Aromatic substitution intramolecular

Reports of reactions characteristic of nitrenes (aromatic substitution, intramolecular C—H insertion and hydrogen abstraction) obtained by photolysis of various alkyl azides proved to be... 

Aromatic Substitution (Carey Sundberg, Chapter 11) Intramolecular Wittig Reaction Sigmatropic Rearrangements... 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

Intramolecular aromatic substitution in transition metal complexes. G. W. Parshall, Acc. Chem. Res., 1970,3,139-144 (51). 

Fuchita, Y, leda, H. and Yasutake, M. (2000) First intramolecular aromatic substitution by gold(III) of a ligand other than pyridine derivatives. 

The benzocarbacephems 22 (Fig. 11.12), with (X = Cl or F) or without (X = H) a halogen leaving group, were synthesized by a copper-mediated intramolecular aromatic substitution as the main step.73 74 These tricyclic (3-lactams are also competitive inhibitors of (3-lactamases and not substrates. 

Joyeau, R. Dugenet, Y. Wakselman, M. Synthesis of fused P-lactams by copper promoted intramolecular aromatic substitution. J. Chem. Soc. Chem. Common. 1983, 431 432. 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

Intramolecular electrophilic aromatic substitution to give tricyclic products 142 is also a viable process, with trapping efficiency related to the electron density of the arene trap (equation 3)67. With a simple phenyl group pendant, rearrangement to the 2-pyrone was... 

In 1984, we demonstrated that A-alkoxy-A-acyl nitrenium ions 15 could be generated by the reaction of A-alkoxy-A-chloroamides 14 with Lewis acids such as Ag + and Zn2+ and used these to form heterocycles by intramolecular aromatic substitution reactions (Scheme 2).90 In this manner, several novel A-acyl-3,4-dihydro-2,l-benzoxazines 16a and A-acyl-4,5-dihydro-( I //,3//)-2,1-benzoxazepines 16b were made. Subsequent work91,92 and that of Kikugawa93 96 produced numerous syntheses involving alkoxynitrenium ions including formation of natural products.97 99... 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

Thus /i-carbolincs can be obtained in a tandem hydroformylation/Pictet-Spengler-type intramolecular electrophilic aromatic substitution of polymer bound olefins (Scheme 26) [80]. 

In a similar fashion, hydroformylation of N-allyl-pyrrols leads to 5,6-dihydroindolizines via a one-pot hydroformylation/cyclization/dehydration process (Scheme 27) [81,82]. The cyclization step represents an intramolecular electrophilic aromatic substitution in a-position of the pyrrole ring. This procedure was expanded to various substrates bearing substituents in the al-lyl and in the pyrrole unit. 

Excited-state intramolecular nucleophilic aromatic substitutions are known as photo-Smiles rearrangements. Ealier, these were reported for 2,4-dinitrophenyl ethers and. v-lriazinyl ethers32. The exploratory33 and mechanistic34 studies on photo-Smiles rearrangements of p-(nitrophenoxy)- >-anilinoalkanes were carried out (equation 28). 

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

Intramolecular nucleophilic aromatic substitution on 243 allowed l,4-dihydropyridazin-3(2//)-one ring construction (Equation 58) . Similarly, a tetrahydropyridazine unit could be constructed starting from 244 (Equation 59) . 

Dibenzo[f,. ]cinnolines 259 have been obtained from 2-naphthylanilines 258 via diazotization followed by intramolecular electrophilic aromatic substitution (Equation 65) <2003BMC1475>. 

A nucleophilic attack of an N-tethered phenethyl substituent is shown in Scheme 50. The protonated thiazine ring brings about an intramolecular electrophilic aromatic substitution on the aryl substituent, whether this is a phenyl <1992CHE832> or a veratryl ring <1980JHC449>. 

Friedrichsen and co-workers (133) approached substituted benzotropolones from an aromatic substituted carbonyl ylide with a tethered alkyne as the intramolecular dipolarophUe (Scheme 4.67). Starting from an aromatic anhydride, Friedrichsen was able to make the tethered alkyne via addition of either pentyn-ol or hexyn-ol, then transform the recovered benzoic acid to the a-diazocarbonyl cycloaddition precursor. Addition of rhodium acetate resulted in the tandem formation of cyclic carbonyl ylide followed by cycloaddition of the tethered alkyne producing the tricyclic constrained ether 252. Addition of BF3 OEt2 opened the ether bridge, forming the benzotropylium ion, which subsequently rearranged to form the tricyclic benzotropolone (253). 

An equally important general type of synthesis which proceeds via heterocyclization with formation of a ring bond y to the heteroatom involves acid-catalyzed intramolecular electrophilic aromatic substitution, especially those in which a carbonyl group functions as the electrophile. The most common structural requirements are summarized in (18)-(2l) ... 

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