Intramolecular cyclization-elimination mechanism

Fig. 8.11. Simplified reaction mechanism of intramolecular cyclization-elimination of anthra-nilamide phenylcarbamates (8.135) [173]...

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

In troponoid chemistry cine substitution occurs frequently. In many cases it can be explained by the intermediacy of dehydrotropolone species ( tro-polonyne ) as trapped, for example, by azides (Section II,A,3,h Scheme 34). An alternative mechanism may be a Michael-type addition followed by elimination. The intramolecular cyclizations depicted in Scheme 47 very likely proceed via Michael-type attack (73CRV293, p.351). 

As a consequence of the conformational mobility of the thiepane 1-oxide ring (115) it was possible to form the necessary planar five-membered cyclic transition state for a thermal E elimination reaction (equation 19). The acyclic sulfenic acid intermediate was not isolated but rearranged to c/s-2-methylthiane 1-oxide by an intramolecular cyclization mechanism (75TL2235). 

Whereas the intermolecular Heck reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and many cyclic compounds can be prepared by the intramolecular Heck reaction [37]. The stereospecific synthesis of an A ring synthon of la-hydroxyvitamin D has been carried out. Cyclization of the (7T)-alkene 88 gives the (fT)-exo-diene 90, and the (Z)-alkene 91 affords the (Z)-exo-diene 92 [38]. These reactions are stereospecific, and can be understood by cis carbopalladation to form 89 and the. sun-elimination mechanism. 

When the chlorine elimination pathway prevails, one observes mainly products from intramolecular cyclization (10, 33, 34). Although no inserted SiCl2 group is involved in the products, the reaction mechanism [Eq. (30)] is related to the insertion reactions described above. 

Palladium salts also promote the addition of nucleophiles to alkenes and alkynes. The Pd-catalyzed additions of nucleophiles to alkynes, which is useful for intramolecular cyclizations such as the isomerization of 2-alkynylphenols to benzofurans, proceeds by exactly the same mechanism as does the Hg-catalyzed reaction. However, the Pd-catalyzed additions of nucleophiles to alkenes takes the course of substitution rather than addition because alkylpalladium complexes are unstable toward /3-hydride elimination. The Pd-catalyzed nucleophilic substitutions of alkenes are discussed later in this chapter (Section 6.3.6). 

Presumably, the oxidative cyclization of 1 commences with direct palladation at the orfAo-position, forming o-arylpalladium(II) complex 3 in a fashion analogous to a typical electrophilic aromatic substitution (this notion is useful in predicting the regiochemistry of oxidative cyclizations). The mechanism of the second formal C—H bond functionalization step is not fully elucidated, but may occur either via (a) an intramolecular carbopalladation reaction (migratory insertion) followed by czHft-P-hydride elimination from 4 (Path A) (b) by o-bond metathesis (through a four-centered transition state) followed by reductive elimination (Path B) (c) by electrophilic aromatic substitution followed by C—C bond-forming reductive elimination (PathC) [9]. 

According to the proposed reaction mechanism (Scheme 44), carbopalla-dation of benzyne with the 7i-allyl palladium complex gives intermediate 157. Insertion of CO in the palladium-aryl bond then leads to the acyl palladium complex 158, which undergoes intramolecular cyclization and subsequent P-hydride elimination, affording indanone 156 [78]. 

Cycloisomerization of enynes has been employed to construct an array of natural products.f " Although the precise mechanistic details of the reaction have not been elucidated, and may vary from case to case, one potential mechanism is shown in Scheme 28. Generation of an alkyl- or hydridopaUadium complex in the presence of enyne 183 may lead to carbo- or hydridopalladation to give an alkenyl palladium intermediate 184. Intramolecular cyclization (184 185) then follows to form five-, six-, or seven-membered rings followed by /3-hydride elimination to yield 1,4-diene 186 and/or 1,3-diene 187. There are also examples of yne-yne cyclizations in natural product synthesis. ... 

Surprisingly, methyl esters are also suitable substrates whereby intramolecular cyclization occurs with concomitant loss of methyl iodide. Larock used internal alkynes as coupling partners for lactone synthesis (Scheme 2.33) [74]. The proposed mechanism involves oxidative addition of Pd(0) to the aryl iodide, followed by addition across the alkyne and cyclization of the carbonyl O of the ester to form an oxonium ion. Reductive elimination followed by loss of the methyl group then yields the product [74]. Shen and coworkers also reported a variant utilizing o-2,2-dibromovinylbenzoates (Scheme 2.34) [79]. 

In 1985 both Magnus and Schore independently proposed identical mechanisms based on stereochemical and regiochemical preferences observed in the product. Magnus s hypothesis was based on the stereochemical results for an intramolecular cyclization. He proposed that the product arose from formation of a metallocycle intermediate 7 or 8, carbon monoxide insertion to give 9, acyl migration fi om cobalt to carbon and reductive elimination of cobalt to form 10. The relative thermodynamic stability of the metallocycles 7 and 8 controlled the final product ratio. In the... 

The first step in the mechanism is the reaction of DICY with epoxy to form the alkylated DICY. This was confirmed by the imide IR peak at 1570 cm The second step involves further alkylation of the nitrogen that reacted in step 1, to form the AA(-dialkyldicyandiamide. No alkylation of the other amino group was suggested. The third step is the intramolecular cyclization step to form a zwitteri-onic five-membered intermediate. This involves the intramolecular reaction of the secondary alcohol formed in step 2 with the imide functionality (—C=N—). This is in contrast with the Zahir mechanism (112) where the intramolecular cyclization involves the hydroxy and the nitrile groups. The fourth step involves the elimination of ammonia and the formation of 2-cyanimidooxazolidine. The formation of this heterocycle is consistent with the observed bathocromic IR shift from 1570 cm to 1650 cm The ammonia that is eliminated can then react with epoxy to form a trifimctional cross-hnk. The last step involves the hydrolysis of the oxa-zolidine to form the oxazoUdone and cyanamide. The hydrolysis step accounts for the formation of the carbonyl group. 

Studies clarifying the mechanism of the intramolecular cyclization reactions were described in the paper. They showed that these reactions involve rate-limiting oxidative addition of the Pd(0) to the aryl halide and that both the base-induced formation and the reductive elimination from arylpalla-dium enolate intermediates were faster than the oxidative addition. A mechanism was proposed by the authors (Scheme 8.41). Lee and Hartwig [77] also demonstrated that the Pd(OAc)2/PCyj catalyst system can afford the combined intermolecular and intramolecular arylation reaction of Af-methyl-ortfro-bromoacetanilide to form 3-aryloxindoles in good yields (Scheme 8.42). 

Mechanism 28.2 illustrates some of the key steps of the Edman degradation. The nucleophilic N-terminal NH2 group adds to the electrophilic carbon of phenyl isothiocyanate to form an A-phenylthiourea, the product of nucleophilic addition (Part [1]). Intramolecular cyclization followed by elimination results in cleavage of the terminal amide bond in Part [2] to form a new peptide with one fewer amino acid. A sulfur heterocycle, called a thiazolinone, is also formed, which rearranges by a multistep pathway (Part [3]) to form an A-phenylthiohydantoin. The R group in this product identifies the amino acid located at the N-terminal end. 

Fluoro-2-perfluoroalkyl-4-(trifluoromethyl)oxazoles were formed by reduction of perfluoroacyUmines with some metals. The reaction is promoted by catalytic amounts of Cul salts and crown ethers. Among the metals (magnesium, tin, aluminum, and zinc) only zinc and tin exerted as a defluorinating effect. The best yields of oxazoles were attained in the presence of zinc [22, 23]. A similar single electron transfer mechanism was described for cyclization of other hexafluoroacetone imines with metals. The role of crown ether is apparently reduced to the assistance in the elimination of ZnF with formation of 0-anion, which results in the intramolecular cyclization to oxazoles. 

Intramolecular Cyclizations.—Base-induced 1,3-bonding occurs in the conversion of (24) into (25) even though the reaction is a 1,7-elimination. A spiro-product is also obtained in the dehydration of (26) with dicyclohexyl-carbodi-imide (DCQ. The mechanism of the 1,3-elimination from 3-phenyl-propyltrimethylammonium iodide with potassium amide in liquid ammonia has been investigated. The reaction is concurrent with 1,2-elimmation and shows a nitrogen kinetic isotope effect = 1.022 + 0.001). This and deuterium-... 

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