Ozonation of
4-(4-aminophenyl)morpholin-3-one (
Moreover, the 4-(4-aminophenyl)morpholin-3-one moiety is present in various factor Xa inhibitors, which entered clinical and preclinical studies [
Two main approaches for the preparation of
In our view, the use of ozone could represent an interesting metal-free alternative. Ozonation is widely used in water and wastewater treatment, and it is particularly appealing to reduce trace organic contaminants [
Ozonation of aliphatic tertiary amines in water and in various organic solvents is already reported [
Here we report the results of an experimental investigation about the selective ozonation of tertiary
In the first set of experiments 4-(4-nitrophenyl)morpholine (
Conversion and isolated yields in 4-(4-nitrophenyl)-morpholin-3-one (
Entry |
|
|
Solvent | Ozonea | Conversionb (%) |
|
Other |
---|---|---|---|---|---|---|---|
1 | 25 | 1.5 | ACN | excess | 100 | 18 |
|
2 | 0 | 1 | ACN | excess | 100 | 35 |
|
3 | 0 | 3 | ACN | 2 : 1 | 100 | 54 |
|
4 | 0 | 3 | ACN | 1 : 10 | 11 | 8 | — |
5 | 0 | 3 | DCM | 2 : 1 | 91 | 29 |
|
6 | 0 | 3 | n-Hexane | 2 : 1 | 80 | 24 |
|
7 | 0 | 3 | Acetone | 2 : 1 | 100 | 52 |
|
8 | 0 | 3 | EA | 2 : 1 | 98 | 34 |
|
9 | 5 | 0.5 | Water PH = 7 | excess | 87 | 2 | — |
10 | 5 | 3 | Water pH = 3 | 8 : 1 | 74 | 1 | — |
11 | 5 | 3 | Water pH = 12 | 8 : 1 | 81 | 0 | — |
12 | 5 | 3 | n-Butanol | 6 : 1 | 72 | 2 | — |
13 | 0 | 3 | ACN | none | 2 | 0 | — |
15d | 0 | 0.5 | ACN | 1 : 40 | 74 | 56 |
|
a100 mg of 4-(4-nitrophenyl)-morpholine (
bConversions are calculated on the recovered 4-(4-nitrophenyl)morpholine.
cGC-MS yield.
dFor the conditions see the experimental section.
Products deriving from the ozonation of 4-(4-nitrophenyl)morpholine (
Differently, the reactions carried out in organic aprotic solvents (Table
In particular, conversions were high by using an excess of ozone (Table
Better results were achieved by using a limited amount of ozone; with a ozone/substrate ratio = 2 : 1 in acetonitrile at 0°C for 3h, 4-(4-nitrophenyl)morpholin-3-one was obtained in 54% yield (Table
Plausible rearrangement mechanisms of aryl-morpholinyl hydrotrioxide intermediate formed by ozonation of 4-(4-nitrophenyl)morpholine (
Higher substrate concentration in the reaction media gave higher selectivity in
Hence, we submitted this procedure a set of cyclic tertiary amines.
Synthesis of
Entrya | Substrate | Conversionb | Product | Yield %c |
---|---|---|---|---|
1 |
|
68% |
|
52 |
| ||||
2 |
|
70% |
|
63 |
| ||||
3 |
|
74% |
|
71 |
| ||||
4 |
|
20% |
|
18 |
aFor the condition see the experimental part.
bConversions are calculated on the recovered starting material.
cIsolated yield after silica gel chromatography.
Ozonation in organic solvent was demonstrated to be a valuable metal-free approach to introduce a carbonyl function on
Starting materials were purchased from Sigma-Aldrich. Solvents were solvent grade from Fluka. Compounds
20 mmol of the selected amines were added to a solution of 100 ml of acetonitrile, kept at 0°C under a continuous stream of ozone (5 mg/min) for a total reaction time of 30 minutes. The residue was evaporated under a nitrogen stream and extracted with alkaline water. Products were isolated by flash chromatography over silica gel (
Supplementary data associated with this paper are available online at doi:10.5402/2012/281642.
The authors thank their students Lorenzo Beretta and Andrea Bosisio, for their collaboration in the experimental work. This work was financialy supported by University of Milan-Bicocca FAR 2011.