TBPEH-TBPB Initiate the Radical Addition of Benzaldehyde and Allyl Esters

Tert-butylperoxy-2-ethylhexanoate (TBPEH) and tert-butyl peroxybenzoate (TBPB) promote the radical acylation of allyl ester with benzaldehyde to synthesize new carbonyl-containing compounds under solvent-free and metal-free conditions. This reaction is compatible with electron-donating and halogen groups and has excellent atom utilization and chemical selectivity. Furthermore, the synthetic compounds can further apply to the preparation of lactone, piperidine, tetrazole and oxazole.


Introduction
The functionalization of alkenes is an important part of organic synthesis, which is widely used in various fields, such as synthetic drugs, natural products, and advanced materials [1][2][3][4][5][6][7]. Among them, the acylation of alkenes is a hotspot in chemical synthesis. For instance, the free radical addition reaction in the synthesis of glufosinate-ammonium by Hoechst company [8,9], which involved the alkene radical phosphorylation of the key intermediate 1-cyanoallyl acetate (ACA), was found to have the advantages of high rate, simple conditions and high atom economy. Moreover, the cyanohydrin [10][11][12][13][14][15][16][17] and carboncarbon double bond [18][19][20][21][22][23] structure possessed by this compound have a wide range of applications in the chemical field and pharmaceutical synthesis, which determines its excellent practicability and ductility. However, few studies were conducted on 1-cyanoallyl acetate-related responses.
What's worth mentioning, though, is that the addition of benzaldehyde and olefins has attracted much attention because many asymmetric ketones or complex molecular skeletons that are difficult to synthesize by traditional methods can be constructed by the addition reaction of benzaldehydes with alkenes [24][25][26][27].
Hence, inspired by those mentioned above, according to the process conditions of glufosinate-ammonium and without changing the structure of cyanohydrin, the method development and structural modification of 1-cyanoallyl acetate were studied by taking benzaldehyde as the acylation reagent and TBPEH-TBPB as the initiators. Furthermore, the addition reactions of benzaldehyde with different kinds of allyl esters, like allyl hexanoate and allyl acetoacetate, were developed.

Synthesis of Target Compounds
The synthetic pathway to target compound 3 is shown in Scheme 1. yield when the amount of TBPEH and TBPB was increased to 2 equiv. (entry 6). In addition, DMF and DMSO were selected as the solvents, but no target compounds were detected (entries [7][8]. When the amount of benzaldehyde 1a was reduced to 1.5 equiv., the yield of the desired product decreased to 26% (entry 9). From the subsequent reaction mechanism, it can be seen that benzaldehyde 1a is the main source of H + , so 2 equiv. of benzaldehyde is needed, at least. According to Scheme 1, entry 6 was selected as the optimal condition. Scheme 1. Synthetic route of compounds 3. Initially, we screened our approach by optimizing the reaction conditions of benzaldehyde 1a and 1-cyanallyl acetate 2a, and the influence of different reaction conditions on the yields is shown in Table 1. We found that peroxide, solvent and temperature affected the reaction critically. In the beginning, the radical addition initiated by TBPEH showed a higher yield than that by TBHP, TBPB and other initiators (entries 1-3). The temperature was further screened, and it was found that lowering the temperature had a significant effect on the yield (entry 4). Subsequently, it was surprising that when we mixed TBPEH and TBPB under the same condition, the desired compound 3a was isolated with a yield of 43% (entry 5). It was supposed that TBPEH plays the role of medium-temperature initiator and TBPB plays the role of high-temperature initiator, which means TBPEH decomposes and releases heat after being heated so that TBPB decomposes rapidly at a lower temperature [33,34]. Meanwhile, TBPB is decomposed to generate benzoyl radical, which is conducive to the reaction. Moreover, the corresponding product 3a was afforded in 57% yield when the amount of TBPEH and TBPB was increased to 2 equiv. (entry 6). In addition, DMF and DMSO were selected as the solvents, but no target compounds were detected (entries 7-8). When the amount of benzaldehyde 1a was reduced to 1.5 equiv., the yield of the desired product decreased to 26% (entry 9). From the subsequent reaction mechanism, it can be seen that benzaldehyde 1a is the main source of H + , so 2 equiv. of benzaldehyde is needed, at least. According to Scheme 1, entry 6 was selected as the optimal condition. tate. Finally, compounds 3a-3y, 4a-4u and 5a-5o were synthesized in one step, which can further apply to the preparation of lactone, piperidine, tetrazole and oxazole [28][29][30][31][32].

Synthesis of Target Compounds
The synthetic pathway to target compound 3 is shown in Scheme 1. Initially, we screened our approach by optimizing the reaction conditions of benzaldehyde 1a and 1-cyanallyl acetate 2a, and the influence of different reaction conditions on the yields is shown in Table 1. We found that peroxide, solvent and temperature affected the reaction critically. In the beginning, the radical addition initiated by TBPEH showed a higher yield than that by TBHP, TBPB and other initiators (entries 1-3). The temperature was further screened, and it was found that lowering the temperature had a significant effect on the yield (entry 4). Subsequently, it was surprising that when we mixed TBPEH and TBPB under the same condition, the desired compound 3a was isolated with a yield of 43% (entry 5). It was supposed that TBPEH plays the role of medium-temperature initiator and TBPB plays the role of high-temperature initiator, which means TBPEH decomposes and releases heat after being heated so that TBPB decomposes rapidly at a lower temperature [33,34]. Meanwhile, TBPB is decomposed to generate benzoyl radical, which is conducive to the reaction. Moreover, the corresponding product 3a was afforded in 57% yield when the amount of TBPEH and TBPB was increased to 2 equiv. (entry 6). In addition, DMF and DMSO were selected as the solvents, but no target compounds were detected (entries 7-8). When the amount of benzaldehyde 1a was reduced to 1.5 equiv., the yield of the desired product decreased to 26% (entry 9). From the subsequent reaction mechanism, it can be seen that benzaldehyde 1a is the main source of H + , so 2 equiv. of benzaldehyde is needed, at least. According to Scheme 1, entry 6 was selected as the optimal condition.  Next, we further explored the substrate scope of benzaldehydes under optimal conditions ( Figure 1). We found that benzaldehydes substituted with electron-donating groups (R, OR) and halogens (F, Cl, Br) were suitable for this reaction, while the electron-donating groups contributed to the yields. This can be explained by the electron-donating effect, as the electron-donating groups made acyl radicals easier to generate, and the yield was higher than the benzaldehyde substituted with the electron-withdrawing group. For example, the order of yields was 3o (4-OCH 3 ) > 3a (H) > 3y (4-Br). As the results progressed, it was found that the strong electron-withdrawing groups (CN, NO 2 ) were completely incompatible with this system. Besides the electronic effect of various functional groups, the position of the substitutes on the benzene ring also has a great influence on the yields. Due to the steric effect, the yield of ortho-position groups is lower than that of meta-position and para-position. In case as follow, compounds 3b (ortho-, 40%), 3c (meta-, 48%) and 3d (para-, 61%). Additionally, 1-cyanoallyl acetate can hardly react with those benzaldehydes substituted with larger groups on the ortho position, such as 2-Br. In short, this reaction had high atom utilization and good chemical selectivity. Acyl radicals were always added at the 1-position of the alkenyl group. This special selectivity can be attributed to the anti-Markovnikov addition initiated by peroxides [35]. butyl peroxybenzoate; TBPEH = tert-butylperoxy-2-ethylhexanoate.
Next, we further explored the substrate scope of benzaldehydes under optimal conditions ( Figure 1). We found that benzaldehydes substituted with electron-donating groups (R, OR) and halogens (F, Cl, Br) were suitable for this reaction, while the electrondonating groups contributed to the yields. This can be explained by the electron-donating effect, as the electron-donating groups made acyl radicals easier to generate, and the yield was higher than the benzaldehyde substituted with the electron-withdrawing group. For example, the order of yields was 3o (4-OCH3) > 3a (H) > 3y (4-Br). As the results progressed, it was found that the strong electron-withdrawing groups (CN, NO2) were completely incompatible with this system. Besides the electronic effect of various functional groups, the position of the substitutes on the benzene ring also has a great influence on the yields. Due to the steric effect, the yield of ortho-position groups is lower than that of meta-position and para-position. In case as follow, compounds 3b (ortho-, 40%), 3c (meta-, 48%) and 3d (para-, 61%). Additionally, 1-cyanoallyl acetate can hardly react with those benzaldehydes substituted with larger groups on the ortho position, such as 2-Br. In short, this reaction had high atom utilization and good chemical selectivity. Acyl radicals were always added at the 1-position of the alkenyl group. This special selectivity can be attributed to the anti-Markovnikov addition initiated by peroxides [35].  Subsequently, taking steric effect and application into consideration, the radical additions of substituted benzaldehyde with allyl hexanoate and allyl acetoacetate were performed under optimal conditions. The results are shown in Figures 2 and 3, respectively. Compared to 1-cyanoallyl acetate, there was a slight yield increase in the reactions of allyl hexanoate (longer chain) with various substituted benzaldehyde, which may be due to the absence of the electron-withdrawing group (-CN). As for allyl acetoacetate, by-products formed, and the yields decreased. In the meantime, the steric effect was more obvious, and allyl acetoacetate could hardly react with ortho-substituted benzaldehyde. Overall, the electronic effect and steric effect of various substituents on the benzene ring still showed the same corresponding effects. the absence of the electron-withdrawing group (-CN). As for allyl acetoacetate, by-products formed, and the yields decreased. In the meantime, the steric effect was more obvious, and allyl acetoacetate could hardly react with ortho-substituted benzaldehyde. Overall, the electronic effect and steric effect of various substituents on the benzene ring still showed the same corresponding effects.
On the basis of these results and previous reports [20,38], we, therefore, proposed a possible mechanism, as shown in Scheme 2. The first step involves TBPEH and TBPB cleavage initiated by thermal conditions to give tert-butoxy radical, which then abstracts aldehydic hydrogen of 1a to obtain benzoyl radical A. The addition of A to an alkene forms intermediate B, which in turn abstracts a hydrogen radical from another aldehyde

Mechanism
When benzaldehyde 1a and 1-cyanoallyl acetate 2a were reacted with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) under the standard conditions [36,37], the TEMPO-trapped product 6a (detected by GC-Mass analysis) was obtained, and the formation of 3a was completely inhibited. It clearly supports that this reaction was a free radical reaction.
On the basis of these results and previous reports [20,38], we, therefore, proposed a possible mechanism, as shown in Scheme 2. The first step involves TBPEH and TBPB cleavage initiated by thermal conditions to give tert-butoxy radical, which then abstracts aldehydic hydrogen of 1a to obtain benzoyl radical A. The addition of A to an alkene forms intermediate B, which in turn abstracts a hydrogen radical from another aldehyde to give compound 3a.
On the basis of these results and previous reports [20,38], we, therefore, proposed a possible mechanism, as shown in Scheme 2. The first step involves TBPEH and TBPB cleavage initiated by thermal conditions to give tert-butoxy radical, which then abstracts aldehydic hydrogen of 1a to obtain benzoyl radical A. The addition of A to an alkene forms intermediate B, which in turn abstracts a hydrogen radical from another aldehyde to give compound 3a. Scheme 2. Plausible mechanism.

General Information
1 H and 13 C NMR spectra were recorded on a Bruker 500 MHz spectrometer in CDCl3 with TMS as the internal standard. GC-Mass spectra were determined on an Agilent 7890B spectrometer. High-resolution electrospray mass spectra (HR-ESI-MS) were determined using a UPLC H-CLASS/QTOF G2-XS mass spectrometer (Waters, Milford, MA, USA). All products were identified by 1 H and 13 C NMR and HRMS. The starting materials were purchased from Macklin, Rhawm, Adamas or TCI and used without further purification.

General Information
1 H and 13 C NMR spectra were recorded on a Bruker 500 MHz spectrometer in CDCl 3 with TMS as the internal standard. GC-Mass spectra were determined on an Agilent 7890B spectrometer. High-resolution electrospray mass spectra (HR-ESI-MS) were determined using a UPLC H-CLASS/QTOF G2-XS mass spectrometer (Waters, Milford, MA, USA). All products were identified by 1 H and 13 C NMR and HRMS. The starting materials were purchased from Macklin, Rhawm, Adamas or TCI and used without further purification. The characterization data for all synthesized compounds are provided in the Supporting Information file (Figures S1-S184).

General Synthesis of Compounds 3a-3y
Substituted benzaldehydes (0.4 mmol), 1-cyanoallyl acetate (0.2 mmol), tert-butyl peroxybenzoate (0.4 mmol) and tert-butylperoxy-2-ethylhexanoate (0.4 mmol) were added to a flask. The mixture was reacted at 110 • C for 30 min. TLC was used to track the reaction progress. After the reaction was completed, it was separated by column chromatography to give the corresponding compound 3a-3y.   13   14 (s, 3H); 13  is proposed. This reaction is compatible with electron-donating and halogen groups, and a total of 61 new compounds (aromatic ketone esters) were synthesized in moderate yields under solvent-free and metal-free conditions, which can be further applied to the preparation of lactone, piperidine, tetrazole and oxazole. It also has excellent atomic utilization and chemical selectivity. Further studies on free radical addition to synthesizing various functionalized ketones are ongoing in our laboratory.
Author Contributions: B.S., X.T., Y.W., Y.S., X.F., W.W., M.T., Y.C., J.W., C.W. carried out experimental work, B.S. prepared the manuscript, C.T. designed the material and supervised the project. C.T. and S.Y. revised the paper. All authors have read and agreed to the published version of the manuscript.