Nucleophilic addition-elimination reagents

In contrast, the addition of amines results in nucleophilic addition/elimination at the opposite a-position, resulting in substitution of the a-oxygen substituent, a reaction consistent with the Fischer carbene character embedded into this architecture (Equation 2) <2004JOM2000>. This regioselectivity difference almost certainly arises from the reversible nature of addition reactions using such weakly nucleophilic reagents. 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

As we begin now to explore the syntheses of carboxylic acid derivatives, we shall find that in many instances one acid derivative can be synthesized through a nucleophilic addition—elimination reaction of another. The order of reactivities that we have presented gives us a clue as to which syntheses are practical and which are not. In general, less reactive acyl compounds can be synthesissed from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents. 

The vinylic substitution of Z- and E-P-bromostyrenes 1 with MeS occurs via the stepwise nucleophilic addition-elimination route. The reaction is very fast in dipolar aprotic solvents like HMPA, DMSO and DMF, which due to their ability as cation solvators enhance the nucleophilicity of the reagent. 

The nucleophilic attack of nitrogen bases leads to a variety of products as the result of addition or addition-elimination reactions The regioselectivity resembles that of attack by alcohols and alkoxides an intermediate carbanion is believed to be involved In the absence of protic reagents, the fluorocarbanion generated by the addition of sodium azide to polyfluonnated olefins can be captured by carbon dioxide or esters of fluonnated acids [J 2, 3] (equation I)... 

When written in this way it is clear what is happening. The mechanisms of these reactions are probably similar, despite the different p values. The distinction is that in Reaction 10 the substituent X is on the substrate, its usual location but in Reaction 15 the substituent changes have been made on the reagent. Thus, electron-withdrawing substituents on the benzoyl chloride render the carbonyl carbon more positive and more susceptible to nucleophilic attack, whereas electron-donating substituents on the aniline increase the electron density on nitrogen, also facilitating nucleophilic attack. The mechanism may be an addition-elimination via a tetrahedral intermediate ... 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

In this context, an avalanche of studies were devoted to acid-base reactions in their broadest sense (i.e., the Lewis picture), also involving complexation reactions, to the typical organic reactions of addition, substitution, and elimination types, involving nucleophilic and electrophilic reagents including the case of radicalar reactions and excited states (for a review see Ref. [11]) in which our group has... 

Two substitutions are occurring here H to Br, and Br to MeO. Looking at the order of reagents, the first substitution is H to Br. Br2 is electrophilic, so the a-C of the acyl bromide must be made nucleophilic. This is done by enolization. The substitution of Br with MeO occurs by a conventional addition-elimination reaction under acidic conditions. 

There is wide diversity in the nature of organohalogen compounds but, of necessity, we have restricted this chapter to alkyl, cycloalkyl, alkenyl, alkynyl, and aryl halides. Some of the chemistry of the carbon-halogen bonds already will be familiar to you because it involves the addition, substitution, and elimination reactions discussed in previous chapters. To some extent, we will amplify these reactions and consider nucleophilic substitution by what are called the addition-elimination and elimination-addition mechanisms. Subsequently, we will discuss the formation of carbon-metal bonds from carbon-halogen bonds. The latter type of reaction is of special value because compounds that have carbon-metal bonds are potent reagents for the formation of carbon-carbon bonds, as we will show later in this chapter. 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

The addition-elimination reaction between 2-chlorocarbonyI-lfl-pyr-rolizin-l-one and chlorine has been described (see Section III,B,2,c). The 2,5-dichloro derivative 21b isolated in the same reaction must presumably be derived from an electrophilic substitution on the initially formed 2-chloro-pyrrolizinone.26 The iminopyrrolizine 270 can be methylated, first with Meerwein s reagent and then by methyl iodide to give the quaternary salt 271, which reacts readily with nucleophiles (see Section III,B,5). 

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