Acid sensitive functional groups

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

In general, hydroboration—protonolysis is a stereoselective noncatalytic method of cis-hydrogenation providing access to alkanes, alkenes, dienes, and enynes from olefinic and acetylenic precursors (108,212). Procedures for the protonolysis of alkenylboranes containing acid-sensitive functional groups under neutral or basic conditions have been developed (213,214). 

For starting materials containing base- and/or acid-sensitive functional groups, modified procedures have been developed—e.g. using oxidizing agents. ... 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

Addition of a proton occurs to give the more-substituted carbocation, so addition is regioselective and in accord with Markovnikov s rule. A more detailed discussion of the reaction mechanism is given in Section 6.2 of Part A. Owing to the strongly acidic and rather vigorous conditions required to effect hydration of most alkenes, these conditions are applicable only to molecules that have no acid-sensitive functional groups. The reaction is occasionally applied to the synthesis of tertiary alcohols. 

The intramolecular coupling of enolethers with enolethers, styrenes, alkyl-substituted olefins, allylsilanes, and vinylsilanes was systematically studied by Moeller [69]. Many of these coupling reactions turned out to be compatible with the smooth formation of quaternary carbon atoms (Eq. 11) [70], which were formed diastere-oselectively and led to fused bicyclic ring skeletons having a ds-stereochemistry [71]. The cyclization is compatible with acid-sensitive functional groups as the allylic alkoxy group. Moeller has demonstrated in some cases that these reactions can be run without loss of selectivity and yield in a simple beaker with either a carbon rod or reticulated carbon as anode without potential control and a 6-V lantern battery as power supply [71]. 

Notes A weak acid, useful for substrates with acid-sensitive functional groups. Has been used to place and remove alcohol protecting groups ... 

Acid-sensitive functional groups could thus be preserved as an acetal in the example below ... 

One of die most common methods for the preparation of ketones is by the oxidation of secondary alcohols. The use of chromic acid (Jones reagent) is easy, safe, and effective for the oxidation of secondary alcohols to ketones. Furthermore Jones reagent gives a nearly neutral solution and thus can be used with a variety of acid-sensitive functional groups. 

When the Clemmensen method fails, or when strongly acidic conditions are precluded owing to the presence of acid-sensitive functional groups, the Wolff-Kishner reduction or the Huang-Minlon modification of it may succeed. The latter method is also discussed in Section 6.1.1, p. 827, and illustrated in Expt 6.4, Method A. 

Reaction of an alcohol with the reagent o-phenylene phosphorochloridite followed by treatment of the alkyl o-phenylene phosphite so obtained with iodine in dichloromethane at room temperature results in a good yield of alkyl iodide. This method, exemplified by the preparation of 1-iodoheptane (Expt 5.60), is the preferred procedure when acid-sensitive functional groups are present. 

In effect, this reaction converts a dialkyl ether into two alkyl halides. The conditions are very strong, however, and the molecule must not contain any acid-sensitive functional groups. 

The reaction of an epoxide with hydroxide ion leads to the same product as the acid-catalyzed opening of the epoxide a 1,2-diol (glycol), with anti stereochemistry. In fact, either the acid-catalyzed or base-catalyzed reaction may be used to open an epoxide, but the acid-catalyzed reaction takes place under milder conditions. Unless there is an acid-sensitive functional group present, the acid-catalyzed hydrolysis is preferred. 

Reaction of secondary or primary alcohols occurs under more drastic conditions, which may destroy other acid-sensitive functional groups. 

The principal problem in the deployment of fetf-butyl ethers is deprotection under conditions mild enough to accommodate acid-sensitive functional groups. Both protic and Lewis acids cleave ter/-butyl ethers rapidly. Typical reagents and conditions include anhydrous trifluoroacetic add (1-16 h, 0-20 °C), HBr-HOAc (30 min. 20 °C), 1 M HCl-dioxane, reflux, 3 h However, the method is mild enough to be useful in peptide synthesis. For example, a synthesis of the... 

Titanium tetrachloride and a tertiary amine are a useful catalyst for Knoevenagel condensation [149] as shown in Eq. (45) [150]. Because the reaction can be performed under mild conditions, acid-sensitive functional groups survive the reaction conditions and the optically active center at the enolizable position did not racemize (Eq. 45). More examples of the titanium-catalyzed Knoevenagel condensation are shown in Table 5. Alkylation of an (unsaturated) (iV,0)-acetal with active methylene compounds was performed analogously in the presence of TiCU and NEts (Eq. 46) [154]. Depending on the structure of the active methylene compounds, carbon-carbon bond... 

Ti-HMS modified Pd-C was found to accelerate the hydrogenolysis of simple benzyl ethers in the presence of acid-sensitive functional groups. The use of benzyl protection for polymer-supported syntheses has been a problem because of trapping of the catalyst by the polymer. This problem is partially solved by the use of Pd nanoparticles which result in efficient benzyl group hydrogenolysis from polymer supports. ... 

I he last two examples show that acid-sensitive functional groups can be present. The reaction was used in a convenient synthesis of ( )-mevalonolactone (11, The Grignard reaction of ethyl acetate and allylmagnesium bromide gives the tertiary alcohol (1). This was ozonized and the crude ozonide reduced with... 

Electrophilic aromatic substitution as a route to differentially substituted products is well established. The often forcing conditions, the incompatibility of this process with acid-sensitive functional groups, and the need for mild and selective syntheses have been the driving forces in the search for new methods of synthesis. A large range of methods has been developed over the past 20 years they include the trimerization of alkynes, the directed orfho-metallation, the benzannellation via metal carbenes, and transition metal-catalyzed carbon-carbon and carbon-heteroatom bond formation. Aromatic C-H activation, while still in its beginning stages, is another area of promise. 

A little (dba)3Pd2-CHCl3 and tri-o-tolylphosphine stirred for 3-5 min at room temp., treated with acetic acid and excess (up to 10-fold) of triethylsilane in benzene, stirred for 5 min, startg. diyne added in one portion, and stirred at 0° to room temp, for 1 h product. Y 70%. Acid-sensitive functional groups, e.g. silylated triple bonds, silyl ethers, acetals, and allyl ethers, as well as other reactive functional groups remained unaffected. F.e.s. B.M. Trost, D.C. Lee, J. Am. Chem. Soc. 110, 7255-8 (1988). 

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