Annulation reactions carbon nucleophiles

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 reactions described in this chapter include some of the most useful synthetic methods for carbon-carbon bond formation the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related olefination methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. 

In an a,P-unsaturated carbonyl system, the addition could be either 1,2 or 1,4, i.e. simple or conjugate. With Grignard reagents, the nucleophilic addition can be either 1,2 or 1,4, and often depends upon any steric factors that are present in the substrate. When an a,P-unsaturated carbonyl compound is treated with a carbanion, particularly one that is stabilised by a carbonyl group, the resultant 1,4-addition with the formation of a new carbon/carbon bond is called the Michael reaction. If the reaction occurs intramolecularly, it is called the Robinson annulation reaction. 

In 2012, Alexakis and co orkers disclosed the first stereoselective annulation reaction between ynals and a-cyano-l,4-diketones which is mediated by a catalytic amount of a triazolium salt precatalyst and a weak carboxylate base. This transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon, and affords privileged bicyclic scaffolds in 61-90% yields with up to 20 1 diastereomeric preference. A mechanistic rationalization for the NHC-catalyzed annulation of a-cyano-l,4-diketones with ynals is proposed as the following. Initially, the free carbene condenses with a molecule of ynal to form the key d,p-unsaturated acylazolium intermediate followed by a direct nucleophilic conjugate addition of 1,4-diketone. Subsequent intramolecular H-migration and an irreversible lactonization furnish the observed bicyclic product and liberate free carbene for the next catalytic cycle (Scheme 7.98). 

In 1986, we found that alkynyl-A3-iodanes serve as good Michael acceptors toward soft nucleophiles, because of the highly electron-deficient nature of the /3-acetylenic carbon atom. This conjugate addition of nucleophiles constitutes a key step of a highly versatile cyclopentene annulation of alkynyl-A3-iodanes via the tandem Michael-carbene insertion (MCI) reaction [Eq. (103)] [185]. 

Novel carbon frameworks have been developed from polycyclic hydrocarbons. Thus, Kuck and coworkers143 have recently reported an unexpected tandem reaction, which formally consists of a condensation/cyclodehydrogenation sequence starting from triptidan-9-one 233 leading to the fn/wso-tetracyclic propellane 234 (Scheme 72). The reaction of the tribenzo[3.3.3]propellane ketone 233 with benzylhthium/TMEDA afforded an efficient one-pot peri annulation of a dihydronaphthalene (Scheme 72). The key step of this unexpected tandem reaction was determined to be a nucleophilic cychzation followed by hydride elimination. 

The classical methods of constructing six-membered rings are the Diels-Alder reaction or the Robinson annulation, which consist of the union of two fragments, one with two carbon atoms and the other with four carbons. A conceptually different method from the above involves the condensation of two three-carbon units, one with two nucleophilic sites and the other containing two electrophilic sites. Furthermore, the regiochemistry of the reaction is controlled by the differential reactivities of these sites. 

Several examples of aza-annulation have been reported with substrates in which the nitrogen involved in formation of the S-Iactam product was a constituent of a pyridine ring. In general, (1) the nucleophilic carbon of the substrate was activated by carbonyl functionality, (2) these substrates require reaction with doubly activated Michael acceptors, and (3) generation of the unsaturated pyridone ring was an important driving force for aza-annulation. 

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... 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

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