Vent for the aminohalogenation of methyl cinnamate (4a). To prove the
Vent for the aminohalogenation of methyl cinnamate (4a). To prove the synthetic value on the methodology, other prevalent principal or secondary amines, have been tested within the reaction under optimized situations (Table two). The use of aliphatic amines, for example methylamine (Table two, entry 2), dimethylamine (Table two, entry three) and ammonia remedy (Table 2, entry 4), bring about the formation from the aziridine as the sole item in 88 , 83 , 91 yield, respectively. Notably, a complicated mixture was obtained when 1,2-ethanediamine was employed in this reaction (Table two, entry 1).Outcomes and DiscussionAccording towards the prior reports around 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 providing a sole item.Scheme 1: An anomalous outcome with benzylamine as organic base.Scheme 2: Transformation of vicinal haloamines by the usage of organic amines.Beilstein J. Org. Chem. 2014, ten, 1802807.Table 1: Optimization of common reaction circumstances.aentry 1 2 3 four five 6 7 eight ERRγ site 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.five 0.5 1 1 1 1 3 six 1yield ( )c 83 75 91 93 63 28d 59d 60d 89conditions: 1a (0.five 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)solution ( )b 3a 5a1 2 3aReaction1,2-ethanediamine (2) methylamine (2) dimethylamine (two) ammonia remedy (2)conditions: 1a (0.5 mmol), acetonitrile (three mL), base.rt rt rt rtbIsolated30 30 30yieldsplex mixture 88 83After obtaining the optimized situations, we then combined the aminohalogenation and the remedy of benyzlamine to IL-3 drug create a one-pot procedure with ,-unsaturated esters as starting materials. 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 had been studied to evaluate the yield and stereochemical outcome of these reactions (Table three). As shown in Table 3, practically all of the tested substrates worked effectively beneath the optimized situations providing rise to the corresponding ,-diamino ester merchandise, even though the aromatic ring was substituted by sturdy elec-tron-withdrawing groups (fluoro, Table three, entries six, 10 and 12; trifluoromethyl, entry 15) or an electron-donating group (methoxy, Table three, entry eight). Inside the case of ethyl ester, the reaction showed lower reactivity (Table three, entry two), 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 in conjunction with a moderate chemical yield (53 , Table 3, entry 13). Notably, when the phenyl was replaced by 1-naphthyl 4n (Table three, entry 14), it was also properly performing in this reaction providing rise towards the target item in 64 yield. For the substrates with ortho-substituents (Table 3, entries 13 and 16), the yields have been slightly bit reduced than the yields of the meta- and para-Beilstein J. Org. Chem. 2014, ten, 1802807.Table 3: One-pot reaction.