Asymmetric Transformation of -7-Methoxy-l,2,3,4-tetrahydronaphthalen-2-amine

Following an initial resolution step with 0.5 mol equivalents (R)-mandelic acid in TBME, the crystalline product was filtered and tlie waste isomers in the mother liquors (39% ee) were washed with base and then subjected to racemization with the SCRAM catalyst. Upon completion, the catalyst precipitated and was screened, fresh racemic amine was added, and the whole was resolved a second time. The process was repeated several times, giving the results summarized in Table 13.2. 

Carried out on a small multi-gram scale, the overall yield over the four recycle loops in the unoptimized process was 49% (based on the amount of racemate added throughout the investigation) compared to a traditional single-step resolution yield of -30% of the N-benzyl amine, demonstrating some improvement from an early stage. The product was isolated in 80-90% ee over each loop and required a final crystallization of the combined material from acetone to bring it up to the required specification. The main losses were to the imine, and, in a separate experiment, treatment of this under the SCRAM racemization conditions in the 

Cycle number Resolution yield (%) Mother liquors ee (%) Racemization yield (%) 

Screening several amine racemization catalysts, we found that the SCRAM and the Shvo catalyst would both racemize the (S)-enantiomer at temperatures above 11() G. Interestingly, no dimeric products were found. The best racemization conditions were found to be using toluene or TBME at 150°C in a pressure vessel with 1 mol% SCRAM or 5 mol% Shvo catalyst over 24 h, providing quantitative conversion. In the presence of (R, R)-dibenzoyltartaric acid the racemization slowed, possibly because of unfavorable coordination of the alkylammonium substrate or acid quenching of the iridium hydride catalyst intermediate. 

It can be seen that the de does not reach zero, as the benzylic chiral center induces diastereoselective imine reduction, depending upon the system thermodynamics (that is catalyst, solvent, and temperature). Since the epimerization is first order with respect to the (IS, 4R) isomer but zero order with respect to the mixture of isomers, the process is unaffected by concentration and was conveniently run at the same high concentration as that of the mother liquors from the resolution process. A critical part of the process was the separation of the catalyst from the product, and its removal after the amine epimerization was preferred as this provided the greatest potential for its recycle. Removal of the catalyst was achieved by forming an insoluble ammonio complex formed by bubbling gaseous 

---