Trifluoromethoxylation of arenes via intramolecular trifluoromethoxy group migration

Patent metadata

Field	Value
Publication number	US-10118890-B2
Application number	US-201515516610-A
Country	US
Kind code	B2
Filing date	Oct 9, 2015
Priority date	Oct 10, 2014
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The present invention provides a process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure:

wherein

A is an aryl or heteroaryl, each with or without subsutitution; and

R 1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl)—NH-(aryl), —NH-(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 a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure:

and

(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

First claim

What is claimed is:

1. A process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure:

wherein
A is an aryl or heteroaryl, each with or without substitution; and
R 1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl)—NH-(aryl), —NH-(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 a trifluoromethylating agent in a first suitable solvent under conditions to produce a compound having the structure:

and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

2. A process of claim 1 comprising:
(a) reacting a compound having the structure:

with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure:

and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

3. The process of claim 1 , wherein step (a) and step (b) are performed by a sequential one-pot synthesis.

4. The process of claim 1 , wherein step (a) and step (b) are performed by a sequential one-pot synthesis without purification or work-up in between step (a) and step (b).

5. The process of claim 1 , wherein trifluormethylating agent is Togni reagent I or Togni reagent II.

6. The process of claim 1 , wherein A is a phenyl, pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, isooxazole, isothiazole, naphthalene, anthracene, pyrimidine, pyrazine, pyridazine, indole, indoline, benzofuran, benzothiophene, or quinolone.

7. The process of claim 1 , wherein the compound produced has the structure:

wherein
R 1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and
R 2 , R 3 , R 4 and R 5 is 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 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl)—CO 2 -(aryl), —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, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridinyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, naphthalenyl, anthracenyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indolinyl, benzofuranyl, benzothiophenyl, or quinolinyl.

8. The process of claim 1 , wherein the compound produced has the structure:

wherein
R 1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and
R 2 , R 3 and R 5 is 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 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl)—CO 2 -(aryl), —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, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridinyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, naphthalenyl, anthracenyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indolinyl, benzofuranyl, benzothiophenyl, or quinolinyl;
or the structure:

wherein
R 1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl) 2 , —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl); and
R 3 , R 4 and R 5 is 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 -(alkyl), —CO 2 -(alkenyl), —CO 2 -(alkynyl)—CO 2 -(aryl), —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, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), pyridinyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, naphthalenyl, anthracenyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indolinyl, benzofuranyl, benzothiophenyl, quinolinyl, pyrazolinyl, triazolyl, benzimidazolyl, benzotriazolyl, azaindolyl or purinyl.

9. The process of claim 1 comprising:
(a) reacting a compound having the structure:

with Togni reagent II in the presence of a base in a first suitable solvent under conditions sufficient to produce a compound having the structure:

and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

10. The process of claim 1 comprising:
(a) reacting a compound having the structure:

Assignees

• Ngai Ming Yu
• Hojczyk Katarzyna N
• Univ New York State Res Found

Inventors

• Ngai Ming-Yu
• Hojczyk Katarzyna N

Classifications

• C07D473/40

  with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6 · CPC title

• C07C255/60

  at least one of the singly-bound nitrogen atoms being acylated · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D239/91

  with aryl or aralkyl radicals attached in position 2 or 3 · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title