Copper‐Catalyzed Azide–Ynamide Cyclization to Generate α‐Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N‐Heterocycles

Abstract

Here an efficient copper‐catalyzed cascade cyclization of azide‐ynamides via α‐imino copper carbene intermediates is reported, representing the first generation of α‐imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N‐heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX‐Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.

Copper‐Catalyzed Azide–Ynamide Cyclization to Generate α‐Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N‐Heterocycles

“…> 20/1) were achieved in all cases.T he molecular structure of 2k was confirmed by X-ray diffraction. [18] In addition to N-allyl benzyl-tethered (azido)ynamides, this copper-catalyzed cascade cyclization also occurred efficiently with N-propargyl benzyl-tethered (azido)ynamides [11d, 14c, 19] at room temperature by employing 10 mol %o f Cu(CH 3 CN) 4 PF 6 as catalyst and 2equiv of DDQ as oxidant, [16] thus allowing the synthesis of 3H-pyrrolo [2,3-c]isoquinolines 4.N otably,t he background formation of pyrrolefused indenes via C À Hinsertion into copper carbenes was not detected. [14c] As shown in Table 3, initial investigation of Nprotecting groups of the ynamides 3 demonstrated that the reaction could proceed smoothly with different sulfonyl groups,a ffording the desired tricyclic heterocycles 4a-4d in 58-80 %y ields.I na ddition, as eries of different arylsubstituted N-propargyl (azido)ynamides were also examined, and the corresponding pyrrole-fused isoquinoline products 4e-4nwere formed in 70-94 %yields.Moreover,thienyland methyl-substituted N-propargyl (azido)ynamides were readily tolerated to produce the desired products 4oand 4pin 72 %a nd 66 %y ields,r espectively.T his cascade cyclization also occurred efficiently for various phenyl rings bearing both electron-withdrawing and -donating groups,and products 4q-4u were obtained in 78-91 %yields.T he molecular structure of 4m was confirmed by X-ray diffraction.…”

“…[14c] As shown in Table 3, initial investigation of Nprotecting groups of the ynamides 3 demonstrated that the reaction could proceed smoothly with different sulfonyl groups,a ffording the desired tricyclic heterocycles 4a-4d in 58-80 %y ields.I na ddition, as eries of different arylsubstituted N-propargyl (azido)ynamides were also examined, and the corresponding pyrrole-fused isoquinoline products 4e-4nwere formed in 70-94 %yields.Moreover,thienyland methyl-substituted N-propargyl (azido)ynamides were readily tolerated to produce the desired products 4oand 4pin 72 %a nd 66 %y ields,r espectively.T his cascade cyclization also occurred efficiently for various phenyl rings bearing both electron-withdrawing and -donating groups,and products 4q-4u were obtained in 78-91 %yields.T he molecular structure of 4m was confirmed by X-ray diffraction. [18] Thus,t his cascade cyclization provides ahighly convenient and practical route for preparation of useful 3H-pyrrolo [2,3-c]isoquinolines. [20] Besides intramolecular trapping of the presumable aimino copper carbenes by the alkene and alkyne moieties,this copper-catalyzed tandem reaction could also be applicable to intermolecular trapping by olefins.Asshown in Equation 1, the treatment of azide-ynamides 5 with 10 equiv of styrene at 60 8 8Cb ye mploying 10 mol %o fC u(CH 3 CN) 4 BF 4 as catalyst led to the efficient formation of spiro-cyclopropane products 6a-6b in 76-80 %y ields with excellent diastereoselectivities (d.r.…”

“…Them olecular structure of 6a was confirmed by X-ray diffraction. [18] It is notable that no intramolecular ortho-aryl CÀHi nsertion was observed, and in particular, this insertion product was not detected even in the absence of styrene. [16] After establishing ag eneral and reliable method for this copper-catalyzed tandem reaction of azide-ynamides,w e focused on the development of ac hiral copper complexcatalyzed enantioselective version.…”

“…[10c] Subsequent b-elimination under basic conditions delivered the final tricyclic isoquinoline 2avbearing exclusive Z configuration of the double bond in 62 %y ield, and its structure was confirmed by X-ray diffraction. [18] In addition, Suzuki coupling of chiral (À)-2ah with arylboronic acid produced the corresponding product (À)-2aw in 89 %y ield with well-maintained enantioselectivity.T he molecular absolute configuration of (À)-2aw was confirmed by X-ray diffraction analysis, [18] which also determined the absolute configuration of the above chiral tetracyclic products (À)-2.F inally,s ome derivatizations of the tricyclic heterocycle 4a were also carried out. Thet reatment of 4a,a lso synthesized on ag ram scale in 73 %y ield, with KOHa nd phosphorus ylide could afford the corresponding deprotection product 4aa in 88 %y ield and alkenylation product 4ab in 71 %yield, respectively.…”

Copper-Catalyzed C—H Bond and N—H Bond Insertion Reaction Based on Azide-Ynamide Cyclization

“…近年来, 炔酰胺化学受到了极大的关 注 [9] . 我们课题组发展了廉价金属铜催化的叠氮-炔酰 胺的胺化反应用于产生 α-亚胺铜卡宾 [10] , 并实现了该 类反应的不对称催化, 以高非对映选择性和高对映选择 性实现了手性氮杂环化合物的高效构建 [10a] . 以此为基 础, 本文继续拓展了该类 α-亚胺铜卡宾的应用范围, 发 展了对分子间吲哚衍生物碳氢键以及对苯胺类衍生物 氮氢键 [11] 的插入反应, 高效构筑了一系列异喹啉-吲哚 和异喹啉-苯胺类化合物.…”