2- phenol cyclisation

American scientists have been studying intramolecular phenolic cyclisations of the type 1 to 2, and yields are generally good. The transformation 3 to 4, which proceeds in 80% overall yield, has been described in a review article as "a fantastically short and efficient synthesis of such tropone systems". 

Tetramethoxyisoflavone (5) was the target of the cyclisation reaction of 3,4-dimethoxy-phenol (7) with formyl-(3,4-dimethoxyphenyl)acetic acid (2) in the presence of polyphosphoric acid. 

Atmospheres polluted by oxidising agents, e.g. ozone, chlorine, peroxide, etc. whose great destructive power is in direct proportion to the temperature, are also encountered. Sulphuric acid, formed by sulphur dioxide pollution, will accelerate the breakdown of paint, particularly oil-based films. Paint media resistant both to acids, depending on concentration and temperature, and oxidation include those containing bitumen, acrylic resins, chlorinated or cyclised rubber, epoxy and polyurethane/coal tar combinations, phenolic resins and p.v.c. 

The distribution of products obtained from the benzannulation reaction may be influenced by the concentration of alkyne substrate [18]. In strongly coordinating solvents the ratio of the phenolic benzannulation product over five-membered cyclisation products increases with the concentration of the alkyne (Scheme 10). 

The two saturated rings of the cannabinoid nucleus are formed with the correct stereochemistry at C-6, C-6a and C-lOa but without selectivity at C-9 in a single acid-catalysed cyclisation step from the phenol 51. Stabilisation of a cationic intermediate by the alkyne group is proposed to account for the facile cyclisation . 

Michael addition of di- and tri-hydric phenols to /V-cinnamoylimidazoles followed by a lactonisation offers a route to 4-aryI-3,4-dihydrocoumarins and their [/]-benzologues <00S123>. The lactonisation of the naphthoquinone derivative 66 is sensitive to the acidic cyclising medium and it is possible to obtain the thermodynamically less stable o-quinone derivative exclusively (Scheme 44) <00TL3007>. Some related quinones have been obtained from 1-benzylisoquinolines via an arylnaphthoquinone <00T6O23>. 

The first enantioselective total synthesis of the sesquiterpenoid heliannuol D 56 has been reported by Shishido and co-workers. The key step was a base-mediated (NaOH) intramolecular cyclisation of the phenolic epoxide mixture 55 (R1 = MOM, R2 = H and R1 = H, R2 = MOM). Heliannuol D (and the eight-membered congener, heliannuol A) is an allelopathic agent isolated from cultivated sunflowers (Helianthus annuus L.SH-222) <00JCS(P 1)1807>. 

Another important investigation of a quantitative nature of the pre-war era is that of Ziegler et al. (1937), who studied the kinetics of the base-promoted cyclisation of o-(co-bromoalkoxy)phenols (43) in ethanol solution... 

Dienes, 11 addition to, 194-198 cisoid conformation, 197, 350 conjugated, 11 Cope rearrangement, 354 cyclisation, 346 cycloaddition to, 348 Diels-Alder reaction, 197, 349 excited state, 13 heat of hydrogenation, 16,194 isolated, 11 m.o.s of, 12 polymerisation, 323 Dienone intermediates, 356 Dienone/phenol rearrangement, 115 Dienophiles, 198, 350 Digonal hybridisation, 5 Dimedone, 202 Dimroth s Ej- parameter, 391 solvatochromic shifts, 391 solvent polarity, 391 Y and,392 Dinitrofluorobenzene proteins and, 172... 

An excellent survey of the various methods of synthesis is available53 this section includes some of the illustrative methods of synthesis of the simpler analogues. These methods may be considered under the following headings (a) the oxidation of hydrocarbons (b) the oxidation of phenols and the oxidative coupling of phenols (c) the oxidation of dihydric phenols and aminophenols and (d) the cyclisation of aroylbenzoic acids. 

Concentrated sulphuric acid is generally used as the condensing agent for simple monohydric phenols and /J-ketoesters, although phenol itself reacts better in the presence of aluminium chloride (Expt 8.45). The mechanism of the reaction is thought to involve the initial formation of a -hydroxy ester, which then cyclises and dehydrates to yield the coumarin. 

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

Maritidine. It was observed that a variety of alkoxyl or silyloxy phenols 340 (Scheme 51), on oxidation with the non-toxic pheny 1 iodo-tos-trifluoroacetate, instead of customary heavy metal reagents such as trivalent thallium or pentavalent vanadium salts, in the weakly nucleophilic solvent, trifluoroethanol at low temperature, furnished consistently improved yields of cyclisation products 341 [89],... 

Application of the above procedure to the known N-protected phenol 342, derived from L-tyrosine and veratraldehyde, resulted in smooth oxidative cyclisation to the dienone 343 in 66% yield. Since the latter had been previously converted [90] via (+)-epimaritidine (344) into (+)-maritidine (345) [91] in six steps with an overall yield of 1.26%, the preparation of 343 constituted a formal synthesis of the alkaloid. 

It turns out that we must protect the phenol as its methyl ether 127 and that 126 is best used as an amidine-ester rather than the double enamine. The synthesis is then quite short. We have barely scratched the surface of aromatic heterocyclic synthesis in this chapter but the encouraging message is that cyclisation is easy and that cyclisations to form aromatic compounds are the easiest of all. Disconnect with confidence ... 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

Benzo[a] and benzo[c] xanthene and dibenzo[a,c]xanthene have been synthesised by the Pd-catalysed cyclisation of aromatic 2-(arylmethyl)phenol triflate esters through S-0 bond cleavage <02T5927>. 

The procedure for the synthesis of the crown ether BPP34C10, 12, that is outlined below is representative of caesium-templated cyclisations of phenol derivatives with ditoluenesulfonates. 

Phenols and naphthols are converted to chromans in a one-pot reaction with isoprene. The specific catalyst AgOTf promotes tandem alkylation, via a 1,4-addition, and cyclisation by O-C bond formation (Scheme 10). With other dienes, 2-naphthol preferentially forms dihydronaphthofurans <06JOC6705>. The Bi(OTf)3-catalysed [1,3] rearrangement of (4-substituted aryl) 3-methylbut-2-enyl ethers to 2-prenylphenols is spontaneously followed by a cationic cyclisation to chromans <06S3963>. 

A stereoselective synthesis of (-)-gallocatechin illustrates a general approach to flavan-3-ols. Mitsunobu coupling of a phenol and an epoxyalcohol provides access to a l-aryl-3-bromo-2-hydroxypropyl 2-iodoaryl ether which is cyclised to the flavanol by a halogen-metal exchange (Scheme 13) <06CL1006>. 

The synthesis of 2,4-diarylchromen-2-ols through the reaction of phenols with an excess of a chalcone in TFA involves sequential Friedel-Crafts alkylation, cyclisation to a 4/7-1-benzo-pyran, an intermolecular hydrogen transfer generates the 4-arylflavylium ion which is hydrated to give the final product (Scheme 12) <07JOC9383>. 

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