Carboxylic acids phthalides

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 second illustration above is a phthalide THIQ, and these phenethylamines are sometimes referred to as secophthalide-isoquinolines. Here, the oxygen atom of the original isofuranone ring is substituted on the newly formed double bond. This structure can easily open up to the corresponding ketonic carboxylic acid. These seco-modifications of the attacked isoquinoline (first example, illustrated with an aporphine) and the simpler 1-substituted isoquinolines (second example, as illustrated by the isobenzofuranone) are the only ones included in this book. The standard phenethylamines that are commonly found in cacti, compounds which are not from these seco-mecha-nisms, have been tabulated in TIHKAL and will not be repeated here. 

Esters and lactones can be oxidized at the alcoholic parts to give carboxylic acids with the same number of carbon atoms. 2-Fluoroheptyl acetate is transformed in 78-84% yield into 2-fluoroheptanoic acid by heating for 25 h at 48 °C with nitric acid and acetic acid [472]. 3,5-Dimethoxy-phthalide is converted into 3,5-dimethoxyphthalic acid in 90% yield by treatment with alkaline potassium permanganate at 0 °C for 12 h and at room temperature for 24 h (equation 468) [879]. 

A stereospecific conversion of berberine into ( )-/3-hydrastine has been reported. Photolytic oxidation of oxyberberine yields the lactol (123), the N-methyl quaternary salt of which can be reduced with sodium borohydride to give racemic jS-hydrastine in 95% yield. Both phthalide-isoquinolines (e.g. adlumine) and spirobenzylisoquinolines e.g. corydaine) have been synthesized from /3-phenethylamines and methylenedioxyphthalide carboxylic acid (124). Several ethers of narcotoline have been prepared and converted into derivatives of nornarceine. The biotransformation of narcotine in rats has been examined and di-O-desmethylnarcotine, cotarnine, hydrocotarnine, oxocotarnine, and O-demethylmeconine have been isolated from urine. " Bicuculline, which has... 

As illustrated in Scheme 9.9, the proposed mechanism of forming phthalides and iso-coumarins involves orthopalladation of the carboxylic acid, subsequent alkenylation and nucleophihc cyclization or Wacker-type oxidative cyclization. The observed differences in product distributions from the reactions using n-butyl acrylate and styrene suggest that the electronic nature of the alkene plays an important role in product formation, although the exact origin of the difference remains unclear. 

Li and Shi [48] also reported a cationic Rh(III)-catalyzed synthesis of phthalides 165 utilizing C-H activation as a key step (Scheme 3.43). In this case, benzoic acids 168 were the substrates, which could undergo carboxylic acid-directed ortho C-H... 

Biosynthesis of phthalides is associated with biosynthesis of styrylpyrones, as both types of compounds are ketides, but phthalides are derived from aliphatic carboxylic acids (the corresponding acyl-CoAs). Phthalides in plants have various regulatory functions at the cellular level. They exhibit spasmolytic, hypotensive, sedative and diuretic effects. 

Copper chromite/sodium hydroxide Carboxylic acids from phthalides s. 13,111... 

Phthalides from carboxylic acid amides via o-substitution... 

A direct formation of y-lactone 17 through benzylic oxidation of aryl carboxylic acid 16 using a hypervalent iodine(III) reagent 18 and KBr was presented by Dohi and Kita [16] (Scheme 7). This reaction was successfully applied to the synthesis of phthalides from o-alkyl benzoic acids. 

After the seminal work reported by Satoh and Miura in early 2011 on ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes [17], Ackermann demonstrated a ruthenium(ll)-catalyzed cross-dehydrogenative C-H bond alkenylations of benzoic acid derivatives with acrylonitrile or alkyl acrylates. Following the oxidative C—H bond alkenylation reaction, subsequent intramolecular oxa-Michael reaction occurred leading to phthalides in good yields (Eq. (7.12)) [18]. The reactions took place with water as an environmentally benign medium under mild conditions. 

The phytochemicals dihydrophthalic acid, ligusti-lide, butylidene, phthalide, and -valerophenone-0-carboxylic acid have been isolated from Angelica root (Angelica sinensis). They are likely to contribute to the observed circulatory modulating effects of Angelica root, including increasing coronary flow, modulation of myocardial muscular contraction, and antithrombotic effects. 

Iodine phosphorus Carboxylic acids from phthalides... 

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... 

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