Intramolecular SRN1 Reactions

Although the intramolecular SrnI reaction has been studied to a lesser extent as compared to the intermolecular process, it has been shown to represent a highly useful route for the synthesis of various heterocyclic compounds. For example, the SrnI cyclization of N-alkyl-N-acyl-o-haloaniUnes and N-acyl-N-methyl-o-chlorobenzylamines (Equation 13.5) gives N-aUcylindol-2-one and 1,4-dihydro-2H-isoquinolin-3-ones in moderate to good yields [21]. lodoketone 1 reacts under SrnI conditions to provide the complex heterocyclic compound 2 with excellent yield (Equation 13.6) [22]. 

An intramolecular SrnI reaction was used as key step in the synthesis of the alkaloid 0-demethyleupoularamine 3. The intermediately formed SrnI product is readily transformed by photochemical oxidative biaryl formation and subsequent methylation to the target compound 3 in good yield (Equation 13.7) [23]. The SrnI cyclization of l-(2-bromobenzyl)-l,2,3,4-tetrahydroisoquinolin-7-ol derivatives 4 was recently applied to the synthesis of aporphine alkaloids 5 (Equation 13.8) [24] and, by using the same approach, homoaporphine alkaloids can also be synthesized. 

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The key step in the synthesis of the azaphenanthrene alkaloid eupoulauramine 27 (56% yield) is an intramolecular SRN1 reaction, followed by in situ stilbene photo-cyclization, and further methylation (Scheme 10.52) [68]. 

One of the first reports of an intramolecular SRN1 reaction is the synthesis of cephalotaxinone (43). The iodoketone 42 cyclizes in liquid ammonia under photostimulation affording product 43 in excellent yields (Sch. 45). 

The SRN1 mechanism represents an excellent alternative to accomplishing the following intramolecular cyclization reaction (Scheme 10.42), which constitutes one of the steps in the synthesis of rugulovasines A and B (20, a-H and P-H), novel structures within the family of ergot alkaloids [58]. 

Barolo, S.M., Teng, X., Cuny, G.D. and Rossi, R.A. (2006) Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via SRn1 reactions in liquid ammonia. Journal of Organic Chemistry, 71, 8493—8499. 

Alternatively, the intramolecular ET to the second C-Y a bond results in fragmentation to form a radical 5, which by coupling with a second molecule of the nucleophile affords the disubstitution compound 6 (Sch. 2). In this case, the monosubstitution product 4 is not an intermediate in the formation of compound 6. However, in some systems, the monosubstitution product 4 is indeed an intermediate to form 6 by two consecutive SRN1 reactions. 

Intramolecular examples of photostimulated SRN1 reactions implying excited anions with a demonstrated chain mechanism have been reported as in the case of anilide anions and JV-acyl benzylamines used as precursors of oxindoles and isoquinolines [129]. 

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]. 

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 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. 

The reaction generally proceeds in good yield and could involve an addition-elimination, though the regiochemistry appears to be incorrect for this. An alternative would be an SRN1 process involving (86). The reaction has been applied to the preparation of (87) from the silacyclopropene photolysis then leads to the novel tetracycle (88) through an intramolecular [2+ 2]-cyclo-addition 87>. 

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