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Rapid Dehydroxytrifluoromethoxylation of Alcohols

Summary 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.


INTRODUCTION
The trifluoromethoxy group (CF 3 O) has received a great deal of attention in medicinal chemistry and agrochemistry (Jeschke et al., 2007) because of its strong electron-withdrawing nature and high lipophilicity (Hansch et al., 1973). CF 3 O-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., 2014;Lin et al., 2015;Tlili et al., 2016). However, the installation of such functionality remains a challenging task. Traditional approaches including chlorine-fluorine exchange (Feiring, 1979;Salomé et al., 2004) and deoxyfluorination (Sheppard, 1964) suffer from harsh reaction conditions and narrow substrate scopes. Trifluoromethylation of alcohols is quite effective and has received increasing attention (Brantley et al., 2016;Koller et al., 2009;Umemoto et al., 2007). Recently, Qing and co-workers realized trifluoromethylation of phenols (Liu et al., 2015a) and alcohols (Liu et al., 2015b) based on the concept of oxidative trifluoromethylation (Chu and Qing, 2014). 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., 2015b;Huang et al., 2011;Zha et al., 2016) and Pd-catalyzed (Chen et al., 2015a) 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., 2017). The need for a hazardous agent, CF 3 OX (X=F, Cl, etc.), limits the applicability of conventional radical approaches (Tlili et al., 2016). On the basis of their discovery of intramolecular CF 3 O migration of N-OCF 3 substrates (Feng et al., 2016;Hojczyk et al., 2014;Lee et al., 2016aLee et al., , 2016b, Ngai developed an N-OCF 3 -type reagent to achieve radical trifluoromethoxylation (Zheng et al., 2018). The nucleophilic reaction is also a widely used strategy (Feng et al., 2016;Hojczyk et al., 2014;Jiang et al., 2018;Lee et al., 2016b;Marrec et al., 2010aMarrec et al., , 2010bZhou et al., 2018). Hu recently developed a mild nucleophilic trifluoromethoxylation reagent and applied this reagent to trifluoromethoxylation of arynes to give CF 3 O arenes (Zhou et al., 2018). Because the trifluoromethoxy anion (CF 3 O À ) would readily undergo decomposition to produce carbonyl fluoride (CF 2 =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., 2018). Owing to the high instability of the key trifluoromethoxy intermediates, including CF 3 O À and CF 3 OM (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 CF 3 O moiety. In continuation of our research interest in the chemistry of R F X (R F = fluoroalkyl group; X = heteroatom) installation (Yu et al., 2017;Zheng et al., 2015Zheng et al., , 2017, we have now investigated the trifluoromethoxylation of alcohols. We found that the Ph 3 P/ICH 2 CH 2 I system could effectively activate the hydroxyl group to achieve dehydroxytrifluoromethoxylation of alcohols with the CF 3 O À anion. In contrast to Tang's approach for the dehydroxytrifluoromethoxylation, which required a reaction time of 26 hr (Jiang et al., 2018), the reaction in our protocol proceeded very rapidly, and full conversion was observed within 15 min (Scheme 1, Equation 2).

The Optimization of Reaction Conditions
Our initial attempt at the trifluoromethoxylation of alcohol 1a was successful with the use of the Ph 3 P/ICH 2 CH 2 I system in slight excess ( 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 AgOCF 3 (entry 8). Decreasing or increasing the loading of Ph 3 P/ICH 2 CH 2 I led to a slight decrease in the yield (entries 9 and 10). The reaction was monitored using 19 F 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 CsOCF 3 instead of AgOCF 3 could give a moderate yield, indicating that the silver ion is not essential for this reaction (entry 14).

Substrate Scope Investigation
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. CF 3 O-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 (Ph 2 PCH=CH 2 ) 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-OCF 3 bond may be formed in preference to C-I bond due to the higher C-O bond strength.

Mechanistic Investigations
Apparently, the R 3 P/ICH 2 CH 2 I (R 3 P=Ph 3 P or Ph 2 PCH=CH 2 ) system in DMF generates key intermediates that could activate alcohols in this dehydroxytrifluoromethoxylation reaction. Both Ph 3 P and Ph 2 PCH=CH 2 react very quickly with ICH 2 CH 2 I in DMF. The mixing of Ph 3 P and ICH 2 CH 2 I in DMF would immediately lead to the full consumption of both Ph 3 P and ICH 2 CH 2 I. ICH 2 CH 2 I was converted into ethylene, which was detected by 1 H NMR spectroscopy, and Ph 3 P was transformed into Ph 3 P=O and an unknown species A (d = 11.9 ppm), as detected by 31 P NMR spectroscopy ( Figure 1A). The processes were too quick, which did not allow us to determine and understand how the Ph 3 P=O and species A were formed. Fortunately, the reaction of Ph 3 P with ICH 2 CH 2 I occurred slowly in chloroform (CHCl 3 ) probably due to its lower polarity. CDCl 3 was then used as the reaction solvent to determine what the Ph 3 P/ICH 2 CH 2 I system would be transformed into. Scheme 3. Dehydroxytrifluoromethoxylation of Alkyl Alcohols Isolated yields. Reaction conditions: alcohol 1 (0.5 mmol), AgOCF 3 (2.0 mmol), Ph 2 PCH=CH 2 (1.3 mmol), ICH 2 CH 2 I (0.6 mmol), DMF (3 mL), 100 C, 15 min, N 2 atmosphere. The yield of product 3i was determined by 19 F NMR spectroscopy. See also Figures S61-S88.
iScience 5, 110-117, July 27, 2018 113 the reported corresponding phosphorus signals ( Figure 1B). ICH 2 CH 2 I was almost completely converted into CH 2 =CH 2 , as detected by 1 H NMR spectroscopy. The large amount of Ph 3 P that remained was because of the reversible equilibrium between Ph 3 P and Ph 3 PI 2 (Ph 3 PI 2 %Ph 3 P + I 2 ) (Morcillo et al., 2011), otherwise Ph 3 P would have been almost fully consumed.
The formation of species B and C was due to strong P-I halogen bonding (Gilday et al., 2015). 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 Ph 3 P=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 Ph 3 P=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., 2011;Hepburn and Hudson, 1976), 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 Ph 3 P=O by-product was the reaction solvent DMF. However, the conversion of 18 O-labeled alcohol 1a showed that Ph 3 P= 18 O was also obtained (Scheme 5), suggesting that another key intermediate was  (Appel, 1975;de Andrade and de Mattos, 2015) and this species was also converted into Ph 3 P=O in the dehydroxytrifluoromethoxylation reaction. No 18 O-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 AgOCF 3 by precipitating AgI, giving the final trifluoromethoxylation product. On the other hand, complex A could also undergo P-O bond formation to release Ph 3 P=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 S N 1 process (see Supplemental Information, Procedure D. See also Figure S91).
As it has been reported that iodophosphonium salt B (Ph 3 P + -I I À ) could also be formed by the reaction of Ph 3 P with I 2 (Morcillo et al., 2011;Pathak and Rokhum, 2015), I 2 was then used instead of ICH 2 CH 2 I 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 R 3 P/I 2 system, which is not quite effective for the conversion of alkyl alcohols (Equation 2) and suffers from the toxicity of I 2 , the R 3 P/ICH 2 CH 2 I 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.

DISCUSSION
In summary, we have described the dehydroxytrifluoromethoxylation of alcohols promoted by a R 3 P/ICH 2 CH 2 I system in DMF. The combination of R 3 P and ICH 2 CH 2 I 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 Ph 3 P/ICH 2 CH 2 I system in DMF for highly effective dehydroxylation may find synthetic utility in other research areas.   Table   Table S1. Screening conditions for trifluoromethoxylation of alkyl alcohols a , Related to Scheme 3  Chen et al., 2015 ) and 18 O-labeled alcohol 1a (Jiang et al., 2018) were prepared according to the literature procedures.

Scheme 2
Into the solution of alcohol 1 (0.5 mmol, 1.0 equiv.) and Ph 3 P (0.7 mmol, 183.6 mg, 1.4 equiv.) in DMF (3 mL) was added 1,2-diiodoethane (0.7 mmol, 197.3 mg, 1.4 equiv) in a 10 mL sealed tube under N 2 atmosphere. After the reagents were completely dissolved, CH 3 CN-solvated AgOCF 3 (2.0 mmol, 2 mL, 1.0 M, 4.0 equiv) was added. The tube was sealed and the resulting mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperature and filtered through a plug of silica gel. The solid was washed with EtOAc. The filtrate was concentrated, and the residue was subjected to flash column chromatography to give product 2.

Procedure B for the dehydroxytrifluoromethoxylation of alkyl alcohols, Related to Scheme 3
Into the solution of alcohol 1 (0.5 mmol, 1.0 equiv.) and Ph 2 P(C 2 H 3 ) (1.3 mmol, 0.25 mL, 2.6 equiv.) in DMF (3 mL) was added 1,2-diiodoethane (0.6 mmol, 169.2 mg, 1.2 equiv) in a 10 mL sealed tube under N 2 atmosphere. After the reagents were completely dissolved, CH 3 CN-solvated AgOCF 3 (2.0 mmol, 2 mL, 1.0 M, 4.0 equiv) was added. The tube was sealed and the reaction mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperature and filtered through a plug of silica gel. The solid was washed with EtOAc. The filtrate was concentrated, and the residue was subjected to flash column chromatography to give product 3.

Procedure D for the conversion of an enantiopure alcohol, Related to Scheme 6
Into the solution of enantiopure alcohol 1v (0.5 mmol, 99 mg, 1.0 equiv.) and Ph 3 P (0.7 mmol, 183.6 mg, 1.4 equiv.) in DMF (3 mL) was added 1,2-diiodoethane (0.7 mmol 197.3 mg, 1.4 equiv) in a 10 mL sealed tube under N 2 atmosphere. After the reagents were completely dissolved, CH 3 CN-solvated AgOCF 3 (2.0 mmol, 2 mL, 1.0 M 4.0 equiv) was added. The tube was sealed and the reaction mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperature and filtered through a plug of silica gel. The solid was washed with EtOAc. The filtrate was concentrated, and the residue was subjected to flash column chromatography to give product 2v. Enantiomeric excess was determined by HPLC with a Chiralpak adh (0.46 x 25 cm, 5μm) (CO 2 :MeOH = 98:2, 21 nm, 2 mL/min); enantiomer rt = 2.695 min and 2.909 min. HPLC spectrum is shown in Figure S91.

Related to Scheme 7
Into the solution of alcohol (0.1 mmol, 1.0 equiv.) and Ph 3 P (0.14 mmol, 36.8 mg, 1.4 equiv.) in DMF (1.5 mL) was added molecular iodine (0.14 mmol, 35.5 mg, 1.4 equiv) in a 5 mL sealed tube under N 2 atmosphere. After the reagents were completely dissolved, CH 3 CN-solvated AgOCF 3 (0.4 mmol, 0.4 mL, 1.0 M, 4.0 equiv) was added. The tube was sealed and the resulting mixture was stirred at 80 °C for 15 min. S95 The reaction mixture was cooled to room temperature. The yield of product 2a was determined by 19 F NMR spectroscopy.
Into the solution of alcohol (0.1 mmol, 1.0 equiv.) and Ph 2 P(C 2 H 3 ) (0.26 mmol, 51 μL, 2.6 equiv.) in DMF (1.5 mL) was added molecular iodine (0.12 mmol, 30.5 mg, 1.2 equiv) in a 5 mL sealed tube under N 2 atmosphere. After the reagents were completely dissolved, CH 3 CN-solvated AgOCF 3 (0.4 mmol, 0.4 mL, 1.0 M, 4.0 equiv) was added. The tube was sealed and the reaction mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperature. The yield of product 3a was determined by 19 F NMR spectroscopy.