Ortiz KG,
Brusoe AT,
*,
An J,
Chong E,
Wu L.
Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, USA
Green Synthesis of Morpholines via Selective Monoalkylation of Amines.
ChemRxiv 2024;
DOI:
10.26434/chemrxiv-2024-5vwkp-v2
Key words
ethylene sulfate - morpholines - zwitterions - monoalkylation
Significance
Morpholine heterocycles are a prevalent feature in agrochemicals and pharmaceuticals,
with the most common approach for their formation being through an annulation reaction
of a 1,2-aminoalcohol to form the desired ring system. While conceptually simple,
the key challenge to executing this strategy is achieving mono-alkylation of the parent
amine, and for this reason an initial acylation reaction is carried out, leading to
the formation of morpholinone products, which can then be reduced to the desired parent
ring system. However, the additional reduction step presents challenges with functional
group tolerance and generation of excess waste, and though alternatives have been
developed, these also have intrinsic limitations including reagent cost and limitations
in substrate scope. The current report enables a two-step synthesis (that can be carried
out in one pot) utilizing ethylene sulfate (ES) as the electrophile, which upon reaction
with a 1,2-aminoalcohol forms a zwitterionic intermediate. The latter can often be
isolated by crystallization, which then cyclizes upon treatment with base to form
the morpholine derivative.
Comment
Model studies evaluated the reaction of ES with N-benzylethanolamine in a range of solvents without the addition of an exogenous base
to enable crystallization of the zwitterionic product whilst purging residual starting
materials and impurities. A broad range of 1,2-aminoalcohols were demonstrated to
be successful substrates, providing the desired products in high yields and high purities.
Surprisingly, subsequent studies indicated that the formation of the monoalkylated
products was not promoted by their selective crystallization, but is instead a function
of the reacting nucleophile as well as special properties imparted by ES. Screening
of base, solvent, and temperature was carried out to identify the optimal conditions
for the cyclization sequence with the reaction applied to a series of diversely substituted
and pharmaceutically relevant morpholine derivatives. The sequence was adapted to
a one-pot protocol avoiding isolation of the intermediate zwitterion, and was also
exemplified on hectogram-scale.