Advances in the chemistry of isochroman

The Oxa‐Pictet–Spengler Reaction: A Highlight on the Different Efficiency between Isochroman and Phthalan or Homoisochroman Derivative Syntheses

“…In addition we proved that hydroxyisochromans could spontaneously form in extra virgin olive oil by the isolation, from this matrix, [4] of small amounts of 1-phenyl-6,7-dihydroxyisochroman and 1-(4-hydroxy-3-methoxy-phenyl)-6,7-dihydroxyisochroman.…”

“…In previous papers, [1,2] we reported the high-yield synthesis, performed under very mild conditions, of a series of 1substituted hydroxyisochromans from suitable hydroxyphenylethyl alcohols and carbonyl compounds. This onepot synthesis is based on a modified oxa-Pictet-Spengler reaction, [3][4][5] in which the aromatic carbon atom involved in the heterocyclic ring closure is strongly activated by a para-hydroxy or a para-methoxy functionality and thus acts as a nucleophile. Here we report the synthesis of 1-substituted hydroxyphthalans and 1-substituted hydroxyhomoisochromans performed by the same reaction in order to verify if this synthetic pathway could still be successfully applied to obtain different heterocyclic ring structures.…”

Catalytic Enantioselective Approaches to the oxa-Pictet–Spengler Cyclization and Other 3,6-Dihydropyran-Forming Reactions

“…14 While it was found that phenylethanol can condense directly with formaldehyde or paraformaldehyde in the presence of aqueous HCl to form isochroman without the need to first isolate 1, this approach inadvertently leads to side products containing chloromethyl groups on the phenyl ring (not shown). 14,15 As outlined in Scheme 1, the general mechanism of the oxa-Pictet-Spengler reaction involves the formation of an oxo-…”

Boosting Molecular Complexity with O2: Iron‐Catalysed Oxygenation of 1‐Arylisochromans through Dehydrogenation, Csp3−O Bond Cleavage and Hydrogenolysis

“…A case in point is the oxidation of isochroman and its derivatives, which can lead to products of widely ranging bioactivities but has generally been performed with toxic, expensive and/or environmentally hazardous terminal oxidants, such as CrO 3 /H 2 SO 4 , 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ), ceric ammonium nitrate (CAN), SeO 2 , CrO 3 /H 5 IO 6 and KMnO 4 . Of particular note is the oxidative cleavage of the endocyclic Csp 3 −O bond in 1‐arylisochromans, which has been exploited by medicinal chemists for the synthesis of benzodiazepines, benzodiazepinones and benzodiazepinethiones, analogues of the neuroprotective agent GYKI52466 and the related LY300164 and tofisopam (Scheme A) .…”

“…[7] However,t he development of similarc atalysts for the selective aerobic oxidation of ethers, particularly the oxidative cleavage of ethereal CÀOb onds, has received much less attention, [7c, 8] although such reactions could provide new pathways for the synthesis of bioactive molecules and new insight into the mechanisms of ether degradation by oxygenases and drug metabolism. [9] Acase in point is the oxidation of isochroman andits derivatives, which can lead to products of widely ranging bioactivities but has generally been performedw ith toxic, expensive and/or environmentally hazardous terminal oxidants, [10,11] such as CrO 3 /H 2 SO 4 , [12] 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), [13] ceric ammonium nitrate (CAN), [14] SeO 2 , [15] CrO 3 / H 5 IO 6 [16] and KMnO 4 . [17] Of particularn ote is the oxidative cleavage of the endocyclic Csp 3 ÀOb ond in 1-arylisochromans, which has been exploited by medicinal chemists fort he synthesis of benzodiazepines, benzodiazepinones and benzodiazepinethiones, analogues of the neuroprotective agent GYKI52466 and the related LY300164 and tofisopam (Scheme 1A).…”