Carbon nucleophiles, also

In addition to enolate ions, other kinds of carbon nucleophiles also add to a jjS-iinsaturated acceptors in Michael-like reactions. Among the most important such nucleophiles, particularly in biological chemistry, are enamines, which are... 

Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi-Sakurai reaction. The allylsilane will add to the carbonyl compound directly if it is not part of an a,P-unsaturated system (Example 2), giving rise to an alcohol. 

As with the dithiane derivatives, the reaction of a-stannyl sulfides 20-22 with various carbon nucleophiles also proceeded smoothly and P-keto sulfides 23-25 were obtained in excellent yield (Table 4). ... 

Other carbon nucleophiles also tend to attack at the less substituted position of an unsymmetrical epoxide. This holds true for cyanide, which can be conveniently prepared in situ from methyllithium and acetone cyanohydrin 82. In a one-pot reaction, the epoxy ether 81 is... 

Reactive carbon nucleophiles also include metalated metallocene and (arene)metal complexes. Equation 6 shows an example of the former treating the suspension of dUithoferrocene-tmeda conplex in Et20 with i-Pr2SiCl2 gave 3 in 34% yield.An example of the latter is shown in eq 7 conplex 4 was metalated with 2 equiv n-BuLi in the presence of pentamethyldiethylenetriamine (pmdta) in pentane, the dilithi-ated intermediate was isolated and then treated with i-Pr2SiCl2 in heptane to give complex 5. ... 

Based on this reaction, allylic alkylation of alkenes is possible. Active methylene compounds, such as malonates and /8-keto esters, can be introduced to a steroid skeleton by the reaction of the steroidal jr-allylpalladium complex in DMSO (eq 20). 4 Jijg reaction of carbon nucleophiles also proceeds in the presence of an excess of triphenylphosphine (eq 21). ... 

Formation of a Tr-allylpalladium complex 29 takes place by the oxidative addition of allylic compounds, typically allylic esters, to Pd(0). The rr-allylpal-ladium complex is a resonance form of ir-allylpalladium and a coordinated tt-bond. TT-Allylpalladium complex formation involves inversion of stereochemistry, and the attack of the soft carbon nucleophile on the 7r-allylpalladium complex is also inversion, resulting in overall retention of the stereochemistry. On the other hand, the attack of hard carbon nucleophiles is retention, and hence Overall inversion takes place by the reaction of the hard carbon nucleophiles. 

Facile reaction of a carbon nucleophile with an olefinic bond of COD is the first example of carbon-carbon bond formation by means of Pd. COD forms a stable complex with PdCl2. When this complex 192 is treated with malonate or acetoacetate in ether under heterogeneous conditions at room temperature in the presence of Na2C03, a facile carbopalladation takes place to give the new complex 193, formed by the introduction of malonate to COD. The complex has TT-olefin and cr-Pd bonds. By the treatment of the new complex 193 with a base, the malonate carbanion attacks the cr-Pd—C bond, affording the bicy-clo[6.1,0]-nonane 194. The complex also reacts with another molecule of malonate which attacks the rr-olefin bond to give the bicyclo[3.3.0]octane 195 by a transannulation reaction[l2.191]. The formation of 194 involves the novel cyclopropanation reaction of alkenes by nucleophilic attack of two carbanions. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

Alkynyl)oxiranes also react with carbon nucleophiles to afford furan derivatives. Furanes of different types are obtained depending on the structure of the substrates. 7-Methyl-2-ethynyloxirane (95) reacts with acetoacetate to give the furan 97 by the elimination of formaldehyde from the cyclized product 96. The hydroxy ester of the alkylidenefuran 98 and the corresponding lactone 99 are obtained by the reaction of i-methyl-2-(2-propynyI)oxirane[40, 42]. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Ring-atomic centers can undergo attack by electrophiles, easily at the ring nitrogen and less easily at ring carbons. Nucleophilic attack is also possible at ring carbons or hydrogens. 

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

The reaction of A-acyliminium ions with nucleophilic carbon atoms (also called cationic x-amidoalkylation) is a highly useful method for the synthesis of both nitrogen heterocycles and open-chain nitrogen compounds. A variety of carbon nucleophiles can be used, such as aromatic compounds, alkcncs, alkyncs, carbcnoids, and carbanions derived from active methylene compounds and organometallics. 

Nucleophilic substitution at an allylic carbon can also take place by an Sn2 mechanism, in which case no allylic rearrangement usually takes place. However, allylic rearrangements can also take place under Sn2 conditions, by the following mechanism, in which the nucleophile attacks at the y carbon rather than the usual... 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

Enantioselectivity (which is hnked to the regioselectivity of the attack of the nucleophile to the coordinated allyl) in the allylic amination of 1,3-diphenyl-allyl ethyl carbonate was also very low compared to the P-N system. This was attributed to the comparable fran -influence of P and NHC functionalities, leading to poor regioselec-tion of the two aUyl termini trans to the P and NHC ligands by the nucleophile [95],... 

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