3- phthalide reduction

Treatment with PCI5 gives phthalyl chloride reduction with zinc and ethanoic acid or NaOH gives phthalide. Fusion with urea gives phthalimide. 

One of the more complex local anthetics in fact comprises a basic ether of a bicyclic heterocyclic molecule. Condensation of 1-nitropentane with acid aldehyde, 79, affords the phthalide, 81, no doubt via the hydroxy acid, 80. Reduction of the nitro group... 

Preparation of the key intermediate to this series begins by reduction of the methylene phthalide, 12a, with hydriodic acid and red phosphorus. Cyclization of the acid (26) thus obtained affords the tricyclic ketone, 27. Reaction with the Grignard reagent from 3-dimethylamino-2-methylpropyl chloride affords the... 

Phthalide (16, 7r) In a 90 per cent yield by electrolytic reduction of ammonium... 

Chapter 4 is concerned with a technically important group of leuco compounds which like the spiropyrans are not formed by reduction of the parent dye, but by formation of a spiro structure from the dye in such a way that the newly created sp3 center destroys the conjugation, and hence, the color of the chromophore. These are the phthalides (spirolactones) and the position of equilibrium is determined by pH rather than a redox process. Such materials are used mainly as color formers in pressure-sensitive... 

Kondo et al. (182,183) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54) with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with m-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2 -acetylpapaveraldine (129) (Section III,B,1). 

The first examples of a homogeneous reduction of this type were reported in 1971. Cobalt carbonyl was found to reduce anhydrides such as acetic anhydride, succinic anhydride and propionic anhydride to mixtures of aldehydes and acids. However, scant experimental details were recorded [94]. In 1975, Lyons reported that [Ru(PPh3)3Cl2] catalyzes the reduction of succinic and phthalic anhydrides to the lactones y-bulyrolaclone and phthalide, respectively [95], The proposed reaction sequence for phthalic anhydride is shown in Scheme 15.15. Conversion of phthalic anhydride was complete in 21 h at 90 °C, but yielded an equal mixture of the lactone, phthalide (TON = 100 TOF 5) and o-phthalic acid, which is presumably formed by hydrolysis of the anhydride by water during lactoniza-tion. Neither acid or lactone were further hydrogenated to any extent using this catalyst system, under these conditions. 

Some of these processes have been developed for technical conversions and have been summarized in Ref. [228, 229]. The anodic technical production of t-butylbenzaldehyde has been coupled with the cathodic reduction of phthahc anhydride to phthalide in a paired electrosynthesis in a capillary gap cell [230]. Indirect oxidations with Mn +/Mn + or as mediators... 

Phenylacetyl chloride and hydrocin-namoyl chloride are reduced at mercury to form both acyl radicals and acyl anions as intermediates [76]. From electrolyses of phenylacetyl chloride, the products include 1,4-diphenyl-2-butene-2,3-diol diphenylac-etate, phenylacetaldehyde, toluene, 1,3-diphenylacetone, and l,4-diphenyl-2,3-butanediol, and analogous species arise from the reduction of hydrocinnamoyl chloride. Reduction of phthaloyl dichloride is a more complicated system [77] the electrolysis products are phthalide, biph-thalyl, and 3-chlorophthalide, but the latter compound undergoes further reduction to give phthalide, biphthalyl, and dihydrobi-phthalide. 

Results of reductions of cyclic anhydrides to lactones with sodium amalgam or with zinc are inferior to those achieved by complex hydrides [1020]. However, 95.6% yield of phthalide was obtained by reduction of phthalimide with zinc in sodium hydroxide [1021]. 

A second way of synthesizing it is from 2 -carboxy-4-chlorobenzophenone (21.3.21), which during reduction with zinc in acetic acid transforms into 3-(4 -chlorophenyl)phthalide (21.3.27). Sulfonylchlorination of this gives the corresponding snl-fonylchloride (21.3.28), which upon reaction with phosphorous pentachloride is chlorinated into 3-(4 -chlorophenyl-3 -chlorosulfo)-3-chlorophtalide (21.3.25). This is reacted with aqueous ammonia in the aforementioned manner, and it rearranges into chlorothalidone (21.3.26) [50]. 

In the case of flexible molecules all chiral conformers contribute to the observed CD spectrum. This usually leads to substantial reduction of the magnitude of the exciton Cotton effect. Nevertheless, if the conformation of the main contributor is established independently (e.g.. by molecular mechanics or NMR spectroscopy), its absolute configuration can be deduced from the exciton Cotton effect. Thus, for 3-(l-naphthalenyl)phthalide 5, the preferred conformation is 5 a. The negative couplet is in accordance with the left-handed screw between the phthalide 1 Ld and the naphthalene lBb transition dipole moment vectors, when the absolute configuration is R121. 

Deuterated isobenzofurans are also available. Reduction of phthalides with complex metal deuterides yields hydroxyphthalans, which can be converted to the corresponding isobenzofurans (84T4597 85CJC735, 85JOC5902). 

Alternatively (V) may be prepared by reduction of 2-thenylidene-phthalide obtained from 2-thi-... 

On the other hand, the reduction of phthalic anhydride to phthalide is simpler. The key step in this synthesis is the electrochemical reduction of ammonium phthalamates... 

Electrochemical reduction of phthaloyl dichloride (73) at a carbon or mercury cathode in acetonitrile containing TEAP led to a complex array of products. Six cathodic waves observed in the CV for the reduction of phthaloyl dichloride arise from the reductions of different electrolysis products, as well as from hydrolytically formed phthalic anhydride (74),. caused by the presence of residual water in the solvent/supporting electrolyte (equation 45). From controlled potential electrolyses of phthaloyl dichloride, a variety of products including 3-chlorophthalide (75), phthalide (76), biphthalyl (77) and dihydrobiph-thalide (78) can be obtained69,70. Reduction of glutaryl dichloride (79) at a mercury cathode in acetonitrile containing 0.1M TEAP results in the formation of 5-chlorovalerolactone (80) and valerolactone (81) as minor products, and a polymeric material (equation 46)68. 

With some dibasic acids, the yields of the corresponding dialdehydes were unsatisfactory. For example, the reduction of succinyl dichloride267 and phthaloyl dichlo-ride268,269 gave, respectively, y-butyrolactone and phthalide as major products. With m- and / -phthalic dichlorides, however, the corresponding dialdehydes were obtained in 83 and 81% yields, respectively. 

The present procedure is based upon the method of Reissert. Phthalide has also been prepared by reduction of phthalic anhydride, and by bromination of o-toluic acid followed by hydrolysis. ... 

In general, the dissolving metal or electrochemical reductions of acyl halides or acyclic anhydrides are not useful for the preparation of primary alcohols. Such reductions invariably provide acyloin esters, ene-diolate diesters or related species. Cyclic anhydrides may be reduced to give lactones. For example, the reduction of phthalic anhydride at a mercury cathode has been used in the synthesis of phthalide (90%). In general, however, such reduction are not widely employed in synthesis. 

Interestingly, electrochemical reductions of alkylidenephthalides (14), which might conceivably give radicals isomeric in the heterocyclic moiety with 13, resulted either in the addition of two electrons or in ring scission, although phthalide radicals such as 15, which is not heteroaromatic, may be prepared. ... 

Upon being electrolyzed at carbon or mercury in MeCN containing TEAP, phthal-oyl dichloride [224] is converted into 3-chlorophthalide, phthalide, and biphthalyl. However, this system is complicated by the fact that 3-chlorophthalide can itself be reduced (at a potential only slightly more negative than that needed for reduction of phthaloyl dichloride) to afford phthalide, biphthalyl, and dihydrobiphthalide. 

Presumably for similar reasons, cathodic reduction of diethyl terephthalate and diethyl furan- and thiophene-2,5-dicarboxylate [51-53] in a buffered ethanolic solution of pH 4.2 affords the aldehyde ester under controlled potential electrolysis (CPE) conditions (in the interval between —1.50 and —1.65 V). Diethyloxalate [77] is reduced at a mercury cathode in acidic medium to give the ethyl hemiacetal of ethyl glyoxylate (38-50% yield). In contrast, diethyl and monoethyl phthalate gave phthalide under similar conditions [21,78]. 

Controlled potential electrolyses of phthalic and pyromellitic anhydrides at the potential of the first wave gave highly colored, oxygen-sensitive solutions, which later were shown to give well-resolved esr spectra of the corresponding radical ions [55]. Phthalic anhydride has been reduced to phthalide on a preparative scale [109], but the reaction conditions employed (ethanol-water-ammonium carbonate) indicate that monoethyl phthalate must have been the actual substrate. An interesting reduction of 3,6-diphenylphthalic anhydride in the presence of trimethylsilyl chloride gives two types of dimeric species [110] ... 

Shihunine, C12H13O2N (mp 79° picrate, mp 163°-164°) (I) was obtained from Dendrobium lohohense Tang et Wang (4) its phthalide-pyrrolidine structure was established by reduction and decarboxylation to 1-methyl-2-phenylpyrrolidine, by oxidation to phthalic acid, and with the help of IR-spectral data. 

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