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.

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10 responses to “Tetrazole synthesis, Part II: Harnessing the tetrazole-azidoazomethine equilibrium”

  1. Will Pearson says :

    Check out this very nice recent paper by Hulme at Arizona on the synthesis of tetrazoles by the Ugi-Azide reaction (carbonyl compound + primary amine + isocyanide + TMSN3). The tetrazole is produced by an azidoazomethine electrocyclization as discussed in this blog post. http://bit.ly/z9PaBR

  2. Morris Slutsky says :

    Beautiful stuff! I’ve done quite a few diazotizations and have in fact had to deal with unwanted cyclicization products here and there. Guess there’s a good side and a bad side to every reaction pathway. Interesting to see that all of these use aqueous conditions – I made a few attempts, with various hydrophobic compounds, to use t-butyl nitrite conditions, with moderate though not spectacular success.

  3. Dominik says :

    damn! should’ve stumbled over this website earlier – not just one day before seminar talk about tetrazoles. too much knowledge, too little time… 😉
    though, i found a nice paper starting without any functional groups (except for double bond): Jiao et al, Angew. Chem. Int. Ed. 2011 (50), 11487

  4. pash says :

    In the case of tertiaryamine/secondary amine hydrochloride catalyzed tetrazole formations sodium azide, running the reaction in the corresponding amine as the solvent has accelerating effect on the tetrazole formation. This is far far superior when compared to running the reaction in toluene/DMF/NMP.

  5. Ulhas Bhatt says :

    I wrote a chapter on tetrazoles for “Modern Heterocyclic Chemistry” which covers a variety of methods for the synthesis of tetrazoles upto 2009.
    http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527332014,subjectCd-CH84.html

  6. muna says :

    Is it possible to prepare tetrazole from the reaction between schiff bases with sodium Azaid

  7. The Heterocyclist says :

    A new review “Synthesis and Functionalization of 5-Substituted Tetrazoles” just appeared by Roh, et al., at Charles University in Prague: http://bit.ly/NrYqOS

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