Alkoxides as Nucleophiles

In an exploratory study, Cu-alkoxides were found to be superior to Zn-alkoxides, and tert-butyl cinnamyl carbonate superior to methyl cinnamyl carbonate, which underwent transesterificahon. Both, arylallyl and alkylallyl carbonates were successful as substrates. 

The optimized reaction conditions were successfully applied to alkoxides derived from primary as well as secondary alcohols. With tertiary alkoxides, the regiose-lectivihes and yields were excellent but the enantioselechvities were comparatively low. Applicahons of the method are presented in Sechons 9.5.5 and 9.6. 

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Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Scheme 9.34 Allylic substitutions with alkoxides as nucleophiles.

Promoted by copper iodide, a large array of 3-methylenetetrahydrofurans were synthesized from propargylic alkoxides as nucleophiles and activated alkenes as Michael acceptors. One of these reactions is shown below <02TL2609>. 

Mixed disulfides can be synthesized by the reaction of alkyldithioformic esters with thiols (95) through a soft-soft interaction. However, attempts to extend the reaction to prepare sulfenate esters using alkoxides as nucleophiles led to dialkyl trisulfides (96) instead. If a H8AB analysis was performed prior to experiments, the authors would not have been surprised by the results. The hard alkoxide ions would of course elect to attack the ester carbonyl. 

The use of alkoxides as nucleophiles is not common in the area of DKR. In 1997, Camps et al. reported, however, the asymmetric synthesis of a-hydroxyacids based on the DKR of a diastereomeric mixture of a-bromoesters derived from (R)- or (S)-3-hydroxy-4,4-dimethyl-l-phenyl-2-pyrrolidinone with p-methoxyphenoxide in the presence of tetra- -hexylammonium iodide (Scheme 1.6). ... 

Compound 58 clearly offers more possibilities for disconnection. Disconnections are available at or near the carbon atom bearing the OH group, but also at or near both carbonyl carbons. The larger number of functional groups leads to more choices. Does the chemistry of the alcohol, the aldehyde, or the ketone offer the best choice for a disconnection The chemistry of alcohols is associated with oxidation and reduction (Chapter 17, Section 17.2 Chapter 19, Sections 19.2,19.3.4,19.4.1), formation and reactions of alkoxides as nucleophiles (Chapter 11, Section 11.3.2) and as bases (Chapter 12, Section 12.1), and formation of esters (Chapter 20, Section 20.5). Alcohols are converted to alkyl halides (Chapter 11, Section 11.7). Aldehydes and ketones are formed by the oxidation of alcohols (Chapter 17, Section 17.2), are reduced to alcohols (Chapter 19, Sections 19.2, 19.3.4, 19.4.1), undergo acyl addition (Chapter 18, Sections 18.1-18.7), and participate in enolate anion reactions (Chapter 22, Sections 22.2, 22.4, 22.6). Based on these reactions, several disconnections are shown, but several more are possible. 

An alternate rearrangement known as benzilic ester rearrangement occurs in presence of alkoxide as nucleophile. The rearrangement product is the corresponding benzilic ester. 

As exemplified by the macrolide antibiotic RK-397 (15, Scheme 14.4), proximal 1,3-arrays of hydroxyl-bearing stereogenic centers present the most prevalent structural phenotypes in a wide variety of polyketides [1]. Inspired by the cascade concept reported above, we desired a more direct synthesis to this structural synthon. As shown in Scheme 14.5, this involves the addition of a homo-allylic alcohol 5 to a suitable carbonyl compound 18, giving the corresponding hemi-acetal alkoxide (step 1). Formation of an electrophilic Jt-allyl complex (step 2) then results in the generation of intermediate 17, which finally undergoes an intramolecular allylic substitution reaction to the desired 1,3-allylic alcohols 16 in a suitably protected form (step 3). Notably, this sequence presents one of the first examples of hemiacetal alkoxides as nucleophiles in allylic substitution reactions. 

Under stoichiometric conditions, the postulated diorganopalladium(II) c -ArPdNu(L-L) complexes are formed with hard nucleophiles Grignard reagents, alkoxides, - and amides. cw-ArPdNu(L-L) complexes in which the nucleophile is a carbanion (L-L = dppp, dppf) have been characterized in situ by P NMR spectroscopy performed at low temperatures but have not been isolated due to fast reductive elimination. The stability of cis-ArPdNu(L-L) (L-L = BINAP, Tol-BINAP, dppf) with alkoxides as nucleophiles strongly depends on the ligand and the aryl group for a given alkoxide. - Complexes in which the nucleophile is an amide (with L-L = dppf) are more stable and have been isolated. 

Alcohols are weak acids, 16-18, but their conjugate bases form easily. We have seen that the reaction of alkoxides as nucleophiles is an important feature of the chemistry of alcohols. In contrast, amines are very weak acids, pA 35. The difference in acidities of alcohols and amines agrees with the periodic trends for CH4NH2 and H2O. Because amines are very weak acids, the chemistry of their conjugate bases is quite limited. In fact, the conjugate bases of amines such as hthium diisopropyl-amide are used only to form conjugate bases of compounds such as enolates of carbonyl compounds. 

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). 

Many other examples are known of non-selective reactions of halo groups in pyridopyridazines with amines, alkoxides, sulfur nucleophiles such as hydrosulfide and thiolate ions, or thiourea, hydrazine(s), cyanide ion and dimethyl sulfoxide, or on catalytic reduction. 

A variant is represented by the benzilic ester rearrangement, where an alkoxide is used as nucleophile. The alkoxide should not be sensitive towards oxidation. The reaction product is the corresponding benzilic acid ester 5 ... 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

In addition to alkoxides, carbonyl oxygens have occasionally been recruited to function as nucleophiles in allylic etherification processes. The cyclization reactions of ketones containing internal allylic systems occur through O-allylation under Pd catalysis to give rise to vinyl dihydrofurans203 or vinyl dihydropyrans (Equation (51))204,205 in good yields. 

Vinylsilane to copper transmetallation has entered the literature,93 93a,93b and a system suitable for catalytic asymmetric addition of vinylsilanes to aldehydes was developed (Scheme 24).94 A copper(l) fluoride or alkoxide is necessary to initiate transmetallation, and the work employs a copper(ll) fluoride salt as a pre-catalyst, presumably reduced in situ by excess phosphine ligand. The use of a bis-phosphine was found crucial for reactivity of the vinylcopper species, which ordinarily would not be regarded as good nucleophiles for addition to aldehydes. The highly tailored 5,5 -bis(di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino-4,4 -bis(benzodioxolyl) (DTBM-SEGPHOS) (see Scheme 24) was found to provide the best results, and the use of alkoxysilanes is required. Functional group tolerance has not been adequately addressed, but the method does appear encouraging as a way to activate vinylsilanes for use as nucleophiles. 

It is often preferable to use basic conditions with hydroxide or alkoxide as a better nucleophile, though this may lead to elimination and alkene formation as a competing reaction (see Section 6.4). 

Base-induced ring-openings require a strong base because the strongly basic O is displaced as part of the alkoxide. Acid-induced ring-openings are achieved with weak bases, such as nucleophilic solvents, because now the very weakly basic OH, formed by protonation of the O atom, is displaced as part of the alcohol portion of the product. 

It is of interest that the ZnU bound thiophenolate attacks at a methyl carbon atom as electrophilic site, while the Znn-bound alkoxides, as described in Section II, attack at the P atom. In 32, zinc(II) assembles and protects (from oxidation) the four strong nucleophiles CeH5S. While alcohols and water (pKa both ca. 15) need zinc(II) to be activated at physiological pH, thiophenol (pKa ca. 7) may not require zinc(II) for activation. 

A second more subtle effect may also be operative in the metal ion control of nucleophilic reactions. When amines, thiolates or alkoxides are used as nucleophiles, they are expected to be highly reactive and hence relatively unselective. However, we saw in Chapter 2 that the proximity of the metal cation to the nucleophile reduces the charge density on the donor atom, and is thus expected to reduce the reactivity. We can use the reduced reactivity, and greater selectivity, of such co-ordinated nucleophiles to direct reaction towards the cyclic products. 

Alkyllithium compounds and alkali cyanides, mercaptides, and alkoxides,322,323 etc. have been used as nucleophilic reagents in reactions with the enamine salts. Nitrile groups can be removed by reduction or by treatment with acids. Treatment of cotarnine (100)... 

Reaction of cyclopropenes with bases such as alkoxide or amide ions often leads to a methylenecyclopropene by removal of an allylic hydrogen and reprotonation 6 9-71) though other reactions such as nucleophilic addition (see Section 5) or metallation at a vinylic position (see Section 2) may compete. Thus the ester (209) is isomerised by KOH to (210), and under more vigorous conditions to (211)144) ... 

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