Direct stereospecific synthesis of unprotected aziridines from olefins
A method for the direct stereospecific conversion of structurally diverse mono-, di-, tri- and tetra-substituted olefins to N—H, N-alkyl, N-cycloalkyl, or N-aralkyl aziridines using a hydroxylamine amination agent with transition metal catalyst. The method is operationally simple (i.e., one-pot), scalable and fast at ambient temperature.
1. A process for making an aziridine of the formula AP-1
where R 1A is selected from H, unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, and aralkyl;
each of R a , R b , R c , and R d is independently selected from: H, substituted and unsubstituted aryl, unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, C 2 -C 18 alkenyl, C 3 -C 8 cycloalkenyl, and C 2 -C 18 alkenyl, or wherein R c and R d form a ring;
the method comprising:
reacting an olefin of formula O-1
with a hydroxylamine amination agent in the presence of a transition metal catalyst selected from copper and rhodium catalysts in a polar, hydroxylic and non-nucleophilic solvent, a carboxylic solvent or mixtures of the same at a temperature less than 30° C.;
wherein the hydroxylamine amination agent is selected from compounds of formulas AA-1, AA-2, AA-5, AA-6, AA-7, AA-8:
wherein each R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, —Si(R 3 ) 3 , allyl, aralkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
wherein R 1 and R 2 can be connected to form a cyclic amine having from 4 to 7 carbocyclic ring members;
each R 3 is independently selected from unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro and substituted or unsubstituted aryl;
each R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from hydrogen, nitro, fluoro, chloro, bromo, unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N + —, and (R 20 ) 2 P(O)—;
R 9 is selected from unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, and C 3 -C 8 cycloalkyl;
R 10 and R 11 are independently selected from substituted and unsubstituted aryl;
wherein the number of substituents for substituted aryl may be from 1 to 5 and independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N + , (R 20 ) 2 P(O)—, PEG m -, and o-furanyl;
R 12 is selected from unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, C 1 -C 18 alkenyl, C 3 -C 8 cycloalkenyl, substituted and unsubstituted aryl;
wherein the number of substituents for substituted aryl may be from 1 to 5 and independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N + —, (R 20 ) 2 P(O)—, PEG m -, and o-furanyl;
R 13 is selected from substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro, C 3 -C 8 cycloalkyl, and CCl 3 , or when R 13 forms an aromatic or other ring system with R 15 , then R 13 is selected from O, N, and C—R 20 ;
wherein the number of substituents for substituted aryl may be from 1 to 5 and wherein the number of substituents for substituted heteroaryl may be from 1 to 4 and each substituent is independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N+—, and (R 20 ) 2 P(O)—, PEG m -, and o-furanyl;
R 14 is absent or selected from H, substituted and unsubstituted aryl, C 3 -C 8 cycloalkyl, and unsubstituted C 1 -C 18 alkyl or C 1 -C 18 alkyl substituted with fluoro,
wherein the number of substituents for substituted aryl may be from 1 to 5 and wherein the number of substituents for substituted heteroaryl may be from 1 to 4 and each substituent is independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N + —, and (R 20 ) 2 P(O)—, PEG m -,
R 15 is selected from selected from substituted and unsubstituted aryl, unsubstituted C 1 -C 8 alkyl or C 1 -C 18 alkyl substituted with fluoro, and C 3 -C 8 cycloalkyl, or when R 15 forms an aromatic or other ring system with R 13 , then R 15 is CH or CH 2 ;
wherein the number of substituents for substituted aryl may be from 1 to 5 and each substituent is independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, R 16 R 17 NC(O)—, R 18 O 2 C—, (R 19 ) 4 N + —, and (R 20 ) 2 P(O)—, PEG m -,
where each m is independently from 1 to 6;
each R 16 , R 17 , R 18 , R 19 , R 20 is independently selected from H, C 3 -C 8 cycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and unsubstituted C 1 -C 18 alkyl and C 1 -C 18 alkyl substituted with fluoro;
wherein the number of substituents for each substituted aryl may be from 1 to 5 and the number of substituents for each substituted heteroaryl may be from 1 to 4 and each substituent is independently selected from nitro, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, arylsulfonyl, alkylsulfonyl, mono-/di-/tri-fluoroalkylsulfonyl, trifluoromethyl, PEG m .
2. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-1.
3. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-2.
4. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-5.
5. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-6.
6. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-7.
7. The process of claim 1 , wherein the hydroxylamine amination agent is of formula AA-8.
8. The process of claim 1 , wherein the transition metal catalyst is a copper catalyst.
9. The process of claim 1 , wherein the transition metal catalyst is a rhodium catalyst.
10. The process of claim 1 , wherein the catalyst is selected from: Rh 2 (OAc) 4 , Rh 2 (octanoate) 4 , and Rh 2 (esp) 2 .
11. The process of claim 1 , wherein the polar, hydroxylic and nonnucleophilic solvent comprises trifluoroethanol.
12. The process of claim 1 , wherein the transition metal catalyst is incrementally introduced in batches of about 1 mol %.
13. The process of claim 1 , wherein R c and R d form a ring.
14. The process of claim 10 , wherein R c and R d form a ring.