Phosphine–Thiourea‐Organocatalyzed Asymmetric C−N and C−S Bond Formation Reactions

Abstract

Phosphine-thiourea based-organocatalysts derived from l-proline promoted CÀN or CÀS bond formation of tert-butoxycarbonyloxy-Morita-Baylis-Hillman adducts with phthalimide or alkyl thiols, respectively. Good yields and enantioselectivities up to 93 % were achieved.Over the past decade, asymmetric Morita-Baylis-Hillman (MBH) and aza-MBH reactions have been studied intensively by many research groups owing to their advantages such as atom economy, non-metal catalyst, mild conditions, and especially ease of access to functionalized and complex molecules.[1] The transformations of MBH adducts have attracted considerable interest of organic chemists who focused on the development of new organocatalytic procedures, [2,3] in particular the allylic substitution.[3] The conversion of the allylic hydroxyl group of the MBH adduct into a better leaving group such as an acetate (OAc) or a tert-butoxycarbonyloxy (OBoc) group creates an electrophilic character at the allylic position of the MBH adduct. However, due to the steric hindrance at the allylic position, the nucleophilic substitution of MBH adducts proceeds through successive S N 2'-S N 2' reactions in the presence of a Lewis base (LB) catalyst (Scheme 1). [4] Chiral phosphine or amine-catalyzed asymmetric allylic substitution reactions have been powerful and versatile tools for the CÀC, CÀN, CÀO, and CÀP bond construction.[4] However, if several organocatalytic procedures exist for the CÀS bond formation, [5] examples including the allylic substitution of modified MBH adducts are very scarce.[6] To our knowledge, only one example of an asymmetric allylic substitution of alkyl thiols with MBH carbonate adducts catalyzed by a chiral amine has been reported. Indeed, Cheng and Zhu described the synthesis of a-methylene-b-mercapto esters in good yields and with excellent enantioselectivities.[DHQD] 2 PHAL was found to be the best catalyst and the presence of MgSO 4 is essential for increasing the reaction rate. [7] It should be noted that all catalytic systems used for the CÀS bond formation started from modified MBH adducts are tertiary amine-based organocatalysts. [5][6][7] No example of a phosphine-catalyzed allylic substitution of MBH acetate or carbonate adducts for CÀS bond formation has been reported so far.In continuation of our research on the design and synthesis of new chiral organocatalysts, we have recently reported the synthesis of new bifunctional chiral phosphine-thiourea organocatalysts A, B and C, derived from l-proline (Figure 1). We have also described their applications in the asymmetric [3+2] cyclization between ethyl-butan-2,3-dienoate and N-benzylidene-p-toluenesulfonamide.[8] Herein, we report the use of these phosphine-thioureas in the asymmetric allylic substitu-

Phosphine Organocatalysis

“…These reactions were the first examples of phosphine-catalyzed allylic substitutions for C–S bond formation (Scheme 532). 599 The nonasymmetric reaction of the MBH carbonate with alkylthiols was performed using 20 mol % of triphenylphosphine. The asymmetric versions were explored using five different chiral phosphine-thioureas ( P69a – e ) as organocatalysts, affording α -methylene- β -mercapto esters in moderate to excellent yields and with moderate to excellent enantioselectivities.…”

Palladium-Catalyzed Regioselective C3-Allylic Alkylation of 2-Aryl Imidazopyridines with MBH Carbonates

“…All MBH adducts were prepared using previous literature precedent, and characterization data of the compounds such as 2a , 2c , 2d , 2g , 2h , 2i , 2k , 2l , 2m , 2n , and 2o were found to match with previous reports.…”

Phosphine-Catalyzed Asymmetric Organic Reactions

“…191 Toffano, Vo-Thanh and co-workers described the utilization of thiols as nucleophiles in allylic substitution of the MBH adducts (Scheme 104). 192 In the presence of a number of Zhang group (Scheme 105). 193 With the employment of multifunctional phosphine catalyst P107, the allylic addition of trifluoromethyl ketimines 352 to the MBH adducts 257 led to the formation of optically enriched trifluoromethyl amines 353 bearing a tertiary stereocenter.…”

“…Toffano, Vo-Thanh and co-workers described the utilization of thiols as nucleophiles in allylic substitution of the MBH adducts (Scheme ). In the presence of a number of novel l -Pro-derived multifunctional catalysts, P87, P88 , P89 , and P90 , the allylic substitution products 349 were obtained with ee values up to 92% (eq a). While the use of alkyl thiols led to the formation of allylic substitution products via an S N 2′–S N 2′ pathway, aromatic thiols went through only one S N 2′ reaction to yield different allylic products 351 (eq b).…”