Since this is so well known and used so often, I wanted to indicate a few of the modifications that have been used for indole construction, either as a substituted indole itself or as a fused carbazole…..by a Fischer indole ring forming process. Just for a second let’s take a quick look at our organic text book — remember a substituted ketone and a substituted aryl hydrazine will provide the desired heterocycle. Of course the opposite disconnection has been used as well with the advent of the Buchwald amine coupling method. As you would think in an acidic mediated ring closure, most modifications have utilized B&L acids.

Screen Shot 2013-11-13 at 7.49.24 AM

Fischer Indole

Here are a few recent examples:

The Journal of Heterocylic Chemistry (2011)- In this example, the group started by using ZnCl2 to form 1,2,3,4-tetrahydrocarbazole with phenylhydrazine and cyclohexanone in 3 minutes in the microwave (one-pot). Albeit in decent yield, when they switched to p-TsOH (cat)there was a tremendous boost in yield.

Indian Journal of Chemistry Sec B 2011 – In this example, the group screened the ring formation post arylhydrazone formation to examine the efficiency of the acid and also to look at some of the selectivity patterns in the carbazole formation.

Screen Shot 2013-11-13 at 7.47.30 AM

Ring Formation

Screen Shot 2013-11-13 at 7.47.41 AM

Montmorillonite KSF cyclization

Tetrahedron Letters 2011 – In this example, several indoles and carbazoles were synthesized with proylphonic anhydride (T3P) as the acid catalyst. The reaction takes place in minutes with EtOAc as the solvent, indicating that the work for this type of method can be broadened.

Angewendte Chemie 2010 — For those of you looking for a twist and the ability to gain some additional substitution, Knochel’s group will always help you look for organozinc alternatives to traditional methods. In the following example, the group utilized specifically constructed organozinc reagents to couple with susbtituted aryl diazonium salts with a triflate activating group followed by ring formation under microwave irradiation (125C, 30 min) to provide the requisite indole.

Screen Shot 2013-11-13 at 7.59.20 AM

Knochel zinc/indole Fischer modification

There are numerous examples of acid-catalyzed ring formations, modifications of the traditional Fischer process and substitution patterns in the literature that should entice your appetite when there is a need for an indole or carbazole. One of the nice results that comes out of some of this work in the microwave is that there are many starting points to provide a method to use and given the short reaction times, you will have a result promptly. A final example illustates that the ring formation can come in late in a synthesis or as a set-up for additional substitution with a 2-substituted pyridyl indole formation.

Organic Letters 2006 – By choosing a late-stage ketone it is possible to obtain some  substitutions that are otherwise very difficult to obtain through other methods. In this example a methyl ketone on a fused pyridine is set up to react with an aryl hydrazine followed by a microwave induced Fischer indole (ZnCl2/TEG) reaction. And what we learned earlier is that maybe it can even be modified through a little screening effort to be done in a one-pot fashion and show the power of both the Fischer method and improvements in the microwave approach.

Screen Shot 2013-11-13 at 8.15.59 AM

MW Fisher ring closure

Happy Reading! Good to be back!

 

Advertisements