3,4-Dihydroisocoumarins

Dihydrocoumarins and Dihydroisocoumarins. - The potential of thalHum compounds in organic synthesis continues to be developed in a variety of reactions. One of these was the synthesis of dihydrocoumarins by oxidative cyclization of 3-arylpropionic acids, e.g. (177), by thallium(in) trifluoro-acetate-trifluoracetic acid (TTFA). The coumarin was accompanied by methyl 3-(2-hydroxyphenyl)propionate (178), which was formed by ring- 

Conversion of pyrans into pyridines is well established, but an example of the converse reaction was recently described in which the benzylisoquinoline (181 R = 6,7-dimethoxy) was treated with cyanogen bromide to give the iso-chroman (182). Oxidation of alpinigenine (183), which is present in several species of poppies, gave the isochromanone (184).  

Berger-Josephs, T. Yehezkel, H. E. Gottlieb, and E. C. Levy, /. Chem. Soc., Perkin Trans. 1, 1981, 1019. 

The spirodihydroisocoumarins (185) and (186) show promise in preventing the release of histamine from mast cells, and a number of variations on these structures have been made in order to study the relationship between structure and activity.  

Coumarins. - There is interest in the synthesis of 3-substituted coumarins cyclization of substituted salicylaldehydes with cyanoacetamide, followed by treatment with phosphoryl chloride in DMF, has given coumarin-3-carbonitriles. High yields of 3-phenylcoumarins were obtained when ortho-hydroxy-aldehydes or -ketones were treated with phenylacetyl chloride-potassium carbonate.When cyclohexane-1,3-diones (187) were condensed with triethyl orthoformate and either urea and thiourea and the initial product (188) was allowed to condense with nitriles, the 3-carboxamide (189) was obtained in good yield.The antibacterial activity of some sulphones has prompted the synthesis of 3-arylsulphonyl-coumarins by oxidation of sulphides.  

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Chloroisocoumarin reacted by addition with chlorine to give a high yield of 3,3,4-trichloro-3,4-dihydroisocoumarin (73JOU2160). 

The locked substrate may bind to the enzyme in a different way from an unrestricted substrate. If the phenyl portion of D-24 binds in the aromatic subsite, then its acylamido group cannot bind at the usual acylamido subsite (82). Cohen justifies this proposal from the fact that some cyclized compounds lacking the acylamido group, e.g., Dmethyl-3,4-dihydroisocoumarin-3-carboxy-late, 39, are good substrates for the enzyme. 

KUROSAKI, F KIZAWA, Y., NISHI, A., Derailment product in NADPH-dependent synthesis of a dihydroisocoumarin 6-hydroxymellein by elicitor-treated carrot cell extracts, Eur. J. Biochem., 1989,185, 85-89. 

DC037 Sarkar, S. K., and Phan Chon Ton. Biosynthesis of 6-hdroxy-8-methoxy-3-methyl-3,4-dihydroisocoumarin and 5-hydroxy-7-methoxy-2-methylchromone in carrot root tissues... 

Good stereoselectivity is observed in the synthesis of 3,4-dihydroisocoumarins from the oxazoline 49 and the protected leucinal 50 (Scheme 29). Further reaction with an azetidinone introduces a dipeptide unit at C-3 <99JCS(P1)1083>. 

Catalytic reduction of isocoumarins leads to 3,4-dihydroisocoumarins but LAH opens the pyranone ring to form phenethyl alcohols. 

N-Methylbenzamides have been used as isocoumarin precursors (71T6171). Directed ortho metallation followed by reaction with ethylene oxide gave the dihydroisocoumarin via the alcohol (Scheme 184). 

Oxidation of dihydroisocoumarins is conveniently achieved through bromination with NBS followed by dehydrohalogenation with triethylamine (62JOC4337, 71T6171). Since the oxidation of isochromans to isochromanones proceeds readily using chromium trioxide, this method effectively constitutes a synthesis of isocoumarins from isochromans. 

The three isomers which are discussed in this section are isochroman-l-one or 3,4-dihydroisocoumarin (617), isochroman-3-one (618) and isochroman-4-one (619). None of them enjoy an extensive chemistry although a small number of natural products contain an isochromanone nucleus. 

Krohn K, Bahramsari R, Florke U, Ludewig K, Kliche-Spory C, Michel A, Aust H-J, Draeger S, Schulz B, Antus S (1997) Dihydroisocoumarins from Fungi Isolation, Structure Elucidation, Circular Dichroism and Biological Activity. Phytochemistry 45 313... 

Substituted 3,4-dihydroisocoumarins (61) have been prepared enantioselectively by two diastereoselective processes addition of aldehydes (RCHO) to laterally lithi-ated chiral 2-(0-tolyl)oxazolines, followed by lactonization.254... 

Hydroxyisocoumarins are accessible from 3-hydroxybenzyl ketones using directed lithiation as the key step (95G 111) and isocoumarins have been prepared from 2-iodobenzoic acid and alkynes through a Pd-mediated annulation (95JOC3270, 3711). The cyclisation of tertiary alcohols derived from the reaction of o-cyanobenzyllithium with aldehydes and ketones yields 3,4-dihydroisocoumarins (95S1102). 

R)-l-[4-Methoxy-3-[(triisopropylsilyl)oxyphenyl)-2-[3-(methoxymethoxy)phenyl]ethanol 1123 undergoes selective hydrogen metal exchange followed by carbonylation to form the lithiated intermediate 1124, which undergoes cyclization in acid conditions to provide the dihydroisocoumarin 1125, a key intermediate during an enantioselective synthesis of phyllodulcin (Scheme 279) <1996JOC5371>. 

Radical reaction of 2-iodobenzoic acid with benzene affords the cyclohexadiene intermediate 1126 as a mixture of regiosomers, which cyclize in the presence of phenylselenium bromide to afford the dihydroisocoumarin 1127 in good yield (Scheme 280) <2002T3319>. 

Tellurides 1129 prepared from a-bromo-o-toluylesters 1128 undergo lithium-tellurium exchange to give the corresponding benzylic anions 1130, which react with aldehydes or ketones to afford dihydroisocoumarins in high yield (Scheme 281) <1997SL1047>. 

The (E)- and (Z)-regioisomers of 6-ethylidenedioxadisilacyclohexane 1134 undergo palladium catalyzed-cross coupling with methyl-2-iodobenzoate to furnish dihydroisocoumarins with excellent (E)- or (Z)- selectivity (Scheme 282) <20030L1119>. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

During the synthesis of the isocoumarin moiety of heliquinomycin, diethyl bromomalonate and phthalaldehydic acid 1137 condense to form the dihydroisocoumarin 1138 in excellent yield (Equation 442) <2000TL29>. 

Lateral lithiation of (d )-4-isopropyl-2-(o-tolyl)oxazoline and reaction with aldehydes provides the addition products 1148 with moderate to good diastereoselectivity. The addition of TMEDA is vital for any diastereoselectivity to be observed. The major (,S,A)-products lactonize faster under acidic conditions providing dihydroisocoumarins 1149 in up to ee 97% (Scheme 286, Table 53) <2005T3289>. Similarly, the addition of laterally metallated o-toluates to chiral aldehydes provides a key dihydroisocoumarin during a total synthesis of AI-77-B <1999J(P1)1083>. 

Table 53 Formation of addition products 1148 and their conversion to dihydroisocoumarins 1149 (Scheme 286)...

The nitroanthranilic acid 1150 reacts with allyl bromide in the presence of v -butyl nitrite to furnish the dihydroisocoumarin 1151 in poor yield (Equation 443) <2003JOC1911>. 

Dihydroisocoumarin is accessible from a microwave promoted palladium-catalyzed reaction of the aryl bromide 1153 with Mo(CO)6 as a source of carbon monoxide (Equation 445) <2004TL4635>. 

A variety of oxidative conditions can be used to effect the transformation of isochromans to dihydroisocoumarins (Equation 447). 

Treatment of 3,4-dihydroisocoumarins with 2-methylthiophenoxide results in cleavage of the pyran ring and formation of 2-thioethylbenzoic acid derivatives. Sequential cyclization, bromination and dehydrobromination afford the isothiocoumarins via the 3,4-dihydroisothiocoumarin (Scheme 198) <2000T6763>. 

Three New Dihydroisocoumarins from the Greek Endemic Species Scorzonera... 

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