2-Substituted chromans

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>. 

For the asymmetric synthesis of the 2-substituted chromane 7 via the intramolecular Michael addition reaction of 6, Merschaert et al. also employed natural cinchona alkaloids such as HCD as catalysts (Scheme 9.3) [3]. Here again, the 9-0 functionalization and dehydroxylation of the natural alkaloid showed a large negative effect, indicating that the presence of the 9-OH group is needed to achieve both good kinetics and enantioselectivity. Moreover, C3 modifications of this parent alkaloid did not lead to any significant improvement in the results in terms of the enantioselectivity and catalytic activity. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

NMR examination shows that the chroman system exists in a half-chair conformation. Reactions with electrophiles, for example, SeAt processes, occur on the benzene moiety on C-6 as expected. 2-Substituted chroman-4-ones 3 undergo ring opening by attack of alkali hydroxide on C-2 and formation of a,P-unsaturated (2-hydroxy)phenyl ketones 4, acids bring about recyclization. Flavanones 5 are ring opened by traces of alkali ( 6). 

A series of similar reactions was examined in the course of synthesis of substituted chromanes.155 The reactions are thought to proceed through TS M in preference to N because of steric interactions with the phenyl ring on the chiral hydroxylamine. 

The NMR spectra of various substituted chroman-4-ones occur in papers largely concerned with their synthesis. The spectra of some rotenoids such as (61), which contain the chromanone unit, have been analyzed and their structures elucidated (62JCS775,66JCS(C)542, 72JOC1636). 

Chromans exhibit a C—O stretching vibration at 1260-1215 cm-1 (64CB682). A detailed analysis of the spectrum of 2,2-dimethylchroman is reported (68JCS(C)1837> and information on variously substituted chromans is available (81HC(36)l). 

Substituted chroman-4-ols behave in a similar manner and yield 3-substituted chromenes, and the dehydration of 3-phenylchromanols provides a convenient route to isoflavenes (66JCS(C)629). 

The condensation of salicylaldehyde derivatives with alkenes in the presence of boron trifluoride yields 4-substituted chromans (64CB682). The use of the acetal (276 R = OEt) leads to 4-ethoxychromans (277 R = OEt), but of more interest is the formation of chroman-4-carbamates (277 R = NHC02Et) from the biscarbamic ester (276 R = NHC02Et Scheme 70). 

Although some workers have found difficulty in purifying the product, a particularly convenient preparation of chroman involves the cyclization of l-chloro-3-phenoxypropane in the presence of tin(IV) chloride (equation 11) (52CR(234)1787). The synthesis is readily adapted to give many substituted chromans. A surprising result was obtained using 3-chloro-... 

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. 

During a study of dihydrocoumarins (68JOC1202) it was observed that 4-(2-bromoethyl)-3,4-dihydrocoumarin (291) was converted into a 4-substituted chroman on reaction with an amine. Ring opening occurs through nucleophilic attack at C-2 and this is followed by an intramolecular nucleophilic substitution. In a similar manner, chroman-4-ylacetic acid results on reaction with potassium hydroxide in methanol. 

Tocopherols comprise a methyl-substituted chroman-6-ol ring attached at C-2 to a saturated iso-prenoid side chain. Tocotrienols are analogous structures whose side chains contain three trans double bonds. The tocopherols and tocotrienols are designated as a, (S, y, and 8, according to the number and position of the methyl substituents in the chromanol ring (Fig. 5). 

Ring opening of a bi- or tricyclic /3-lactam, which does not have a bridgehead nitrogen atom and whose relative stereochemistry is known, gives /3-amino acid derivatives where the relative stereochemistry is also known. This idea has been used extensively. For instance, methanolysis of the tricyclic /3-lactams 117 gave a series of 3-amino 4-substituted chromane-2-carboxylic esters 118 (Equation 12) whose relative stereochemistry is known <1999T5567>. 

In the synthesis of some biologically active 3-substituted chroman 4-ols, for example, 395, it was found that reductions of 3-piperidino-, morpholino-, and pyrrol idino l//-chrornoncs could be efficiently achieved by sodium borohydride in methanol (Scheme 63) <2002SC2227>. 

The Fischer carbene complex 518 undergoes a benzannulation reaction with 1-hexyne to furnish the highly substituted chroman 519 (Equation 213) <1998TL2851>. Treatment of the same complex with various functionalized alkynes provides tricyclic chromans <1998SL61>. 

The tandem 5-exo [67], and 6-exo-trig cyclization-SRNl [69] reactions afford 3-substi-tuted dihydrobenzofuranes and dihydronaphtho[2,l-k]furanes (28) for the former, and 4-substituted chromanes and benzo[f]chromanes (29) for the latter. In these reactions, at least one C—C bond is formed and the products obtained are feasible for further synthetic transformation (Scheme 10.53). Another approach to O-hetero-cycles is provided via SRN1 substitutions followed by a copper-catalyzed reaction (see Scheme 10.8). 

Bardag,f J.I., Vaillard, S.E. and Rossi, R.A. (2007) Synthesis of 4-substituted chromanes and 4-substituted benzo[f] chromanes by tandem 6-exo-trig cyclization-SRNlreactions. ARKIVOC, IV, 73-83. 

The one-pot reaction of 0-BOC protected salicylaldehydes and salicyl alcohols with electron-rich alkenes and a Grignard reagent involves a diastereoselective cycloaddition to an o-quinone methide and offers access to a wide range of 4-substituted chromans <02JOC6911>. 

Deshpande, P. R Baker, D. C. A simple approach to the synthesis of the chiral substituted chroman ring of calophyllum coumarins. Synthesis, 1995, 630-632. 

A radical cation is involved in the direct synthesis of chromans by an intramolecular oxidative cyclisation of 3-arylpropanols 32 brought about by a hypervalent iodine(III) reagent <04TL2293> and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 <04JA3416>. 3-Allenylchroman-4-ols result from a one-pot reaction between salicylaldehydes and 1,4-dibromobut-2-yne in which the intramolecular cyclisation of the intermediate ether is mediated by In metal <04SL45>... 

Several benzo-fused tetrahydropyrans have been prepared either from aryl-propanhydroperoxides in the presence of iron(II) and copper(II) salts, from the corresponding arylpropanol either by oxidation with FeS20g, or in a photochemical reaction with iodine and mercury(II) oxide (type III radical precursors). These reactions are considered to proceed via alkoxyl radical intermediates which add to the aromatic part of the molecule. Subsequent C- or O-migration in spirocyclized intermediates affords substituted chromanes. However, ionic cyclizations may significantly interfere with the key step of the C-O bond formation [57-59]. 

Substituted chromans are formed from chroman-3-one through the Pd-catalysed coupling of its triflate with trialkyltin and boronic acid derivatives and subsequent hydrogenation <97TL5501>. 

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