SYNTHESIS OF SUBSTITUTED INDENE COMPOUNDS (05-Aug-2004)

            Functionalized indenes, such as 2-methyl-4-phenylindene, are prepared from substituted phenols (E=O), anilines (E=NH), or allylic halides (or pseudohalides) in a simple, high yield process entailing four primary steps as shown in Scheme 1.  The four steps are:

1)      Formation of an allylic ether or amine through alkylation of a phenol or aniline (illustrated) or by coupling of an aryl halide with an allylic alcohol or amine (not illustrated).

2)      Claisen rearrangement of the allylic aryl ether or amine. 

3)      Conversion of the phenol or amine group to a suitable halide, sulfonate, phosphate, or diazonium cation leaving group (X). 

4)      Intramolecular coupling to form the indene ring via either:

(a) Heck coupling of the resultant Ar-X with the olefinic C‑H bond; or

      (b) 1) Olefin cross-metathesis of the olefin with a vinyl boronic acid or ester, and

     2) Suzuki coupling of the resulting vinyl boronic acid or ester with Ar-X.  (The
         boronic acid may be converted to a boronic ester prior to the coupling, if desired).

Example

Step 1 – Allylic Alkylation of a Phenol; example where R₁=R₃=R₄=H and R₂=Me (scheme 1); preparation of  2‑biphenyl (2-methyl-2-propenyl) ether:

           A total of 10.0 g of 2-phenylphenol and 20.3 g of potassium carbonate were combined in 100 mL of acetonitrile.  6.0 mL of 3‑chloro‑2‑methylpropene were added and the sample was heated to 60°C for 15 hours.  3.0 mL of methallyl chloride were added and heating was continued at 70°C for 16 h.  The solution was filtered and the solids were extracted with an additional 100 mL of acetonitrile.  The combined organics were reduced in vacuo to obtain the alkylated phenol in quantitative yield as a yellow oil. 

Step 2 – Claisen Rearrangement; preparation of  2‑(2-methyl-2-propenyl)‑6-phenylphenol:

           A total of 13.6 g of the allylic ether was added to 20 mL of N,N’‑diethylaniline and heated to 220°C for 2 hours.  The mixture was held at 130°C for 16 hours and then heated to 225°C for 3-4 hours.  The mixture was cooled and diluted with 50 mL of 1.0M HCl, then adjusted to pH~1 by careful addition of concentrated HCl.  The organics were extracte...