US 12,338,193 B2
Methods for enantioselective preparation of chiral tetraarylmethanes
Jianwei Sun, Hong Kong (CN); and Xingguang Li, Hong Kong (CN)
Assigned to The Hong Kong University of Science and Technology, Hong Kong (CN)
Appl. No. 17/424,220
Filed by The Hong Kong University of Science and Technology, Hong Kong (CN)
PCT Filed Jan. 2, 2020, PCT No. PCT/CN2020/070124
§ 371(c)(1), (2) Date Jul. 20, 2021,
PCT Pub. No. WO2020/156022, PCT Pub. Date Aug. 6, 2020.
Claims priority of provisional application 62/918,404, filed on Jan. 29, 2019.
Prior Publication US 2022/0112138 A1, Apr. 14, 2022
Int. Cl. C07D 207/32 (2006.01); B01J 31/02 (2006.01); C07B 53/00 (2006.01); C07D 209/08 (2006.01); C07D 403/06 (2006.01); C07D 409/06 (2006.01); C07D 413/14 (2006.01); C07D 417/06 (2006.01); C07D 417/14 (2006.01)
CPC C07B 53/00 (2013.01) [B01J 31/0258 (2013.01); C07D 207/32 (2013.01); C07D 209/08 (2013.01); C07D 403/06 (2013.01); C07D 409/06 (2013.01); C07D 413/14 (2013.01); C07D 417/06 (2013.01); C07D 417/14 (2013.01); B01J 2531/0266 (2013.01)] 13 Claims
 
1. An enantioselective method for preparing a tetraarylmethane, wherein the tetraarylmethane has Formula Ia:

OG Complex Work Unit Chemistry
wherein
m is 0, 1, 2, or 3;n is 1, 2, 3, or 4;
p is 0, 1, 2, or 3;
t is 0, 1, 2, or 3;
Ar1 is:

OG Complex Work Unit Chemistry
Ar2 is:

OG Complex Work Unit Chemistry
X is NH;
Y is NH;
R1′ is selected from the group consisting of —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3; or two instances of R1 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two instances of R2 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; and
R4 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R4 taken together with the nitrogen to which they are attached form a 3-6 membered heterocycloalkyl; or one instance of R3 and one instance of R4 taken together with the atoms to which they are attached form a 4-6 membered heterocycloalkyl;
each R9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3;
R9′ is —OH;
R10 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and halide; and
each R12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3; or two instances of R12 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and the method comprises:
contacting a compound of Formula IIa, wherein the compound of Formula IIa is

OG Complex Work Unit Chemistry
wherein Ar1 is selected from the group consisting of:

OG Complex Work Unit Chemistry
m is 0, 1, 2, or 3;
n is 1, 2, 3, or 4;
p is 0, 1, 2, or 3;
X is NH;
R1′ is selected from the group consisting of —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
each R9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3;
R9′ is —OH; and
R10 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and halide;
with a heteroaromatic nucleophile in the presence of a chiral Brønsted acid under conditions that facilitate an electrophilic aromatic substitution reaction thereby forming the compound of Formula Ia, wherein the heteroaromatic nucleophile is represented by the Formula IV:

OG Complex Work Unit Chemistry
wherein
t is 0, 1, 2, or 3;
Y is NH; and
each R12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3; or two instances of R12 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and
the chiral Brønsted acid is a chiral phosphoric acid represented by Formula IIIa, Formula IIIb, or Formula IIId:

OG Complex Work Unit Chemistry
wherein
Q is O, S, or NSO2R16;
Z is O, S, or Se;
each of R5 and R5′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or triarylsilane;
each of R6 and R6′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
each of R7 and R7′ is independently alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane; or R6′ and R7′ taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl and R6 and R7 taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl;
each of R14 and R14′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
each of R15 and R15′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane; and
R16 is alkyl or aryl.