US 12,454,502 B2
Synthesis of deuterated aldehydes
Wei Wang, Tucson, AZ (US)
Assigned to ARIZONA BOARD OF REGENTS ON BEHALF OF ATHE UNIVERSITY OF ARIZONA, Tucson, AZ (US)
Appl. No. 17/639,750
Filed by ARIZONA BOARD OF REGENTS, Tucson, AZ (US)
PCT Filed Aug. 12, 2020, PCT No. PCT/US2020/045935
§ 371(c)(1), (2) Date Mar. 2, 2022,
PCT Pub. No. WO2021/045879, PCT Pub. Date Mar. 11, 2021.
Claims priority of provisional application 62/895,472, filed on Sep. 3, 2019.
Prior Publication US 2022/0356139 A1, Nov. 10, 2022
Int. Cl. C07C 45/00 (2006.01); B01J 31/02 (2006.01); B01J 31/22 (2006.01); C07B 59/00 (2006.01); C07C 45/50 (2006.01); C07C 67/28 (2006.01); C07C 67/30 (2006.01); C07C 67/39 (2006.01); C07C 201/12 (2006.01); C07C 253/30 (2006.01); C07C 269/06 (2006.01); C07D 209/08 (2006.01); C07D 209/12 (2006.01); C07D 209/86 (2006.01); C07D 213/61 (2006.01); C07D 215/18 (2006.01); C07D 317/54 (2006.01); C07D 319/08 (2006.01); C07D 319/18 (2006.01); C07D 333/22 (2006.01); C07D 333/56 (2006.01); C07D 403/10 (2006.01); C07D 491/052 (2006.01); C07D 498/08 (2006.01)
CPC C07C 45/00 (2013.01) [B01J 31/0202 (2013.01); B01J 31/0204 (2013.01); B01J 31/0231 (2013.01); B01J 31/0244 (2013.01); B01J 31/0271 (2013.01); B01J 31/2273 (2013.01); C07B 59/001 (2013.01); C07B 59/002 (2013.01); C07B 59/005 (2013.01); C07C 45/50 (2013.01); C07C 67/28 (2013.01); C07C 67/30 (2013.01); C07C 67/39 (2013.01); C07C 201/12 (2013.01); C07C 253/30 (2013.01); C07C 269/06 (2013.01); C07D 209/08 (2013.01); C07D 209/12 (2013.01); C07D 209/86 (2013.01); C07D 213/61 (2013.01); C07D 215/18 (2013.01); C07D 317/54 (2013.01); C07D 319/08 (2013.01); C07D 319/18 (2013.01); C07D 333/22 (2013.01); C07D 333/56 (2013.01); C07D 403/10 (2013.01); C07D 491/052 (2013.01); C07D 498/08 (2013.01); B01J 31/0247 (2013.01); C07B 2200/05 (2013.01); C07C 2601/14 (2017.05); C07C 2601/16 (2017.05); C07C 2602/42 (2017.05); C07C 2603/24 (2017.05)] 23 Claims
 
1. A method for preparing a deuterated aldehyde of formula
RZ—C(O)-D,
wherein
RZ 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 Ra, and RZ is optionally deuterated;
Ra 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
RZ′—C(O)—H
with an N-heterocyclic carbene catalyst in a solvent comprising D2O, thereby producing the deuterated aldehyde,
wherein RZ′ 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 Rb;
Rb 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)

OG Complex Work Unit Chemistry
wherein
W is S or NRA;
“-” in Q1-Q2 is a single bond, wherein
Q1-Q2 is CRx1Ry1—CRx2Ry2;
RA and RB are each independently an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
RC, and RD 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;
RA and RC, RB and RD, and/or RC and RD alternatively together with the N or C atoms to which they are attached form a ring;
RB alternatively is an alkylene forming a dimer;
Rx1, Ry1, Rx2, and Ry2 are each independently hydrogen or alkyl; and
X− is counter ion.