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Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: Sulfenylation of Enaminones Using Dimethyl Sulfoxide as an Oxidant Yogesh Siddaraju and Kandikere Ramaiah Prabhu* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India

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ABSTRACT: Synthesis of polyfunctionalized aminothioalkenes has been demonstrated using iodine as a catalyst (30 mol %) and dimethyl sulfoxide as an oxidant under metal-free reaction conditions. This methodology allows a facile sulfenylation of enaminones with a broad range of heterocyclic thiols and thiones using cross dehydrogenative coupling methods. In addition, this strategy is highly practical as it employs inexpensive and readily available iodine and DMSO with a short reaction time. The current methodology is one of the simplest methods and provides a straightforward approach to sulfenylation of enaminones via the cross dehydrogenative coupling method.

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enaminones using KIO3 as a catalyst and air as an oxidant.9 Loh and his group reported a similar transformation using a Pdcatalyzed C−H functionalization strategy.10 Although enamine sulfenylation has been studied extensively, there are no methods available for the sulfenylation of a broad range of heterocyclic thiols and thiones using CDC methods (Scheme 1). Unlike simple thiols, most of the heterocyclic thiols and thiones do not smell bad and are stable compounds that can be directly used in CDC reactions. Heterocyclic thiols and thiones are useful precursors for synthesizing a variety of pharmaceutically active and medicinally important compounds. Hence, the development of efficient functionalization strategies using heterocyclic thiols and thiones is in demand.11 In our effort to develop iodine- and DMSO-promoted reactions1h,i and metal-free reactions,12 we describe herein a successful sulfenylation of enaminones catalyzed by iodine.

INTRODUCTION In recent years, the use of dimethyl sulfoxide as an oxidant is emerging as one of a research topic of great interest and utility.1 Because of growing concerns about environmental protection and waste generation, considerable effort has been directed toward finding alternative sustainable methods. The interest in designing reactions using DMSO as an oxidant arises from the fact that DMSO is (i) less expensive, (ii) abundant, (iii) less toxic and, (iv) environmentally benign.1 The persiut of environmentally benign reactions led to the discovery of cross dehydrogenative coupling (CDC) reactions, which have become a powerful strategy for the construction of carbon− carbon and carbon−heteroatom bonds. Additionally, the CDC reactions offer shorter, atom economical, and environmentally benign synthetic routes.2 In this direction, there is great interest among synthetic chemists in using enaminones as precursors under CDC reaction conditions. As a result, continuing effort has been spent on the formation of C−O and C−N bonds under CDC reaction conditions.3,4 The group of Du and Zhao developed a mild CDC method for β-acyloxylation of enamines with carboxylic acids using iodosobenzene as an oxidant.3 Later, the same group reported another CDC method for the oxidative coupling of enamines with electron deficient amines using a combination of TBAI and TBHP.4 However, only a few methods have been reported for the sulfenylation of enamines leading to C−S bond formation. The available methods employ nucleophilic attack of thiols on enol-tosylates, which involve the prefunctionalized enamine.5 Tokumitsu and Hayashi developed a method for sulfenylation of enaminones using sulfenyl chloride.6 The method developed by Yang and Deng involves silver salt-mediated sulfenylation of enamides with disulfide.7 Recently, the groups of Du and Wan independently reported sulfenylation of enaminones under metal-free conditions.8,9 Du and co-workers reported oxidative coupling of enamines with disulfides by using TBAI as a catalyst and TBHP as an oxidant,8 whereas Wan and co-workers reported sulfenylation of © 2017 American Chemical Society

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RESULTS AND DISCUSSION Optimization of Reaction Conditions. To identify the optimal conditions, we started the investigation using 1-phenyl1H-tetrazole-5-thiol (1a) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2a) as model substrates and screened a variety of solvents (Table 1). The initial screening reaction began with the treatment of 1a and 2a with 20 mol % iodine. As shown in Table 1, the solvent screening studies revealed that DMSO is the most suitable solvent, which furnished product 3a in 70% yield (entry 1 of Table 1). Solvents such as DMF, DMA, CH3CN, DCE, and EtOAc were found to be not suitable for promoting the reaction (entries 2−6, respectively, of Table 1; see Table S1 for more details). Other iodine sources such as KI and KIO3 furnished 3a in trace amounts and 29%, respectively (entries 7 and 8, respectively, of Table 1). Screening of electrophillic halogens such as NBS and NCS also furnished 3a Received: January 11, 2017 Published: February 23, 2017 3084

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

Article

The Journal of Organic Chemistry Scheme 1. Approach for Sulfenylation of Enamines

corresponding sulfenylated products in good yields [3d−3j (Scheme 2)]. The scope of the reaction has been further evaluated using enaminone derivatives that contain naphthyl, thiophene, and furan moieties. Thus, the naphthyl derivative of enaminone furnished coupled product 3k in 80% yield, whereas thiophene and furan derivatives of enaminones underwent a smooth reaction, furnishing sulfenylated products 3l and 3m in good to moderate yields [65 and 52% yields, respectively (Scheme 2)]. Similarly, cyano- and nitro-substituted enamines successfully participated in the reaction, affording 3n and 3o in good to moderate yields (61 and 54%, respectively). Estersubstituted enaminones were found to be less reactive and afforded corresponding sulfenylated product 3p in 34% yield, whereas the cyclic enaminone was found to be more reactive, furnishing coupled product 3q in 82% yield. Encouraged by these results, we turned our attention to the sulfenylation of N,N-dimethylamino enaminone derivatives uisng a variety of thiol and thione derivatives (Scheme 3). The reactivity of various thiophenol derivatives was tested with (E)-4-[3-(dimethylamino)acryloyl]benzonitrile under the standard conditions. It was found from these reactions that thiophenol and 2-methylbenzenethiol furnished products 4a− 4c in 67, 65, and 68% yields, respectively (Scheme 3). The reactions of halogen-substituted thiophenol derivatives were examined by reacting a variety of halo-thiols with (E)-4-[3(dimethylamino)acryloyl]benzonitrile. Thus, the reactions of 2-

in trace amounts (entries 9 and 10, respectively, of Table 1). Increasing or decreasing the number of equivalents of 1a and 2a did not bring any noticeable change (entries 11 and 12, respectively, of Table 1). Increasing the amount of iodine to 30 mol % resulted in the formation of product 3a in 76% yield. Further increasing the amount of iodine to 50 mol % did not remarkably change the yield (entries 13 and 14 of Table 1). The reaction also proceeded well under an argon atmosphere in the absence of any oxidants (entry 15 of Table 1). Using TBHP in decane (5.5 M) as an oxidant also led to the formation of 3a in 70% yield (entry 16 of Table 1). The reaction did not proceed in the absence of iodine (entry 17 of Table 1). With these screening studies, the reaction of thiol (1 equiv) with enamine (1.1 equiv) in DMSO (1 mL) as a solvent at 80 °C for 1 h (entry 13 of Table 1) has been established as the optimal reaction. Under the optimized reaction conditions, the scope of this methodology has been studied by reaction of a variety of acyclic and cyclic enaminones with 1-phenyl-1H-tetrazole-5-thiol (1a). As shown in Scheme 2, the reactions were very clean and expected coupled products were obtained in good to moderate yields. The enaminones bearing electron-releasing groups furnished their corresponding sulfenylated products 3b and 3c, each in 68% yield. Enaminones that contain halogen substitutions and electron-withdrawing groups underwent a smooth reaction under the optimal conditions, affording their 3085

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The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

entry

catalyst or additive (mol %)

solvent

isolated yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) KI (20) KIO3 (20) NBS (20) NCS (20) I2 (20) I2 (20) I2 (30) I2 (50) I2 (30) I2 (30) none

DMSO DMF DMA CH3CN DCE EtoAc DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO

70 18 trace trace not detected not detected trace 29c trace trace 62d 72e 76 77 72f 70g not detected

thiol underwent sulfenylation with (Z)-4-aminopent-3-en-2one, furnishing corresponding sulfenylated products 5d−5f in good to moderate yields (Scheme 4). However, these reactions required 50 mol % iodine, whereas 5-methyl-1,3,4-thiadiazole2-thiol required a stoichiometric amount of iodine (see Table S6 for more details). Similarly, heterocyclic thiones such as benzo[d]thiazole2(3H)-thione, 5-methoxybenzo[d]thiazole-2(3H)-thione, and 4-methylthiazole-2(3H)-thione furnished their corresponding sulfenylated products 5g−5i in 91, 88, and 74% yields, respectively (Scheme 4). Among these thiones, benzo[d]oxazole-2(3H)-thione was found to be less reactive and afforded 5j in poor yield (30%). These reactions are performed by using 50 mol % iodine (see Table S7 for more details). Similarly, under the optimal reaction conditions, 4-bromobenzenethiol and naphthalene-2-thiol underwent a smooth sulfenylation reaction with (Z)-4-aminopent-3-en-2-one, affording coupled products 5k and 5l in 82 and 78% yields, respectively (Scheme 4). To gain insight into the mechanism, a few control experiments were performed. First, the reaction of 1-phenyl1H-tetrazole-5-thiol (1a) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2a) under the optimal reaction conditions in the presence of TEMPO was found proceed well to form product 3a in 72% yield, indicating that the reaction is not proceeding through a radical mechanism (Scheme 5a). To confirm the role of DMSO as an oxidant, a reaction was performed using 3 equiv of DMSO and 30 mol % iodine in dichloroethane as a solvent, which afforded product 3a in 58% yield, whereas the same reaction in the absence of DMSO did not furnish sulfenylated product 3a (Scheme 5b). It is relevant to recall that the reaction of 1a with 2a in DMSO proceeded well under an argon atmosphere (entry 15 of Table 1). These experiments clearly support the role of DMSO as an oxidant. The reaction of 2a proceeded well with disulfides such as 1,2bis(1-phenyl-1H-tetrazol-5-yl)disulfane and 1,2-bis(benzo[d]thiazol-2-yl)disulfane in the presence of a catalytic amount of iodine [10 and 20 mol % iodine, respectively (Scheme 5c,d)]. These reactions clearly indicate that the disulfide is an intermediate in the reaction. Under the optimal reaction conditions, the reactions of benzo[d]thiazole-2(3H)-thione or 1-phenyl-1H-tetrazole-5-thiol (1a) in the absence of enaminone resulted in the decomposition of starting material (Scheme 5e; see Table S8 for more details). Similarly, for the reaction of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one in the absence of thiol or thione, there was no reaction observed, and the enaminone was recovered (Scheme 5f). Benzenethiol under the optimal reaction conditions afforded 1,2-diphenyldisulfane (6) in 78% yield (Scheme 5g). On the basis of these control experiments and the literature precedent,1 a tentative mechanism has been proposed in Scheme 6. 1-Phenyl-1H-tetrazole-5-thiol (1a) reacts with iodine to form a 1,2-bis(1-phenyl-1H-tetrazol-5-yl)disulfane (II) and HI. 1,2-Bis(1-phenyl-1H-tetrazol-5-yl)disulfane (II) reacts with DMS:I2 or I2 to form an intermediate that contains a S−I bond (III). In addition, nucleophilic displacement of an iodo group by enaminone forms product 3a and byproduct HI. Also, iodine is regenerated by the reaction of HI with DMSO, and the cycle continues (Scheme 6).

a Reaction conditions: 1a (0.56 mmol), 2a (0.62 mmol), and catalyst (0.17 mmol) in 1 mL of solvent at 80 °C. bIsolated yield. cReaction at 80 °C for 6 h. dWith 1.5 equiv of 1a and 1 equiv of 2a. eWith 1.5 equiv of 2a. fReaction under an argon atmosphere. gOne equivalent of TBHP in 5.5 M decane.

fluorobenzenethiol, 3-chlorobenzenethiol, 4-chlorobenzenethiol, and 4-bromobenzenethiol with (E)-4-[3(dimethylamino)acryloyl]benzonitrile were found to be facile, furnishing coupled products 4d−4g in 66, 80, 73, and 80% yields, respectively (Scheme 3). Similarly, the reaction of naphthalene-2-thiol with (E)-4-[3-(dimethylamino)acryloyl]benzonitrile furnished corresponding sulfenylated product 4h in 66% yield (Scheme 3). The scope of this sulfenylation has been further extended by coupling heterocyclic thiols or thiones with enamenones. Thus, 1-methyl-1H-tetrazole-5-thiol underwent a sulfenylation to form 4i in moderate yield (58%), whereas benzo[d]thiazole-2(3H)-thione was successfully coupled with enaminone derivatives to afford corresponding coupled products 4j−4l in 54, 64, and 82% yields, respectively (Scheme 3). However, these three reactions were performed using 50 mol % iodine. After successfully examining the sulfenylation of (E)enaminones, we further evaluated the substrate scope using (Z)-enaminones such as (Z)-4-aminopent-3-en-2-one, (Z)-4(phenylamino)pent-3-en-2-one, and methyl (Z)-3(phenylamino)but-2-enoate. (Z)-Enaminones that contain a free NH2 group such as (Z)-4-aminopent-3-en-2-one furnished coupled product 5a in 81%, whereas enaminones that have an aromatic group substituted on NH2 furnished correspoding sulfenylated products 5b and 5c in 69 and 45% yields, respectively (Scheme 4). Next, the substrate scope was further evaluated by performing the sulfenylation reaction with a variety of heterocyclic thiols, thiones, and thiophenol derivatives (Scheme 4). Heterocyclic thiols such as pyridine2-thiol, pyrimidine-2-thiol, and 5-methyl-1,3,4-thiadiazole-2-

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CONCLUSION In conclusion, we have described an iodine-catalyzed sulfenylation of enaminones under metal-free reaction con3086

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The Journal of Organic Chemistry Scheme 2. Substrate Scope with Heterocyclic Thiolsa,b

a

Reaction conditions: 1a (0.56 mmol), 2a (0.62 mmol), and catalyst (0.17 mmol) in DMSO (1 mL) at 80 °C for 1 h. bIsolated yield. signal (CDCl3, δ 77.00; DMSO-d6, δ 39.5) was used as an internal standard for 13C NMR. IR spectra were recorded using an FT-IR spectrometer. Mass spectra were recorded with a Q-TOF mass spectrometer (HRMS). Flash column chromatography was conducted by packing glass columns with commercial silica gel 230−400 mesh (commercial suppliers), and thin-layer chromatography was performed using silica gel GF-254. All catalysts and reagents were procured from commercial suppliers. Dichloroethane solvent was distilled over calcium hydride, stored over molecular sieves, and used for all procedures. Other solvents, used for workup and chromatographic procedures, were purchased from commercial suppliers and used without any further purification. Typical Experimental Procedure for Sulfenylation of Enaminones. Heterocyclic thiol (0.56 mmol) and enaminone (0.62 mmol) were dissolved in DMSO (1 mL), and iodine (0.17 mmol) was added (direct addition of iodine for thiols without solvent is highly exothermic, and decomposition of thiol was observed). The reaction mixture was stirred at 80 °C for 1 h. After the completion of the reaction (monitored by TLC), water (25 mL), a dilute sodium thiosulfate solution (5 mL), and an extract product with ethyl acetate

ditions using DMSO as an oxidant that shows a broad substrate scope. We believe that this is one of the simplest methodologies that provide a straightforward approach for sulfenylation of heterocyclic thiols, heterocyclic thiones, and thiophenol derivatives under CDC conditions. The salient features of this methodology are (1) the reaction being performed in the absence of metals, (2) the utility of commercially available materials, (3) the operational simplicity and short reaction time, (4) the lack of a requirement for an inert atmosphere or dry solvent, and (5) the reaction being tolerant to a broad range of thiols and thiones with various enaminone derivatives, which is most important.

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EXPERIMENTAL SECTION

General Information. NMR spectra were recorded on a 400 MHz spectrometer in CDCl3 or DMSO-d6. Tetramethylsilane (TMS; δ 0.00) for 1H NMR in CDCl3 and a residual nondeuterated solvent peak (δ 2.50) in DMSO-d6 served as an internal standard. The solvent 3087

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

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The Journal of Organic Chemistry Scheme 3. Substrate Scope Thiol and Thione Derivativesa,b

a Reaction conditions: 1 (0.5 mmol), 2a (0.55 mmol), and iodine (0.15 mmol) in DMSO (1 mL) at 80 °C for 1−3 h. bIsolated yield. cWith 50 mol % iodine used.

(3 × 20 mL) were added. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using 30−80% EtOAc/hexane to obtain the pure products. (Z)-3-(Dimethylamino)-1-phenyl-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3a). Pale yellow oily liquid: 76% yield (151 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3059, 2969, 2925, 1773, 1707, 1627, 1559; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.55−7.50 (m, 3H), 7.46 (d, J = 6.8 Hz, 2H), 7.41−7.32 (m, 3H), 3.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 193.7, 159.4, 155.7, 140.6, 133.8, 129.9, 129.8, 129.5, 128.0, 127.8, 124.2, 91.3; HRMS (ESI-TOF) calcd for C18H17N5OS (M+ + Na) m/z 374.1052, found m/z 374.1052. (Z)-3-(Dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]-1-(ptolyl)prop-2-en-1-one (3b). Pale yellow oily liquid: 68% yield (140 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3059, 2923, 2856, 2316, 1685, 1638, 1587, 1499, 1408; 1H NMR (400 MHz, CDCl3) δ 7.72−7.68 (m, 3H), 7.55−7.49 (m, 3H), 7.38 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 3.27 (s, 6H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.6, 159.2, 155.8, 140.1, 137.6, 133.8, 129.8, 129.5, 128.6, 128.1, 124.2, 91.4, 21.3; HRMS (ESI-TOF) calcd for C19H19N5OS (M+ + Na) m/z 388.1208, found m/z 388.1207. (Z)-3-(Dimethylamino)-1-(4-methoxyphenyl)-2-[(1-phenyl-1Htetrazol-5-yl)thio]prop-2-en-1-one (3c). Yellow viscous liquid: 68% yield (145 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3067, 3005, 2923, 2843, 1676, 1635, 1594, 1502; 1H NMR (400 MHz, CDCl3) δ 7.72−7.71 (m, 3H), 7.57−7.48 (m, 5H), 6.86 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H), 3.29 (s, 6H); 13C NMR (100 MHz, CDCl3) δ

193.0, 161.2, 159.1, 155.9, 133.9, 132.7, 130.3, 129.9, 129.5, 124.2, 113.3, 91.3, 55.3; HRMS (ESI-TOF) calcd for C19H19N5O2S (M+ + Na) m/z 404.1157, found m/z 404.1158. (Z)-3-(Dimethylamino)-1-(4-fluorophenyl)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3d). Yellow viscous liquid: 78% yield (162 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3066, 2924, 1681, 1638, 1591, 1500, 1410; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 2H), 7.58−7.49 (m, 5H), 7.05−7.01 (m, 2H), 3.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.5, 163.6 (d, J = 255 Hz), 159.1, 155.7, 136.6 (d, J = 3 Hz), 133.8, 130.3 (d, J = 9 Hz), 130.0, 129.6, 124.1, 115.0 (d, J = 22 Hz), 91.1; HRMS (ESITOF) calcd for C18H16FN5OS (M+ + Na) m/z 392.0957, found m/z 392.0957. (Z)-1-(3-Chlorophenyl)-3-(dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3e). Yellow oily liquid: 80% yield (173 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3064, 3002, 2925, 2810, 1638, 1586, 1499, 1413; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.65−7.63 (m, 2H), 7.57−7.49 (m, 3H), 7.42 (s, 1H), 7.36−7.25 (m, 3H), 3.31 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.1, 159.2, 155.6, 142.4, 134.0, 133.7, 130.0, 129.8, 129.6, 129.3, 127.7, 125.9, 124.1, 90.9; HRMS (ESI-TOF) calcd for C18H16ClN5OS (M+ + Na) m/z 408.0662, found (M+ + Na) m/z 408.0663. (Z)-1-(4-Chlorophenyl)-3-(dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3f). Yellow viscous liquid: 79% yield (170 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3065, 2924, 2316, 1638, 1588, 1497, 1408, 1294; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 2H), 7.57−7.51 (m, 3H), 7.42− 7.39 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.31 (s, 6H); 13C NMR (100 3088

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The Journal of Organic Chemistry Scheme 4. Substrate Scopea,b

Reaction conditions: 1 (0.5 mmol), 2a (0.55 mmol), and iodine (0.15 mmol) in DMSO (1 mL) at 80 °C for 1−3 h. bIsolated yield. cWith 50 mol % iodine used. dOne equivalent of iodine used. a

MHz, CDCl3) δ 192.6, 159.1, 155.6, 139.0, 135.9, 133.7, 130.0, 129.6, 129.4, 128.2, 124.1, 91.0; HRMS (ESI-TOF) calcd for C18H16ClN5OS (M+ + Na) m/z 408.0662, found m/z 408.0662. (Z)-1-(4-Bromophenyl)-3-(dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3g). Pale brown solid: mp 141−144 °C; 76% yield (182 mg); Rf = 0.4 (70% EtOAc/hexane); IR (KBr, cm−1) 3738, 3612, 2924, 2376, 2314, 1638, 1585, 1499, 1416; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.56−7.51 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.34−7.29 (m, 2H), 3.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.5, 159.0, 155.5, 139.4, 133.6, 131.1, 129.9, 129.5, 129.5, 124.1, 124.0, 90.9; HRMS (ESITOF) calcd for C18H16BrN5OS (M+ + Na) m/z 452.0157, found m/z 452.0159. (Z)-4-{3-(Dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]acryloyl}benzonitrile (3h). Yellow oily liquid: 81% yield (170 mg); Rf = 0.3 (70% EtOAc/hexane); IR (neat, cm−1) 3065, 2925, 2854, 2228, 1639, 1584, 1498, 1411; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.62−7.49 (m, 9H), 3.34 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 192.1, 159.0, 155.4, 145.1, 133.5, 131.8, 130.1, 129.6, 128.1, 123.9, 118.2, 113.1. 90.4; HRMS (ESI-TOF) calcd for C19H16N6OS (M+ + Na) m/z 399.1004, found m/z 399.1006. (Z)-3-(Dimethylamino)-1-(4-nitrophenyl)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3i). Yellow oily liquid: 79% yield (175 mg); Rf = 0.3 (70% EtOAc/hexane); IR (neat, cm−1) 3106, 3069, 3007, 2854, 2451, 1734, 1640, 1585, 1415; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.57−7.52 (m, 7H),

3.35 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 191.7, 159.0, 155.3, 148.1, 147.0, 133.4, 130.0, 129.6, 128.3, 123.8, 123.1, 90.4; HRMS (ESI-TOF) calcd for C18H16N6O3S (M+ + Na) m/z 419.0902, found m/z 419.0900. (Z)-3-(Dimethylamino)-1-(3-nitrophenyl)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3j). Red oily liquid: 81% yield (180 mg); Rf = 0.3 (70% EtOAc/hexane); IR (neat, cm−1) 3079, 3007, 2925, 2859, 2812, 2442, 1640, 1587, 1529, 1498; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.22−8.19 (m, 1H), 7.83 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.56−7.50 (m, 6H), 3.36 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 191.1, 159.1, 155.3, 147.5, 142.2, 133.7, 133.5, 130.1, 129.6, 129.2, 124.3, 123.9, 122.6. 90.0; HRMS (ESI-TOF) calcd for C18H16N6O3S (M+ + Na) m/z 419.0902, found m/z 419.0902. (Z)-3-(Dimethylamino)-1-(naphthalen-1-yl)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]prop-2-en-1-one (3k). Yellow oily liquid: 80% yield (180 mg); Rf = 0.5 (70% EtOAc/hexane); IR (neat, cm−1) 3058, 3003, 2925, 2809, 1639, 1584, 1500, 1414; 1H NMR (400 MHz, CDCl3) δ 7.63−7.78 (m, 4H), 7.44−7.33 (m, 9H), 3.21 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 194.1, 159.3, 155.8, 139.0, 133.6, 133.2, 130.3, 129.8, 129.3, 128.7, 127.9, 126.5, 126.1, 125.4, 124.6, 124.0, 123.9, 92.7; HRMS (ESI-TOF) calcd for C22H19N5OS (M+ + Na) m/z 424.1208, found m/z 424.1209. (Z)-3-(Dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]-1-(thiophen-2-yl)prop-2-en-1-one (3l). Yellow solid: mp 141−143 °C; 65% yield (130 mg); Rf = 0.5 (70% EtOAc/hexane); IR (KBr, cm−1) 3073, 3003, 2924, 1626, 1576, 1500, 1412; 1H NMR (400 MHz, CDCl3) δ 3089

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

Article

The Journal of Organic Chemistry Scheme 5. Control Experiments

8.08 (s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.58−7.46 (m, 5H), 7.01 (t, J = 4.0 Hz, 1H), 3.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 183.9, 158.7, 155.7, 143.3, 133.8, 131.3, 130.7, 130.0, 129.6, 126.8, 124.2, 90.0; HRMS (ESI-TOF) calcd for C16H15N5OS2 (M+ + Na) m/z 380.0616, found m/z 380.0618. (Z)-3-(Dimethylamino)-1-(furan-3-yl)-2-[(1-phenyl-1H-tetrazol-5yl)thio]prop-2-en-1-one (3m). Brown solid: mp 103−107 °C; 52% yield (99 mg); Rf = 0.5 (70% EtOAc/hexane); IR (KBr, cm−1) 3116, 2924, 2854, 2376, 2315, 1682, 1629, 1580, 1499, 1465; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.56−7.46 (m, 4H), 7.03 (d, J = 3.2 Hz, 1H), 6.44 (dd, J = 3.2, 1.6 Hz, 1H), 3.37 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 178.6, 158.6, 155.8, 152.7, 144.5, 133.9, 129.9, 129.6, 124.2, 116.9, 111.4, 90.0; HRMS (ESITOF) calcd for C16H15N5O2S (M+ + Na) m/z 364.0844, found m/z 364.0845. (Z)-3-(Dimethylamino)-2-[(1-phenyl-1H-tetrazol-5-yl)thio]acrylonitrile (3n). Pale yellow solid: mp 118−120 °C; 61% yield (96 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 2923, 2185, 1620, 1498, 1432, 1399; 1H NMR (400 MHz, CDCl3) δ 7.61−7.53 (m, 5H), 7.08 (s, 1H), 3.32 (s, 3H), 3.13 (s, 3H); 13C NMR (100

Scheme 6. A Tentative Reaction Mechanism

3090

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

Article

The Journal of Organic Chemistry MHz, CDCl3) δ 159.7, 154.9, 133.4, 130.2, 129.7, 124.0, 119.7, 55.3, 46.8, 37.9; HRMS (ESI-TOF) calcd for C12H12N6S (M+ + Na) m/z 295.0742, found m/z 295.0737. (Z)-N,N-Dimethyl-2-nitro-2-[(1-phenyl-1H-tetrazol-5-yl)thio]ethen-1-amine (3o). Pale yellow solid: mp 186−188 °C; 54% yield (88 mg); Rf = 0.2 (70% EtOAc/hexane); IR (KBr, cm−1) 2923, 1629, 1489, 1446, 1378, 1251; 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.73−7.71 (m, 2H), 7.63−7.55 (m, 3H), 3.46 (s, 3H), 3.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 155.0, 153.3, 133.5, 130.4, 129.8, 124.3, 107.3, 49.1, 39.1; HRMS (ESI-TOF) calcd for C11H12N6O2S (M+ + Na) m/z 315.0640, found m/z 315.0638. Ethyl (Z)-3-Morpholino-2-[(1-phenyl-1H-tetrazol-5-yl)thio]acrylate (3p). White solid: mp 170−172 °C; 34% yield (68 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3060, 2970, 2918, 2858, 1673, 1587; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.61−7.54 (m, 3H), 4.13 (q, J = 7.6 Hz, 2H), 3.85−3.82 (m, 4H), 3.78−3.75 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 155.0, 154.4, 133.7, 130.0, 129.6, 124.0, 78.1, 66.5, 60.9, 14.3; HRMS (ESI-TOF) calcd for C16H19N5O3S (M+ + Na) m/z 384.1106, found m/z 384.1107. 5,5-Dimethyl-2-[(1-phenyl-1H-tetrazol-5-yl)thio]-3(phenylamino)cyclohex-2-en-1-one (3q). Pale yellow solid: mp 192− 194 °C; 82% yield (180 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3348, 3068, 2962, 2856, 1625, 1593, 1462; 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.61−7.52 (m, 3H), 7.46−7.42 (m, 2H), 7.35 (t, J = 6.8 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 2.51 (s, 2H), 2.40 (s, 2H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.6, 167.3, 153.0, 136.9, 133.9, 130.0, 129.6, 129.6, 127.5, 126.3, 124.2, 94.6, 50.7, 41.4, 32.4, 28.1; HRMS (ESI-TOF) calcd for C21H21N5OS (M+ + Na) m/z 414.1365, found m/z 414.1366. (Z)-4-[3-(Dimethylamino)-2-(phenylthio)acryloyl]benzonitrile (4a). Yellow solid: mp 130−133 °C; 67% yield (103 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 2922, 2222, 2154, 1622, 1531, 1416; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.10−7.05 (m, 3H), 3.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.6, 158.0, 145.8, 140.3, 131.2, 128.9, 127.7, 124.7, 124.5, 118.5, 112.4, 92.6; HRMS (ESI-TOF) calcd for C18H16N2OS (M+ + Na) m/z 331.0881, found m/z 331.0878. (Z)-4-[3-(Dimethylamino)-2-(o-tolylthio)acryloyl]benzonitrile (4b). Yellow solid: mp 115−118 °C; 65% yield (105 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3016, 2923, 2229, 2103, 1630, 1563, 1461, 1418; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.04−6.97 (m, 3H), 3.26 (s, 6H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.6, 158.1, 145.9, 139.0, 133.7, 131.1, 129.9, 127.6, 126.5, 124.4, 124.1, 118.5, 112.2, 92.2, 19.3; HRMS (ESI-TOF) calcd for C19H18N2OS (M+ + Na) m/z 345.1038, found m/z 345.1039. (Z)-4-[3-(Dimethylamino)-2-(p-tolylthio)acryloyl]benzonitrile (4c).9 Yellow solid: mp 151−154 °C; 68% yield (110 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3028, 2921, 2853, 2223, 1627, 1554, 1484, 1454; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.29 (s, 6H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.8, 157.9, 146.0, 136.8, 134.5, 131.2, 129.7, 127.8, 124.7, 118.6, 112.4, 93.1, 20.7; HRMS (ESI-TOF) calcd for C19H18N2OS (M+ + Na) m/z 345.1038, found m/z 345.1033. (Z)-4-{3-(Dimethylamino)-2-[(2-fluorophenyl)thio]acryloyl}benzonitrile (4d). White solid: mp 158−160 °C; 66% yield (107 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3067, 2923, 2853, 2228, 1712, 1634, 1572, 1462, 1399; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.09− 7.05 (m, 3H), 6.96−6.92 (m, 1H), 3.29 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.2, 158.5 (d, J = 242 Hz), 158.4, 145.6, 131.3, 127.8, 127.1 (d, J = 16 Hz), 126.8 (d, J = 3 Hz), 126.2 (d, J = 7 Hz), 124.5 (d, J = 3 Hz), 118.4, 115.2 (d, J = 21 Hz), 112.5, 90.7; HRMS (ESI-TOF) calcd for C18H15FN2OS (M+ + Na) m/z 349.0787, found m/z 349.0786. (Z)-4-{2-[(3-Chlorophenyl)thio]-3-(dimethylamino)acryloyl}benzonitrile (4e). Yellow solid: mp 99−101 °C; 80% yield (137 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3052, 2923, 2807,

2227, 1732, 1632, 1566, 1456; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.06−7.02 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 3.29 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 194.2, 158.3, 145.6, 142.5, 135.0, 131.4, 130.0, 127.7, 124.9, 124.2, 122.7, 118.4, 112.6, 92.0; HRMS (ESI-TOF) calcd for C18H15ClN2OS (M+ + Na) m/z 365.0491, found m/z 365.0490. (Z)-4-{2-[(4-Chlorophenyl)thio]-3-(dimethylamino)acryloyl}benzonitrile (4f). Yellow solid: mp 147−150 °C; 73% yield (125 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3058, 2922, 2223, 1631, 1564, 1468, 1420, 1303; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.29 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.4, 158.2, 145.6, 138.9, 131.4, 130.5, 129.0, 127.8, 125.9, 118.4, 112.6, 92.5; HRMS (ESI-TOF) calcd for C18H15ClN2OS (M+ + Na) m/z 365.0491, found m/z 365.0490. (Z)-4-{2-[(4-Bromophenyl)thio]-3-(dimethylamino)acryloyl}benzonitrile (4g). Pale yellow solid: mp 132−135 °C; 80% yield (155 mg); Rf = 0.2 (50% EtOAc/hexane); IR (KBr, cm−1) 3049, 2921, 2818, 2220, 1632, 1563, 1464, 1417; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 3.29 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.5, 158.2, 145.6, 139.7, 132.0, 131.4, 127.8, 126.2, 118.5, 118.4, 112.7, 92.4; HRMS (ESI-TOF) calcd for C18H15BrN2OS (M+ + Na) m/z 408.9986, found m/z 408.9985. (Z)-4-[3-(Dimethylamino)-2-(naphthalen-2-ylthio)acryloyl]benzonitrile (4h). Pale yellow oily liquid: 66% yield (118 mg); Rf = 0.2 (50% EtOAc/hexane); IR (neat, cm−1) 2924, 2808, 2227, 1630, 1562, 1417; 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.51−7.37 (m, 7H), 7.18 (dd, J = 8.4, 1.6 Hz, 1H), 3.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.9, 158.2, 145.8, 138.1, 133.9, 131.3, 131.2, 128.6, 127.7, 126.7, 126.6, 125.1, 123.4, 122.0, 118.5, 112.5, 92.2; HRMS (ESI-TOF) calcd for C22H18N2OS (M+ + Na) m/z 381.1038, found m/z 381.1038. (Z)-3-(Dimethylamino)-2-[(1-methyl-1H-tetrazol-5-yl)thio]-1-(4nitrophenyl)prop-2-en-1-one (4i). Yellow solid: mp 155−158 °C; 58% yield (97 mg); Rf = 0.3 (70% EtOAc/hexane); IR (KBr, cm−1) 3105, 3074, 3005, 2929, 2857, 2812, 1639, 1639, 1582; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 4.05 (s, 3H), 3.46 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 191.5, 159.2, 154.6, 148.2, 146.9, 128.5, 123.3, 91.4, 33.8; HRMS (ESITOF) calcd for C13H14N6O3S (M+ + Na) m/z 357.0746, found m/z 357.0745. (Z)-2-(Benzo[d]thiazol-2-ylthio)-3-(dimethylamino)-1-phenylprop-2-en-1-one (4j). Yellow oily: 54% yield (92 mg); Rf = 0.4 (70% EtOAc/hexane); IR (neat, cm−1) 3059, 2922, 1634, 1587, 1457, 1423, 1308, 1282; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.40− 7.33 (m, 4H), 7.27−7.21 (m, 1H), 3.25 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 194.5, 173.8, 158.8, 154.8, 140.5, 135.3, 129.9, 127.9, 127.8, 125.9, 123.7, 121.4, 120.8, 94.2; HRMS (ESI-TOF) calcd for C18H16N2OS2 (M+ + Na) m/z 363.0602, found m/z 363.0600. (Z)-4-[2-(Benzo[d]thiazol-2-ylthio)-3-(dimethylamino)acryloyl]benzonitrile (4k). Brown solid: mp 156−158 °C; 64% yield (117 mg); Rf = 0.4 (70% EtOAc/hexane); IR (KBr, cm−1) 3062, 3000, 2924, 2853, 2801, 2228, 1635, 1583, 1458; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.60 (s, 4H), 7.39 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 3.30 (br, 6H); 13C NMR (100 MHz, CDCl3) δ 193.2, 172.9, 158.4, 154.7, 145.0, 135.1, 131.6, 128.0, 126.1, 123.9, 121.6, 120.9, 118.3, 112.9, 92.4; HRMS (ESI-TOF) calcd for C19H15N3OS2 (M+ + Na) m/z 388.0554, found m/z 388.0553. 3-Amino-2-(benzo[d]thiazol-2-ylthio)-5,5-dimethylcyclohex-2en-1-one (4l). Pale yellow solid: mp 198−200 °C; 82% yield (125 mg); Rf = 0.2 (70% EtOAc/hexane); IR (KBr, cm−1) 3289, 3079, 2927, 2793, 1743, 1675, 1599, 1521; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.44 (s, 1H), 2.52 (s, 2H), 2.38 (s, 2H), 1.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.2, 170.7, 169.3, 154.3, 135.3, 125.9, 124.0, 121.4, 120.7, 95.9, 50.7, 43.5, 3091

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

Article

The Journal of Organic Chemistry 31.8, 28.3; HRMS (ESI-TOF) calcd for C15H16N2OS2 (M+ + Na) m/z 327.0602, found m/z 327.0603. (E)-4-Amino-3-[(1-phenyl-1H-tetrazol-5-yl)thio]pent-3-en-2-one (5a). White solid: mp 154−156 °C; 81% yield (112 mg); Rf = 0.2 (30% EtOAc/hexane); IR (KBr, cm−1) 3408, 3282, 3130, 2924, 2854, 1600, 1502, 1462; 1H NMR (400 MHz, CDCl3) δ 11.03 (d, J = 4.8 Hz, 1H), 7.64−7.53 (m, 5H), 7.28 (s, 1H), 2.29−2.28 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 198.2, 170.5, 156.1, 133.6, 130.1, 129.8, 123.7, 88.2, 28.4, 23.2; HRMS (ESI-TOF) calcd for C12H13N5OS (M+ + Na) m/z 298.0739, found m/z 298.0744. (E)-3-[(1-Phenyl-1H-tetrazol-5-yl)thio]-4-(phenylamino)pent-3en-2-one (5b). White solid: mp 99−102 °C; 69% yield (121 mg); Rf = 0.2 (20% EtOAc/hexane); IR (KBr, cm−1) 3289, 3059, 2961, 2927, 1670, 1640, 1587, 1547, 1494; 1H NMR (400 MHz, CDCl3) δ 13.98 (s, 1H), 7.67−7.55 (m, 5H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.5, 169.2, 155.4, 137.7, 133.7, 130.1, 129.8, 129.2, 127.1, 125.7, 123.7, 90.5, 28.7, 18.9; HRMS (ESI-TOF) calcd for C18H17N5OS (M+ + Na) m/z 374.1052, found m/z 374.1050. Methyl (E)-2-[(1-Phenyl-1H-tetrazol-5-yl)thio]-3-(phenylamino)but-2-enoate (5c). White solid: mp 160−163 °C; 45% yield (83 mg); Rf = 0.2 (20% EtOAc/hexane); IR (KBr, cm−1) 3163, 2921, 2852, 2322, 2163, 1643, 1562, 1492; 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 7.68−7.66 (m, 2H), 7.60−7.53 (m, 3H), 7.39 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 3.67 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 168.3, 155.6, 138.1, 133.9, 129.8, 129.6, 129.2, 126.7, 125.7, 123.8, 79.2, 51.7, 18.9; HRMS (ESI-TOF) calcd for C18H17N5O2S (M+ + Na) m/z 390.1001, found m/z 390.1002. (E)-4-Amino-3-(pyridin-2-ylthio)pent-3-en-2-one (5d). Pale yellow solid: mp 70−72 °C; 54% yield (56 mg); Rf = 0.3 (50% EtOAc/ hexane); IR (KBr, cm−1) 3734, 3265, 3076, 2920, 2852, 2146, 1666, 1581, 1456, 1357; 1H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.55−7.50 (m, 1H), 7.04−6.99 (m, 1H), 6.98− 6.96 (m, 1H), 6.38 (s, 1H), 2.32 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 169.6, 162.9, 149.5, 136.7, 119.2, 118.2, 93.2, 28.6, 23.4; HRMS (ESI-TOF) calcd for C10H12N2OS (M+ + Na) m/z 231.0568, found m/z 231.0569. (E)-4-Amino-3-(pyrimidin-2-ylthio)pent-3-en-2-one (5e). Pale yellow oily liquid: 36% yield (37 mg); Rf = 0.2 (70% EtOAc/hexane); IR (neat, cm−1) 3321, 2922, 2852, 1597, 1556, 1467, 1379, 1263; 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 8.53 (d, J = 4.8 Hz, 2H), 6.99 (t, J = 4.8 Hz, 1H), 6.24 (s, 1H), 2.30 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 173.4, 169.2, 157.5, 116.7, 93.1, 28.6, 23.4; HRMS (ESI-TOF) calcd for C9H11N3OS (M+ + Na) m/z 232.0521, found m/z 232.0519. (E)-4-Amino-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]pent-3-en-2one (5f). White solid: mp 170−172 °C; 72% yield (83 mg); Rf = 0.3 (70% EtOAc/hexane); IR (KBr, cm−1) 3412, 3123, 2981, 2925, 2850, 1605, 1457, 1400; 1H NMR (400 MHz, CDCl3) δ 11.07 (s, 1H), 6.44 (s, 1H), 2.68 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.2, 174.4, 169.9, 164.8, 95.2, 28.6, 23.4, 15.7; HRMS (ESI-TOF) calcd for C8H11N3OS2 (M+ + Na) m/z 252.0241, found m/z 252.0240. (E)-4-Amino-3-(benzo[d]thiazol-2-ylthio)pent-3-en-2-one (5g). Pale yellow oily: 91% yield (120 mg); Rf = 0.2 (30% EtOAc/hexane); IR (neat, cm−1) 3311, 3140, 3061, 2999, 2922, 2850, 1595, 1462, 1357; 1H NMR (400 MHz, CDCl3) δ 11.20 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H), 2.40 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.4, 176.0, 170.7, 154.9, 134.8, 126.0, 123.7, 121.1, 120.8, 94.0, 28.3, 23.0; HRMS (ESI-TOF) calcd for C12H12N2OS2 (M+ + Na) m/z 287.0289, found m/z 287.0289. (E)-4-Amino-3-[(5-methoxybenzo[d]thiazol-2-yl)thio]pent-3-en2-one (5h). Pale brown solid: mp 191−193 °C; 88% yield (129 mg); Rf = 0.2 (30% EtOAc/hexane); IR (KBr, cm−1) 3275, 3108, 2955, 2829, 1604, 1467, 1423, 1355; 1H NMR (400 MHz, CDCl3) δ 11.19 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.42 (s, 1H), 3.86 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.8, 176.9, 170.3, 158.9,

156.4, 126.8, 121.1, 113.3, 104.6, 94.5, 55.5, 28.5, 23.4; HRMS (ESITOF) calcd for C13H14N2O2S2 (M+ + Na) m/z 317.0394, found m/z 317.0395. (E)-4-Amino-3-[(4-methylthiazol-2-yl)thio]pent-3-en-2-one (5i). Pale yellow oily liquid: 74% yield (84 mg); Rf = 0.2 (30% EtOAc/ hexane); IR (neat, cm−1) 3307, 3109, 2920, 2856, 1703, 1597, 1525, 1467, 1409, 1357; 1H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 6.73 (s, 1H), 6.68 (s, 1H), 2.38 (s, 6H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.8, 172.9, 170.2, 154.1, 112.5, 94.7, 28.3, 23.1, 17.2; HRMS (ESI-TOF) calcd for C9H12N2OS2 (M+ + Na) m/z 251.0289, found m/z 251.0291. (E)-4-Amino-3-(benzo[d]oxazol-2-ylthio)pent-3-en-2-one (5j). Brown solid: mp 150−152 °C; 30% yield (37 mg); Rf = 0.2 (30% EtOAc/hexane); IR (KBr, cm−1) 3290, 3124, 2924, 2852, 1602, 1489, 1458, 1350, 1259; 1H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.29−7.22 (m, 2H), 6.63 (s, 1H), 2.39 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.3, 169.8, 165.9, 152.0, 141.9, 124.3, 123.8, 118.5, 110.0, 89.8, 28.8, 23.6; HRMS (ESI-TOF) calcd for C12H12N2O2S (M+ + Na) m/z 271.0517, found m/z 271.0515. (E)-4-Amino-3-[(4-bromophenyl)thio]pent-3-en-2-one (5k). White solid: mp 164−166 °C; 82% yield (117 mg); Rf = 0.2 (20% EtOAc/hexane); IR (KBr, cm−1) 3489, 3269, 3093, 2920, 2735, 2360, 1886, 1589, 1465; 1H NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.10 (s, 1H), 2.29 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 169.5, 139.5, 131.8, 125.6, 117.8, 93.5, 28.5, 23.3; HRMS (ESI-TOF) calcd for C11H12BrNOS (M+ + Na) m/z 307.9721, found m/z 307.9719. (E)-4-Amino-3-(naphthalen-2-ylthio)pent-3-en-2-one (5l). Pale brown solid: mp 148−150 °C; 78% yield (100 mg); Rf = 0.2 (20% EtOAc/hexane); IR (KBr, cm−1) 3483, 3269, 3101, 2987, 2920, 2270, 2154, 1919, 1589, 1462, 1352; 1H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H), 7.58−7.66 (m, 3H), 7.44−7.34 (m, 3H), 7.25 (t, J = 7.2 Hz, 1H), 5.99 (s, 1H), 2.35 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0, 169.6, 137.8, 133.9, 131.2, 128.4, 127.7, 126.7, 126.5, 124.8, 123.5, 120.8, 93.8, 28.6, 23.4; HRMS (ESI-TOF) calcd for C15H15NOS (M+ + Na) m/z 280.0772, found m/z 280.0774. 1,2-Diphenyldisulfane (6).13 White solid: mp 58−60 °C; 78% yield (78 mg); Rf = 0.6 (2% EtOAc/hexane); IR (KBr, cm−1) 3059, 1571, 1467, 1434, 1296; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 4H), 7.29 (t, J = 7.6 Hz, 4H), 7.21 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 137.0, 129.0, 127.5, 127.1; HRMS (ESI-TOF) calcd for C12H10S2 (M+ + Na) m/z 241.0122, found m/z 241.0120.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00073.

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Optimization data and 1H and 13C NMR spectral data for all compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kandikere Ramaiah Prabhu: 0000-0002-8342-1534 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

Financial support from IISc, SERB (SB/S1/OC-56/2013), New Delhi, CSIR [02(0226)15/EMR-II], New Delhi, and RL Fine Chem is gratefully acknowledged. Y.S. thanks CSIR for an SPM fellowship. 3092

DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093

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The Journal of Organic Chemistry

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REFERENCES

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DOI: 10.1021/acs.joc.7b00073 J. Org. Chem. 2017, 82, 3084−3093