Benzyl alcohol rearrangement

Acid-catalyzed dehydration (Section 5.9) This is a frequently used procedure for the preparation of alkenes. The order of alcohol reactivity parallels the order of carbocation stability R3C" > R2CH " > RCH2 ". Benzylic alcohols react readily. Rearrangements are sometimes observed. 

An unusual by-product was obtained in small yield in palladium-catalyzed reduction of 2-amino-4,5-dimethoxyindanone hydrochloride, The reduction was done in two stages first, a rapid absorption of 1 mol of hydrogen at 38 C to give the amino alcohol, and then a much slower reduction in the presence of HCIO4 at 70 "C. The rearranged by-product was shown to arise from attack of acid on the amino alcohol (50), Resistance to hydrogenolysis is characteristic of / -amino aromatic alcohols (56), a fact that makes reduction of aromatic oximino ketones to amino benzyl alcohols a useful synthetic reaction. 

In studies on l-diazo-2-ketosulfones, Shioiri et at. found that the thermal decomposition of benzoyl(sulfonyl)diazomethanes 6 with benzyl alcohol in acetonitrile also gave two products.<82CPB526> One is the 4-sulfonyloxazole 7 whereas the other product 8 results from rearrangement and reaction with the alcohol. The ratio of products varies with the nature of the sulfone substituent with the benzyl group giving highest yields of oxazole (Scheme 5). 

The ketone produced in the rearrangement can be captured by benzyl alcohol in base to give (8) directly. Synthesis ... 

DMSO or other sulfoxides react with trimethylchlorosilanes (TCS) 14 or trimefhylsilyl bromide 16, via 789, to give the Sila-Pummerer product 1275. Rearrangement of 789 and further reaction with TCS 14 affords, with elimination of HMDSO 7 and via 1276 and 1277, methanesulfenyl chloride 1278, which is also accessible by chlorination of dimethyldisulfide, by treatment of DMSO with Me2SiCl2 48, with formation of silicon oil 56, or by reaction of DMSO with oxalyl chloride, whereupon CO and CO2 is evolved (cf also Section 8.2.2). On heating equimolar amounts of primary or secondary alcohols with DMSO and TCS 14 in benzene, formaldehyde acetals are formed in 76-96% yield [67]. Thus reaction of -butanol with DMSO and TCS 14 gives, via intermediate 1275 and the mixed acetal 1279, formaldehyde di-n-butyl acetal 1280 in 81% yield and methyl mercaptan (Scheme 8.26). Most importantly, use of DMSO-Dg furnishes acetals in which the 0,0 -methylene group is deuter-ated. Benzyl alcohol, however, affords, under these reaction conditions, 93% diben-zyl ether 1817 and no acetal [67]. 

The availability of Nafion on silica has not only lowered the cost of the resin but also has made it versatile (Sun et al., 1997 Harmer et al., 1998). A number of industrially important reactions have been attempted, with considerable success, with these catalysts. Consider the Fries rearrangement of phenyl acetate to p-acetyl phenol (/t-hydroxy acetophenone). This has been accomplished by Hoelderich and co-workers (Heidekum, 1998). In the ca.se of alkylation of benzene with benzyl alcohol, Amberlyst-15 and p-toluene sulphonic acid are ineffective and Nafion on silica works well at 80 °C. 

Scheme 10.3 gives some examples of pinacol and related rearrangements. Entry 1 is a rearrangement done under strongly acidic conditions. The selectivity leading to ring expansion results from the preferential ionization of the diphenylcarbinol group. Entry 2, a preparation of 2-indanone, involves selective ionization at the benzylic alcohol, followed by a hydride shift. 

Reaction of 2-amino-benzyl alcohol and 2-chloroH-phcnylaminopyrimidinc forms the intermediate cation 204, which contains ene and iminium functionalities and undergoes electrocyclic rearrangement to the 2-phenylamino-6//-pynmido[2,l-2 ]quinazoline 205 (Scheme 32). The cation 204 is stabilized by the aryl groups. The 2-NHPh stmcture of the product was confirmed by 111 NMR spectroscopy <2002TL1303>. 

Normally, only a small stoichiometric excess (2-30 mol%) of silane is necessary to obtain good preparative yields of hydrocarbon products. However, because the capture of carbocation intermediates by silanes is a bimolecular occurrence, in cases where the intermediate may rearrange or undergo other unwanted side reactions such as cationic polymerization, it is sometimes necessary to use a large excess of silane in order to force the reduction to be competitive with alternative reaction pathways. An extreme case that illustrates this is the need for eight equivalents of triethylsilane in the reduction of benzyl alcohol to produce only a 40% yield of toluene the mass of the remainder of the starting alcohol is found to be consumed in the formation of oligomers by bimolecular Friedel-Crafts-type side reactions that compete with the capture of the carbocations by the silane.129... 

The diazoketone first formed is decomposed in a high-boiling solvent (benzyl alcohol or octanol 2) at 160°-180°. Although no catalyst is required, but the addition of a collidine base improves the yield. The second step is the rearrangement of the diazoketone which is also called Wolff rearrangement. 

Hexamethylbenzene reacts with DMDO via three pathways (i) to an arene oxide, which rapidly rearranges to an oxepin tautomer that then is oxidized to a cw-diepoxide and then to a cis, cis,trans-triepoxide (ii) a methyl group migrates in the first epoxide to give a cyclohexadienone, which then reacts to give a frani -diepoxide (iii) C—H insertion to give the benzyl alcohol and then the corresponding benzoic acid. ... 

Tellurium-tetrachloride-promoted rearrangement of cycloheptatriene to benzylic alcohols... 

Miscellaneous The treatment of allyl 1-bromo-2-naphthyl ether 43 with f-BuLi affords benzyl alcohol 44 via a sequential reaction consisting of bromine-lithium exchange, and anion translocation, followed by a [1,2]-Wittig rearrangement (equation 23). ... 

Another powerful approach to prepare a-amino acids bearing an aromatic or unsaturated side chain in /I (but also many other compounds) is based on the reactivity of 5-fluoro-4-trifluoromethyloxazole, a starting material easily accessible from hexafluoroacetone. The fluorine atom in the 5 position is easily displaced by an allylic or benzylic alcohol. Then, the obtained ethers spontaneously undergo a Claisen rearrangement to afford, after acidic hydrolysis, an a-trifluoromethyl amino acid... 

Further elaboration of the sulfur cycloadducts could be achieved by the use of a Pummerer rearrangement in the syntheses of 5-(hydroxymethyl)prolines. Oxidation of adduct 298 to sulfoxide 299, followed by treatment with TEA in DCM and quenching with either methanol or benzyl alcohol, delivered the Pummerer products 300 in 57% yield for R = Me and 38% for R = Bn as single diastereoisomers. Raney Ni desulfurization and Pearlman s catalyst mediated hydrogenolysis, for R = Bn furnished the final enantiopure proline derivative (Scheme 3.99). 

The one-pot reaction of the a-(difluoromethyl)-p-sulfinylenamine 70 with trifluoroacetic anhydride in CHCI3, followed by treatment with silica gel affords 4-(difluoromethyl)-5-p-tolylthio-2(3//)-oxazolone 74 (Fig. 5.18). This reaction proceeds via a Pummerer-type rearrangement, followed by [l,3]-proton shift and the simultaneous elimination of trifluoroacetic acid and benzyl alcohol. ... 

Beckmann rearrangement of, 729,741 p-Benzoquinone, 745 Benzoylacetone, 865 o-Benzoylbenzoic acid, 728, 739 Benzoyl chloride, 791, 792 Benzoyl glycine, 584 Benzoyl peroxide, 807 determination of, 809 Benzoyl piperidine, 489, 492 P-Benzoylpropionic acid, 728, 737 P-Benzoylpropionitrfle, 911, 912 Benzoyl-p-toluidide, 582, 583 Benzyl acetate, 780, 783 Benzylacetophenone, 726, 734 Benzyl alcohol, 706,711, 811,812,884 N-Benzylamid es 394 table of, 395 ... 

The 2-chloro-l,2-difluorovinyl ether of furfuryl alcohol also rearranges at — 35l C despite loss of aromaticity. Methanolysis then affords ester 12, which requires heating to 90 C for rearoma-tization. The 2-chloro-l,2-difluorovinyl ether of benzyl alcohol is sufficiently stable to be isolated but rearranges at room temperature methanolysis affords chlorofluoro(2-tolyl)acetic acid ester 13. Apparently, a 1,3-benzyl shift is not favored in this case, as opposed to other fluorine-containing vinyl benzyl ether systems discussed in Section 5.1.3. 

Use of benzyl alcohol resulted in formation of the benzyl ether corresponding to allyl ethers 52, but attempted Claisen rearrangement resulted in an 82 % yield of the product of a 1,3-benzyl shift (see Section 5.1.3.).20 To demonstrate the utility of the methodology outlined in Table 14, x-oxoester 53a was converted into the corresponding x-amino acid by hydrolysis and reductive animation.20... 

When the double bond of the allyl fragment is part of a benzene ring, i.e. when benzyl alcohols are used, a 1,3-benzyl shift takes place instead of the Claisen rearrangement (see Section 5.I.3.).28... 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

Triflic acid is also efficient in the alkylation of electron-rich aromatics (anisole, 1,3-dimethoxybenzene, 2-methylfurane, pyrrole, benzofurane, indole) with secondary benzylic alcohols and 3-phenylallyl alcohols (50°C, 1-9 h, 66-95% yield).201 Benzene, toluene, and halobenzenes are also alkylated with hydroxy-biindantetraone 53 in triflic acid within 1-2h202 [Eq. (5.78)]. Suprisingly, however, the primary products (with the exception of the 4-methylphenyl-substituted compound) undergo rearrangement upon prolonged treatment to yield alkenes... 

---