{'fraction_non_alphanumeric': 0.04733315465022782, 'fraction_numerical': 0.0317877244706513, 'mean_word_length': 4.46455770357352, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 4, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
HOTf-Catalyzed Alkyl-Heck-type Reaction

Summary The Heck reaction, along with other cross-coupling reactions, led to a revolution in organic chemistry. In the last 50 years, metal-catalyzed, photo-induced, or base-mediated Heck and Heck-type reactions have been elegantly developed. Brønsted acid-catalyzed Heck (or Heck-type) reactions are still unknown, however. By introducing alkyl peroxides as the key intermediates, primary, secondary, and tertiary aliphatic carboxylic acids are therefore applied here in a one-pot Brønsted acid-catalyzed Heck-type reaction, to deliver E-alkenes exclusively in most cases. The use of HOTf is vital to the reaction, whose mechanism is supported by both experimental and computational results. This method can be expanded to the direct alkylation of complex natural products.

As is well known, alkyl halides are one of the most frequently used alkyl functionalities for alkyl-Heck-type reactions (Kambe et al., 2011;Weix, 2015;Tellis et al., 2016;Choi and Fu, 2017). However, their shortcomings, such as limited availability and perceived instability might prevent more extensive applications (Qin et al., 2016). Furthermore, there are still significant challenges remaining for alkyl-Heck-type reactions such as E/Z selectivity, use of metal catalysis, and diversity of alkyl sources (Scheme 1A). Carboxylic acids are inexpensive, stable, non-toxic, and structurally diverse feedstock chemicals that have been widely used in numerous reactions. For example, they have been utilized in cross-coupling with prefunctionalized alkenes such as vinyl halides or their derivatives to generate alkenes (Mai et al., 2013;Noble et al., 2015;Toriyama et al., 2016;Wang et al., 2016;Edwards et al., 2017;Xu et al., 2017;Zhang et al., 2017) (Scheme 1B). However, the decarboxylative cross-couplings of aliphatic acids or their derivatives with alkenes (X = H) are very rare (Wang et al., 2018). As part of our ongoing interest in the application of aliphatic acids as the alkyl source Ge et al., 2017;Jian et al., 2017;Qian et al., 2017;Ye et al., 2017;Zhu et al., 2017) and our interests in the discovery of different reaction models of alkyl peroxides, we have developed the first Brønsted acid-catalyzed alkyl-Heck-type reaction of alkenes with aliphatic acids via alkyl peroxide intermediates (Scheme 1C).

Optimization Study
We commenced our studies by screening a variety of Brønsted acids for the alkyl-Heck-type reaction of styrene with aliphatic acid. The aliphatic acid was converted into alkyl peresters in the presence of trifluoroacetic anhydride (TFAA) and tert-butyl hydroperoxide (TBHP) and used in situ for the subsequent step (Donchak et al., 2006). The best Brønsted acid was found to be HOTf, which offered the desired alkylated alkene 3 exclusively as a single E-isomer in 88% yield, determined by 1 H nuclear magnetic resonance (NMR) analysis (Equation 1 and Table 1, entry 1). Studies of acids showed that Tf 2 O had a lower efficiency (Table 1,
entry 2) and other Brønsted acids such as TsOH,H 2 O, CF 3 COOH, HOAc, and MeSO 3 H were ineffective in this reaction (Table 1, entries [3][4][5][6]. When performed at room temperature (rt), the reaction afforded the desired product in 70% yield (Table 1, entry 7). To exclude the possibility of interference of trace amount of metal in HOTf, the HOTf was used after redistillation and the product was obtained in the same yield ( Table 1, entry 8). The role of light was investigated by conducting the reaction in the dark, but no difference in the yield was observed (Table 1, entry 9). In the absence of HOTf, the alkyl peroxide decomposed completely and the styrene remained unchanged (Table 1, entry 10).

Scope of the Investigation
With the identified conditions in hand, we studied the scope of alkenes for this one-pot process ( Figure 1). In most of the cases, the products were obtained as a single E-isomer. Reactions of vinyl arenes containing carbon substituents at the o-, m-, and p-positions afforded the corresponding products (4)(5)(6)(7)(8)(9)(10) in good yield (68-84%). Vinyl arenes containing halides reacted with 2-ethylhexanoic acid to give the desired products (11)(12)(13)(14)(15) in moderate to good yield (54%-80%). Functional groups, such as dimethylaminomethyl, and even free carboxylic acid and boronic acid were compatible with the reaction conditions (20)(21)(22)(23). a-Methylstyrene and a-phenylstyrene participated in the reaction smoothly, providing the products (24,25) in 82% and 93% yields, respectively. Furthermore, an enyne was a suitable substrate for this reaction, and the corresponding terminal-cross-coupled product (26) was obtained in good yield (71%). 1-Octene, an unactivated alkene, examined under the standard reaction conditions was not reactive to this reaction.  Next, we proceeded to study the scope of the reaction with respect to secondary and tertiary aliphatic carboxylic acids ( Figure 2). The desired products (28-43) were obtained in moderate to high yields, using acyclic or cyclic aliphatic acids. The compatibility of various functional groups was good, and many functional groups, such as carbonyl (42), imide (38), amine (43), and ether (36), were tolerated. Most importantly, the E/Z selectivity of this reaction was excellent and only E-alkenes were observed. We then tried to expand this reaction to primary aliphatic acids, but the desired products were obtained in low yields as the methylated vinylic products were observed as by-products (Zhu et al., 2017). To overcome this problem, primary aliphatic acids were converted into alkyl diacyl peroxides and then subjected to the reaction ( Figure 3). With the similar reaction conditions (please see Table S4 for details), generic primary aliphatic acids afforded the corresponding products (44)(45)(46)(47)(48) in good yields (60-77%). Primary aliphatic acids with functionalities, e.g., the bromide (49), chloride (50), ketones (51 and 52), ester (53), or the alkene (54) were well tolerated in the protocol, delivering the corresponding products in moderate to good yields. In every case, the E-alkene was obtained exclusively.

Synthetic Applications
To highlight the synthetic utility of this methodology (Scheme 2), the perester (55), which is readily derived from the corresponding steroidal carboxylic acid, was coupled with styrene in the presence of HOTf. The decarboxylative Heck-type coupling product (56) was obtained in 48% yield as a single isomer. The configuration of the product (56) was reversed, and this was confirmed by X-ray crystallographic analysis (please  see Tables S5 and S6 for details). The reaction of 57 afforded the desired product (58) in 65% yield with E-selectivity. Gemfibrozil 59, an oral drug used to lower lipid levels, could also be converted into the vinylated product (60). These examples demonstrated that this reaction is potentially useful for the functionalization of complex molecules in the late stage.

Mechanistic Study
To probe the mechanism of the reaction, a series of control experiments were performed. The reaction of a-phenylstyrene with 2-cyclopropylacetic acid under the standard conditions afforded the ring-opening product (61) in 62% yield (Scheme 3A), supporting the assumption of the involvement of radical species in the reaction. The competitive reaction of styrene and d 8 -styrene used in 1:1 ratio in the presence of HOTf and lauroyl peroxide (LPO) offered an identical yield of the corresponding products (Scheme 3B). When the reaction of d 8 -styrene with perester 62 was performed in tetrahydrofuran (THF), the desired See also Figures S128-S149.
product (d 7 -3) was isolated (Scheme 3B). Interestingly, the deuterated side products d(OD)-butanol were detected by gas chromatography-mass spectrometry (GC-MS). To further explore the mechanism, possible intermediates 63 and 64 were synthesized and tested with or without HOTf (Scheme 3C). Compounds 63 and 64 are thermally stable in the absence or presence of one equivalent of C 11 H 23 COOH. Even though compounds 63 and 64 can be converted to the desired alkene products in the presence of 0.2 equivalent of HOTf, it is unlikely that they are competent intermediates because the formation of 63 or 64 was not observed using GC-MS when the corresponding Heck reaction was conducted no matter with or without HOTf .

Plausible Reaction Mechanism
As the result shown in entry 10 of Table 1, no desired product was observed in the absence of HOTf, implying that HOTf must play a vital role in the reaction. Density functional theory (DFT) calculations were carried out to gain further insight into the reaction mechanism. As can be seen from Scheme 4, before the catalytic cycle R, radical I-5 can be formed by homolytic dissociation of the alkyl diacyl peroxide, which is a very slow step with a high barrier of 27.5 kcal/mol. However, this is considered as the trigger to invoke the following catalytic cycle. Attack on the styrene substrate by the active species R, radical to form a benzyl radical (I-6) leads to energies lower by 31.3 kcal/mol with a small barrier of 2.8 kcal/mol, indicating that such a reaction is both thermodynamically and kinetically favorable. In the beginning of the catalytic cycle, LPO binding a molecule of HOTf forms a complex I-1 with a strong hydrogen bonding of 10.2 kcal/mol. This complex oxidizes benzyl radical (I-6) to yield a benzyl cation species (I-2), a radical (I-3), and an OTf À anion, which is exothermic by 4.4 kcal/mol. Meanwhile, the generated OTf À deprotonates I-2 to yield the product and regenerate the acid HOTf with a reaction energy of À13.4 kcal/mol. Thus, from the reactions of LPO and I-6 with the product and I-3, a proton-coupled electron transfer process is promoted by HOTf, which serves as the driving force and proton source for the reaction. Thereby, homolytic dissociation of I-3 leads to RCOO, radical (I-4) and RCOOH, which is exothermic by 2.3 kcal/mol without any barrier. Subsequently, C-C cleavage of I-4 is exothermic by 3.8 kcal/mol, which releases the active species R, radical (I-5) and CO 2 to close the catalytic cycle. Alternatively, in the absence of HOTf formation of this radical I-4 with carboxylic acid RCOOH requires high energies (>27 kcal/mol, See Scheme S1), indicating that the strong acidity of HOTf plays a significant role in the formation of I-4. A similar mechanism of reaction starting from perester was also calculated and presented in Scheme S2.

Conclusion
We have developed a Brønsted acid-catalyzed radical alkyl-Heck-type reaction of alkenes with aliphatic acids. This HOTf-catalyzed process has been shown to be an efficient method to deliver only E-alkenes in most cases. Relatively simple and available starting materials are used, and wide substrate scope and good functional group tolerance are observed. Preliminary mechanistic studies illustrated the vital role of HOTf in the reaction, whose proposed mechanism is supported by both the experimental and computational results.

METHODS
All methods can be found in the accompanying Transparent Methods supplemental file.

DATA AND SOFTWARE AVAILABILITY
The data for the X-ray crystallographic structure of 55 and 56 (2) Figure S42. 13 C NMR spectrum of compound 55, related to scheme 2. Figure S43. 1 Figure S164. 13  The perester species has a similar mechanism catalyzed by HOTf. Before the catalytic cycle the R• radical J-5 can be formed by homolytic dissociation of the alkyl diacyl peroxide (perester), which is a very slow step with a high barrier of 24.9 kcal/mol. However, this is considered as the trigger to invoke the following catalytic cycle. Attack on the styrene substrate by the active species R• radical J-5 to form a benzyl radical (J-6) leads to energies lower by 23.7 kcal/mol with a small barrier of 6.7 kcal/mol, indicating that such reaction is both thermodynamically and kinetically favourable. In the beginning of the catalytic cycle, LPO binding a molecule of HOTf forms a complex I-1 with a strong hydrogen bonding of 13.7 kcal/mol. This complex oxidizes benzyl radical (J-6) to yield a benzyl cation species (J-2), a radical (J-3) and an OTf-anion, which is exothermic by 2.2 kcal/mol. Meanwhile, the generated OTfdeprotonates J-1 to yield the product and regenerate acid HOTf with reaction energy of -13.3 kcal/mol. Thus, from the reactions of LPO and J-6 to the product and J-3 stepwise electron and proton transfers are promoted by HOTf, which serves as the driving force and proton source for the reaction. Thereby hydrogen transfer of J-3 leads to RCOO• radical (J-4) and tBuOH, which is nearly thermal neutral of 1.4 kcal/mol without any barrier.
Subsequently, C-C cleavage of J-4 is exothermic by 11.6 kcal/mol in energy which releases the active species R• radical (J-5) and CO2 to close the catalytic cycle.  Table S1. Sources of acids, related to Figure 2 and   (3) Largest diff. peak and hole 0.252 and -0.140 e.Å -3 Table S6. Crystal data and structure refinement for 56, Related to Scheme 2.

Transparent Methods
All reactions were carried out under an atmosphere of nitrogen in flame-dried glassware with magnetic stirring unless otherwise indicated. Commercially obtained reagents were used as received. Solvents were dried by Innovative Technology Solvent Purification System. Liquids and solutions were transferred via syringe. All reactions were monitored by thin-layer chromatography. GC-MS data were recorded on Thermo ISQ QD. 1 H, 13 C and 19 F NMR spectra were recorded on Bruker-BioSpin AVANCE III HD. Data for 1 H NMR spectra are reported relative to chloroform as an internal standard (7.26 ppm) and are reported as follows: chemical shift (ppm), multiplicity, coupling constant (Hz), and integration. Data for 13 C NMR spectra are reported relative to chloroform as an internal standard (77.23 ppm) and are reported in terms of chemical shift (ppm). HRMS data were recorded on Waters Micromass GCT Premier or Thermo Fisher Scientific LTQ FTICR-MS.

Experimental procedures for synthesis of materials Procedure A for the synthesis of alkenes
General procedure (Haubenreisser et al., 2016): The reaction vessel was charged with phosphonium salt (1.2 equiv) in dry THF. To the stirred mixture, n-butyl lithium (1.2 equiv) was added under N2 atmosphere at -78°C. The mixture was stirred at 0 o C for 5 mins and then substituted aldehyde (1.0 equiv.) in dry THF was added dropwise in over 15 min. After stirring at rt for 4 hr, the mixture was quenched with saturated NH4Cl, then extracted three times with dichloromethane and water. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography afford the desired product.

Procedure B for the synthesis of alkenes
General procedure (Huang and Doyle, 2012): A flask was flame dried and charged with phenol (1.0 equiv), dichloromethane, and Et3N (2.0 equiv). The mixture was cooled in a 0 o C ice-water bath, and Tf2O (1.1 equiv) was added dropwise. The mixture was allowed to warm up to room temperature and stirred at room temperature under argon for 5 hr. The resulting brown mixture was diluted with dichloromethane, washed with sat. NH4Cl, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO4, and the filtrate was concentrated. The crude was purified with column chromatography to afford triflate.
A threaded tube was charged with triflate (1.0 equiv), potassium vinyltrifluoroborate (1.2 equiv), PdCl2 (2 mol %), PPh3 (6 mol %), Cs2CO3 (3.0 equiv) were added, then THF and water were added under N2 atmosphere. The mixture was stirred at 85 o C for overnight. The resulting dark brown mixture was allowed to cool to room temperature, diluted with dichloromethane, and washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO4, and the filtrate was concentrated. The crude was purified with column chromatography to afford the desired product.

Procedure C for the synthesis of diacyl peroxides
General procedure : A solution of DMAP (10 mol %), 30% hydrogen peroxide (1.2 equiv), and acid in CH2Cl2 was cooled to -5 o C for about 10 min. Then DCC (1.2 equiv) was added. Then the mixture was stirred at -5 o C to room temperature for 1.5 ~4 hr. The solution was concentrated on a rotary evaporator under vacuum at 10~15 o C and the residue was chromatographed on silica gel to give the diacyl peroxide.

Procedure D for the synthesis of peresters
General procedure (Zhu et al., 2017): A solution of DMAP (10 mol %), TBHP (aqueous solution, 1.2 equiv), and acid in CH2Cl2 was cooled to -5 o C for about 10 min. Then DCC (1.2 equiv) was added. Then the mixture was stirred at -5 o C to room temperature for 4 hr. The solution was concentrated on a rotary evaporator under vacuum at 20~25 o C and the residue was chromatographed on silica gel to give the perester.

Procedure E for the alkyl-Heck-type reaction of alkenes
To a flame-dried Schlenk tube were added 2-ethylhexanoic acid (

Exclusion of possible intermediates
Ester 63 : (0.2 mmol) was charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6 hr. No reaction was observed and the ester 63 was recovered in 92% yield.
Ester 63 (0.2 mmol) and C11H23COOH (1 equiv) were charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6 hr. No reaction was observed and the ester 63 was recovered in 93% yield.
Ester 63 (0.2 mmol) and HOTf (20 mol %) were charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6hr. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aq. NaHCO3. The organic layer was dried (anhydrous Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel affording product 44 in 91% yield.
Benzyl alcohol 64  (0.2 mmol) was charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6 hr. No reaction was observed and the alcohol 64 was recovered in 93% yield.
Benzyl alcohol 64 (0.2 mmol) and C11H23COOH (1 equiv) were charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6hr. No reaction was observed and the alcohol 64 was recovered in 93% yield.
Benzyl alcohol 64 (0.2 mmol) and HOTf (20 mol %) were charged in anhydrous THF (0.5 mL) at 90°C and then stirred for 6hr. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aq. NaHCO3. The organic layer was dried (anhydrous Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel affording product