Modular synthesis of 1,2-azaborines via ring-opening BN-isostere benzannulation

1 . A method for making a 1,2-disubstituted azaborine having the structure:

or a pharmaceutically-acceptable salt thereof, or a solvate thereof, wherein

R 1 is a carbon-linked substituent having no more than 40 non-H atoms;

R 2 is a carbon-linked substituent having no more than 40 non-H atoms;

R 3 is H or a substituent having no more than 40 non-H atoms, and

L 3 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 3 -R 3 is halo, nitro, or cyano;

R 4 is H or a substituent having no more than 40 non-H atoms, and

L 4 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 12 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 4 -R 4 is halo, nitro, or cyano;

R 6 is H or a substituent having no more than 40 non-H atoms, and

L 6 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 6 -R 6 is halo, nitro, or cyano:

wherein

each R 7 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(C 0 -C 6 alkyl)-L-R 8 , —(C 0 -C 6 alkyl)-NR 10 R 9 , —(C 0 -C 6 alkyl)-OR 11 , —(C 0 -C 6 alkyl)-C(O)R 11 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 11 , -halogen, —NO 2 , and —CN, wherein

each L is independently selected

from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—,

—C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O) 0 , —OC(O)—, —C(S)O—,

—OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—,

—SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 —, and —NR 9 SO 2 NR 9 —,

each R 8 , R 10 , and R 11 is independently selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(C 0 -C 6 alkyl)-L-(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-NR 9 —(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-O—(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)—(C 0 -C 6 alkyl), and —(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl),

each R 9 is independently selected from —H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl), and —C(O)O—(C 1 -C 4 alkyl),

each Ar is an optionally substituted aryl,

each Het is an optionally substituted heteroaryl,

each Cak is an optionally substituted cycloalkyl,

each Hca is an optionally substituted heterocycloalkyl, and

each alkyl is optionally substituted, the method comprising:

combining a Lewis acid, an N-substituted 1-cyclopropyl imine, and a B-substituted dihaloborane and allowing them to react to form a B-substituted, N-substituted, 1-halo-N-(6-halohex-3-enyl)boranamine; then

treating the B-substituted, N-substituted, 1-halo-N-(6-halohex-3-enyl)boranamine with a base to provide the 1,2-disubstituted azaborine.

2 . The method of claim 1 , wherein the Lewis acid is ZnBr 2 , Zn(OTf) 21 or BF 3 , and wherein the dihaloborane is a dibromoborane.

3 . The method of claim 1 , wherein the N-substituted 1-cyclopropyl imine has the structure

wherein R 1 is a carbon-linked substituent having no more than 40 non-H atoms;

R 3 is H or a substituent having no more than 40 non-H atoms, and

L 3 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 3 -R 3 is halo, nitro, or cyano;

R 4 is H or a substituent having no more than 40 non-H atoms, and

L 4 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 4 -R 4 is halo, nitro, or cyano;

R 6 is H or a substituent having no more than 40 non-H atoms, and

L 6 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, —NR 7 —, —C(O)NR 7 —, —NR 7 C(O)—, —C(S)NR 7 —, —NR 7 C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O) 1-2 O—, —OS(O) 1-2 —, —S(O) 1-2 NR 7 —, and —NR 7 S(O) 1-2 —, or

-L 6 -R 6 is halo, nitro, or cyano;

wherein

each R 7 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(C 0 -C 6 alkyl)-L-R 8 , —(C 0 -C 6 alkyl)-NR 10 R 9 , —(C 0 -C 6 alkyl)-OR 11 , —(C 0 -C 6 alkyl)-C(O)R 11 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 11 , -halogen, —NO 2 , and —CN, wherein

each L is independently selected

from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—,

—C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—,

—OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 —, and —NR 9 SO 2 NR 9 —,

each R 8 , R 10 , and R 11 is independently selected from H, —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, —(C 0 -C 6 alkyl)-Hca, —(C 0 -C 6 alkyl)-L-(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-NR 9 —(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-O—(C 0 -C 6 alkyl), —(C 0 -C 6 alkyl)-C(O)—(C 0 -C 6 alkyl), and —(C 0 -C 6 alkyl)-S(O) 0-2 —(C 0 -C 6 alkyl),

each R 9 is independently selected from —H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl), and —C(O)O—(C 1 -C 4 alkyl),

each Ar is an optionally substituted aryl,

each Het is an optionally substituted heteroaryl,

each Cak is an optionally substituted cycloalkyl,

each Hca is an optionally substituted heterocycloalkyl, and

each alkyl is optionally substituted.

4 . The method of claim 1 , wherein the Lewis acid is present in an amount of 10 mol % of the N-substituted 1-cyclopropyl imine and the B-substituted dihaloborane, whichever is provided in lesser molar amount.

5 . The method of claim 1 , wherein a molar ratio of the B-substituted dihaloborane to the N-substituted 1-cyclopropyl imine is in a range of 0.7-1.5.

6 . The method of claim 1 , wherein the Lewis acid, the N-substituted 1-cyclopropyl imine, and the B-substituted dihaloborane are allowed to react at a temperature in a range of 40-100° C. for at least one hour.

7 . The method of claim 1 , wherein the base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

8 . The method of claim 1 , wherein R 1 is an optionally-substituted C 1 -C 24 alkyl, an optionally-substituted C 2 -C 24 alkenyl, an optionally-substituted C 1 -C 24 alkynyl, an optionally-substituted C 6 -C 24 aryl, an optionally-substituted C 5 -C 24 heteroaryl, an optionally-substituted C 3 -C 24 cycloalkyl, or an optionally-substituted C 3 -C 24 heterocycloalkyl; or wherein R 2 is an optionally-substituted C 1 -C 24 alkyl, an optionally-substituted C 2 -C 24 alkenyl, an optionally-substituted C 1 -C 24 alkynyl, an optionally-substituted C 6 -C 24 aryl, an optionally-substituted C 5 -C 24 heteroaryl, an optionally-substituted C 3 -C 24 cycloalkyl, or an optionally-substituted C 3 -C 24 heterocycloalkyl.

9 . The method of claim 1 , wherein R 3 is an optionally-substituted C 1 -C 24 alkyl, an optionally-substituted C 2 -C 24 alkenyl, an optionally-substituted C 1 -C 24 alkynyl, an optionally-substituted C 6 -C 24 aryl, an optionally-substituted C 5 -C 24 heteroaryl, an optionally-substituted C 3 -C 24 cycloalkyl, or an optionally-substituted C 3 -C 24 heterocycloalkyl.

10 . The method of claim 4 , wherein L 3 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, and —NR 7 —.

11 . The method of claim 1 , wherein -L 3 -R 3 is halo, nitro, or cyano.

12 . The method of claim 1 , wherein R 4 is an optionally-substituted C 1 -C 24 alkyl, an optionally-substituted C 2 -C 24 alkenyl, an optionally-substituted C 1 -C 24 alkynyl, an optionally-substituted C 6 -C 24 aryl, an optionally-substituted C 5 -C 24 heteroaryl, an optionally-substituted C 3 -C 24 cycloalkyl, or an optionally-substituted C 3 -C 24 heterocycloalkyl.

13 . The method of claim 1 , wherein L 4 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, and —NR 7 —.

14 . The method of claim 1 , wherein -L 4 -R 4 is halo, nitro, or cyano.

15 . The method of claim 1 , wherein R 6 is an optionally-substituted C 1 -C 24 alkyl, an optionally-substituted C 2 -C 24 alkenyl, an optionally-substituted C 1 -C 24 alkynyl, an optionally-substituted C 6 -C 24 aryl, an optionally-substituted C 5 -C 24 heteroaryl, an optionally-substituted C 3 -C 24 cycloalkyl, or an optionally-substituted C 3 -C 24 heterocycloalkyl.

16 . The method of claim 1 , wherein L 6 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O) 1-2 —, —O—, and —NR 7 —.

17 . The method of claim 1 , wherein -L 6 -R 6 is halo, nitro, or cyano.