Reactions with Carbon Nucleophiles

Carbopalladation occurs with soft carbon nucleophiles. The PdCl2 complex of COD (100) is difficult to dissolve in organic solvents. However, when a heterogeneous mixture of the complex, malonate and Na2C03 in ether is stirred at room temperature, the new complex 101 is formed. This reaction is the first example of C—C bond formation and carbopalladation in the history of organopalladium chemistry. The double bond becomes electron deficient by the coordination of Pd(II), and attack of the carbon nucleophile becomes possible. The Pd-carbon n-bond in complex 101 is stabilized by coordination of the remaining alkene. The carbanion is generated by treatment of 101 with a base, and the cyclopropane 102 is formed by intramolecular nucleophilic attack. Overall, the cyclopropanation occurs by attack of the carbanion twice on the alkenic bond activated by Pd(II). The bicyclo[3.3.0]octane 103 was obtained by intermolecular attack of malonate on the complex 101 [11]. 

Another type of carbopalladation is observed in the oxidation of the 2,2-disubstituted alkene attached to the cyclobutanol 104. The shift of the carbon-carbon bond as shown by 105 and ring expansion generate 106. Intramolecular alkene insertion gives the bicyclo[4.3.0]nonane system 107. Finally, 108 is obtained [78], 

Alkenes coordinated by Pd(II) are attacked by carbon nucleophiles, and carbon-carbon bond formation takes place. The reaction of alkenes with carbon nucleophiles via 7r-allylpalladium complexes is treated in Section 3.1. 

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. 

The phenylation of styrene with phenyl Grignard reagents as a hard carbon nucleophile proceeds in 75% yield in the presence of PdCl2, LiCl, and K2CO3 at room temperature to give stilbene (207). Selection of the solvent is crucial and the best results are obtained in MeCN. The reaction can be made catalytic by the use of CuCl2[197]. Methyllithium reacts with styrene in the presence of Pd(acac)2 or Pd(OAc)2 to give /3-methylstyrene (208) in 90% yield[198]. 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I], 

Carbopalladation of the double bond of the benzyl A/ -vinylcarbamate 124 with benzyl acetoacetate, and subsequent carbonylation affords the amino ester 125, which was converted to a y3-lactam [53], 

Intramolecular carbopalladation of the unsaturated jS-diketone 126 catalyzed by the combination of PdCl2 with CuCb at room temperature provided the cyclo-hexenone 127 in very high yield (97 %). In other words, facile oxidative alkylation of an unactivated alkene with a carbon nucleophile took place [54], 

Active carbanions are prone to substitute hydrogen of nitroaromatic compounds the substitution usually takes place either ortho or para to the nitro group. The anionic On-adduct generated as a result of nucleophilic addition can be converted into the final product by various mechanisms [167]. Most often exemplified are vicarious nucleophilic substitution (VNS) and oxidative nucleophilic substitution of hydrogen (ONSH). 

The regioselectivity of the VNS process is dependent mi substituents oti the thiophene ring, the structure of the carbanion and the reaction conditions. Nucleophilic addition to 2-nitrothiophene can occur at two positions C-3 and C-5, but the strong preference is for attack at C-3 [168]. 

All secondary anions react at C-3 of 2-nitrothiophene tertiary carbanions give mixtures of 3- and 5-substituted 2-nitrothiophenes, but still the major substitution occurs at C-3 [168]. It is instructive to compare with nitrobenzenes tertiary carbanions replace only para-hydrogens from nitrobenzenes. Moreover, nitrobenzene is not as reactive under the conditions suitable for the substitution on a thiophene ring f-BuOK as the base in THF [168]. 

2-Nitrothiophenes with a substituent at C-5 also react smoothly under VNS conditions. Even when the substituent at C-5 is Br or I and a low base concentration was used (conditions favouring the S Ar), no products of halogen substitution by S Ar were observed [168]. 

A VNS variation involves 2-nitrothiophenes which are already functionalised at C-3 [161]. Thus 2-nitro-3-bromothiophene with chloromethyl phenyl sulfone 

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Reaction with Carbon Nucleophiles. Unactivated a2iddines react with the lithium salts of malonates or p-keto esters in the presence of lithium salts to yield 3-substituted pyttohdinones (56—59), where R = alkyl and aryl, and R = alkoxyl, alkyl, and aryl. 

Reactions with carbon nucleophiles, e.g. from ketones (73CR(C)(277)703, 74CR(C)(278)427), are sometimes accompanied by deacylation in situ to give alkyl derivatives, e.g. (106)... 

The mfluoromethyl group activates the fluorine in position 4 ofperfluorotolu ene toward reaction with carbon nucleophiles Examples on che use of perfluoro-toluene as an arylation agent abound, and in all cases, the 4-fluonne atom is replaced predommantly or exclusively [% 87,88,89, 90 (equation 48) In perjluoromesity-lene, the aromatic fluorine atoms are activated toward Ar reaction, and a reaction... 

Stereoselective reactions of this type known at present only deal with four- or five-membered cyclic iV-acyliminium ions. The reactions with carbon nucleophiles usually lead to rra/u-substi-tuted compounds with very high stereoselectivity due to steric control by the substituent already present in the ring. 

Electrophilic vinylidene complexes, which can be easily generated by a number of different methods [128], can react with non-carbon nucleophiles to yield carbene complexes (Figure 2.9 for reactions with carbon nucleophiles, see Section 3.1). 

Preparation of Tr-Allylpalladium Complexes from Alkenes and Their Reactions with Carbon Nucleophiles... 

Some carhon-carbon bond forming reactions with carbon nucleophiles cyanide ion, acetylide ion and Grignard reagents. 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

The synthetically important subclass of alkynyl aziridines was included in a recent review <02COC539>, specifically from the standpoint of preparation and ring opening reactions with carbon nucleophiles. Such substrates (e.g. 178) tend to suffer Sn2 attack from Grignard reagents to give aminoallenes (e.g. 179). 

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