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

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-1,5,7-triazabicyclo[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.