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Regioselective synthesis of 3- and 5-aminopyrazoles

Just a bit of sodium ethoxide does the trick …

The Knorr pyrazole synthesis, broadly defined, involves the condensation of hydrazines with 1,3-dielectrophiles, e.g., 1,3-diketones, beta-ketoesters, alpha-cyanoketones, beta-alkoxyacrylonitriles, alkoxymethylenemalonates, etc. When a nitrile electrophile is involved, an aminopyrazole typically results, producing compounds that are very useful in the pharmaceutical field. The first two equations in the general scheme below use hydrazine as the dinucleophile, but what happens when an unsymmetrically-substituted hydrazine is involved?  Wouldn’t it be nice to be able to produce either the 3- or 5-aminopyrazole regioisomer in a selective fashion?

Pyrazole introduction

This problem has been kicking around the literature for a long time. The 5-aminopyrazole is generally the major product, leaving the 3-aminopyrazole as a useful-yet-expensive poor cousin. Much effort has been spent trying to rationalize and predict the outcome of these processes, so a recent paper from Fandrick, et al., from Boehringer Ingelheim is a most welcome arrival.

Heating the nitrile 3 with the alkyl-substituted hydrazine 4 in ethanol produces the 5-aminopyrazole 7, presumably through the adduct 5, a result that is consistent with the prior literature. At first glance, this should be rather surprising, since it is known that alkylhydrazines are more nucleophilic at the most substituted nitrogen, i.e., k1 should be larger than k2, thus producing adduct 6 and the 3-aminopyrazole 8. (Arylhydrazines are different; they are generally more nucleophilic on the unsubstituted nitrogen, though it depends on the nature of the arene.) Fandrick and co-workers proposed that 6 is indeed the kinetically-formed adduct, but its cyclization to 8 (under typical neutral conditions) is slower than isomerization to the more stable adduct 5, producing 7 instead.

Fandrick work

In order to obtain the more rare and often desirable 3-aminopyrazole 8, Fandrick simply introduced sodium ethoxide to the mix with the idea that the kinetically favored 6 might be transformed to 8 before it can isomerize to 5. It worked, producing 3-aminopyrazoles with selectivities of up to 99:1 depending on the exact example.

Increasing the size of the alkyl group on the hydrazine should erode the selectivity for 8 in the kinetically-controlled ethoxide reaction, since the internal nitrogen of the hydrazine, while electronically more nucleophilic, is less accessible due to steric hindrance. Indeed, moving to cyclohexylhydrazine and then t-butylhydrazine leads to diminished and even reversed selectivities of 72:28 and 5:95 for 8:7. Under neutral thermodynamic conditions, cyclohexyl- and t-butylhydrazine gave >99:1 ratios of 7:8, as expected.

Arylhydrazines are known to highly favor 5-aminopyrazoles, which was supported by the current work when employing neutral (thermodynamic) conditions. Interestingly, reasonable quantities of 1-aryl-3-aminopyrazoles 8 were formed under kinetically-controlled (ethoxide) conditions. Hence, with phenylhydrazine, a 1:1 ratio of 8:7 was formed, indicating that a good deal of 6 was formed kinetically. Using the more electron-rich p-methoxyphenylhydrazine under kinetically controlled conditions produced even more of the 3-aminopyrazole, giving a 78:22 ratio of 8:7. This presumably reflects and increase in the nucleophilicity of the internal hydrazine nitrogen due to the resonance donating effect of the p-methoxy substituent.

Tetrazole synthesis, Part II: Harnessing the tetrazole-azidoazomethine equilibrium

Welcome to the second part of our Tour de Tetrazoles. In Part I, we saw that tetrazoles, particularly 5-substituted versions, are often made from nitriles and an azide source. Toxic and explosive hydrazoic acid can be formed in this chemistry, but we saw that there are ways to minimize its production.

Now let’s take a look at another general approach to tetrazoles, namely the concerted electrocyclic ring-closure of azidoazomethines. This chemistry will allow us to access a variety of tetrazoles, including fused-bicyclic versions, often under azide-free (and hydrazoic acid-free) conditions.

The tetrazole-azidoazomethine equilibrium

Azidoazomethines, also known as imidoyl azides, can undergo a concerted electrocyclization reaction to tetrazoles:

The tetrazole-azidoazomethine equilibrium

The position of the equilibrium depends on the nature of the substituents: electron-withdrawing groups on the azomethine nitrogen favor the open form, whereas hydrogen and normal organic substituents favor the tetrazole (leading reference and theoretical studies).

Fascinating, but there’s more: This equilibrium is an excellent entry point for tetrazole synthesis. Anything you can do to make the azidoazomethine will, with the right substituents, lead to the tetrazole.

Accessing azidoazomethines, and thus tetrazoles

If you can make the azidoazomethine, you’ll get the tetrazole. So, how does one make azidoazomethines? There are two primary methods, namely (1) the use of an activated amide to acylate sodium azide and, (2) the diazotization of amidrazones, themselves available by acylation of hydrazine with an activated amide:

Routes to azidoazomethines

Notice that the amidrazone method doesn’t require sodium azide or its equivalents, prompting some to call this an “azide-free” method.  A word of caution, though: It’s conceivable that the azidoazomethine could eliminate azide, so hydrazoic acid may still be lurking.  Use caution.

Example: Azidoazomethines (and thus tetrazoles) by Duncia’s method

John Duncia at du Pont reported a nice way to access azidoazomethines (and thus tetrazoles) from amides and TMSN3 using diethyl azodicarboxylate and triphenylphosphine. Shown below is a more recent application of Duncia’s method by discovery chemists Li, Tino, and co-workers at Bristol-Myers Squibb, who synthesized BMS-317180, a GHS agonist.

BMS discovery route using Duncia's method for tetrazole synthesis

The Process R&D group at BMS later felt that the issues of high exothermicity, TMSN3 safety, and PPh3PO removal warranted another approach to the tetrazole for scale-up.

Example: Azidoazomethines (and thus tetrazoles) from amidrazone diazotization

The BMS process group ultimately decided to avoid azide chemistry altogether by using amidrazone diazotization chemistry. Hydrazinolysis of the oxazoline shown below gave an amidrazone that was then diazotized to give the azidoazomethine (not shown) and thus the tetrazole on a 40 kg scale.  Superb.

BMS's Process for Tetrazole Synthesis on Large Scale

By the way, you can also make 5-substituted tetrazoles from amidrazones, though it’s not as common as the nitrile/azide method discussed in Part I of this post. Here’s an example :

Amidrazone route to 5-substituted tetrazoles

Fused bicyclic tetrazoles: An ideal application of the azidoazomethine-tetrazole equilibrium

Azidoazomethines where the azomethine (imine) is part of a ring, e.g. 2-azidopyridines and 4-azidopyrimidines, undergo electrocyclization to provide fused bicyclic tetrazoles. Historically, this is where the azidoazomethine-tetrazole chemistry began, with work by Bülow (1909; azidopyrimidines), Benson (1954, azidopyrimidines), Boyer (1959, azidopyridines), and McKee (1962, azidopyrimidines). The following example is from McKee’s lab at UNC and Montgomery’s lab at SRI (see also here). Both the azide and diazotization methods were used successfully.

McKee and Montgomery fused tetrazole synthesis

Finally, remember that the position of the azidoazomethine-tetrazole equilibrium depends on the electron density around the tetrazole? McKee used that knowledge to develop a new purine synthesis: Converting the above amine (electron donor) to the imidate shown below (electron acceptor) caused the azidoazomethine-tetrazole equilibrium to shift to favor the latter, which upon heating gave a purine. There’s some great stuff in the old literature.

McKee Purine Synthesis by shifting the tetrazole-azidoazomethine equilibrium

McKee, by the way, was the professor that got me interested in heterocyclic chemistry… see an earlier post for that story.

I hope you’ve enjoyed this Tour de Tetrazoles. I know there are some tetrazole experts out there, so please share some of your knowledge in the Comments.

Tetrazole synthesis, Part I: Azide-based methods and dealing with the danger of hydrazoic acid

Azaphiles, unite! Azaphobes, run! It’s time to delve into the synthesis of tetrazoles (review) in this two-part post. Whatever you think you know about making these hard-core heterocycles, I’ll wager you’ll still find something interesting here. Are you thinking that all tetrazoles are made with azide chemistry and thus you’ll lose a limb to an explosion? Read on.

Full disclosure: I love molecules with several nitrogens in a row. My graduate work involved adding organometallics to azides to produce triazenes and a good deal of my group’s research at the University of Michigan involved azides, triazoles, triazolines, etc. Good times.

Tetrazole flavors

When considering tetrazoles, most organic chemists will likely think first of 5-substituted tetrazoles, long known to be good carboxylic acid biomimetics/bioisosteres in the drug discovery endeavor, their acidity being much the same as those of carboxylic acids (see Meanwell’s excellent review). But there are other important types of tetrazoles that are nonacidic, e.g., disubstituted tetrazoles and fused bicyclic tetrazoles.

Types of tetrazoles under consideration

In the current post, we’ll consider making 5-substituted tetrazoles using azide chemistry. Online IR studies by the process R&D group at Merck Frosst are instructive in dealing with the dangers of hydrazoic acid.

In the next post, we’ll look at the tetrazole-azidoazomethine equilibrium for the synthesis of disubstituted and fused-bicyclic tetrazoles, where we’ll find that one can avoid sodium azide and hydrazoic acid issues entirely. Well, almost entirely.

5-Substituted tetrazoles – dealing with the dangers of hydrazoic acid

A popular procedure for making 5-substituted tetrazoles is the reaction of sodium azide with a nitrile, often in the presence of an ammonium salt. The example shown below is from Organic Syntheses (Novartis Process R&D and Ley’s group at Cambridge), providing the useful enantiocatalyst shown on an 80 mmol scale. The excess sodium azide was destroyed with sodium nitrite and sulfuric acid, which converts hydrazoic acid into nitrogen and nitrous oxide gases.

Novartis/Cambridge example of the reaction of a  nitrile with sodium azide to produce a tetrazole

While the above procedure may be popular, any time you use sodium azide you should be thinking, “hydrazoic acid can be generated, it’s explosive and toxic, and I need to take the appropriate safety precautions.” That’s precisely what happened during some recent process R&D work at Merck Frosst on the steroyl-CoA desaturase inhibitor MK-8245. The discovery chemistry route used NaN3/pyridinium chloride as shown below, but the process group felt that the potential for significant amounts of hydrazoic acid generation was too high.

Merck Frosst Discovery Chemistry Route

Armed with the ability to detect hydrazoic acid in the headspace above the reaction mixture using online IR, the Merck Frosst researchers surveyed alternatives. Sharpless’s zinc bromide procedure, proposed to minimize hydrazoic acid formation by control of the pH, led to a reading of 2000 ppm of HN3 in the headspace, which is below the detonation threshold of 15,000 ppm but was still felt to be undesirable.  In their own survey of conditions, the Merck Frosst scientists found something quite new and significant: Reaction with sodium azide in the presence of a catalytic amount of zinc oxide in aqueous THF (pH 8) proceeded efficiently, and most notably, with only 2 ppm of HN3 in the headspace! They were able to make 7 kg of the tetrazole in one run in nearly quantitative yield. Nice!

Sharpless and Merck Frosst Modifications

I’d be remiss if I didn’t mention Bu3SnN3 and Me3SiN3/Cu(I) as sodium azide surrogates, sometimes used on large scale. Shown below is an application to valsartan (see here and here) with recycling of the tin by-products. The intermediate stannyl tetrazole and leftover Bu3SnN3 were converted with HCl to Bu3SnCl, which was then converted to the fluoride, which was removed by filtration and recycled to Bu3SnCl.

Valsartan synthesis

Next:  The tetrazole-azidomethine equilibrium and its use in tetrazole synthesis.

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.]