Asymmetric addition reactions

Patent metadata

Field	Value
Publication number	US-10464861-B2
Application number	US-201615580838-A
Country	US
Kind code	B2
Filing date	Jun 1, 2016
Priority date	Jun 9, 2015
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

Processes of forming Csp2—Csp3 bonds at the allylic carbon of a cyclic allylic compound starting material are disclosed, in which a racemic mixture of a cyclic allylic compound having a leaving group attached to the allylic carbon is reacted with a compound having a nucleophilic carbon atom in the presence of a Rh(I), Pd(II) or Cu(I) pre-catalyst and a chiral ligand. The reaction products containing the newly-formed Csp2—Csp3 bond are generated in high stereoisomeric excess, and may therefore serve as important organic building blocks in the preparation of new agrochemicals and pharmaceuticals.

First claim

The invention claimed is:

1. A process for the formation of a C sp3 —C sp2 bond at the allylic carbon of a cyclic allylic compound, the process comprising the step of:
a) reacting a racemic mixture of a cyclic allylic compound having a leaving group attached to the allylic carbon with a compound having a nucleophilic carbon atom,
wherein step a) is conducted in the presence of:
i) a pre-catalyst based on Rh(I); and
ii) a chiral ligand

and wherein the formation of the C sp3 —C sp2 bond results in the generation of a product compound in a stereoisomeric excess.

2. The process of claim 1 , wherein in step a), the cyclic allylic compound having a leaving group attached to the allylic carbon also has a hydrogen attached to the allylic carbon.

3. The process of claim 1 , wherein the chiral ligand is non-racemic.

4. The process of claim 1 , wherein the chiral ligand is a phosphorus containing ligand or a diene ligand.

5. The process of claim 1 , wherein the chiral ligand is a monodentate ligand, a bidentate ligand, or a tridentate ligand.

6. The process of claim 1 , wherein the chiral ligand is selected from monophosphines, monophosphites, monophosphinites, monophosphonites, bisphosphines, bisphosphites, bisphosphinites, bisphosphonites, phosphoramidites and dienes.

7. The process of claim 1 , wherein the pre-catalyst based on Rh(I) is selected from [Rh(COD)(OH)] 2 , wherein COD denotes cyclooctadiene, or Rh(acac)(C 2 H 4 ) 2 , wherein acac denotes acetylacetone.

8. The process of claim 1 , wherein the product compound produced in a stereoisomeric excess has a structure according to formula (I) shown below:

wherein
ring A is a 4-8 membered carbocyclyl or heterocyclyl ring optionally fused to one or more rings B, wherein rings A and B are each independently optionally substituted with one or more groups selected from oxo, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 , (O) z Si(OR a ) 3 , 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy;
wherein
each ring B is independently 5-8 membered carbocyclyl, 6-8 membered aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, any of which may be optionally substituted with one or more groups selected from oxo, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 ,(O) z Si(OR a ) 3 , 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy; and

R 1 is selected from aryl or heteroaryl, either of which may be optionally fused to one or more rings C, and optionally substituted with one or more substituents selected from oxo, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 , (O) z Si(OR a ) 3 , 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy;
wherein
each ring C is monocyclic or bicyclic aryl or heteroaryl, any of which is optionally substituted with one or more groups selected from oxo, (1-8C)alkyl, (2-8)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 , (O) z Si(OR a ) 3 , 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy;

or R 1 is a group

wherein
R 2 , R 3 and R 4 are independently selected from
i) H, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 and (O) z Si(OR a ) 3 ; or
ii) 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy, the cyclic moieties of which may be optionally substituted with one or more substituents selected from oxo, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxyl, amino, (1-8C)haloalkyl, (1-8C)alkoxy, (1-8C)haloalkoxy, carboxyl, carbamoyl, sulphamoyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) x R a , SO 2 N(R b )R a , N(R b )SO 2 R a , (CH 2 ) y NR a R b , (O) z Si(R a ) 3 , (O) z Si(OR a ) 3 , 4-6 membered carbocyclyl, 4-6 membered carbocyclyl(1-3C)alkyl, 4-6 membered carbocyclyl(1-3C)alkoxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1-3C)alkyl, 4-6 membered heterocyclyl(1-3C)alkoxy, phenyl, phenyl(1-3C)alkyl, phenyl(1-3C)alkoxy, 5-6 membered heteroaryl, 5-6 membered heteroaryl(1-3C)alkyl, and 5-6 membered heteroaryl(1-3C)alkoxy;
wherein
each of R a and R b are independently selected from H, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl;
each x is independently 0, 1 or 2;
each y is independently 1, 2, or 3; and
each z is independently 0 or 1.

9. The process of claim 1 , wherein, in step a), the cyclic allylic compound having a leaving group attached to the allylic carbon has a structure according to formula (II) shown below:

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Fletcher Stephen P
• Sidera Portela Mireia

Classifications

• C07D333/08

  Hydrogen atoms or radicals containing only hydrogen and carbon atoms · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C2531/24

  Phosphines · CPC title

• C07D309/18

  containing only hydrogen and carbon atoms in addition to the ring hetero atom · CPC title