Oxidative [4+2] annulation of styrenes with alkynes under external-oxidant-free conditions

The sequenced Diels–Alder/oxidation reaction represents a powerful route for the construction of aromatic compounds in organic synthesis. The oxidative Diels–Alder reaction with H2 evolution would be a more ideal approach that can avoid the additional oxidation procedure and stoichiometric oxidant. Herein, an oxidative [4 + 2] annulation reaction of styrene derivatives with electron-rich dienophiles accompanying the H2 generation has been developed by using the synergistic merger of photoredox and cobaloxime catalyst. With respect to atom and step-economy ideals, this dual catalytic system enables the formation of high-value molecules from feedstock chemicals in a single step under room temperature.

S ix-membered aromatic rings are valuable structural motifs that widely existed in natural products, pharmaceuticals, and functional materials. The regioselective synthesis of multi-substituted arenes has long been attracted significant attention in industrial and academic society. Diels-Alder (D-A) reaction represents one of the most powerful tools for the C-C bond-constructing reactions in organic synthesis [1][2][3][4][5] . Followed by sequenced oxidative aromatization, D-A reaction has be utilized into the preparation of multi-substituted aromatic compounds by building up a new six-membered carbocycle (Fig 1a) [6][7][8][9] . By this approach, the regioselective introduction of functional groups on arenes can be guaranteed, since the partial substituents of aromatics are preinstalled into the starting materials.
In the classic D-A reaction, butadiene reacts with ethylene to form cyclohexene, and, overall, one unsaturated bond functionality is lost. The six-membered aromatic rings can be formed by the D-A reaction between the pre-dehydrogenative high-valence reactants. For instance, alkyne and allenyne combine to produce benzene in tetradehydro-Diels-Alder (TDDA) reaction 10 . Beyond that, Hoye et al. have also developed new types of D-A reactions, hexadehydro-Diels-Alder (HDDA) and pentadehydro-Diels-Alder (PDDA) reactions, which are powerful tools for the synthesis of arenes 11,12 . Undoubtedly, a dehydrogenative D-A reaction that can retain unsaturated bond during the formation of a six-membered ring would be a more ideal approach from the view of step-and atom-economy 13 , since the pre-oxidation and stoichiometric oxidants can be avoided. A microwave-assisted intramolecular dehydrogenative D-A reaction of styrene-yne to form naphthalene derivatives without oxidant was developed by Brummond 14 , which was generically called as the dehydro-Diels-Alder (DDA) reaction 8,[15][16][17] . The dehydrogenative [4 + 2] annulation under mild conditions still remains challenging, because high reaction temperature was generally required to overcome the high activation energy in the thermal D-A reaction.
In this work, we developed a highly regioselective oxidative D-A reaction with H 2 evolution by using a photo/cobaloxime dual catalytic system (Fig. 1b). A variety of six-membered aromatic rings can be successfully afforded from [4 + 2] annulation of styrene derivatives with electron-rich dienophiles under room temperature. The alkenes radical cation species was proposed as the key intermediate for the annulation reaction. It is appealing to further apply this method for the synthesis of the important functional compounds because of its mildness and high atom economy features of this method.

Results
Optimization of the reaction conditions. Our initial investigation began with the [4 + 2] annulation of 1,1-diphenylethlene with 4-ethynylanisole. This electronically dismatched D-A cycloaddition would not proceed upon thermal activation (200°C , 24 h, see Supplementary Fig. 3). Encouragingly, the reaction was conducted by employing the Fukuzumi's acridinium 46 as the photosensitizer and Co(dmgH) 2 pyCl (5S-1) as the co-catalyst (Supplementary Table 1, entry 1), the desired naphthalene product 3aa can be isolated in 66% yield after the irradiation of blue LEDs light for 24 h. The single regioselectivity and only a little of dimerization side-product of alkene can be observed. The H 2 can be determined by gas chromatography with thermal conductivity detector (GC-TCD) and some amount of hydrogenation of olefin can be obtained. The exploration of various cobaloxime catalysts revealed that a modified cobaloxime Co(dgmH) 2 py 2 PF 6 (5) would improve the reactivity of this transformation (75%). However, chemoselectivity became particularly problematic when the conditions were used for other easily oxidizable olefin, such as prop-1-ene-1,1-diyldibenzene. It was found that both [2 + 2] cycloaddition and [4 + 2] dehydrogenative annulation can occur. The [4 + 2] pathway is favored by decreasing concentration of reaction (Supplementary Table 2). Control experiments indicated no desired reaction would be observed when each component was individually omitted (Supplementary Table 3).
Substrate scope of the reaction. With this dual photoredox/ cobalt catalytic system in hand, we then examined the scope and limitation of this protocol. This dual catalytic system allows this oxidative [4 + 2] annulation of a wide range of styrenes with alkynes ( Fig. 2). The 1,1-diphenylethene derivatives bearing electron-donating or electron-withdrawing substituents underwent the reaction smoothly with 4-methoxyphenylacetylene to produce the desired naphthalenes (3aa-3ad). When one of the aryl groups was replaced by the alkyl group (3ae, 3af), the transformation process could also proceed with moderate to good yields. The procedure was also applicable for trisubstituted aryl
Next, the scope of the reaction with respect to alkynes was investigated. Various substituted alkynes changing with the electronic and steric properties of substituents were applicable for this protocol (3ba-3br). Electrically neutral phenyl acetylene provided the 1,4-diphenylnaphthalene in 48% yield (3ba). Generally, an electron-rich dienophile promotes this oxidative radical cation D-A reaction due to the higher nucleophilicity. The presence of electron-donating groups (-Me, -OMe, 4-C 5 H 11 , 4-OAc) would increase the reactivity (3bb, 3aa, 3bg, 3bh), while electron-withdrawing groups, such as halides (3bc, 3bd) and acetyl (3bf), provided relatively lower yields. Both ortho-and meta-substituted aromatic alkynes could provide the desired products (3bj, 93% and 3bl, 52%). The 4-chloro-1-ethynyl-2methoxybenzene gave the desired product 3bk in moderate yield (49%). This method could be extended to the heteroaromatic alkyne (3bi). Furthermore, the aliphatic alkyne led to the corresponding products in modest yield, and the cyclopropyl group can be tolerated (3bn). The reactivity of this reaction would be almost shut down when 1,2-diphenylethyne was used as a dienophile might due to electro-withdrawing property of phenyl group. However, the transformation is suitable for the internal alkyne oct-4-yne to form the desired product (3bo). When a conjugated diyne, 1-(buta-1,3-diyn-1-yl)-4-methoxybenzene, was used as a substrate, the [4 + 2] annulation occurred in the terminal alkyne group (3bp). Alkynyl ether can also be compatible in this transformation to form the α-naphthylether compound (3bq). An estrone derivative (3br) was successfully prepared with moderate yield, which highlights the good functional group tolerance and potential applications of this method. Although the conversion of alkyne is high in some examples, the yields are low and other side-product can not be observed. We speculated that a part of the alkynes might polymerize under the light-illumination condition. Notably, this procedure was also applicable for the intramolecular dehydrogenative [4 + 2] cycloaddition reaction of styreneynes (Fig. 3). Compared with the Brommund's report 14 , this dual catalytic system allows the achievement of this transformation without the need of severe reaction temperature. The substrate scope of this photocatalyzed protocol is different from the previously reported thermal reaction. The electron-rich alkynes (7a and 7b) would promote the reaction, while electron-deficient alkynes (7c and 7d) decreased the reactivity. The electro-rich substituent on the para position of styrene can be tolerated to give the product in good yield (7e, 77%). 1-(3-(Cinnamyloxy)prop-1yn-1-yl)-2-methoxybenzene gave the desired product with decreased reactivity due to the steric effect (7f, 55%). The toluenesulfonamide and diethyl malonate substrates can also afford the desired products (7g and 7h). Furthermore, the substitution of the alkyne with alkyl groups could be carried out with ease in good yields (7i and 7j).
Gram synthesis using sunlight. To demonstrate the scalability of this protocol, a gram-scale synthesis of 3aa (10 mmol scale) was  performed by employing only 1 mol% of photosensitizer and 3 mol% of cobaloxime catalyst. Furthermore, this reaction even could be performed by using sunlight source (Fig. 5). When the reaction was placed in a sunny place for 2 days without stir, 55% yield of product can be obtained.
Mechanistic studies. To obtain further insight on the photocatalytic process, the Stern-Volmer studies of photocatalyst were conducted and the results were shown in Fig. 6a. It was found that fluorescence intensity of the excited state of 4 can be linearly quenched by 1,1-diphenylethene (1a) and 4-ethynylaniosole (2a). In contrast, the reactive electron-neutral phenylethyne or alkyl alkyne fail to quench the emission of the excited state of the photosensitizer. Therefore, we proposed that the alkynes preferred to serve as the dienophiles, though the initial oxidation of alkyne cannot be completely ruled out when the strong electronrich aryl alkynes were used. To gain insight of this transformation, the competition experiment between the substrates with electron-rich and electron-deficient substituent was conducted ( Supplementary Fig. 9). The electron-rich substituents would promote the reactivity, which indicated that a positive charge intermediate might be involved in the transformation. The reaction of the same amount of substrate 1a and deuterated substrate 1a-d 10 under the standard conditions for 0.5 h provided a mixture of the products deuterium-3aa and 3aa in 31% combined yield, in which the ratio of 3aa: 3aa-d 10 was 1.04 (Fig. 6b).
The kinetic isotopic effect (KIE) value revealed that the cleavage of aromatic C-H bond might not be the rate-determining step of the transformation.
Proposed mechanism. The proposed mechanism was outlined in Fig. 7. The dimerization of alkene can be detected by GC-MS, which indicated that alkene radical cation might act as an intermediate in the reaction. We believed that the styrene radical cation can be formed upon the electron transfer from the styrene to an excited-state photoredox catalyst 4*. Then, the nucleophilic   Overall, this dehydrogenative [4 + 2] annulation reactions is a powerful tool for the synthesis of polysubstituted aromatics from commercially available materials. Through an in situ-generated alkene radical cation intermediate, the reaction can be carried out under room temperature with good regioselectivity. The mildness and high atom economy of this approach makes it appealing for further application to synthesis of important natural products, pharmaceuticals, and functional materials.

Methods
General procedure for catalytic oxidative [4 + 2] cycloaddition of styrene with alkynes. A schlenk tube equipped with a stir bar was loaded with 2.4 mg (3 mol%, 0.006 mmol) of Acr + -Mes ClO 4 − , 9.5 mg (8 mol%, 0.016 mmol) of Co (dmgH) 2 py 2 PF 6 , 0.26 mmol styrenes 1 and 0.2 mmol alkyne 2 in 14 mL degassed DCE under N 2 atmosphere. The solution was then stirred at room temperature under the irradiation of blue LED lamp for 24 h. After the completion of reaction, the product was determined by thin layer chromatography (TLC) and H 2 can be detected by GC-TCD. The solvent was removed under reduced pressure by an aspirator, then the pure product was obtained by flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane = 10:1) to afford corresponding naphthalene products 3. See Supplementary Methods for further experimental details.
Data availability. The data supporting the findings of this work are available within the article and its Supplementary Information files. All other relevant data supporting the findings of this study are available from the corresponding author on request.  Fig. 7 Proposed mechanism. The plausible mechanism involves oxidation of alkene to generate alkene radical cation, nucleophilic attack of dienophiles and visible-light photoredox/cobaloxime catalyzed formation of sixmembered aromatic rings and H 2