1.3- isobenzofuran, synthesis

A spectacular demonstration of this approach is provided by the stretched isobenzofuran synthesis shown below.Note that the first cycloaddition is with a dienophile able to provide the ortho related carbinol/aldehyde arrangement ready for the formation of another furan ring. 

Use in Isobenzofuran Synthesis. 1,2,4,5-Tetrazine has also been involved in multiple cascade cycloaddition reactions to generate complex substrates. The reactivity of isobenzofuran was delineated with Cgo (eq 5). Starting from a [4+2] cycloaddition between 19 and 1,2,4,5-tetrazine, intermediate 20 was generated. Next, a retro-[4+2] produced the desired isobenzofuran, which... 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

Benzo[c]furans (isobenzofurans) are reactive molecules usually employed as reactive dienes in the synthesis of more complex molecules. In the synthesis of spiro compounds related to fredericamycin A, Kumar generated the trimethylsiloxytrimethylsilylbenzo[c]furan 125 from phthalide via two consecutive deprotonations and silylations of the resulting anions. Diels-Alder reaction of the isobenzofuran as shown below with a spiroenedione leads to the formation of an endo-exo mixtures that can be smoothly converted to the dihydroxydione <00IJC(B)738>. 

The synthesis of cycloproparenes resulting from formal fusion of a cyclopropene to furan and thiophene has been attempted with limited success. Reaction of the dichloro-oxabicyclohexane 180 (X = O) " afforded a cyclopropene 181 which ring-opened to a vinylcatbene 182, but the cycloproparene 183 was not produced. Similarly, the thia-analogue 180 (X = S) could not be converted to 184. The intermediate cyclopropenes and/or vinylcarbenes have been trapped. A cyclopropathiophene derivative 186 was generated, however, from 185. Although it was not isolable, it afforded a bis-adduct 187 when it was produced in the presence of isobenzofuran (45)." ... 

A highly efficient synthesis of l-alkylidene-13-dihydroisobenzofurans and 3-alkylidene isobenzofuran-l(3//)-ones (phthalides) through Pd-Cu-catalysis using acetylenic carbinols as synthons was reported <99SL456>. 

Arylnaphthalide lignans. A novel synthesis of these lignans involves in situ generation of an isobenzofurane (a) from a substrate such as I, which is trapped by a Diels-Alder reaction with methyl acetylenedicarboxylate. The adduct aromatizes lo u naphthol 2 in the presence of an acid. Selective reduction of the 3-... 

This methodology has also been has also applied to the synthesis of other isobenzofurans (90JOC929). 

Simple hydroxyphthalans have also been used for the transient generation of unstable isobenzofurans [83JCS(CC)1197 88JAP(K)62/201880 94CJC42]. An interesting variant for the synthesis of hydroxyphthalans was reported by Rodrigo and co-workers [92JCS(CC)164]. Treatment of aryl iodides of type 42 with butyllithium at -100°C with subsequent acidification yields isobenzofurans (trapped as Diels-Alder adducts). 

In the synthesis of the bisdienophilic phthalocyanine 102, a Diels-Alder reaction of a reactive isobenzofuran (generated by the tetracyclone route) is involved (97CB801). For further work see [95JCS(CC)2449 98ZN(B)1069],... 

The importance of isobenzofurans as building blocks for complex organic molecules was brought to light by A. S. Kende and co-workers in their synthesis of 7-deoxydaunomycinon 104 starting with dimethoxytetralone 103 (77TL3537). 

Benzofurans and dihydrobenzofurans have been prepared on polymeric supports by the palladium-mediated reaction of 2-iodophenols with dienes or alkynes (Entries 1 and 2, Table 15.9). This reaction is closely related to the synthesis of indoles from 2-iodoanilines, and probably proceeds via an intermediate palladacycle (Figure 15.3). Benzofuran and isobenzofuran derivatives have also been prepared on cross-linked polystyrene by intramolecular addition of aryl radicals to C=C double bonds and by intramolecular Heck reaction. 

Another efficient method is the electrochemical oxidation of NADH at 0.585 V vs Ag/AgCl by means of ABTS2- (2,2,-azinobis(3-ethylbenzothiazoline-6-sulfonate)) as an electron transfer mediator [96]. Due to the unusual stability of the radical cation ABTS, the pair ABTS2 /ABTS is a useful mediator for application in large-scale synthesis even under basic conditions. Basic conditions are favorable for dehydrogenase catalyzed reactions. This electrochemical system for the oxidation of NADH using ABTS2 as mediator was successfully coupled with HLADH to catalyze the oxidation of a meso-diol (ws >-3,4-dihydroxymethylcyclohex-l-ene) to a chiral lactone ((3aA, 7aS )-3a,4,7,7a-tetrahydro-3//-isobenzofurane- l-one) with a yield of 93.5% and ee >99.5% (Fig. 18). 

Born and raised in Toronto, Dr. Peter W. Dibble obtained his Ph.D. working with James G. Smith and Russell Rodrigo at the University of Waterloo, Waterloo, Ontario. He did postdoctoral work with Carl Johnson at Wayne State University in Detroit. Dr. Dibble joined the faculty of the University of Lethbridge in 1990 and is now associate professor of chemistry. He has developed methodology for the preparation of a wide variety of isobenzofurans and most recently has been applying bis(isobenzofuran)s to the synthesis of unusual cyclophanes. 

A one-pot synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with chromium cyanocarbene complexes was reported. The reaction involved formation of an isobenzofuran first, which then underwent intramolecular Diels-Alder cycloaddition with the nitrile. One important feature of this process was the deoxygenation of the initial adduct to give the isoquinoline ring <03OL4261>. 

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