Heteroatom nucleophiles acetalizations

Addition of Heteroatom Nucleophiles to Carbonyl Compounds in Combination with Subsequent SN1 Reactions of the Primary Product Acetalizations... 

Addition of Heteroatom Nucleophiles to Carbonyl Compounds Acetalizations... 

Substitution of complexed dienols (244) or dienol acetates with carbon or heteroatom nucleophiles, in the presence of a Lewis acid, occurs with retention of configuration (Scheme 69). (Alkyl aluminum reagents act as both nucleophile and Lewis acid in this process). This reaction is believed to proceed via stereospecific ionization, with anchimeric assistance from the iron, to generate the transoid pentadienyl cation (247) followed by attack of the weak nucleophile on the face opposite to iron. The cross-conjugated pentadienyl cation can also be generated the substitution of (2-acetoxymethyl-l,3-butadiene)Fe(CO)3 (193) has previously been discussed (Section 6.1.1). 

Intermolecular Nucleophilic Substitution with Heteroatom Nucleophiles. A patent issued in 1965 claims substitution for fluoride on fluorobenzene-Cr(CO)3 in dimethyl sulfoxide (DMSO) by a long list of nucleophiles including alkoxides (from simple alcohols, cholesterol, ethylene glycol, pinacol, and dihydroxyacetone), carboxylates, amines, and carbanions (from triphenyhnethane, indene, cyclohexanone, acetone, cyclopentadiene, phenylacetylene, acetic acid, and propiolic acid). In the reaction of methoxide with halobenzene-Cr(CO)3, the fluorobenzene complex is ca. 2000 times more reactive than the chlorobenzene complex. The difference is taken as evidence for a rate-limiting attack on the arene ligand followed by fast loss of halide the concentration of the cyclohexadienyl anion complex does not build up. In the reaction of fluorobenzene-Cr(CO)3 with amine nucleophiles, the coordinated aniline product appears rapidly at 25 °C, and a carefiil mechanistic study suggests that the loss of halide is now rate limiting. 

The presence of a carbon nucleophile rather than a heteroatom nucleophile in the acetal exchange reaction led to alkylation of the acetal (Eqs 243 [559] and 244 [560]). In Eq. (244), the type of methylmetal species alters the stereochemical outcome. 

Far less impoitant for the synthesis of important molecular frameworks are cyclization reactions involving attack of heteroatom nucleophiles on carbonyl derivatives, since these reactions are not concerned with carbon-carbon bond formation but rather with transforming the carbonyl derivatives into other carbonyl derivatives, such as the reductive cyclization of (58) to give the cyclic OJV-acetal (59 Scheme 28). 2... 

Though intensively exploited (e.g. in carbohydrate chemistry), reactions of oxocarbenium ions with heteroatom nucleophiles will not be treated further in this chapter, since they all lead back to carbonyl derivatives such as acetals. Instead, particular emphasis is laid on syntheses of heterocycles that involve carbon-carbon bond formation. 

Allylic aeetates or carbonates can undergo nucleophilic substitutions via palla-dium(0)-catalysis (11). In this paper, we report on the extension of this reaction to unsaturated fatty aeids by the preparation of allyl carbonates and acetates of oleic, linoleic, and 10-undecenoic acid and their substitution with carbon- and heteroatom-nucleophiles by palladium(0)-catalysis. In this way, different substituents can be in-trodueed into the alkyl chain of fatty acids. This leads to fatty acid derivatives in which the properties of biologically active compounds may possibly be combined with the amphiphilic property of the fatty acid. 

Catalytic reactions of allylic electrophiles with carbon or heteroatom nucleophiles to form the products of formal S 2 or S 2 substitutions (Equation 20.1) are called "catalytic allylic substitution reactions." Tliese reactions have become classic processes catalyzed by transition metal complexes and are often conducted in an asymmetric fashion. The aUylic electrophile is typically an allylic chloride, acetate, carbonate, or other t)q e of ester derived from an allylic alcohol. The nucleophile is most commonly a so-called soft nucleophile, such as the anion of a p-dicarbonyl compound, or it is a heteroatom nucleophile, such as an amine or the anion of an imide. The reactions with carbon nucleophiles are often called allylic alkylations. 

The regioselectivity of palladium-catalyzed aUylic substitutions with heteroatom nucleophiles is often much different from that of reactions with carbon nucleophiles. In general, reactions of oxygen and nitrogen nucleophiles form more branched product than do reactions of carbon nucleophiles, at least as the kinetic product of substitution. For example, reactions of aryloxide nucleophiles with mono-substituted aUylic carbonates catalyzed by palladium complexes of Trost s ligand form more branched than linear product (Equation 20.32). Reactions of geminaUy disubstituted aUylic acetates with aziridines, hydroxylamine and hydrazine derivatives catalyzed by palladium complexes of bisphosphines form the branched prenyl product as the major isomer (Equations 2033a and 20.33b). " ... 

The direct, Pd(II)-catalyzed addition of heteroatom and stabilized carbon nucleophiles to alkenes is generally not a successful reaction. An exception is the addition of water, which gives carbonyl compounds and has been developed into an important indnstrial process, the Wacker process. This has been reviewed extensively.By contrast, the stoichiometric addition of nucleophiles such as amines is facile. - However, if alkenes could be converted catalytically into Tr-allylpalladium complexes, the problems with nucleophilic addition to alkenes could be circumvented and amines and other heteroatom nucleophiles could be employed. A range of alkenes have been converted into rr-allyl complexes in a stoichiometric fashion,t "t but catalytic reactions have proved more difficult. However, aUyl acetates and similar compounds readily exchange the acetate group for heteroatom nucleophiles in a Pd(0)-catalyzed reaction, which proceeds via 7T-allylpalladinm(ll) intermediates (Scheme 1). Since this reaction has been developed into a very important synthetic reaction, an efficient procedure for catalytic conversion of alkenes into aUyl acetates would have great synthetic potential. 

A number of intramolecular Pd-catalyzed 1,4-oxidations of conjugated dienes were developed.f In these reactions, two nucleophiles are added across the diene, one of which adds intramolecularly. So far, only heteroatom nucleophiles have been employed. In order to extend these intramolecular 1,4-oxidations to carbon nucleophiles, it was found that a vinylpalladium species can be obtained in situ from an alkyne via a chloropalladation. The approach is particularly attractive since it involves a Pd(II) chloride salt and could be compatible with the rest of the catalytic cycle. Reaction of dienyne with LiCl, and benzoquinone in the presence of palladium acetate as the catalyst, afforded the carbocyclization products. The reaction resulted in an overall stereoselective fltiri-addition of carbon and chlorine across the diene t B (Scheme 23). 

Making acetals that contain A-atoms has been a fairly straightforward effort, following the advent of asymmetric phosphoric acid catalysis [9, 10]. Since the reports of Akiyama and Terada, asymmetric additions of nucleophiles to imines became a well-developed area of asymmetric Brpnsted acid catalysis [11, 12]. Consequently, heteroatom nucleophiles were shown to be viable nucleophiles and various N,N-, N,0-, and A,S -acetals could be prepared for the first time in a catalytic asymmetric fashion. These reactions are briefly summarized in the next section. 

Despite the massive advancements in asymmetric catalysis over the last several decades, the catalytic enantioselective generation of N,N-, N,0-, N.S-, and N,Se-acetals only recently became a possibility with the advent of asymmetric Brpnsted acid catalysis [16-22], Asymmetric syntheses of acyclic NJ -, N,0-, N,S-, and N, Se-acetals catalyzed by chiral phosphoric acids were developed in the Antilla group utilizing the addition of heteroatom nucleophiles to iV-protected imines (Scheme 4) [16-18, 22],... 

Other Heteroatom Nucleophiles. Alcohols and carboxylic acids also add to metal-activated alkenes, and processes for the industrial conversion of ethylene to vinyl acetate and acetals are well established. However, these processes have not been extensively used with more cort5)lex alkenes. In contrast, a number of intramolecular versions of the processes have been developed, a few examples of which are given here. Allylphenols cyclize readily in the presence of palladium(II) to form benzofurans (eq 4). Catalytic amounts of palladium acetate can be used if the reaction is carried out under 1 atm of molecular oxygen with copper diacetate as cooxidant, or in the presence of tert-butyl hydroperoxide. If instead of palladium acetate a chiral jr-allylpalladium acetate complex is used, the cyclization proceeds to yield 2-vinyl-2,3-dihydrobenzofuran with up to 26% ee. ... 

Prins cyclizations, which proceed by intramolecular addition of alkenes to oxocarbenium ions, provide a simple, efficient method for the stereoselective synthesis of carbocycles and cyclic ethers [77]. Halosilanes and (la) have been used for Prins cyclizations not only as Lewis acids but also as heteroatom nucleophiles. For instance, in the presence of MesSil or MesSiBr, and lutidine, mixed acetals (26) are efficiently cyclized to 4-halotetrahydropyrans (27) with high diastereoselectivity [78]. The halide is introduced into the axial site of the C(4) position. The proposed mechanism for the MesSiBr-promoted reaction involves the initial formation of a-bromoethers (28) from (26). Solvolysis of (28) provides the intimate ion pair (29). Cyclization to the chair transition structure (30) and proximal addition of the bromide produces the observed axial adduct (27). The role of lutidine is to suppress a less selective HBr-promoted cyclization (Scheme 9.23). Acetals bearing an alkyne or allene moiety also undergo the halosilane-promoted cyclization to form haloalkenes [79, 80]. 

Allylic nitro groups are readily displaced by nucleophiles via an SNl-type mechanism. Thus, nitro groups with heteroatoms at the OC- or P-positions (for example, a- or P-nitrosulfides) are expected to be cleaved in a similar way. In fact, the nitro group in a-nitrosulfides is replaced by nucleophiles in the presence of a Lewis acid31 or acetic acid.32 The nitro groups in the reaction of Eqs. 7.27 and 7.28 are cleanly replaced by CN, allyl, or PhS group on treatment with MejSiY (Y = CN, allyl) in the presence of SnCl4 or simple treatment with PhSH in AcOH. 

One method is to treat 4-aminophenol with just one molar equivalent of acetic anhydride. The main product is paracetamol, which is produced almost selectively since -NH2 is a better nucleophile than -OH. We can predict this from their pATa values as bases, about 5 for the conjugate acid of a typical aromatic amine, and about —7 for a phenol, i.e. the amine is the stronger base. Although the heteroatoms are not the same (see Section 6.1.2), the pATa values are significantly different and allow us to predict that the amine is also going to be the better nucleophile. The higher the pAfa of the conjugate acid, the better the nucleophile. 

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