Intramolecular base-induced rearrangement

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

An interesting example of a reaction involving conformational equilibria in 3,7,9-substituted bicyclo[3.3.1]nonane systems is the base-induced rearrangement of endo-7,7-dimethylbicyclo[3.3.1]nonan-3-ol-9-one (80) into 81. The rearrangement is rationalized by a reversible intramolecular transfer of hydride from the carbinol methine to the carbonyl carbon (60). The reacting centers at C-3 and C-9 are only placed in proximity when the cyclohexanol ring adopts a boat conformation. The resulting ketol 81 is 2.7 kcal mol 1 more stable than its isomer 80 (60). 

The Nuphar quinolizidine alkaloid nupharotuline (181) and its 7-epi analogue (182) have been prepared in a sequence featuring as the key step the intramolecular, base-induced opening of an epoxide intermediate, in turn available from the Beckmann rearrangement product of a cyclopentane derivative (Scheme 30) <80JOC3644). 

Intramolecular cyclization can yield fluorinated phenoxazines by a Smiles rearrangement (86IZV1855) and 2,3-dihydro-l,4-benzodioxins by a base-induced reaction [81JFC(18)483]. 

Matsumoto, M. Watanabe, N. Ishikawa, A. Murakami, H. Base-induced cydization of 1-benzyloxy-2,2,4,4-tetramethylpentan-3-ones intramolecular nudeophilic addition of an anion of a benzyl ether to the carbonyl moiety without Wittig rearrangement or protophilic decomposition. Chem. Commun. 1997, 2395— 2396. 

Most reactions of this category involve the base-induced generation of alkylidene-carbenes (R2C = C ) which undergo an intramolecular 1,5-carbon-hydrogen insertion providing a useful route for the construction of substituted cyclopentenes a competing intramolecular pathway is rearrangement to alkynes. 

Cyclopropylideneamines were trapped in an intramolecular manner during the Favorskii rearrangement of suitably functionalized a-chloro ketimines 44 bearing a protected nucleophile in the molecule. Base-induced 1,3-dehydrochlorination generates the three-membered ring intermediate 45 which undergoes intramolecular nucleophilic addition of the deprotected nucleophile to form adducts 46. 

The base-induced ring rearrangement of l-(5//-[l]benzopyrano[2,3-A]pyridin-5-yl)-l,3-dimethyl-urea with lithium diisopropylamide at — 40 to 25°C leads via the anion to l,3-dimethyl-4-(2-hydroxyphenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(l//)-one (l).280 The reaction involves the intramolecular substitution of the phenoxy group by the urea anion at the 2-position of the pyridine moiety. 

Schreiber et al. have been able to apply their enediyne intramolecular Diels-Alder approach to the synthesis of dynemicin model systems [268-270], culminating in the total synthesis of di- and tri-O-methyl dynemicin A methyl esters 388 and 389 (Scheme 7-78) [271], derivatives of the natural product itself. Highlights of this synthetic approach include (a) intramolecular lactonization and concomitant Diels-Alder cyclization (380- 381) (b) allylic hydroxylation followed by an allylic diazene rearrangement in order to regiospecifically isomerize a double bond (381 - 382) (c) a-hydroxylation of the lactone 381 and subsequent conversion to the P-ketoester 383 (d) annelation of the anthraquinone unit (383- 384- 385- 386) (e) mild base-induced P-elimination of the N-protecting group of 386 to give the free amine 387 and (f) a final oxidation to complete the anthraquinone (387 - 388). 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

In an extension of previous work, it has been found that Pd(0)-catalysed intramolecular cyclization of allylic acetates (21) can be used to prepare the chrysanthemic acid analogues (22). The potentially useful cw-cyclopropane (23) can be simply obtained by base-induced addition of cyanoacetate to ethyl 2-bromo-3,3-dimethylacrylate followed by decarboxylation oddly, a similar reaction using malonate fails to give a cyclopropane. Optically pure dichloro cw-chrysanthemic acid (26) has been obtained by a Favorskii rearrangement of the chiral cyclobutanone (25) prepared from the keten (24) by sequential [2 + 2]cycloaddition, cine-rearrangement, and resolution (Scheme 3). ... 

The photochromism of 1 is achieved by atom rearrangement into the intramolecular oxygen-atom insertion product 2, in contrast to the frequently reported organic photochromic systems based on photo-induced cyclization, cis/trans isomerization, or H atom transfer [1]. The quantum yield of the photoreaction from 1 to 2 at 509 nm in acetonitrile without 02 is 0.14 0.01. In solution, photoreaction of 1 causes the oxidation reaction by atmospheric oxygen, resulting in a mixture of 2 and further oxidation products such as [(RhCp )2((i-CH2)2( i-S03)] and [(RhCp )2 ( r-CH2)2( t-S04)]. In contrast, in the crystalline state, the photochromic system between 1 and 2 is stable and repeatable with essentially 100% interconversion ratio. 

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