Stereoselective synthesis of trans- and cis-2-aryl-3-(hydroxymethyl)aziridines through transformation of 4-aryl-3-chloro-β-lactams and study of their ring opening

Abstract

trans- and cis-1-Alkyl-4-aryl-3-chloroazetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were transformed into the corresponding non-activated trans- and cis-2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction using LiAlH(4) in Et(2)O. Furthermore, trans-2-aryl-3-(hydroxymethyl)aziridines were transformed into 2-amino-3-arylpropan-1-ols and anti-2-amino-3-aryl-3-methoxypropan-1-ols by means of an unprecedented ring opening by LiAlH(4) and by MeOH, respectively. cis-2-Aryl-3-(hydroxymethyl)aziridines were shown to be highly reluctant to undergo ring opening by LiAlH(4) and MeOH under similar reaction conditions.

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity

“…In accordance with a literature approach [30], the nonactivated trans -2-aryl-3-(hydroxymethyl)aziridines 7 were regio- and stereoselectively converted into anti -2-amino-3-aryl-3-methoxypropan-1-ols 8a – e through heating in methanol under reflux (Scheme 1). Furthermore, in order to provide access to the class of 2-aminopropan-1,3-diols, aziridines 7 were evaluated for the first time as substrates for a water-induced aziridine ring opening in an acidic medium.…”

“…In previous works, we have elaborated the synthetic potential of 3-chloroazetidin-2-ones with a focus on stereoselectivity, thus providing convenient entries into, e.g., aziridines, azetidines and β-aminoalcohols [28–31]. In continuation of our interest in the use of functionalized β-lactams as synthons for further elaboration, racemic trans -4-aryl-3-chloro-β-lactams 5 were prepared by treatment of N -(arylmethylidene)alkylamines (synthesized in high yields through condensation of the corresponding benzaldehydes with the appropriate primary amines in CH 2 Cl 2 in the presence of anhydrous MgSO 4 ) with 1.5 equiv of chloroacetyl chloride and 3 equiv of 2,6-lutidine in benzene according to a literature protocol [30]. Subsequently, β-lactams 5 were subjected to LiAlH 4 -mediated reductive ring opening, furnishing either 2-aminopropan-1-ols 6a – c , by using two molar equiv of LiAlH 4 in Et 2 O under reflux for 20–80 h, or trans -2-aryl-3-(hydroxymethyl)aziridines 7a – h by applying milder reactions conditions (i.e., one molar equiv of LiAlH 4 in Et 2 O at room temperature for 5–8 h) (Scheme 1) [30].…”

“…Thus, treatment of trans -2-aryl-3-(hydroxymethyl)aziridines 7 with one equiv of para -toluenesulfonic acid in a H 2 O/THF (1/1) solvent system [32] furnished novel anti -2-amino-1-arylpropan-1,3-diols 9a – d in good yields after 3 h at 40 °C, again in a regio- and stereospecific way (Scheme 1). The observed regio- and stereoselectivity in aminopropanols 8 and 9 can be rationalized by considering the ring opening of the aziridine moiety at C2 due to benzylic stabilization of the developing carbenium ion in an S N 2 fashion [30]. …”

“…As the use of imines bearing a N - tert -butyl group in combination with a substituent in the ortho -position of the aromatic ring is known to afford the corresponding cis -4-aryl-3-chloroazetidin-2-ones as the major stereoisomers after condensation with chloroketene in benzene [30], racemic cis -3-chloro-β-lactams 10a , b were prepared and converted into cis -2-aryl-3-(hydroxymethyl)aziridines 11a , b upon treatment with two molar equiv of LiAlH 4 in Et 2 O under reflux for 15 h (Scheme 2). Next, the aziridines 11 , which have previously been shown to be unreactive towards LiAlH 4 and methanol and thus unable to undergo ring opening [30], were used as substrates for a water-induced ring opening through initial protonation of the aziridine ring with p -TsOH.…”

LiAlH4‐Induced Selective Ring Rearrangement of 2‐(2‐Cyanoethyl)aziridines toward 2‐(Aminomethyl)pyrrolidines and 3‐Aminopiperidines as Eligible Heterocyclic Building Blocks

“…[1b] In order to study the possible effect of introducing an aryl group on the hydride-induced ring transformation of (2-cyanoethyl)aziridines, the 2-aryl-3-(2-cyanoethyl)aziridines 11 were prepared from the corresponding 3-chloro-b-lactams [14] in af our-step procedure. [15] Then, the same reaction conditions were appliedt ot he 2-aryl-3-(2-cyanoethyl)aziridines 11 (i.e.,2molar equiv of LiAlH 4 ,0 .3 equiv of In(OTf) 3 ,0 8Ct o heatingt or eflux, 1h,N 2 ), affording the 3-aminopiperidines 12 in 56-84% yield through ar egioselective ring opening at the benzylic position (Scheme 4).…”