Nucleophilic cyclizations

There are several methods of preparation of antibacterial quinolones, drugs widely used in the therapy of various bacterial diseases. The most general method is based on the nucleophilic cyclization of 2-halobenzoyl derivatives 402, leading to the key intermediates 403. The methodology is exemplified in Scheme 63 by the synthesis of a broad-spectrum drug ciprofloxacin... 

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

Scheme 7.14. Domino reduction/nucleophilic cyclization procedure in the synthesis of diazonamide A (7-43).

Both successive nucleophilic cyclizations to a ring are kosher because exo-nucleophilic attack is involved in each 12). In any event one can just as easily write on paper, for example ... 

As can be seen in the scheme below, insertion reactions of aldehydes to the C-H bond of aromatic ketimines by using a rhenium catalyst provided benzo[c]furans via a mechanism involving consecutive steps of C-H bond activation, insertion of aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of aniline <06JA12376>. 

The preparation of 2,3,5-trisubstituted 4,5-dihydrofurans 81 with complete regio-control can be realized by an one-pot transformation involving epoxidation of 2-alkenyl-1,3-dicarbonyls by in situ generated dimethyldioxirane, and is followed by a S-exo-ieX intramolecular nucleophilic cyclization under the same basic condition <00TL10127>. 

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

Scheme 21 Nucleophilic cyclization of a carboxylic acid onto an alkene radical cation... 

A y-lactone was formed in excellent yield by the nucleophilic cyclization of a carboxylic acid onto an alkene radical cation generated from a (i-nilrophosphale under tin hydride conditions (Scheme 21) [139]. Related experiments employing the acetate group and an internal carboxylate nucleophile failed, emphasizing the very rapid collapse of the alkene radical cation/acetate ion pair [127]. 

An alternative substrate design, in which the alkene radical cation is substituted only at the internal position, forces the nucleophilic cyclization into the endocyclic mode, leading overall to bicyclic systems with a bridgehead nitrogen (Scheme 31) [139,140]. 

Scheme 31 Nucleophilic cyclization of an alkene radical cation in the endocyclic mode...

Attempts at 4-exo nucleophilic cyclization failed, presumably because of a heterolytic fragmentation of the intermediate radical cation (Scheme 32) [139], not unlike that proposed (Scheme 15) for the decomposition of a mannose-derived alkene radical cation. 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

Annulation of aryl halides with ortho side chains bearing a pendant electi ophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. 

Intramolecular cyclizations. Intramolecular cyclizations of electron-rich chloroacetyl indoles leads to indolo[l,2-d][l,4]benzodiazepin-6-one 20 as a result of a side nucleophilic cyclization at the indole nitrogen (Equation (4), Section 2.1.1.1 (2005T5489)). 

Secondary aliphatic amines were found to give higher yields of thienothiophenes than did tertiary amines, which are weaker bases. A maximum ratio of thienothiophenes to thienothiopyrans of about 4 1 was achieved at 145° with diisopropylamine as cat yst and DMSO as solvent. Only thienothiopyrans were formed in DMF in the presence of the same catalyst The amines promote nucleophilic cyclization of Claisen rearrangement products into thienothiophenes. Since thienothiophenes are resistant to treatment with potassium t-butoxide in DMSO and thienothiopyrans form resinous products under these conditions, the method is a convenient route to pure thienothiophenes 35 and 42 in yields of up to 40%. ... 

Hydrolysis of the hydrazine BOC-protecting group of 90 followed by treatment with sodium hydride gave pyrazolo[4,3-f][l,2,4]triazine-3-one 44 by nucleophilic cyclization onto the 5-ethoxycarbonyl group (Scheme 64) <2006JA5646>. 

Internal nucleophilic cyclization leading to alkoxycyclopropanes is the most typical reaction of reactive metal homoenolates [I, 2]. The nature of stable homoenolates, however, is such that the anionic carbon C-3 forms a covalent bond with the metal atom and does not show high nucleophilic reactivity. 

Intramolecular nucleophilic cyclization of the anion of oxiranylethyl phenyl sulfone, generated by treatment with methylmagnesium iodide in tetrahydrofuran, gave 3-phenylsulfonylcyclobu-tanol (13) in 96% yield. For further examples, sec Table 15.13 14... 

Table 15. Functionalized Cyclobutanols by Intramolecular Nucleophilic Cyclization of (3-Epoxy Sulfones and (3-Epoxynitriles...

By examining the rates of intramolecular nucleophilic cyclization of 13 at different pH values, Kirby has determined the relative reactivity of RCH=CH2, RCH=CHCOO and RCH=CHCOOH towards nucleophilic substitution14. The ratios 1 4000 8 x 107 are in broad agreement with the relative rates, 3 x 104 1, for nucleophilic attack of ammonia on fumaric acid in the neutral and dianionic forms at 135 °C. The relative rates for nucleophilic attack of hydroxide on fumaric acid in the neutral and dianionic forms at 135 °C changed to 3 x 107 1 because of the adverse electrostatic interaction between the hydroxide ion and the dianion15. 

A few representatives of this heterocyclic system 35 were synthesized in very high yield (85-90%) by the intramolecular nucleophilic cyclization of the acetylene derivatives 36 (81RTC10), which in turn were obtained by treatment of alkynyl(chloromethyl) sulfides with one equivalent of Na2Te, the latter being prepared from elemental sodium and tellurium in liquid ammonia. 

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