Sequential addition/elimination reactions

Nucleophilic substitution at an sp carbon usually proceeds via an addition/ elimination sequential pathway. Thus, the reaction of ArS- to, say, 1,1-dichloroethene, in the presence of a catalytic amount ethoxide anion, proceeds via an addition followed by a double elimination, with finally a further addition to yield the 1,2-dithiophenoxy derivative. 

Concurrent with this disclosure, Rossi reports a similar protocol wherein 2-acyl-l-(phenylsulfonyl)-3-iodoindoles 189 undergo room temperature palladium-catalyzed coupling with terminal alkynes to afford the corresponding 3-alkynylindoles 190 <01S2477>. Subsequent treatment with ammonia in methanol leads to formation of the p-carbolines 191 through sequential addition/elimination/cycloamination reactions accompanied by loss of the A -phenylsulfonyl group. 

Recently, elegant synthesis of ruin -MRS carbapenum has been reported. Sequential reaction of nitromethane via conjugate addition-elimination to a,fi-unsanirated esters followed by Pd-catalyzed subsdnidon of the residdng allyl nitro compound with the naphthosultam affords the allyladon product which is an and fEq. 7.20. ... 

Some experimental evidences are in agreement with this proposed mechanism. For example, coordinating solvents like diethyl ether show a deactivating effect certainly due to competition with a Lewis base (149). For the same reason, poor reactivity has been observed for the substrates carrying heteroatoms when an aluminum-based Lewis acid is used. Less efficient hydrovinylation of electron-deficient vinylarenes can be explained by their weaker coordination to the nickel hydride 144, hence metal hydride addition to form key intermediate 146. Isomerization of the final product can be catalyzed by metal hydride through sequential addition/elimination, affording the more stable compound. Finally, chelating phosphines inhibit the hydrovinylation reaction. 

Some examples of the Michael reaction on the exocyclic double bond of an unsaturated oxazolone have been discussed in previous sections. The synthesis of unsaturated 5(4//)-oxazolones from unsaturated 5(4/l/)-oxazolones via an addition-elimination sequence and the sequential reaction of unsaturated 5(4/i/)-oxazolones with a l,3-bis(nucleophile) have already been considered. This section will review Michael additions exclusively and, in this respect, a wide array of nucleophiles has been studied. 

Organometallic substitution of iron-complexed dioxolenes has been reported. The reaction proceeds with net inversion of configuration, the result of a two-step addition-elimination pathway. Dialkyl-cuprates, higher order cyanocuprates and Grignard reagents have all been employed, and sequential dis-... 

The M—A bond which is formed frequently shows a reactivity toward addition and substitution reactions similar to that of the original bond to the metal sequential combinations of the elementary processes of addition, substitution, and elimination are useful in synthesis, especially for organotin derivatives. The individual reactions, and their most important combinations are ... 

As well as those reactions that fall neatly into one or other of the three simple reaction types, there are some reactions where an addition reaction is followed by an elimination reaction, or vice versa, resulting in an overall substitution of a group. These reactions will be considered separately in this book under the heading of sequential addition/elimination reactions. 

Instead of performing the one step bimolecular SN2 reaction, alkenes react via two closely related bimolecular pathways. The first of these is called the tetrahedral mechanism and proceeds via a negatively charged intermediate. This mechanism is sometimes called the addition/elimination reaction, which is given the label Adn/E. This alternative name is unfortunate, because the other pathway is called the addition/elimination mechanism and proceeds via a readily detectable neutral intermediate. This latter mechanism will be considered in the chapter on sequential addition/elimination reactions. In this book, in an attempt to reduce the confusion, we will call the mechanism that proceeds via an anionic intermediate the tetrahedral mechanism, and reserve the name addition/elimination mechanism for the mechanism that proceeds via a neutral species. 

That ends this chapter on elimination reactions. It is apparent from the foregoing discussion that elimination reactions are far less well defined than either the substitution or addition reactions that we had studied previously. However, it was still possible to rationalise the production of the experimentally observed products. We will now look at sequential reactions, in which an addition reaction is followed by an elimination, or vice versa, and so leads to an overall substitution reaction... 

Now that we have studied sequential addition/elimination reactions, we will look at a few reaction sequences that occur in the opposite order, i.e. elimination followed by addition. 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

Diaryl-1,3,5-triazines 9 are obtained from 5-methoxymethylene-2,2-dimethyl-l,3-dioxane-4,6-dione 6 (easily accessible from Meldrum s acid, p 386) by sequential reaction with two molecules of arylamidine [173]. Triazine formation is thought to proceed via condensation of the first amidine with 6 to give 7 and addition of the second amidine moiety to give 8, which unexpectedly cyclizes to 9 with elimination of NH3 and Meldrum s acid. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

Reactions involving sequential addition-elimination processes such as the Wittig reaction serve as useful methods for constructing organic molecules having carbon-carbon double bonds. 

If a methyl ketone is allowed to undergo multiple halogenations under basic conditions, a carboxylic acid will ultimately be produced via the haloform reaction (Eq. 11.10). This reaction involves three sequential halogenations, followed by an addition-elimination. It only works with a methyl ketone, because three halogens are required to create a good enough... 

Primary and sequential reactions of four small uranium oxide/hydroxide anions, U02, UO3, U04, and U03(0H), with methanol, were studied the experimental observations were evaluated by DFT, with the validity of the computational results—structures and reaction mechanisms—confirmed by isotopic labeling experiments (Michelini et al., 2010). The U02 ion was inert, whereas the other three oxoanions reacted with three methanol molecules via the addition or elimination of formaldehyde, water, or dihydrogen to ultimately produce inert uranyl methoxide anion complexes, [U 02(0CH3)2] or [U 02(0CH3)3] . The structure of the U04 ion reveals four discrete U—O bonds with no O—O bonding. Another notable feature of the DFT results that was verified by isotopic labeling is that the stmcture of... 

Among the successful synthetic strategies for carbocyclic compounds that have been introduced can be found the phenylthio radical-catalyzed multiple radical reactions (see Scheme 6). This sequential transformation has also been termed, in a more general context, as addition-elimination methodology [9]. 

In the above-mentioned Heck-type cascade tetracyclizations, substituents in the acycUc precursors can play a major role and cause the sequential reaction to proceed in an unprecedented direction. A particularly striking example is presented in Schone 39. The acycUc precursors differ from those that undergoe the other type of cascade tetracyclization (see above Scheme 33) only by the propargylic methoxy (silyloxy) group, yet yield—under the typical conditions—an unprecedented tetracyclic system, the structure of which has been proved by X-ray analysis. This cascade reaction may involve an unusual -/ hydride elimination as the last step, or an unprecedented dehydrobromination on an alkylpalladium bromide intermediate to yield a palladiumcarbene species that subsequently undergoes an intramolecular cheletropic addition across the distal double bond to yield the cyclopropane ring. 

Developing one-pot reactions or multicomponent reactions. Syntheses that are able to combine several sequential reactions into a single vessel without purification of the intermediates are quite valuable [70-74]. These reactions often save time as well as eliminate the solvents that would have normally been used for chromatographic separation of the intermediates. These processes are often referred to as telescoping or one-pot reactions and have been steadily growing in popularity. The trick with these reactions is to design the syntheses so that the steps are chemoselective for the desired transformation and are not affected by any of the catalysts and additives from the previous reactions. 

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