A trusted Pd-catalyzed amination process is described for the formation of

A trusted Pd-catalyzed amination process is described for the formation of analogues and N-alkyltacrines. have already Rabbit Polyclonal to OR52A4. been synthesized searching for further improvements.3 4 Although bis(7)-tacrine 4a and its own longer tether MLN518 homologues bis(8)- to bis(10)-tacrine had been first made by alkylation from the exocyclic amine of tacrine 1 2 this technique demonstrated unsatisfactory for the formation of short-tether homologues because MLN518 of the intervention of cyclization and elimination pathways.3a A high-temperature nucleophilic aromatic substitution path was thus devised by reacting 2 with diamines (e.g. 3a) in refluxing 1-pentanol (bp 138 °C).3a MLN518 This amination process afforded the entire group of bis(2)- to bis(10)-tacrine in great yields and within the last 10 years continues to be widely used to get ready tacrine heterodimers aswell as homo- and heterodimers of tacrine analogues.3 4 As yet it is not essential to explore additional feasible amination protocols. Yet in our seek out inhibitors with high selectivity for AChE from the malaria mosquito (Anopheles gambiae) 5 we discovered that the standard process cannot dimerize 12-chloro-2-methyl-6 7 8 9 10 11 5 even though the 1-pentanol solvent was changed by the actually higher boiling (bp 195 °C) 1-octanol (Structure 2). The usage of excess amine to cover monomer 7a was unsuccessful also. Structure 2 Attempted transformation of 12-chloro-2-methyl-6 7 8 9 10 11 hexahydrocycloocta[b]quinoline 5 to 6a (x = 0.5) or 7a (x = 3) Provided the widespread achievement of Buchwald-Hartwig protocols to impact amination of aryl halides 6 our interest considered Pd-catalysis. Although Pd-catalyzed amination continues to be applied to a number of different classes of heteroaryl chlorides 7 including 4-haloquinolines 7 to your knowledge there is one released accounts of its software to the formation of an N-alkyltacrine and or analogue. Butini and co-workers reported the usage of 2 mol% Pd(OAc)2 and 2 mol % BINAP to few 2 and 1 4 affording MLN518 8b in 40% produce (Structure 3).7j Structure 3 Synthesis of 8b by Pd-catalyzed amination. Herein we record optimized circumstances for the formation of analogues and N-alkyltacrines via Pd-catalyzed amination. The result of 9-chloro-1 2 3 4 2 and n-heptylamine 3c was used to display for suitable response conditions. We chosen DPEPhos 7 RBINAP 7 j and CyPFtBu7b f as ligands given that they have been used in Pd-catalyzed amination of heteroaryl chlorides (Desk 1). Desk 1 Marketing of Pd-catalyzed amination of 9-chloro-1 2 3 4 2 by n-heptylamine 3c DPEphos was reported to become a highly effective ligand for the cross-coupling of 4-chloroquinoline with α-branched 1° amines 7 and we effectively repeated many of the released aminations of the heteroaryl chloride (data not really shown). Nevertheless we discovered that this ligand isn’t quite effective for Pd(OAc)2-catalyzed coupling of 2 and heptylamine 3c (Table 1 entries 1 2 Interestingly when KOt-Bu was used as base a 95% yield of reduced product 9 was obtained (Table 1 entry 1). When NaOt-Bu was used as base the desired product 8c was obtained in 41% yield albeit at high catalyst/ligand loading (Table 1 entry 2). Use of R-BINAP as ligand (Table 1 entry 3) allowed lower catalyst loadings (1% Pd 2 ligand) but provided 8c in only 47% yield; note this yield is similar to that obtained by Butini and co-workers for 8b (Scheme 3).7j The best results were obtained with the Josiphos ligand CyPFtBu (87% Table 1 entry 4). Hartwig and coworkers have shown that CyPFtBu functions well in Pd-catalyzed couplings of 1° amines with pyridin-2-yl pyridin-4-yl and quinolin-2-yl halides.7b f Reduction of Pd/ligand loadings below 1%/2% gave poor conversion even at longer reaction time (Table 1 cf. entries 4-6). In addition a brief survey of toluene and dioxane suggested that DME is MLN518 the best solvent for the CyPFtBu/NaOtBu system (Table 1 cf. entries 4 7 8 Thus these optimized conditions were used to explore the generality of this Pd-catalyzed amination of 2 with various primary amines 3a-j MLN518 (Table 2).8 In general moderate to good yields were acquired. Using 0.5 equiv of diamine 3a bis-(7)-tacrine 4a can be acquired in 72% produce in 24 h at lower temperature compared to the NAS procedure.