Oxygen nucleophiles intramolecular attacks

Nitrogen nucleophiles such as amines, and in intramolecular reactions amides and tosylamides, readily add to alkenes complexed to Pd derived from PdCl2 (RCN)2 with reactivity and regiochemi-cal features paralleling those observed for oxygen nucleophiles. Intramolecular nucleophilic attack by heteroatom nucleophiles also occurs in conjunction with other palladium-catalyzed processes presented in the following sections. 

In the pH range 2—3.5 the phosphonate (78) hydrolyses with loss of ROH at approximately 10 times the rate of comparable esters lacking the vicinal oxime function or in which this function is methylated on oxygen. An intramolecular general-acid catalysis mechanism was proposed, but it was not possible to exclude entirely an intramolecular nucleophilic attack at phosphorus. Intramolecular attack by the vicinal dimethylamino-group takes place preferentially at carbon rather than phosphorus in the phos-phonofluoridate (79). ... 

Recently, Trost et al. reported the vanadium-catalyzed addition reaction of 2,3-allenols [180], Here the oxygen in 401 served as an intramolecular nucleophile to attack the center carbon atom of allene to form a vanadium enolate 402. Aldol condensation of 402 with an aldehyde afforded (2-hydroxy)alkyl vinylic ketones 403. 

A development of the last two decades is the use of Wacker activation for intramolecular attack of nucleophiles to alkenes in the synthesis of organic molecules [9], In most examples, the nucleophilic attack is intramolecular, as the rates of intermolecular reactions are very low. The reaction has been applied in a large variety of organic syntheses and is usually referred to as Wacker (type) activation of alkene (or alkynes). If oxygen is the nucleophile, it is called oxypalladation [10], Figure 15.4 shows an example. During these reactions the palladium catalyst is often also a good isomerisation catalyst, which leads to the formation of several isomers. 

All penicillins are susceptible to attack in acidic solution via intramolecular attack of the amide carbonyl oxygen on the (3-lactam carbonyl, leading to the complete destruction of the (3-lactam ring, and thus the antibacterial activity. Similarly, penicillins are unstable in basic solution because of (3-lactam ring opening by free basic nucleophiles. Thus, for the antibacterial activity, the stability of the (3-lactam functional group in penicillins is of paramount importance. 

Oxadiazoles (and also other l-oxa-2-azoles) undergo intramolecular nucleophilic displacements of 0(1) of the general type (318 319) via the intramolecular attack on N(2) of oxygen, sulfur, nitrogen, and carbon nucleophiles Z forming the third atom of a side-chain at the 3-position of the heterocycle. 

Larock and co-workers [47] have studied the palladium-catalyzed arylation of 1,3-dienes followed by intramolecular attack by an oxygen nucleophile. o-Iodophenols and o-iodobenzyl alcohol were used as substrates. However these reactions, which are annulation reactions, lead to a 1,2-addition to the conjugated dienes and will not be further treated here. Amides, also, were used as nucleophiles in these reactions. 

Intramolecular reactions of allylic acetates with conjugated dienes catalyzed by Pd(0) lead to a 1,4-addition of a carbon and an oxygen nucleophile to the diene. The reaction, which is formally an isomerization, involves tw different yr-allyl complexes (Scheme 8-4) [44]. Reaction of 22 in the presence of the Pd(0) catalyst Pd2(dba)3-CHCl3 (dba = dibenzyl-ideneacetone) and LiOAc/HOAc in acetonitrile at reflux produces the cyclized isomer 25 in 62% yield. The double bond was exclusively of E stereochemistry, while the ring stereochemistry was a mixture of cis and tram isomers. Oxidative addition of the Pd(0) to the allylic acetate gives the intermediate jr-allyl complex 23. Subsequent insertion of a diene double bond into the allyl-palladium bond produces another jr-allyl intermediate (24), which is subsequendy attacked by acetate to give the product 25. 

In a related reaction, tetraene 26 underwent carbocyclization to give allylic ether 27 [Eq.(26)j [45]. The reaction can be considered as an intramolecular telomerization, and leads to the 1,4-addition of a carbon and an oxygen nucleophile to one of the dienes. The reaction involves a 7r-allyl intermediate, which is subsequendy attacked by the oxygen nucleophile. 

Thus, while nucleophiles are believed to generally attack C2 of pyridine, LiAlD4 and added secondary alcohol are visualized to furnish an alkoxy aluminum deuteride, which docks onto the secondary hydroxy group of the alkaloid (2a-OH —> i). Hydrogen evolved is swept out by nitrogen. Thanks to the lone-pair back-donation from the alkoxy oxygens to aluminum (Scheme 12.5) that the intramolecular attack by... 

Recyclization mechanisms have been considered in order to account for observed exocyclic cleavage in hydrolysis of the cyclic phosphonyl urea system [24] (Scheme 13). The dominance of such a mechanism for exocyclic cleavage of the phenyl ester in the range 0.5 < pH < 2.0 can be discounted for two reasons. First, the build-up and decay of the ring-retained species [24d] has been detected by H nmr spectroscopy, kinetically consistent with the intermediacy of this species (Thatcher, 1985). Secondly, the oxygen of amides and ureas has been shown to be the preferred nucleophile for intramolecular attack on phosphorus (Kluger et al., 1979, 1984a). Observation of the intermediate [24d] is therefore incompatible with a recyclization mechanism (0.5 pH 2.0). 

Hong and Overman reported the intramolecular termination of cascade reactions by oxygen nucleophiles in their studies on a novel synthesis of morphine (Scheme Starting from an iodophenol derivative tethered with an iodophenol silyl ether, intramolecular carbopalladation provided a bicycUc Tr-allylpalladium intermediate, which in turn was attacked by the oxygen functionality (Scheme 37). 

The oxidations of olefins with many oxygen nucleophiles other than water have also been reported. These reactions include the s5mthesis of vinylic and allylic ethers from reactions of olefins with alcohols and phenols, and vinylic and allylic esters from reactions of olefins with carboxylic acids. These reactions have been conducted with both monoenes and 1,3-dienes. Both intermolecular and intramolecular versions of each of these processes have been developed. Some discussion of these reactions was included in Chapter 11 because of their connection to the nucleophilic attack of oxygen nucleophiles on coordinated olefins and dienes. 

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