![1,8-DiazaBicyclo[5.4.0]Undec-7-ene (DBU): unexpected side reactions](https://media.licdn.com/dms/image/v2/D4E12AQGaOgnQ7_aOOw/article-cover_image-shrink_600_2000/article-cover_image-shrink_600_2000/0/1696320862634?e=2147483647&v=beta&t=NzVMUTsKcr_g8XhF6qGw3ut2N5bQJQx5hmOz6RKZ6ZQ)
1,8-DiazaBicyclo[5.4.0]Undec-7-ene (DBU): unexpected side reactions
In 2019, A. M. Hyde and Coll. from the Department of Process Research & Development at Merck (Rahway, New Jersey) published a very interesting and complete study on underappreciated side-reactions of 1,8-DiazaBicyclo[5.4.0]Undec-7-ene (DBU) and related unsaturated nitrogenous bases. [1] DBU belongs to the class of amidine compounds and is known as a base (pKa 24.3 (ACN), pKa 16.8 (THF), pKa 13.9 (DMSO) and pKa 11.5 (water)) which has found a plethora of utilizations for base-mediated reactions. Nevertheless, in contrast to what was generally admitted, the nucleophilic behavior of DBU was pointed out by G. Bertrand and Coll. as early as 1993. [2] A. M. Hyde and Coll. studied through various experiments the propensity of DBU to hydrolysis under mild different conditions (see Scheme below). Furthermore, neat DBU is stable for long periods under dry conditions, but even modest amounts of water (present in an old bottle and/or exposure to atmospheric water) will result in appreciable hydrolysis over time.
?On the other hand, the side reaction of DBU with electrophiles to provide N-functionalized amino-lactam A adducts is also discussed.?
[1] A. M. Hyde, R. Calabria, R. Arvary, X. Wang, A. Klapars, Org. Process Res. Dev. 2019, 23, 1860-1871.
[2] R. Reed, R. Re?au, F. Dahan, G. Bertrand, Angew. Chem., Int. Ed. Engl.1993, 32, 399-401.
Senior Researcher at the Institute of Inorganic chemistry CAS
1 年Significant..!
Principal Scientist Process Development chez The Janssen Pharmaceutical Companies of Johnson & Johnson
1 年Your post reminds me of a project where I faced challenges in determining the structure of an impurity in a reaction that involved the use of DBU. It's worth noting that we have observed varying levels of water and this particular amine across different batches of DBU. If your starting material or product has the potential to react with a primary amine, it's best to quantitatively assess the water content through a KF titration and to conduct a GC analysis to evaluate the quality of the batch. But thanks for sharing that Jacques!
Organic and Medicinal Chemist | Drug Discovery | Chemistry | Executive Management | Cross-Functional Collaborator | Lead Optimization | Waterfall | R&D | Cricket | Vedic Astrology |
1 年Many researchers may miss this observation.
Organic and Medicinal Chemist | Drug Discovery | Chemistry | Executive Management | Cross-Functional Collaborator | Lead Optimization | Waterfall | R&D | Cricket | Vedic Astrology |
1 年Interesting unexpected reaction and a new synthon.
Synthetic Organic Chemist at Osmo. Giving computers a sense of smell
1 年Awareness of this transformation is especially important in high-temperature nucleophilic substitution reactions (particularly SNAr reactions in DMF/DMSO/MeCN). I've observed impurities in several processes where this amine is incorporated, sometimes even in preference to the intended, often more sterically hindered, nucleophile.