Reactions with Other Carbon Nucleophiles

The (la)-promoted reaction of homopropargyl alcohols (31) with aldehydes affords 2,3,5-trisubstituted tetrahydrofurans (32) and (33) via intramolecular addition 

DialkyIzincs couple with 4-acetoxy-l,3-dioxane (49) in the presence of (la) to form 4-alkyl-1,3-dioxanes (50) with good to excellent trans diastereoselectivity [88]. A variety of functionalities can be introduced because of the stability of the C-Zn bond. The diastereoface selectivity is reasonably explained by the kinetically favored 

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Bulky ligands as above have also proved to be effective in other palladium-catalyzed reactions of aryl halides, e.g., amination [16-19], Suzuki-Miyaura reaction [20-22], Mizoroki-Heck reaction [23, 24], Migita-Kosugi-Stille reaction [25], and aryloxylation and alkoxylation [26-28] as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products [29, 30]. The effectiveness of the commercially available simple ligand, P(f-Bu)3, was first described for the amination by Nishiyama et al. [16]. 

Also, from a series of additional experiments with other carbon nucleophiles (RMgCl, MeLi) in place of LiHBEt3, it has been confirmed that the reaction occurs via initial addition of the hydride to the Ta atom, followed by an intramolecular endo-attack of the metal hydride onto the Py Ca atom (Eq. 6.25). 

Nucleophilic displacement of the chlorine atom of 3-chloro-1,2-benzisothiazole has proved to be a popular procedure. Boeshagen and Geiger34 have continued their earlier work on nitrogen nucleophiles, and now include carbon, oxygen, and sulfur nucleophiles.35 In some cases, rearrangements occur, as in the formation of 3-amino-2-acylbenzo[6]thiophenes (20) from reaction of 21 with methyl ketones. Similar results are obtained from the reaction of other carbon nucleophiles, and it has been suggested that attack may be either at the 3-carbon or the sulfur atom.36 The reaction of 3-chloro-1,2-benzisothiazole (8) with the anion of ethyl cyanoacetate, for example,... 

Notice that the aldol addition is a nucleophilic addition reaction. It is just like the nucleophilic addition reactions that aldehydes and ketones undergo with other carbon nucleophiles (Section 17.4). Because an aldol addition occurs between two molecules of the same carbonyl compound, the product has twice as many carbons as the reacting... 

Reactions of Carbonyl Compounds with Other Carbon Nucleophiles... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The reaction of 2,3-butadienyl acetate (843) with soft carbon nucleophiles such as dimethyl malonate gives dimethyl 2,3-butadienylmalonate (844)[520]. On the other hand, the reaction of the 2,3-butadienyl phosphate 845 with hard carbon nucleophiles such as Mg and Zn reagents affords the 2-allcyl-1,3-butadiene 846[520,521]. The 3-methoxy-1,3-butadiene 848 is obtained by the reaction of the 2-methoxy-2,3-butadienyl carbonate 847 with organozinc reagent. 

An alternative approach, in which the anomeric centre of the sugar is reacted with a carbon nucleophile, but the amino group is subsequently inserted at the other side or in both sides at the same time, is reported in Fig. 41 for the synthesis of a- and (3-homogalactonojirimycin.72 Reaction of 2,3,4,6-tetra-O-benzyl-p-D-galactopyranose with methylenetriphenylphosphorane generated an enitol on which the amino group was inserted as phtalimide by a double inversion process of the 5-OH, under Mitsunobu s conditions. 

The scope of allylic electrophiles that react with amines was shown to encompass electron-neutral and electron-rich ciimamyl methyl carbonates, as well as furan-2-yl and alkyl-substituted allylic methyl carbonates. An ort/io-substituted cinnamyl carbonate was found to react with lower enantioselectivity, a trend that has been observed in later studies of reactions with other nucleophiles. The electron-poor p-nitrocinnamyl carbonate also reacted, but with reduced enantioselectivity. Allylic amination of dienyl carbonates also occur in some cases with high selectivity for formation of the product with the amino group at the y-position over the s-position of the pentadienyl unit [66]. Arylamines did not react with allylic carbonates under these conditions. However, they have been shown to react in the presence of the metalacyclic iridium-phosphoramidite catalysts that are discussed in Sect. 4. 

Other carbon nucleophiles may also be employed in such a coupling reaction that provides (3-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the Ai-Boc p-lactam 96 to afford p-aminoketones 97 in 90-96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

Scheme8.5. Palladium-catalyzed cross-coupling reactions of stannanes and other carbon nucleophiles with aryl, allyl, and vinyl bromides [56, 69-72],...

Acyl chloride-functionalized SWCNTs are also susceptible to reactions with other nucleophiles, e.g. alcohols. Haddorfs group reported the preparation of soluble ester-functionalized carbon nanotubes SWCNT-COO(CH2)17CH3 (Fig. 1.6a) obtained by esterification with octadecanol [134]. The syntheses of soluble polymer-bound and dendritic ester-functionalized SWCNTs have been reported by Riggs et al. by attaching poly(vinyl acetate-co-vinyl alcohol) (Fig. 1.6b) [135] and hydrophilic and lipophilic dendron-type benzyl alcohols [119], respectively, to SWCNT-COC1 (Fig. 1.6c). These functional groups could be removed under basic and acidic hydrolysis conditions and thus additional evidence for the nature of the attachment was provided [119, 136]. 

But why are these alkyl iodides made They are needed for reactions with other nucleophiles in which iodide is again displaced. As well as being one of the best nucleophiles for saturated carbon, iodide ion is one of the best leaving groups from saturated carbon (see p. 430). Yields are often higher if the alkyl iodide is prepared than if the eventual nucleophile is reacted directly with the alkyl tosylate or chloride. 

All of these disconnections relied on the reaction of a carbon electrophile with a nucleophilic functional group. The alternative, reaction of a carbon nucleophile (such as a Grignard reagent) with an electrophilic functional group, allows us to do C-C disconnections on alcohols, For example, this compound, which has a fragrance reminiscent of lilac, is a useful perfume for use in soap because (unlike many other perfumes that are aldehydes or ketones) it is stable to alkali. 

Typical carbonyl compounds behave as weak C-H acids. If, for example, one generates the enolate anion of acetone using even a relatively strong conventional base, such as sodium ethoxide, the resultant equilibrium will be shifted far to the left (Scheme 2.21). Carbonyl compounds themselves, as we soon will see, are active electrophiles due to the presence of the partially positive carbonyl carbon. Hence, the nucleophilic enolate generated in the above system can react with non-ionized acetone molecules abundantly present in this equilibrium. This reaction is the well-known aldol condensation (Scheme 2.21). Although useful in its own right, its ease of occurrence creates serious obstacles for the use of an in situ generated enolate anion as a nucleophile in reactions with other electrophiles. 

Chapter 24 concentrates on the second general reaction of enolates—reaction with other carbonyl compounds. In these reactions, one carbonyl component serves as the nucleophile and one serves as the electrophile, and a new carbon-carbon bond is formed. 

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