A Direct Access to Thiocyano-Thioesters from Cyclic Thioacetals via Photoredox Catalysis: An Introduction of Two Functional groups in One-Pot
The cyanation of organic compounds is an important and useful process as it directly provides nitriles which in turn can be utilized for different transformations. Although, thiocyanate salt has emerged as a very mild and environmentally friendly "source of CN" alternative to toxic and metal based cyanating reagents; its synthetic utility for the cyanation is highly limited to very few types of organic compounds. We have explored the reactivity of sodium thiocyanate for directly cyanating cyclic thioacetals for accessing thiocayano-thioesters with two different functional groups in one pot using photoredox catalysis under mild reaction conditions. Based on the reactivity of thiocyanate radical, the protocol has been further extended for the direct cyanation of disulfides and diselenides to access aryl thiocyanates and aryl selenocyanate. A series of control experiments and Stern-Volmer studies have been carried out to validate the mechanistic pathways.
Introduction<!>Scheme 1: Application of thiocyanates in organic transformations<!>Results and Discussion<!>Table 1. Reaction optimization a-f<!>Table 2. Substrate scope<!>Scheme 2. Control experiments<!>Fig. 1. Plausible reaction mechanism<!>Table 3. Substate scope<!>Conclusions<!>EXPERIMENTAL SECTION<!>General procedure A for the synthesis of compounds 1: (1,3dithiane and 1,3-dithiolane protection of aldehyde)<!>General procedure C for the synthesis of aryl thiocyanate 4.<!>S-(2-thiocyanatoethyl) benzothioate (2a):<!>S-(2-thiocyanatoethyl) 2-methoxy-5-(trifluoromethoxy)benzothioate (2f):<!>S-(2-thiocyanatoethyl) 3-chlorobenzothioate (2i):<!>S-(2-thiocyanatoethyl) 3-bromobenzothioate (2k):<!>S-(3-thiocyanatopropyl) benzofuran-2-carbothioate (2ab):<!>2-thiocyanatopyridine (4f):
<p>Organic thiocyanates are very important and useful synthetic intermediates for the synthesis of tetrazoles and different functionalities such as thiols, disulfides, thioethers, trifuloromethyl thioethers, thiocarbamates, thioesters, and sulfonyl cyanides. [1][2][3][4][5][6][7][8][9] Likewise, thioesters are also important synthetic intermediates in many bio-synthetic pathways such as native chemical ligation, protein synthesis and nucleic acid synthesis. 10 Also, thioesters have been utilized in the drug delivery applications, biomolecules labelling. 11 Thioesters have also been employed as important building blocks alongside its synthetic utility as an acyl radical equivalent in many acyl transfer reactions. 12 Traditionally, the cyanation of organic molecules have been achieved using cyanating agents or by exploring the combined "CN source" starting from solvent (as a carbon source) and ammonium iodide/ammonium carbonate/ammonium bicarbonate/urea as nitrogen source under palladium catalysis or stoichiometric amount of copper at an elevated reaction temperature. 13 Most of these protocols relied on stoichiometric amount of oxidants, transition metals, ligands, costly reagents or more importantly usage of extremely toxic "CN sources" (CuCN) at an elevated reaction temperature. In order to overcome this, different thiocyanate salts have been explored as "CN source" that are inexpensive, easily available, comparatively non-toxic and bench-stable. Recently, thiocyanate salt has been used as a source of nitrogen for directly accessing phenylglyoxamides starting from acetophenone (Scheme 1a). 14 The cyanation of aromatic halides has been achieved by CuSCN via palladium catalysis to access a wide variety of aromatic nitriles (Scheme 1b). 15 The reaction of tertiary amines and KSCN under oxidizing reaction condition ( t butoxide as an oxidant) at an elevated temperature afforded the corresponding nitriles (Scheme 1c). 16 The cyanation of in situ generated carbene from the tosylhydrazone has been reported using KSCN and CuI at 80 ℃ under alkaline reaction conditions (Scheme 1d). 17 Very recently for the first time, metal-free cyanation of thiophenol under visible light photoredox condition has been achieved by generating electrophilic thiocyanate radical as a "source of CN" to access a wide variety of aryl thiocyanates under oxygen atmosphere (Scheme 1e). 18</p><!><p>However, this useful and straightforward protocol for the cyanation using non-toxic ammonium thiocyanate salt is limited only to thiophenols. More importantly, the cyanation of thioethers has not been achieved till date to the best of our knowledge. We have been working on photoredox catalysis and our continuous interest on thioacetals led us to focus on developing a protocol for the direct cyanation of organic molecules such as cyclic thioacetals under milder reaction conditions using inexpensive and environmentally benign cyanating reagents. Based on our experience, the formation and the cleavage of the dithioacetals is known to proceed via thiyl radical under photoredox condition. 19a-c Recently our research group has achieved the disulphide-linked-dithioesters starting from dithioacetals using base dependent photoredox catalysis and this transformation has been proved to proceed via the cleavage of C-S bond. 19c Based on the same concept, we have hypothesized that the in situ generated electrophilic thiocyanate radical can be trapped with dithioacetals to generate the molecules with the dual functional groups (thiocyano-thiosesters) in a single step under suitable reaction conditions. We envisaged that thiocyano-thioesters can be synthesized directly from dithioacetals by trapping the thyil radical with thiocyanate salt. Herein, we report the direct generation of two functional groups to access thiocayano-thioesters from dithioacetals under photoredox catalysis in one pot.</p><!><p>In order to validate our hypthesis we commenced with the model reaction of dithiolane 1a and ammonium thiocyanate in presence of K2CO3 as a base, Rhodamine 6G (2 mol%) as a photocatalyst, in dry acetonitrile under oxygen atmosphere by irradiating with blue LEDs for 8 h. The reaction afforded the corresponding desired product 2a albeit in poor yield (15% Table 1, entry 1). Gratfyingly, the reaction of 1a in presence of sodium thiocyanate under the reaction conditions afforded the desired product 2a in very good yields (83%, Table 1, entry 2). In order to further optimize the reaction condition, we screened reaction using different photocatalysts such as Eosin Y, Rhodamine 6G (Rh6G), Ru(bpy)3Cl2, Ir(bpy)3, Acridiniumperchlorate and Pyrillium-tetrafluroborate (Table 1, Entries 2 and 3-6). Among all the photocatalysts, Rh6G found to be optimum photocatalyst for the desired transformation by affording the desired product 2a in very good yield (83% yield, Table 1, entry 2). Later, we screened different solvents and among all anhydrous acetonitrile proved to be advantageous for the smooth transformation of 1a to thiocayano-thioester 2a (Table 1, Entry 2 and 7-11). Among different bases screened, K2CO3 turned out to be most suitable base by providing the desired product 2a in very good yield (83%) (Table 1. Entries 2 and 12-15). There was no significant change in the reactivity of sodium thiocyanate and potassium thiocyanate on the out come of desired product 2a formation (83%, 82% yields respectively, see ESI 1.3, Entry 5 and 6). Later, we screened the desired reaction with variable stiochimetric amounts of sodium thiocyanate. We observed that excess sodium thiocyanate (5 equiv.) was essential for the smooth transformation to access the desired product 2a in very good yield (See ESI, 1.3). The desired reaction did not work in the absence of light, photocatalyst and oxygen indicating these are very essential and ncessary requirement for the smooth and facile transformation (Table 1, entry 16, 18 and 19). While, the reaction in absence of base offered trace amount of desired product 2a (Table 1, entry 17).</p><!><p>In order to valiadate the necessity of anydrous solvent, we carried out the reaction in moist acetonitrile (undried). We observed the reduction in the yield of desired product 2a (71%, Table 1, entry 20). Based on the exhaustive screening, dithiolane 1a (1 equiv.), NaSCN (5 equiv.), K2CO3 (2 equiv.), Rh6G (2 mol%) in dry acetonitrile under O2 atmosphere and blue LEDs (15 W) proved to be optimum reaction condition. Having optimized the reaction condition, we planned to explore diverse substrate scope of dithiolanes so as to generalize this protocol (Table 2). All the electronically neutral dithiolanes (1a-c) under the optimized reaction conditions offered the corresponding thiocyanao-thioesters (2a-c) in very good yields (upto 87%). Elelctron rich substrates (1d-1f) reacted smoothly to afford the desired products (2d-2f) in very good yields (upto 89% optimized reaction conditions to furnish the desired products (2g-m) in a very good yields (upto 82%, Table 1). Naphthalene-1-dithiolane as well as naphthalene-2-dithiolane derivatives (1n, 1o) also offerded the corresponding desired products 2n and 2o in very good yields (upto 83%). Further, dithiolane derived from aromatic aldehyde with electron withdrawing substituent (-CN) also afforded the desired product 2p in good yield and the molecular structure of the 2p was unambiguously confirmed by the single crystal X-ray analysis. 20 Even the dithiolanes derived heterocyclic aldehydes 1q-1r also worked smoothly under the reaction conditions to afford corresponding products 2q-2r in excellent yields (upto 87%, Table 1). Dithiolane substrates containing protecting groups afforded the corresponding products 2s-2u in moderate to good yields (up to 76%) and the all protecting groups tolerated the reaction conditions. Later, reactivity of dithianes (six-membered cyclic thioacetals) have been explored to generalize this protocol. Gratifyingly, different dithianes 1v-1ab derived from electron rich as well as electron difficeint aromatic aldehydes, and</p><!><p>Heteroaromatic aldehydes afforded the corresponding desired products 2v-2ab in good yields (upto 66%, Table 1).</p><p>In order to have an insight into the reaction mechanism, we carried out few control experiments systematically. The reaction of dithiolane 1a in presence of TEMPO did not work thus confirming the radical nature of the transformation (Scheme 2a). The reaction in absence of oxygen (under argon atmosphere) did not work indicating the necessary requirement of oxygen for this reaction (Scheme 2b). Later, in order to investigate the involvement of singlet oxygen if any in the reaction pathway, reaction of 1a was carried out in presence of DABCO (singlet oxygen quencher). We observed that reaction worked smoothly and DABCO did not have any impact in the yield of 2a thus indicating that singlet oxygen has no significant role in the reaction pathway (Scheme 2c). 21 While, the reaction of 1a in presence of p-benzoquinone under standard optimized reaction conditions did not work. This result confirmed the involvment of superoxide radical anion in the reaction mechanism (Scheme 2d). 22 The reaction in presence of water led to significant reduction in the yield of desired product 2a along with the corresponding benzaldehyde as a side product 1a′ (scheme 2e).</p><!><p>While, the reaction in dark but in presence of photocatalyst under standard reaction conditions at an elavated reaction temperature (60 o C) did not work (Scheme 2f). This indicated that not only the photocatalyst but also the light is absolutely essential for this transformation and the temperature do not have any role for the desired product fromation. Further, in order to confirm the possible single electron transfer (SET) event of Rh6G* with dithioacetal or NaSCN, we carried out the Stern-Volmer experiment. This study revealed that the efficiency of the SET of Rh6G* with the NaSCN is much higher than that of 1a (see ESI 1.4). The efficiency of SET of NaSCN with the Rh6G* was further supported by the oxidation potential of NaSCN (E ox = +0.66 V vs SCE) which is less than the reduction potential of Rh6G* (E red = +1.39 V vs SCE). +1.26 V vs SCE) by the reductive quenching pathway to generate the photocatalyst radical anion (Rh6G •− , reduced form) and thiocyanate radical (oxidized form • SCN).</p><!><p>This SET event was unambiguously confirmed by the Stern Volmer experimental studies (ESI 1.4). Further, Rh6G</p><p>Based on the plasuible reaction mechanism, it is evident that after SET process, the in situ generated oxidized thiocyanate radical is more likely to be electrophilic and has high possibility to be attacked by the nucleophilic sulfur atom of dithioacetal followed by the cleavage of bond (with the neighbouring carbon atom). In order to explore the reactivity of thiocyanate radical and to validate this hypothesis, we planned to trap this using suitable compounds such as aryl disulfides (Fig 2).</p><p>In this regard, we commenced with a model reaction of diphenyl disulfide 3a, sodium thiocyanate (5 equiv.) under standard optimum reaction conditions used for obtaining thiocyano-thioesters. Gratifyingly, we obtained the corresponding desired phenyl thiocyanate 4a in excellent yield (93%, Table 3). Encouraged by this initial success, we planned to generalise this protocol as further application and for the wider applicability (Table 3).</p><!><p>Reaction of differen diaryl disulfides 3b-3f, reacted smoothly with sodium thiocyanate under the reaction conditions to afford the corresponding aryl thiocyanates 4b-4f in excellent yields (up to 95%, Table 3). Even diphenyl diselenide 3g reacted smoothly with sodium thiocyanate under the reaction conditions to afford the corresponding phenyl selenocyante 4g in very good yield (89%). This protcol also proved to be very efficient in synthesizing thiocyantes from easily accessible diaryl disulfides in one pot.</p><!><p>In summary, we have successfully developed the safe and environmentally benign protocol for the cyanation of cyclic thioacetals and disulfides to access thiocyano-thioesters and aryl thiocyanates respectively using commercially viable and nontoxic sodium thiocyanate as a cyanating source under visible light conditions. The protocol offers the direct access to a wide range of thiocyano-thioesters and aryl thiocyantes starting from dithioacetals and aryl disulfides respectively for the first time using the photoredox-catalysis under ambient reaction condition. The protocol proved to be efficient and worled under ambient reaction condition using clear energy source and do not require external oxidizing reagent.</p><!><p>General Information: Reagent Information: All reactions were carried out with distilled and dried solvents using oven-dried glass a wares under dry Argon atmosphere, unless otherwise stated. All reagents were purchased from commercial sources and used as received, unless otherwise indicated. Thin layer chromatography (TLC) was performed using silica gel 60 GF254 pre-coated aluminum backed plates (2.5 mm) with detection by UV light. Visualization was accomplished by irradiation with a UV light at 254 nm and vanillin staining agent. Column chromatography was performed using silica gel (100-200 mesh) eluting with petroleum ether and ethyl acetate. Petroleum ether and ethyl acetate mixture was used as gradient elution for column chromatography. Analytical Information: All isolated compounds were characterized by Proton ( 1 H) and carbon ( 13 C) NMR spectra were recorded on a 400 MHz Jeol ECS-400 and Bruker Avance III HD Ascend 400 MHz spectrometer. All Nuclear Magnetic Resonance spectra were recorded in CDCl3. The NMR spectra were recorded using tetramethyl silane (TMS) as the internal standard. 1 H NMR spectra were recorded at 400 MHz and 13 C NMR spectra were recorded at 100/150 MHz (Bruker and Jeol), unless otherwise noted. Chemical shifts (δ) are reported in ppm downfield from CDCl3 (δ = 7.26 ppm) for 1 H NMR and relative to the central CDCl3 resonance (δ = 77.16 ppm) for 13 C NMR spectroscopy. For 1H NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, s = sextet, h = heptet, m = multiplet, br = broad), coupling constants (J) and integration. Coupling constants (J) are reported in Hertz (Hz). Carbon chemical shifts are reported in ppm from tetramethyl silane (TMS) with the solvent resonance as the internal standard (CDCl3 δ 77.0 ppm). coupling constants (J) are given in Hz and integration. 13 C NMR spectra were recorded with complete proton decoupling. 19 F NMR spectra were recorded at 377 MHz. Mass samples were analyzed by high resolution mass spectrometry (HRMS) using ESI TOF. Melting points were measured in an open glass capillary and values are uncorrected. Mass samples were analyzed by High-Resolution Mass Spectrometry (HRMS) using ESI-TOF. Melting points were measured in capillary tubes on a Büchi B-540 apparatus, are uncorrected. Fluorescence emission spectra were obtained on a Fluoromax-4 spectrofluorometer from Horiba Jobin-Yvon, with xenon light source in a 3 mL, Hellma fluorescence cuvette (path length 1.0 cm). 25 To a round bottom flask containing SiO2, PPA (6.5 w/w %) was added DCM (10 mL) and stirred well for 15 min. After that DCM was evaporated to obtain a well mixed SiO2-PPA mixture. To this mixture, DCM (15 mL), aldehyde (1 equiv.; 1.5 mmol) and 1, 2-dithiane (1.2 equiv.), or 1,3-dithiane (1.2 equiv.) were added, and stirred for 6 h at room temperature. After completion of the reaction (monitored by TLC) the solution was filtered through cotton. The filtrate was treated with saturated KOH solution (5 mL) and stirred for 30 min to quench excess dithiane. After which, solution was extracted with dichloromethane (3 x 20 mL). The combined extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was further purified by column chromatography over silica gel to afford the corresponding compound 1.</p><!><p>General procedure B for the synthesis of thioester-thiocyanate 2.</p><p>An oven-dried round bottom flask equipped with a stir bar and rubber septum is charged with dithiolane 1 (0.1 mmol, 1 equiv.), K2CO3 (0.2 mmol, 2 equiv.), NaSCN (0.5 mmol, 5 equiv.) Rhodamin6G (2 mol%), dry MeCN (2 mL). The reaction mixture was initially purged with O2 for 5 min and the oxygen atmosphere was maintained throughout the reaction (using a Oxygen balloon). The reaction mixture was stirred under the irradiation of blue LEDs (15 W) at room temperature for 6-12 h (monitored by TLC). After completion of the reaction, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography over silica gel using mixture of petroleum ether/EtOAc as an eluent to afford the corresponding 2. (Note-The presence of moisture and the impurity of 1, 2-ethanedithiol in dithiolane (1) greatly influences the yield of reaction. Dry solvent is must to avoid the deprotection to corresponding aldehyde. The reaction temperature is 25-30 o C).</p><!><p>An oven-dried round bottom flask equipped with a stir bar and rubber septum is charged with diaryl disulfide 3 (0.1 mmol, 1 equiv.), K2CO3 (0.2 mmol, 2 equiv.), NaSCN (0.5 mmol, 5 equiv.) Rhodamin 6G (2 mol%), MeCN (2 mL). The reaction mixture was initially purged with O2 for 5 min and the oxygen atmosphere was maintained throughout the reaction (using a Oxygen balloon). The reaction mixture was stirred under the irradiation of blue LEDs (15 W) at room temperature for 6-12 h (monitored by TLC). After completion of the reaction, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography over silica gel using mixture of petroleum ether/EtOAc as an eluent to afford the corresponding 2. (Note-The presence of moisture and the impurity of 1, 2-ethanedithiol in dithiolane (1) greatly influences the yield of reaction. Dry solvent is must to avoid the deprotection to corresponding aldehyde. The reaction temperature 25-28 o C).</p><!><p>The compound 2a was prepared following the General Procedure B. colourless liquid (18 mg, 83% yield), Rf = 0.4 (1:15 :: EA:pet ether), 1</p><!><p>The compound 2f was prepared following the General Procedure B. colourless liquid (28 mg, 83% yield); Rf = 0.4 (3:20 :: EA:pet ether), 1</p><!><p>The compound 2i was prepared following the General Procedure B. colourless liquid (19 mg, 73% yield); Rf = 0.4 (1:9 :: EA:pet ether), 1 H NMR (400 MHz, CDCl3): δ 7.91 (t, J = 2.1 Hz, 1H), 7.83 (dt, J = 7.9, 1.3 Hz, 1H), 7.58 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.42 (t, J = 7.9, 1.0 Hz, 1H), 3.49 -3.45 (m, 2H), 3.24 -3.20 (m, 2H). 13</p><!><p>The compound 2k was prepared following the General Procedure B. colourless liquid (25 mg, 82% yield); Rf = 0.4 (1:9 :: EA:pet ether), 1 H NMR (400 MHz, CDCl3): δ 8.07 (t, J = 1.9 Hz, 1H), 7.88 (dt, J = 7.9, 1.4 Hz, 1H), 7.74 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 3.60 -3.37 (m, 2H), 3.28 -3.07 (m, 2H). 13</p><!><p>The compound 2ab was prepared following the General Procedure B. colourless liquid (14 mg, 55% yield); Rf = 0.4 (2:15 :: EA:pet ether), 1 H NMR (400 MHz, CDCl3): δ 7.71 (dt, J = 8.0, 1.0 Hz, 1H), 7.59 (dq, J = 8.5, 0.9 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.49 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.33 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 3.27 (t, J = 6.8 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.26 (p, J = 6.9 Hz, 2H).</p><!><p>The compound 4f was prepared following the General Procedure C. colourless liquid (24 mg, 91% yield); Rf = 0.4 (1:9 :: EA:pet ether), 1 H NMR (400 MHz, CDCl3): δ 8.50 (ddd, J = 4.8, 2.0, 0.9 Hz, 1H), 7.75 (td, J = 7.8, 1.9 Hz, 1H), 7.58 (dt, J = 8.1, 1.0 Hz, 1H), 7.26 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H). 13</p>