Yan Caoa,
Roya Ahmadi
*b,
Mohammad Reza Poor Heravi
c,
Alibek Issakhovde,
Abdol Ghaffar Ebadi
f and
Esmail Vessally
c
aSchool of Mechatronic Engineering, Xi'an Technological University, Xi'an, 710021, China
bDepartment of Chemistry, College of Basic Sciences, Yadegar-e-Imam Khomeini (RAH) Shahre Rey Branch, Islamic Azad University, Tehran, Iran. E-mail: roya_ahmadi_chem@yahoo.com
cDepartment of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran
dDepartment of Mathematical and Computer Modelling, al-Farabi Kazakh National University, 050040, Almaty, Kazakhstan
eDepartment of Mathematics and Cybernetics, Kazakh British Technical University, 050000, Almaty, Kazakhstan
fDepartment of Agriculture, Jouybar Branch, Islamic Azad University, Jouybar, Iran
First published on 13th December 2021
Owing to the prevalence of hydroxyl groups on molecules, much attention has been paid to the synthesis of functionalized organic compounds by dehydroxylative functionalization of parent alcohols. In this context, dehydroxylative trifluoromethylation, trifluoromethoxylation, trifluoromethylthiolation, and trifluoromethylselenylation of readily available alcohols have recently emerged as intriguing protocols for the single-step construction of diverse structures bearing C–CF3, C–OCF3, C–SCF3, and C–SeCF3 bonds, respectively. This Mini-Review aims to summarize the major progress and advances in this appealing research area with special emphasis on the mechanistic features of the reaction pathways.
In recent years, direct dehydroxylative functionalization of alcohols has become one of the hottest research topics in organic chemistry because it is a powerful and general strategy for the construction of various valuable functionalized organic compounds from inexpensive and abundantly available alcohols without isolation of intermediates.10 In this regard, dehydroxylative trifluoro-methylation, -methoxylation, -methylthiolation, and -methylselenylation of alcohols have captured the imagination of the organic chemical community and have become promising synthetic methods for constructing C–CF3, C–OCF3, C–SCF3, and C–SeCF3 bonds, respectively. These synthetic processes are advantageous because the starting materials possess high selectivity and stability, are abundant and inexpensive, with low toxicity, and there is no need for isolation of intermediates. In continuation of our interest in organofluorine chemistry11 and modern organic synthesis,12–18 in this Mini-Review, we will highlight the most important advances and progress in the arena of dehydroxylative trifluoro-methylation, -methoxylation, -methylthiolation, and -methylselenylation of alcohols (Scheme 2), with a particular emphasis on the mechanistic aspects of the reaction pathways.
Scheme 2 Direct dehydroxylative trifluoro-methylation, -methoxylation, -methylthiolation, and -methylselenylation of alcohols. |
Scheme 3 Cu-catalyzed deoxytrifluoromethylation of (a) allylic alcohols 1; (b) propargylic alcohols 4; and (c) (hetero)benzylic alcohols 6 with phenyl bromodifluoroacetate 2 developed by Altman. |
Scheme 4 The plausible mechanism for the reactions in Scheme 2. |
In another report, this research group also developed [1,1′-biphenyl]-4-yl-2-bromo-2,2-difluoroacetate (BBDFA) as an efficient trifluoromethylating reagent for Cu-catalyzed dehydroxylative trifluoromethylation of alcohols.21 The reagent was synthetized on a 100 g scale in 93% yield via chlorination of commercially available bromodifluoroacetic acid with oxalyl chloride in the presence of a catalytic amount of DMF, followed by esterification of the resulting acid chloride with 4-phenylphenol, and it showed good thermal stability and high ability for trifluoromethylation of examined alcohols. However, the usefulness of this reagent was only demonstrated by deoxytrifluoromethylation of cinnamyl alcohol and 2-naphthalenemethanol, without any substrate scope exploration.
Drawing inspiration from these works, very recently, the Wu group, in collaboration with the Xiao group, described an interesting Cu(0)-catalyzed dehydroxylative trifluoromethylation of a library of (hetero)benzylic alcohols 8 with Chen's reagent (methyl fluorosulfonyldifluoroacetate; 9) in the presence of the Ph3P/ICH2CH2I system, which acted as the activator of the hydroxyl group.22 The reactions were performed in DMF at 80 °C, tolerated a series of synthetically useful functionalities (e.g., –Br, –I, –CO2Me, –CN, –NO2), and provided the desired (2,2,2-trifluoroethyl)arenes 10 in modest to good yields (Scheme 5a).
Scheme 5 (a) Wu-Xiao's synthesis of (2,2,2-trifluoroethyl)arenes 10. (b) The proposed pathways for the formation of (2,2,2-trifluoroethyl)arenes 10. |
Regarding the influence of electronic effects of substituent groups in the phenyl ring periphery of benzylic alcohols, electron-rich substrates afforded higher yields compared to electron-poor ones. It is noteworthy that although aryl bromides remained intact under these conditions, undesired trifluoromethylation of C–I bonds was observed in the case of aryl iodides. Regrettably, alkyl alcohols did not exhibit reactivity under standard reaction conditions. It was noteworthy that under relatively similar conditions, dehydroxylative difluoromethylation and trifluoromethylthiolation of a diverse range of aliphatic alcohols with TMSCF2H and AgSCF3, respectively, also effectively proceeded to afford the corresponding difluoromethylated and trifluoromethylthiolated compounds in reasonable yields. While the detailed mechanistic picture remains unclear, the authors speculated that phosphonium A, iminium C, or (hetero)benzyl halide D might be key intermediates for this trifluoromethylation reaction (Scheme 5b).
Scheme 6 Metal-free direct dehydroxytrifluoromethoxylation of alcohols 11 with trifluoromethyl tosylate 12. |
Based on mechanistic studies (isotope labelling and 19F NMR experiments), the author proposed a plausible mechanistic pathway for the above transformation, as depicted in Scheme 7.24 The reaction begins with the release of trifluoromethoxide anion (CF3O−) from reagent 12 under the action of a fluoride salt. Subsequently, CF3O− undergoes decomposition to produce carbonic difluoride A which, upon esterification with alcohol 11, generates alkyl fluoroformate intermediate B. Finally, nucleophilic substitution reaction of activated species B with in situ-generated CF3O− affords the final product 13. Of note, the studies indicated that the presence of TMABr in the reaction mixture is crucial for improving the nucleophilicity of OCF3 anion, while in the absence of any quaternary ammonium salt, inferior results in terms of product yield were observed.
In an attempt to further demonstrate the strength of this novel and interesting alkyl trifluoromethyl ether synthesis, Lin and Xiao along with their co-workers documented an elegant Ph3P/ICH2CH2I-promoted trifluoromethoxylation of aliphatic alcohols using AgOCF3 as a nucleophilic trifluoromethoxylating reagent, which allowed very rapid access to the corresponding dehydroxytrifluoromethoxylated products.25 Through exploration and optimization of this dehydroxylative functionalization, the authors identified that the reaction rate is highly dependent on the nature of solvent. Among several solvents tested (e.g., DMSO, DMF, NMP, and toluene), DMF was found to be the most effective. Furthermore, the outcome of this transformation was also dramatically dependent on the reaction temperature. The best results were obtained by performing the process at 80 °C. A higher or lower temperature resulted in lower yields. With these optimized reaction conditions, 25 trifluoromethyl ethers 15 were synthesized in 16–76% yields from the corresponding aryl/benzyl/allyl/propargyl alcohols 14 (Scheme 8). Notably, a diverse range of functional groups such as fluoro, chloro, bromo, iodo, cyano, nitro, ester, and ether functionalities were demonstrated to be well-tolerated by this protocol. However, the major drawback of this synthetic protocol was its very low efficiency for functionalization of alkyl alcohols. Intriguingly, the authors nicely solved this problem by replacing Ph3P with Ph2PCHCH2 and performing the process at 100 °C. However, the only reported case of a secondary alkyl alcohol led to a mediocre yield.
Scheme 8 Ph3P/ICH2CH2I-promoted dehydroxylative trifluoromethoxylation of aliphatic alcohols 14 using AgOCF3 as a nucleophilic trifluoromethoxylating reagent. |
Mechanistically (Scheme 9), the reaction may be initiated by the reaction of Ph3P with ICH2CH2I to give diiodophosphonium salt A, which upon coordination with the reaction solvent DMF, furnishes complex B. Subsequently, substitution of an alcohol 14 with a DMF molecule in complex B yields complex C, and after nucleophilic attack by trifluoromethoxy anion, generated from AgOCF3 by precipitating AgI, affords the observed alkyl trifluoromethyl ether 15. In another possibility, a sequential P–O bond formation and C–O bond cleavage process converts complex B into a triphenylphosphine oxide (Ph3PO) and the Vilsmeier–Haack-type intermediate D. Later, nucleophilic substitution of alcohol 14 with intermediate D leads to the formation of intermediate E, which after nucleophilic trifluoromethoxylation with CF3O−, provides the final product 15.
Scheme 10 Lewis acid-mediated dehydroxylative trifluoromethylthiolation of benzylic alcohols 16 with CuSCF3, as reported by Rueping. |
Other Brønsted or Lewis acids such as MsOH, TsOH, TFA, Sc(OTf)3, Bi(OTf)3, and In(OTf)3 were also tested and proved to be completely ineffective. The identical reaction conditions were also applied for trifluoromethylthiolation of allylic alcohols to give the corresponding allylic trifluoromethyl thioethers in good to excellent yields (9 examples, 73–96% yield) and high regioselectivities, in which regardless of the substitution pattern, conjugated aryl/olefin products were predominantly formed in the case of aryl-substituted allyl alcohols. Mechanistic investigations indicated that the reaction may occur via an SN1-type process, as evidenced by the formation of racemic products from enantiopure alcohols.
Immediately after, Qing and collaborators developed a similar dehydroxytrifluoromethylthiolation of alkyl alcohols 18 with AgSCF3, employing a large excess of the mild reagent n-Bu4NI as activator and toluene as solvent (Scheme 11).27 The reaction was shown to be quite general, and a diverse range of primary aliphatic, benzylic, allylic, and propargylic alcohols participated in the trifluoromethylthiolation. Moreover, secondary alcohols also accomplished production of the corresponding products albeit the addition of a very large amount of another activator, KI (8 equiv.), and elevated reaction temperature (120 °C) were needed to prevent the competitive elimination reaction. However, tertiary alcohols were not suitable substrates for this transformation.
Interestingly, several biologically active alcohols such as idebenone 18a (an anti-Alzheimer's drug), galantamine 18b (an anti-Alzheimer's and anti-dementia drug), and epiandrosterone 18c (a steroid hormone) also responded to the reaction. Notably, the authors observed that changing the ratio of AgSCF3/n-Bu4NI from 1:3 to 1:1 led to the selective formation of alkyl fluorides instead of the expected alkyl trifluoromethylthioethers. A plausible mechanism based on previous studies is outlined in Scheme 12.
Scheme 12 Proposed reaction mechanism for the synthesis of trifluoromethylthioethers 19 starting from alcohols 18 with AgSCF3. |
In their subsequent studies, this research group extended the scope of their methodology to enols.28 Thus, a library of (Z)-ethyl 2-(aryl)-3-hydroxyacrylates 20 were reacted with AgSCF3, n-Bu4NI, and KI in toluene at 120 °C leading to the respective α-aryl-β-(trifluoromethylthio)acrylates 21 in moderate to excellent yields and satisfactory stereoselectivities in favor of the (E)-products (Scheme 13). Under the same conditions, they also executed the direct dehydroxytrifluoromethylthiolation of a small series of 3-(hydroxymethylene)indolin-2-one derivatives 22, offering a decent yield of the desired 3-(((trifluoromethyl)thio)methylene)indolin-2-ones 23 (Scheme 14). Interestingly, two electron-deficient phenols were also tested and gave products in satisfactory yields. To the best of our knowledge, this is the first and only reported example of dehydroxylative trifluoromethylthiolation of C(sp2)–OH bonds.
Scheme 14 Synthesis of 3-(((trifluoromethyl)thio)methylene)indolin-2-ones 23 via nBu4NI-mediated dehydroxytrifluoromethylthiolation of 3-(hydroxymethylene)indolin-2-one derivatives 22 with AgSCF3. |
At the outset of 2016, Billard's research group devised an elegant metal-free method for dehydroxylative trifluoromethylthiolation of alkyl alcohols 24 using the second-generation trifluoromethanesulfenamide reagent 25 as an SCF3 source and n-Bu4NI as an activator in refluxing acetone to afford the corresponding alkyl trifluoromethylthioethers 26 in an efficient manner (Scheme 15a).29 The experiments demonstrated that the outcome of this reaction was not highly sensitive to the electronic nature of substrates, and therefore benzylic alcohols with either neutral, electron-donating, or electron-withdrawing substituents gave the trifluoromethylthiolated products in relatively similar yields. However, the steric effect was very strong (92% yield for benzyl alcohol to 46% for α-methylbenzyl alcohol). Unfortunately, the applicability of tertiary alcohols as starting materials was not explored in this study.
A presumptive mechanism for this dehydroxylative trifluoromethylthiolation reaction is represented in Scheme 16. Subsequently, a straightforward and greener approach for the synthesis of alkyl trifluoromethylthioethers 28 by the reaction between alkyl alcohols 27 and 1-n-butyl-3-methylimidazolium trifluoromethylthiolate ([bmim][SCF3]) generated in situ from [bmim][I] and AgSCF3 was reported by Pégot, Magnier, and co-workers.30 The reactions were implemented under microwave irradiation and solvent-free conditions, tolerated primary, secondary, as well as tertiary alcohols, and rapidly provided the desired products in poor to excellent yields (Scheme 15b). Recycling tests indicated that the ionic liquid can be reused in several consecutive trials without significant loss of its activity (from 96% in the first run to 96% in the fifth run).
In 2019, Hopkinson and co-workers designed and synthesized a new bench-stable 2-trifluoromethylthio-substituted benzothiazolium salt (BT-SCF3; 29) through visible-light-induced, Ir-catalyzed trifluoromethylthiolation of inexpensive 2-mercaptobenzothiazole disulfide (MBTS) with the Langlois reagent (NaSO2CF3) and subsequent reaction of the generated 2-SCF3-substituted benzothiazole with MeOTf in DCM at room temperature (Scheme 17a).31 The activity of this purely organic trifluoromethylthiolating reagent has been evaluated in the dehydroxylative trifluoromethylthiolation of a broad set of alkyl/benzyl/propargyl alcohols 30 in the presence of Hünig's base (NEt(iPr)2) in MeCN. Moderate to almost quantitative yields of the target trifluoromethyl thioethers 31 were obtained within 1–2 h at room temperature (Scheme 17b). The reaction exhibited satisfactory tolerance for an array of catalytically reactive functional groups (e.g., F, Cl, Br, I, CF3, CO2Me, SMe, NO2), and thus, promised further elaboration of the end products. It is worthwhile to note that the authors nicely adapted this approach to the direct construction of SeCF3-substituted compounds from alcohols by developing a similar trifluoromethylselenyl-substituted benzothiazolium salt (BT-SeCF3).
Scheme 17 Hünig's base-mediated dehydroxylative trifluoromethylthiolation of alkyl/benzyl/propargyl alcohols 30 with benzothiazolium reagent 29. |
As for the mechanism, the authors speculated that the reaction most likely proceeds through the formation of key electrophilic 2-alkoxybenzothiazolium species A via nucleophilic attack of the alcohol 30 in the presence of NEt(iPr)2 at the C2-position of the BT-SCF3 reagent 29 and subsequent nucleophilic substitution reaction with in situ generated –SCF3 anion (Scheme 18). Guided by the same principle, a similar dehydroxylative functionalization strategy was applied by the same research group towards the synthesis of various perfluoroalkyl thioethers32 and thioesters.33
In a recent report, Wu, Xiao, and colleagues accomplished the direct conversion of alcohols 32 into the corresponding trifluoromethyl thioethers 33 using AgSCF3 as a source of F3CS group and the Ph3P/ICH2CH2I/n-Bu4NI combination as an activation system in a 2:1 mixture of DMF and MeCN.22 The reaction was compatible with a variety of functionalized benzylic alcohols, as well as heterobenzylic alcohols such as hydroxymethyl pyridines, quinolines, thiazoles, benzothiols, even simple allylic and propargylic alcohols (Scheme 19). As for alkyl alcohols, the corresponding products were obtained in poor yields. In this case, when Ph2PCHCH2 was used instead of Ph3P, the product yields were significantly increased. The plausible mechanism for this transformation is analogous to the one depicted in Scheme 5. It should be mentioned that this mechanism is tentative and lacks experimental evidence.
Scheme 19 Ph3P/ICH2CH2I/n-Bu4NI-mediated direct conversion of alcohols 32 into the corresponding trifluoromethyl thioethers 33 using AgSCF3. |
In 2020, using [Me4N][SeCF3] salt as a stable, non-volatile, and readily accessible source of nucleophilic SeCF3, Zhang and colleagues engineered the direct dehydroxylative trifluoromethylselenylation of alcohols 37 for the synthesis of valuable alkyl trifluoromethyl selenoethers 38 under catalyst-free conditions.35 By employing 3-phenylpropyl alcohol as the model reactant, several additives such as CaF2, CaCl2, CaBr2, Ca(OTf)2, Ca(C2O4), CaSO4, HCl, and LiI were carefully screened. Among them, excellent results were obtained for this transformation with CaCl2, whereas MeCN was found to be the most effective solvent among the other common organic solvents tested (DMA, DMF, NMP, DMSO, MeCN, DCM, toluene, and 1,4-dioxane).36 Evaluation of the substrate scope clearly demonstrated that the reaction was tolerant to a variety of primary and secondary aliphatic alcohols (Scheme 21). However, tertiary alcohols provided complicated mixtures. In order to elucidate the mechanism of the reaction, the authors performed several control experiments, such as GC-MS analyses, 19F NMR studies, and others.37
Scheme 21 Selected examples of CaCl2-promoted dehydroxylative trifluoromethylselenylation of alcohols 37 with [Me4N][SeCF3]. |
From these results, the authors proposed two possible pathways for this transformation. The first pathway (Scheme 22, path A) starts with the formation of carbonoselenoic difluoride intermediate A through the decomposition of −SeCF3 with CaCl2 as a fluoride scavenger, which after reaction with another two equivalents of −SeCF3 in the presence of Ca2+ cations provides bis(trifluoromethyl)-carbonotriselenoate B (this intermediate was detected by 19F NMR and GC-MS analyses). Subsequently, the nucleophilic substitution of key intermediate B by alcohol 37 leads to a carbonoselenoate C. Finally, the nucleophilic attack of intermediate C with −SeCF3 anion provides the target trifluoromethylselenylated product 38. The key steps of the second possible route (Scheme 22, path B) are the generation of O-alkyl carbonofluoridoselenoate D via straightforward reaction of intermediate A with alcohol 37 and its nucleophilic substitution by −SeCF3 to form the observed product 38. According to the authors, pathway B is not likely the major process in the Ca-mediated dehydroxy trifluoromethylselenylation,38 especially when using a large excess of [Me4N][SeCF3].
Scheme 22 Mechanistic proposal for the reaction in Scheme 21. |
As illustrated, various aliphatic and benzylic alcohols were applicable in these reactions. However, aromatic alcohols were mainly unsuitable substrates. Therefore, many more studies are needed to develop efficient procedures that allow trifluoro-methylation, -methoxylation, -methylthiolation, and -methylselenylation reactions of aromatic alcohols. Moreover, there are insufficient reported examples for some reactions such as trifluoromethylselenylations, and thus, additional study is necessary to determine the scope and limitations of these reactions.
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