Silyl alkyl acetals

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

Both silyl- and alkyl esters derived from primary AN are readily involved in C,C-coupling reactions with silyl ketene acetal (Scheme 3.208, Eq. 1) (484). 

However, C,C-coupling reactions of sterically less hindered alkyl nitronates derived from secondary AN with silyl ketene acetal were successfully performed (Eq. 3). These reactions produced the target mixed nitroso acetals in moderate yields. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

For the anionic polymerization of methacrylonitrile (MAN), many initiators have been developed, which include alkali-metal alkyls such as butyllithium [42], triphenylmethylsodium [43], phenylisopropylpotassium [43], the disodium salt of living a-methylstyrene tetramer [44], alkali-metal amides [45], alkoxides [46], and hydroxide [47], alkali metal in liquid NH3 [48], quaternary ammonium hydroxide [49], and a silyl ketene acetal coupled with nucleophilic or Lewis acidic catalysts [50]. However, only a single example of the synthesis of PMAN with narrow molecular-weight distribution can be cited, and the reported number-average molecular weights were much higher than those calculated from the stoichiometry of the butyllithium initiator [42]. 

The carbenoid from Et2Zn/CH2I2 [17], particularly when generated in the presence of oxygen [18], is more reactive than the conventional Simmons-Smith reagents. The milder conditions required are suitable for the preparation of 1-[16, 19] or 2-alkoxy-l-siloxycyclopropanes [20], which are generally more sensitive than the parent alkyl substituted siloxycyclopropanes (Table 2). Cyclopropanation of silyl ketene acetals is not completely stereospecific, since isomerization of the double bond in the starting material competes with the cyclopropanation [19]. 

Co2(CO)8-catalyzed reactions of benzylic acetates with trimethylsilane and CO proceed under mild reaction conditions to give trimethylsilylethers of /3-phenethylalcohol in 43-76% yield. The highest yields are observed for benzyl acetates with electron-donating substituents.111 Secondary alkyl acetates are also good substrates in the reaction system, yielding enol silyl ethers.112 In addition, the cobalt complex is an effective catalyst for siloxymethylation of five-membered cyclic ortho esters, as shown in Eq. (41).113... 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

Except for the well-documented conjugate additions of diethylaluminum cyanide,92 triethylaluminum-hydrogen cyanide and Lewis acid-tertiary alkyl isonitriles,93 examples of Lewis acid catalyzed conjugate additions of acyl anion equivalents are scant Notable examples are additions of copper aldimines (233),94, 94b prepared from (232), and silyl ketene acetals (234)940 to a,(3-enones which afford 1,4-ketoal-dehydes (235) and 2,5-diketo esters (236), respectively (Scheme 37). The acetal (234) is considered a glyoxylate ester anion equivalent. 

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

The nucleophilic reactivities of silyl enol ethers (58, R1 = alkyl) and silyl ketene acetals (58, R1 = 0-alkyl) have been measured for the triphenylsilyl (R2 = H5) substrate, and its perfluoro analogue (R2 = F5), using benzhydrylium cations as reference electrophiles.224 The triphenyl compound is 10 times less reactive than its trimethyl equivalent, but the perfluorination causes the C=C nucleophilicity to drop by 3-4 orders of magnitude. The new compounds have been placed on scales of nucleophilicity taken from the literature. 

The addition of phenyldimethylsilane to the double bond of enamides (or vinyl ureas) in the presence of catalytic amounts of rhodium acetate, leads to Ma-silyl)alkyl amides (or ureas). Rhodium catalyst are known to move double bonds, and indeed the same type of RSMA are obtained from an /V-ally I urea, albeit in low yield. On the other hand, hydrosilylation of A-allyl imides takes place at the terminal carbon atom in high yields.211... 

Hydroxyferrocene is prepared by hydrolysis of ferrocene acetate, and it undergoes many of the same organic transformations (alkylation, silylation, acylation, acetal formation) that are carried out with phenol. Access to thioferrocene or dithioferrocene is easily accomplished by treatment of anions (322) or (323) with elemental sulfur. 

Both silyl enolates and allylsilanes are excellent nucleophiles for alkylation by other stabilized carbocations such as the tertiary alkyl cations 111 or 112 (Scheme 2.42). Similarly, Michael-like additions, for example, the coupling of 113 with silyl ketene acetal 114, can be also achieved.Owing to the high electrophilicty of the enone system, this reaction proceeds smoothly in polar solvents, even in the absence of Lewis acids. 

The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2 6.4 1. In contrast, 3.0 m LPDE afforded an excellent yield (90 %) of 86 and 87 (5.8 1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol 89 (Sch. 44). 

A remarkable finding is the sensitivity of this reaction to the substituents of the starting silyl ketene acetals. Reactions of silyl ketene acetals derived from more common ethyl esters are totally stereo-random, and give a mixture of erythro and threo isomers in even ratios with improved chemical yields. In sharp contrast, the use of silyl ketene acetals generated from phenyl esters leads to good diastereo- and enantios-electivity and excellent chemical yields. The reason for this is unclear, but certain secondary interaction between electron-rich silyl ketene acetals derived from alkyl esters and Lewis acid might be responsible. 

Other possibilities are four-step sequences comprising full protection of the acetal diols, followed by removal of the acetal and, finally, regioselective protection of the obtained diol (Scheme 3.25). For example, 2,6-protection (acetylation, benzoylation or benzylation) of a 3,4-0-isopropylidene derivative and successive acetal cleavage yields the 3,4-diol. Subsequent 3-0-protection via tin-activated silylation, alkylation or acylation, or 4-O-protection via orthoester or benzylidene (endo) formation-opening sequences is then possible. 

For the BDA-acetal, 2,6-protection and acetal removal yields the 3,4-diol. This diol can then be 3-0-protected through tin-activated silylation, alkylation or acylation (Scheme 3.27). Other ways to diols are tin activation and subsequent alkylation yielding the 3,6-protected 2,4-diol derivative, which can be transformed into a 3,6-diol. Opening of 2,3 4,6-di-0-benzylidene derivatives yields various diols depending on the reagents used and the stereochemistry of the 2,3-O-acetal (e.g., the 2,4-diol). 

Bis(silyl)ketene acetals undergo silatropic ene reaction with nitrosobenzene to give N-hydroxyamino acid derivatives. When allylmagnesium chloride is reacted with nitroarenes, unstable adducts result. Reduction of these adducts with LAH in the presence of palladium on charcoal leads to A -allyl-W -aryl-hydroxylamines (73 Scheme 15). With alkyl Grignard reagents this reaction is negligible. ... 

Alkylation of carbonyl compounds. The presence of two metallic centers in reagent 1 makes it easy to attain a six-center transition state therefore, much more efficient transfer of an alkyl group to aldehydes is noted. In comparison with the 2,6-dimethylphenoxy (dialkylaluminum) reagents the improvement is remarkable (e.g., 84% vs 0%, 52% vs 10%, the latter seems to be the best case for the mononuclear phenoxide). Contrary to TiCl which promotes ionization of dimethylacetal unit, 1 activates a carbonyl group preferentially toward nucleophiles such as allyltributylstannane and silyl ketene acetals. ... 

Alkylations Allyl and benzyl acetates serve as adequate alkylating agents to nucleophiles such as silyl ketene acetals when magnesium triflimide is used to activate them. In most cases this reagent is superior to magnesium perchlorate. 

In view of the remarkable stability of metal homoenolates of esters, the existence of homoenolate species containing a 3-halo substituent, i.e. zinc carbenoid moiety connected to an ester group, appeared to be possible. Indeed, when a silyl ketene acetal is treated with a carbenoid generated from CHBrj and Et2Zn, two types of highly intriguing reactions ensue [58]. With a purely aliphatic substrate, Eq. (61), an alkyl cyclopropylcarboxylate due to intramolecular p-CH-insertion of the intermediate zinc carbenoid formed. When the substrate contained an olefmic double bond in the vicinity of the carbenoid function, Eq. (62), in particular an intermediate derived from an a,P-unsaturated ester, internal cyclo-propanation occurred to give bicyclic or tricyclic product (Table 15). 

S-Alkyl, 0-silyl ketene acetals can be derived from the corresponding thioesters in a manner analogous to the generation of dialkoxy ketene acetals... 

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