Annulation reactions nucleophilic substitution

In addition to the synthesis of heterocycles, the Corey-Chaykovsky reaction bestows an entry to carbocycles as well. The reaction of (trialkylsilyl)vinylketene 89 with substituted ylide 90 led exclusively to rrans-4,5-dimethyl cyclopentenone 91. The substituted ylide 90 here serves as a nucleophilic carbenoid reagent in the formal [4 +1] annulation reaction. 

Vicarious nucleophilic substitution reactions of azolopyridazines have been found to be controlled by methyl substituents.35 On treatment with bromomethyl phenyl sulfone in DMSO-r-BuOK, azolopyridazines yield mainly typical reaction products, whereas 7-methylazolopyridazines under the same conditions undergo annulation. These competitive reactions illustrate the role of charge distribution and steric hindrance for the course of the nucleophilic substitution. 

Although ring-annulated and highly substituted borepins have been known for some time, simple 1-substituted borepins have only been thoroughly studied over the past decade. The discovery of a facile synthetic ronte to 1-snbstituted borepins through tin-boron exchange has much opened up the chemistry of these 7-membered boracycles. The chloro-substituted borepin (145) serves as a highly useful precursor to many other borepin derivatives via substitution reactions with nucleophiles (Scheme 20). In addition, several transition metal complexes of 1-borepins have been reported. 

Carbanions of a-haloalkyl aryl sulfones, sulfonates and sulfonamides react with quinoxalines according to two general pathways vicarious nucleophilic substitution of hydrogen and/or bis-annulation to bis(azirino)quinoxaline derivatives. The charge distribution in the anionic (T-adducts and reaction conditions influence the direction of these reactions. ... 

The cis or trans configuration of the annulated system normally is not changed in nucleophilic substitution. Such a cisitrans isomerization, however, has been observed in a few nucleophilic substitution reactions of various bicyclo[9.1.0]dodecane derivatives. ... 

Radiolabeled 4-[ F]fluoropyridine can be synthesized by no-carrier-added nucleophilic aromatic substitution with K[ F]F-K222- In another instance, the nucleophilic substitution reaction was also employed for the synthesis of steroids-containing 4-fluoropyridine motif, and for the synthesis of 4-fluoropyridines annulated with pyrrole (azoindoles).Substantial difference in the reactivity of the pyridinium ring toward nucleophilic substitution in 5-iodo-2,4-difluorpyridine was effectively used for the preparation of 4-fluoropyridines 93 and 94 using difluoropyridine 92 as starting material (Scheme 6.31). 

Abstract Palladium readily catalyzes the cross-coupling of functionally substituted aryl or vinylic halides and alkynes to afford a wide variety of heterocycles and carbocycles in one efficient step. Terminal alkynes presumably initially generate aryl (vinylic) alkynes, which under the reaction conditions are rapidly cyclized by the palladium or copper salts employed in the first step to produce the final product. Internal alkynes apparently react by carbo-palladation of the alkyne and subsequent intramolecular nucleophilic substitution of the palladium moiety to generate the observed products. A variety of other closely related processes have also been reported, including the simultaneous annulation of alkynes and car-... 

Both linear and angular annulated 2-methylfurobenzopyranones can be prepared by this route <94BCJ1972>. Benzofuran-3-ones (3-hydroxybenzofurans) are available by an intramolecular nucleophilic substitution reaction (Scheme 45), (Auwers-Pohl reaction). 

Both fused 1,4-dioxanes and substituted naphthalenes can be obtained from the pentacyclic acetals derived from 1,4-dioxene. A sequence of nucleophilic substitution, annulation and an intramolecular Friedel-Crafls reaction is involved (Scheme 50) <01TL231>. 

The Larock method for annulation between vicinal iodo-arylamines and 1,2-dienes in the preparation of indoles can be adapted for preparation of azaindoles using corresponding azine substrates. Thus, substituted-3//-pyrrolo[2,3-fc]pyridin-3-ones can be prepared from 2-amino-3-iodopyridine derivatives by a palladium carboannulation process with al-lenic compounds (Scheme 104). The bicychc products, the methylene derivatives 308, and the alkylidenes 309 can be oxidatively cleaved with ketone formation. The reaction may proceed by formation of a pyridinylpaUadium complex followed by the rr-allyl complexa-tion of aUenic derivatives 310. Since the polar substituents on terminal carbons of the 7r-allyl system influence the regiochemistry of the reactions, nucleophilic attack of the nitrogen atom on the most electron-deficient carbon atom of the rr-allyl system affords either of the... 

Tu, Li, and coworkers also developed a new allylic functionalization without the use of metal catalysts [59-61]. Efficient annulation of enaminones 57 with arylglyoxal monohydrates 58 and the subsequent allylic functionalization with aliphatic carboxylic acids 38 as nucleophile reagents provided multifunctionalized indoles 98 with 75-89% yields (Scheme 12.38) [59]. To further explore the scope of this domino reaction, N-substituted 3-aminocyclohex-2-enones were employed. Interestingly, two molecules of arylglyoxal mono hydrate and N-substituted... 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Palladium-catalyzed annulation reactions of conjugate acceptors and allenyl boronic ester provide substituted cyclopentenes in high yields and diastereose-lectivities (Scheme 6.24). These reactions are hypothesized to commence by the conjugate addition of a nucleophilic propargyl-palladium complex. Transmetalation of allenylboronic acid pinacol ester with a Pd(II) catalyst proceeds via an SE2 mechanism to provide the propargyl-palladium complex, which on conjugate attack on the electrophile furnishes an allene intermediate. Finally, endo carbopalladation of the pendant allene and protodepalladation generates the cyclopentene [28]. 

The role of the trimethylsilyl group is to stabilize the intermediate carbanion formed by conjugate addition. The silyl group is removed under conditions similar to those required for the dehydration the removal occurs by nucleophilic attack on silicon resulting in displacement of the ketone. The advantage of the substituted methyl vinyl ketone is that it permits the annulation reaction to be carried out in aprotic solvents under conditions where enolate equilibration does not take place. The annulation of unsymmetrical ketones can therefore be controlled by using specific enolates generated by the methods described in Chapter 1. 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

The reaction of (trialkylsilyl)vinylketenes with nucleophilic carbenoid reagents, such as sulfur ylides and diazo compounds, has been used for synthesis of substituted cyclopentenones by stereoselective 4 + 1-annulation (Scheme 12). The strategy relies on the remarkable ability of silyl substituents to stabilize ketenes and suppress their tendency to undergo dimerization and 2 - - 2-cycloaddition. 

Yokozawa reported that the 2-substituent strongly affects the reactivity of a 2-substituted-oxazoline 360 with dimethyl 2,2-dicyano-3-ethoxy-l,l-dicarboxylate as shown in Scheme 8.115. Thus, oxazoline itself, 360 (R = H), gave the annulated bicyclic product 361 that resulted from collapse of the zwitterionic intermediate 362, whereas simple 2-alkyloxazolines, 360 (R = Me, Et), gave an alternating (1 1) copolymer. 2-Phenyloxazoline, 360 (R = Ph), was unreactive under the reaction conditions. The zwitterionic intermediate 362 (R = Me) was trapped by acetic acid to give the open-chain adduct 363 that resulted from nucleophilic ring opening at the 5-position of the oxazolinium zwitterion. 

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