Isocoumarins, formation

Isocoumarin formation from an indanone has been effected through involvement of an enol trifluoroacetate followed by ozonolysis. 

A final example in this section is isoquinolone formation via 6-endo-dig cycloisomerization (Scheme 19.77). Sashida and Kawamukai reported the palladium-catalyzed cyclization of 2-ethynylbenzamides 281 giving rise to isoquinolones 282 in good yields, similar to the aforementioned isocoumarin formation [143]. Ruthenium complexes are also useful for this transformation [146]. Recently, a 6-endo-dig cyclization/oxidative Heck coupling cascade of283 was also reported [147]. 

Figure 1.36 (a) Ir-catalyzed isocoumarin formation [86] and (b) Rh-catalyzed phosphaiso-coumarin formation [87]. 

Aryl- or alkenylpalladium comple.xcs can be generated in situ by the trans-metallation of the aryl- or alkenylmercury compounds 386 or 389 with Pd(Il) (see Section 6). These species react with 1,3-cydohexadiene via the formation of the TT-allylpalladium intermediate 387, which is attacked intramolecularlv by the amide or carboxylate group, and the 1,2-difunctionalization takes place to give 388 and 390[322]. Similarly, the ort/trt-thallation of benzoic acid followed by transmetallation with Pd(II) forms the arylpalladium complex, which reacts with butadiene to afford the isocoumarin 391, achieving the 1,2-difunctionalization of butadiene[323]. 

Irradiation of mixtures of 2-methylbenzoyl cyanide and benzoyl cyanide results in the exclusive formation of the mixed cycloadduct, from which elimination of HCN leads to isocoumarins <96CJC221>. 

The choice of catalyst controls the intramolecular cyclisation of 2-(l-alkynyl)benzoic acids, with AgNCh effecting efficient formation of 3-substituted isocoumarins, but Ag powder favouring a 5-exo-dig-cyclisation to the phthalide (Scheme 45) <00T2533>. 

The cumulation reactions, which start from carboxylic acids and esters usually lead to the formation of pyrone derivatives. Methyl (Z)-3-iodoacrylate and 3-hexyne gave, for example, 5,6-diethyl-2-pyrone in acceptable yield (4.38.). Inclusion of the acrylate into a six membered ring starting from ethyl 2-bromocyclohexen-l-carboxylate, led to a condensed ring system, giving a partially reduced isocoumarin derivative.50... 

The coupling of 2-iodobenzoic acid and phenylacetylene under Sonogashira coupling conditions was found to give a mixture of an isocoumarin derivative and a phthalide (4.40.), The proper choice of the catalyst system led to the preferential formation of the latter compound.53 The process might also be diverted towards the formation of the isocoumarin derivative by isolation of the intermediate o-cthynyl-benzoic acid and its subjection to carefully selected cyclization conditions54... 

The reduction of isocoumarin with LAH results in ring opening and the formation of 2-(2 -hydroxymethylphenyl)acetaldehyde (184). Cyclization to the isochromene occurs on boiling in acetic anhydride (Scheme 33) (58CB2636, 65CB3279). The isochromene (186) is obtained directly from the reduction of the dihydronaphthocoumarin (185 equation 5) (56JCS4535). 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

Carboxybenzyl aryl ketones are formed together with the isocoumarin when homophthalic anhydride (isochroman-l,3-dione) is used to acylate aromatic molecules under Friedel-Crafts conditions (51JOC1064) and the 7-methoxy derivative behaves in a similar fashion (66JIC615). Some care in the choice of Lewis acid is necessary in view of the formation of the tropone derivative (504) in the acylation of hydroquinone (Scheme 181) (55JCS2244). 

In a related manner, sodium 2-bromobenzoates have been converted into 2-allylbenzoic acids. A palladium-catalyzed cyclization involving nucleophilic attack of the carboxylate on the palladium-complexed alkene yielded an isocoumarin. However, in situ catalytic hydrogenation results in the formation of an isochroman-l-one. 

The study of this cycloaddition and its mechanism is complicated by the formation in small yield of additional photoproducts. Irradiation of phenanthraquinone (308) in, for example, 2-methylpropene affords the oxetane (309), arising by 1,2-cycloaddition of the alkene to the carbonyl, in addition to the expected 1,4-dioxene (310).334 Oxetanes are the principal products of photoaddition of phenanthraquinone to benzofuran, furano[3,2-y]coumarin, and isocoumarin.329 A further product has the structure (311), and is undoubtedly the... 

Iridium(m) hydrides catalyze a 6-endo-dig cyclization of ortho-alkynyl benzoic acids to afford isocoumarins (Equation 323) <2005OL5437>. Likewise, the intramolecular cyclization of ortho-alkynyl benzoic acids can be catalyzed by palladium(ll) and silver(ll) to afford isocoumarins as the major product along with formation of the 5-endo-dig cyclization product (Equation 323) <1999S1145, 2000T2533>. 

The isocoumarin (128) gives a weak molecular ion peak at m/e 280. A prominent peak at m/e 262 corresponds to an [M-H20]t fragment. Its formation is rationalized in Scheme 12 (65BSF3025). 

A final group of covalent small-molecule inhibitors of proteases are mechanism-based inhibitors. These inhibitors are enzyme-activated irreversible inhibitors, and they involve a two-hif mechanism that completely inhibits the protease. Some isocoumarins and -lactam derivatives have been shown to be mechanistic inhibitors of serine proteases. A classic example is the inhibition of elastase by several cephalosporin derivatives developed at Merck (Fig. 8). The catalytic serine attacks and opens the -lactam ring of the cephalosporin, which through various isomerization steps, allows for a Michael addition to the active site histidine and the formation of a stable enzyme-inhibitor complex (34). These mechanism-based inhibitors require an initial acylation event to take place before the irreversible inhibitory event. In this way, these small molecules have an analogous mechanism of inhibition to the naturally occurring serpins and a-2-macroglobin, which also act as suicide substrates. 

An explanation of these results and determination of the mechanism(s) of inhibition by the isocoumarins required a complex series of kinetic analyses and X-ray crystallographic studies [186]. These studies showed that the mechanistic pathway (see Figure 2.8) was pH-dependent [187] and that different forms of the inhibited enzymes, illustrated by (8a), (8c) and (8d), could be isolated. Ring-opening results in formation of an intermediate acyl-enzyme (8a), which, in some cases, can be isolated but which can also eliminate chloride to produce a reactive quinone imine methide (8b). This reactive intermediate is either trapped by solute or solvent, to produce a second acyl-enzyme (8c) [188] or alkylated by His-57 to produce an irreversibly inactivated enzyme (8d) [189]. The ratio between (8c) and (8d) has been shown to vary widely. 

The mechanism of inhibition by benzoxazinones Figure 2.9) is believed to be similar [196, 197] to that of the alternate-substrate isocoumarins, and formation of a covalent acyl-enzyme complex with PPE has been confirmed by X-ray crystallographic studies [198], However, when is a hydrogen atom, deacylation of the acyl-enzyme via intramolecular ring closure can either reform the starting benzoxazinone (O attack) or lead to an isomeric quinazolinedione (N attack). It was shown for HLE and a-chymotrypsin that formation of the quinazolindione occurs faster than normal hydrolysis to the anthranilic acid. 

Citrinin (4.41) is a mycotoxin that is formed in quite large amounts by Penicillium citrinum, where it co-occurs with related metabolites such as the isocoumarins 4.42 and 4.43, the phenols 4.44 and 4.45, and decarboxycitrinin. Some dimers have also been isolated. Citrinin was first isolated by Raistrick in 1931 and its structure was proposed by Robertson in 1948. Although it exists as a quinone-methide in the crystalline state, it forms a hydrate rather rapidly. Much of the chemistry of citrinin can be understood in terms of the ready formation of this hydrate. The lactol of citrinin hydrate is readily oxidized to a... 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

CA can prevent C2H4 induced formation of bitter isocoumarins in carrots (94) and can aid in removal of tanins and resulting astringency from persimmons (95.961. 

Substitution reactions. Alkyl 2-alkynylbenzoates are activated by the Au(I) salt toward formation of isocoumarin, thereby weakening the O—C(aik) bond of the esters. Attack of nucleophiles results in the cleavage of the esters.Particularly noteworthy is the formation of tetralins by way of an intramolecular reaction involving an aromatic ring (a C-nucleophile). ... 

The formation of oxetanes by photochemical (2 + 2)-cycloaddition of carbonyl compounds, such as aldehydes, ketones, and quinones, with carbon-carbon double bonds has been reported for various heterocyclic compounds. Maleic anhydride,142 isocoumarin (and its derivatives),143,144 benzol 61 thiophene 1,1-dioxide,144 l,3-dihydroimidazol-2-ones,131,132... 

Coumarins (and isocoumarins) are quantitatively hydrolysed to give yellow solutions of the salts of the corresponding cis cinnamic acids (coumarinic acids) which cannot be isolated since acidification brings about immediate relactonisation prolonged alkali treatment leads to isomerisation and the formation of the trans acid (coumaric acid) salt. 

Evans et al. used the same reaction conditions for ether formation in the synthesis of lonomycin A [8]. The hindered alcohol in a cyclic polyether was efficiently methylated with trimethyloxonium tetrafluoroborate and Proton Sponge (1) (5 equiv. each, 0 °C) to give the desired ether along with 16% recovery of the starting material (Scheme 8.3). In this reaction, other methylation conditions examined were ineffective, and elevated temperature caused the decomposition of the starting polyether. De Brabander et al. reported the selective formation of anisole derivative from phenol using Meerwein s salt and Proton Sponge (1) in combination, without formation of isocoumarin by-products [9,10] (Scheme 8.3). 

Reaction with homophthalic acid. If the reaction of homophthalic acid with POCI3 and DMF is carried out at 0°, the major product is the isochromane-1,3-dione (2). If the reaction is conducted at 100°, the major product is the iso-quinolone (3). Treatment of (2) with hydrochloric acid in methanol results in formation of the methyl ester of isocoumarin-4-carboxylic acid (4). 

The strategy incorporated methyl isocoumarin (132) as the starting point and then focussed attention to built the naphtholic acid intermediate [104] (135). Its subsequent transformation into the diacid (136) was efficiently formulated with LDA and diethylcarbonate followed by the preparation of isocoumarin (137) (Scheme 26). The annulation of 137 into 138 gave unexpected difficulties. For example, treatment of 137 with ethanolamine in refluxing ethanol formed 139 as a sole product. We believe that mechanistically the formation of 139 occurs through 138. In order to terminate this reaction at this stage of 138, a host of reaction conditions were tried. Fortunately, treatment... 

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