Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 29;28(13):5087.
doi: 10.3390/molecules28135087.

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC

Haley Hinton  1 , Jack Patterson  1 , Jared Hume  1 , Krunal Patel  1 , Julie Pigza  1
Affiliations

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC

Haley Hinton et al. Molecules. .

Abstract

This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).

Keywords: MAC; masked acyl cyanide; scalable; synthetic equivalent; synthon; umpolung.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Utility of TBS-MAC 1 and other masked acyl cyanides.
Scheme 2
Scheme 2
Prior syntheses of protected MAC derivatives [2,22,28,29].
Scheme 3
Scheme 3
Three-step synthesis of TBS-MAC 1 from malononitrile 6.
Figure 1
Figure 1
Sodium enolate 8.
Figure 2
Figure 2
Acetylmalononitrile 7 before (a) and after (b) a hexanes slurry.
Figure 3
Figure 3
TBS-MAC 1 before (a) and after (b) chromatography.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Nemoto H., Kubota Y., Yamamoto Y. Development of a New Acyl Anion Equivalent for the Preparation of Masked Activated Esters and Their Use To Prepare a Dipeptide. J. Org. Chem. 1990;55:4515–4516.
    1. He X., Buchotte M., Guillot R., Deloisy S., Aitken D.J. A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-Lphenylalaninal with anti diastereoselectivity: Preparation of (2S,3S)-allophenylnorstatin esters. Org. Biomol. Chem. 2022;20:1761–1781. doi: 10.1039/D1OB02411F. - DOI - PubMed
    1. Nemoto H. e-EROS Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons, Ltd.; Hoboken, NJ, USA: 2007. Protected Dicyanomethanol. - DOI
    1. Seebach D. Methods of Reactivity Umpolung. Angew. Chem. Int. Ed. 1979;18:239–258. doi: 10.1002/anie.197902393. - DOI
    1. Hase T.A., Koskimies J.K. A Compilation of References on Formyl and Acyl Anion Synthons. Aldrichimica Acta. 1981;14:73–77.

LinkOut - more resources