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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7 responses to “Deconstructing the Knorr pyrrole synthesis”

  1. milkshake says :

    One lovely example of traditional Knorr synthesis is a condensation of omega-aminolevulinic acid NH2CH2COCH2CH2CO2H with 1,3-diketones. The aminolevulinic acid is surprisingly stable as a HCl salt, you mix it with a diketone in water, add sodium acetate and heat a little and beautiful flakes of substituted pyrrolepropionic acid snow out… I can do that every day, its so satisfying.

  2. Will Pearson says :

    Thanks, Milkshake, that’s a great tip. Do you have a reference you can share?

    • milkshake says :

      I think the reference is Tetrahedron 49, 7017-26 (1993) but I cannot check it. The recipe is always the same: dissolve omega-aminolevulinic aci. HCl in water (5-10 ml per gram), add the 1,3-diketone or beta-ketoester 1 equivalent plus 2 equivalents of sodium (or potassium) acetate, reflux for 30 min to 4 hours (depending on the reactivity of the diketo partner), cool to room temp, filter the product, wash it with small portions of 30% ethanol in water on the Buchner funnel and dry. The purity should be pretty good without need recrystallization (if you are using unsubst 1,3-cyclohexadione check the purity, the commercial product is oftein gooey and partly oligomerized), with a very greasy 1,3-dicarbonyl partner that does not want to go to solution you can add some ethanol etc as a co-solvent. Unsymmetrical 1,3-diketo compounds condense the amino group of aminolevulinic acid preferentially to the less hindered/more reactive carbonyl group (so you get a good regioselectivity with acetoacetates and also with the isomer of dimedone 4,4-dimethyl-1,3-hexadione (the product is 5,5-dimethyl-4-keto-4,5,6,7-tetrahydroindole-3-propionic acid).
      The typical yields are in the 60-85% range

      Aminolevulinic acid from Aldrich is very expensive, I think we used to have it made for us by a custom synthesis contractor from omega bromolevulinic acid.
      Also alpha amino acetophenones(HCl salt) work for this reaction, providing arylpyrroles byt the overal yields are only in the 50-60% range and the aminoacetophenones require 4-6 hours of reflux, depending on the aryl substitution. The aminoacetophenone precursors are easy to make (bromoacetophenone + urotropine, 2 days @ RT in chloroform, the urotroponium slat precipitates out and is hydrolyzed by dissolving it in a 2:1 mix of ethanol with conc. HCl and letting the mix crystallize over 2 days at RT, (The precipitate containing a crude aminoacetophenone.HCl is typically good enough to be used for the next step.

      • Will Pearson says :

        Great information. Here’s the key reference: “Reactions of some diketones with 5-aminolevulinic acid in acidic solution,” A. R. Butler and S. D. George, Tetrahedron 1993, 49, 7017-7026 (Link).

        You can download a free copy of a later paper, “Some Reactions of 5-Aminolevulinic Acid with Cyclic beta-Diketones,” E. G. Brown and A. R. Butler, J. Chem. Res. (S) 1998, 458-459 (Link).

        In the first paper, they generally got the Knorr connectivity, 3-acyl-4-(2′-carboxyethyl)pyrroles, but in other cases they got mixtures containing the Fischer-Fink connectivity, i.e., 2-(3′-carboxy-1-oxopropyl)pyrroles. In the second paper, cyclic beta-diketones are used to make tetrahydroindol-4-one-3-propionic acids (the Knorr connectivity).

  3. Anonymous says :

    This is great, I’ve been reading Aromatic Heterocyclic Chemistry by David T. Davies and it gave a basic introduction to Knorr pyrrole synthesis but the [3+2]-a,d mechanism isn’t mentioned at all so this is a real eye-opener! Thanks

  4. John Bryant Paine III says :

    I find your mechanistic nomenclature interesting. [I have not done any searching to see whether the following is already done.] It occurs to me that the nomenclature could be further refined, by including SUBSCRIPTS to the letters to indicate the probable order in which the two new bonds are formed. Thus, the Paine-Dolphin-Kleinspehn reaction involving diethyl aminomalonate (DEAM) would normally be free-base amine condensing with the less-hindered protonated carbonyl group in the usual manner, to give a [3+2]-a1,d2 mechanism. However, it may be that DEAM can also function as an YLID, with the amine group being protonated, adjacent to the carbanion form of the malonate diester component. Then, the ylid carbanion would form the first bond, with the less-hindered/more reactive carbonyl group, to give a [3+2]-a2,d1 mechanism. This might help explain our finding that pivaloylacetone gave the 5-t-butylpyrrole-2-carboxylate ester as the only pyrrolic product (albeit in low yield). [Presumably the pivaloyl group enforces an uncyclizable E-configuration on the principal enaminone formed, which would result from an attempt at the [3+2]-a1,d2 pathway.]

    • Will Pearson says :

      John, thanks for your comments. I agree there’s much more that could be done with these descriptors. I use them extensively in my short course on Heterocyclic Chemistry, but only as an organizational tool, i.e., it’s a way to group heterocycle syntheses by the bonds that are formed in the key step(s). As such, it doesn’t attempt to classify reactions on the basis of mechanism or the timing of bond formation, but it certainly could. Nice idea! Thanks for stopping by with a valuable comment.

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