1,4-addition of a nucleophile

Addition of a nucleophile diastereoselectively produces the a-enolate 4 due to approach of the nucleophile from the less-hindered side of the iron atom. Quenching of 4 by electrophiles is also controlled by the iron center, and diastereocontrolled alkylation of the a-carbon occurs from the less hindered face of elaborated enolate 4 (see also Section 1.1.1.3.4.1.3.) to produce complex 5. 

Tomalia developed the polyamidoamine (PAMAM) dendrimers via the repetition of a simple two-step procedure (1)1,4-addition of a nucleophilic core (e.g. ammonia, ethylene diamine or tris(2-aminoethyl)amine) to methyl acrylate followed by amida-tion of the resulting ester with an amine functionality (e.g. ethylene diamine, propylene diamine) [188, 189] (see Fig. 18). PAMAM dendrimers could be synthesised as high as generation seven, due to the high yield of the synthetic procedure. From that point the steric considerations began to dominate, making the addition of any subsequent generations difficult [168]. 

The overall sequence could be realized by 1,4-addition of a nucleophile to the enone and subsequent quenching at the a-position followed by B-elimination of the initial nucleophilic component. Such multistep processes will not be discussed here. However direct hydroxylation methods are scarce. Mo-riarty has reported that a,3-unsaturated ketones are oxidized by phenyliodosyldiacetate at the a-site in preference to the a -position, e.g. (138) to (139), although no yield has bWn indicated. There is no available mechanistic rationale, although the intermediacy of the a,B-epoxide is precluded. 

The anodic oxidation of phenylenediamines parallels that of aminophenols (see Sec. III.A.l) and has been reviewed by Adams [108]. If unsubstituted at the nitrogens, the two-electron oxidation leads to the quinone dimine. This compound either undergoes hydrolysis to the quinone inline and benzoquinone, or a 1,4-addition of a nucleophile, for example, the parent phenylenediamine itself, to the quinoidal systems occurs. Further oxidation of the products may take place. In acetonitrile, the one-electron oxidation to the cation radical predominates [109]. Under these conditions,/7-phenylenediamine also leads to 1,4-coupling products [110,111]. A-Substituted phenylenediamines are forming more stable cation radicals. For example, tetrakis(/7-bromophenyl)/7-phenylenediamine ( °= 0.91V vs. NHE) and tetrakis(2,4-dibromophenyl)-/7-phenylenediamine E° = 0.94 V vs. NHE) in acetonitrile even show reversible behavior for the second oxidation step to the dication [78]. 

De Waard has developed a modification of the Ramberg-BScklund rearrangement in which the intermediate a-sulfonyl carbanion is generated by 1,4-addition of a nucleophile to a vinyl sulfone the Mi-... 

Also known as conjugate addition, Michael addition is the 1,4-addition of a nucleophile to an a,P-unsaturated system. 

Michael Addition. The Michael addition is a conjugate nucleophilic addition of a carbanion to electron-deficient olefins (Fig. 13) (54). A base is used to form the carbanion by abstraction of protons from activated methylene donors which attack the olefin acceptor forming an enolate ion. The mechanism is 1,4-addition of a nucleophile to the conjugated system. 

All the reactions we ve been discussing to this point have involved the addition of a nucleophile directly to the carbonyl group, a so-called 1,2 addition. Closely related to this direct addition is the conjugate addition, or 1,4 addition, of a nucleophile to the C=C bond of an a,/3-unsaturated aldehyde or ketone. (The carbon atom next to a carbonyl group is often called the a carbon, the next... 

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]. 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic... 

Nucleophilic additions of amines to acceptor-substituted dienes were examined as early as 1950. Frankel and coworkers98 found that the reaction of 2,4-pentadienenitrile with various secondary amines proceeded regioselectively to furnish the 1,6-addition products (equation 29). In some cases, these could converted into the 2,4-diamino-substituted pen-tanenitriles by isomerization and 1,4-addition of a second molecule of amine. Analogous results were reported by other groups17,99 100 and extended to hydrazine as nucleophile101 and to vinylcyclobutenones48 and dienoates102-104 as Michael acceptors. 

Addition of various nucleophiles to the o o-double bond of 5-alkylidene-l,3-dioxane-4,6-diones has been reported in the literature. Two different pathways have been examined (1) the addition of a nucleophile followed by aqueous (protic) workup and (2) the transition metal-catalyzed successive addition of a nucleophile and an electrophile to the double bond (Scheme 16). 

Exceptionally high diastereoselectivity has been found for the methylation of 23 and the protonation of 2610. These enolates were prepared by 1,4-addition of a bulky nucleophile 28 or 29. Both reactions, i.e., methylation of 23 and protonation of 26, are in agreement with a transition state conformation 21 as discussed previously. The bulkiness of the nucleophiles 28 and 29, respectively, is the reason for the much higher diastereoselectivity as compared to those in references 7-9. 

Substitution of a carbon monoxide ligand of complexes, such as 1, by the more electron-donating triphenylphosphane group (see Section 1.1.1.3.4.1.3.) provides chiral monophos-phane complexes, such as 3. Monophosphane complexes in general lack sufficient electrophilic-ity to react with amines or thiols, but react readily with amine anions at the /J-position, producing enolate anions such as 4, which may be quenched stereoselectively at the a-carbon by electrophiles46 (see Section 1.1.1.3.4.1.3.). The conformational and stereochemical issues involved are essentially identical to those already discussed in this section for the 1,4-additions of carbon nucleophiles. 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

The mechanism of this reduction probably involves the initial addition of a sulphite ion to the diazonium group to give an azosulphonate which undergoes further conjugate (1,4-) addition of the nucleophilic sulphite ion. The resulting intermediate is protonolytically cleaved on heating under acidic conditions ... 

However, reaction of acyclic dienamines with hydrazoic acid gives a mixture of products derived by 1,2-, 1,4- and 3,4 + 1,2-addition of HN3 to the diene system. In this case C-protonation is followed immediately by addition of the strongly nucleophilic azide anion, so that equilibrium of the C-protonated enamines cannot occur3c. Treatment of the morpholine dienamine of isophorone with trichloroacetic acid in boiling benzene resulted in decarboxylation and the 1,4-addition of a proton and the trichloromethyl anion. Basic hydrolysis of the adduct gave dienoic acid 54 (Scheme 4). 

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