Practical and stereoselective electrocatalytic 1,2-diamination of alkenes

The 1,2-diamine motif is widely present in natural products, pharmaceutical compounds, and catalysts used in asymmetric synthesis. The simultaneous introduction of two amino groups across an alkene feedstock is an appealing yet challenging approach for the synthesis of 1,2-diamines, primarily due to the inhibitory effect of the diamine products to transition metal catalysts and the difficulty in controlling reaction diastereoselectivity and regioselectivity. Herein we report a scalable electrocatalytic 1,2-diamination reaction that can be used to convert stable, easily available aryl alkenes and sulfamides to 1,2-diamines with excellent diastereoselectivity. Monosubstituted sulfamides react in a regioselective manner to afford 1,2-diamines bearing different substituents on the two amino groups. The combination of an organic redox catalyst and electricity not only obviates the use of any transition metal catalyst and oxidizing reagent, but also ensures broad reaction compatibility with a variety of electronically and sterically diverse substrates.

Building on our experience with electrochemical alkene difunctionalization 37,38 , herein we report a diastereoselective electrocatalytic 1,2-diamination reaction of di-and tri-substituted alkenes using easily available and stable sulfamides as amino donors. A wide variety of 1,2-diamines, where the two amino groups are functionalized with different substituents, can be prepared via regio-and diastereoselective diamination using monosubstituted sulfamides. The electrosynthetic method employs an organic redox catalyst and proceeds through H 2 evolution, while obviating the need for transition metal catalysts and external chemical oxidants.

Results
Design plan. Inspired by our previously work on electrochemical alkene dioxygenation reactions 38 , we envisioned the trapping of an electrocatalytically generated alkene radical cation II •+ with a sulfamide III to generate a carbon radical IV (Fig. 2a). [39][40][41][42][43] Single-electron transfer oxidation of IV by I •+ would produce a carbocation V, which could then undergo cyclization to afford the cyclic sulfamide VI. Cyclization of V has a key role in governing the stereoselectivity of the 1,2-diamination, in which the alkeneoriginated substituents R 1 and R 2 are positioned on opposite sides of the nascent five-membered ring to minimize steric repulsion.
The electrons that the alkene loses to the anode would eventually combine with the protons at the cathode to form H 2 , thereby obviating the need for external electron and proton acceptors. The controlled formation of alkene radical cations at low concentrations is essential to overcome their strong propensity toward self-dimerization or reaction with the alkene precursors, especially on electrode surface [44][45][46] . This could be accomplished by conducting electrolysis indirectly in the presence of a redox catalyst rather than direct electrolysis. Measuring catalytic current through cyclic voltammetry 33,47 , with tris(2,4-dibromophenyl) amine (1, E p/2 = 1.48 V vs saturated calomel electrode (SCE)) as the redox catalyst, confirmed the facile electrocatalytic oxidation of the alkenes 2 (E p/2 = 1.66 V vs SCE) and 3 (E p/2 = 1.80 V vs SCE) that bears an electron-withdrawing ester group (Fig. 2b, c).
Reaction optimization. The 1,2-diamination of aryl alkene 2 with sulfamide 4 was chosen as a model reaction for optimizing the electrochemical conditions. The electrolysis was conducted at RT and at a constant current in a three-necked round-bottomed flask equipped with a reticulated vitreous carbon (RVC) anode and a platinum plate cathode. The optimal reaction system consisted of triarylamine 1 (10 mol %) as redox catalyst, i PrCO 2 H (2 equiv) and BF 3 •Et 2 O (0.5 equiv) as additives, Et 4 NPF 6 as supporting electrolyte to increase conductivity, and MeCN/ CH 2 Cl 2 (1:2) as solvent. Under these conditions, the diamination product 5 was obtained in 72% yield with excellent diastereoselectivty ( > 20:1 dr) even though a starting mixture of Z/E isomers of 2 was used (in a ratio of 5.6:1) ( Table 1, entry 1). Independent reaction using a pure Eor Z-isomer of 2 afforded the same trans diastereomer 5 in 65% and 69% yield, respectively. Similar results could also be obtained when the reaction was performed in ElectraSyn 2.0, a commercial apparatus (Table 1, entry 2). The use of MeCN as solvent instead of MeCN/CH 2 Cl 2 resulted in a lower yield of 50% (Table 1, entry 3). Other triarylamine derivatives such as 6 (E p/2 = 1.06 V vs SCE), 7 (E p/2 = 1.26 V vs SCE), and 8 (E p/2 = 1.33 V vs SCE) were found to be less effective in promoting the formation of 5 probably because of their lower oxidation potentials (   Fig. 2 Proposed reaction design. a The proposed reaction mechanism. The process combines anodic oxidation and cathodic proton reduction to achieve the alkene 1,2-diamination via H 2 evolution. The electrocatalytic activation of the alkene through single-electron transfer (SET) oxidation generates the alkene radical cation II •+ , which is trapped by the sulfamide III to give radical IV. Further SET oxidation and diastereoselective cyclization of V afford diamination product VI. Evaluation of substrate scope. We next explored the scope of alkenes by using sulfamide 4 as the coupling partner ( Table 2). The aryl ring in the 1,2-disubstituted alkene could be functionalized with an electronically diverse set of substituents, including Me (9), t Bu (10), halogens (F, Cl, Br, I; 11-16), and ester (17 and 18), at various positions of the phenyl ring. Alkenes carrying a 2,5-disubstituted phenyl ring were also found to be suitable substrates (19 and 20). The β-position of the styrenyl alkene showed broad tolerance for alkyl substituents of different sizes, such as Me (21), cyclohexyl (Cy; 22), and t Bu (23). Terminal alkenes were less-efficient substrates probably owing to the facile dimerization/oligomerization of these alkenes 44,49 . As an example, the reaction of 1,1-diphenylethylene with 4 afforded the desired product 24 in 40% yield. One the other hand, trisubstituted cyclic (25) and acyclic (26 and 27) alkenes reacted smoothly to afford the corresponding cyclic sulfamides in good to excellent diastereoselectivity. Meanwhile, 1,2-diamination of 1,3dienes showed satisfactory regioselectivity in favor of the alkenyl moiety distal to the phenyl group (28 and 29). Note that triarylamine 6 was employed as redox catalyst to overcome the relatively low oxidation potentials of 1,3-dienes (E p/2 = 1.29 V vs SCE) and avoid oxidizing the remaining alkene moiety in the products. Furthermore, the electrochemical alkene 1,2-diamination reaction was compatible with alkylbromide (30 and 31), alkylchloride (32), ester (17,18,33), sulfonic ester (34), sulfonamide (35), amide (36), heterocycles such as furan (37) and thiophene (38), cyclic ether (39), and even oxidation-labile secondary and tertiary amines (40)(41)(42). Alkenes derived from estrone (43), fasudil (44), and quinine (45) reacted with similar success. The electron-rich amino groups in the cases of 40-42, 44, and 45 were masked as ammonium salts by the addition of HBF 4 to prevent oxidative decomposition. The electrochemical method also proved capable of generating 1,2-diamine products that carry two differently decorated amino groups, or cyclic 1,2-diamines ( Table 2). For example, we succeeded in the 1,2-diamination with a wide array of asymmetric sulfamides bearing a single alkyl group on one of its nitrogen atoms. In these cases, the alkyl substituent could be primary (46,47), secondary (48), tertiary (49,50), or functionalized with ester (51), CF 3 (52), alkylchloride (53), carboxylic acid (54), free alcohol (55), alkene (56), or alkyne (57). These asymmetric sulfamides reacted in a strictly regioselective manner. Notably, bridged bicyclic products (58-60) could be obtained by 1,2diamination of cyclic sulfamide substrates. The structure of 59 was further confirmed by single crystal X-ray analysis.
Gram scale synthesis and product transformations. To further demonstrate the synthetic utility of our electrochemical method, we reacted alkene 61 or 62 with sulfamide 4, 63, or 64 on gram or even decagram scale and obtained the corresponding products (21,22,48, and 59) in good yields (Fig. 3). Deprotection of theses cyclic sulfamides with HBr or hydrazine furnished diamines 65-67, 69, and 70. Protection of the free amino group in 67 with Boc 2 O resulted in the formation of 68, whose two amino groups carries different substituents and therefore is amenable to further chemoselective derivatization. On the other hand, 48 could be converted to diamine 69, also with differently decorated amino groups, through methylation and subsequent sulfonyl removal.