Investigating the Underappreciated Hydrolytic Instability of 1,8-Diazabicyclo[5.4.0]undec-7-ene and Related Unsaturated Nitrogenous Bases

Abstract

The widespread use of amidine and guanidine bases in synthetic chemistry merits a thorough understanding of their chemical properties. The propensity of these reagents to hydrolyze under mild conditions and generate aminolactams and aminoureas, respectively, has not been adequately described previously. During the synthesis of uprifosbuvir (MK-3682), we became aware of this liability for 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) by observing the formation of an unexpected reaction impurity and traced the root cause to low levels of N-(3-aminopropyl)-ε-caprolactam present in the commercial bottle. A controlled stability study over a period of two months at 25 °C demonstrated that, above a threshold water content, DBU steadily hydrolyzed over time. Rates of hydrolysis for DBU, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 7-methyl-1,5,7triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and N,N,N′,N′-tetramethylguanidine (TMG) in organic, aqueous, and mixed solvent systems were then measured to gain a more general appreciation of what conditions to avoid in order to maintain their integrity. Our findings indicate that these bases are hydrolytically unstable in unbuffered and very basic solutions but become significantly more stable in buffered solutions at pH values below 11.6.

DBU: A Reaction Product Component

“…The proposal agrees with the sensitivity of DBU to hydrolysis, especially using water as the solvent. [2,9] F-Substitution of 1-fluoro-2-nitrobenzene in water containing a nonionic surfactant was reported by Lipshutz and coworkers (Scheme 39c) who assumed a reaction via nucleophilic addition of DBU followed by ring opening. [66] Actually, such a reaction in water probably arose as proposed by Brzezinski's team.…”

“…1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU) is a bicyclic and sterically hindered amidine possessing strong basic properties (pKa � 12 in water) [1][2][3] which has been used in a variety of organic reactions. [1,4,5] Although often regarded as a hindered and nonnucleophilic strong base, it nevertheless possesses nucleophilic properties [6] as exemplified with the DBU-catalyzed efficient Baylis-Hillman reaction (Scheme 1).…”

“…DBU could also be a product component of other types of reaction. Besides, DBU is sensitive to hydrolysis, its half-life for a 0.657 M water solution being 33 min at 35°C, [9] giving 1-(3-aminopropyl)azepan-2-one (Scheme 2), [2,[10][11][12][13][14] which may contribute to the scaffold of the final product. Due to the above sensitivity, adventitious water may participate to reactions involving DBU intermediates.…”

Quantitative Raman spectroscopy for the Ioncell® process: Part 2—quantification of ionic liquid degradation products and improvement of prediction performance through interval PLS

“…The formation of APP in the liquid streams may lower or even suppress the cellulose dissolution power of the IL and ultimately lead to the irreversible formation of APPAc. Recently, Hyde and coworkers showed that the hydrolysis reaction could be avoided by controlling the pH (Hyde et al 2019). Limiting the hydrolysis reaction is hence possible but will not be discussed in this paper.…”

Tuned Bis-Layered Supported Ionic Liquid Catalyst (SILCA) for Competitive Activity in the Heck Reaction of Iodobenzene and Butyl Acrylate

“…The results show that among the tested catalysts, SILCA 2 gives the highest value of isoelectric point ~6.9 pH, and potentially the strongest basicity and capability to stabilize palladium, and at the same time, that those with lower value of IEP are more active in the reaction (probably due to the faster Pd leaching) such as in the case of SILCAs 9-12. However, since ζ-potential measurements were conducted in an aqueous solution of the catalyst, they should be considered with skepticism due to the possibility of TMG hydrolysis [35]. Other potential important insight gained by this analysis is the stability of the materials, namely, for many of the catalysts two additional isoelectric points were detected, above 6 pH (IEP2) and around 7 pH (IEP3), as well as lack of IEP in the case of SILCAs 7 and 8.…”