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