Letter Cite This: ACS Catal. 2018, 8, 5842−5846
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Cooperative Catalysis: A Strategy To Synthesize Trifluoromethylthioesters from Aldehydes Satobhisha Mukherjee, Tuhin Patra, and Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
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S Supporting Information *
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
T
Scheme 1. Protocols To Synthesize Trifluoromethylthioesters
he 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 πR= 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). Because of high toxicity and instability of these reagents, the scope and utility of such methodologies is limited. More recently, Chen and co-workers 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 hydrogen atom transfer (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 © 2018 American Chemical Society
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 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 the 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 Received: April 18, 2018 Revised: May 14, 2018 Published: May 21, 2018 5842
DOI: 10.1021/acscatal.8b01519 ACS Catal. 2018, 8, 5842−5846
Letter
ACS Catalysis Table 1. Optimization of Reaction Conditionsa
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 the Presence of Either PhthSCF3 or Substrate (Benzaldehyde). (C) Radical Trapping Experimenta
entry
reagent
HAT catalyst
concn
yield (%)b
1 2 3 4 5 6
2a 2a 2a 2b 2c 2d 2a 2a 2a 2a
PhCOONBu4 PhCOONBu4 PhCOONa PhCOONa PhCOONa PhCOONa TBHP PhCOONa PhCOONa
0.1 M 0.2 M 0.2 M 0.2 M 0.2 M 0.2 M 0.2M 0.2 M 0.2 M 0.2 M
60 70 85(80)f 42 65 71 -
7c,d,e 8d 9 10e a
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. bNMR yield. cTBHP (0.20 mmol), at 84 °C for 24 h. dno light. eno photocatalyst. fisolated yield. LED, lightemitting diode; TBHP, tert-butylhydroperoxide.
*[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−1 s−1).11 Hence, under the catalytic conditions employed it would serve as the 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). The nucleophilic acyl radical would then readily react with the electrophilic N-(trifluoromethylthio)phthalimide (PhthSCF3, 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. We started our investigation by subjecting benzaldehyde and N-(trifluoromethylthio)phthalimide to visible light irradiation in the presence of [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 and
a
By adding Tempo (2.0 equiv) to the standard reaction conditions. Io = luminescence intensity without the quencher; I = luminescence intensity in the presence of the quencher.
tetrabutylammonium benzoate tBu4N+PhCOO− (3)10 quenching the highly oxidizing excited state of the photocatalyst 5843
DOI: 10.1021/acscatal.8b01519 ACS Catal. 2018, 8, 5842−5846
Letter
ACS Catalysis Scheme 3. Scope of the Reactiona
a
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.
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 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 the 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. Notably, for the products 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 the sole product in 53−72% yields, with no decarbonylated side product being observed.13 All the compounds reported herein are neither moisture- nor airsensitive. No detectable decomposition of the compounds was observed after more than two months of storage at ambient 5844
DOI: 10.1021/acscatal.8b01519 ACS Catal. 2018, 8, 5842−5846
ACS Catalysis
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Scheme 4. Trifluoromethylthiolation of Complex Moleculesa
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b01519. Experimental details, characterization data, mechanistic experiments, and copies of NMR spectra of new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Frank Glorius: 0000-0002-0648-956X Notes
The authors declare no competing financial interest.
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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.
a
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: 1,2dichloroethane.
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REFERENCES
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temperature. However, because of high volatility of certain products, we have low isolated yields in those cases. Because of the 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 latestage 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 trifluoromethylthioesters against various functionalities. Additionally, biorelevant 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 HAT 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 functionalization 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. 5845
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DOI: 10.1021/acscatal.8b01519 ACS Catal. 2018, 8, 5842−5846
