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.

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3 responses to “Tetrazole synthesis, Part I: Azide-based methods and dealing with the danger of hydrazoic acid”

  1. milkshake says :

    I have used the Sharpless ZnBr2/NaN3/water reflux conditions for aromatic nitriles many times in medchem and I loved it. One relatively underused old-fashioned method of making tetrazoles is a spontaneous cyclization of RN=CR’-N3 to tetrazoles. For example 2-azido pyridines and pyrimidines exist exclusively in the cyclized form as tetrazoles. Also S-alkylation of thiosemicarbazone followed by diazotation of the hydrazino group produces RS- substituted tetrazoles in the 5-position in excellent yield.

    • Will Pearson says :

      Stay tuned for Part II, where the azidoazomethine-to-tetrazole chemistry you mention will be prominently featured. It will include fused tetrazoles from azidopyridines and azidopyrimidines, non-fused versions, and plenty of amidrazone diazotization chemistry. Coming later this week!

      Thanks for the perspective and the tips.

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