Acid-mediated Reactions

Lewis acids have served as catalysts in numerous fields of organic synthesis. By temporary coordination to basic sites substrates can be activated resulting in enhanced reaction rates. Immobilization of Lewis acids to a solid support has been carried out in order to overcome work-up problems, for complexing ligands or for generating distinct reaction environments. 

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The latter method typically requires less severe conditions than the former because of the labile nature of the organic anhydride (87,137). Both of these reactions can result in explosions and significant precautions should be taken prior to any attempted synthesis of a peracid (87). For soHd peracids the reaction mixture can be neutralized with sodium hydroxide and the resulting fUtercake washed with water. In the case of the sulfuric acid mediated reaction the peracid has sodium sulfate incorporated in the cake (135). The water of hydration present in the sodium sulfate is desirable to prevent detonation or deflagration of the soHd peracid when isolated in a dry state (87,138,139). 

The Lewis acid mediated reaction of a-alkoxycarbamates 1 with -/-oxygenated alkylLin compound 2 proceeds in certain cases with very high diastereoselectivity83. The yield and the diastereomeric ratio appear to depend highly on the Lewis acid used and the substituents in the carbamate. While with R1 = C6H5 and R2 = CH, sole formation of the on//-isomer was observed, for other substituents the, y -isomer is obtained either exclusively or predominantly. The reason for this variable diastereoselectivity is not clear at present. 

More recently, the Lewis acid promoted asymmetric 1,4-addition of trimethyl(2-propenyl)silane to chiral a,/ -unsaturated /V-acylamides has been published33. Lewis acid mediated reactions of trimethyl(2-propenyl)silanes with a,/I-unsatu rated AT-acyloxazolidinones or iV-enoylsultams show high chemical yield with good diastereomeric excess. The absolute configuration of the new asymmetric center is controlled by the nature of the Lewis acid used. 

In the Lewis acid mediated reaction the developing carbenium ion in C is stabilized by the nearby 7t-electrons of the titanium or aluminum enolate. This generates as the major diastereomer the 3,3a-/r .v-relationship between the substitution at the ring junction and the vinyl group at C-3 via a synclinal transition state. 

Lewis-acid-catalyzed reactions often occur with unique reactivity and selectivity, and the reactions proceed under mild conditions. Many Lewis-acid-mediated reactions are now used not only in laboratories but also in industry. This chapter summarizes these Lewis acid-mediated reactions successfully used in organic synthesis they are organized mainly by the element of the Lewis-acid catalyst. Due to limitations of space, the focus is on more recent publications.1-3... 

Aluminum(III) complexes are amongst the most common Lewis acids. In particular, aluminum halide species (e.g., A1C13, AlBr3) are commercially available and are widely used for various reactions. Other types of Lewis acid such as aluminum alkoxides, alkylaluminum halides, and trialkylaluminum species are also used for many kinds of Lewis-acid-mediated reactions. 

In this chapter Lewis-acid-mediated reactions have been summarized. While more than stoichiometric amounts of the Lewis acids were employed in conventional reactions, many efforts have been made to reduce the amounts of Lewis acid needed, and many truly catalytic reactions have been developed. Chiral Lewis-acid catalysis has been of great interest in the 1990s and early 2000s, and various combinations of metals and ligands have been investigated. Importantly, the established understanding that Lewis acids are easily hydrolyzed in water has been exploded. Water-compatible Lewis acids are stable in air and moisture, and are easily recovered and reused in many cases. These Lewis acids may solve recent environmental issues, and will be used further in many reactions in future. 

Detailed NMR assignments for a range of bispyranones and some dihydro derivatives have followed their unambiguous syntheses through the Lewis acid-mediated reaction between 4-hydroxypyranones and a,P-unsaturated acids, a reaction which has potential in natural product synthesis (Scheme 39) <00TL1901>. 

A series of analogous py rrolo[ 2,1 -c [ 1,4]oxazine-8-carboxy latcs 188 and 189 (Scheme 28) were obtained by cycloaddition of azomethine ylide 187 with dipolarophiles. The ylide was formed by /(-toluene sulfonic acid-mediated reaction of the benzotriazolyl chiral morpholinone 186, which can be considered as a stable crystalline azomethine ylide precursor <2001SL1841>. This procedure was applied also to morpholinone 190 that generated ylide 191 by reaction with... 

Scheme 6. Lewis acid-mediated reaction via alkylideneallyl cation.

The product ratio of 8K/9K is similar to that of the Lewis acid-mediated reaction of 4a-c. These products of the C2-C3 bond cleavage (8K and 9K) may be formed via alkylideneallyl cation intermediate, which is formed by the oxygen protonation of 4. Thus, the product ratio of 10/(8K + 9K) is controlled by the protonations at the olefinic carbon and at the acetal oxygen of 4. 

As discussed previously [33-36], the Lewis acid-mediated reaction of 1,2-alleny] silanes with aldehydes or ketones can also afford homopropargylic alcohols 75 or five-membered 2,3-dihydrofurans 76 [37]. The type of reaction depends on the structure of the allenylsilanes, the substituent of the silyl group and the reaction conditions. 

The Lewis acid-mediated reaction of A -phenyl-5 -(4-methylphenyl)sulfonimidoyl chloride (352) with 1,1-disubstituted alkenes yields benzothiazines (353) with low stereoselectivity in moderate yields (33-57%). ... 

Section B of Scheme 9.4 gives some additional examples of Lewis acid-mediated reactions of allylic silanes with aldehydes and acetals. 

The development of new methods for the synthesis of homoallylic amine derivatives is an important area of synthetic efforts. Homoallylic amines are extremely important compounds as biologically active molecules [1], The Lewis acid-mediated reactions of imines with allyl silanes are among the most efficient for... 

The aldehyde group in 197 bears a potential for C-C bond elongation reactions. For example, 198 was obtained in 89% yield by the reaction with a stabilized ylide as an E-isomer (> 95 5) (Figure 4.9). Additionaly Lewis-acid-mediated reactions are possible. The reaction of the aldehyde 197 with aUyltributyltin and TiCl4 gave the homoallylic alcohol 199 in 86% yield. 

The Lewis acid-mediated reactions of 2-aza-l,3-dienes and aldehydes, resulting in tetrahydro-l,3-oxazin-4-one derivatives, were explained in terms of the competitive existence of two reaction pathways a [4+2] hetero-Diels-Alder cycloaddition reaction and a Mukaiyama aldol reaction <2001TA439>. 

A Lewis acid-mediated reaction of 1 equiv of acrolein (as enone) with 2 equiv of an aldehyde gave access to stereochemically pure 4-hydroxy-1,3-dioxanes when the reaction was carried out in the presence of stoichiometric amounts of BU4NI (Equation 78). Interestingly, an iodomethyl group rather than the expected exocyclic double bond was formed in the product <19990L1383>. 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

An alternative approach to difluoroenoxy silanes developed by the Reims group was described in Sect. 2.3.1 (Eq. 16). Lewis acid-mediated reactions with aldehydes and with alkyl halides were also described, constituting a valuable complementary approach to the Ishihara chemistry. The third approach to the... 

A potential method for the preparation of novel amino acids via the highly selective addition of radicals to the glyoxylic oxime derivative of Oppolzer s camphor sultam (88) has been reported.181 Both Lewis acid and non-Lewis acid-mediated reaction conditions for the addition of alkyl radicals generated from alkyl iodides and Et3B/Bu3SnH were examined. A new chiral auxiliary based upon (R,R)-2,5-diphenylpyiTolidine has been used in the addition of phenylthiyl radicals to unsaturated methacrylamides. The selectivity was found to be better than that reported for the structurally related 2,5-dimethylpyrrolidine derivative.182... 

Cainelli and coworkers have reported the synthesis of a class of 4-(2-oxoethy-lidene)azetidin-2-ones (IV, Fig. 14) that could be carried out by a novel Lewis acid mediated reactions of 4-acetoxyazetidin-2-ones with a-diazocarbonyl compounds [277]. 

A Friedel-Crafts-type reaction can be utilized in a Lewis acid-mediated reaction to yield tetrahydroquinolines (Equation 53) <1999J(P1)179, 1999TA255>. 

A Lewis-acid-mediated reaction of tungsten linked alkynes 209 with aldehydes forms the intermediate tungsten-r 1 -oxacarbenium salts 210 treatment with base and subsequent demetalation affords 3,4-dihydropyrans 211 that are classed as oxacyclic dienes (Scheme 62) <1997JA4404, 1998JOC7289, 1998JA4520, 2000JOC3761>. 

This protocol involves first a base-catalyzed methanolysis and then an acid-mediated reaction as outlined in Scheme B (Figure 4-25). 

As demonstrated below, a Lewis acid-mediated reaction was utilized in the synthesis of dihydro[b furan-based chromen-2-one derivatives from l-cyclopropyl-2-arylethanones and allenic esters <070L4017>. The TiCh-catalyzed anti-Markovnikov hydration of alkynes, followed by a copper-catalyzed O-arylation was applied to the synthesis of 2-substituted benzo[6]furan <07JOC6149>. In addition, benzo[6]furan-based heterocycles could be made from chloromethylcoumarins <07SL1951>, substituted cyclopropanes <07AGE1726>, as well as benzyne and styrene oxide <07SL1308>. On the other hand, DBU-mediated dehydroiodination of 2-iodomethyl-2,3-dihydrobenzo[6]furans was also useful in the synthesis of 2-methylbenzo[Z>]furans <07TL6628>. 

Hydroxyindoles may be accessed using the Nenitzescu reaction, as illustrated by preparation of the indole 381 from the enamine 382 and 1,4-benzoquinone (Equation 107) <1996JOC9055>. Additional applications of this strategy encompass syntheses of 1 -alkyl-5 -hydroxynaltrindole derivatives <2005JME635>, and lO-hydroxy-5,6-dihydroindolo[2,l- ]isoquinolines <2001JOC4457>. An alternative approach to 5-hydroxyindole derivatives involves Lewis acid-mediated reactions of benzoquinone monoimines with enol ethers <1997TL6135>. 

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