Base-sensitive functionalities

The procedures presented here are simple, Inexpensive, and may be used on a large scale. The use of potassium hydroxide In this reaction may, however, prove Incompatible with certain base-sensitive functional groups. 

Bismuth(III) triflate is also a powerful acylation catalyst that catalyzes reactions with acetic anhydride and other less reactive anhydrides such as benzoic and pivalic anhydrides.113 Good results are achieved with tertiary and hindered secondary alcohols, as well as with alcohols containing acid- and base-sensitive functional groups. 

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

For cyclopropanation of alkenes devoid of base-sensitive functional groups a one-pot procedure has been developed [649]. In this procedure diazomethane is generated in a biphasic system from A-methyl-A-nitrosourea and potassium hydroxide in the presence of a palladium complex (e.g. Pd(acac)2, (PhCN)2PdCl2, or Pd[P(OPh)3]4) and the alkene. In this way the handling of diazomethane is elegantly avoided. 

Alkyl carbamates are generally more stable towards nucleophiles than amides, and are therefore of limited utility as protective groups. Amines lacking other base-sensitive functionalities can, however, be protected as alkyl carbamates. An illustrative example of the use of ethyl carbamate as a protective group is sketched in Figure 10.11 [188]. 

TEMPO-mediated oxidations can be performed under almost neutral conditions. Therefore, acid- and base-sensitive functionalities and protecting groups can remain unchanged during TEMPO-mediated oxidations. 

It is important to note that under the slightly basic conditions (pH 8.6-9.8) employed under the standard Anelli s protocol, many base-sensitive functional groups remain unaffected, including the ubiquitous ester groups.44 On the other hand, it may be advisable to limit the reaction time in order to minimize the hydrolysis of acetates.16... 

The Oppenauer oxidation presents two important limitations on one side it is unable to oxidize certain alcohols because of unfavourable thermodynamics, and on the other side, base-induced reactions between the oxidant and the product may become dominant. That is why, it is seldom employed for the obtention of aldehydes because these compounds react readily under basic conditions. On the other hand, although aluminium alkoxides promote aldol condensations, many base-sensitive functional groups such as most esters but not formates—25 resist its action. 

Although aluminium alkoxides are able to promote base-induced reactions, the basic conditions involved are not extremely strong and many base-sensitive functional groups remain unaffected during Oppenauer oxidations, including alkyl halides,51 epoxides52 and most esters.53 On the other hand, the very sensitive formate esters are hydrolyzed under Oppenauer conditions and the resulting alcohols are oxidized in situ.25... 

Many base-sensitive functionalities, such as carbonates79 or epoxides,75b resist the mild basic conditions of the Mukaiyama oxidation. 

Silver acetylides also reacted with epoxides yielding propargylic alcohols.27 As for related alkylations with silver acetylides (see Section 10.6.1), this reaction required zirconocene dichloride and catalytic amount of silver triflate. This method proved useful for both electron-rich and electron-deficient alkynes and compatible with various acid- and base-sensitive functional groups (Table 10.2). 

Bromohydrins. The reagent reacts with epoxides regioselcctively to yield a trans-bromohydrin with bromine predominantly at the less hindered position. Acid- and base-sensitive functional groups are stable to the reagent. 

Enantiomerically pure carboxylic acids are routinely obtained from N-acylsultams by Hydrogen Peroxide assisted saponification with Lithium Hydroxide in aqueous THF. 4 Alternatively, transesterification can be effected under neutral conditions in allyl alcohol containing Titanium Tetraisopropoxide, giving the corresponding allyl esters which can be isomerized/hydrolyzed with Wilkinson s catalyst (Chlorotris(triphenylphosphine)rhodium(I)) in Et0H-H20. This provides a convenient route to carboxylic acids containing base-sensitive functionality. Primary alcohols are obtained by treatment with L-Selectride (Lithium Tri-s-butylborohydride) in THF at ambient temperature. ... 

Numerous methods are now available in the literature for the deprotection of TBS ethers under a variety of conditions. One of the most effective ways for the cleavage of silyl ethers is based on the exploitation of the high affinity of silicon towards fluoride ions. Thus, a number of reagents involving one form of fluoride or another, such as tetrabutylammonium fluoride [292], BF3-Et20 [301], hydrofluoric acid [302], fluorosilicic acid [303], ammonium fluoride [304], silicon fluoride [305], lithium tetrafluoroborate [306], and chlorotrimethylsilane/potassium fluoride dehydrate [307] have been developed for the deprotection of TBDMS ethers. Among these, TBAF is most frequently used but the strong basicity of the fluoride anion makes it inappropriate for base sensitive functionalities. 

The C-acylation reactions of magnesium monomethyl malonate proceed in the presence of acid- and base-sensitive functionality, as illustrated in the reaction sequence shown belowH ... 

Selective amination of 2,3-dichloropyridine with 2-aminopyrazine produced 2-pyrazinyl-(3-chloro-2-pyridyl)amine (152) in 91% yield [74]. The use of mild amination conditions resulted in maximum selectivity with tolerance of base sensitive functional groups. 

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