Acid-sensitive functionalities

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). 

The 1,3-dioxolane group is probably the most widely used carbonyl protective group. For the protection of carbonyls containing other acid-sensitive functionality, one should use acids of low acidity or pyridinium salts. In general, a molecule containing two similar ketones can be selectively protected at the less hindered carbonyl, assuming that neither or both of the carbonyls are conjugated to an al-kene. ... 

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 present method is successful with a wide variety of ketones (see Table). Cyclic ketones (entries 1-4, 8) produce benzoannelated products in excellent overall yields. There is no need to purify the intermediate both the nucleophilic addition of methallylmagnesium chloride and the aromatic cyclization take place cleanly. Acyclic ketones (entries 5-7) also provide high yields of benzoannelated product. Aromatic ketones are particularly interesting substrates for this reaction since they provide substituted biphenyls, which are potentially useful materials for liquid crystal synthesis and whose preparation through classical methodology is often not straightforward. The conditions for the cationic cyclization step can be modified to accommodate acid-sensitive functionality. For example, cyclization of 3 to 4, the latter a precursor for 3-methyl-8,14-dehydromorphinan, was accomplished in 77% yield by treatment of 3 at... 

The classical method for introducing the fluorine atom to the anomeric center is to treat per-O-acetylated sugars with hydrogen fluoride [15], using which a-glycosyl fluorides can be prepared stereoselectively, however, the procedure is incompatible with any acid-sensitive functionalities present in the molecule. In addition, hydrogen fluoride is highly corrosive, which makes this method unattractive to many... 

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]. 

A closely related reaction having the phenol protected with a trimethylsilyl group was also examined (Scheme 31) [45]. Unlike the earlier examples, the cyclization reaction resulting from this substrate did not require the presence of a mild acid. The anodic oxidation in methanol solvent with no acetic acid led to a 73% yield of the tricyclic product. In a nearly identical reaction, an anodic oxidation of the trimethylsilyl-protected substrate in the presence of 2,6-lutidine led to the cyclized product in a 60% yield. The use of the silyl group expanded the utility of the anodic C-C bond-forming reaction being studied by allowing for the use of neutral and basic conditions. Hence, it would appear that the cyclization reactions are compatible with the presence of both base and acid sensitive functionality. 

This method works very well for reactive glycosyl acceptors such as primary alcohols. It can be carried out without affecting other acid sensitive functionalities including acetonides and even orthoesters. Nishimura and co-workers successfully employed this method to prepare the ttisaccharide monomer 344 (Scheme 8.107). After deprotection, the product was copolymerized with acrylamide to give a biologically interesting glycoprotein model. 

In recent years, dioxiranes have become workhorses for a variety of selective transformations in organic synthesis, from epoxidation of alkenes to the conversion of alcohols into fee corresponding ketones <99CJC308>. Dioxirane-mediated epoxidation continues to be the method of choice for complex substrates wife acid-sensitive functionality. Thus, fee dimethyl-dioxirane (DMD)-mediated epoxidation of the silylated stilbene lactam 159 has been reported as a key step in fee synthesis of protoberberines <99JOC877>. 

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 ... 

Anhydrous tetrahydrofuran contributes to the selectivity of the reagent because of the stability of Brf in this solvent. Moreover, tetrahydrofuran acts as a buifer by reaction with the liberated hydrobromic acid which is why PTT in tetrahydrofuran can also be very useful if the molecule bears acid-sensitive functions. It must be emphasized that anhydrous tetrahydrofuran must be used because small amounts of water can greatly retard the rate of bromination of ketones with resulting decreased selectivity. 

Although the presence of pyridinium cations makes PDC slightly acidic, very acid sensitive functionalities are able to withstand the action of PDC. Some sodium acetate can be added as a buffer for a completely acid-free oxidation.124... 

Pyridinium trifluoroacetate is such a mild acidic catalyst that it can hardly affect acid-sensitive functionalities. Thus, for example the very acid-sensitive Boc-protected amines49 and r-butyl esters,50 as well as glycosides51 and acetals,52 remain unchanged under Pfitzner-Moffatt conditions. 

As expected, acid sensitive functionalities, including THP,135 Tr,136 TBS137 and t-Bu138 ethers, orthoesters,139 acetals140 and glycosides,137a 141 as well as Boc-protected142 amines, are resistant to Omura-Sharma-Swern oxidations. 

As activated DMSO and activated alcohols have a certain acidity, a prolonged alcohol activation before the addition of base may cause decomposition of very acid-sensitive functionalities. 

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. 

The A -unsubstituted (3-lactams are important building blocks for the synthesis of several biologically active antibiotics. However, solution phase techniques normally include acidic conditions, which are not tolerable with acid-sensitive functionalities. In an elegant approach, Banik et al. [133] developed a solid phase synthetic route to access A -unsubstituted (3-lactams directly using Rink resin as the solid support. The method for construction of (3-lactam ring was based on Staudin-ger reaction and subsequent cleavage from the solid support was done with TFA in dichloromethane (Scheme 30). 

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. 

However, the ability of gold(III) chloride to provide protic catalysis under exceptionally mild conditions is further demonstated by two recent examples the hydroxyallene 35 bearing a silyl protecting group is efficiently cyclyzed to give the 2,5-dihydrofuran 36 without deprotection [20] other acidic catalysts which in principle sufficiently promote this type of cyclization - such as HC1 gas or Amberlyst 15 resin - are of course much less compatible with acid sensitive functionalities. Also for the formation of macrocycle 39 gold(III) chloride turned out to be the catalyst of choice [21],... 

In addition to Lewis acid catalysts, chiral bases catalyze the Diels-Alder reaction.100101 Although the use of bases as catalysts does show promise, especially for acid-sensitive functionality, the current level of asymmetric induction may not be acceptable for scale up. In addition, only a limited number of dienes and dienophiles have been shown to undergo the chiral-base catalyzed Diels-Alder reaction. 

Benzylation with benzyl trichloroacetimidate and a catalytic amount of triflic acid (TfOH) is a mild and efficient procedure (Scheme 2.1c).5 The acid protonates the nitrogen of the imidate moiety converting it into a very good leaving group. Nucleophilic attack by an alcohol introduces a benzyl ether. The procedure is often compatible with base- and acid-sensitive functionalities with esters, (7-isopropylidene and (7-benzylidene acetals. Benzyl trichloroacetimidate is commercially available but can easily be prepared by reaction of benzyl alcohol with trichloroacetonitrile in the presence of a mild base. 

---