Intramolecular replacement

An example of intramolecular replacement of fluonne is found m the thermal rearrangement of syn-S, 16-difluoro[2,2]metacyclophane In the cA-difluoro intermediate, one fluonne atom rearranges while the other is lost as HF in an interesting path to 1-fluoropyrene [85] (equation 47). 

Intramolecular replacement of sulfur by nitrogen has been reported in the complex of [Pt(dien)]2+ with S-guanosyl-L-homocysteine (sgh) according to reaction 2,... 

Intramolecular replacement of fluorine by nitrogen has been used for the formation of fused heterocycles, i.e. derivatives of indole,187 - 189 2,3-dihydroindole.190 benzopyrazole.191 benzo-pyridazine,192 benzoxazine,193194 bcnzothiadiazole,193 quinoline,196-198 and benzothiazinc (e.g., 9).194 1"-200... 

Conditions were found under which 2,4,6-trinitrostyrene adds nucleophiles (thio-phenol, aniline, and aliphatic amines) at the vinyl moiety to form the corresponding / -X-ethyl-2,4,6-trinitrobenzenes (X = PhS, PhNH, or R2N). In the reactions with primary aromatic amines, the initially formed adducts undergo an intramolecular replacement of the nitro group followed by aromatization of the indolines, giving rise to the corresponding A-substi Luted 4,6-dinitroindoles.219... 

A series of similar heterocyclizations were performed with 2-chloroquinoxaline 190. Thus, furoquinoxaline 192 was obtained in 15% yield by treating 190 with methyl-t-butylketone enolate 191 (Scheme 57) (82JOC1036). The pathway includes C-nucleophilic attack of the enolate ion on unsubstituted atom C(3) followed by intramolecular replacement of chlorine in dianionic aH-adduct 193. Finally,... 

Some efficient oxidative and reductive intramolecular carbon-radical additions can be carried out. /pra-replacement of toluenesulfonyl by tributylstannyl radical occurs readily at C-2 (but not at C-3) as does intramolecular replacement by carbon radicals. " ... 

For the case of intramolecular energy transfer from excited vibrational states, a mixed quantum-classical treatment was given by Gerber et al. already in 1982 [101]. These authors used a time-dependent self-consistent field (TDSCF) approximation. In the classical limit of TDSCF averages over wave functions are replaced by averages over bundles of trajectories, each obtained by SCF methods. 

In principle, the direct hydride addition or catalytic hydrogenation, which did not give chlorins, was replaced by an electrocyclic intramolecular addition which is much easier with the above system. Complete regioselectivity was also achieved since electrocyclization did not occur with the resonance-stabilized ring C. 

Other approaches to inhibiting intramolecular cycli2ations of erythromycin have also proven successhil. Erom a series of O-alkyl derivatives of erythromycin, clarithromycin (6-0-methylerythromycin) (37) was selected for clinical development (146,147). Another approach replaced the C-8 proton of erythromycin with duorine, which was accompHshed by both chemical and bioconversion methods to yield durithromycin (38) (148). 

In addition, the frequency cooo, as well as the tunneUng distance can also be extracted from the same empirical data. Thus all the information needed to construct a PES is available. Of course, this PES is a rather crude approximation, since all the skeleton vibrations are replaced by a single mode with effective frequency cooo and coupling parameter C. From the experimental data it is known that the strong hydrogen bond (roo < 2.6 A) is usually typical of intramolecular hydrogen transfer. 

An intramolecular 8 Ar2 mechanism (19) is possible in the replacement of 0X0 substituents with chloro or mercapto groups by means of phosphorus oxychloride or pentasulfide, respectively, via the intermediates shown. In the former, an intermolecular mechanism (20) is perhaps more likely. Frequently a base is not added in such reactions. 

The versatility of the Diels-Alder reaction becomes especially obvious, when considering the hetero-variants. One or more of the carbon centers involved can be replaced by hetero atoms like nitrogen, oxygen and sulfur. An illustrating example is the formation of the bicyclic compound 31, by an intramolecular hetero-Diels-Alder reaction ... 

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]. 

Many examples of retention of activity in the face of replacement of benzene by thiophene have been noted so far. Application of this stratagem to a clozapine-like antipsychotic constitutes yet another example where activity is retained. The seven-membered ring of the compound in question is established by intramolecular amide formation on intermediate 102. Treatment of amide 103 with N-methylpiperazine in the presence of titanium tetrachloride affords flumezapine (104) [20]. 

Hodgson et al. showed that a series of bis- and tris-homoallylic terminal epoxides underwent intramolecular cydopropanation to give a range of bicydic alcohols. A short asymmetric synthesis of sabina ketone based on this chemistry was demonstrated (Scheme 5.20). A practical advantage with this process is that the volatile epoxides can be replaced with readily available chlorohydrins, an extra... 

Ce4+ is a versatile one-electron oxidizing agent (E° = - 1.71 eV in HC10466 capable of oxidizing sulfoxides. Rao and coworkers66 have described the oxidation of dimethyl sulfoxide to dimethyl sulfone by Ce4+ cation in perchloric acid and proposed a SET mechanism. In the first step DMSO rapidly replaces a molecule of water in the coordination sphere of the metal (Ce v has a coordination number of 8). An intramolecular electron transfer leads to the production of a cation which is subsequently converted into sulfone by reaction with water. The formation of radicals was confirmed by polymerization of acrylonitrile added to the medium. We have written a plausible mechanism for the process (Scheme 8), but there is no compelling experimental data concerning the inner versus outer sphere character of the reaction between HzO and the radical cation of DMSO. 

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