Difluoromethoxylation and trifluoromethoxylation compositions and methods for synthesizing same

Patent metadata

Field	Value
Publication number	US-11760701-B2
Application number	US-201916975704-A
Country	US
Kind code	B2
Filing date	Feb 26, 2019
Priority date	Feb 27, 2018
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Univ New York State Res Found
• The Research Foundation For The State Univ Of New Yrok

Inventors

• Ngai Ming-Yu
• Zheng Weijia
• Lee Johnny

Classifications

• C07D249/18 Primary

  Benzotriazoles · CPC title

• C07B41/04 Primary

  of ether, acetal or ketal groups · CPC title

• C07D235/18

  with aryl radicals directly attached in position 2 · CPC title