Nitrogen radical-triggered trifunctionalizing ipso-spirocyclization of unactivated alkenes with vinyl azides towards new spiroaminal frameworks


 Radical-mediated spirocyclization is a powerful and efficient tool to forge complex spirocyclic frameworks. Radical-mediated non-dearomative double-cyclization of linear precursors for the concomitant construction of both rings is more challenging but highly attractive. Herein, we report the first example of non-dearomative trifunctionalizing ipso-spirocyclization of unactivated alkenes through photoredox-catalyzed, nitrogen radical-triggered cyclization-trapping-translocation-cyclization cascade, providing a single-step modular access to architecturally new and fascinating spiroaminal frameworks through simultaneous formation of one C−C bond and two geminal C−N bonds. The developed protocol utilizes not only internal or terminal olefinic oxime esters but also olefinic amides as nitrogen radical precursors, and features broad substrate scope, varied functional group compatibility, easy scalability, and potential for product derivatization and late-stage functionalization of biologically active molecule. Importantly, the mechanistic studies including DFT calculations indicate that such photocatalytic trifunctionalizing ipso-spirocyclization undergoes a radical relay cascade of intramolecular 5-exo-trig cyclization, intermolecular radical trapping, 1,5-hydrogen atom transfer, and sequential 5-endo-trig cyclization, which would open up a new reaction mode of alkenes.

atom transfer, and sequential 5-endo-trig cyclization, which would open up a new reaction mode of alkenes.
Spirocyclic skeletons widely occur in a plethora of naturally occurring products with broad structural diversities and diverse biological activities [1][2][3][4] , and are increasingly being incorporated into drug candidates 5,6 (Fig. 1a). Furthermore, the inherent three-dimensional (3D) conformational constraint character of the spirocyclic skeletons enables them as one of the excellent ligand 7-10 and organocatalyst 11,12 frameworks in the field of asymmetric catalysis. In this context, an elegant radical-mediated spirocyclization for the construction of the spirocyclic compounds, including dearomative 13 and non-dearomative 14 strategies, has been developed rapidly in the past decade. To the best of our knowledge, the existing approaches for the radical-mediated spirocyclization are solely based upon the elaboration of aromatic or aliphatic monocyclic precursors on which the second ring is newly appended, and compared with the former dearomative strategies, the latter non-dearomative strategies could provide structurally distinct spirocyclic compounds with varied functionality (Fig. 1b).
However, radical-mediated non-dearomative double-cyclization of linear precursors for the concomitant construction of both rings has remained unexploited to date. Thus, the development of novel spirocyclic skeletons and evermore-effective non-dearomative spirocyclization strategies using different classes of linear starting materials are highly desirable but challenging.
On the other hand, alkenes are energetic and versatile synthons that engage in diverse organic transformations because of their abundance and rich reactivity. In recent years, the difunctionalization of alkenes is one of the most important and valuable strategies in organic synthesis, since it allows the rapid, efficient, and synergistic incorporation of two functional groups onto one C-C double bond in an atom-and step-economic fashion for enhancing the molecular complexity and diversity.
Among them, the 1,2-difunctionalization of alkenes, including intermolecular and intramolecular reactions, was extensively developed as a powerful tool for the creation of two new vicinal chemical bonds [15][16][17][18][19][20] . Compared with the vigorous increasing achievements of 1,2-difunctionalization, the 1,1-difunctionalization of alkenes to access geminal difunctionalized alkanes is still underdeveloped 21 ；for example, the scope of alkene geminal diamination is limited to activated alkenes as well as ethylenediamine derivatives as nitrogen sources [22][23][24] . Notwithstanding the remarkable advances achieved toward the difunctionalization of alkenes, only sparsely have the more challenging trifunctionalization of alkenes been exploited, which significantly restricted their application for the assembly of diversely multifunctionalized molecules (Fig. 1c). The reason might be mainly attributed to the lack of an effective approach to realize the trifunctionalization. For the purpose of providing structurally diverse and complex functional molecule libraries derived from privileged scaffolds (particularly spirocyclic skeletons) to meet the ever-increasing demand for the development of new drugs, ligands and organocatalysts, the exploration of novel, straightforward, and efficient approaches for the trifunctionalization of alkenes is of special interest and great significance.
Successfully merging the difunctionalization of alkenes with the selective functionalization of C(sp 3 )-H bonds might be one of the reliable and effective approaches to reach the formidable trifunctionalization of alkenes. Accordingly, the strategies employed for such trifunctionalization can be largely divided into two categories: 1) very few "innate trifunctionalization", aliphatic C(sp 3 )-H functionalization of the newly generated difunctionalized intermediates, such as β-keto sulfones derived from activated alkenes including vinyl azides 25

Results
Reaction optimization. To test the described hypothesis, iminyl radical precursor O-4-trifluoromethylbenzoyl oxime ester 1a and vinyl azide 2a were initially chosen as the model substrates to explore the reaction conditions (Table 1) other solvents delivered no more significant improvement than that of DMSO (entries 6−8). It was worth mentioning that the yields of the desired product declined slightly when the reaction was conducted without the addition of base or argon protection (entries 9 and 10). As anticipated, no desired product could be detected without either light or photocatalyst, indicating the indispensability of both light and photocatalyst in such photocatalytic CTTC cascade (entry 11).  LG = p-CF3-C6H4CO2-(OBz CF3 ). b Yields were determined by 1 H NMR using dibromomethane as an internal standard. Isolated yields in parentheses.

Substrate scope on the vinyl azides.
With the optimized reaction conditions in hand, we next sought to investigate the substrate scope on the trifunctionalizing ipso-spirocyclization enabled by the iminyl radical-triggered CTTC cascade (Table 2).
First, the generality of this ipso-spirocyclization with regard to vinyl azides was examined with olefinic oxime ester 1a as the iminyl radical precursor. A variety of vinyl azides with different electronic groups at the para-(3aa−3al), meta-(3am−3ap), or ortho-position (3aq) of the phenyl rings reacted smoothly with 1a to afford the corresponding spirobi[pyrrolines] in acceptable yields. Gratifyingly, this photocatalytic trifunctionalizing ipso-spirocyclization tolerated a broad range of diverse functionalities such as alkyl (3aa−3ae, and 3am), phenyl (3ag), methoxyl (3ah, 3an, and 3aq), and trifluoromethyl (3ai), as well as halogen (3aj−3al, 3ao, and 3ap) which could be employed as a handle for further derivatization. Furthermore, heteroaryl-substituted vinyl azides including thiophene (3ar) and pyridine (3as) displayed good reactivity in our protocol. Notably, alkyl-substituted vinyl azide was also proved to be suitable substrate for this spirocyclization and provided 44% yield of the expected spirobi[pyrroline] 3at. As illustrated in Table 3, a panel of aromatic oxime esters bearing electronic variation on the phen rings were also well-tolerated in this transformation, affording the corresponding spirobi[pyrrolines] 3ba−3ga in moderate to good yields. Furthermore, 2-naphthyl-(3ha) and heteroaryl-substituted oxime esters (3ia) were also subjected to the present protocol. Additionally, aromatic oxime esters with alkyl chain units at the α position were used as the substrates in this protocol and smoothly transformed into the corresponding spirobi[pyrrolines] 3ja and 3ka in 45% and 58% isolated yields, respectively. Notably, the structure of 3ka was unambiguously confirmed by X-ray crystallographic analysis (CCDC 2061499). Importantly, in addition to 1,2,2-trisubstituted olefinic oxime esters, 1,2-disubstituted (3la−3na) and 1-substituted olefinic oxime esters (3oa) could also be employed as competent substrates in this transformation to provide the desired products. Substrate scope on the amidyl radical-triggered trifunctionalizing ipso-spirocyclization. Encouraged by the success of the unprecedented trifunctionalizing ipso-spirocyclization enabled by the iminyl radical-triggered CTTC cascade, we speculated that the high electrophilic amidyl radical 41,42 could also trigger such CTTC cascade to achieve the desired trifunctionalizing ipso-spirocyclization of unactivated alkenes for rapid construction of another new spiroaminal framework.
Excitingly, upon the facile screening of parameters, amidyl radical precursor olefinic amides were indeed capable partners and readily underwent such photocatalytic trifunctionalizing ipso-spirocyclization (Table 4). Similarly, vinyl azides with various electron-donating or electron-withdrawing groups reacted smoothly with 4a to furnish the structurally novel spiropyrroline lactams in satisfactory yields. Olefinic amides with a hindered N-Cy group (5ba), N-Ph group (5ca), as well as a removable N-Bn group (5da) could successfully participate in this trifunctionalizing ipso-spirocyclization. Furthermore, olefinic amide with alkyl chain unit at the α position could be applied as well to deliver the corresponding product 5ea. In addition, the proposed approach could address 6-exo-trig cyclization of unactivated alkene to generate 6-membered ring lactam 5fa. Interestingly, N-protected amine was compatible with the photoredox catalysis and provided the desired spiropyrroline pyrrolidine 5ga in moderate yield.

Products transformation.
To demonstrate the potential application of the protocol, a gram-scale reaction containing 3.0 mmol of oxime ester 1a was performed under the standard conditions to afford the target product 3aa with a satisfactory isolated yield, demonstrating the synthetic practicality and scalability of our photocatalytic trifunctionalizing ipso-spirocyclization (Fig. 2a). Moreover, the synthetic utility of the method was further confirmed by facile derivatization of the formed spirobi [pyrroline] 3aa to yield structurally diverse and valuable molecules (Fig. 2b). Rather surprisingly, in the presence of protonic acid or trifluoroacetic anhydride, 3aa can be smoothly transformed into the aromatized 1H-pyrrole derivatives (6 and 7) in 75% and 68% yields, respectively. Moreover, [3 + 2] cycloaddition reaction between 3aa and N-hydroxybenzimidoyl chloride allowed access to the 1,2,4-oxadiazoline-fused sipropyrroline 8. When spirobi[pyrroline] 3aa was treated with N-chlorosuccinimide (NCS) at 80 °C for 24 h, the multi-halogen-substituted spiroaminal 9 was obtained with excellent isolated yield. Delightfully, estrone-derived vinyl azide 2w readily engaged in such photocatalytic transformation with olefinic oxime ester 1a to give the structurally more complex and intriguing compound 3aw, demonstrating the potential application of this methodology (Fig. 2c). Additionally, when 1,1-disubstituted terminal olefinic oxime esters were subjected to the reaction system, the desired 1,5-HAT process did not proceed smoothly and thus no corresponding spirobi[pyrroline] was detected.
Interestingly, using vinyl azide 2-azidoallyl diphenylmethyl ether 2x as the coupling partner, the second iminyl radical derived from vinyl azide underwent intramolecular 1,5-HAT (from nitrogen to benzyl carbon atom) and further cyclization to afford a panel of the oxazoline-based pyrrolines 10px−10ux (Fig. 2d). Notably, terminal olefinic oxime ester 1o could also be converted into the expected oxazoline-based pyrroline 10ox albeit with somewhat low yield. Mechanistic studies. To rationalize the mechanism of this photocatalytic trifunctionalizing ipso-spirocyclization reaction, several control experiments were carried out. As shown in Scheme 3, upon the addition of electron-transfer scavenger p-dinitrobenzene (DNB) or radical scavenger 2,2,6,6-tetramethyl-piperidinyloxyl (TEMPO) into the model reaction, the formation of the desired product 3aa was completely inhibited (Fig. 3a). And the corresponding 1a-derived TEMPO-trapped adduct was detected through LC−HRMS analysis. When the model reaction was performed in the presence of quintessential radical-trapping reagent 1,1-diphenylethylene (DPE), the yield of 3aa declined slightly from 71% to 43%, and the radical-trapping products (3aa' and 3aa'') were detected through LC−HRMS analysis (Fig. 3a). Subsequently, in the absence of vinyl azide 2a, the hydroimination product 1a' and olefination product 1a'' were obtained in 23% and 32% yield, respectively (Fig. 3b). These results indicate that not only a single electron transfer (SET)/radical process but also the carbon-radical intermediates generated through iminyl radical-triggered intramolecular cyclization might be involved in the present transformation. Additionally, no desired product 3aa was detected when vinyl azide 2a was replaced with 3-phenyl-2H-azirine 2a' generated from the denitrogenative decomposition of vinyl azide under the standard conditions, suggesting that 2H-azirine intermediates might be ruled out in this transformation (Fig. 3c).

Discussion
In conclusion, we successfully developed a novel, selective, and efficient strategy to realize trifunctionalizing ipso-spirocyclization of unactivated internal and terminal alkenes by photoredox-catalyzed, nitrogen radical-triggered relay cascade involving were added under Ar flow. The tube was placed approximately 2 cm from 30 W blue LEDs, and then stirred at room temperature for 6 h. After completion, the reaction was quenched with H2O (4.5 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography on silica gel to afford the desired product 3. Note: for olefinic amides 4 (MeCN was used instead of DMSO), the reaction mixture was filtered after completion, concentrated under reduced pressure, and purified by column chromatography on silica gel to afford the desired product 5.

Additional Information
Supplemental Information can be found with this article online. The

Author contributions
D.Y. and X.D. conceived and designed the study, and wrote the paper. Z.Y.Q., Z.J.Z., L.Y., D.Z.
performed the experiments and mechanistic studies. Q.F. and S.P.W. performed the DFT calculations. All authors contributed to the analysis and interpretation of the data.