Tag Archive | ketoester

Deconstructing the Knorr pyrrole synthesis

It’s time for some “oldie-but-goodie” heterocyclic chemistry, namely the Knorr pyrrole synthesis.  What’s left to be said about this venerable route to pyrroles?  Well, I’d like to point out that it should probably be termed the Knorr pyrrole syntheses (plural).  As usual with chemistry, things are more complex than they first appear.

Here’s the upshot:  There are two fundamentally different pyrrole connectivities that are produced under the Knorr umbrella.  Let’s look at what they are and then delve a little deeper into the connectivity that is often overlooked.

What is the conventional Knorr synthesis?

If you were to consult a reference source or ask someone to describe “the Knorr pyrrole synthesis,” you’d probably find something like this:

The Knorr is usually considered to be the condensation of an α-aminocarbonyl compound with another carbonyl compound, typically an active methylene compound such as a β-ketoester, in the fashion shown above, generally proceeding by (i) condensation of the amine with the other carbonyl compound and (ii) an intramolecular aldol (Knoevenagel) condensation.  Using an organizational system that I employ in my heterocyclic chemistry course, it’s a [3+2]-a,c approach, i.e., it makes the bonds at the “a” and “c” faces of the pyrrole by combining a three-atom component and a two-atom component.

Getting specific, one of my favorite examples is Hamby and Hodges’ 1993 work at Parke-Davis, featuring a Weinreb amide approach to the α-aminocarbonyl compound and reductive deprotection to the amine in the presence of the β-ketoester:

Most [3+2]-a,c Knorr examples produce pyrroles with an electron-withdrawing group (EWG) at the 3-position, but there are examples without it.

The Fischer-Fink variant of the Knorr pyrrole synthesis

If you look a bit further into the Knorr synthesis, you find examples that I would classify as [3+2]-a,d variants.  Here, the α-aminocarbonyl compound contributes two pyrrole atoms rather than three; the other carbonyl compound (typically a 1,3-diketone) contributes three atoms rather than two.  These reactions proceed by (i) condensation of the amine with the other carbonyl compound to form bond a and (ii) an intramolecular aldol condensation to form bond d.  If the amine bears two electron-withdrawing groups (as it does in much of the early work), one is lost during the reaction.

This variant of the Knorr synthesis is perhaps best termed the Fischer-Fink variant after the discoverers of traces of these compounds in traditional Knorr syntheses that employ ethyl acetoacetate (H. Fischer and E. Z. Fink, Hoppe-Seyler’s Z. Physiol. Chem. 1944, 280, 290 and 1948, 283, 152 and this link).

It was Kleinspehn in 1955 who figured how to obtain a majority of the [3+2]-a,d connectivity: simply use diethyl malonate rather than ethyl acetoacetate.  Paine and Dolphin later improved Kleinspehn’s method by preforming the amine rather than carrying out an oxime reduction in situ.  The Paine/Dolphin method is notable in that it works regioselectively with unsymmetrical 1,3-diketones and has found wide application in porphyrin synthesis.

Let’s look at a couple of my favorite examples of the Fischer-Fink variant of the Knorr pyrrole synthesis.

Elliott and co-workers at BioCryst used an α-cyano aldehyde rather than a 1,3-diketone, producing a 2-carboxy-3-aminopyrrole, an intermediate in their synthesis of some PNP-inhibitory pyrrolopyrimidinones (9-deazaguanines):

Prashad and co-workers in the process group at Novartis later used the Elliott chemistry to prepare a related PNP-inhibitor.  Both the BioCryst and Novartis groups used cyanamide as the cycloguanidinylating agent to produce the pyrrolopyrimidinones, a method that can be traced back to the work of my early mentor Robert McKee at UNC-CH, the subject one of my earlier posts.

The Fiesselmann-type modification of the Fischer-Fink variant

Okay, that’s a mouthful, but I think it’s worth treating this [3+2]-a,d method separately.  In the Fischer-Fink chemistry, a 2-aminomalonate is used, one of the esters being lost in the cyclization reaction.  Starting in the 1980s, examples began to appear where a simple glycinate is used; the second ester is omitted.  Thus, the condensation of simple α-amino esters with 1,3-diketones or their equivalents produces 2-carboxypyrroles as shown in the following example by Mataka (Synthesis, 1983, 157-159):

As far as I can tell, there isn’t a standard way to refer to these reactions.  They remind me of the Fiesselmann thiophene synthesis, which involves the condensation of α-mercaptoacetates with 1,3-diketones and their equivalents, so I’ll call these Fiesselmann-type modifications of the Fischer-Fink variant of the Knorr pyrrole synthesis.

Here are a few more examples of the Fiesselmann-type pyrrole syntheses.  Note the complementary regiochemistry of the last two examples.

Bottom line

The greater Knorr synthesis umbrella produces two basic connectivities resulting from [3+2]-a,c or [3+2]-a,d constructions.

Knorr-o-philes please weigh in.

[Jan. 21, 2012:  Edited Fischer-Fink citation to include earlier work.]

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