Direct ole fi nation of benzaldehydes into 1 , 3-diarylpropenes via a copper-catalyzed heterodomino Knoevenagel-decarboxylation-Csp 3H activation sequence †

In the last two decades, there has been increasing interest in the development of more efficient and environmentally friendly methods for chemical syntheses. One of the related research areas is the development of sequential formation of multiple C–C bonds in one pot. In general, these processes eliminate intermediate recovery steps, thereby considerably decreasing the amount of waste generated. For the past few years, a number of notable domino sequence reactions involving decarboxylation have been developed using simpler substrates like benzaldehydes. However, to the best of our knowledge, examples of utilizing benzaldehydes for one pot methylenation coupling into 1,3-diarylpropenes have not been explored. Furthermore, 1,3-diarylpropenes are often known to be privileged structures or key intermediates in the synthesis of natural products and the development of biologically active compounds. Traditionally, strategies toward the syntheses of 1,3-diarylpropenes include allylic arylation/alkenylation (Scheme 1, route a), allylic selective defunctionalization (route b), decarboxylation of cinnamic acids (route c), cross-coupling reactions of potassium alkenyltrifluoroborates with benzyl halides (route d) and alkylation of benzene (route e). However, most of the above methods have to bear disadvantages such as limited substrates, multistep procedures and necessary prefunctionalization. Encouraged by the ecological and economic advantages of domino reactions, we wish to report herein the synthesis of unsymmetrical 1,3-diarylpropenes through a domino Knoevenagel-decarboxylation-Csp-H activation sequence (Scheme 1).


Introduction
In the last two decades, there has been increasing interest in the development of more efficient and environmentally friendly methods for chemical syntheses. 1One of the related research areas is the development of sequential formation of multiple C-C bonds in one pot. 2 In general, these processes eliminate intermediate recovery steps, thereby considerably decreasing the amount of waste generated. 3For the past few years, a number of notable domino sequence reactions involving decarboxylation have been developed using simpler substrates like benzaldehydes. 4 However, to the best of our knowledge, examples of utilizing benzaldehydes for one pot methylenation coupling into 1,3-diarylpropenes have not been explored.
Furthermore, 1,3-diarylpropenes are often known to be privileged structures or key intermediates in the synthesis of natural products and the development of biologically active compounds. 5Traditionally, strategies toward the syntheses of 1,3-diarylpropenes include allylic arylation/alkenylation (Scheme 1, route a), 6 allylic selective defunctionalization (route b), 7 decarboxylation of cinnamic acids (route c), 8 cross-coupling reactions of potassium alkenyltrifluoroborates with benzyl halides (route d) 9 and alkylation of benzene (route e). 10 However, most of the above methods have to bear disadvantages such as limited substrates, multistep procedures and necessary prefunctionalization. Encouraged by the ecological and economic advantages of domino reactions, we wish to report herein the synthesis of unsymmetrical 1,3-diarylpropenes through a domino Knoevenagel-decarboxylation-Csp 3 -H activation sequence (Scheme 1).

Results and discussion
We started our research by using benzaldehyde (1a) as the standard substrate.The combination of malonic acid, CuO, di-t-butyl peroxide (DTBP) and piperidine in toluene at 115 °C (oil bath temperature, unless otherwise noted) gave the desired product 1,3-diarylpropenes (2a) in 68% GC yield within 12 h (Table 1, entry 1).Other copper catalysts (entries 2 and 3), oxidants (entry 6), bases (entry 7), or solvents (entry 8) decreased the yield. 11Employment of Fe 3 O 4 or ferrocene resulted in a dramatic decrease in yield (entries 4 and 5).Modifying the quantity of oxidant, base, catalyst and time did not afford better results (entries 9-11 and 15). 11Higher yields were obtained when the reaction was carried out at an elevated temperature.Particularly, trace amounts of the target product were detected below the boiling point of toluene (entry 12) and a good result in 77% GC yield was achieved at 125 °C (entry 13).However, when the reaction was conducted under an air atmosphere, the yield decreased to 49% (entry 14).A control experiment showed that the domino reaction was poorly efficient when the reaction was carried out in the absence of a copper catalyst (entry 16).Under the optimized reaction conditions, the allylation of a variety of benzaldehyde derivatives was examined.As shown in Table 2, benzaldehydes bearing a variety of substituents were found to afford exclusively 1,3-diarylpropenes in moderate to good yields (3-1a-3-1h).Obviously, an electron-donating group at the para-position, such as the methoxy substituent in 3-1b, afforded a higher yield compared with an electron-withdrawing group, such as a cyano group substituent in 3-1g.para-Substituted benzaldehydes (3-1b) gave a superior product yield compared to that of ortho-or meta-substituted benzaldehydes (3-1i and 3-1j).The domino reaction with 4-nitrobenzaldehyde (3-1h) was also successful.OH-, Cl-and Br-substituted compounds (3-1d, 3-1e and 3-1f ) were also well tolerated.It turned out that multiple substituent groups (3-1k, 3-1l and 3-1m) would decrease the reaction efficiency.
Considering the effects of electronic parameters on the reaction, it was found that the yield roughly decreased with the increase of Hammett constant (σ) values of the substituents on benzaldehyde.For example, the yield of 3-1b ( p-CH 3 O, σ p = −0.27) is 78%, and the yield of 3-1g ( p-CN, σ p = 0.66) is 53% as shown in Table 4.The exceptional substrates are p-hydroxyl a Catalytic conditions: benzaldehyde (0.3 mmol), malonic acid (0.5 mmol), toluene (0.5 mmol), solvent (2 mL), base (0.2 mmol), catalyst (20 mol%), oxidant (4 equiv.),115 °C, 12 h, N 2 atmosphere.b GC yields were given using dodecane as the internal standard.c The reaction was conducted within 24 h.d 0.1 mmol of piperidine was used.e 2 equiv. of DTBP was used.f The reaction was conducted at 105 °C under a N 2 atmosphere.g The reaction was conducted at 125 °C under a N 2 atmosphere.h The reaction was conducted at 125 °C under an air atmosphere.i 10 mol% of CuO was used.a Catalytic conditions: benzaldehydes (1) (0.3 mmol), malonic acid (0.5 mmol), toluene (2a) (2 mL), piperidine (0.2 mmol), CuO (20 mol %), DTBP (4 equiv.),125 °C, 12 h, N 2 atmosphere.b Isolated yields based on benzaldehyde.benzaldehyde and m,m,p-tri-methoxyl benzaldehyde, which might be dominated by other factors such as hydrogen bonds and steric hindrance.However, a similar approach for benzylic hydrocarbons is not applicable.
Based on previous observations and literature reports, 4h,8 we proposed a plausible catalytic cycle (Scheme 2).The reaction involves a domino anionic-metal catalyzed pathway, 2a,4h wherein an incipient cinnamic acid (formed in situ from the K-D reaction) continuously undergoes copper catalyzed cross coupling and decarboxylation, leading to 1,3-diarylpropenes in one pot. 8

Conclusions
In summary, we have developed the first copper-catalyzed one step direct olefination of benzaldehydes into 1,3-diarylpropenes via a novel domino Knoevenagel-decarboxylation-Csp 3 -H activation sequence.The unsymmetrical 1,3-diarylpropenes were obtained in moderate to good yields.All of the substrates were economical, simple and readily available.

General information
All reactions were carried out under an N 2 atmosphere.CuO was purchased from Aladdin-reagent with high purity (99.5%).All reagents were used as supplied without further purification and drying.Flash column chromatography was performed over silica gel (48-75 μm) and reactions were monitored by thin layer chromatography (TLC) using UV light (254 nm). 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer using d 6 -DMSO as a solvent and tetramethylsilane as an internal standard (s = singlet, d = doublet, t = triplet, m = multiplet).MS analyses were performed on an Agilent 5975 GC-MS instrument (EI).HRMS analyses were performed on a Waters Micromass GCT instrument (EI).

General procedures for copper-catalyzed allylation of benzaldehydes
Malonic acid (52 mg, 0.5 mmol) and CuO (4.8 mg, 0.06 mol) were added into a 10 mL Schlenk flask.Then toluene (2 mL), benzaldehyde (31 µl, 0.3 mmol), DTBP (120 µl, 1.2 mmol), and piperidine (20 µl, 0.2 mmol) were added at room temperature.The reaction vessel was purged with N 2 three times.The mixture was stirred at 125 °C for 12 h.After cooling to room temperature, the mixture was diluted with CH 2 Cl 2 and water.The organic phase was washed with brine, dried with MgSO 4 , and concentrated under reduced pressure.The residue was purified by silica gel chromatography ( petroleum ether-ethyl acetate = 100 : 1) to afford the corresponding product.

Table 1
Optimization of the conditions for copper catalyzed domino olefination of benzaldehydes into 1,3-diarylpropenes a

Table 2
Substrate scope of the copper-catalyzed domino reaction of different benzaldehydes 1 with 2a a,b

Table 3
Substrate scope of the copper-catalyzed domino reaction of 4-methoxybenzaldehyde (1b) with