3- phthalide preparation

The synthesis of key synthon 93 was our desired subgoal, but the overall yield was not satisfactory and moreover large quantities of this intermediate would be needed as synthesis progressed. In addition the urge to establish the correct stereostructure to the phthalide prepared earlier had to be satisfied. The new strategy for 93 was formulated to circumvent both the drawbacks pointed out above [87]. 

In this new strategy, methyl 3,5-dihydroxybenzoate was subjected to the Gatterman reaction and the resulting product was transformed by chloro-methylation into 90 (Scheme 17), which was found to be different from the phthalide prepared earlier and therefore suggested that the correct structure for the previously prepared phthalide was 89. 

Alternatively, a ruthenium catalyst could be applied in phthalide preparation. In 2011, Ackermann s group developed a ruthenium-catalyzed cross-dehydrogenative C-H bond alkenylation reaction. The methodology used water as a solvent, benzoic acids and terminal alkenes as substrates good yields of the desired phthalides were isolated (Scheme 2.164). The reaction sequence consisted of cross-dehydrogenative alkenylation and a subsequent intramolecular oxa-Michael reaction. Mechanistic studies provided strong evidence that the oxidative alkenylation proceeds by an irreversible C-H bond metalation via acetate assistance. 

Table 11.2 Diverse phthalides prepared using i-PrMgCl LiCl.

The isocoumarin 151 is prepared by the intramolecular reaction of 2-(2-propenyDbenzoic acid (149) with one equivalent of PdCbjMeCN) . However, the (Z)-phthalide 150 is obtained from the same acid with a catalytic amount of PdjOAc) under 1 atm of Oi in DMSO, alone is remarkably efficient in reoxidizing Pd(0) in DMSO. The isocoumarin 151 is obtained by the reaction of 2-(l-propenyl)benzoic acid (152) under the same conditions[4], 2-Vinylbenzoic acid (153) is also converted into the isocoumarin 154, but not to the five-membered lactone) 167,170],... 

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... 

B) Preparation of o- 2-Thienyl-(2 )-Ethyl]Benzoic Acid 24.0 g of thenylidene-(2)-phthalide, 8.8 g of red pulverized phosphorus, 240 ml of hydrochloric acid (d = 1.7) and 240 ml of glacial acetic acid are heated to boiling under nitrogen and while stirring vigorously. 70 ml toluen are then added and 6.0 g of red phosphorus added in small portions over a period of 1 hour. It is then poured into 3 liters of ice water, stirred with 300 ml of chloroform and the phosphorus removed by filtration. 

Acid Curing. Urea-formaldehyde resins and resol-phenol-formaldehyde resins can be acid-cured by wastes from the production of maleic anhydride [1902]. The waste from the production of maleic anhydride contains up to 50% maleic anhydride, in addition to phthalic anhydride, citraconic anhydride, benzoic acid, o-tolulic acid, and phthalide. The plugging solution is prepared by mixing a urea-formaldehyde resin with a phenol-formaldehyde resin, adding the waste from production of maleic anhydride, and mixing thoroughly. 

Since the introduction of carbonless copying papers, CVL has undoubtedly found the most widespread use as a phthalide color former. Hence, it is appropriate to describe in detail the various approaches to its synthesis, particularly as they are representative of the preparations of various other phthalides described herein. 

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. 

From a commercial viewpoint the most important compounds of this class are the 3,3-(bisindol-3-yl)phthalides. The first synthesis47 involved Route B as described in Scheme 7, in which a second indole derivative condenses with the indolylbenzoylbenzoic acid in acetic anhydride. However, for the preparation of symmetrical derivatives it has been shown61 that a one-pot process, avoiding isolation of the intermediate and use of aluminum chloride, is more convenient. 

Reaction of 2-formylbenzoic acids with 1, 1-bisdialkylaminoethylenes in acetic anhydride has been found91 to yield phthalides such as 21. These color formers are claimed to yield blue to green images, but have also been described92 as intermediates for the preparation of divinyl phthalides by a route identical to that described in Scheme 3, for which they are probably of more significance. (See Section 4.6.2.)... 

Introduction of two diaminophenylethylene moieties at the 3-position of the phthalide ring naturally also produces color formers exhibiting infrared absorption. As in Section 4.6.1, the first report93 encompasses a vast number of compounds such as 22 which was prepared by treating phthalic anhydride with 2 mol of 1,1-bisdimethylaminophenylethylene in acetic anhydride. 

Finally, bisindolylethylenes have also been reacted with tetrahaloph-thalic anhydrides to yield color formers showing absorption in the near infrared.99 The chief advantage over the diarylethylenes is the availability of the starting materials. The bisindolylethylenes may be prepared in situ by reaction of an indole with acetyl chloride and then converted directly to the phthalide without isolation. 

Fusion of the two arylamino groups of a triarylmethane phthalide color former results in the formation of spirofluorene phthalides. Due to the increased planarity of this system, a bathochromic shift results leading also to color formers showing infrared absorption when developed. This was first exemplified in 1983102 by preparation of phthalide 26 as shown in Scheme... 

The reaction of the keto acids (66) with 4-alkoxydiphenylamines (75 R = CH3, C2H5) is widely used to prepare fluoran compounds developing green or black colors. The reaction in concentrated sulfuric acid gives intermediate phthalide compounds (76), which are then treated with base to convert into 2 -anilino-6 -aminofluorans (77) (Eq. 5). 

The original synthesis of 206 was performed by heating pyrroles with phthaiic anhydride and acetic acid in a sealed tube. Oddo and co-workers prepared pyrrolene-phthalides in various ways from pyrrolylmagnes-ium bromides and phthaiic anhydride or 3,3-dichlorophthalide (23G265 25G235 34G289, 34G714). 

The phthalide used by the submitters and by the checkers was a commercial product, obtained from E. I. du Pont de Nemours and Company, Wilmington, Delaware. This product is no longer available. Phthalide may be prepared in 82.5 per cent yields by hydrogenation of phthalic anhydride in benzene at 270° under 3000 lb. pressure in the presence of copper chromite 1 or, in yields of 61-71 per cent, from phthalimide according to the procedure given in Org. Syn. 16, 71 Coll. Vol. 2, 1943, 526. 

By analogy, benzocyclopropene (1) is formed in low yield via biradical cycliza-tion upon irradiation of benzocyclobutenone (79), upon its flash vacuum pyrolysis, or upon pyrolysis of indan-2,3-dione (80). Reaction of phthalide 81 in a RF plasma leads also to However, these latter extrusion methods are of no preparative interest. 

The preparation of lactones via intramolecular catalytic esterification can be carried out by the Tishchenko reaction of dialdehydes. Alkaline earth metal oxides have been shown to be active not only for the intermolecular Tishchenko reaction, but also for the intramolecular Tishchenko lactonization. Thus, these solid catalysts have been applied for the Tishchenko reaction of o-phthalaldehyde to phthalide 182) (Scheme 34). 

T1991). However, the desired lithio derivative 186 was successfully prepared via halogen-metal exchange on the analogous bromide, and subsequent manipulations led to the synthesis of chiral phthalides 187 (83T1991). 

The diazotization of o-diaminobenzene derivatives is the most common synthetic route to benzo-triazoles. Triazolo[6,7- /]phthalide (791) is synthesized in a seven-step sequence from phthalide in 24% overall yield as shown in Scheme 159. Triazolo[6,7-c ]dihydrocoumarin is similarly prepared in nine steps from dihydrocoumarin in 20% overall yield <92JHC1519>. Benzo[l,2-tf 4,5-tf jbistriazole (795) is synthesized from w-dichlorobenzene in five steps and 54% overall yield (Scheme 160). The hydrogenation of (792) is carried out in ethanol to give (793), which, without isolation, is diazotized at 0°C to afford diacetyl bistriazole (794) in 96% yield <86JOC979>. 

Activated alkynes have been shown to react in a Diels-Alder style with phthalans to furnish polysubstituted naphthalenes (80CJC2573). 1,1-Diethoxyphthalan (41) was prepared by alkylation of phthalide (40) with triethyloxonium fluoroborate, followed by treatment... 

TBDMSC1 yields l-silyloxy-3-arylisobenzofurans (trapped with dienophiles) (84CL1263). Phthalide itself with LDA/Me3SiCl gives l-trimethylsilyl-3-trimethylsilyloxyisobenzofuran, a potentially useful precursor for linear polycyclic compounds (92TL2769). l-Cyano-3-trimethylsilyloxyisobenzo-furans are prepared similarly (96TL6797). 

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

The diesters (625), prepared from ethyl 2-chloromethylbenzoate, are cyclized by sodium ethoxide in a classical Dieckmann reaction (71BSF1351). When R = Me, the formation of phthalide was observed, which was thought to arise by attack of the ethoxide at the methyl group with loss of ethyl acrylate (Scheme 243). 

Miscellaneous a-Substituted Peroxides. 3-Aryl-3-(tert-alkylperoxy)-phthalides (8) are prepared from the corresponding 3-chlorophthalides and iert-alkyl hydroperoxide. 2-Methyl-2-((erl-alkylperoxy)-l,3-benzodioxan-4-ones (9) are obtained from o-acetylsalicyloyl chloride and tert-alkyl hydroperoxides. Trisubstituted 2-(ferr-alkylperoxy)-l,3-dioxolan-4-ones (10) are synthesized from sterically favored cr-acyloxy acid chlorides and tert-alkyl hydroperoxides. 

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

This method is remarkably useful for the synthesis of some phthalide alkaloids which have been hitherto prepared by the Bishler-Napieralsky reaction. Condrastine I and II54, for instance, have been prepared from 2-methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium iodide 52 and 3-bromomeconine 53 in the total yield of 77% (ratio I II = 42 35) 38). 

The sequence can be extended to preparation of optically active phthalides... 

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