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• W2850356645 abstract "•Rapid dehydroxytrifluoromethoxylation of alcohols is described•R3P/ICH2CH2I is an efficient reagent system for the dehydroxylation of alcohols•Unusual P-I halogen bond is the driving force to generate the key intermediates The CF3O functional group is a unique fluorinated group that has received a great deal of attention in medicinal chemistry and agrochemistry. However, trifluoromethoxylation of substrates remains a challenging task. Herein we describe the dehydroxytrifluoromethoxylation of alcohols promoted by a R3P/ICH2CH2I (R3P = Ph3P or Ph2PCH=CH2) system in DMF. P-I halogen bonding drives the reaction of R3P with ICH2CH2I in DMF to generate iodophosphonium salt (R3P+I I−) and a Vilsmeier-Haack-type intermediate, both of which could effectively activate alcohols, thus enabling a fast (15 min) trifluoromethoxylation reaction. A wide substrate scope and a high level of functional group tolerance were observed. The CF3O functional group is a unique fluorinated group that has received a great deal of attention in medicinal chemistry and agrochemistry. However, trifluoromethoxylation of substrates remains a challenging task. Herein we describe the dehydroxytrifluoromethoxylation of alcohols promoted by a R3P/ICH2CH2I (R3P = Ph3P or Ph2PCH=CH2) system in DMF. P-I halogen bonding drives the reaction of R3P with ICH2CH2I in DMF to generate iodophosphonium salt (R3P+I I−) and a Vilsmeier-Haack-type intermediate, both of which could effectively activate alcohols, thus enabling a fast (15 min) trifluoromethoxylation reaction. A wide substrate scope and a high level of functional group tolerance were observed. The trifluoromethoxy group (CF3O) has received a great deal of attention in medicinal chemistry and agrochemistry (Jeschke et al., 2007Jeschke P. Baston E. Leroux F.R. α-Fluorinated ethers as exotic entity in medicinal chemistry.Mini. Rev. Med. Chem. 2007; 7: 1027-1034Crossref PubMed Scopus (103) Google Scholar) because of its strong electron-withdrawing nature and high lipophilicity (Hansch et al., 1973Hansch C. Leo A. Unger S.H. Kim K.H. Nikaitani D. Lien E.J. Aromatic substituent constants for structure-activity correlations.J. Med. Chem. 1973; 16: 1207-1216Crossref PubMed Scopus (1397) Google Scholar). CF3O-containing pharmaceuticals and agrochemicals such as Delamanid, Riluzole, Sonidegib, Metaflumizone, and Indoxacarb have been continuously developed. The high demand for biologically active molecules has stimulated significant efforts to develop efficient methods for the installation of trifluoromethoxy functionality (Landelle et al., 2014Landelle G. Panossian A. Leroux F. Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery.Curr. Top. Med. Chem. 2014; 14: 941-951Crossref PubMed Scopus (245) Google Scholar, Lin et al., 2015Lin J.-H. Ji Y.-L. Xiao J.-C. Recent advances in C-H trifluoromethylthiolation and trifluoromethoxylation reactions.Curr. Org. Chem. 2015; 19: 1541-1553Crossref Scopus (38) Google Scholar, Tlili et al., 2016Tlili A. Toulgoat F. Billard T. Synthetic approaches to trifluoromethoxy-substituted compounds.Angew. Chem. Int. Ed. 2016; 55: 11726-11735Crossref PubMed Scopus (152) Google Scholar). However, the installation of such functionality remains a challenging task. Traditional approaches including chlorine-fluorine exchange (Feiring, 1979Feiring A.E. Chemistry in hydrogen fluoride. 7. A novel synthesis of aryl trifluoromethyl ethers.J. Org. Chem. 1979; 44: 2907-2910Crossref Scopus (108) Google Scholar, Salomé et al., 2004Salomé J. Mauger C. Brunet S. Schanen V. Synthesis conditions and activity of various Lewis acids for the fluorination of trichloromethoxy-benzene by HF in liquid phase.J. Fluor. Chem. 2004; 125: 1947-1950Crossref Scopus (33) Google Scholar) and deoxyfluorination (Sheppard, 1964Sheppard W.A. α-fluorinated ethers. I. Aryl fluoroalkylEthers1.J. Org. Chem. 1964; 29: 1-11Crossref Scopus (106) Google Scholar) suffer from harsh reaction conditions and narrow substrate scopes. Trifluoromethylation of alcohols is quite effective and has received increasing attention (Brantley et al., 2016Brantley J.N. Samant A.V. Toste F.D. Isolation and reactivity of trifluoromethyliodonium salts.ACS Cent. Sci. 2016; 2: 341-350Crossref PubMed Scopus (67) Google Scholar, Koller et al., 2009Koller R. Stanek K. Stolz D. Aardoom R. Niedermann K. Togni A. Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents.Angew. Chem. Int. Ed. 2009; 48: 4332-4336Crossref PubMed Scopus (251) Google Scholar, Umemoto et al., 2007Umemoto T. Adachi K. Ishihara S. CF3oxonium salts, O-(Trifluoromethyl)dibenzofuranium salts: in situ synthesis, properties, and application as a real cf3+ species reagent.J. Org. Chem. 2007; 72: 6905-6917Crossref PubMed Scopus (177) Google Scholar). Recently, Qing and co-workers realized trifluoromethylation of phenols (Liu et al., 2015aLiu J.B. Chen C. Chu L. Chen Z.H. Xu X.H. Qing F.-L. Silver-mediated oxidative trifluoromethylation of phenols: direct synthesis of aryl trifluoromethyl ethers.Angew. Chem. Int. Ed. 2015; 54: 11839-11842Crossref PubMed Scopus (109) Google Scholar) and alcohols (Liu et al., 2015bLiu J.B. Xu X.H. Qing F.-L. Silver-mediated oxidative trifluoromethylation of alcohols to alkyl trifluoromethyl ethers.Org. Lett. 2015; 17: 5048-5051Crossref PubMed Scopus (74) Google Scholar) based on the concept of oxidative trifluoromethylation (Chu and Qing, 2014Chu L. Qing F.-L. Oxidative Trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl)trimethylsilane as a nucleophilicCF3 source.Acc. Chem. Res. 2014; 47: 1513-1522Crossref PubMed Scopus (576) Google Scholar). Wide substrate scopes were observed, but the use of strong oxidants was required. Compared with trifluoromethylation of alcohols, direct trifluoromethoxylation would also be an efficient and straightforward strategy and thus is highly desirable. Trifluoromethoxylation strategies include transition-metal-promoted, radical, and nucleophilic reactions (Scheme 1, Equation 1). After the pioneering work on Ag-mediated (Chen et al., 2015bChen S. Huang Y. Fang X. Li H. Zhang Z. Hor T.S.A. Weng Z. Aryl-BIAN-ligated silver(I) trifluoromethoxide complex.Dalton Trans. 2015; 44: 19682-19686Crossref PubMed Google Scholar, Huang et al., 2011Huang C. Liang T. Harada S. Lee E. Ritter T. Silver-Mediated trifluoromethoxylation of aryl stannanes and arylboronic acids.J. Am. Chem. Soc. 2011; 133: 13308-13310Crossref PubMed Scopus (158) Google Scholar, Zha et al., 2016Zha G.F. Han J.B. Hu X.Q. Qin H.L. Fang W.Y. Zhang C.-P. Silver-mediated direct trifluoromethoxylation of alpha-diazo esters via the -OCF3 anion.Chem. Commun. 2016; 52: 7458-7461Crossref PubMed Google Scholar) and Pd-catalyzed (Chen et al., 2015aChen C. Chen P. Liu G. Palladium-catalyzed intramolecular aminotrifluoromethoxylation of alkenes.J. Am. Chem. Soc. 2015; 137: 15648-15651Crossref PubMed Scopus (105) Google Scholar) trifluoromethoxylation, a breakthrough in transition-metal-promoted approaches was reported recently by Tang, who described a Ag-catalyzed asymmetric intermolecular bromotrifluoromethoxylation of alkenes with trifluoromethylarylsulfonate (TFMS) (Guo et al., 2017Guo S. Cong F. Guo R. Wang L. Tang P. Asymmetric silver-catalysed intermolecular bromotrifluoromethoxylation of alkenes with a new trifluoromethoxylation reagent.Nat. Chem. 2017; 9: 546-551Crossref PubMed Scopus (90) Google Scholar). The need for a hazardous agent, CF3OX (X=F, Cl, etc.), limits the applicability of conventional radical approaches (Tlili et al., 2016Tlili A. Toulgoat F. Billard T. Synthetic approaches to trifluoromethoxy-substituted compounds.Angew. Chem. Int. Ed. 2016; 55: 11726-11735Crossref PubMed Scopus (152) Google Scholar). On the basis of their discovery of intramolecular CF3O migration of N-OCF3 substrates (Feng et al., 2016Feng P. Lee K.N. Lee J.W. Zhan C. Ngai M.-Y. Access to a new class of synthetic building blocks via trifluoromethoxylation of pyridines and pyrimidines.Chem. Sci. 2016; 7: 424-429Crossref PubMed Google Scholar, Hojczyk et al., 2014Hojczyk K.N. Feng P. Zhan C. Ngai M.-Y. Trifluoromethoxylation of Arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.Angew. Chem. Int. Ed. 2014; 53: 14559-14563Crossref PubMed Scopus (112) Google Scholar, Lee et al., 2016aLee K.N. Lee J.W. Ngai M.-Y. Synthesis of trifluoromethoxylated (hetero)arenes via OCF3 migration.Synlett. 2016; 27: 313-319PubMed Google Scholar, Lee et al., 2016bLee K.N. Lei Z. Morales-Rivera C.A. Liu P. Ngai M.-Y. Mechanistic studies on intramolecular C-H trifluoromethoxylation of (hetero)arenes via OCF3-migration.Org. Biomol. Chem. 2016; 14: 5599-5605Crossref PubMed Google Scholar), Ngai developed an N-OCF3-type reagent to achieve radical trifluoromethoxylation (Zheng et al., 2018Zheng W. Morales-Rivera C.A. Lee J.W. Liu P. Ngai M.Y. Catalytic C-H trifluoromethoxylation of arenes and heteroarenes.Angew. Chem. Int. Ed. 2018; https://doi.org/10.1002/anie.201800598Crossref PubMed Scopus (67) Google Scholar). The nucleophilic reaction is also a widely used strategy (Feng et al., 2016Feng P. Lee K.N. Lee J.W. Zhan C. Ngai M.-Y. Access to a new class of synthetic building blocks via trifluoromethoxylation of pyridines and pyrimidines.Chem. Sci. 2016; 7: 424-429Crossref PubMed Google Scholar, Hojczyk et al., 2014Hojczyk K.N. Feng P. Zhan C. Ngai M.-Y. Trifluoromethoxylation of Arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.Angew. Chem. Int. Ed. 2014; 53: 14559-14563Crossref PubMed Scopus (112) Google Scholar, Jiang et al., 2018Jiang X. Deng Z. Tang P. Direct dehydroxytrifluoromethoxylation of alcohols.Angew. Chem. Int. Ed. 2018; 57: 292-295Crossref PubMed Scopus (42) Google Scholar, Lee et al., 2016bLee K.N. Lei Z. Morales-Rivera C.A. Liu P. Ngai M.-Y. Mechanistic studies on intramolecular C-H trifluoromethoxylation of (hetero)arenes via OCF3-migration.Org. Biomol. Chem. 2016; 14: 5599-5605Crossref PubMed Google Scholar, Marrec et al., 2010aMarrec O. Billard T. Vors J.-P. Pazenok S. Langlois B.R. A deeper insight into direct trifluoromethoxylation with trifluoromethyltriflate.J. Fluor. Chem. 2010; 131: 200-207Crossref Scopus (68) Google Scholar, Marrec et al., 2010bMarrec O. Billard T. Vors J.-P. Pazenok S. Langlois B.R. A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-dinitro(trifluoromethoxy)benzene.Adv. Synth. Catal. 2010; 352: 2831-2837Crossref Scopus (59) Google Scholar, Zhou et al., 2018Zhou M. Ni C. Zeng Y. Hu J. Trifluoromethyl benzoate: a versatile trifluoromethoxylation reagent.J. Am. Chem. Soc. 2018; 140: 6801-6805Crossref PubMed Scopus (79) Google Scholar). Hu recently developed a mild nucleophilic trifluoromethoxylation reagent and applied this reagent to trifluoromethoxylation of arynes to give CF3O arenes (Zhou et al., 2018Zhou M. Ni C. Zeng Y. Hu J. Trifluoromethyl benzoate: a versatile trifluoromethoxylation reagent.J. Am. Chem. Soc. 2018; 140: 6801-6805Crossref PubMed Scopus (79) Google Scholar). Because the trifluoromethoxy anion (CF3O−) would readily undergo decomposition to produce carbonyl fluoride (CF2=O), which is an electrophilic species that could react with alcohols to form fluoroformate, Tang used TFMS to generate trifluoromethoxy anions followed by carbonyl fluoride to activate alcohols, allowing for the subsequent dehydroxylative nucleophilic trifluoromethoxylation (Jiang et al., 2018Jiang X. Deng Z. Tang P. Direct dehydroxytrifluoromethoxylation of alcohols.Angew. Chem. Int. Ed. 2018; 57: 292-295Crossref PubMed Scopus (42) Google Scholar). Owing to the high instability of the key trifluoromethoxy intermediates, including CF3O− and CF3OM (M = metal), trifluoromethoxylation reactions usually have to be performed at low temperatures (room temperature or even lower), and therefore long reaction times are usually required (>10 hr in most cases) to overcome the free energy barriers. Alcohols are readily available starting materials; therefore, trifluoromethoxylation of alcohols would be an attractive protocol for the installation of CF3O moiety. In continuation of our research interest in the chemistry of RFX (RF = fluoroalkyl group; X = heteroatom) installation (Yu et al., 2017Yu J. Lin J.-H. Xiao J.-C. Reaction of thiocarbonyl fluoride generated from difluorocarbene with amines.Angew. Chem. Int. Ed. 2017; 56: 16669-16673Crossref PubMed Scopus (72) Google Scholar, Zheng et al., 2015Zheng J. Wang L. Lin J.-H. Xiao J.-C. Liang S.H. Difluorocarbene-derived trifluoromethylthiolation and [18F]trifluoromethylthiolation of aliphatic electrophiles.Angew. Chem. Int. Ed. 2015; 54: 13236-13240Crossref PubMed Scopus (87) Google Scholar, Zheng et al., 2017Zheng J. Cheng R. Lin J.-H. Yu D.H. Ma L. Jia L. Zhang L. Wang L. Xiao J.-C. Liang S.H. An unconventional mechanistic insight into SCF3 formation from difluorocarbene: preparation of 18F-labeled alpha-SCF3 carbonyl compounds.Angew. Chem. Int. Ed. 2017; 56: 3196-3200Crossref PubMed Scopus (72) Google Scholar), we have now investigated the trifluoromethoxylation of alcohols. We found that the Ph3P/ICH2CH2I system could effectively activate the hydroxyl group to achieve dehydroxytrifluoromethoxylation of alcohols with the CF3O− anion. In contrast to Tang's approach for the dehydroxytrifluoromethoxylation, which required a reaction time of 26 hr (Jiang et al., 2018Jiang X. Deng Z. Tang P. Direct dehydroxytrifluoromethoxylation of alcohols.Angew. Chem. Int. Ed. 2018; 57: 292-295Crossref PubMed Scopus (42) Google Scholar), the reaction in our protocol proceeded very rapidly, and full conversion was observed within 15 min (Scheme 1, Equation 2). Our initial attempt at the trifluoromethoxylation of alcohol 1a was successful with the use of the Ph3P/ICH2CH2I system in slight excess (Table 1, entry 1). A brief survey of the reaction solvent (entries 1–4) revealed that N,N-dimethylformamide (DMF) was a suitable solvent. Elevating the reaction temperature from 60°C to 80°C increased the yield to 65% (entry 6). A higher or lower temperature resulted in lower yields (entry 6 versus entries 1, 5, and 7). A good yield was obtained by increasing the loading of AgOCF3 (entry 8). Decreasing or increasing the loading of Ph3P/ICH2CH2I led to a slight decrease in the yield (entries 9 and 10). The reaction was monitored using 19F nuclear magnetic resonance (NMR) spectroscopy; surprisingly, a good yield was obtained within 15 min (entry 12). Because the key trifluoromethoxylation intermediates are so fragile, the trifluoromethoxylation reactions usually have to be performed under an inert gas atmosphere. To our delight, the expected product could be obtained in 63% yield (entry 13) even if the reaction was performed in an unsealed tube (the reaction system was exposed to air). The use of CsOCF3 instead of AgOCF3 could give a moderate yield, indicating that the silver ion is not essential for this reaction (entry 14).Table 1Optimization of Reaction ConditionsEntryaReaction conditions: substrate 1a (0.1 mmol), AgOCF3, Ph3P and ICH2CH2I in DMF (1.5 mL) at the indicated temperature under a N2 atmosphere.Molar RatiobMolar ratio of 1a:AgOCF3:Ph3P:ICH2CH2I.SolventTemperature (°C)TimeYield (%)cThe yields were determined by 19F NMR spectroscopy.11:3.0:1.4:1.4DMF605 hr3621:3.0:1.4:1.4DMSO605 hrtrace31:3.0:1.4:1.4NMP605 hr2141:3.0:1.4:1.4Toluene605 hr1451:3.0:1.4:1.4DMF705 hr4561:3.0:1.4:1.4DMF805 hr6571:3.0:1.4:1.4DMF905 hr6081:4.0:1.4:1.4DMF805 hr8091:4.0:1.2:1.2DMF805 hr73101:4.0:1.6:1.6DMF805 hr75111:4.0:1.4:1.4DMF801 hr76121:4.0:1.4:1.4DMF8015 min7813dThe reaction was performed in an unsealed tube (exposed to air).1:4.0:1.4:1.4DMF8015 min6314eCsOCF3 was used instead of AgOCF3; rt, room temperature.1:3.5:1.5:1.5DMFRt14 hr50NMP, 1-methylpyrrolidin-2-one.a Reaction conditions: substrate 1a (0.1 mmol), AgOCF3, Ph3P and ICH2CH2I in DMF (1.5 mL) at the indicated temperature under a N2 atmosphere.b Molar ratio of 1a:AgOCF3:Ph3P:ICH2CH2I.c The yields were determined by 19F NMR spectroscopy.d The reaction was performed in an unsealed tube (exposed to air).e CsOCF3 was used instead of AgOCF3; rt, room temperature. Open table in a new tab NMP, 1-methylpyrrolidin-2-one. With the optimized reaction conditions in hand (Table 1, entry 12), we then investigated the substrate scope of the dehydroxytrifluoromethoxylation of alcohols. As shown in Scheme 2, a wide substrate scope and a high level of functional group tolerance were observed. The conversion of various benzyl alcohols occurred smoothly. Electron-rich, electron-neutral, and electron-deficient substrates could be converted into the desired products in moderate to good yields (2a-2p). The transformation was not very sensitive to steric effects, as evidenced by the moderate yields of products 2e, 2g, and 2h. CF3O-containing heteroarenes could be synthesized by this protocol (2q-2s). Besides benzyl alcohols, allyl alcohols (2t) and propargyl alcohols (2u) also underwent the expected conversion under these conditions. Compared with primary alcohols, lower yields were obtained for secondary alcohols (2v-2x). However, the optimal conditions were not suitable for efficient dehydroxytrifluoromethoxylation of alkyl alcohols (3a). The low yield of product 3a prompted us to further optimize the reaction conditions for the conversion of alkyl alcohols. After a detailed survey of the reaction conditions (see Supplemental Information, Table S1), we found that the replacement of triphenylphosphine with diphenyl(vinyl)phosphane (Ph2PCH=CH2) at a reaction temperature of 60°C could afford the expected product in 60% yield (3a). A good isolated yield (76%) was obtained by elevating the reaction temperature to 100°C. The substrate scope was then investigated under the optimal conditions (Scheme 3). Like the reaction of benzyl alcohols, the transformation of alkyl alcohols proceeded rapidly, and a 15-min reaction time provided moderate to good yields (3a-3k). Heteroarene-containing alcohols could also be well converted (3g-3i). The conversion of primary alcohols proceeded smoothly, but secondary alcohols could not be effectively transformed (3l). Although iodide anion could also act as a nucleophile, no iodination product was observed in the above dehydroxytrifluoromethoxylation reactions. This is because iodide anion was excluded from the reaction system by forming AgI precipitate and C-OCF3 bond may be formed in preference to C-I bond due to the higher C-O bond strength. Apparently, the R3P/ICH2CH2I (R3P=Ph3P or Ph2PCH=CH2) system in DMF generates key intermediates that could activate alcohols in this dehydroxytrifluoromethoxylation reaction. Both Ph3P and Ph2PCH=CH2 react very quickly with ICH2CH2I in DMF. The mixing of Ph3P and ICH2CH2I in DMF would immediately lead to the full consumption of both Ph3P and ICH2CH2I. ICH2CH2I was converted into ethylene, which was detected by 1H NMR spectroscopy, and Ph3P was transformed into Ph3P=O and an unknown species A (δ = 11.9 ppm), as detected by 31P NMR spectroscopy (Figure 1A ). The processes were too quick, which did not allow us to determine and understand how the Ph3P=O and species A were formed. Fortunately, the reaction of Ph3P with ICH2CH2I occurred slowly in chloroform (CHCl3) probably due to its lower polarity. CDCl3 was then used as the reaction solvent to determine what the Ph3P/ICH2CH2I system would be transformed into. After stirring the mixture at room temperature for 15 hr, three phosphorus species were observed, which were determined to be iodophosphonium salt B[Ph3P+I I−] (Garegg et al., 1987Garegg P.J. Regberg T. Stawinski J. Stroemberg R. A phosphorus nuclear magnetic resonance spectroscopic study of the conversion of hydroxy groups into iodo groups in carbohydrates using the iodine-triphenylphosphine-imidazole reagent.J. Chem. Soc. Perkin Trans. 1987; 2: 271-274Crossref Google Scholar, Morcillo et al., 2011Morcillo S.P. Alvarez de Cienfuegos L. Mota A.J. Justicia J. Robles R. Mild method for the selective esterification of carboxylic acids based on the Garegg-Samuelsson reaction.J. Org. Chem. 2011; 76: 2277-2281Crossref PubMed Scopus (51) Google Scholar), triphenylphosphine, and diiodotriphenylphosphane C (Ph3PI2) (Garegg et al., 1987Garegg P.J. Regberg T. Stawinski J. Stroemberg R. A phosphorus nuclear magnetic resonance spectroscopic study of the conversion of hydroxy groups into iodo groups in carbohydrates using the iodine-triphenylphosphine-imidazole reagent.J. Chem. Soc. Perkin Trans. 1987; 2: 271-274Crossref Google Scholar) based on the reported corresponding phosphorus signals (Figure 1B). ICH2CH2I was almost completely converted into CH2=CH2, as detected by 1H NMR spectroscopy. The large amount of Ph3P that remained was because of the reversible equilibrium between Ph3P and Ph3PI2 (Ph3PI2⇄Ph3P + I2) (Morcillo et al., 2011Morcillo S.P. Alvarez de Cienfuegos L. Mota A.J. Justicia J. Robles R. Mild method for the selective esterification of carboxylic acids based on the Garegg-Samuelsson reaction.J. Org. Chem. 2011; 76: 2277-2281Crossref PubMed Scopus (51) Google Scholar), otherwise Ph3P would have been almost fully consumed. The formation of species B and C was due to strong P-I halogen bonding (Gilday et al., 2015Gilday L.C. Robinson S.W. Barendt T.A. Langton M.J. Mullaney B.R. Beer P.D. Halogen bonding in supramolecular chemistry.Chem. Rev. 2015; 115: 7118-7195Crossref PubMed Scopus (900) Google Scholar). Although triphenylphosphine may easily undergo quaternization with alkyl iodides to give alkylphosphonium salts, 1,2-diiodoethane acted as a halogen bond donor to form a halogen bond with triphenylphosphine (Scheme 4, Equation 1), instead of alkylating triphenylphosphine. The driving force for the halogen bonding was the generation of small ethylene molecules and the good leaving ability of the iodide anion. An equilibrium between B and C explained the observation of C. Clearly, the reaction solvent DMF was involved in the formation of Ph3P=O and species A from intermediate B (Equation 2). Intermediate A should be a complex formed by the coordination of intermediate B with DMF, because intermediate B can be considered as a Lewis acid. This coordination activated DMF and allowed for the attack of an iodide anion at the amide carbon to produce intermediate D, which could readily undergo C–O bond cleavage to release Ph3P=O and a Vilsmeier-Haack-type intermediate E. Because it is known that the Vilsmeier-Haack-type intermediate could well activate hydroxyl groups (Dai et al., 2011Dai C. Narayanam J.M. Stephenson C.R. Visible-light-mediated conversion of alcohols to halides.Nat. Chem. 2011; 3: 140-145Crossref PubMed Scopus (295) Google Scholar, Hepburn and Hudson, 1976Hepburn D.R. Hudson H.R. Factors in the formation of isomerically and optically pure alkyl halides. Part XI. Vilsmeier reagents for the replacement of a hydroxy-group by chlorine or bromine.J. Chem. Soc. Perkin Trans. 1976; 1: 754-757Crossref Scopus (95) Google Scholar), the question arises as to whether species E was the only intermediate that activated the alcohols in the above trifluoromethoxylation reaction. If yes, the only oxygen source for the Ph3P=O by-product was the reaction solvent DMF. However, the conversion of 18O-labeled alcohol 1a showed that Ph3P=18O was also obtained (Scheme 5), suggesting that another key intermediate was involved in the activation of the alcohols. The intermediate involved should be species A, because iodophosphonium salts have been proved to be powerful intermediates for the activation of alcohols (Appel, 1975Appel R. Tertiary phosphane/tetrachloromethane, a versatile reagent for chlorination, dehydration, and P-N linkage.Angew. Chem. Int. Ed. 1975; 14: 801-811Crossref Scopus (933) Google Scholar, de Andrade and de Mattos, 2015de Andrade V.S.C. de Mattos M.C.S. New reagents and synthetic approaches to the Appel reaction.Curr. Org. Synth. 2015; 12: 309-327Crossref Scopus (34) Google Scholar) and this species was also converted into Ph3P=O in the dehydroxytrifluoromethoxylation reaction. No 18O-labeled trifluoromethoxylation product was observed, which indicated that this reaction was a dehydroxylation process. Based on the above results, we proposed a plausible reaction mechanism, as shown in Scheme 6. The P-I halogen bonding drives the formation of iodophosphonium salt B, which immediately coordinates with the reaction solvent DMF to form complex A. Ligand exchange of an alcohol with a DMF molecule in complex A furnishes complex G. The alcohol is then activated by coordination and would be easily attacked by a trifluoromethoxy anion generated from AgOCF3 by precipitating AgI, giving the final trifluoromethoxylation product. On the other hand, complex A could also undergo P-O bond formation to release Ph3P=O and the Vilsmeier-Haack-type intermediate E. Intermediate E could activate the alcohols by forming intermediate F, at which the attack of trifluoromethoxy anion also afforded the final product. The generation of the racemic product 2v from enantiopure alcohol indicated that the final attack at G or F may involve an SN1 process (see Supplemental Information, Procedure D. See also Figure S91). As it has been reported that iodophosphonium salt B (Ph3P+-I I−) could also be formed by the reaction of Ph3P with I2 (Morcillo et al., 2011Morcillo S.P. Alvarez de Cienfuegos L. Mota A.J. Justicia J. Robles R. Mild method for the selective esterification of carboxylic acids based on the Garegg-Samuelsson reaction.J. Org. Chem. 2011; 76: 2277-2281Crossref PubMed Scopus (51) Google Scholar, Pathak and Rokhum, 2015Pathak G. Rokhum L. Selective monoesterification of symmetrical diols using resin-bound triphenylphosphine.ACS Comb. Sci. 2015; 17: 483-487Crossref PubMed Scopus (17) Google Scholar), I2 was then used instead of ICH2CH2I in the dehydroxytrifluoromethoxylation reaction (Scheme 7). Desired products were obtained for the conversion of both benzyl alcohol 1a (Equation 1) and alkyl alcohol 1a’ (Equation 2), further supporting the proposed mechanism. Compared with the R3P/I2 system, which is not quite effective for the conversion of alkyl alcohols (Equation 2) and suffers from the toxicity of I2, the R3P/ICH2CH2I system is more attractive due to the high efficiency for dehydroxytrifluoromethoxylation. In addition, the P-I halogen bond between a trivalent phosphine and an alkyl iodide is quite unusual, and this unexpected observation may offer new opportunities for other chemistry. In summary, we have described the dehydroxytrifluoromethoxylation of alcohols promoted by a R3P/ICH2CH2I system in DMF. The combination of R3P and ICH2CH2I in DMF could rapidly activate alcohols, resulting in the successful development of an efficient protocol for fast trifluoromethoxylation. A moderate yield was obtained even if the reaction was performed under an air atmosphere. The convenient Ph3P/ICH2CH2I system in DMF for highly effective dehydroxylation may find synthetic utility in other research areas. All methods can be found in the accompanying Transparent Methods supplemental file. We thank the National Basic Research Program of China (2015CB931903), the National Natural Science Foundation (21421002, 21472222, 21502214, 21672242), the Chinese Academy of Sciences (XDA02020105, XDA02020106), Key Research Program of Frontier Sciences (CAS) (QYZDJ-SSW-SLH049), and the Syngenta PhD Fellowship awarded to W.Z. for financial support. W.Z. and J.C. performed the experiments. J.-H.L. analyzed the data and wrote the manuscript. J.-C.X. designed the experiments and wrote the manuscript. Y.-C.G. designed some experiments. There are no conflicts to declare. Download .pdf (5.33 MB) Help with pdf files Document S1. Transparent Methods, Figures S1–S91, and Table S1" @default.
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• W2850356645 title "Rapid Dehydroxytrifluoromethoxylation of Alcohols" @default.
• W2850356645 cites W1738832878 @default.
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