Acid- and base-sensitive substrates

HF pyridine complex in methanol or THF is commonly used for the removal of TBS ethers. With acid- and base-sensitive substrates, the reaction can be buffered with additional pyridine.65 At a late stage in the synthesis of Calyculin A, a potent protein phosphatase inhibitor, a primary TBS ether was cleaved selectively in the presence of three secondary TBS ethers by using HF pyridine complex in THF-pyridine [Scheme 4.43].66... 

Aryl and alkyl trimethylsilyl ethers can often be cleaved by refluxing in aqueous methanol, an advantage for acid- or base-sensitive substrates. The ethers are stable... 

Aryl and alkyl trimethylsilyl ethers can often be cleaved by refluxing in aqueous methanol, an advantage for acid- or base-sensitive substrates. The ethers are stable to Grignard and Wittig reactions and to reduction with lithium aluminum hydride at —15°. Aryl -butyldimethylsilyl ethers and other sterically more demanding silyl ethers require acid- or fluoride ion-catalyzed hydrolysis for removal. Increased steric bulk also improves their stability to a much harsher set of conditions. An excellent review of the selective deprotection of alkyl silyl ethers and aryl silyl ethers has been published. ... 

NOH - -CNH1. TiCl, is known to reduce oximes to imines (4,506). If this reduction is conducted in the presence of NaBHjCN (buffered), the inline is reduced to an amine before it is hydrolyzed to a ketone. This mild method is particularly useful for complex substrates with acid- and base-sensitive groups.1... 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

The fact that stronger bases speed up both the coupling and the hydrolytic deboronation means that the choice of base is not always obvious. Although aqueous carbonate is the one most commonly used, stronger alkoxide bases appear to yield the best results for stericaUy hindered boronic acids. For base-sensitive substrates, bicarbonate can be used successfully when THF is the organic cosolvent. However, this base is less successful when employed with mostly nonaqueous reaction conditions. On the other hand, fluoride, an even weaker base, appears to work well with both aqueous and nonaqueous protocols. ... 

Miscellaneous Reactions. Trimethylsilyldiazomethane converts acid- and base-sensitive maleic anhydride derivatives into the corresponding bis(methyl esters) (eq 70). Terminal silyl enol ethers are conveniently prepared from aldehydes by first treating the carbonyl compound with TMSC(Li)N2, followed sequentially by methanol and Rh2(OAc)4 (eq 71). The method works well with base-sensitive substrates and is superior to the attempted regioselective deprotonation/O-silylation of the corresponding methyl ketone. ... 

Bu4N F , THF, 25°, I h, >90% yield. Fluoride ion is very basic, especially under anhydrous conditions, and thus may cause side reactions with base-sensitive substrates. The strong basicity can be moderated by the addition of acetic acid to the reaction, as was the case in the following reaction, after all others methods failed to remove the TBDMS group. ... 

Trost published a desulphonylation procedure for aryl alkyl sulphones using an excess of sodium amalgam in buffered ethanol126 (equation 52). Trost claimed that this is superior to earlier reactions using sodium amalgam in ethanol because of a couple of factors the use of the acid phosphate buffer to prevent formation of significant amounts of sodium methoxide is particularly important, since this can cause isomerizations in base-sensitive substrates, and the temperature should be kept low, but optimized for each substrate. 

Benzyl and substituted benzyl protecting groups are ubiquitous in organic synthesis. For base-sensitive substrates, the benzyl imidate, e.g. 6, is often used to install this group. Amit Basu of Brown University reports (Tetrahedron Lett. 44 2267,2003) that in situations such that the usual acidic promoters do not work, metal triflates can be effective. Lanthanum triflate worked particularly well, giving both high yield and high conversion in five minutes at room temperature. 

Acid scavengerCesium fluoride is recommended as a scavenger for HF and IIBE4 in place of tricthylaminc in reactions involving base-sensitive substrates. An example is the esterification formulated in equation (1). No racemization occurs in the traiiseslerilicalitm of equation (II), although it is extensive when tricthylamine is nscil. 

For most of these operations, isolated dioxirane solutions are more convenient, because simpler work-up procedures are involved. Furthermore, hydrolytically and acid/base-sensitive substrates may be employed, because the reaction is conducted under strictly anhydrous and neutral conditions. Solvents inert toward dioxirane oxidation may be used for dilution purposes in these oxidations, which include acetone, butanone, cyclohexanone, CH2C12, CHC13, CC14, benzene, and CH3CN. Alcohols (except t-BuOH) and ethers normally should be avoided as solvents, because they react slowly with dioxiranes, especially TFD [37]. 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

Under these conditions, base-sensitive substrates may undergo decomposition. To avoid this drawback, protic and Lewis acid can be utilized, such as p-toluenesulfonic acid, zinc chloride, cobalt chloride or scandium triflate. 

Lewis-acid-promoted Michael additions complement the enolate (2) and enamine reactions (vide supra). Since a variety of methods exist for the generation of enol ethers and ketene acetals, often with good stereochemical and regiochemical control (vide infra), the Mukaiyama-Michael reaction often permits a degree of stereochemical and regiochemical control that is not easily possible in enolate and enamine reactions. Additionally, the reaction occurs under formally acidic conditions, so it can be used with base-sensitive substrates. 

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