Copper-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of Propargylic Acetates with Hydrazines: Enantioselective Synthesis of Optically Active 2-Pyrazolines

Abstract

A catalytic asymmetric [3 + 2] cycloaddition of hydrazines to bis-electrophilic C3 synthons generated from propargylic acetates, followed by an intramolecular 1,3-H migration, for the regio-and enantioselective construction of chiral 2-pyrazolines has been reported. By employment of copper catalysis in combination with a structurally rigid tridentate P,N,Nligand, a variety of chiral 2-pyrazolines were obtained in good yields and with high enantioselectivities (up to 96% ee). A possible transition state has been proposed to explain the origin of the regio-and enantioselectivities. P yrazolines are privileged and valuable five-membered azaheterocycles, which are found in many bioactive compounds with antidepressant, anti-inflammatory, anticancer, antibacterial, and antiviral activities, 1 and also serve as important intermediates for organic synthesis. 2 The development of new chemical reactions for the synthesis of these azaheterocycles, in particular in catalytic asymmetric versions, has therefore become an important issue. However, the number of available synthetic methodologies for the stereoselective construction of optically active pyrazolines is still very limited, and the methods mostly rely on two prominent strategies: (1) catalytic asymmetric 1,3-dipolar cycloadditions of diazoalkanes, 3 nitrile imine dipole precursors, 4 and azomethine imines 5 with alkenes or alkynes; (2) catalytic asymmetric Fischer's pyrazoline synthesis via a sequential aza-Michael addition/cyclocondensation process. 6,7 Despite these achievements, the development of novel strategies for the enantioselective construction of optically active pyrazolines with functional diversity remains a challenging and highly desirable task.Recently, Nishibayashi's 8 and our 9 groups have demonstrated that propargylic derivatives can be used as bis-electrophilic C3 synthons via metal-allenylidene intermediates for the catalytic [3 + 3] cycloaddition, affording six-membered hetero-and carbocyclic motifs. However, the use of this new type of biselectrophilic C 3 synthons in other cycloadditions remains unexploited. 10 In particular, no catalytic asymmetric [3 + 2] cycloaddition has yet been realized, thus severely narrowing their synthetic utility. To this end, we wondered about the possibility of a catalytic [3 + 2] cycloaddition of propargylic esters with hydrazines, possessing two adjacent nucleophilic nitrogen atoms, which should represent a novel strategy for stereoselectively producing optically active pyrazolines. However, the initial screening of the catalytic reaction of propargylic acetates with N,N′-diphenylhydrazine did not lead to any cycloadducts (Table 1, entry 1), clearly expressing the methodological difficulties. We envisioned that monosubstituted hydrazines should be more suitable bis-nucleophiles for realizing this transformation due to the clearly different steric properties of two nitrogen atoms toward the cycloaddition, which may be crucial to initiate the reaction in a chemo-and regioselective form. As a result, herein we dis...

Scope and advances in the catalytic propargylic substitution reaction

“…Hu and coworkers in the year 2015 have reported a highly regio-and enantioselective Cu-catalyzed [3 + 2] cycloaddition of propargylic acetates 123 with monosubstituted hydrazines 149, followed by a spontaneous 1,3-proton migration, for the stereoselective construction of optically active 2-pyrazolines, Scheme 65. 94 Interestingly, instead of the expected 3-pyrazoline the thermodynamically more stable 2-pyrazoline 131 was obtained, suggesting a cycloaddition via "pathway-a" took place, followed by a spontaneous 1,3-proton shi under the reaction condition, Scheme 66.…”

Desilylation‐Activated Propargylic Transformation: Enantioselective Copper‐Catalyzed [3+2] Cycloaddition of Propargylic Esters with β‐Naphthol or Phenol Derivatives

“…Compared with the terminal alkyne 1 , as shown in Table , the target cycloaddition with 2 a in the presence of ( S )‐ L1 a proceeded smoothly, and exclusively gave the cycloadduct 4 aa in nearly quantitative yield and with a significantly improved enantioselectivity of 76 % ee (entry 4). The sterically hindered ( S )‐ L1 a , recently developed by us, has been demonstrated to be highly efficient in many copper‐catalyzed asymmetric propargylic transformations –,–. 3‐Triethylsilyl‐propargylic acetate ( 2 a′ ) also performed well (entry 5), however, 2 a′′ , bearing a tert ‐butyldimethylsilyl group, inhibited the cycloaddition, presumably because of the steric hindrance (entry 6).…”

Architecture and synthesis of P,N-heterocyclic phosphine ligands

“…Application References pyridyl phosphines OLEDs [13] Heck coupling [14] metal organic frameworks [15] polymerization of lactides [16] alkene hydroxylation [17] addition reaction [18] ethylene oligomerization [19] synthesis of pyrazolines [20] triazolyl phosphines Suzuki cross coupling [21] asymmetric hydrogenation [22] luminescence [23] hydroformylation [24] pyrazolyl phosphines coordination polymers [25] Heck coupling [26] imidazolyl phosphines Suzuki coupling [27] hydroamination [28] OLEDs [29] ethylene oligomerization [30] amination [31] olefin metathesis [32] hydroformylation [33] pyrrolyl phosphines hydroformylation [34,35] ethylene polymerization [36] oxazolyl phosphines asymmetric cycloaddition [37] asymmetric hydrogenation [38] carbonylation of alkynes [39] allylic substitution [40] asymmetric addition [41] allylic amination [42,43] The presence of soft donor atoms such as phosphorus results in the formation of hemilabile ligands. These are multidentate ligands having hard P-donor and soft N-and/or O-donor atoms [44].…”