Diaryl ether condensation reactions
One aspect of the present invention relates to novel reaction conditions that allow the efficient synthesis of diaryl ethers from arenes bearing a leaving group and arenols under relatively mild conditions. Another aspect of the present invention relates to the dramatic effects of acidic activators on Ullmann-type couplings involving electron-poor and/or relatively insoluble substrates.
1 . The method depicted in generalized reaction scheme 1:
wherein
Ar and Ar′ independently represent optionally substituted monocyclic or polycyclic aromatic or heteroaromatic moieties;
X represents Cl, Br, 1, —O 3 S(alkyl), or —O 3 S(aryl);
Y represents O, S, Se, NR, PR, or AsR;
Z represents H, a group that is lost under the reaction conditions to generate a negative charge on Y, or a group that is replaced by H under the reaction conditions;
R represents H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, trialkylsilyl, acyl, or sulfonyl;
catalyst represents a transition metal complex;
co-catalyst represents a uncharged molecule comprising a Lewis basic pair of electrons; and
alkali or alkaline earth salt represents a salt selected from the group consisting of alkali and alkaline earth bicarbonates, carbonates, carboxylates, phosphates, alkoxides, silicates, amides, and sulfides.
2 . The method of claim 1 , wherein X represents Br or I.
3 . The method of claim 1 , wherein Y represents O, S, Se, or NR.
4 . The method of claim 1 , wherein Y represents O or S.
5 . The method of claim 1 , wherein Y represents 0.
6 . The method of claim 1 , wherein Z represents H.
7 . The method of claim 1 , wherein Ar and Ar′ independently represent optionally substituted monocyclic aryl or heteroaryl moieties.
8 . The method of claim 1 , wherein Ar and Ar′ independently represent optionally substituted phenyl.
9 . The method of claim 1; wherein the reaction occurs in a non-polar, aprotic solvent.
10 . The method of claim 1 , wherein the reaction occurs in an aromatic hydrocarbon solvent.
11 . The method of claim 1 , wherein the reaction occurs in toluene.
12 . The method of claim 1 , wherein the reaction occurs at a temperature in the range of about 75-150 C.
13 . The method of claim 1 , wherein the reaction occurs at a temperature in the range of about 90-135 C.
14 . The method of claim 1 , wherein the reaction occurs at a temperature in the range of about 100-120 C.
15 . The method of claim 1 , wherein the alkali or alkaline earth salt comprises cesium.
16 . The method of claim 1 , wherein the alkali or alkaline earth salt is cesium carbonate.
17 . The method of claim 1 , wherein the co-catalyst is an ester.
18 . The method of claim 1 , wherein the co-catalyst is an acetate.
19 . The method of claim 1 , wherein the co-catalyst is ethyl acetate.
20 . The method of claim 1 , wherein the catalyst comprises copper.
21 . The method of claim 1 , wherein the catalyst is a copper salt.
22 . The method of claim 1 , wherein the catalyst is selected from the group consisting of copper carboxylates, copper carbonates, copper sulfates, copper sulfonates, copper halides, copper trifluoroborates, and copper phosphates.
23 . The method of claim 1 , wherein the catalyst is copper triflate.
24 . The method of claim 1 , wherein the catalyst and co-catalyst are independently present in the range of about 0.01 to 20 mol % relative to Ar′YZ.
25 . The method of claim 1 , wherein the catalyst and co-catalyst are independently present in the range of about 0.1 to 10 mol % relative to Ar′YZ.
26 . The method of claim 1 , wherein the catalyst and co-catalyst are independently present in the range of about 1 to 5 mol % relative to Ar′YZ.
27 . The method of claim 1 , wherein X represents Br or I; Y represents O, S, Se, or NR; Ar and Ar′ independently represent optionally substituted monocyclic aryl or heteroaryl moieties; the reaction occurs in a non-polar, aprotic solvent; the reaction occurs at a temperature in the range of about 75-150 C; the alkali or alkaline earth salt comprises cesium; the co-catalyst is an ester; the catalyst comprises copper; and the catalyst and co-catalyst are independently present in the range of about 0.01 to 20 mol % relative to Ar′YZ.
28 . The method of claim 1 , wherein X represents Br or I; Y represents O or S; the reaction occurs in an aromatic hydrocarbon solvent; the alkali or alkaline earth salt is cesium carbonate; the reaction occurs at a temperature in the range of about 90-135 C; the co-catalyst is an acetate; the catalyst is selected from the group consisting of copper carboxylates, copper carbonates, copper sulfates, copper sulfonates, copper halides, copper trifluoroborates, and copper phosphates; and the catalyst and co-catalyst are independently present in the range of about 0.1 to 10 mol % relative to Ar′YZ.
29 . The method of claim 1 , wherein X represents Br or 1; Y represents 0; Z represents H; the reaction occurs in toluene; the alkali or alkaline earth salt is cesium carbonate; the catalyst is copper triflate; the co-catalyst is ethyl acetate; the reaction occurs at a temperature in the range of about 100-120 C; and the catalyst and co-catalyst are independently present in the range of about 1 to 5 mol % relative to Ar′YZ.
30 . The method of claim 2 , wherein Y represents O or S.
31 . The method of claim 2 , wherein Y represents O or S; the alkali or alkaline earth salt is cesium carbonate; and the catalyst comprises copper.
32 . The method of claim 2 , wherein Z represents H; and the catalyst comprises copper.
33 . The method of claim 2 , wherein the co-catalyst is ethyl acetate; the catalyst is copper triflate; the reaction occurs in toluene; and the alkali or alkaline earth salt is cesium carbonate.
34 . The method of any one of claims 1 - 33 , wherein the reaction is intramolecular.
35 . The method depicted in generalized reaction scheme 2:
wherein
Ar and Ar′ independently represent optionally substituted monocyclic or polycyclic aromatic or heteroaromatic moieties;
X represents Cl, Br, 1, —O 3 S(alkyl), or —O 3 S(aryl);
Y represents O, S, Se, NR, PR, or AsR;
Z represents H, a group that is lost under the reaction conditions to generate a negative charge on Y, or a group that is replaced by H under the reaction conditions;
R represents H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, trialkylsilyl, acyl, or sulfonyl;
catalyst represents a transition metal complex;
co-catalyst represents a uncharged molecule comprising a Lewis basic pair of electrons;
acid activator is selected from the group consisting of carboxylic acids, amides, hydroxamic acids, phosphoric acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfenic acids, alkylboronic acids, arylboronic acids, silicic acids, alcohols, and thiols; and
alkali or alkaline earth salt represents a salt selected from the group consisting of alkali and alkaline earth bicarbonates, carbonates, carboxylates, phosphates, alkoxides, silicates, amides, and sulfides.
36 . The method of claim 35 , wherein X represents Br or I.
37 . The method of claim 35 , wherein Y represents O, S, Se, or NR.
38 . The method of claim 35 , wherein Y represents O or S.
39 . The method of claim 35 , wherein Y represents 0.
40 . The method of claim 35 , wherein Z represents H.
41 . The method of claim 35 , wherein Ar and Ar′ independently represent optionally substituted monocyclic aryl or heteroaryl moieties.
42 . The method of claim 35 , wherein Ar and Ar′ independently represent optionally substituted phenyl.
43 . The method of claim 35 , wherein the reaction occurs in a non-polar, aprotic solvent.
44 . The method of claim 35 , wherein the reaction occurs in an aromatic hydrocarbon solvent.
45 . The method of claim 35 , wherein the reaction occurs in toluene.
46 . The method of claim 35 , wherein the reaction occurs at a temperature in the range of about 75-150 C.
47 . The method of claim 35 , wherein the reaction occurs at a temperature in the range of about 90-135 C.
48 . The method of claim 35 , wherein the reaction occurs at a temperature in the range of about 100-120 C.
49 . The method of claim 35 , wherein the alkali or alkaline earth salt comprises cesium.
50 . The method of claim 35 , wherein the alkali or alkaline earth salt is cesium carbonate.
51 . The method of claim 35 , wherein the co-catalyst is an ester.
52 . The method of claim 35 , wherein the co-catalyst is an acetate.
53 . The method of claim 35 , wherein the co-catalyst is ethyl acetate.
54 . The method of claim 35 , wherein the acid activator is selected from the group consisting of alkyl and aryl carboxylic acids, alkyl and aryl phosphonic acids, alkyl and aryl sulfonic acids, and alkyl and aryl boronic acids.
55 . The method of claim 35 , wherein the acid activator is selected from the group consisting of alkyl and aryl carboxylic acids.
56 . The method of claim 35 , wherein the acid activator is selected from the group consisting of aryl carboxylic acids.
57 . The method of claim 35 , wherein the acid activator is 1-naphthoic acid.
58 . The method of claim 35 , wherein the catalyst comprises copper.
59 . The method of claim 35 , wherein the catalyst is a copper salt.
60 . The method of claim 35 , wherein the catalyst is selected from the group consisting of copper carboxylates, copper carbonates, copper sulfates, copper sulfonates, copper halides, copper trifluoroborates, and copper phosphates.
61 . The method of claim 35 , wherein the catalyst is copper triflate.
62 . The method of claim 35 , wherein the catalyst and co-catalyst are independently present in the range of about 0.01 to 20 mol % relative to Ar′YZ.
63 . The method of claim 35 , wherein the catalyst and co-catalyst are independently present in the range of about 0.1 to 10 mol % relative to Ar′YZ.
64 . The method of claim 35 , wherein the catalyst and co-catalyst are independently present in the range of about 1 to 5 mol % relative to Ar′YZ.
65 . The method of claim 35 , wherein X represents Br or I; Y represents O, S, Se, or NR; Ar and Ar′ independently represent optionally substituted monocyclic aryl or heteroaryl moieties; the reaction occurs in a non-polar, aprotic solvent; the reaction occurs at a temperature in the range of about 75-150 C; the alkali or alkaline earth salt comprises cesium; the acid activator is selected from the group consisting of alkyl and aryl carboxylic acids, alkyl and aryl phosphonic acids, alkyl and aryl sulfonic acids, and alkyl and aryl boronic acids; the co-catalyst is an ester; the catalyst comprises copper; and the catalyst and co-catalyst are independently present in the range of about 0.01 to 20 mol % relative to Ar′YZ.
66 . The method of claim 35 , wherein X represents Br or I; Y represents O or S; the reaction occurs in an aromatic hydrocarbon solvent; the alkali or alkaline earth salt is cesium carbonate; the reaction occurs at a temperature in the range of about 90-135 C; the acid activator is selected from the group consisting of alkyl and aryl carboxylic acids; the co-catalyst is an acetate; the catalyst is selected from the group consisting of copper carboxylates, copper carbonates, copper sulfates, copper sulfonates, copper halides, copper trifluoroborates, and copper phosphates; and the catalyst and co-catalyst are independently present in the range of about 0.1 to 10 mol % relative to Ar′YZ.
67 . The method of claim 35 , wherein X represents Br or I; Y represents 0; Z represents H; the reaction occurs in toluene; the alkali or alkaline earth salt is cesium carbonate; the catalyst is copper triflate; the acid activator is 1-naphthoic acid; the co-catalyst is ethyl acetate; the reaction occurs at a temperature in the range of about 100-120 C; and the catalyst and co-catalyst are independently present in the range of about 1 to 5 mol % relative to Ar′YZ.
68 . The method of claim 36 , wherein Y represents O or S.
69 . The method of claim 36 , wherein Y represents O or S; the alkali or alkaline earth salt is cesium carbonate; and the catalyst comprises copper.
70 . The method of claim 36 , wherein wherein Z represents H; and the catalyst comprises copper.
71 . The method of claim 36 , wherein the co-catalyst is ethyl acetate; the catalyst is copper triflate; the reaction occurs in toluene; the acid activator is 1-naphthoic acid; and the alkali or alkaline earth salt is cesium carbonate.
72 . The method of any one of claims 35 - 71 , wherein the reaction is intramolecular.