Phthalide hydrolysis

Phthalaldehyde Acid (16, 68) By chlorination of phthalide, followe by hydrolysis with boiling water and crystallization from benzene. Austin and Bousquet, U. S. pat. 2,047,946 [C. A. 30,6on (rg36)]. 

The phthalide 25, obtainable by condensation of 4,4 -bisdimethyl-aminobenzophenone-2-carboxylic acid with 3-dimethylaminoacetanilide and subsequent hydrolysis, was diazotized in sulfuric acid and the resultant diazonium salt treated with copper powder to yield 26. However, better yields are reportedly obtained by carrying out ring closure of the diazonium salt in phosphoric acid.103 A further synthetic route has also been described in which phthalides undergo intramolecular cyclization in the presence of aluminum chloride and urea.104,105 Thus, Crystal Violet lactone (2) has been directly converted into phthalide 26.106... 

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. 

The first case presented is that of 2-[(acyloxy)methyl]benzamides of the general structure 8.187 (Fig. 8.22) [239]. Two model compounds were examined (NRR = MeNH or morpholino, R" = Me) they reacted, as expected, to give the secondary amine and phthalide in quantitative yields. At pH 9.3 and 60°, chemical hydrolysis was 2-10 times faster than the subsequent cyclization-elimination. At pH 7.4 and 37°, the chemical hydrolysis was slow (f1/2 ca. 400 h), while hydrolysis in human plasma was fast (tm 3.2 and 1.4 h, respectively). 

In contrast to the above benzonitriles, 2-methylbenzonitrile (11.88) did undergo cyano hydrolysis, but by a very indirect route involving cytochrome P450 catalyzed hydroxylation of the 2-Me group to form 2-(hydroxyme-thyl)benzonitrile (11.89), followed by intramolecular nucleophilic addition. The cyclization reaction yielded an unstable imino ether derivative (11.90), which hydrolyzes to phthalide (11.91). The conversion of 2-(hydroxyme-thyl)benzonitrile to phthalide followed first-order kinetics with a f1/2 value of 2.8 h at pH 7.4 and 37° [124],... 

Reaction of the carbonium ion with water could be reduced if overlap occurred with the carboxylate anion of aspartic acid-52 either during or after the glycoside-cleavage step. Since the carboxylate anion would be held adjacent to the carbonium ion in the active site, equilibrium should be far to the side of the acylal. Reaction of acylal with H2O would then very probably be ratedetermining in the forward direction. Evidence has been obtained that the solvent is directly involved in the hydrolysis of the cyclic acylal 2-(p-nitrophenoxy)phthalide where steric factors are similar... 

Hydralazine Hydralazine, 1-hydrazinonaphthalazine (22.6.4), is synthesized by the oxidative chlorination of phthalide with simultaneous hydrolysis of product, which results in hydroxyphthalide (22.6.1), which upon reaction with hydrazine changes to phthalazone (22.6.2). This undergoes a reaction with phosphorous oxychloride, forming 1-chloroph-thalazine (22.6.3), in which substitution of the chlorine atom with hydrazine gives the desired hydralazine (22.6.4) [14-16]. 

The distilled product is pure enough for use in the subsequent hydrolysis, but it may be purified by recrystallization from 100 cc. of carbon tetrachloride. Upon cooling, 100 g. of pure 2-bromo-phthalide melting at 75° is obtained. An additional 30 to 40 g. of slightly yellow material is obtained by concentrating the mother liquor-. 

Homophthalic acid has been prepared from naphthalene via phthalonic acid 1 from hydrindone by nitrosation, hydrolysis, and hydrogen peroxide oxidation 2 from hydrindene by oxidation with chromic and sulfuric acids 3 and from o-toluic acid by bromination of the acid chloride followed by treatment with alcohol and sodium cyanide and hydrolysis with 50 per cent sulfuric acid.4 Since phthalide has become commercially available, the preparation outlined above, essentially that described by Wis-licenus 5 fifty-six years ago, is by far the simplest and most economical. 

Pseudoesters, for example, 221, in which the alcohol portion is a fragrance (such as geraniol), have been developed for the slow release of scent. Alkaline hydrolysis of compound 221 requires time so that the rate at which scent is released is prolonged over that of simple evaporation <2001J(P2)438>. A similar approach involves the preparation of acyclic esters 222 and 223 from phthalide 224 and phthalic anhydride 225, respectively. In this case, the slow release of fragrance is the result of an intramolecular transesterification processes <2003USP20030148901>. 

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. ... 

When pure 3-bromophthalide is allowed to stand, its melting point is depressed, owing apparently to some decomposition. It may, therefore, be desirable to prepare the compound in smaller quantities than specified here. A sample of 3-bromophthalide, prepared by using 20 g. of phthalide and 26.6 g. of N-bromosuccinimide, amounted to 29.8 g. (93.4%) of crude product. Hydrolysis of the crude material gave phthalaldehydic acid, m.p. 96-98°. 

Hydrolysis of in acidic medium gave the phthalide 1. In order to assess the absolute configuration of the lactones, particularly those with a dialkyl substitution pattern, which are not known in the literature, an x-ray study was performed using the -bromophenyl acetophenone, (R = Me, R -Bromophenyl, configuration). Pure enantiomers of were obtained by MPLC-assisted resolutions of followed by hydrolysis with acid. 

Figure 9. Preparation of phthalide, 25, by treatment of o-benzoyloxazoline, 24, with Grignard reagent followed by hydrolysis.

Fig. 7.P23. (a) pH-Rate profile for hydrolysis of 2-carboxy (solid circles) and 4-carboxy (open circles) benzylidene acetals of rc n5 -l,2-cyclohexanediol. (b) pH-Rate profile for 3-( ra 5 -2-hydroxycyclohexyloxy)phthalide, an intermediate isolated from the 2-carboxy derivative. Reproduced from J. Am. Chem. Soc., 118, 12956 (1996), by permission of the American Chemical Society.

Reductive hydrolysis of phthalides is achieved in good yield by catalytic hydrogenation on palladium-charcoal in presence of sodium hydroxide sol-... 

Dimethyibenz a anthracene synthesis. The key step in a new synthesis of this system is the reaction of 1 with methyl 2-naphthyl ketone (2) to give, after acid hydrolysis, the phthalide 3 in 62% yield. This product is reduced to 4 with zinc in alkali. Remaining steps involve introduction of the 12-methyl group and cyclization. Similarly, methyl 1-naphthyl ketone affords lO-methoxy-7,12-dimethylbenz[a]anthracene in 277o overall yield. 

A route for the synthesis of phthalide-isoquinoline alkaloids from Reissert compounds has been reported. The Reissert compound (111) reacts with methyl opianate in the presence of sodium hydride to give the isoquinoline (112), hydrolysis of which yields dehydrohydrastine (113) this can be reduced in... 

Several studies of the polar effect of various groups on the velocity of ring opening of phthalide and its derivatives showed considerable lowering of the hydrolysis rates by NHg groups when... 

Table 20. Rate coefficients of basic hydrolysis of substituted phthalides . ...

Finally, the Hammett equation has been applied in a few instances to heterocycles of the indole-benzofuran type. The double p method of q. (3) was first designed for this type of system and was here applied. When this approach was originally proposed, the only truly heterocyclic system to which it was applied was the substituted phthalids 14, and pertinent data on the hydrolysis of these compounds are included in Table IX. 

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