SRN1 reactions substitution

Since the publication of the review on Single Electron Transfer and Nucleophilic Substitution in this same series,1 reviews or research accounts have appeared concerning several particular points among those addressed here, namely, dynamics of dissociative electron transfer,2-6 single electron transfer and Sn2 reactions,2,7 9 and SRN1 reactions.10,11... 

The base may deprotonate either C3 or C4. Deprotonation of C3 makes it nucleophilic. We need to form a new bond from C3 to C8 via substitution. The mechanism of this aromatic substitution reaction could be addition-elimination or Sr I. The requirement of light strongly suggests SRN1. See Chap. 2, section C.2, for the details of drawing an SRN1 reaction mechanism. 

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). 

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). 

The mechanism of the reaction depicted in Scheme 4-6 differs from the SN1 or SN2 mechanism in that it involves the stage of one-electron oxidation reduction. The impetus of this stage may be the easy detachment of the bromine anion followed by the formation of the fluorenyl radical. The latter is unsaturated at position 9, near three benzene rings that stabilize the radical center. The radical formed is intercepted by the phenylthio anion. That leads to the anion radical of the substitution product. Further electron exchange produces the substrate anion radical and the final product in its neutral state. The reaction takes place and consists of radical (R) nucleophilic (N) monomolecular (1) substitution (S), with the combined symbol of SRN1. Reactions of SrnI type may have both branch-chain and nonchain character. 

The previous material has illustrated the ability of spin traps to act as one-electron oxidizers. This property is even more pronounced in the interactions of traps with anion radicals. Traps can block the ion radical pathway. In other words, they inhibit the whole reaction, including the ion radical step. This may be explained by both oxidation of the substrate anion radical and chain termination due to oxidation of the product anion radical. An illustrative example is the inhibition of SRN1 nucleophilic substitution of 2-chloroquinoxaline by the radical trap bis(te/f-butyl)nitrone (Carver, Hubband, Wolfe, 1982). 

The results obtained in the photostimulated SRN1 reaction between carbanions from 2,4,4-trimethyl-2-oxazoline or 2,4-dimethylthiazole and 2-bromopyridine are also consistent with the incomplete formation of the carbanions in the KNH2-NH3(iiq ) system. In these cases, 2-aminopyridine is formed alongside the corresponding pyridyl-2-methylene oxa-zolinyl or thiazolyl substitution products (Wong et al. 1997). When the SRN1 pathway is impeded by conducting the reaction in the dark or in presence of di(tert-butyl) nitroxide, the ionic animation reaction dominates. 

Unlike conventional nucleophile substitution, the cyclopropane ring does not cleave during a SRN1 reaction. 

They carried this reaction out under pseudo-first-order conditions (excess of 2-nitro-propanate ions) in acetonitrile at 25°C, under argon atmosphere in a light-protecting vessel. The 2-nitropropanate ion was introduced as the tetramethylammonium salt. Two products were formed (Scheme 8-10). One of the products was the expected C-substituted compound. The other was an unstable species, which decomposed into the 4-nitrocumyl alcohol during workup and was ascribed to O-substitution. In 1975, Komblum had obtained the same products. He considered the C-substitution as an SRN1 reaction and the O-substi-... 

The SrnI character of the reaction was ascertained by the effect of light irradiation and the addition of a radical trap. Namely, under light irradiation, the half-reaction time was considerably shortened (3 instead of 41 min). Addition of di-tert-butyl nitroxide completely quenched the reaction Neither the C-substitution nor the O-substitution was observed after 4 hr. The radical trap may only react with the R radicals that escaped the solvent cage where R, Nu, and X- have been formed. This means that, in the absence of the trap, the R radical does react with Nu before diffusing out of the cage. The fact that the radical trap quenches the formation of both the C- and O-substitution products confirms that both species result from an SRN1 reaction. 

In the reaction of 1-naphthoxide ions, a mixture of 2- and 4-aryl-, along with 2,4-diaryl-l-naphthol, is formed. However, substitution occurs only at C4 with the 2-Me-substituted anion (50-70% yields) [1[. On the other hand, 2-naphthoxide ions react with ArX to give substitution only at Cj of the naphthalene ring [32, 33]. The reactivity of the 2-naphthoxide ions allows the synthesis of naphthylpyridines, naphthylquinolines, and naphthylisoquinolines via their coupling reactions with the corresponding halo arenes, in good to excellent yields (50-95%) [33], The photostimulated reaction between 2-naphthoxide ions and l-iodo-2-methoxy-naphthalene was explored in liquid ammonia, as a novel approach to the synthesis of [1,1 ] binaphthalenyl-2,2 -diol (BINOL) derivatives (Scheme 10.23). This procedure has also been applied to the synthesis of BINOL in moderate yield (40%), which represents the first report of an SRN1 reaction in water [34]. 

Me3 Sn ions are one of the most reactive nucleophiles in the SRN1 reaction, affording substitution products in high yield (88-100%) with ArCl in liquid ammonia and under irradiation. Conversely, ArBr and Arl react via an HME pathway [38]. 

The reactivity of sulfur-centered nucleophiles such as thiourea anion [46] and thioacetate anion [17] in photoinduced SRN1 reaction has been reported as a one-pot, two-step method for the synthesis of several sulfur-aromatic compounds from moderate to good yields. Without isolation, the ArS ions obtained by the aromatic substitution are quenched with Mel to yield ArSMe in a one-pot procedure, together with Ar2S in variable yields, from an SRN1 between ArS- and aryl radicals (Scheme 10.3). 

The synthesis of indoles by the photoinduced substitution reaction of o-haloanilines (22) with carbanions derived from aliphatic ketones in liquid ammonia is an important example of the SRN1 reaction followed by a spontaneous ring closure in the reaction media in moderate to excellent yield (53%-100%) [1]. Although the enolate anions of aromatic ketones do not react in liquid ammonia with 22, they will cyclize to indoles in DM SO under photoinitiation (Scheme 10.44) [60, 61]. 

The synthesis of 3-substituted isoquinolinones and fused isoquinolinones can be performed by the photoinduced SRN1 reactions in DMSO of o-iodobenzamide with the enolates of acyclic aromatic and aliphatic ketones and cyclic ketones, respectively. These reactions proceed from moderate to good yields (Schemes 10.47 and 10.48) [65],... 

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... 

Rossi, R.A., Pierini, A.B. and Santiago, A.N. (1999) Aromatic substitution by the SRN1 reaction, in Organic Reactions,... 

Photochemical aromatic substitution initiated by a reductive step as in SRN1 reactions can be used for the synthesis of cephalotaxinone (15). The corresponding iodoketone precursor cyclizes in liquid ammonia under photolysis [15]. 

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>. 

Photostimulated SRN1 reactions of bridgehead halides [119, 120] and of tertiary chlorides [122] has been examined and considered as a possible route to nucleophilic substitution of these normally unreactive substrates. In the case of the reaction of 1-iodoadamantane with ketone enolates, the photosubstitution product yield was improved in the presence of 18-crown-6 [103], This is probably related to the ion pairing effect already discussed in a preceding section. 

A typical reaction is the photostimulated substitution of aryl halides by ketone [121-131] (and much less efficiently aldehyde [124]) enolate anions (Scheme 5), both inter- [121-128] and intramolecularly [129-131]. The SRN1 reaction with o-bromoacetophenones is a useful method for the construction of an aromatic ring (Scheme 24) [132-133], with o-halophenylalkyl ketones for macrocycles (Scheme 25) [134], with o-haloanilines for indoles [123], with o-halobenzylamines for isoquinolines [135], and several other heterocyclic syntheses are possible [136]. 

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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