Vent for the aminohalogenation of methyl cinnamate (4a). To prove the
Vent for the aminohalogenation of methyl cinnamate (4a). To prove the synthetic value in the methodology, other prevalent main or secondary amines, had been tested in the reaction beneath optimized conditions (Table two). The use of aliphatic amines, like methylamine (Table 2, entry 2), dimethylamine (Table 2, entry three) and ammonia answer (Table two, entry four), bring about the formation with the aziridine as the sole item in 88 , 83 , 91 yield, respectively. Notably, a complicated mixture was obtained when 1,2-ethanediamine was utilised within this reaction (Table 2, entry 1).Results and DiscussionAccording towards the earlier reports on the derivatization of aminohalogenation reactions, the vicinal haloamines typically underwent elimination or aziridination reactions after they have been treated with organic bases (Scheme two) [33-35]. Nonetheless, when benzylamine was added to haloamine 1a in acetonitrile, the reaction could also proceed smoothly giving a sole product.Scheme 1: An anomalous outcome with benzylamine as organic base.Scheme 2: Transformation of vicinal haloamines by the use of organic amines.Beilstein J. Org. Chem. 2014, 10, 1802807.Table 1: Optimization of typical reaction conditions.aentry 1 two 3 4 5 6 7 8 9aReactionamount (mL)b 4 four 4 two 0.five 0.1 0.1 0.1 2solvent CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH2Cl2 CHClT ( ) rt 50 rt rt rt rt rt rt rt rttime (h) 0.5 0.5 1 1 1 1 three 6 1yield ( )c 83 75 91 93 63 28d 59d 60d 89conditions: 1a (0.5 mmol), solvent (3 mL). bAmount of benzylamine. c Isolated yields. d2 mL triethylamine was added.Table two: Examination of other organic bases.aentrybase (mL)T ( )time (min)item ( )b 3a 5a1 2 3aReaction1,2-ethanediamine (2) methylamine (2) dimethylamine (two) ammonia resolution (2)circumstances: 1a (0.five mmol), acetonitrile (three mL), base.rt rt rt rtbIsolated30 30 30yieldsplex mixture 88 BACE1 site 83After getting the optimized circumstances, we then combined the aminohalogenation as well as the therapy of benyzlamine to develop a one-pot procedure with ,-unsaturated esters as beginning supplies. Around the initial reaction step the cinnamic ester underwent a copper(II) trifluoromethanesulfonate-catalyzed aminohalogenation reaction with TsNCl2 as nitrogen supply. Immediately after getting quenched by saturated sodium sulfite, the resulting mixture was stirred with benzylamine. Many ,-unsaturated esters were studied to evaluate the yield and stereochemical outcome of these reactions (Table 3). As shown in Table three, pretty much all of the tested substrates worked effectively under the optimized situations giving rise towards the corresponding ,-diamino ester merchandise, even though the aromatic ring was substituted by powerful elec-tron-withdrawing groups (fluoro, Table 3, entries six, ten and 12; trifluoromethyl, entry 15) or an electron-donating group (methoxy, Table three, entry eight). Inside the case of ethyl ester, the reaction showed reduce reactivity (Table 3, entry 2), and 70 chemical yield was obtained comparing to 79 yield from methyl ester (Table three, entry 1). A cinnamic ester with double-substituted aromatic ring 4m was also tolerated in this reaction together with a moderate chemical yield (53 , Table three, entry 13). Notably, when the phenyl was replaced by 1-naphthyl 4n (Table three, entry 14), it was also effectively performing in this reaction providing rise towards the BRDT custom synthesis target product in 64 yield. For the substrates with ortho-substituents (Table three, entries 13 and 16), the yields have been just a little bit decrease than the yields with the meta- and para-Beilstein J. Org. Chem. 2014, ten, 1802807.Table three: One-pot reaction.