ortho-Ethynyl group assisted regioselective and diastereoselective [2+2] cross-photocycloaddition of alkenes

A highly regioselective and diastereoselective [2+2] cross-photocycloaddition between the electron-poor and electron-rich/electron-neutral alkenes under visible-light irradiation was developed. In the absence of an external photocatalyst, the substrates 1 and 4 reacted with rigid cyclic alkoxyethenes to generate cis - anti -head-to-head heterocoupled [2+2] products in high yields with regiospecificity and good diastereoselectivity. Meanwhile, the reactions of 1 and 4 with ( Z )- and ( E )-1,2-diphenylethenes yielded the desired products in good yields with a high ratio of d.r.. It is important to note that no geometric isomerization of olefins was observed during the reaction. Mechanistic studies and DFT calculations suggested that 1 and 4 having ortho -ethynyl and cyano groups as a self-photocatalyst play a very important role in the reaction and a five-membered ring diradical intermediate (Int1) was formed via an intramolecular radical addition. The obtained regioselectivity and diastereoselectivity were confirmed by X-ray structural analysis of the representative products. ortho -(cyclopropyl)ethynyl, ortho -( n -butyl)ethynyl and ortho -( n -pentyl)ethynylbenzaldehyde ( 1y  1z’’ ) were also well tolerated in this transformation, and the desired products ( 3ya  3z’’a ) were obtained in 50%  81% yields with good diastereoselectivity. Furthermore, this intermolecular [2+2] cycloaddition of 1a with 2a was scaled up to 2.0 mmol for practical applications, generating 3aa with a 71% yield. structures of 5aa and 5(aa)’ were confirmed by X-ray crystal diffraction analysis. The influence of the substituents (R 2 = Me, F, MeO) on the aromatic alkyne units, and the substituents (R 1 = Me, MeO) from the arylaldehydes on the reactions indicated that they are well tolerated, neglecting electronic effect and steric hindrance. In summary, we have developed a highly regioselective and diastereoselective intermolecular [2+2] photocycloaddition reaction between the electron-poor and electron-rich/electron-neutral alkenes under visible-light irradiation without an external photocatalyst. The reaction provides an efficient method for the synthesis of highly energy-rich and strained cyclobutanes. The electron-poor alkenes having ortho -ethynyl and cyano groups ( 1 and 4 ) undergo cycloaddition with the electron-rich and electron-neutral alkenes, including rigid cyclic and nonrigid acyclic alkoxyethenes ( 2 ), and styrenes ( 6 ) to generate the corresponding heterocoupled [2+2] products in high yields with regiospecificity and good diastereoselectivity. It should be noted that no geometric isomerization of the olefins is observed during the reaction. Mechanistic studies and DFT calculations suggest that 1 and 4 with ortho -ethynyl and cyano groups function as a self-photocatalyst to enhance the reactivity and exhibit high selectivity, which is confirmed by X-ray structural analysis of the representative products. Furthermore, the present strategy can overcome the problems of the low yield and low selectivity in the crossed [2+2] photocycloaddition between the different olefins in solution. Further studies to gain an in-depth understanding of the reaction mechanism and the new synthetic applications of this strategy are being conducted in our laboratory.

The cycloaddition reaction is a versatile and straight forward route to form cyclic compounds. 1,2 In general, alkenes react with each other to construct two new single bonds at both carbon atoms of the double bond.
Except for the Diels−Alder reaction, the [2+2] photocycloaddition of two alkenes is the most frequently used method to access cyclobutanes under ultraviolet or visible-light irradiation conditions. 3,4,5 The cyclobutane-skeleton is widely found in natural products with remarkable biological activities. 6,7 It is reported that the [2+2] photo-homodimerization of chalcones and cinnamic acid derivatives is a unique strategy to form cyclobutanes, which are used as building blocks for a variety of biologically active molecules and natural products. 8−10 To overcome the competition of facile geometric isomerization of nonrigid alkenes, the stereo-controlled syntheses of complex cyclobutanes have focused on solid-state, molten-state, or host-guest template systems under UV-light irradiation. 11−13 For the regioselectivity of the cross-[2+2]-photocycloaddition, the reaction has the possibility of providing two regioisomers, which are referred to as head-to-head (HH) and head-to-tail (HT) products (Fig. 1a).
Generally, a head-to-tail product is generated when R is an electron-donating group (EDG), while a head-to-head product is formed when R is an electron-withdrawing group (EWG) (Fig. 1b). 6,14−17 To achieve diastereoselectivity of the reaction, Yoon, 18,19,20 Wu, 9   In addition, the heterodimerization of two alkenes is highly dependent on the steric and electronic properties of the monomers. For the heterodimerization of two similar monomers, a photochemical approach could be complicated. Owing to the high diversity of the selectivity, construction of cyclobutane rings, especially regioselectivity and stereoselectivity, is a significant challenge in synthetic chemistry. In this strategy, molecular design of the substrate is based on the introduction of CN group as electron-acceptor for enhancing photoluminescence efficiency, 30,31 ortho-ethynyl group installed on the conjugated system as visible-light photo-sensitizer for avoiding the external photocatalyst, 32,33 and increasing the diastereoselectivity via a neighboring group participation (Fig. 1f). Here, we wish to describe the results of the intermolecular [2+2] photocycloaddition reactions between the electron-poor and electron-rich/electron-neutral alkenes induced by visible light irradiation without an additional photocatalyst to provide the corresponding products in good yields with high regioselectivity and diastereoselectivity.

Results
Molecular design of substrate 1. According to our strategy outlined in Fig. 1f, a representative substrate 2-(2-(phenylethynyl)benzylidene)malononitrile (1a) was prepared via a condensation of ortho-phenylethynyl benzaldehyde with malononitrile. Initially, when the reaction of 1a with 3,4-dihydro-2H-pyran (2a, a rigid classical olefin) was carried out in the absence of additional photocatalyst (PC) in a solvent of 1,2-dichloroethane (DCE) under the irradiation of a blue light-emitting diode (LED, 410415 nm) at room temperature for 8 h, a mixture of cis-anti-head-to-head (HH) heterocoupled [2+2] product (rac-3aa) and trans-anti-head-to-head one [rac-3(aa)'] was isolated in 36% and 5% yield, respectively (Table 1, entry 1). The structures of 3aa and 3(aa)' were characterized by 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS), and they were unequivocally assigned by X-ray crystal diffraction analysis (ESI for detail). Subsequently, the position effect of ethynyl group in substrate 1 was investigated.

Homo-[2+2] photocycloaddition.
To demonstrate the possibility of homo-[2+2] cycloaddition, the reaction of 1a or 1i, 4a or 4d was carried out in DCE in the absence of an electron-rich or an electron-neutral alkene partner under the irradiation of blue LED (410415 nm) at room temperature for 12 h, generating a cis-head-to-tail product (8aa or 8ii) or a trans-head-to-tail product (9aa or 9dd) in 18%, 21%, 15% or 18% yield, respectively (Fig. 6). The structures of 8aa and 9aa were confirmed by X-ray crystal diffraction analysis. When the reaction of 2a was performed in DCE without an electron-poor alkene and an external photocatalyst under the standard reaction condition, no homo-[2+2] cycloaddition product was detected.

Further transformation of the product. For further transformation of the alkynyl unit in this intermolecular
[2+2] cycloaddition product, its synthetic application was demonstrated by follow-up chemistry with 7ac as the starting material (Fig. 7). Encouragingly, an ICl/AgNO 3 co-catalyzed radical oxidation of 7ac into 1,2-diketone (10) was achieved with 64% yield (Fig. 7a). 34 Furthermore, a corresponding benzoin bis-ether product (11) was obtained with 57% yield in methanol under visible light irradiation (Fig. 7b). 35  Furthermore, the ultraviolet-visible spectra of 1a indicated that they had stronger absorption in the range of 410-415 nm and acted as photo-sensitizers, avoiding the external photocatalyst (ESI, Supplementary Figure  143). These results implied that the ortho-phenylethynyl group introduced into the substrates plays an important role in the reaction.
In this reaction, we speculated that the intermolecular [2+2] photocycloaddition proceeded through an energy transfer rather than an electron transfer. It was expected that isomerization would compete with crossed-[2+2] cycloaddition because triplet acyclic olefins would lead to isomerization. 36 Indeed, under our irradiation conditions, little geometric isomerization of 1 and 4, as well as 2 and 6 was observed, which was confirmed by X-ray crystal structures of 5aa, (5aa)', 7bc and 7bd.
In theory, a crossed [2+2] cycloaddition of two different unsymmetrical chain olefins can yield sixteen head-to-head and sixteen head-to-tail stereoisomers (ESI, Supplementary Scheme 1). As outlined above, the major products in all cases were found to be the ()-(trans,trans)-anti-head-to-head (I) isomer derived from an electron-poor and an electron-rich olefin. Importantly, only head-to-head isomers were found and no head-to-tail isomers were observed, illustrating the regiospecificity of the reaction. Moreover, among the isolated head-to-head isomers, I was obtained in the majority and ()-(cis,trans)-syn-head-to-head (I') was isolated in the minority with good diastereoselectivity, demonstrating almost no geometric isomerization of the olefins during the [2+2]-cycloaddition. Computational studies. To understand the high regiospecificity and diastereoselectivity of the crossed-[2+2]-photocycloaddition between the electron-poor and electron-rich alkenes, the density functional theory (DFT) calculations at the M06-D3/def2-TZVPP level 37 were performed using 2-(2-(phenylethynyl)benzylidene)malonoitrile (1a) and 3,4-dihydro-2H-pyran (2a) as a model. The energy diagram for the suggested mechanism is display in Fig. 8. After photo-excitation of 1a, an intersystem crossing to triplet ( T 1a) takes place. The calculations show that T 1a undergoes a ring closure process between the β-carbon of alkene moiety and the α-carbon of ortho-alkyne unit to form a five-membered ring diradical intermediate T lnt1, which is exergonic by 5.1 kcal/mol. From T lnt1, four different pathways leading to four different regio-and stereoisomers are considered, namely cis-HH, trans-HH, cis-HT, and trans-HT (Fig. 8). The optimized transition states for the first CC bond formation is shown in the Supporting Information (ESI, Supplementary Figures 146149). As shown in Fig. 8, this process turns out to be the rate-limiting step for the [2+2] cycloaddition. Importantly, the cis-HH pathway is the most favorable one, and the corresponding transition state T TS1 cis-HH was calculated to be 20.4 kcal/mol relative to T lnt1, and the formation of T lnt2 cis-HH is endergonic by 7.6 kcal/mol. Direct CC bond formation between T 1a and 2a has a barrier of 21.9 kcal/mol, which is 1.5 kcal/mol higher than from T lnt1. In addition, the trans-HH pathway ( T TS1 trans-HH ) has a 1.3 kcal/mol higher barrier than the cis-HH pathway ( T TS1 cis-HH ). Furthermore, the alternative HT pathways have even higher barrier. These results are consistent with the experimental fact that only HH products were observed and the ortho-ethynyl moiety is crucial for this [2+2] reaction. The calculated barrier difference of 1.3 kcal/mol gives a product ratio of about 9:1 for 3aa (cis-HH product): 3(aa)' (trans-HH product), which is in excellent agreement with the experimental product ratio of 7.2:1. From T Int2, the opening of the five-membered ring by CC bond cleavage proceeds via T TS3, which is coupled with a spin crossing from triplet to singlet downhill from T TS3. This results in the formation of a zwitterionic intermediate Int3, which undergoes very facile CC bond formation to form the final product 3aa. Proposed mechanism. Based on the control experiments and DFT calculations, as well as previous reports, [3][4][5][6]9,38,39 a plausible mechanism is proposed in Fig. 9. First, 1a is excited by the blue LED irradiation (410−415 nm) to generate the excited singlet species 1a*, which decays to its triplet exciplex 1a** through an intersystem crossing (ISC) process with formed another 1a* along with the formation of 1a via an energy transfer (ET) step. The obtained 1a** undergoes an intramolecular radical addition to afford a five-membered ring diradical intermediate Int1, which was trapped by 2,6-di-tert-butyl-4-methylphenol (BHT) 40 using 4a as substrate instead of 1a and the corresponding product was confirmed by X-ray crystal analysis (ESI, Supplementary Figure 144 41 and the captured product was detected by high-resolution mass spectrum (HRMS) analysis (ESI, Supplementary Figure 145). Finally, Int3 undergoes an intramolecular nucleophilic addition to form the desired cyclobutane derivative (3aa) through a facile carbon-carbon formation.  Fig. 9 Proposed mechanism for the formation of 3aa.
In summary, we have developed a highly regioselective and diastereoselective intermolecular [2+2] photocycloaddition reaction between the electron-poor and electron-rich/electron-neutral alkenes under visible-light irradiation without an external photocatalyst. The reaction provides an efficient method for the synthesis of highly energy-rich and strained cyclobutanes. The electron-poor alkenes having ortho-ethynyl and cyano groups (1 and 4) undergo cycloaddition with the electron-rich and electron-neutral alkenes, including rigid cyclic and nonrigid acyclic alkoxyethenes (2), and styrenes (6) to generate the corresponding heterocoupled [2+2] products in high yields with regiospecificity and good diastereoselectivity. It should be noted that no geometric isomerization of the olefins is observed during the reaction. Mechanistic studies and DFT calculations suggest that 1 and 4 with ortho-ethynyl and cyano groups function as a self-photocatalyst to enhance the reactivity and exhibit high selectivity, which is confirmed by X-ray structural analysis of the representative products. Furthermore, the present strategy can overcome the problems of the low yield and low selectivity in the crossed [2+2] photocycloaddition between the different olefins in solution. Further studies to gain an in-depth understanding of the reaction mechanism and the new synthetic applications of this strategy are being conducted in our laboratory.