Imines reductive silylation

Reductive Silylation of Imines, Nitriles and Cyano Derivatives... 

Reductive silylotions. In the presen imines undergo reductive silylation by a h> under these conditions. 

These silyl imines are generated in situ from the corresponding aldehydes resulting in a reduction of the number of reaction steps and simplifies the work-up procedures (figure 8). Another option is to convert the aldehyde into a N-tosyl or a N,N-dimethylsulfamoyl irnine23. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

If HMPA is used in stoichiometric amount in THF as the solvent, then substitution of the chlorine atom occurs providing the corresponding C-silylated imine, the precursor of the acylsilane pivaloylsilane. This imine can also be regarded as a good precursor of an SMA through its reduction. Reduction of the iminoylchloride into the non-silylated imine is a side reaction. 

Alternatively, compound 14 was oxidized with sodium periodate, followed by reduction with sodium borohydride in ethanol to afford 18 (Scheme 3). Hydrolysis of the isopropy-lidene group in 18 with 50% aqueous trifluoroacetic acid followed by hydrogenation of the azide group and then intramolecular reductive amination and protection of the imine group afforded 19. Selective mesylation of the primary hydroxyl group in 19 followed by silylation and subsequent removal of the benzyloxycarbonyl group and then cyclization with sodium acetate afforded 20. Deprotection of 20 led to me50-quinuclidine-3,5-diol (3). 

While only 1.0 equiv. of PMHS is needed to complete the reduction of some ketones e. g. a,a,a-trifluoroacetophenone (Ic) and methyl phenylglyoxylate (Id), excess PMHS is necessary in most cases. As shown in Table 1, inconplete conversions are mostly observed for the reduction of relatively acidic substrates i. e. y ketoesters If and Ig and /0-ketoamides Ih and li (pKa = 10-13). Therefore, a likely hypothesis is that the [Zn-diamine]/PMHS system is active not only for the reductive reaction of the carbonyl function, but also for the oxidative silylation of any enolisable group. Thus, the enol-silyl ether produced would hydrolyze back in methanol to the free enol, accounting for the consumption of extra equiv. of PMHS. Nevertheless, this hypothesis does not accotmt for the reduction of imine 3a, since no inqirovement in the conversion is noted on doubling the amount of PMHS (Scheme 3, Table 1). Other imines e. g. 3b, are readily reducible with the present Zn-diamine-methanol system. 

Over the last decade, a considerable number of reactions has been studied (11,35) (i) olefins oxidation (38,39), hydroboration, and halogenation (40) (ii) amines silylation (41,42), amidation (43), and imine formation (44) (iii) hydroxyl groups reaction with anhydrides (45), isocyanates (46), epichloro-hydrin and chlorosilanes (47) (iv) carboxylic acids formation of acid chlorides (48), mixed anhydrides (49) and activated esters (50) (v) carboxylic esters reduction and hydrolysis (51) (vi) aldehydes imine formation (52) (vii) epoxides reactions with amines (55), glycols (54) and carboxyl-terminated polymers (55). A list of all the major classes of reactions on SAMs plus relevant examples are discussed comprehensively elsewhere (//). The following sections will provide a more detailed look at reactions with some of the common functional SAMs, i.e hydroxyl and carboxyl terminated SAMs. 

Starting from commercially available Merrifield resin, silyl enol ether 57 was generated in two steps. Lewis acid catalysed addition of 57 to a variety of imines gave amino thioesters 58 which upon reduction with LiBH afforded amino alcohols 59 in moderate to good yields (50-80%). After reduction, the resin was recovered in its thiol form and could be further acylated and re-used. 

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