Synthesis of deuterated aldehydes

Patent metadata

Field	Value
Publication number	US-12454502-B2
Application number	US-202017639750-A
Country	US
Kind code	B2
Filing date	Aug 12, 2020
Priority date	Sep 3, 2019
Publication date	Oct 28, 2025
Grant date	Oct 28, 2025

Abstract

Described are methods for preparing a deuterated aldehyde using N-heterocyclic carbene catalysts in a solvent comprising D 2 O. The methods may be used to convert a wide variety of aldehydes (e.g., aryl, alkyl, or alkenyl aldehydes) to C-1 deuterated aldehydes under mild reaction conditions without functionality manipulation.

First claim

What is claimed is:

1. A method for preparing a deuterated aldehyde of formula
R Z —C(O)-D,

wherein
R Z is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more R a , and R Z is optionally deuterated;
R a at each occurrence is independently halogen, —CN, —OH, nitro, —O-benzyl, —NH(t-butoxycarbonyl), —NH(benzyloxycarbonyl), alkyl, alkenyl, alkynyl, alkoxy, —OC(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, cycloalkyl, aryl, —O-aryl, —C(O)-aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, —OC(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, cycloalkyl, aryl, —O-aryl, —C(O)-aryl, heteroaryl, or heterocyclyl is optionally substituted; and
the level of deuterium incorporation of the —C(O)-D moiety is at least 90%;
the method comprising:
contacting an aldehyde of formula
R Z ′—C(O)—H

with an N-heterocyclic carbene catalyst in a solvent comprising D2O, thereby producing the deuterated aldehyde,
wherein R Z ′ is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more R b ;
R b at each occurrence is independently halogen, —CN, —OH, nitro, —O-benzyl, —NH(t-butoxycarbonyl), —NH(benzyloxycarbonyl), alkyl, alkenyl, alkynyl, alkoxy, —OC(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, cycloalkyl, aryl, —O-aryl, —C(O)-aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, —OC(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, cycloalkyl, aryl, —O-aryl, —C(O)-aryl, heteroaryl, or heterocyclyl is optionally substituted, and
wherein the N-heterocyclic carbene catalyst is a compound of formula (I)

wherein
W is S or NR A ;
“-” in Q 1 -Q 2 is a single bond, wherein
Q 1 -Q 2 is CR x1 R y1 —CR x2 R y2 ;

R A and R B are each independently an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
R C , and R D are each independently hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
R A and R C , R B and R D , and/or R C and R D alternatively together with the N or C atoms to which they are attached form a ring;
R B alternatively is an alkylene forming a dimer;
R x1 , R y1 , R x2 , and R y2 are each independently hydrogen or alkyl; and
X − is counter ion.

2. The method of claim 1 , wherein R Z is an optionally substituted aryl or an optionally substituted heteroaryl.

3. The method of claim 1 , wherein R Z is an optionally substituted alkenyl or an optionally substituted cycloalkenyl.

4. The method of claim 1 , wherein R Z is an optionally substituted alkyl or an optionally substituted cycloalkyl.

5. The method of claim 1 , wherein R Z and R Z ′ are the same.

6. The method of claim 1 , wherein the solvent further comprises an organic solvent.

7. The method of claim 1 , wherein W is NR A .

8. The method of claim 7 , wherein
R A and R B are each independently an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl; and
R C and R D are each independently hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl.

9. The method of claim 7 , wherein R A and R C , R B and R D , or R C and R D together with the N or C atoms to which they are attached form a ring.

10. The method of claim 1 , wherein R A and R B are each independently an optionally substituted aryl.

11. The method of claim 1 , wherein the N-heterocyclic carbene catalyst is a compound of formula (I-a)

12. The method of claim 11 , wherein R Z is an optionally substituted aryl or an optionally substituted heteroaryl.

13. The method of claim 12 , wherein the N-heterocyclic carbene catalyst is

14. The method of claim 12 , wherein R Z is

each of which is optionally substituted.

15. The method of claim 11 , wherein R Z is an optionally substituted alkenyl or an optionally substituted cycloalkenyl.

16. The method of claim 15 , wherein R Z is

wherein
R 1 and R 2 are independently hydrogen, alkyl, aryl, or heteroaryl, wherein the alkyl, aryl, and heteroaryl are optionally substituted; and
R 3 is hydrogen, alkyl, or aryl, wherein the alkyl and aryl are optionally substituted, or
R 1 and R 3 together with the carbon atoms to which they are attached form a 6- to 8-membered ring, which is optionally substituted.

17. The method of claim 13 , wherein R Z is an optionally substituted alkyl or an optionally substituted cycloalkyl.

18. The method of claim 17 , wherein N-heterocyclic carbene catalyst is

19. The method of claim 17 , wherein R Z is R W —(CR aa R bb ) p —, wherein
R W is hydrogen, deuterium, —NH(benzyloxycarbonyl), alkenyl, alkynyl, aryl, —C(O)-aryl, heteroaryl, or heterocyclyl, wherein the alkenyl, alkynyl, aryl, —C(O)-aryl, heteroaryl, and heterocyclyl are optionally substituted;
R aa and R bb at each occurrence are independently hydrogen, deuterium, alkyl, —NH(t-butoxycarbonyl), or —O-benzyl; and
p is 1, 2, 3, 4, 5, 6, 7, or 8.

20. The method of claim 1 , wherein X − is Cl − , Br − , I − , or BF − 4 .

21. The method of claim 1 , wherein the N-heterocyclic carbene catalyst is selected from the group consisting of

in which Mes is

and Dipp is

22. The method of claim 1 , further comprising isolating the produced deuterated aldehyde.

23. The method of claim 1 , wherein the level of deuterium incorporation of the —C(O)-D moiety is at least 95%.

Assignees

• Univ Arizona
• Arizona Board Of Regents On Behalf Of Athe Univ Of Arizona

Inventors

• Wang Wei

Classifications

• C07D319/08

  condensed with carbocyclic rings or ring systems · CPC title

• B01J31/0271

  also containing elements or functional groups covered by B01J31/0201 - B01J31/0231 · CPC title

• B01J31/0231

  Halogen-containing compounds · CPC title

• C07D317/54

  Radicals substituted by oxygen atoms · CPC title

• B01J31/0247

  Imides, amides or imidates (R-C=NR(OR)) · CPC title