Substituted Phthalides

Phthalic anhydride condenses with the aniline derivative in the presence of zinc or aluminum chlorides to yield the intermediate benzoyl-benzoic acid, which subsequently reacts with l,3-bis-V,V-dimethylaniline in acetic anhydride to yield the phthalide. The above compound gives a violet-gray image when applied to a clay developer. Clearly this synthesis is also very flexible and variations in shades of color formers have been obtained by varying the aniline components and also by using phthalic anhydrides substituted, for example, by nitro groups or chlorine atoms. Such products have excellent properties as color formers and have been used commercially. Furthermore, this synthetic route is of great importance for the preparation of heterocyclic substituted phthalides, as will be seen later. 

When the partial structures corresponding to the substituted phthalides, 88 and 89, are incorporated into the alkaloids, 81-86 there was relatively little change in chemical shifts from those of the models except for the expected changes at the benzylic carbon atoms (C-T). 

Substituted phthalides can be prepared in a [2+2+2] cycloaddition of two molecules of methyl propiolate with propargyl alcohol. This cyclotrimerization, which is catalyzed by a cobalt(ll)-DPPE complex in the presence of catalytic amounts of zinc, affords the reaction products in acceptable to good yields (Equation 150) <2005CC4955>. 

Benzofuran 213 has been patented for use as a UV absorber in cosmetics and as a UV stabilizer in plastics <1997USP5665334>. A wide range of 3-substituted phthalides, for example, 214, and 3-alkylidene phthalides 215, are used in dermatological formulations to protect dibenzoylmethane compounds in the compositions from UV radiation <2003FRP2827509>. 

The enantioselective synthesis of phthalide 227 (the (3 )-isomer), and other substituted phthalides, and the determination of their absolute configuration has been reported <2005CH218>. In a different approach to the same compounds, 2-alkylbenzoic acids were fed to microorganisms known to affect asymmetric hydroxylation. Lactonization of the resulting alcohols yielded the phthalides, used as scents in cosmetics and soaps <1997JPP10243794>. There is sufficient interest in these optically pure compounds for a chiral gas chromatography (GC) stationary phase to have been developed to quantify stereoisomeric mixtures. A silylated /3-CD was employed... 

The principle enunciated above may be extended to obtain other polysubstituted phthalides. The substituents are chosen with due consideration of the trends in orientation in aromatic lithiation reactions. A list of substituted phthalides, synthesised by lithiation reaction, has recently been published... 

A novel synthesis of antofine 22, an indolizidine alkaloid, and cryptopleurine 23, a quinolizidine alkaloid, involves lithiation of trimethoxy-fihenanthrene-carbox mide. The key step in both these cases is the generation of substituted phthalides 92)... 

A general route to l,3-diaryl-benzo[c]thiophenes starts with the synthesis of an aryl-substituted phthalide, reaction of this with an aryl (heteroaryl) Grignard reagent, then thionation using Lawesson s reagent. ... 

In this review, the natural phthalides of plant origin are classified into four types based on chemical structure (Fig. (2-6)) 1) 3-substituted phthalides 2) non-3-substituted phthalides 3) phthalide dimers and 4) phthalide isoquinolines. The 3-substituted phthalide derivatives are further classified into two subtypes, namely non-alkaloid phthalides (Fig. (2 and alkaloid phthalides (Fig. (3 . Phthalide alkaloids without the isoquinoline structure are always 3-substituted and are accordingly subclassified as the... 

The details of the classifications and chemical structures of four types of natural phthalides are illustrated in Figs. (2-6). Most of the isolated natural phthalides belong to the 3-substituted phthalide type, which accounts for about 61% of the total known naturally occurring phthalides, and of these, non-alkaloid phthalides constitute the most important subtype due not only to their abundance in nature (75 compounds identified) but also their extensively reported pharmacological activities. The pharmacological activities of individual phthalides are discussed in the following Biological Activity Section. 

Naito et al. investigated reduction of blood viscosity by nine phthalides [301]. Among the compounds tested, two phthalide dimers tokinolide B (118) and senkyunolide P (116), and three 3-substituted phthalides butylphthalide (30), cnidilide (41) and senkyunolide A (58), significantly reduced blood viscosity in Wistar rats. The blood viscosity reduction was 7.3%, 9.4%, 9.4%, 18.5% and 12.8% for phthalides 30, 41, 58, 115 and 117, respectively. The other four phthalides 20, 47, 111 and 113 did not significantly affect blood viscosity. 

Phthalide derivatives are of major importance in the dye industry, particularly in the area of recording material color formers. Pressure-sensitive carbonless copy paper and thermal recording paper are typical applications. Five principal structural classes have been developed extensively the xanthene dyes (fluorans (208)), 3,3-diarylphthalides (209), spirofluorenes (210), 3,3-bis(di-arylethylene)phthalides (211), and 3-substituted phthalides <84Mi 208-03>. Some of these structures are common to many familiar acid/base indicators, dyes, biological stains, or laser dyes such as fluorescein (212) and phenolphthalein (213) ,... 

Aromatic Alcohols Aromatic Amino Acids Aromatic Amino Alcohols Aromatic Thiols Aromatic Amines Aromatic Sulfoxides Mandelic Acid Analogs Aryl-Substitute Phthalides Aryl-Substituted Lactams Aryl-Substituted Succinimides Aryl-Substituted Hydantoins a-Hydroxy-a-Aryl Phosphonates Aryl Propionic Acids Phenoxy benzy 1 amine s (P-Blockers)... 

Chiral 3-substituted phthalides are central structures in a number of biologically active compounds. The synthesis of chiral phthalides has been achieved by Witulski and Zimmerman, starting with enantiopure substituted propargylic alcohols 409 (Scheme 2-38). The chiral ester-linked diyne 410 was cyclotrimerized with acetylene by using RhCl(PPh3)3 as the catalyst to afford enantiopure phthalides 411 in good yields. 

During the end of the 20th century, Shim and co-workers developed a series of palladium-catalyzed carbonylative transformations of 2-bromo benzaldehydes with different nucleophiles. With the same catalyst system, 3-substituted phthalides were produced ingood5delds (Scheme 2.161). ... 

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

In 2010, Hu and coworkers [14] reported an interesting innovation regarding the rhodium-catalyzed aryl addition to aldehydes. Using 2-formylbenzoates as substrates and arylboronic acids, 3-substituted phthalides were efficiently obtained with rhodium-spinol-based phosphites... 

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