Visible-light-induced oxidant and metal-free dehydrogenative cascade trifluoromethylation and oxidation of 1,6-enynes with water

Unprecedented light-induced oxidant and metal-free tandem radical cyclization–trifluoromethylation and dehydrogenative oxygenation of 1,6-enynes have been achieved using a photoredox catalyst, CF3SO2Na, and water as the oxygen source.


Introduction
C 3 -Aryloylated benzofurans, benzothiophenes, indoles, and related fused polyheterocycles are privileged structures with numerous applications in materials, drugs, and biology ( Fig. 1). [1][2][3][4][5] Benzbromarone 2 is being used for the treatment of gout as a urate lowering drug (ULD) and amiodarone 3 is a potent inhibitor of the human cytochrome P-450 (CYP) 2 C 19 responsible for metabolizing commonly prescribed drugs. The C 3 -aryloylated benzothiophenes, 4 raloxifene and tubulin, which are antimitotic agents, act as an estrogen receptor and inhibitor for the polymerization of tubulin and growth of tumour cells, respectively. Similarly, 2-methyl-C 3aryloylated indoles, 5 namely pravadoline, WIN55212-2, and clometacin, are nonsteroidal anti-inammatory drugs, which are used against pain and inammation. However, the construction of C 3 -aryloylated benzofuran, indole, and thiophene scaffolds is still challenging (vide infra) despite the availability of advanced synthetic strategies. [15][16][17] The incorporation of a triuoromethyl group (-CF 3 ) into drug molecules can dramatically change their properties, such as their solubility, lipophilicity, metabolic stability, etc. 6 As a result, several triuoromethylated heterocycles, such as efavirenz and celecoxib, are used as potential drugs for the treatment of various diseases. 7 It is worth noting that the synthesis of triuoromethylated C 3 -aryloyl heterocycles (shown in Fig. 1) has not been reported to date.
The triuoromethylation and oxygenation of alkene and alkyne substrates have been achieved using various triuoromethylating reagents and peroxides, persulfates, hypervalent iodine salts and oxygen as the oxidant and/or transition metal catalytic system (Scheme 1, eqn (1)). [8][9][10][11][12][13][14] Although different valuable approaches appear to have been incorporated into the -CF 3 group, still there is demand for mild and sustainable synthetic methods that avoid oxidants and heavy metals and are applicable to sensitive substrates for the construction of functionalized advanced heterocycles.
The cyclization of 1,6-enynes can be a powerful transformation that allows for the construction of C 3 -aryloyl/acylated heterocycles (Scheme 1, eqn (2)). [15][16][17] 1,6-Enyne substrates under transition metal (TM)-catalyzed reaction conditions are rearranged to benzofuran, 15 benzothiophene 16 and indole 17 heterocycles, and thus restrict the use of TM to access the desired C 3 -aryloylated heterocycles. On the other hand, the use of oxidants such as hypervalent iodine reagents, peroxides, and oxygen, which are required for the generation of the CF 3 radical and as a source of oxygen under TM-free conditions, led to the cleavage of the vinylic carbon-heteroatom (oxygen, sulfur, nitrogen, etc.) 8c bond and thus provided undesired phenol, thiophenol and aniline as the main side products, respectively (eqn (3)). It is a natural inherent property of oxygen (bi-radical) to form a peroxide that leads to the cleavage of the labile carbon-heteroatom bond and thus imposes a major challenge to functionalize such a vinylic carbon-carbon double bond. 8f Consequently, keeping the ether linkage intact throughout the triuoromethylation of the vinylic C-C double bond adjacent to the heteroatom has not been reported to date, despite the presence of this skeleton in various molecules of pharmaceuticals, agrochemicals, materials, and ne chemicals.
Photocatalyzed cascade radical reactions have gained much attention in recent times as these reactions provide access to complex molecules in one pot with step and atom economy. 18,19 Although several photocatalyzed triuoromethylation reactions viz. aromatic triuoromethylation, 20a conversion of alkynes into tetra-substituted triuoromethylated alkenes, 20b and radical triuoromethylation/cyclization cascade for CF 3 -containing pyrazolines and isoxazolines 20c have been described, cascade oxy-triuoromethylation has not been explored. Water is the most abundant reactant that can be used as an oxygen source in photocatalytic reactions. The incorporation of water for the oxygenation of substrates requires a strong one-electron oxidant. Alternatively, water can be added as a nucleophile to an organic substrate followed by its oxidation by weaker oxidants under light driven conditions, which could lead to the oxygenation of organic molecules. 21 In the continuation of our research interest in TM-free C-C and C-heteroatom coupling reactions, 22 here, we disclose a photocatalyzed reaction that not only activates CF 3 SO 2 Na for the generation of the CF 3 radical but also facilitates water towards the oxygenation of organic molecules. This approach enables the oxygenation of labile 1,6-enyne substrates along with the generation of hydrogen gas under oxidant-free conditions, which circumvents an undesired, over-oxidized product. The mechanistic investigations by labelling experiments, UV-visible and ESR spectroscopy and cyclic voltammetry studies, corroborated by DFT calculations, have been carried out to understand the role of the photoredox catalyst (PC) in the oxy-triuoromethylation reaction of 1,6-enynes under oxidant and metal-free conditions.
Next, we envisaged that the UV-visible irradiation of the reaction system in the presence of diketones would bring about oxy-triuoromethylation in 1,6-enyne as n / p* triplet-excited ketones have been successfully exploited in several photoinduced chemical transformations. 23 Consequently, a-diketones (A-D) and ortho-quinones 1,10-phenanthroline-5,6-dione (PQD) and phenanthrene-9,10-dione (PQ) were investigated for their UV-visible absorption properties (Fig. 2). A-D show strong absorption in the ultraviolet range below 380 nm, whereas ortho-quinones PQD and PQ exhibit absorption bands in the visible range (380-420 nm). The absorption bands for PQ appeared in the visible light region (420 and 505 nm) 24 in acetone solvent, which shows a slight red shi in acetonitrile (ESI, page S12 and S13 †). The electronic excitation would lead to a rst triplet excited state (T1) of the carbonyl group having a diradicaloid nature. The triplet states of aromatic ketones are long-lived, and also the electronic character and reactivity of the lowest triplet state can be tuned by the solvent polarity. 25 9,10-Phenanthrenequinone PQ shows an n / p* transition of an aromatic ketone that could reverse the charges on the C]O group, thus making the oxygen atom electron decient. Due to the electron-decient oxygen atom and "radical-like" characteristic of carbonyl in PQ, its reduction is enabled 26 by the abstraction of an electron from CF 3 SO 2 Na and the generation of a CF 3 radical, which can indeed initiate a cascade reaction.
The reaction system under UV-irradiation in acetone, which acts as a solvent and radical initiator, 20n and under oxygen atmosphere provided only traces of 2a (Table 1, entry 3). Similar results were obtained with A-C under UV-irradiation and also with D, PQD and PQ under visible light and oxygen atmosphere ( Table 1, entries 4-9). In the absence of oxygen, no product formation was realized, as expected (Table 1, entry 10). Surprisingly, when the reaction was performed in the absence of oxygen in a mixture of an organic and water solvent system, a noticeable increase in the yield of the desired product 2a was observed, moreover, the formation of undesired side product was minimized to <10% yield ( Table 1, entries [11][12][13][14][15][16]. The reactions presented here were optimized under sun-light irradiation. In a separate experiment, a household CFL bulb (23 W) was used, which provided nearly the same yield of 2a (69% vs. 76% in sunlight) although a longer time (6 h for sunlight vs. 16 17), PQ, which has been explored for the rst time, 27 provided optimum yield of the desired oxy-triuoromethylated benzofuran 2a under sunlight irradiation.
The substrate scope of the light-induced oxy-triuoromethylation reaction to phenolic 1,6-enynes Next, the substrate scope was studied on phenolic 1,6-enynes (1a-1r) 28 under the optimized reaction conditions (Table 1, entry 15). Substrates 1b-1j, with electron donating as well as electron withdrawing substituents on the ethynyl ring, showed compatibility with the optimized reaction conditions and afforded respective triuoromethylated benzofurans 2b-2j in 57-75% yields (Scheme 2). Moreover, the phenolic-1,6-enyene substrate 1c with OH functionality and an acidic proton was tolerated to provide hydroxyl benzofuran 2c in good yield. The heteroaromatics pyridyl and thiophenyl and other aromatic naphthyl, as the ethynyl ring containing substrates 1k-1m, were also amenable to the reaction and transformed into the respective benzofurans 2k-2m. Next, the n-and sec-alkyl substituted substrates 1n-1o underwent an oxy-triuoromethylation reaction to afford the acylbenzofurans 2n-2o, albeit in low yields. Substitution on the phenolic ring was also explored under the optimized conditions. Substrate 1p, containing a naphthyl ring, and substrates 1q-1r, having uoro and methyl substituents on the phenolic ring, afforded respective triuoromethylated benzofurans 2p and 2q-2r without any noticeable loss in the yields (55-69%).
Substrate scope with regard to thiophenolic 1,6-enynes In order to explore the synthesis of triuoromethylated C 3 -aryloyl benzothiophenes, thio-linked 1,6-enyne substrates 3a-3m were prepared from 2-bromo-benzenethiols in moderate yields (Scheme 3, for details see the ESI, page S28 and S29 †). In  general, the sulfur-containing substrates showed sluggish reactivity under TM-catalyzed reaction conditions due to the poisoning of the catalyst by sulfur. Earlier synthetic methods involve inter or intramolecular coupling of alkynyl and sulfoxide in the presence of high loading of the Au, Hg and Pdcatalysts. 16d,e To our delight, a TM-free cyclization reaction yielded C 3 -aryloyl triuoromethylated benzothiophenes 4a-4m in nearly the same yields (73-36%) as those obtained for benzofurans. Moreover, a similar substrate scope was realized as thio-linked 1,6-enyne substrates 3b-3m with electron donating methyl, methoxy, [1,3]-dioxole, and tri-methoxy and electron withdrawing CF 3 and F and also naphthyl, thiophenyl, and n-butyl substituents provided unaltered yields of 2-tri-uoromethyl C 3 -aryloyl/acylated benzothiophenes 4b-4m. The cyclopropyl substituted substrate 3l also underwent ring opening of the cyclopropyl ring by the triuoromethyl radical to yield an unexpected di-triuoromethylated benzothiophene 4l as the major product and a di-triuoromethylated product as the minor product.
Substrate scope with regard to anilinic 1,6-enynes Next, N-tosyl (Ts) and N-tert-butyloxycarbonyl (Boc) protected 1,6-enyne 29 substrates were prepared to construct tri-uoromethylated C 3 -aryloyl indoles, which are prevalent heterocycles in many drugs and materials (Scheme 4). 5a,b Indeed, N-tosylated substrates 5a-5g underwent an oxy-triuoromethylation reaction. Moreover, the removal of the tosyl (Ts) group was realized in the same pot leading to Nunprotected triuoromethylated C 3 -aryloyl indoles 6a-6g in 67-56% yields. Next, we sought for the synthesis of N-protected triuoromethylated C 3 -aryloyl indoles. Substrates 5h-5l, which were protected by a N-tert-butyloxycarbonyl (Boc) group, provided triuoromethylated indoles in moderate (10-57%) yields. Both N-Ts and Boc-protected 1,6-enyne substrates, having bromo, uoro, diuoro, methoxy, methyl and pyridyl, naphthyl and thiophenyl rings, were amenable to the oxidant and metal-free oxy-triuoromethylation reactions. A more Scheme 3 Synthesis of CF 3 -benzo[b]thiophenes. The reaction of 0.1 mmol of 3a, 0.3 mmol of CF 3 SO 2 Na and 0.01 mmol of photocatalyst PQ in CH 3 CN and H 2 O was irradiated under Ar and the progress of the reaction was monitored by TLC. 4l was obtained from cyclopropane substituted substrate 3l, as the major along with the minor (n ¼ 1) product (see the ESI, page S56 and S57, and the spectra on pages S203-S207 †).
Scheme 2 CF 3 -Benzo[b]furans: the scope with regards to the ethynyl and vinyloxy rings; the reactions were carried out at 0.1 mmol of 1a using 0.3 mmol of CF 3 SO 2 Na and 0.01 mmol of photocatalyst PQ in CH 3 CN + H 2 O (0.9 + 0.1 mL) under Ar, and the progress of the reaction was monitored by TLC for 4- 8 h. efficient electron delocalization occurs with the N-protected carbonyl group of carbamate rather than the sufonyl moiety of the tosyl group. The weak mesomeric effect indicates that the sulfur-centered group had increased electron density on the nitrogen, which reected the higher aromaticity of the indole. 30 As a consequence, tosyl becomes a better leaving group than carbamate. Thus the deprotection of the tosyl protecting group under the optimized reaction conditions is attributed to its labile nature. The C 3 -aryloyl triuoromethylated indoles 6c and 6d, benzofuran 2c, and benzothiophene 4k are also characterized by X-ray single crystal structure analysis (for details, see ESI, pages S80-S106 †).

Synthesis of CF 3 -bearing drugs
The synthesis of triuoromethylated drug molecules was explored from synthesized 2-triuoromethyl-C 3 -aryloyl benzofuran 2c and indole 6f by late-stage functionalization (Scheme 5). The bromination of benzofuran 2c using N-bromosuccinimide afforded novel triuoromethylated benzbromarone 7a in 40% yield. The N-alkylation of the synthesized oxy-triuoromethylated indole 6f was observed to be difficult by known methods using KOH in DMSO, Cs 2 CO 3 in DMSO or K 2 CO 3 in DMF and failed to yield N-alkylated indole 7b and instead a decomposed product was realized. 31 The addition of NaH in DMF along with n-propyl iodide at 0 C provided the triuoromethylated JWH-105 7b drug in moderate yield (54%).

Mechanistic study
Labelling and  hydrogen evolution in the reaction mixture (see the ESI, page S7-S8 for details †). 32 Next, a reaction was carried out in CH 3 CNd 3 to study the role of the solvent. Expectedly, 1 H NMR spectroscopy shows the formation of H 2 , which suggests that acetonitrile does not participate in the reaction. When D 2 O was used in the reaction, the formation of H-D (d ¼ 4.55 ppm, J ¼ 42.8 Hz) and H 2 was realized in the 1 H NMR spectrum, revealing the involvement of water in the hydrogen gas evolution (Fig. 3 and Scheme 6). The formation of H 2 gas is attributed to H 2 O in deuterated solvents and it is the result of hydrogen and deuterium exchange (page S8 †).

ESR investigation
To investigate the reaction pathways, EPR experiments were conducted on the reaction mixture. For this purpose, the generated reactive CF 3 radical in the reaction was trapped by the 2-methyl-2-nitrosopropane (MNP) dimer, and its EPR spectrum was monitored (Scheme 7). CF 3 SO 2 Na and MNP in the presence of CH 3 CN/H 2 O under light irradiation provided a triplet centred at 3364.5 G with a coupling constant 14.7 G, which is attributed to the dissociation of MNP to a tert-butyl nitroxide radical (see the ESI, Fig. S6 †). The formation of the tert-butyl nitroxide radical is largely suppressed in CH 2 Cl 2 /H 2 O and the formation of the tertbutyl-triuoromethyl nitroxide radical 7c (Scheme 7) is observed predominantly as the EPR spectrum shows a sextet centered at g ¼ 2.0054 with a coupling constant 12.27 G. 33 A reaction mixture of MNP, CF 3 SO 2 Na and 1a under dark conditions was realized to be EPR silent. Upon light irradiation, the reaction mixture shows a similar well-resolved sextet centered at g ¼ 2.0089 with a coupling constant 12.38 G (Scheme 7 and Fig. 4). The intensity of the EPR signals gradually decreased with time and completely diminished aer 25 minutes. The second time irradiation of the same reaction mixture again showed a sextet signal in the EPR spectrum. This suggests that continuous irradiation of the reaction mixture is necessary for the generation of the CF 3 radical to achieve maximum conversion.

Absorption spectra
UV-visible spectroscopic studies were performed on the reaction mixture to understand the role of PQ. The spectra of PQ shows well-resolved absorption maxima at 420 and 510 nm in CH 3 CN and H 2 O (9 : 1) mixtures (Fig. 5). An equimolar mixture of PQ and CF 3 SO 2 Na did not lead to any change in the absorption spectrum under dark conditions.
The reaction mixture of PQ, CF 3 SO 2 Na and substrate 1a provided a similar absorption spectrum under dark conditions. Further, the impact of light on the reaction progress was studied for 3 h at 30 min time intervals. Upon sunlight irradiation (30 min) of the reaction mixture, the characteristic peaks of PQ completely disappeared (Fig. 5) suggesting the involvement of PQ in the oxy-triuoromethylation reaction.
The absorption spectra of the standard reaction mixture remained nearly unchanged at various time intervals. It seems that photocatalyst PQ is transformed into another species, Scheme 7 The reaction with a radical trapping reagent. The reaction was carried out using CF 3 SO 2 Na (0.3 mmol), 1a (0.1 mmol) and MNP (0.2 mmol) in an EPR tube in CH 2 Cl 2 /H 2 O.  presumably phenanthrene-9,10-diol (PQH 2 ), which might be the dominant species observable by UV-visible spectroscopy under the reaction conditions (Fig. S13, see the ESI page S14 †). A slight increase in the absorption at 420 nm was observed with an increase in time, which could be attributed to the partial regeneration of PQ aer the completion of the reaction. Further, the regeneration of PQ is conrmed by 13 C NMR spectroscopy and mass spectrometry (ESI, page S16 and S17 †).

Cyclic voltammetric study
To gain insights into the redox behaviour of photocatalyst PQ, a cyclic voltammetry study was performed (Fig. 6). The cyclic voltammogram (CV) of PQ shows reversible two-electron reduction processes at À0.52 and À0.70 V (E red 1/2 ) attributed to the quinone / semiquinone and semiquinone / catechol redox couples, respectively (Scheme 8). 35 The considerably lower reduction potentials of PQ, presumably due to the presence of conjugation adjacent to the 9 and 10-positions of the C]O group, provide stability to the radical PQcH and diol PQH 2 . Also, photocatalyst PQ exhibited high stability under the electrochemical redox process as it underwent 12-cycles without any loss in the redox activity.
Photocatalyst PQ has a triplet excited state energy of 2.116 V. 36a Thus, the excited state reduction potential E red 1/2 * ( 3 PQ*/PQc À ) of PQ is 1.6 V (ref. 27f and 36b) and Langlois' reagent exhibits an oxidation potential of 1.05 V (vs. SCE), 37 which suggests that PQ is strong enough for the oxidation of CF 3 SO 2 Na by single electron transfer (DG PET ¼ À12.7 kcal mol À1 ).

Control experiments
To study whether water alone is enough to initiate the reaction, substrate 1a was treated with water in the absence of CF 3 SO 2 Na under optimized reaction conditions (Scheme 9). The hydroxylation of the alkene or alkyne was not observed and 1,6-enyne 1a was recovered quantitatively. It seems that the substrate does not undergo photohydration of the alkynes 34 to provide 1phenyl-2-(2-(vinyloxy)phenyl)ethan-1-one, which is suggestive of the reaction procession being less likely via oxygenation followed by triuoromethylation of substrate 1a.
When the reaction was performed in the presence of a radical scavenger, TEMPO, the formation of 2a was not observed. Instead, the coupling between CF 3 and TEMPO was realized (see ESI, S11 †).

Mechanism, quantum yield and DFT calculations
Based on the control and labelling experiments, it is reasonable to assume that the photoredox catalyst PQ, excited by visible light, activates CF 3 SO 2 Na by single electron transfer to produce a CF 3 radical and SO 2 (Scheme 10). The triuoromethylated radical would add to the vinylic carbon-carbon double bond of the substrate 1a, forming a radical species I, which intramolecularly translocated to the alkyne bond via 5-exo-dig cyclization and thus rearranged to the vinylic radical IIa. The electron transfer from vinylic radical IIa to PQ would lead to vinylic carbocation III and PQH 2 . Although, vinylic carbocations have low thermodynamic stability due to the sp-hybridization of the carbenium centre and as a consequence show poor S 1 N -reactivity. However, the sp-sp 2 rehybridization in the high energy state could account for its electrophilic nature. 38 The second electron accepting ability of the photoredox catalyst PQ would facilitate the formation of vinylic carbocation III.
Alternatively, the alkyl ether radical I may transfer an electron to PQcH intermolecularly and convert into carbocation IIb, which may proceed by an intramolecular cationic cyclization to provide vinylic carbocation III. 39 Fig. 6 The cyclic voltammogram of PQ in CH 3 CN/H 2 O (9 : 1) vs. SCE.

Scheme 9
The attempted hydroxylation of 1,6-enyne 1a. The reaction was carried out using 0.1 mmol of 1a, 0.3 mmol of CF 3 SO 2 Na and 0.01 mmol of PQ in CH 3 CN and H 2 O in a 5 mL round bottom flask.
The slow addition of water to vinylic carbocation III shall provide aquated intermediate IV, which upon release of the proton converts into enol intermediate V. Further, the photoaromatization of enol V would furnish 2-triuromethylation C 3aryloyl benzofuran 2a along with the concomitant release of hydrogen gas. 40 As inferred from the UV-visible study (vide supra), PQH 2 would be the predominant species in the catalytic cycle. PQH 2 could regenerate to PQ by the transfer of its electrons to sulfur dioxide 37 and/or the triuoromethyl radical to form a HSO 2 radical and/or uoroform, respectively.
The quantum yield (QY) can in particular provide valuable insight into the mechanistic understanding of the photocatalytic reaction, which involves radical chain propagation. The QY of the developed reaction, substrate 1a to product 2a, was studied using the photodecomposition of potassium ferrioxalate, which is a well-explored chemical actinometer. 41 The determined QY is 4 ¼ 27 (for details, see the ESI page S17 †) which suggests that 27 equivalents of product 2a are formed for every photon absorbed by the photocatalyst PQ. Therefore, the reaction may proceed via a chain mechanism. The generated HSO 2 radical propagates the radical chain by reacting with Langlois' reagent, which again provides a CF 3 radical, thus continuing the radical chain reaction.
DFT calculations were explored to examine the mechanism of the reaction (Fig. 7 and Scheme 10). The thermodynamic feasibility of the intermediates and oxygenation by water were computed using DFT-B3LYP/6-31+G(d) in a Gaussian 09 suite in CH 3 CN (see the ESI, page S65-S80 †). The Gibbs free energy of the reaction suggests that the proposed intermediates I-V are Scheme 10 Proposed mechanism for C 3 -aryloyl benzofuran. stable under the reaction conditions. 38 The vinylic cation III could be obtained from radical I by two paths A and B (Fig. 7) as the energy difference between them is 2.03 kcal mol À1 . The attack of a water molecule on vinylic cation III could be the key step in the transformation and may occur through a transition state TS. The energy barrier (DG # ) for the step is +16.47 kcal mol À1 , which could be feasible under the reaction conditions. Further, the abstraction of the proton from the hydronium ion IV by PQH À provides a stabilization to intermediate V by the energy difference of 63.52 kcal mol À1 and the subsequent removal of hydrogen gas from the intermediate V lowers the energy by 6.78 kcal mol À1 .

Conclusions
In summary, we have unveiled an oxidant and TM-free visible light induced oxy-triuoromethylation of enynes that enables access to biologically important carboxy-triuoromethylated benzofurans, thiophenes, and indoles. The mild reaction conditions tolerate electronically diverse substrates, regardless of the substitution pattern on either ethynylic or vinylic arene, and as a consequence the methyl group in benzbromarone and JWH015 drugs has been substituted by a triuoromethyl group. This protocol relies on the universal solvent as a source of oxygen for the oxygenation of enynes. The use of a highly practical 9,10-phenanthrequinone photoredox catalyst, which has a two electron redox property, seems crucial for the transformation as it not only generates tri-uoromethyl radicals from the Langlois' reagent by an electron transfer, but it also brings about one electron oxidation of enynes by a second electron transfer, which in turn facilitates oxygenation utilizing water followed by hydrogen gas evolution under oxidant and TM-free mild conditions. Moreover, we have shown that the di-functionalization of the vinylic double bond adjacent to the heteroatom, which is a formidable task due to the cleavage of the labile carbon-heteroatom bond, can be achieved under the developed conditions. The nding of oxy-triuoromethylation of enyne substrates under metal and oxidant-free conditions opens a new avenue for the synthesis of triuoromethylated advance heterocyclic molecules under atom and step economical pathways.