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Home > Hydrogen bonding promoted simple and clean photo-induced reduction of C–X bond with isopropanol
Hydrogen bonding promoted simple and clean photo-induced reduction of C–X bond with isopropanol
Dawei Cao, Chaoxian Yan, Panpan Zhou, Huiying Zeng and Chao-Jun Li
Reducing C–halogen bonds to C–H bonds is not only a fundamental organic transformation in organic synthesis but also an important tool for detoxification of environmentally hazardous organic halides. While classical methods utilized tributyltin hydride via radical reaction,3 a variety of alternative radical- based methods have been developed to avoid the toxicity of tin reagents.4 However, metal or metal organic chemicals are generally required for these transformations. In recent studies, transition-metal-free reduction of C–X bond was promoted by strong base,5 and sodium hydride was used as a hydride resource to reduce C–Br bond.6 Photo-induced metal catalyzed reduction7 and photo-induced organic photoredox catalyst- based reduction8 were also developed. Recently, photo-induced catalyst-free reductions of C–X bond were reported using BNAH (1-benzyl-1,4-dihydronicotinamide),9 TMSS (tristrimethylsilyl- silane),10 borohydrides11 and triethylamine12 as reducing reagents, respectively. Nevertheless, all these methods require stoichio- metric reducing reagents.
The Meerwein–Ponndorf–Verley (MPV) reduction is a classical reaction to reduce ketones to alcohols via hydrogen-transfer from isopropanol.13 This reaction was generally catalyzed by metal alkoxyl to form six-membered ring transition state (Scheme 1a). Inspired by this classical reaction, we hypothesized that organic halides can be irradiated by light to generate the excited state, which can form a six-membered ring transition state similar to the MPV reaction via a weak hydrogen bonding between the halogen and the hydroxyl group of isopropanol (Scheme 1b). Subsequent ‘‘intramolecular’’ hydrogen-transfer will generate the reduced product, with isopropanol being concurrently oxidized to form acetone.
To test the feasibility of this hypothesis, methyl 4-iodo- benzoate (1a) was selected as a model substrate under UV (254 nm) irradiation in 1 mL of isopropanol solvent, using DBU as base under an argon atmosphere at room temperature (Table 1, entry 1). To our delight, 93% yield of the reduction product was detected! Encouraged by this result, different light sources (such as blue LED, CFL or without light) were examined, and only trace or no desired product was detected (Table 1, entries 2–4). These results indicate that the light resource is very important to this reaction. The influence of solvent was also investigated and showed that isopropanol is the best solvent (Table 1, entries 5–8). Interestingly, 89% yield of reduction product 2a was also obtained without adding any base (Table 1, entry 9). When the volume of solvent was increased, the yield was slightly increased accordingly (Table 1, entries 10 and 11). For economical reason, 1.5 mL of solvent was chosen for subsequent studies. Reducing the reaction time to 6 h gave the product in 72% yield (Table 1, entry 12). However, prolonging the reaction time to 24 h did not change the yield (Table 1, entry 13). It is noteworthy that even when this reaction was performed under an atmosphere of air, almost the same excellent yield (95%) was obtained (Table 1, entry 14). Consequently, the reaction was carried out in 1.5 mL of isopropanol under UV irradiation (254 nm) utilizing quartz reactor (please see ESI†) under air at room temperature for 12 h.
With the optimized reaction conditions in hand, we explored the generality of this reaction (Table 2). Gratifyingly, a broad range of aryl halides containing either electron-donating or electron- withdrawing groups proved to be competent substrates, providing the reduction products in moderate to excellent yields. Notably, the reaction system also exhibited high chemoselectivity: various functional groups including ester (1a–e), carboxyl (1f), methoxy (1g–l), dimethoxy (1m), alkyl (1n–q), phenyl (1r), amine (1t), hydroxy (1u–v), hydroxymethyl (1w–x), trifluoromethyl (1y), cyano (1z) and heterocyclic compounds (1ab–1ai) were tolerated, thereby providing handles for further product diversifications. Among them, we also studied different halogen-substituted (–Cl, Br, I,) substrates (1a–c, 1d–e, 1h–j, 1k–l, 1o–p, 1u–v), all of them were reduced with high to excellent yields. It is noteworthy that 3.85 grams of compound 1a was also successfully dehalogenated in 73% yield by prolonging the reaction time to 36 h. The substrates with methoxy group (1g–1l) generated slightly lower yields, due to isolation loss caused by the lower boiling points of these compounds. Much to our satisfaction, the substrates containing strong electron-withdrawing group, such as trifluoro- methyl group (1y) and cyano group (1z) were tolerated and not reduced under our reaction system. 1-Iodonaphthalene (1aa) also furnished the desired products with excellent yield. Meanwhile, bromine-substituted indole substrates on different positions (1ab–ad) were dehalogenated in 68% to 78% yields, respectively. In addition, different halogen-substituted heterocyclic compounds (1ae–ai) could also be reduced with moderate to high yields.
To further investigate the scope of this reduction system, polyhalogen substituted substrates were tested, and the results were summarized in Table 3. Polyhalides 1aj and 1ak can be chemo-selectively reduced to obtain the chlorinated products when we controlled the reaction time. It is noteworthy that different fluoroaryl compounds bearing iodo-, bromo- or chloro-group were reduced smoothly to generate the desired fluorinated compounds up to 89% yields (1al–an). To our delight, the iodo-substituted polyfluoroarene 1ao could also be selectively reduced with high yield in 12 h.
As is well known, dioxins are highly environmentally persistent organic pollutants. Detoxification of dioxins was investigated by our method. To our delighted, all of the C–Cl bonds of 2,3-dichlorodibenzo[b,e][1,4]dioxin (3) and the most dangerous dioxins 2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin (TCDD)14 (4) were successfully reduced in the presence of strong base, and the detoxification compound dibenzo[b,e][1,4]dioxin (5) was obtained in this case with 81% and 83% yield (Scheme 2), respectively.
To understand the mechanism, free radical trap and deuterium experiments were performed (Scheme 3). When 1 to 3 equiv. of TEMPO were added to this reaction system under standard reaction conditions, the reaction still proceeded smoothly, to give 82% to 61% yields of the reduced product. The same result was obtained when 2 equiv. of BHT was added as the free radical trap (Scheme 3a). These experiments suggested the absence of free aryl radical during the course of this reaction. Deuterium product methyl 4-d-benzoate (6) was isolated when isopropanol-d8 was used as solvent. To further exclude the possibility that the deuterium atom originated from hydroxyl group or methyl group of isopropanol. Normal water (0.4 mL) was added to the isopropanol-d8. The product 6 was obtained in 85% yield with 100% deuteration at C-4 position (Scheme 3b).15 This result eliminated the possibility of deuterium originated from the hydroxyl group. 1,1,1,3,3,3-Hexafluoro- propanol-d2 was also selected as solvent, the deuterated product 6 was also obtained. Combining these three deuterium experiments, we can speculate that the deuterium atom of product originated from C-2 position of isopropanol.
Based on the mechanistic studies above, we proposed a plausible reaction mechanism, and corresponding density functional theory (DFT) calculations were also carried out at M06-2X16/6-31+G(d,p)/IEFPCM17 (2-propanol) level of theory.
As described in Fig. 1 (for the whole free energy profile, please see ESI,† Fig. S1), the ground state bromobenzene goes through UV light excitation and intersystem crossing (isc) successively to form the first triplet excited state PhBr (T1). Both ‘‘intra-’’ and intermolecular pathways are investigated (black and grey, respectively). For the ‘‘intramolecular’’ pathway (black), hydrogen atom transfer (HAT) and C–Br bond cleavage can take place synchronously in TS1 with a six-membered ring structure to generate the radical IM3 and reduced product benzene. For the intermolecular pathway (grey), homo-cleavage of C–Br bond in PhBr (T1) will form benzene radical. Then, HAT occurs via TS10 to form the reduced product benzene and radical IM3.
DFT calculation shows that there is 14.7 kcal mol—1 free energy increase from PhBr (T1) to TS10 in the grey pathway. In comparison, the black pathway only has 5.1 kcal mol—1 free energy change from PhBr (T1) to TS1. The result indicates that the black pathway is more favorable than the grey pathway.
This stabilization may be due to the larger dipole moment of TS1 (please see ESI,† Table S2). With the existence of O–H·· ·Br–C hydrogen bond of TS1, there is apparent charge separation (large red and blue clouds), leading to large dipole moment. In contrast, there is less charge separation in TS10 (please see ESI,† Fig. S2).
In conclusion, we have developed a simple and clean metal- free reduction of C–X bond under air at room temperature. Isopropanol was used as both reducing reagent and solvent. A wide range of functional groups, such as acids, esters, alcohols, anilines, phenols, indoles, pyridines, cyano group, trifluoromethyl group and heterocyclic compounds, were all tolerated. Different organic halides comprising C–I, C–Br and C–Cl bonds were reduced with good to excellent yields. Poly- halides were also chemoselectively reduced. DFT calculation showed that a six-member ring transition state containing C–Br·· ·H–O hydrogen bonding has lower energy. This strategy provides greener approach for C–halogen bond reduction and detoxification of environmentally hazardous organic halides.
We thank the Recruitment Program of Global Experts (Short- Term B) to C.-J. L., the Fundamental Research Funds for the Central Universities (lzujbky-2018-62, lzujbky-2018-79), the International Joint Research Centre for Green Catalysis and Synthesis, Gansu Provincial Sci. & Tech. Department (No. 2016B01017, 18JR3RA284, 18JR4RA003) and Lanzhou University for support of our research. We also thank the Canada Research Chair (Tier I) foundation, the E. B. Eddy endowment fund, the CFI, NSERC, and FQRNT to C.-J. L. We thank Dr Haining Wang for his helpful discussions about the DFT calculation and Mr Shuo Zhang in this group for reproducing the results presented substrates 1r, 1v and 1ag in Table 2 and substrate 1aj in Table 3.
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