoinduced SRN1 process... 

Ph3Sn- ions are also reactive nucleophiles for the photoinitiated SRN1 process. This anion gives substitution products in good yields (62-100%) with ArX (X = Cl, Br, 0P(0)(Et0)2) in liquid ammonia [38, 42]. Additionally, the reaction of p-C6H4Cl2 with Ph3Sn- ions gives 75% yield of disubstitution in liquid ammonia [38],... 

For substrates with EWGs or 2-substituted-ArX, the yields of ArSMe are good (49-87%) (Scheme 10.28). In these reactions, the competitive SRN1 process of the ArS- ions with the aryl radical is retarded since the reactivity of ArS- ions is diminished [46]. 

Substituted 2,3-dihydro-l-H-indoles 26 are accessible by the versatile application of a 5-exo ring closure process during the propagation cycle in the SRN1 reaction [67]. Following the initial ET and fragmentation of the radical anion of the substrate, the... 

The photostimulated reaction of 1,8-diiodonaphthalene with p-methyl-benzenethio-late ions in DMSO yields the substituted cyclized product 10-methyl-7-thia-benzo[de] anthracene (31) in moderate yield (Scheme 10.58) [54], The mechanism proposed to explain product 31 involves an intramolecular radical cyclization after monosubstitution in the propagation cycle of the SRN1 process. 

Nitrocumyl chloride undergoes smooth light-induced substitution by nucleophiles such as phenolate and thiophenolate, benzenesulfinate, azide, cyanide or amines, and the process has been proven to involve a SRN1 mechanism [55,77,78]. 

The novelty of this work involves the versatile application of 5-exo ring closure processes during the propagation cycle of the SRN1 reaction the alkyl radical intermediates formed then reacted with the nucleophiles to afford the ring closure-substituted heterocycles. The factors governing the observed product distribution are discussed and one of the examples is illustrated below <02JOC8500>. 

Electron-catalyzed (or electron-stimulated) processes constitute a relatively new class of reactions of great potential synthetic interest (Zelenin and Khidekel, 1970 Linck, 1971). Foremost among these ranks the SRN1 mechanism, which is an electron-initiated radical-chain mechanism of nucleophilic substitution (21-24 X- = halide ion) (for reviews, see Kornblum, 1975 Bunnett, 1978, 1982). The initiation step (21) can be performed photochemically, electrochemically, or by adding alkali metal (Pinson and Saveant, 1978 Amatore et al., 1979 van Tilborg et al., 1977, 1978 Saveant, 1980). 

Besides halogenated derivatives, the aromatic substrates liable to substitution via the SRN1 process include compounds containing other leaving groups,... 

An important group of reactions pertaining to this class is the nucleophilic substitution of a chloro or a nitro group at the benzylic position of p-nitrocumyl derivatives similarly to the SRN1 ring substitution (Sect. 2.1.4) the process is accelerated by light absorption (possibly on the part of a nucleophile-substrate ground state complex) and proceeds via a chain mechanism (Scheme 36) [192-194]... 

The SRN1 reaction thus appears as a reaction in which single electron transfer plays a pre-eminent role but is by no means a single elementary step. A different problem is that of the possible involvement of single electron transfer in reactions that are not catalysed by electron injection (or removal). A typical example of such processes is another substitution reaction, namely,... 

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