Neutral carbon nucleophiles

The tetrahedral intermediate produced by addition of organolithiums or Grignard reagents to esters collapses to a ketone which is more reactive titan the original ester electrophile. A second equivalent adds to give a tertiary alcohol as tlte product. This process cannot be controlled by temperature or by mode of addition since tlte intermediate product is more reactive than the starting material. 

Other types of carbon nucleophiles such as uncharged enol derivatives and other 7r -bonded systems are only weakly nucleophilic and consequently unreactive 

A variety of Lewis acids can be used. Among the more commonly used ones are AICI3, TiCU, S11CI4, Z11CI2, BF3, and TMSOTf (trimethylsilyl triflate). The choice of Lewis acid is often critical to the success of the reaction and is usually made by referring to similar transformations that have been successfully reported in the literature. Often it is not possible to rationalize why one Lewis acid works and another one does not, so the initial choice of catalyst is normally made by literature precedent. With the arsenal of Lewis acids available a suitable catalyst can usually be found. 

By this strategy, reactive carbon electrophiles can be generated for successful reaction with a variety of weak carbon nucleophiles. More important examples include the Friedel-Crafts reaction in which aromatic compounds (nucleophiles) react with alkyl and acyl halides (electrophiles in the presence of Lewis acids). 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

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Addition of C-nucleophiles to nitrile oxides is of special interest. There are examples of reactions with both carbanions and neutral carbon nucleophiles. To the former group belong reactions of nitrile oxides with organometallic... 

While no unified synthetic approach to diazoalkanes can furnish all manner of substituted diazo compounds, the various methods and reagents surveyed here go far in enabling access to a rich inventory of these fascinating molecules. Further improvements will serve not only to popularize known applications of the neutral carbon nucleophiles, but also to spur interest in the development of related new reactions. Our focus in the next section is modernized, catalytic carbon insertion methodologies involving both stabilized and nonstabilized diazoalkane reagents. 

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

Since allylation with allylic carbonates proceeds under mild neutral conditions, neutral allylation has a wide application to alkylation of labile compounds which are sensitive to acids or bases. As a typical example, successful C-allylation of the rather sensitive molecule of ascorbic acid (225) to give 226 is possible only with allyl carbonate[l 37]. Similarly, Meldrum s acid is allylated smoothly[138]. Pd-catalyzed reaction of carbon nucleophiles with isopropyl 2-methylene-3,5-dioxahexylcarbomite (227)[I39] followed by hydrolysis is a good method for acetonylation of carbon nucleophiles. 

No reaction of soft carbon nucleophiles takes place with propargylic acet-ates[37], but soft carbon nucleophiles, such as / -keto esters and malonates, react with propargylic carbonates under neutral conditions using dppe as a ligand. The carbon nucleophile attacks the central carbon of the cr-allenylpal-ladium complex 81 to form the rr-allylpalladium complex 82, which reacts further with the carbon nucleophile to give the alkene 83. Thus two molecules of the a-monosubstituted /3-keto ester 84, which has one active proton, are... 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Methylation of relatively acidic (pKa < 13) carbon nucleophiles occurs at neutral pH in aqueous media when substituted methylsul-fonium and -selenonium salt are used as electrophiles (e.g., 6.2).37... 

Addition of carbon nucleophiles to furfural tosylhydrazone provides 5-substituted 2E,4E-pentadienyls in good yields <00TL2667>. The ab initio calculations at the RHF/3-21G level have been utilized to study the origins of diastereoselectivity of the vinylogous Mannich reaction of 2-methylfuran with pyrrolinium ion . A simple procedure for isomerization of 2-furylcarbinols to cyclopentenones under neutral condition was reported and a new mechanism was proposed <00H(52)185>. 

Next to iodine there is also another class of neutral Lewis acids known. Tetracyanoethylene, dicyanoketene acetals and derivatives can catalyse reaction due to their tt-Lewis acid properties. They promoted the alcoholysis of epoxides [238], tetrahydropyranylation of alcohols [239], monothioacetahzation of acetals [240], and carbon-carbon bond formation of acetals [241,242] and imines [243] with silylated carbon nucleophiles. 

The HC1 generated in this reaction destroys one equivalent of diazomethane. This can be avoided by including a base, such as triethylamine, to neutralize the acid.74 Cyclic z-diazoketones, which are not available from acyl chlorides, can be prepared by reaction of an enolate equivalent with a sulfonyl azide. This reaction is called diazo transfer 5 Various arenesulfonyl azides76 and methanesulfonyl azide77 are used most frequently. Several types of compounds can act as the carbon nucleophile. These include the anion of the hydroxymethylene derivative of the ketone78 or the dialkylaminomethylene derivative of... 

Mechanism. The neutral amine nucleophile attacks the carbonyl carbon to form a dipolar tetrahedral intermediate. The intramolecular proton transfer from nitrogen and oxygen yields a neutral carbinolamine tetrahedral intermediate. The hydroxyl group is protonated, and the dehydration of the protonated carbinolamine produces an iminium ion and water. Loss of proton to water yields the imine and regenerates the acid catalyst. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

The following equations depict the intramolecular substitution of an allylic oxy group by a -hybridized carbon nucleophile [63]. A silyl group effectively directs its adjacent carbon to neutralize the allyl cation. 

By using the neutral enamine as the carbon nucleophile rather than an eno-late anion, the biological system avoids the need for strongly basic reaction conditions in aldol addition. 

The nucleophiles discussed so far have been either carbon nucleophiles, or homogenous sets of amine or neutral oxygen nucleophiles. The TV+ relationship embraces a wide variety of anionic nucleophiles with different reacting atoms. As already demonstrated, reactivities of these nucleophiles strikingly fail to correlate with equilibrium constants for their reactions. 

Type III reaction proceeds by an attack of a nucleophile at the central sp carbon of the allenylpalladium. Soft carbon nucleophiles such as / -keto esters and malonates react with propargylic carbonates under neutral conditions using DPPE as a ligand [35], The 2,3-disubstituted propenes 151 and 152 are obtained by the reaction of 2-propynyl carbonate (145) with two moles of malonate under neutral conditions in... 

The formal addition of a C-H bond at activated methylenes and methynes (pronucleophiles) to activated alkenes in the presence of a base is well known as the Michael reaction (Scheme 1, Type A) [1]. In modem organic syntheses, the use of transition metal (TM) catalysts enables the C-H addition of activated methylenes and methynes to activated alkenes perfectly under neutral conditions (Scheme 1, Type B) [2]. In general, the nonfunctionalized carbon-carbon multiple bonds (for example, EWG2 = H in Scheme 1) are unreactive toward carbon nucleophiles because of their electron rich Jt-orbitals. The pioneering efforts by various research groups resulted in the development of transition metal-catalyzed addition of a C-H bond at active alkanes to such unactivated C-C multiple bonds. This reaction consists of the formal addition of a C-H bond across the C-C multiple bonds and is called a hydrocarbonation reaction. As a milestone in this hydro-carbonation area, early in the 1970s, Takahashi et al. reported the Pd-catalyzed addition of the C-H bond of pronucleophiles to 1,3-dienes [3], The first Pd-catalyzed reaction of activated methylenes with unsubstituted allenes was apparently reported by Coulson [4]. The synthetic applications of this reaction were very limited. In the last decade, the Pd-catalyzed addition of C-H bonds to various unacti-... 

Fig. 8. 3. Zwitterion mechanism of the decomposition of neutral carbonic acid (derivatives) in a heterocumulene and a hetereo-nucleophile—examples carbonic acid (B), carbonic acid monomethylester (E), carbonic acid mono-tert-butylester (H), carbamic acid (K), and urea (M).

Neutral carbon electrophiles usually have a Jt bond as the nucleophilic portion of the molecule. 

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