Phthalides from aldehydes

Scheme 6.2 (a) Synthesis of 3-substituted phthalides from aldehydes and aromatic acids and (b) synthesis of 3-alkylidenephthalides from benzoic acids. 

Scheme 3.42 Synthesis of phthalides from benzimidates and aldehydes.

Scheme 3.43 Synthesis of phthalides from benzoic acids and aldehydes.

Moreover, they are versatile building blocks for the synthesis of functionalized naphthalenes, anthracenes, and naphthacene natural products [8]. Recently, Rh-catalyzed C-H activation followed by nucleophilic addition to aldehydes emerged as a powerful alternative to access phthalides. In 2012, Li and coworkers developed a novel Rh(III)-catalyzed synthesis of three substituted phthalides from benzoic acids and aldehydes through carboxylate-directed ortho-C-H functionalization and subsequent intramolecular cyclization (Scheme 6.2a) [9]. In 2013, GooCen and coworkers described the straightforward synthesis of S-alkylidenephthalides from benzoic acids and aliphatic acids or anhydrides in the presence of [Rh(cod)Cl]2 and CsF (Scheme 6.2b) [10]. 

This procedure is capable of considerable variation, by which other indenones may be secured. For example, the benzalphthalide may be replaced by other phthalides made from (a) other aldehydes, or (b) other anhydrides the phenyl-magnesium bromide can be replaced by other Grignard reagents. 

Chiral phthalides are synthesized from an o-iodobenzoic ester that forms a zinc compound. With a P-chiral diphosphinocobalt complex 50 present the addition to aldehydes follows an asymmetric course. ... 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

Stage, prior to deprotection. Because it was undesirable to expose aldol 26 to base at elevated temperatures, the carbonylation would also precede the key aldol reaction. Fully substituted aldol 43 would be derived from the aldol reaction of phthalide 44 and aldehyde 9d in analogy to the earlier strategies (Scheme 16, cf. Schemes 7 and 12). Phthalide 44 would in turn be constructed via dihydroxylation, iodination, and carboalkoxylation of previously synthesized methyl ketone 27, available from the Suzuki coupling of trifluorobora-toamide 11 and bromide 28. 

Lactone products can also be formed via Grignard-type addition to aldehydes from o-iodobenzoates [116]. The Cheng group developed an enantioselective Co-catalyzed method for preparation of 5-membered phthalide products from methyl o-iodobenzoate and aldehydes (Scheme 2.61). While Ni and Pd catalysts were ineffective, the authors propose a Co(I)/Co(III) mechanism involving oxidative addition of the sp C—I bond followed by addition and ring closure [116]. Co(III) is reduced to Co(I) by the zinc metal present in solution. 

According to this new reaction network, the starting material is converted to the wanted product PA by three parallel routes via phthalic aldehyde and phthalic acid (reactions 8,9,10), via tolylic acid and phthalide (reactions 5,6,7) and via phthalide (reactions 4 and 7). Phthalic anhydride when formed is very stable but it is converted in part via bencoic acid (reaction 26) over a rather complex reaction scheme to maleic anhydride (MA). Maleic anhydride is formed directly from o-xylene via tolylic aldehyde (reaction 1) and toluene (reaction 11) by two routes and via dimethylben-zochinone (DMBQ) (reaction 15). Toluene and DMBQ are converted over a series of reaction steps to acetic acid. The main by-products, CO and CO2, are predominantly formed directly from o-xylene according to this mechanistic study. 

Butenolides.—A full report has been published on the useful palladium(O)-catalysed carbonylation procedure for the conversion of iodo-alcohols (76) into butenolides (77). Very little catalyst is required, and only low pressures of carbon monoxide are used. The reaction can also be applied to the preparation of phthalides and jS-lactones. Bis-a-phenylsulphenylbutyrolactone, readily obtainable from the parent lactone, reacts with ethyl Grignard to give the enolate (78), which condenses smoothly with aldehydes to provide a-substituted butenolides (79) following oxidative desulphurization. a-Substituted butenolides can also be obtained by an ene reaction between a-ethylid-enebutyrolactone and triazoline-3,5-dione. ... 

The aryl-lithium (99), derived from (5)-2-(anilinomethyl)pyrrolidine and 2-bromobenzaldehyde, reacts with aldehydes at low temperatures (-100 C) to give, after hydrolysis and oxidation, the phthalides (100) with enantiomeric enrichments of around 80 /o when R is a simple alkyl group. Electrochemical... 

The phthalisoimidium salt (83), readily available from phthalic anhydride, reacts with Knoevenagel-type enolates to give the ylidene-phthalides (84). The related isoimidium perchlorate (85), on deprotonation with triethylamine, affords the butenolide (86) which with aromatic aldehydes and carbon disulphide forms the ene -type adducts (87) and (88) respectively. 

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