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Cooperative Catalysis: A Strategy to Synthesize Trifluoromethyl-thioesters from Aldehydes Satobhisha Mukherjee, Tuhin Patra, and Frank Glorius ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01519 • Publication Date (Web): 21 May 2018 Downloaded from http://pubs.acs.org on May 21, 2018
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ACS Catalysis
Cooperative Catalysis: A Strategy to Synthesize Trifluoromethyl-thioesters from Aldehydes Satobhisha Mukherjee, Tuhin Patra and Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
ABSTRACT: A cooperative catalysis between a photoredox and a Hydrogen Atom Transfer (HAT) catalyst has been developed to synthesize trifluoromethylthioesters from aldehydes. This reaction is mild, highly selective, operationally simple, works under redox neutral condition and exhibits a broad substrate scope with high functional group tolerance. The synthetic utility of this method is demonstrated by the late stage functionalization of bioactive molecules, making it amenable for drug discovery. KEYWORDS: acyl radicals, C–H activation, Hydrogen Atom Transfer, photocatalysis, trifluoromethylthioester The development of new synthetic methodologies for the incorporation of fluoroalkyl groups into organic molecules has attracted much interest in recent years.1 Owing to their unique chemical, physical and biological properties, the incorporation of such organo-fluorinated moieties has become a routine exercise to develop new drug candidates.2 An important representative of this class is the trifluoromethylthio (–SCF3) group. The high lipophilic electron-withdrawing nature (Hansch parameter R= 1.44) and transmembrane permeability of trifluoromethylthio (–SCF3) group can lead to improved metabolic stability when incorporated into bioactive molecules.3 As a result, powerful strategies enabling direct C−SCF3 bond construction have been developed.1, 4 Unlike, trifluoromethylthioethers, the number of methods for the synthesis of trifluoromethylthioesters is rather limited.5 To this end, seminal work by the group of Man5a and Yagupolskii5b showed that the synthesis of trifluoromethylthioesters could be achieved by the reaction of acid chlorides with Hg(SCF3)2 and NMe4SCF3 (Scheme 1). Due to high toxicity and instability of these reagents, the scope and utility of such methodologies is limited. More recently, Chen and coworkers reported the synthesis of trifluoromethylthioesters by treating acid chlorides with (bpy)CuSCF3 (Scheme 1).5c However, such methods require the use of stoichiometric amounts of metallic reagents for transferring trifluoromethylthio (–SCF3) group, therefore increasing the propensity of metal contamination in the products. Given the widespread availability of aldehydes, we questioned whether the overall synthesis of trifluoromethylthioesters from aldehydes could be achieved in a selective and sustainable fashion under milder conditions by merging photoredox and HAT catalysis. Photoredox mediated HAT catalysis has become a conceptually and strategically popular method for selective C–H bond functionalizations.6–8 In this regard, our laboratory has disclosed strategies for selective functionalization of C–H bonds by employing benzoate as the HAT reagent.9 The critical design element was the choice of a proper hydridophilic small molecule HAT reagent that facilitates selective abstraction of the hydrogen atom from the most hydridic C–H bond in the molecule
Scheme 1. Protocols to synthesize trifluoromethylthioesters.
leading to its selective functionalization. Herein, we describe the successful implementation of this concept for the synthesis of trifluoromethylthioesters by direct aldehydic C(O)–H bond functionalization in presence of an electrophilic trifluoromethylthio (–SCF3) group transferring reagent.4d,e The detailed mechanism of our proposed transformation is outlined in Scheme 2A. Here, the reaction would initiate with tetrabutylammonium benzoate tBu4N+PhCOO− (3)10 quenching the highly oxidizing excited state of the photocatalyst *[Ir(dF(CF3)ppy)2(dtbbpy)]+ ( Ir-F, 2) (E1/2 red [*IrIII/IrII] = +1.21 V vs the saturated calomel electrode (SCE) in CH3CN, Scheme 2B) to form the hydridophilic benzoyloxy radical PhCOO • (4) intermediate. At room temperature the rate of decarboxylation of the benzoyloxy radical PhCOO• (4) (k = 106 s-1) is known to be slower than the rate of competitive hydrogen atom abstraction event (k = 107 M-1s-1).11 Hence, under the catalytic conditions employed it would serve as the Hydrogen Atom Transfer (HAT) catalyst, which would selectively abstract the hydrogen atom from the most hydridic C(O)–H bond in the molecule, thereby generating the acyl radical intermediate (6), (Scheme 2C).
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ACS Catalysis A. Mechanistic Proposal
The nucleophilic acyl radical would then readily react with the electrophilic N-(trifluoromethylthio)phthalimide (Phth-SCF3, 7) to afford the desired product (8) with simultaneous elimination of the phthalimide radical Phth• (9). Finally, the phthalimide radical (Phth•) would be reduced by the reduced photocatalyst to the phthalimide anion (Phth−) (10), which would return the photocatalyst to its original oxidation state. The phthalimide anion (Phth−) would then subsequently serve as an internal base to deprotonate the benzoic acid (12) (pKa= 8.3 for phthalimide against 4.2 for benzoic acid in water), to regenerate the HAT catalyst and complete both catalytic cycles. Alternatively phthalimide radical (9) can serve as a chain carrier and do HAT from aldehyde to carry forward the reaction. Thus, to determine the contribution of radical chain mechanism to the overall product formation, quantum yield of the reaction was measured by chemical actinometry at 415 nm under the reaction condition. The low value of quantum yield (Φ =1.17) of the reaction suggests very little contribution of this alternate pathway to the overall reaction.
B. Stern-Volmer Quenching Experiment 1.6 1.5 1.4 y = 128.77x + 1 R² = 0.9879
I0/I
1.3 1.2 1.1 1 0.9
Entry
0.8 0
0.001
0.002
0.003
Reagent
HAT
Conc.
Yield (%)a
Catalyst
0.004
Quencher (PhCOONBu4) Concentration (M)
I0/I
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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B1.
1.60 1.50 1.40 1.30 1.20 1.10 1.00 0.90 0.80 0
0.01
0.02
0.03
0.04
Concentration of Quencher (M) Ir-F + PthalSCF3 Ir-F + Substrate Linear (Ir-F + PthalSCF3) Linear (Ir-F + Substrate)
B2.
1
2a
PhCOONBu4
0.1 M
60
2
2a
PhCOONBu4
0.2 M
70
3
2a
PhCOONa
0.2 M
85(80)e
4
2b
PhCOONa
0.2 M
42
5
2c
PhCOONa
0.2 M
65
6
2d
PhCOONa
0.2 M
71
7b,c,d
2a
TBHP
0.2M
-
8c
2a
PhCOONa
0.2 M
-
9
2a
0.2 M
-
10d
2a
0.2 M
-
PhCOONa
Table 1: Optimization of reaction conditions. General reaction conditions: Benzaldehyde (0.10 mmol), 2a-d (0.15 mmol), photocatalyst (1 mol%), benzoate salt (5 mol%) in MeCN under Ar with 5W blue LED irradiation at room temperature for 16 h, unless otherwise noted. a) NMR yield, b) TBHP (0.20 mmol), at 84°C for 24h, c) no light, d) no photocatalyst, e) isolated yield. LED, light-emitting diode; TBHP, tert-butylhydroperoxide.
C. Tempo Trapping Experiment
Scheme 2. A) Mechanistic Proposal. B) Stern- Volmer Quenching Experiment. B1. Quenching of the excited state of the photocatalyst by tetrabutylammonium benzoate in acetonitrile solution, B2. No quenching of the photocatalyst was observed in presence of either Phth-SCF3 or substrate (benzaldehyde). C) Radical Trapping Experiment. By adding Tempo (2.0 equiv.) to the standard reaction conditions. Io = luminescence intensity without the quencher; I = luminescence intensity in presence of the quencher.
We started our investigation by subjecting benzaldehyde and N-(trifluoromethylthio)phthalimide to visible light irradiation in presence of [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 and PhCOONBu4 in acetonitrile (0.1 M) (Table 1, entry 1). To our delight, we observed the formation of the product (1) in 60% yield. Increasing solvent concentration to 0.2 M afforded the desired product
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ACS Catalysis
Scheme 3. Scope of the reaction. General reaction conditions: aldehyde (0.30 mmol), Phth-SCF3 (0.45 mmol), photocatalyst (1 mol%), sodium benzoate (5 mol%), in MeCN (0.2 M) under Ar with 5W blue LED irradiation at room temperature, unless otherwise noted. All yields reported are isolated yields. The regioselectivity was determined by 19F NMR.
in 70% yield (entry 2). After a base screen, we switched to the sodium salt of benzoic acid, which was found to be superior, improving the yield to 85% (entry 3). Next, the trifluoromethylthiolating source was varied (entries 4–6). However, N-(trifluorometylthio)phthalimide proved to be optimal for this reaction. The reaction was additionally performed under thermal condition in presence of TBHP following a currently reported protocol for the synthesis of difluoromethylthioesters from aldehydes, 12 however no product formation was observed under this condition (entry 7). Control experiments revealed that the light, the benzoate salt, and the photocatalyst were all crucial for the success of the reaction (entries 8–10). With the optimized conditions in hand, the generality of the transformations was investigated with respect to different aldehydes (Scheme 3). The inherent reactivity and selectivity of this reaction in substrates containing aldehydic C(O)–H as well as tertiary C–H bonds was studied. Pleasingly, the C–H trifluoromethylthiolation always took place at the aldehydic C(O)–H bond with high regioselectivity, and the major products (2–5) were isolated in 70–75% yields. It is to be noted, for the prod-
ucts 2–4, the minor regioisomers are being referred to the trifluoromethylthioethers formed by the trifluoromethylthiolation at the geminal dimethyl site. A substrate bearing a strained cyclopropyl ring was also tolerated under the reaction conditions, affording the product (6) in 65% yield. The scope of the reaction with respect to the different substituents on the aromatic aldehydes was then studied. In general, substrates containing electron donating groups on the phenyl ring worked better than substrates with electron withdrawing groups. Aryl aldehydes containing common functional groups such as halides (7–10), alkyls (11–14), ether (15–17), ester (18), phenyl (19), trifluoromethyl (20), were found to be compatible under the reaction conditions, giving the products in moderate to high yields. Naphthaldehyde gave the corresponding product (21) in excellent yield of 82%. The reaction proceeded smoothly with various heteroaryl aldehydes, giving the desired products (22–23) in 60–78% yields. Finally, the scope of the reaction with respect to the aliphatic aldehydes was explored. Gratifyingly, primary, secondary, tertiary were all found to be suitable substrates, affording the corresponding trifluoromethylthioesters (24–28) as
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tionalization tool has also been demonstrated through the successful trifluoromethylthiolation of bio relevant steroidal molecules. We anticipate that this dual catalytic strategy for direct functionalization of C−H bonds will find widespread application in organic synthesis and pharmaceutical science.
ASSOCIATED CONTENT Supporting Information. Experimental details, characterization data, mechanistic experiments and copies of NMR spectra of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected] Scheme 4. Trifluoromethylthiolation of complex molecules. General reaction conditions: aldehyde (0.30 mmol), Phth-SCF3 (0.45 mmol), photocatalyst (1 mol%), sodium benzoate (5 mol%), in MeCN (0.2 M) under Ar with 5W blue LED irradiation at room temperature for 24 h, unless otherwise noted. a) MeCN: DCE (1:1) (0.2 M), b) MeCN: DCE (1:1)(0.1 M). All yields reported herein are isolated yields. Selectivity determined by 19F NMR. DCE: 1,2-dichloroethane.
the sole product in 53–72% yields, with no decarbonylated side product being observed.13 All the compounds reported herein are neither moisture nor air sensitive. No detectable decomposition of the compounds was observed after more than two months of storage at ambient temperature. However, due to high volatility of certain products, we have low isolated yields in those cases. Due to biological relevance of fluoroalkylthio groups, 14,2b a mild and selective method for late stage introduction of trifluoromethylthio (–SCF3) group in complex molecules will be highly desirable in drug modification strategies. Thus, to test the practicality of this method in late stage functionalization, an additive-based robustness screening experiment15 was performed to study the average minimal adverse effect of different functional groups on the reaction yield. The reaction shows high functional group tolerance and good functional group preservation was also observed.16 This further validates the sufficient stability of trifluorothioesters against various functionalities. Additionally, bio relevant steroidal molecules containing multiple C–H functionalization sites were subjected to our trifluoromethylthiolation protocol. Gratifyingly, all of them underwent trifluoromethylthiolation at the desired aldehydic C(O)–H bond with excellent regioselectivity (Scheme 4). In summary, direct trifluoromethylthiolation of aldehydes employing photoredox-mediated Hydrogen Atom Transfer strategy has been developed. This method operates under mild redox-neutral condition at room temperature with aldehyde as the limiting reagent and exhibits a broad substrate scope with good functional group tolerance. The aforementioned transformation benefits from using commercially available, stable aldehydes as the carbonyl group source and offers an expedient alternative to traditional methods for synthesizing trifluoromethylthioesters. The utility of this method as a late stage func-
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENTS Generous financial support from the Humboldt Foundation (T.P.) and the Deutsche Forschungsgemeinschaft (Leibniz Award) are gratefully acknowledged. We thank Dr. Michael J. James, and Michael Teders (Westfälische Wilhelms-Universität Münster) for helpful discussions.
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ACS Catalysis Glorius, F. Visible Light‐Promoted Decarboxylative Di‐ and Trifluoromethylthiolation of Alkyl Carboxylic Acids. Chem. Eur. J. 2016, 22, 4753-4756. d) Shao, X.; Xu, C.; Lu, L.; Shen, Q. Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation. Acc. Chem. Res. 2015, 48, 1227-11236. e) Li, M.; Zhou, B.; Xue, X.-S.; Cheng, J.-P. Establishing the Trifluoromethylthio Radical Donating Abilities of Electrophilic SCF3-Transfer Reagents. J. Org. Chem. 2017, 82, 8697-8702. (5) a) Man, E. H.; Coffman, D. D.; Muetterties, E. L. Synthesis and Properties of Bis-(trifluoromethylthio)-mercury. J. Am. Chem. Soc. 1959, 81, 3575-3577. b) Kremlev, M. M.; Tyrra, W.; Naumann, D.; Yagupolskii, Y. L. S-Trifluoromethylesters of Thiocarboxylic acids, RC(O)SCF3. Tetrahedron Lett. 2004, 45, 6101-6104. c) Zhang, M.; Chen, J.; Chen, Z.; Weng, Z. Copper-Mediated Effective Synthesis of S-trifluoromethylesters by Trifluoromethylthiolation of Acid Chlorides. Tetrahedron 2016, 72, 3525-3530. (6) a) Cuthbertson, J. D.; MacMillan, D. W. C. The Direct Arylation of Allylic sp3 C–H Bonds via Organic and Photoredox Catalysis. Nature 2015, 519, 74-77. b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035-10074. c) Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate Activation in Photocatalyzed Organic Synthesis. Eur. J. Org. Chem. 2017, 20562071. (7) a) Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C. O-H hydrogen Bonding Promotes H-Atom Transfer from α C-H Bonds for C-Alkylation of Alcohols. Science 2015, 349, 1532-1536. b) Wang, Y.; Li, G.X.; Yang, G.; He, G.; Chen, G. A Visible-Light-Promoted Radical Reaction System for Azidation and Halogenation of Tertiary Aliphatic C–H Bonds. Chem. Sci. 2016, 7, 2679-2683. c) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Catalytic Alkylation of Remote C–H Bonds Enabled by Proton-Coupled Electron Transfer. Nature 2016, 539, 268-271. (8) a) Li, J. D.; Wang, D. J. Visible-Light-Promoted Photoredox Syntheses of α,β-Epoxy Ketones from Styrenes and Benzaldehydes under Alkaline Conditions. Org. Lett. 2015, 17, 5260-5263. b) Iqbal, N.; Cho, E. J. Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation. J. Org. Chem. 2016, 81, 1905-1911. c) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp3)−H Functionalization under Mild Reaction Conditions. Angew. Chem. Int. Ed. 2016, 55, 1872-1875. d) Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H. S.; Knowles, R. R. Catalytic Ring-Opening of Cyclic Alcohols Enabled by PCET Activation of Strong O–H Bonds. J. Am. Chem. Soc. 2016, 138, 10794-10797. e) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Controllable Remote C-H Bond Functionalization by Visible-Light Photocatalysis. Angew. Chem. Int. Ed. 2017, 56, 1960-1962. f) Zhang, X.; MacMillan, D. W. C. Direct Aldehyde C–H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis. J. Am. Chem.Soc. 2017, 139, 11353-11356.
g) Vu, M. D.; Das, M.; Liu, X.-W. Direct Aldehyde Csp2-H Functionalization through Visible-Light Mediated Photoredox Catalysis. Chem. Eur. J. 2017, 23, 15899-15902. (9) a) Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. VisibleLight-Promoted Activation of Unactivated C(sp3)–H Bonds and Their Selective Trifluoromethylthiolation. J. Am. Chem. Soc. 2016, 138, 16200-16203. b) Mukherjee, S.; Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Glorius, F. Alkynylation of Csp2 (O)-H Bonds Enabled by Photoredox-Mediated Hydrogen-Atom Transfer. Angew. Chem. Int. Ed. 2017, 56, 14723-14726. (10) Despite the reported potentials showing thermodynamic disfavorability (Ir*III/IrII = 1.21 V, PhCOO−/ PhCOO• = 1.4 V), the SternVolmer analysis clearly shows PhCOO− to be a good quencher (Ksv = 5.60 × 107 M–1s–1), indicating feasibility of the proposed oxidation. (11) Rate constants for the decarboxylation (k in s-1): a) Aroyloxy radical 4-ClC6H5C(O)O. 1.4 ± 0.3 × 106 (CCl4): Chateauneuf, J.; Luszytyk, J.; Ingold, K. U. Spectroscopic and Kinetic Characteristics of Aroyloxyl Radicals. 2. Benzoyloxyl and Ring-Substituted Aroyloxyl Radicals. J. Am. Chem. Soc. 1988, 110, 2886-2893. b) Chateauneuf, J.; Luszytyk, J.; Ingold, K. U. Spectroscopic and Kinetic Characteristics of Aroyloxyl Radicals. The 4-Methoxybenzoyloxyl Radical. J. Am. Chem. Soc. 1988, 110, 2877-2885. (12) Guo, S.-H.; Zhang, X.-L.; Pan, G.-F.; Zhu, X.-Q.; Gao, Y.-R.; Wang, Y. Synthesis of Difluoromethylthioesters from Aldehydes. Angew. Chem. Int. Ed. 2018, 57, 1663-1667. (13) Chatgilialoglu, C. Chemistry of Acyl Radicals. Chem. Rev. 1999, 99, 1991-2070. (14) Larsson, K.; Rosenhall, L. Anti-Inflammatory Treatment in Clinical Practice: A Summary. Clin. Exp. Allergy 1996, 26, 18-19. (15) a) Collins, K. D.; Rühling, A.; Glorius, F. A Robustness Screen for the Rapid Assessment of Chemical Reactions. Nature Chem. 2013, 5, 597-601. b) Gensch, T.; Teders, M.; Glorius, F. Approach to Comparing the Functional Group Tolerance of Reactions. J. Org. Chem. 2017, 82, 9154-9159. (16) See Supporting Information for further details.
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