Photoredox-Catalyzed Hydrocarboxymethylation of Alkenes

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Oct 2021Photoredox-Catalyzed Hydrocarboxymethylation of Alkenes Jie Fang, Qiang Hu, Wan-Li Dong, Guo-Qiang Xu, Xiu-Qin Hu, Yong-Chun Luo and Peng-Fei Xu Jie Fang State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 Institute of Applied Chemistry, Jiangxi Academy of Sciences, Nanchang 330096 , Qiang Hu State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 , Wan-Li Dong State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 , Guo-Qiang Xu State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 , Xiu-Qin Hu State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 , Yong-Chun Luo State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 and Peng-Fei Xu *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 https://doi.org/10.31635/ccschem.021.202000542 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Direct introduction of a carboxyl group into molecules is one of the most useful methods for the preparation of carboxylic acids, which avoids the conversion of various preexisting functional groups and features good step- and atom-economy. However, the methods for the direct synthesis of two-carbon added carboxylic acids from the precursors remain rare. Herein, we first report a general and mild method for the direct synthesis of a range of aliphatic acids by photoredox-catalyzed hydrocarboxymethylation of alkenes with good toleration of various functional groups in which bromoacetic acid is utilized as an ideal two-carbon synthon. The synthetic utility of this hydrocarboxymethylation protocol is further demonstrated by the concise synthesis of two marketed drugs, sensipar and tirofiban, from commercially available starting materials. Download figure Download PowerPoint Introduction Aliphatic carboxylic acids are valuable chemicals that exist widely in natural products, agrochemicals, and pharmaceuticals, which perform a diverse range of industrial functions including the manufacture of rubber, plastics, soaps, detergents, and dyes.1 Conventional approaches toward the synthesis of carboxylic acids involve oxidation and hydrolysis which nonetheless require the preexisting functional groups such as esters, aldehydes, or cyano groups.2 Moreover, the harsh conditions (using strong oxidants, acids, and bases) of these conversions often hamper their potential utility in late-stage functionalization and other diversification steps. Therefore, the methods for the direct introduction of carboxyl groups into molecules should be of considerable value to the synthetic community. Indeed, over the past decades, significant progress has been made toward the production of carboxylic acids through catalytic carboxylation with carbon dioxide (CO2) owing to its inexpensive and renewable properties (CO2, as a C1 source).3–13 However, the synthesis of two-carbon added fatty acids from precursors commonly rely on classical methods, such as Michael-type additions of malonate compounds to activated alkenes, whereby the generated 1,3-carbonly compounds undergo hydrolysis and decarboxylation to deliver the two-carbon ( C2) added carboxylic acids (Scheme 1a).14–19 This multiple reaction sequence undoubtedly suffers from low conversion efficiency, especially in complex molecules construction. It will be highly desirable to develop a general protocol for the rapid construction of two-carbon added carboxylic acids in a single step from simple starting materials. For example, a dual nickel- and photocatalyzed cross-coupling between aryl halides and α-chloro carbonyls was reported by Chen and MacMillan20 providing a unified method for the α-arylation of diverse activated alkyl chlorides, wherein arylacetic acid products were constructed via an in situ silyl masking protocol by using chloroacetic acid as a two-carbon synthon. Scheme 1 | (a and b) The methods for synthesis of two-carbon added acids from alkenes. Download figure Download PowerPoint Photoredox catalysis has recently emerged as a powerful platform for the direct functionalization of C(sp3) centers via open-shell pathways.21–24 These advances include the generation of C(sp3)-centered radicals from α-electron-withdrawing group (EWG) halides for subsequent addition to alkenes, and typically feature atom transfer radical addition (ATRA) leading to analogous difunctionalized motifs.25–31 Encouraged by the research on photoredox-catalyzed hydrofunctionalization of alkenes,32–48 we started to develop a facile access to two-carbon added fatty acids from inexpensive feedstock olefins in a single step (Scheme 1b). This late-stage functionalization process leading to C(sp3)-rich fatty acids could increase their likelihood of success in the drug discovery pipeline.49–51 It is essential that the ATRA difunctionalized products generated in chain propagation be suppressed by a hydrogen atom donor (HAD) via polarity matched hydrogen atom transfer (HAT) pathway to afford the hydrocarboxymethylation product.52,53 Experimental Methods General procedure An oven-dried 10 mL vial equipped with a rubber plug and magnetic stir bar was charged with [Ir(ppy)2dtbbpy]PF6 (0.002 mmol, 1 mol %), diphenyl disulfide (0.06 mmol, 30 mol %), bromoacetic acid (0.4 mmol, 2 equiv), hantzsch ester (HE) (0.4 mmol, 2 equiv), and 1.5 mL of solvent. The reaction mixture was degassed by three cycles of freeze–pump–thaw. Trifluoroacetic acid (TFA) (0.3 mmol, 1.5 equiv) and the appropriate alkenes (0.2 mmol, 1.0 equiv) were then added. The reaction mixture was then stirred and irradiated with two 12 W blue light-emitting diodes (LEDs) with a fan placed beside it for cooling. After 12 h, the reaction mixture was added to the saturated aqueous NaHCO3 and stirred for 30 min, and then washed with dichloromethane (20 mL × 2). Then the aqueous phase was acidized by HCl and extracted three times with ethyl acetate (30 mL × 3). The organic parts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. Purification of the crude product by flash column chromatography gave the desired acids (petroleum ether∶ethyl acetate∶acetic acid = 15∶1∶1% ∼ 1∶1∶1%). (General condition A: dioxane as solvent for unactivated alkenes; general condition B: N, N-dimethylacetamide [DMA] as solvent for styrenes.) Results and Discussion We began our investigation by exposing readily available alkene 1a and bromoacetic acid 2a to blue LED under nitrogen atmosphere in the presence of the photocatalyst Ir(ppy)3, diphenyl disulfide (HAD), and HE in chlorobenzene (Table 1). To our delight, the desired anti-Markovnikov hydrocarboxymethylation product 10 was obtained in a 31% isolated yield, while the ATRA-type product 10′ was not detected (entry 1). After screening various photocatalysts, it was found that [Ir(ppy)2dtbbpy]PF6 increased the desired product yield to 40% with a trace amount of 10′ also produced. To further improve the reaction efficiency, we then investigated the influence of different solvents, and it was found that MeCN and 1,2-dichloroethane (DCE) could accelerate the reaction to 6 h with 63% and 68% yield, respectively; however, the yield of undesired ATRA-type byproduct was also increased to 12% and 15%, respectively, probably owing to the faster bromine atom transfer of chain propagation in polar aprotic solvents (entries 6 and 7). Replacing chlorobenzene with dimethylformamide (DMF) failed to improve the yield (entry 8). To our surprise, product 10 was exclusively obtained when ether solvents were used, and dioxane exhibited even better reactivity (entries 9 and 10). Furthermore, an evaluation of additives showed that the reaction proceeded smoothly in the presence of TFA (entry 12), while Na2CO3 reduced the reaction efficiency (entry 11). The best yield was obtained by increasing the amount of diphenyl disulfide to 0.3 equiv (entry 13). Decreasing the amount of TFA gave a lower yield (entry 14). Finally, no product was detected in the absence of light (entry 15), but hydrocarboxymethylation product 10 was obtained in 15% yield when the reaction proceeded without the photocatalyst54 (entry 16). Table 1 | Optimization of Hydrocarboxymethylation of Unactivated Alkene 1a with Bromoacetic acida,b Entry Photocatalyst Additive Solvent Yield (10) Yield (10′) 1 Ir(ppy)3 — Ph-Cl 31% — 2 Acr+-Mes·ClO4− — Ph-Cl Trace — 3 4CzIPN — Ph-Cl 15% — 4 [Ir(dF(CF3)ppy)2dtbbpy]PF6 — Ph-Cl 17% — 5 [Ir(ppy)2(dtbbpy)]PF6 — Ph-Cl 40% Trace 6c [Ir(ppy)2(dtbbpy)]PF6 — MeCN 63% 12% 7c [Ir(ppy)2(dtbbpy)]PF6 — DCE 68% 15% 8 [Ir(ppy)2(dtbbpy)]PF6 — DMF 41% — 9 [Ir(ppy)2(dtbbpy)]PF6 — Dioxane 71% ND 10 [Ir(ppy)2(dtbbpy)]PF6 — THF 47% ND 11 [Ir(ppy)2(dtbbpy)]PF6 Na2CO3 Dioxane 55% ND 12 [Ir(ppy)2(dtbbpy)]PF6 TFA Dioxane 84% ND 13d [Ir(ppy)2(dtbbpy)]PF6 TFA Dioxane 87% ND 14d,e [Ir(ppy)2(dtbbpy)]PF6 TFA Dioxane 83% ND 15d,f [Ir(ppy)2(dtbbpy)]PF6 TFA Dioxane NR NR 16d,g [Ir(ppy)2(dtbbpy)]PF6 TFA Dioxane 15% ND Abbreviations: THF, tetrahydrofuran; ND, not detected; NR, no reaction. aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), photocatalyst (1 mol %), HE (2 equiv), additive (1.5 equiv), and diphenyl disulfide (20 mol %) in 1.5 mL solvent at 25 °C under nitrogen with blue LED irradiation for 12 h. bIsolated yield. cIrradiation for 6 h. dDiphenyl disulphide (30 mol %). eTFA (1.0 equiv) was added. fWithout visible light irradiation. gNo photocatalyst. With reaction conditions optimized, we next sought to examine the scope of the transformation with unactivated monosubstituted alkenes. As shown in Table 2, simple alkenes like 1-octene and vinylcyclohexane delivered the expected products in moderate to good yields ( 1 and 2). Other alkenes with various functional groups, such as phenyl ( 3 and 4), halides ( 5 and 6), hydroxyl ( 7), silyl ( 8), ester ( 9 and 10), tosylate ( 11), carbazole ( 12), phthalimide ( 13), ether ( 14 and 15), and ketone ( 16), were well tolerated. To be noted, the reaction of alkenes containing protected primary and secondary amine could also afford the desired amino acids with moderate to good yields, which provided a potential approach for the direct synthesis of new amino acids ( 17– 19). This mild protocol was also applied smoothly to the synthesis of biologically relevant molecules, such as the carboxylic acids constructed from an amino acid and a fructose-derived alkene, respectively ( 20 and 21). Table 2 | Substrate Scope of Unactivated Monosubstituted Alkenesa aReaction condition A: alkenes (0.2 mmol), 2a (0.4 mmol), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %), diphenyl disulfide (30 mol %), HE (0.4 mmol), and TFA (0.3 mmol) in 1.5 mL dioxane at 25 °C under nitrogen with blue LED irradiation for 12 h. Yields of isolated products. After examining the substrate scope of monosubstituted alkenes, the generality of this process was subsequently probed with respect to unactivated 1,1-disubstituted and internal alkenes (Table 3). Satisfactorily, it was found that the reactivities of disubstituted alkenes were generally better than monosubstituted alkenes, and various carboxylic acids could be prepared in moderate to good yields from corresponding gem-disubstituted alkenes ( 22– 29). For instance, a rigid alkene derived from 2-adamantanone reacted smoothly to afford the desired acid in 88% yield ( 25). Similarly, products involving protected pyrrolidine and piperidine could also be obtained in 51% and 86% yields, respectively, which further demonstrated the practicability of this method for the direct synthesis of value-added carboxylic acids ( 30 and 31). Furthermore, the internal alkenes bearing an ester ( 32), a four-member ring ( 33), and protected piperidine ( 34) afforded the corresponding branched carboxylic acids in good yields. Cyclenes such as cyclohexene, cyclooctene, and even norbornene also delivered the fatty acid products in moderate yields ( 35– 37). To demonstrate the potential of this transformation in late-stage functionalization, we applied this protocol to the derivatization of alkene-containing biologically active molecules. A hydrocarboxymethylated estrone derivative was obtained in good yield ( 38) and hydrocarboxymethylation of stanolone-derived alkene with bromoacetic acid could produce 39 without affecting the alcohol group. Surprisingly, both of 38 and 39 exhibited good diastereoselectivity (d.r. > 15:1), and the dominant conformations were determined by X-ray crystallographic analysis (see Supporting Information for more details). Table 3 | Substrate Scope of Unactivated 1,1-Disubstituted and Internal Alkenesa,b aReaction condition A: alkenes (0.2 mmol), 2a (0.4 mmol), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %), diphenyl disulfide (30 mol %), HE (0.4 mmol), and TFA (0.3 mmol) in 1.5 mL dioxane at 25 °C under nitrogen with blue LED irradiation for 12 h. Yields of isolated products. bd.r. > 15∶1. Due to the wide use of phenylbutyric acids, we next turned our attention to explore styrene substrates. As illustrated in Table 4, a diverse array of arylbutyric acids were synthesized conveniently with the change of the reaction solvent only (condition B, see Supporting Information for more details). The readily available styrene was facile to deliver the 4-phenylbutyric acid in excellent yield ( 40), which is a key intermediate for the synthesis of sodium phenylbutyrate, a marketed drug for the treatment of urea circulation disorders. A range of styrenes bearing either electron-withdrawing or electron-donor substituents afforded the phenylbutyric acids in moderate to excellent yields ( 41– 48). Intriguingly, 4-vinylbenzoic acid, which possesses an acidic proton, produced the desired hydrocarboxymethylation product 49 effectively. In addition, various naphthalene ethylenes were also well accommodated ( 50 and 51). 1,1-Disubstituted styrenes could be used to give branched products in excellent yields ( 52 and 53), while 1,1-diphenylethylene showed low efficiency ( 54). It is important to note that this transformation was not restricted to styrene systems. Indeed, aryl vinyls containing benzofuran, thianaphthene, and indole were also found to be effective substrates for this transformation, affording heteroarylbutyric acids in moderate to good yields ( 55– 59). Furthermore, modification of menthol and estrone derivatives resulted in the corresponding carboxylic acids in good to excellent yields ( 60 and 61), which illustrated the capability of this method for the direct construction of complex carboxylic acids without the need of multistep transformations. Table 4 | Substrate Scope of Styrenesa aReaction condition B: alkenes (0.2 mmol), 2a (0.4 mmol), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %), diphenyl disulfide (30 mol %), HE (0.4 mmol), and TFA (0.3 mmol) in 1.5 mL DMA at 25 °C under nitrogen with blue LED irradiation for 12 h. Yields of isolated products. CF2-containing compounds play an important role in pharmaceuticals, agrochemicals, and material science, and great efforts have been focused on the introduction of the CF2 group into various molecules.55,56 In addition, α-diF-substituted carboxylic acids are usually regarded as difluoroalkyl radical precursors to introduce a CF2 moiety into complex molecules,20,57–64 but the efficient methods toward aliphatic α-diF-substituted carboxylic acids are still to be desired. Therefore, we next explored the possibility to construct CF2-containing carboxylic acids by using bromodifluoroacetic acid as the coupling precursor. Satisfactorily, the expected carboxylic acids were synthesized conveniently from multifarious unactivated alkenes in good to excellent yields ( 62– 64). Furthermore, CF2- and quaternary carbon-containing carboxylic acids ( 65) could also obtained in good yields from the challenging tetra-substituted alkenes (Table 5). However, the reaction resulted in a complex system when it was conducted with styrene, and the desired product could not obtained. The reason for the formation of this complex system might be the reaction between the carboxydifluoromethyl radical and styrene, which were both highly reactive. Table 5 | Hydrocarboxydifluoromethylation of Alkenes with Bromodifluoroacetic Acida aReaction condition A: alkenes (0.2 mmol), bromodifluoroacetic acid (0.4 mmol), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %), diphenyl disulfide (30 mol %), HE (0.4 mmol), and TFA (0.3 mmol) in 1.5 mL dioxane at 25 °C under nitrogen with blue LED irradiation for 12 h. Yields of isolated products. Through the products obtained by our method, we could easily synthesize the synthetic building blocks and marketed drugs (Scheme 2). For example, lactone 66 could be synthesized from 40 under the action of a hypervalent iodine reagent (Scheme 2a), and carboxylic acid 61 derived from estrone could undergo intramolecular cyclization to yield 67 (Scheme 2b). To further demonstrate the synthetic utility of this hydrocarboxymethylation protocol, we applied it to the synthesis of the calcimimetic drug sensipar and the antiplatelet drug tirofiban. As shown in Scheme 2c, arylbutyric acid 45 was synthesized under condition B in good yield (65% yield, 5 mmol scale), which could be easily transformed into the corresponding alkyl iodide ( 68), subsequent simple amination of 68 giving sensipar 70 in 95% yield. Similarly, 4-(1-(Boc)piperidin-4-yl)butanoic acid (t-butyloxycarbonyl [Boc]) 19 was obtained from corresponding alkene under condition A in 59% yield (5 mmol scale), which could be reduced to alcohol 71 by BH3 solution. Alkyl iodide 72 was easily available from alcohol 71 by using I2 as the iodine reagent, and then alkyl iodide underwent nucleophilic substitution with tyrosine derivative 73, affording the protected product 74 in moderate yield. Finally, tirofiban 75 was obtained by acidic deprotection (Scheme 2d). Scheme 2 | (a–d) Diversification of carboxylic acid products and concise synthesis of sensipar and tirofiban. Download figure Download PowerPoint Several experiments were also conducted to elucidate the mechanism. A mixture of hydrocarboxymethylation and ATRA-type difunctionalized products were obtained when the reaction was carried out in condition A without diphenyl disulfide, while a single product 10 was obtained in good yield by using thiophenol as the hydrogen transfer reagent (Scheme 3a). These results indicated that the intermediate thiophenol generated from diphenyl disulfide was indispensable in the selective hydrocarboxymethylation process.53 In addition, the reaction was totally suppressed in the presence of 2,2,6,6-tetramethylpiperidinooxy (TEMPO) (Scheme 3b). Furthermore, ring-opening product 76 with an E/Z ratio of 5∶3 was observed when alkenylcyclopropane 1b participated in this reaction (Scheme 3c). N-Boc diallylamine 1c was also found to be a suitable substrate, affording cyclization pyrrolidine product 77 in moderate yield with a cis/trans ratio of 1∶1.5 (Scheme 3d). These results indicated that the hydrocarboxymethylation of alkenes proceeded via a radical pathway. Moreover, the deuterium experiments showed that the hydrogen atoms in the products were derived from protons in the system, not from the methylene groups on the HE (see Supporting Information for more details). Scheme 3 | (a–d) Mechanism studies. Download figure Download PowerPoint Based on mechanistic investigations above, a mechanism was proposed for our hydrocarboxymethylation protocol (Scheme 4). First, [Ir(dtbbpy)(ppy)2]PF6 is photoexcited to *IrIII and reduced by the HE to IrII (HE quenches the photoexcited *IrIII effectively, see Supporting Information for more details). Meanwhile, homolytic cleavage of diphenyl disulfide under LED light generates the benzene sulfide radical, which is then reduced to benzene sulfide anion by IrII, which finally captures a proton to generate the key intermediate thiophenol. Addition of carboxymethyl radical A produced by one-electron reduction of bromoacetic acid with olefins to obtain intermediate B, subsequent HAT from thiophenol furnishes the desired anti-Markovnikov hydrocarboxymethylation adduct (path a). However, we cannot rule out the possibility of a carbanion mechanism (path b). It is worth mentioning that the thiophenol (HAD) can successfully inhibit the production of ATRA products in a mechanism of chain growth (path c). Scheme 4 | Proposed mechanism. Download figure Download PowerPoint Conclusion We have established a robust strategy for the hydrocarboxymethylation of unactivated alkenes and styrenes with bromoacetic acid under mild conditions. This efficient method affords a general route to the direct synthesis of two-carbon added acids from abundant alkenes, and has advantages over traditional methods where maleates were used as the critical two-carbon synthon. The mild reaction conditions have been further confirmed by good functional groups tolerance. A variety of fatty acids have been constructed which are widely utilized as chemical feedstocks for the preparation of drugs and other biologically active compounds. Supporting Information Supporting Information is available. Supporting Information is available and includes experimental procedures, mechanistic experiments, characterization data, NMR spectra of compounds and X-ray crystal structure files for compound 38, 39. Conflict of Interest There is no conflict of interest to report. Acknowledgments The authors gratefully acknowledge the NSFC (nos. 21632003 and 21871116), the Key Program of Gansu Province (no. 17ZD2GC011), and the "111" Program from the MOE of China for financial support. References 1. Szilagyi M.Aliphatic Carboxylic Acids: Saturated. In Patty's Toxicology; Bingham E., Cohrssen B., Eds.; Wiley, New Jersey: 2012; Vol. 3, Ch. 48, pp. 471–532. Google Scholar 2. Smith M. B.; March J.March's Advanced Organic Chemistry; John Wiley & Sons, Inc.: Hoboken, NJ, 2007; pp. 1251–1476, 1703–1869. Google Scholar 3. 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