Difluoromethoxylation and trifluoromethoxylation compositions and methods for synthesizing same
The present invention provides a compound having the structure: a processing of making the compound; and a process of using the compound as a reagent for the difluoromethoxylation and trifluoromethoxylation of arenes or heteroarenes.
1. A compound having the structure:
Y 1 is N or C—X 1 , Y 2 is N or C—X 2 , Y 3 is N or C—X 3 , Y 4 is N or C—X 4 and Y 6 is N or C—X 6 ,
wherein X 1 , X 2 , X 3 , X 4 , and X 6 are each, independently, —H, halogen, —CF 3 , —NO 2 , —SO 2 Me, —CN, —OCF 3 , —OCF 2 H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —C(O)—R 1 , —C(O)—OR 1 , —C(O)—SR 1 , —OR 1 , —SR 1 , —NR 1 R 2 , or —C(O)—NR 1 R 2 ,
wherein R 1 and R 2 are each, independently, —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —C(O)—R 3 , —C(O)—OR 3 , —C(O)—NR 4 R 5 , —C(O)—SR 3 , —C(S)—R 3 , —C(S)—OR 3 , —C(S)—NR 4 R 5 , —C(S)—SR 3 , —C(NR 5 )—R 3 , —C(NR 5 )—OR 3 , —C(NR 6 )—NR 4 R 5 or —C(NR 6 )—SR 3 ,
wherein R 3 , R 4 , R 5 and R 6 are each, independently, —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl) or -(heteroaryl);
Y 5 is N or N + —X 5 ,
wherein X 5 is —H, -alkyl, —C(O)-alkyl, —C(O)-aryl, —C(O)—heteroaryl, —C(O)—O-alkyl or —C(O)—O-aryl;
X 7 is CF 3 , CF 2 H, CFH 2 , perfluoroalkyl or polyfluoroalkyl; and
Z is OTf, BF 4 , B(aryl) 4 , SbF 6 , PF 6 , halogen, —OS(O) 2 OR 7 , —OS(O) 2 —R 7 , ClO 4 or —OP(O)(OR 8 )(OR 9 ), wherein R 7 , R 8 , and R 9 are each, independently, —H, -(alkyl), -(aryl), -(heteroaryl);
wherein when Y 6 is N, then Y 5 is N + —X 5 and Z − is present, or wherein
when Y 6 is C—X 6 , then Y 5 is N and Z − is absent.
2. The compound of claim 1 , wherein
i) Y 1 is N or C—X 1 , Y 2 is N or C—X 2 , Y 3 is N or C—X 3 and Y 3 is N or C—X 3 and Y 4 is N or C—X 4 ,
wherein X 1 , X 2 , X 3 , X 4 are each, independently, —H, halogen, —CF 3 , —NO 2 , —SO 2 Me, —CN, —OCF 3 , —OCF 2 H;
Y 5 is N or N + —X 5 ,
wherein X 5 is alkyl;
Y 6 is N or C—X 6 ,
wherein X 6 is substituted aryl or substituted heteroaryl;
X 7 is CF 3 or CF 2 H; and
Z is OTf, BF 4 , B(aryl) 4 , SbF 6 , PF 6 , halogen, —OS(O) 2 OR 7 , —OS(O) 2 —R 7 , ClO 4 or —OP(O)(OR 8 )(OR 9 ), wherein R 7 , R 8 , and R 9 are each, independently, —H, -(alkyl), -(aryl), -(heteroaryl);
wherein when Y 6 is N, then Y 5 is N + —X 5 and Z − is present, and when Y 6 is C—X 6 , then Y 5 is N and Z − is absent;
or
ii)
Y 1 is N or C—X 1 , Y 2 is N or C—X 2 , Y 3 is N or C—X 3 and Y 4 is N or C—X 4 , wherein X 1 , X 2 , X 3 and X 4 are each, independently, —H, —Cl, —Br, —F, —CF 3 , —NO 2 or —SO 2 Me
Y 5 is N or N + —X 5 ,
wherein X 5 is alkyl;
Y 6 is N or C—X 6 ,
wherein X 6 is substituted aryl;
X 7 is CF 3 or CF 2 H; and
Z is OTf, BF 4 , B(aryl) 4 , SbF 6 , PF 6 , halogen, —OS(O) 2 OR 7 , —OS(O) 2 —R 7 , ClO 4 or —OP(O)(OR 8 )(OR 9 ), wherein R 7 , R 8 , and R 9 are each, independently, —H, -(alkyl), -(aryl), -(heteroaryl);
wherein when Y 6 is N, then Y 5 is N + —X 5 and Z − is present, and when Y 6 is C—X 6 , then Y 5 is N and Z − is absent.
3. The compound of claim 1 , wherein
i) Y 2 is C—X 2 ,
wherein X 2 , is halogen, —CF 3 , —NO 2 , —SO 2 Me, —CN, —OCF 3 or —OCF 2 H;
or
ii)
Y 2 is C—X 2 , and
Y 4 is C—X 4
wherein X 2 and K 4 are each, independently, halogen, —CF 3 , —NO 2 , —SO 2 Me, —CN, —OCF 3 or —OCF 2 H;
or
iii) at least two of Y 1 , Y 2 , Y 3 and Y 4 are other than C—H.
4. The compound of claim 1 , wherein Z is OTf.
5. The compound of claim 1 , having the structure:
wherein
Y 2 is C—X 2 ; and
Y 4 is C—X 4 ,
wherein X 2 and X 4 are each, independently, halogen, —CF 3 , —NO 2 , —SO 2 Me, —CN, —OCF 3 or —OCF 2 H;
or
having the structure:
wherein X 7 is —CF 2 H or —CF 3 .
6. A process for preparing the compound of claim 5 having the structure:
wherein X 5 is alkyl and X 7 is —CF 2 H,
comprising
(a) reacting the compound having the structure:
with a difluoromethylating agent in a first suitable solvent,
wherein the difluormethylating agent is diethyl (bromodifluoromethyl)phosphonate;
under conditions sufficient to produce the compound having the structure:
wherein X 7 is —CF 2 H; and
(b) reacting the product of step (a) with an alkylating agent bearing a Z group in a second suitable solvent under conditions sufficient to produce the compound.
7. The process of claim 6 for preparing the compound having the structure:
comprising
(a) reacting the compound having the structure:
with a difluoromethylating agent in a first suitable solvent,
wherein the difluormethylating agent is diethyl (bromodifluoromethyl)phosphonate;
under conditions sufficient to produce the compound having the structure:
(b) reacting the product of step (a) with a methylating agent bearing a triflate group in a second suitable solvent under conditions sufficient to produce the compound.
8. A process for preparing the compound of claim 5 having the structure:
wherein X 5 is alkyl and X 7 is —CF 3 ,
comprising
(a) reacting the compound having the structure:
with a trifluoromethylating agent in a first suitable solvent, wherein the trifluormethylating agent is Togni reagent I or Togni reagent II,
under conditions sufficient to produce the compound having the structure:
wherein X 7 is —CF 3 ;
(b) reacting the product of step (a) with an alkylating agent bearing a triflate group in a second suitable solvent under conditions sufficient to produce the compound.
9. The process of claim 8 for preparing the compound having the structure:
comprising
(a) reacting the compound having the structure:
with a trifluoromethylating agent in a first suitable solvent, wherein the trifluormethylating agent is Togni reagent I or Togni reagent II,
under conditions sufficient to produce the compound having the structure:
(b) reacting the product of step (a) with a methylating agent bearing a triflate group in a second suitable solvent under conditions sufficient to produce the compound.
10. A process of fluoromethoxylating an arene or heteroarene, or an aryl or heteroaryl group of an aryl or heteroaryl containing compound, wherein at least one carbon of the arene or heteroarene, or aryl or heteroaryl group, is unsubstituted, comprising reacting the arene or heteroarene, or aryl or heteroaryl group, with the compound of claim 1 under conditions sufficient to thereby produce the fluoromethoxylated arene or heteroarene, or aryl or heteroaryl group,
wherein the arene or heteroarene is a phenyl, pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran, benzothiophene or quinolone.
11. The process of claim 10 , wherein the reaction occurs in the presence of a metal catalyst;
or
wherein the reaction occurs in the presence of a Ruthenium catalyst or Iridium catalyst;
or
wherein the reaction occurs under irradiation with visible light.
12. The process of claim 10 for producing a fluoromethoxylated compound having the structure:
wherein
A is an aryl or heteroaryl; and
R is —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl), —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl); and
n is 0-7,
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the fluoromethoxylated compound.
13. The process of claim 12 for producing a difluoromethoxylated compound having the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the difluoromethoxylated compound, or
for producing a difluoromethoxylated compound having the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), -φ 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the difluoromethoxylated compound, or
for producing a difluoromethoxylated compound having the structure:
wherein
R 15 , R 16 , R 17 and R 18 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the difluoromethoxylated compound.
14. The process of claim 12 for producing a trifluoromethoxylated compound having the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated compound, or
for producing a trifluoromethoxylated compound having the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated compound, or
for producing a trifluoromethoxylated compound having the structure:
wherein
R 15 , R 16 , R 17 and R 18 are each, independently, —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated compound.
15. The compound of claim 5 , wherein X 7 is —OCF 3
and/or
wherein
X 6 is
wherein R 19 , R 20 and R 21 are each, independently, —H, —Cl, —Br, —F, —CF 3 , —NO 2 or —SO 2 Me.
16. The process of preparing the compound of claim 5 , comprising reacting the compound having the structure:
with a trifluoromethylating agent in a suitable solvent under conditions sufficient to thereby produce the compound,
wherein the trifluormethylating agent is Togni reagent I or Togni reagent II.
17. A process of trifluoromethoxylating an arene or heteroarene, wherein at least one carbon of the arene or heteroarene is unsubstituted, or the aryl or heteroaryl group of an aryl or heteroaryl containing compound, wherein at least one carbon of the aryl or heteroaryl is unsubstituted, comprising reacting the arene, heteroarene, aryl or heteroaryl with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated arene, heteroarene, aryl or heteroaryl,
wherein the arene or heteroarene is a phenyl, pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran, benzothiophene or quinolone.
18. The process for producing a trifluoromethoxylated compound having the structure:
wherein
A is an aryl or heteroaryl; and
R is —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl); and
n is 0-7,
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated compound;
or
wherein
A is an aryl or heteroaryl,
wherein the aryl or heteroaryl is a phenyl, pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran, benzothiophene or quinolone; and
R is —H, halogen, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —CO 2 H, —CO 2 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl) —CO 2 -(aryl), —C(—CO 2 -(heteroaryl), —C(O)NH-(alkyl), —C(O)NH-(alkenyl), —C(O)NH-(alkynyl) —C(O)NH-(aryl), —C(O)NH-(heteroaryl), —C(O)N(alkyl) 2 , —OH, —OAc, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(O)-(aryl), —C(O)-(heteroaryl), —OCO 2 -(alkyl), —OCO 2 -(alkenyl), —OCO 2 -(alkynyl), —OCO 2 -(aryl), —OCO 2 -(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl) or —S-(heteroaryl),
wherein the aryl or heteroaryl is a phenyl, pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran, benzothiophene or quinolone; and
n is 0-7,
comprising (a) reacting a compound having the structure:
with the compound of claim 8 under conditions sufficient to thereby produce the trifluoromethoxylated compound.
19. A product or composition produced by the process of, or by the process comprising the process of claim 6 .
20. A kit comprising the compound of claim 1 in a container and instructions for use of the compound.