Ketimines Subject

The large scale preparation of the drug candidate 2 was accomplished via the Sugasawa reaction (an ortho-selective Friedel-Craft acylation on anilines) and the asymmetric addition to ketimines. Understanding the reaction mechanism and reaction parameters is the only way to gain confidence that the reactions will perform as required upon scale up. Below we discuss both subjects in detail. 

Prior to imide formation, the imide-aryl ether ketimine copolymers were converted to the imide-aryl ether ketone analogue by hydrolysis of the ketimine moiety with para-toluene sulfonic acid hydrate (PTS) according to a literature procedure [51,52,57-59]. The copolymers were dissolved in NMP and heated to 50 °C and subjected to excess PTS for 8 h. The reaction mixtures were isolated in excess water and then rinsed with methanol and dried in a vacuum oven to afford the amic ester-aryl ether ether ketone copolymer, 2e (Scheme 8.)... 

The ketimine (13a), prepared from desoxybenzoin and aniline, is also subject to a solvent-dependent tautomerism called imine/enamine tautomerism. The enamine content of a solution of (13a) increases in the order tetrachloromethane (31 cmol/mol at 35 °C), [Dsjpyridine (47.5 cmol/mol at 55 °C), and [Dejdimethyl sulfoxide (67 cmol/mol at 55 °C) [69], Hydrogen-bond acceptor solvents favour the enamine form (13b) due to hydrogen-bonding, whereas in less polar and apolar solvents the equilibrium is shifted towards the imine form / 13a) [69]. 

The formation of 49 is strong evidence that aldimine 48, like other aldimines, is a reactive sulfur acceptor and that thiaiziridine 51 is a likely intermediate in this reaction that undergoes an intramolecular stabilization via its ring opening accompanied by a hydrogen shift. The claimed intermediacy of thiaziridine 50 derived in this case, from ketimine 52, cannot be denied since, if formed, it would have been subjected to a sulfur extrusion. 

Compared with aldehydes and ketones, aldimines and ketimines are less reactive towards nucleophilic addition. Furthermore, imine additions are subject to steric constraints, and rapid deprotonation proceeds with imines bearing ot-hydrogen atoms. The Lewis acid promoted addition methodology has provided a solution to these problems. 

Johnston and coworkers reported a base-free aryl amination method based on radical additions to azomethines through nonconventional addition pathways (equation 6)42,43. By this route, the aryl radical adds to nitrogen, rather than to the carbon of the ketimines. For example, the ketimine prepared from o-bromophenethylamine and acetophenone was subjected to tributylstannane and the radical initiator AIBN to give the corresponding indoline in 87% yield. The only side product observed was the directly reduced compound. The fact that only the intramolecular radical addition can afford the high yield limited its application in synthesis of other arylamines. 

Asymmetric hydrocyanation of ketimines with TMSCN, a more challenging subject, has been reported by Vallee et al. They investigated the utility of chiral Ti-BI-NOL complexes for hydrocyanation of the N-benzylketimine derived from acetophenone [663]. The best result (80% conversion, 56% ee) was obtained by catalytic use of Ti(Oi-Pr)2(BINOL) (10 mol%) in the presence of TMEDA (20 mol%). More recently they have found that Sc(BINOL)2Li works as an efficient chiral catalyst for the same hydrocyanation (10 mol% of the catalyst >95% conversion, 88% ee) [664]. 

A study comparing asymmetric borane reductions of kctoxime ethers and /V-substituted ketimines mediated by selected chiral oxazaborolidines 8-14 has been carried out. The corresponding amines were obtained with up to 99% ee50-52. The enantioselective reduction of imines using chiral dialkoxyboranes has also been the subject of a study60. 

Figure 11.13 Reactions at a-carbon of a-amino acids catalyzed by pyridoxal enzymes All three substituents at C are subject to labilization in the three types of a-carbon reactions. The hydrogen is labilized in recemization reactions, the amino group is labUized in the transamination and the carboxyl group is labilized in decarboxylation. a-Amino acid condenses with pyridoxal phosphate to yield pyridoxylidene imino acid (an aldimine). The common intermediate, aldimine and distinct ketimines leading to the production of oxo-acid (in transamination), amino acid (in racemization) and amine (in decarboxylation) are shown. The catalytic acid (H-A-) and base (-B ) are symbolic both can be from the same residue such as Lys258 in aspartate aminotransferase.

The possibilities for the formation of carbon—carbon bonds involving aromatic compounds have been enormously enhanced by the use of transition metal catalysts, and this area has been the subject of several reviews. Some of these concentrate on the applications of specific metals, and there have been surveys of the use of compounds of silver, copper and nickel,mthenium, and palladium in catalysis. The metalation of carbon-hydrogen bonds, preceding functionalization, may be aided by carboxylate ions, and this subject has also been reviewed. There is evidence here for concerted base-assisted deprotonation as shown in (10). In the carboxylate-assisted reaction of aryl ketimines with alkyl halides, a ruthenium-bonded intermediate (11) has been proposed, which subsequently adds the alkyl halide. " ... 

To a dry flask filled with nitrogen were added the ketimine (0.2 mmol) and allenoate (0.4 mmol) in 2mL CHCI3. PPhj (0.04 mmol) was added. This solution was stirred at 60 °C until the complete consumption of the starting material as monitored by TLC. After the removal of the solvent, the residue was subjected to chromatography on a silica gel (60-120mesh) column using 20 1 petroleum ether/ethyl acetate solvent mixture as eluent to afford the aza-bicyclo[3,3,0]octane derivative. 

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