Chroman phenol

Unless great care is taken in control of phenol/acetone ratios, reaction conditions and the use of catalysts, a number of undesirable by-products may be obtained such as the o-,p- and o-,o- isomers of bis-phenol A and certain chroman-type structures. Although tolerable when the bis-phenol A is used in epoxy resins, these have adverse effects on both physical properties and the colour of polycarbonate resins. 

Stokes, S. M. J. Ding, F. Smith, R L. Keane, J. M. Kopach, M. E. Jervis, R. Sabat, M. Harman, W. D. Formation of o-quinone methides from T 2-coordinated phenols and their controlled release from a transition metal to generate chromans. Organometallics 2003,22, 4170-4171. 

For the enantioselective synthesis of chiral chromanes such as 2-213, a chiral Lewis acid complex, formed in situ from Mg(OTf)2 and 2-212, is assumed to catalyze the domino transformation of the phenols 2-210 and the p,y-unsalurated a-ke-toesters 2-211 (Scheme 2.50). 2-213 was obtained in excellent diastereoselectivity, but only in mediocre enantioselectivity. 

Hydrogenation of the carbon-carbon double bond occurs without alteration of the ester function when citronellyl acetate is treated with 2.5 equivalents of trifluoroacetic acid and two equivalents of triethylsilane in 2-nitropropane.205 The reduced product is obtained in 90% yield after 22 hours at room temperature in the presence of one equivalent of added lithium perchlorate (Eq. 82). The yields are lower in the absence of this added salt. Similar reduction of an unsaturated phenolic chroman derivative occurs to give an 85% yield of product with only the carbon-carbon double bond reduced (Eq. 83).205... 

Chromene acetals 39 are accessible from 2-vinyl-substituted phenols via the allylic acetals 38 through oxypalladation of benzyloxypropa- 1,2-diene and a subsequent Ru-catalysed RCM. 2-Substituted chromenes can be derived from the acetals 39 by conversion into the 1-benzopyrylium salts which are then trapped by nucleophiles (Scheme 26) <00TL5979>. In a like manner, 2-aIkoxychromans have been converted into various 2-substituted chromans by sequential treatment with SnCl4 and a silyl enol ether <00TL7203>. 

When, furthermore, phenols (368) are coupled with 1 in the presence of a Pd° catalyst, the phenoxy-methyl-1,3-dienes 369 are produced [158]. As aryl allyl ethers, these can be made to undergo a Claisen rearrangement (205 °C, DMF) and the ensuing 2-(l,3-dienylmethyl)phenols 370 finally cydize in the presence of a trace of acid to a mixture of exo-methylene chromans 371 (major product) and dihydrobenzofur-ans 372 - a remarkable generation of functional and structural complexity from simple starting materials with 100% atom economy and underlining impressively the synthetic versatility of modern allene chemistry ... 

Intramolecular reactions of a phenolate were also reported (Scheme 9.33) [22a]. The preparation of a chromane derivative is described below, where the catalyst was activated with the base TBD. As in the case of intramolecular aminations, these cyclizations could be run at concentrations as high as 0.5-1 M. 

SnCl4 is also superior to 22 SnCl4, and is effective for the enantioselective cyclization of 2-(polyprenyl)phenol derivatives to give polycyclic terpenoids bearing a chroman skeleton.The synthetic utility of 26 SnCl4 is demonstrated by very... 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

A phenol synthesis reaction induced by gold catalysts without steric limitations for the substituents was also reported [169]. These results provided a very helpful tool for organic synthesis of a large variety of derivatives such as biaryls, iso-chromanes, benzofurans, tetrahydroisoquinolines and other natural products [133, 170, 171]. 

When chroman is heated on alumina at 250-350 °C, 2-methyl-2,3-dihydrobenzo[6]furan is formed, the amount of product increasing with temperature. At the higher end of this temperature range, 2-methyl-, 2-ethyl- and 2-propyl-phenols are formed (71MI22302). At 300-400 °C in the presence of activated carbon, some 2-methylbenzo[Z>]furan (589) is also produced (75CHE278). 

A 2-amino group in chroman is more labile than its isomers and is hydrolyzed to the alcohol by acids for example both the amines (699) and (700) give the corresponding alcohols by treatment with nitrous acid and 50% hydrochloric acid, respectively. 6-Amino-chromans are of interest because of their chemical and biological resemblance to the tocopherols. The tocopheramines (701 R1, R2, R3 = H or Me) show antioxidant and other properties of the corresponding phenols and are no more toxic. They may be obtained by catalytic or chemical reduction of the nitrochromans (81HC(36)189). 

However, the related chloro (248) and the benzyl ether (249) analogues do not cyclize to chromans under the same conditions, implicating the second phenolic hydroxy group of... 

Chromans arise through the reaction of phenols with a variety of unsaturated molecules such as alkenols, halogenoalkenes and dienes. However, the chroman is usually but one of several products and the reaction is therefore often of limited synthetic value (21CB200, 63JOC798). A comprehensive discussion of these reactions is included in the review by Livingstone <81HC(36)7), but some examples merit attention. 

S526, 81T1437). m-Substituted dihydric phenols give a mixture of the 5- and 7-hydroxy-chromans. 

Another well-used synthesis is based on the cyclization of 1,3-diphenoxypropane (63JCS2094). Later work has extended the route to a variety of substituted chromans and to dihydronaphthopyrans (65JCS5718). The m-substituted compounds give a mixture of the 5- and 7-isomers (Table 4). Formation of the chroman probably involves simultaneous ring closure and displacement of a phenolic residue, since under the reaction conditions a carbocation intermediate is not expected. 

Several chromans have been synthesized using the Parham cycloalkylation technique (76JOC1184). l-Bromo-3-(2-bromophenoxy)propane, prepared from phenol and 1,3-dibromopropane, is treated with n-butyllithium at — 100 °C. Halogen-lithium exchange yields the aryllithium (278) which cyclizes either at — 100°C or in some instances only at an acceptable rate at higher temperatures. This method offers the advantage of regio-specificity since cyclization is controlled by the location of the o-bromine atom (Scheme 72). 

It is pertinent at this point to refer briefly to the sources of quinone methides, though these have been reviewed (B-74M122400). The general approach used in chroman syntheses involves the thermal elimination of HX from an -substituted phenol. Commonly the eliminated molecules are water, methanol or dimethylamine (287 X = OH, OMe, NMe2, respectively). However, these methods are not entirely suitable because the eliminated molecules may promote side reactions. In the case of 1,2-naphthoquinone 1-methide, the thermal dissociation of the spirodimer (288) is a better source than the other methods. Its formation represents another example of dimerization by a [4+2]-cycloaddition, since it is prepared by heating l-dimethylaminomethyl-2-naphthol in dodecane or xylene with careful exclusion of moisture (73JCS(P1)120,81CJC2223). 

The reaction between a phenol and an unsaturated acid or a derivative in the presence of a Lewis acid has also been widely used for the preparation of chroman-4-ones. The solvents employed are generally those utilized in the previous method, namely carbon disulfide or nitrobenzene, but a wider range of catalysts has been used. There is also a greater choice in the unsaturated component, the acid, acid chloride and acid anhydride being especially valuable. 

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