Metallaphotoredox-Catalyzed C−H Activation: RegioSelective Annulation of Allenes with Benzamide

We have developed an ecient annulation of benzamides with allenes using cobalt and photoredox dual catalysis under an oxygen atmosphere. This reaction provides a mild and environmentally friendly method for the construction of isoquinolinon scaffolds in good to excellent yields, which demonstrates broad substrate scopes, high regioselectivity, and good functional group compatibility. Notably, this transformation feathers an alternative strategy for the regeneration of cobalt catalyst with the aid of Eosin Y. Preliminary mechanism studies reveal that a radical-mediated cascade annulation is involved in this reaction.


Introduction
Transition-metal-catalyzed direct C − H functionalizations have emerged as e cient, powerful, and straightforward approaches for the construction of carbon-carbon and carbon-heteroatom bonds over the past few decades [1][2][3][4][5][6]. Recently, low-cost and earth-abundant rst-row transition metals seem to be an appealing alternative to noble metals [7][8][9][10]. Among the rst-row transition metals, the unique properties of cobalt in varied oxidation states have witnessed the powerful ability to manipulate various chemical bonds as a result of the chelation-assisted direct metalation of azobenzene [11][12][13][14][15][16]. Among such elegant transformations, a number of C − H activation and oxidative annulation reactions with various unsaturated coupling partners, such as alkynes and alkenes, have garnered considerable attention for molecule diversity in step-and atom-economical strategies [17].
In recent years, signi cant progress has been achieved based on visible light-mediated photoredox catalysis [64][65][66][67][68][69][70], which emerged as a sustainable and versatile platform for the development of practically synthetic methodologies. Among these, the merge of transition metal catalysis and photocatalysis, termed metallaphotoredox catalysis, affords a distinct reaction environment, with both oxidation and reduction of organic and organimetallic species simultaneously possible [71][72][73][74][75][76][77][78]. On the basis of the huge advantage of metallaphotoredox catalysis in organic synthesis, we imagined that the development of cobalt-catalyzed C − H annulation of allenes with benzamide could be an important complement to the reported strategies.
Previous cyclic voltammetry study showed that Co(OAc) 2 revealed high oxidation potential, which meant the cobalt (III) could not be easily generated from Co(II) with common photocatalysts. However, the in situ generated cobalt catalyst between Co(OAc) 2 and benzamide substrate showed a lower oxidation potential at 1.19 V SCE , indicating an accessible photoredox mediated cobalt (II/III) single-electron oxidation [79] (Scheme 1b). Thus, we sought to regenerate the cobalt catalyst through a single electron transfer (SET) process assisting with a photocatalyst under the irradiation of light, which might avoid the use of metal oxidants (Scheme 1b). Herein, we reported the application of dual cobalt and photoredox catalysis strategy into annulation of benzamides with allenes, which provided an economic and atome cient approach for the synthesis of isoquinolinones (Scheme 1c).

Materials And Methods
In an oven dried Schlenk tube charged with magnetic stirrer, benzamide (0.1 mmol, 1.0 equiv.), Co(acac) 2 (0.02 mmol, 20 mol%), potassium tri uoride mesylate (0.02 mmol, 20 mol%) and Eosin Y disodium salt (0.005 mmol, 5 mol%) were added. Freshly prepared allene was subsequently added to the reaction mixture followed by freshly distilled 2,2,2-tri uroethanol (1.5 mL) as solvent. The Schlenk tube was evacuated and purged with oxygen. Then, the resulted solution was placed under 15 W CFL irradiation at room temperature for 24 h. The reaction process was detected by thin-layer chromatography (TLC). Upon completion, the reaction mixture was evaporated under reduced pressure and passed through the column for puri cation. Petroleum ether and ethyl acetate mixture was used as an eluent.

Results And Discussion
As illustrated in Table 1, benzamides(1a) and benzyl buta-2,3-dienoate (2a) were exploited as model substrates with 10 mmol % Co(acac) 2 , 0.2 equiv. of NaOPiv and 5.0 mol % photoredox catalysis under visible light irradiation (15W CFL) for 24 h at room temperature under an oxygen atmosphere. The model reaction was preferentially performed using 2,2,2-tri uoroethanol as a solvent, mainly because of which is facilitated to pair with hydrogen-bond acceptor groups and interfere with the catalytic cycle [80]. To our delight, the desired product 3a could be obtained when [Ru(bpy) 3 ] 2+ Cl 2 was used as a photoredox catalyst (entry 1). It was found that [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 did not effectively promote this cyclization (entry 2). Instead of [Ru(bpy) 3 ] 2+ Cl 2 , Na 2 -eosin Y slightly increased the annulation yields under the similar reaction conditions (entry 3). Further experiment revealed that the use of KOTf as a base could accelerate the reaction and effectively improve the yield of 3a (entry 5). Interestingly, a slight increase in the amount of cobalt made signi cant effect in promoting the reaction, and the excellent yield was obtained when the annulation reaction was performed with 20 mmol% Co(acac) 2 under the similar reaction conditions (entry 6). In addition, control experiments indicated that in the absence of either Co(acac) 2 or oxygen, the reaction was completely inhibited (entry 9 and 10). It is worthy to note that the light played a crucial role for the annulation reaction, and it stopped at 14% yield when the reaction was performed without photocatalyst in dark (entry 11). Using unprotected benzamides with weaker directing groups instead of 1a, the desired product was not obtained under standard conditions, and the corresponding starting materials were decomposed or fully recovered.

Optimization the reaction conditions
With the optimized conditions in hand, the annulation reaction scope was investigated between various substituted benzamides and allenes, and the results were presented in Scheme 1. We found that a number of arylamides bearing different substitutions at the ortho-, metal-, and para-positions were compatible with the optimized conditions (Scheme 2, 3a-3p). For para-substituents in the carboxamides, such as halogen (3f-3 h), acetyl (3i), cyano (3j), or electron-donating methyl (3 k), cyclohexyl (3 l), methoxyl (3 m) groups, the desired isoquinolinones were produced in excellent yields. It was found that the reaction of meta-substituted benzamide furnished two expected regioisomers in good yields (3n). On the other hand, the ortho-substituted substrates with incorporation of electron-withdrawing substituents, such as halogen (3b-3c) and tri uoromethyl (3d), were e ciently transformed into the corresponding products in excellent yields. Replacing with methoxyl in the ortho-position (3e), the cyclization process took a short reaction time, but slightly reduced product yield was observed. In the case of disubstituted benzamide (3o), this reaction also gave the desired product in good yield. Additionally, the naphthoamide (3p) was smoothly converted into the three rings fused heterocycle in good yield. Scheme 2 Scope of benzamides with benzyl buta-2,3-dienoate Next, the scope of allenes was investigated extensively. As summarized in Scheme 3, various allenes were smoothly reacted with benzamides under the optimal conditions, and the corresponding isoquinolinones were got in good to excellent yields. Notably, it was found that the cyclization reaction featured excellent chemo-and regioselectivity, and solely occurred at the allenes' terminal position. Various electronically diverged allenes (2b-2f) were e ciently converted into the desired products (4a-4p).
Generally, the electronical properties of allenes have a great in uence on the reactivity of annulation. Interestingly, various isoquinolinones with exo-double bonds were obtained by coupling benzamides with propa-1,2-dien-1-ylbenzene (2 g), which demonstrated the diverse reactivity of allene. A number of ary amides (5a-5d), and heterocyclic derivative, such as thiophene (5e) showed good compatibility with the reaction condition. To our delight, when terminal di-substituted allene (2 h) was used as a coupling partner, the reaction also afforded the corresponding exo-cyclic isoquinolinones (5 g-5i) in moderate to good yields. These results might provide an interesting perspective for the mechanism information on the migratory allene insertion/isomerization manifold. To gain further mechanistic insights, a series of control experiments were carried out. A mixture of benzamide [D5]-1a/1a (1:1) was used to react with allenylphosphonate (2e) under optimized conditions, and the KIE experiments gave a k H /k D value of 1.1. This phenomenon indicated that C − H bond activation might not be involved in the rate-determining step (Scheme 5a). Furthermore, no D/H exchange was observed when [D5]-1a was treated with phosphateallene under standard conditions. Similarly, no deuterium incorporation in the product 4n was observed when 1c was treated with isotopically labelled CD 3 OD as a cosolvent. These results suggested that the C − H cobaltation step should be irreversible (Scheme 5a). A control reaction was performed in the presence of stoichiometric 2,2,6,6-tetramethyl-1piperidinyloxy (TEMPO, a common radical scavenger), and no the desired product was obtained under the standard condition (Scheme 5b). This gave some clues that a highly radical species might be involved in the catalytic cycle. Additionally, the cyclization reaction conducted under an oxygen atmosphere in the

Conclusion
In conclusion, we have developed an e cient protocol for the construction of isoquinolinones by merging cobalt(II)-catalyzed C − H functionalization with visible light mediated photoredox catalysis. Notably, no metal oxidants are required in this transformation. This reaction provides a mild and environmentally friendly route for the construction of isoquinolinones in good to excellent yields. A wide range of substrate scopes, high level of chemoselectivity and regioselectivity, and broad functional group tolerance were observed. Preliminary mechanism studies reveal that a radical-mediated cascade annulation is involved in this reaction. Further studies about synthetic applications and reaction mechanism are currently ongoing in our laboratory.

Supporting Information
Supporting Information is available and includes synthetic procedures and characterizations of all new compounds, computational details, and additional computational results. absence of Eosin Y did not generate the desired product (Scheme 5c). It excluded the possibility of oxygen acting as a single oxidant which was used to regenerate the cobalt catalyst. On the other hand, intermolecular competition studies suggested that the electron-rich amide was slightly more favorable, which could be rationalized an electrophilic-type substitution C − H metalation. Based on the mechanistic experiments described above and relevant literature reports [81][82], a plausible mechanism for this reaction was proposed in Scheme 6. The rst step began with oxidation of Co(II) to give Co(III)-species assisted simultaneously by reduction of Na 2 Eosin Y*. A following ligand exchange and coordination of 8-aminoquinoline derived benzamide (1a) generated Co(III)-species  2 and benzamide substrate showed a oxidation potential at 1.19 V vs SCE) [79] might be oxidized by the photoexcited Na 2 Eosin Y* (0.83 V vs SCE) [77,86]. Thus the Co(III) species could be regenerated, and a strong reductant, Na 2 Eosin Y radical anion (-1.06 V vs SCE) [86] was simultaneously generated.
The Na 2 Eosin Y radical anion might be oxidized to the ground state by O 2 to complete the photoredox cycle [86]. At last, the intermediate G undergoes 1,3-hydrogen shift to furnish the corresponding nal product H.

Declarations Con ict of Interest
The authors declare that they have no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper.