3- phthalides

Phthalides are lactones of 2-hydroxymethyl benzoic acid. They are also called as benzofuran derivatives. Phthalides are found in some oils of Apiaceae, such 

Phthalides. - Complimentary procedures for the synthesis of aryl lignans have been developed hydrogenation [Rh(I) cat., Hjr 160eC] of anhydrides (432) leads almost exclusively to lignan (433) whereas dehydrogenation of diols (434) gives very largely the isomeric 

A full account has been given of the preparation of phthalides 

Valerolactones. - Dianions (441), derived from the parent acrylic acids using t-butyl lithium, condense smoothly with epoxides in the presence of BF2-OEt2 to give generally excellent yields of the unsaturated lactones (442), useful as precursors to a wide range of valerolactones 

A relatively rare example of the creation of chiral quaternary carbons has been uncovered in Michael addition-elimination reactions between lactone enolates [e.g. (444)] and a chiral nitro-alkene (445)  

Michael-aldol sequence forms the basis of a stereoselective approach 

Phthalides are an important class of oxygen-containing heterocycles found in natural products and exhibit a broad spectrum of biological activities [7]. 

Transition Metal-Catalyzed Heterocycle Synthesis via C—HActivation, First Edition. Edited by Xiao-Feng Wu. 2016 Wiley-VCH Verlag GmbH Co. KGaA. Published 2016 by Wiley-VCH Verlag GmbH Co. KGaA. 

All of these phthalides in which the phthalide ring is not substituted by electron-donating groups are yellow to orange color formers, and useful as 

A variety of routes to substituted hydroxy-phthalides (378) have been developed which mostly rely on diverse types of metallations of benzene derivatives although a Diels-Alder 

Valerolactones. - Enantioselective reduction using Baker s yeast, a method most often associated with chiral 3-hydroxy-ester preparation, has also been applied to generation of the 

) the potential utility of the diol is demonstrated by its conversion into both enantiomers of the hornet pheromone 

Aspergillus amino acylase which hydrolyses only the (S)-acetyl 

New routes to the related lactone Malyngolide (386) have also 

The process is reversible and therefore provides an easily visible method for measuring pH change in the range of 8.5-9.0. The ionisation reactions of sulfophthaleins follow a similar pathway. Substitution in the phenolic rings of the phthaleins and sulfophthaleins provides a variety of coloured dianions, which change colour over different ranges of pH (see section 1.4.2.1). 

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

Phthalide. In a 1 litre bolt-head flask stir 90 g. of a high quality zinc powder to a thick paste with a solution of 0 5 g. of crystallised copper sulphate in 20 ml. of water (this serves to activate the zinc), and then add 165 ml. of 20 per cent, sodium hydroxide solution. Cool the flask in an ice bath to 5°, stir the contents mechanically, and add 73-5 g. of phthalimide in small portions at such a rate that the temperature does not rise above 8° (about 30 minutes are required for the addition). Continue the stirring for half an hour, dilute with 200 ml. of water, warm on a water bath imtil the evolution of ammonia ceases (about 3 hours), and concentrate to a volume of about 200 ml. by distillation vmder reduced pressure (tig. 11,37, 1). Filter, and render the flltrate acid to Congo red paper with concentrated hydrochloric acid (about 75 ml. are required). Much of the phthalide separates as an oil, but, in order to complete the lactonisation of the hydroxymethylbenzoic acid, boil for an hour transfer while hot to a beaker. The oil solidifles on cooling to a hard red-brown cake. Leave overnight in an ice chest or refrigerator, and than filter at the pump. The crude phthalide contains much sodium chloride. RecrystaUise it in 10 g. portions from 750 ml. of water use the mother liquor from the first crop for the recrystaUisation of the subsequent portion. Filter each portion while hot, cool in ice below 5°, filter and wash with small quantities of ice-cold water. Dry in the air upon filter paper. The yield of phthalide (transparent plates), m.p. 72-73°, is 47 g. 

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],... 

Isobenzofuranone — see Phthalides, 552 Isobenzopyrylium salts isocoumarin synthesis from, 3, 834 synthesis, 3, 862, 863, 867, 868 Isobenzopyrylium salts, l-amino-3-aryl-synthesis, 3, 867 Isobenzopyrylium salts, 1-aryl-NMR, 3, 592... 

Phthalides — see Benzo[c]furan-l (3H)-one Phthalimide, 2-amino-pyridazine synthesis from, 3, 53 Phthalimide, N-cyclohexylthio-as vulcanization accelerator, 1, 404 Phthalimide. methylidine-polymerization, 1, 273 Phthalimide, N-(trichloromethylthio)-biocide, 1, 399 Phthalimide, 1-vinyl-polymerization, 1, 273 Phthalimide, N-vinyl-copolymer... 

It was found that phthalides espeeially Z-ligustilide (90%) were the major eomponents of the oil of young yellow leaves and as the leaves get green the amount of phthalides deereases (22.5%). 

It is considered that in these new forms racemisation or reversible inversion has occurred at the centre of asymmetry in the phthalide group, and that the centre of asymmetry in the isoquinoline nucleus is unaffected. The melting-point, 176°, of each new isomeride is depressed by addition of the corresponding a-narcotine and the specific rotation of l-j3-narcotine, W548 is 101° (CHCI3) or — 59-2° (N. HCl), that of i-a-narcotine, under the same conditions being — 246° and -f 50-4° respectively. 

Capnoidine, C43H45O3N. (Items 24, 25 list, p. 171.) M.p. 238°, gives a crystalline hydrochloride, m.p. 244°. It contains no methoxyl groups, is isomeric with adlumine and possibly belongs to the phthalide-fsoquinoline group. See also base F 38 (Item 44 list, p. 173). 

Opium (Papaver somniferum) Benzylfsoquinolines Phthalide isoquinolines Morphine Sub-group, Sinomenium acutum Other Papaver spp. Rhoeadine, etc.. ... 

Methoxymethylene, 231 Ethoxymethylene, 231 Dimethoxymethylene, 232 1 -Methoxyethylidene, 232 1 -Ethoxyethylidine, 232 Methylidene, 233 Phthalide, 233... 

CH2CI2, Pyr, 71-88% yield) and is cleaved with thiourea to release the alcohol that closes to the phthalide, releasing the carbohydrate.Its use for nitrogen protection was unsuccessful. 

Carboxyphenyl-(2-methyl-3-indoleninjdidene)methanol (303) was said to be formed by the action of phthalic anhydride on 2-methyl-indole magnesium bromide. Skatole magnesium bromide, on the other hand, apparently gave 2-carboxyphenyl-(3-methyl-2-indole-ninylidene)methanol (304) and 3-hydroxy-3-(3-methyl-l-indolyl)-phthalide (305) on treatment with 1 mole of phthalic anhydride. The derivative 305 was easily hydrolyzed in alkali, giving skatole and phthalic acid, and was thus formulated as a 1-skatolyl derivative. ... 

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... 

Condensation of an appropriately substituted phenylacetic acid with phthalic anhydride in the presence of sodium acetate leads to aldol-like reaction of the methylene group on the acid with the carbonyl on the anhydride. Dehydration followed by decarboxylation of the intermediate affords the methylenephthal-ides (12). Treatment of the phthalides with base affords directly the indandiones, probably via an intermediate formally derived from the keto-acid anion (13). The first agent of this class to be introduced was phenindandione (14) this was followed by anisindandione (1S) and chlorindandione (16). ... 

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... 

To a hot solution of 20.6 g of sodium in 400 ml of absolute ethanol, there is added a solution of 110 g of phthalide and 110 g of p-methoxybenzaldehyde. A vigorous reaction ensues and one-helf of the alcohol is distilled off over a two hour period. Ice and water are added to the red solution end the diluted solution is ecidified with hydrochloric acid. The resulting gum solidifies end the aqueous phase is removed by decantation. The crude solid is recrystallized twice from two liters of ethenol yielding 2-(p-methoxyphenyl)-1,3-indandione as pale yellow crystals, MP155°-156°C. 

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. 

A fine suspension of 25.18 grams (0.05 mol) of potassium salt of enamine protected ampicillin and 10.65 grams (0.05 mol) 3-bromophthalide were reacted in a 1 2 mixture of acetone/ethyl acetate (1,500 ml) for 24 hours. After filtration the organic layer was washed twice with 250 ml portions of 1 N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Addition of ether crystallized the phthalide enamine protected a-aminophenylacetamido penicillanate in 85% yield. 

The addition products were used for the total synthesis of racemic aporphine, protoberine, quettamin, and phthalide alkaloids26,24. 

The sequence was successfully applied to the synthesis of the phthalide isoquinoline hemiacetals (-)-egenine (6) and (-)-corytensine (7) from the bis-oxygenated precursor 513,14. 

Phthalide enolates 4 add to Schiff bases to produce intermediate adducts 5 which cyclize to mixtures of cis- and Rcws-isoquinolones 6 and 724. The er.y-product predominates consistently by — 2 1 over a series of nonenolizable arylintines. 

The preference for the civ-isomer has been explained by a cyclic transition state in which the steric interactions of the a-substituent of the iminc arc minimized by placing it gauche to the lactone. 8 shows the proposed transition state involved in the addition of phthalide enolates to imines24. 

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