[3+2] annulation to produce 5-membered heterocyclic compounds
The present invention relates to various organic reactions including a method for producing heterocyclic compounds using a [3+2] annulation; a method for producing fluorinated heteroaromatic compounds; and a method for alkylating a meta-position of a phenolic compound.
1. A method for producing a diastereomerically enriched 3-pyrroline compound of the formula:
said method comprising:
deprotonating an α,β-unsaturated compound of the formula:
with a base under condition sufficient to produce a deprotonated intermediate; and
reacting said deprotonated intermediate with an enantiomerically enriched imine compound of the formula:
under conditions sufficient to produce said diastereomerically enriched 3-pyrroline compound of Formula I,
wherein
R is hydrogen, alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, heteroaryl or ester functional group;
X is a leaving group;
Y is a chiral auxiliary group of the formula —S*(═O)R a , wherein * denotes a chiral center and R a is alkyl, cycloalkyl, aralkyl, alkenyl, aralkenyl, heteroalkyl, or heteroaryl; and
Z is an electron withdrawing conjugated group.
2. The method of claim 1 , wherein said imine compound of Formula III has enantiomeric excess (e.e.) of at least 90% e.e.
3. The method of claim 2 , wherein the diastereomeric excess (d.e.) of said 3-pyrroline compound is at least 90% d.e.
4. The method of claim 3 , wherein the diastereomeric excess (d.e.) of said 3-pyrroline compound is at least 95% d.e.
5. The method of claim 1 , wherein R a is alkyl.
6. The method of claim 5 , wherein R a is tert-butyl.
7. The method of claim 1 , wherein * is an (S)-isomer.
8. The method of claim 1 , wherein * is an (R)-isomer.
9. The method of claim 2 , wherein said imine compound of Formula III has enantiomeric excess of at least 95% e.e.
10. The method of claim 2 , wherein said imine compound of Formula III has enantiomeric excess of at least 99% e.e.
11. The method of claim 3 , wherein the diastereomeric excess of said 3-pyrroline compound is at least 99% d.e.
12. The method of claim 1 further comprising the steps of removing the chiral auxiliary group from said 3-pyrroline compound of Formula I to produce a free 3-pyrroline compound of Formula IA:
wherein
R and Z are those defined in claim 1 .