Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00073 • Publication Date (Web): 23 Feb 2017 Downloaded from http://pubs.acs.org on February 23, 2017

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The Journal of Organic Chemistry

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 *E-mail: [email protected].

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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 enables a facile sulfenylation of enaminones with a broad range of heterocyclic thiols and thiones under cross dehydrogenative coupling methods. Besides, this strategy is highly practical as it employs inexpensive and readily available iodine and DMSO during short reaction time. The current methodology is one of the simplest methods and provides a straightforward approach for sulfenylation of enaminones under cross dehydrogenative coupling method.


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Introduction In recent years, use of dimethyl sulfoxide as an oxidant is emerging as one of the research topics of great interest and utility.1 Due to the increased concerns about the environmental protection and waste generation, a considerable effort has been directed towards 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 on environmenatlly benign reactions led to the discovery of cross dehydrogenative coupling (CDC) reactions, which have become one of the powerful strategies for the construction of carbon-carbon and carbon-hetero atom bonds. Additionally, the CDC reactions offer shorter, atom economical and environmentally benign synthetic routes.2 In this direction, there is a great interest among synthetic chemists for using enaminones as precursors under CDC reaction conditions. As a result, a continued effort has been witnessed for the formation of C–O and C–N bonds under CDC reaction conditions.3,4 Du and Zhao group developed a mild CDC method for β-acyloxylation of enamines with carboxylic acids using iodosobenzene as an oxidant.3 Later same group reported another CDC method for the oxidative coupling of enamines with electron difficient amines using TBAI and TBHP combination.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 an enoltosylates, which involve the prefucnctionalized 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 disulphide.7 Recently, Du and Wan groups, independently, reported sulfenylation of enaminones under metalfree 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 3 ACS Paragon Plus Environment


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sulfenylation of enaminones using KIO3 as a catalyst and air as an oxidant.9 Loh and his group reported similar transformation using Pd-catalysed 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 under CDC methods (Scheme 1). Unlike simple thiols, most of the heterocyclic thiols and thiones are not bad smelling and are stable compounds, which can be directly used in CDC reactions. Heterocyclic thiols and thiones are useful precursors for synthesizing a variety of pharmaceutically active and and medicinal important compounds. Hence the development of efficient functionalization strategies using heterocyclic thiols and thiones is well sought after.11 In persuit of our efforts in developing iodine-DMSO promoted reactions1h,1i and metal-free reactions,12 herein we describe a successful sulfenylation of enaminones catalyzed by iodine.


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Scheme 1. Approach for Sulfenylation of Enamines



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Results and Discussion Optimization of reaction conditions In order to find the optimal conditions, we started investigation using 1-phenyl-1H-tetrazole-5thiol (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 by treating 1a and 2a with iodine 20 mol %. As can be seen in Table 1, the solvent screening studies revealed that the DMSO is the most suitable solvent, which furnished the product 3a in 70% yield (entry 1, Table 1). Solvents such as DMF, DMA, CH3CN, DCE, or EtOAc were found to be not suitable for promoting the reaction (entries 2-6, Table 1, see Table S1 of the Supporting Information for more details). Other iodine source such as KI and KIO3 furnished 3a in trace amounts and 29%, respectively (entries 7-8, Table 1). Screening of electrophillic halogens such as NBS and NCS also furnished 3a in trace amounts (entries 9-10). Increasing or decreasing the equiv of 1a or 2a did not bring any noticeable change (entries 11-12, Table 1). Increasing the amount of iodine to 30 mol% resulted in the formation of the product 3a in 76% yield. Further increasing the amount of iodine to 50 mol% did not bring any remarkable change in the yield (entries 13-14, Table 1). Reaction also proceed well in argon atmosphere in the absence of any oxidants (entry 15, Table 1). Using TBHP in decane (5.5 M) as an oxidant also led to the formation of 3a in 70% yield (entry 16, Table 1). The reaction did not proceed in the absence of iodine (entry 17, Table 1). With these screening studies, the reaction of thiol (1 equiv) with enamine (1.1equiv) in DMSO (1 mL) as a solvent at 80 °C for 1 h (entry 13, Table 1) has been established as the optimal recation conditions.


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Table 1. Optimization of Reaction Conditions a

entry 1 2 3 4 5 6 7 8 9 10 11 12

catalyst or additive (mol %) I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) KI (20) KIO3 (20) NBS (20) NCS (20) I2 (20) I2 (20)

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

isolated yield (%) b 70 18 trace trace ND ND trace 29 c trace trace 62 d 72 e

13 I2 (30) DMSO 76 14 I2 (50) DMSO 77 15 I2 (30) DMSO 72 f 16 I2 (30) DMSO 70 g 17 none DMSO ND a Reaction conditions: 1a (0.56 mmol), 2a (0.62 mmol), catalyst (0.17 mmol) in 1 mL of solvent at 80 °C. b Isolated yield, c reaction at 80 °C for 6 h. d 1a 1.5 equiv and 2a 1 equiv. e 1.5 equiv of 2a used. f reaction under argon atmosphere. g 1 equiv of TBHP in decane 5.5 M used. ND = Not detected. With the optimized reaction conditions, the scope of this methodology has been studied by reacting a variety of acyclic and cyclic enaminones with 1-phenyl-1H-tetrazole-5-thiol (1a). As can be seen in Scheme 2, the reactions were very clean and expected coupled products were 7 ACS Paragon Plus Environment


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obtained in good to moderate yields. The enaminones bearing electron releasing groups furnished their corresponding sulfenylated products 3b, and 3c in 68 and 68% yields. Enaminones that contain halogens substitutions and electron withdrawing groups underwent a smooth reaction under the optimal conditions affording their corresponding sulfenylated products in good yields (3d–3j, Scheme 2). The scope of the reaction has been further evaluated using enaminones derivatives that contain naphthyl, thiophene and furan moieties. Thus, the naphthyl derivative of enaminone furnished the coupled product 3k in 80% yield, whereas thoiphene and furan derivatives of enaminones underwent a smooth reaction furnishing the 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). Ester substituted enaminones found to be less reactive and afforded the corresponding sulfenylated product 3p in 34% yield, where as cyclic enaminone was found to be more reactive furnishing the coupled product 3q in 82%.


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Scheme 2: Substrate Scope with Heteraocyclic Thiols a,b

a

Reaction conditions: 1a (0. 56 mmol), 2a (0.62 mmol), catalyst (0.17 mmol) in DMSO (1 mL) at 80 °C, 1 h. b Isolated yield. 9 ACS Paragon Plus Environment


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Encouraged by these results, we turned our attentions towards the sulfenylation of N,N dimethylamino enaminone derivatives uisng a variety of thiol and thione derivatives (Scheme 3). The

reactivity

of

various

thiophenol

derivatives

were

tested

with

(E)-4-(3-

(dimethylamino)acryloyl)benzonitrile under the standard conditions. It was found from these reactions that thiophenol and 2-methylbenzenethiol furnished the products 4a, 4b and 4c in 67, 65 and 68% yields, respectively (Scheme 3). The reactions of halogens substituted thiophenol derivatives

were

examined

by

(dimethylamino)acryloyl)benzonitrile. chlorobenzenethiol,

reacting Thus,

4-chlorobenzenethiol

a the and

variety

of

reactions

halo-thiols of

with

(E)-4-(3-

2-fluorobenzenethiol,

4-bromobenzenethiol

with

3-

(E)-4-(3-

(dimethylamino)acryloyl)benzonitrile were found to be facile furnishing the coupled products 4d, 4e, 4f, and 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 teh 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, 1methyl-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 the corresponding coupled products 4j, 4k, and 4l in 54, 64 and 82% yields, respectively (Scheme 3). However, these three reactions were performed using 50 mol % of iodine.


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Scheme 3: Substrate Scope Thiol and Thione Derivatives a,b

a

Reaction conditions: 1 (0.5 mmol), 2a (0.55 mmol), iodine (0.15 mmol) in DMSO (1 mL) at 80 °C 1-3 h. b Isolated yield. c 50 mol% of iodine used. After successfully examining the sulfenylation of E-enaminones, the substrate scope was

further

evaluated

using

Z-enaminones

such

as

(Z)-4-aminopent-3-en-2-one,


(Z)-4-


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(phenylamino)pent-3-en-2-one and methyl (Z)-3-(phenylamino)but-2-enoate. Z-enaminones that contain free NH2 group such as (Z)-4-aminopent-3-en-2-one furnished the coupled product 5a in 81%. Where as enaminones that have aromatic group substituted on NH2 furnished the correspoding sulfenylated products 5b and 5c in 69 and 45% yields, respectively (Scheme 4). Next, the substrate scope was further evaluated by carrying out the sulfenylation reaction with a variety of heterocyclic thiols, thiones and thiophenol derivatives (Scheme 4). The heterocyclic thiols such as pyridine-2-thiol, pyrimidine-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol underwent sulfenylation with (Z)-4-aminopent-3-en-2-one furnishing the corresponding sulfenylated products 5d, 5e and 5f in good to moderate yields (Scheme 4). However, these reactions required 50 mol % of iodine, where as 5-methyl-1,3,4-thiadiazole-2-thiol required stochiometric amount of iodine (see Table S6 of the Supporting Information for more details). Similarly,

heterocyclic

thiones

such

as

benzo[d]thiazole-2(3H)-thione,

5-

methoxybenzo[d]thiazole-2(3H)-thione and 4-methylthiazole-2(3H)-thione furnished their corresponding sulfenylated products 5g, 5h and 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% of iodine (see Table S7 of the Supporting Information 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 the coupled products 5k and 5l in 82 and 78% yields, respectively (Scheme 4).


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Scheme 4: Substrate Scope a,b

a

Reaction conditions: 1 (0.5 mmol), 2a (0.55 mmol), iodine (0.15 mmol) in DMSO (1 mL) at 80 °C, 1-3 h. b Isolated yield. c 50 mol % of iodine used. d 1 equiv of iodine used.



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To get insight into the mechanism, a few control experiments were performed. First, the reaction of 1-phenyl-1H-tetrazole-5-thiol (1a) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1one (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 is an oxidant, a reaction was performed using 3equiv of DMSO and 30 mol % of iodine in dichloroethane as a solvent, which afforded the product 3a in 58% yield, whereas the same reaction in the absence of DMSO did not furnish the sulfenylated product 3a (Scheme 5b). It is relevant to recall that the reaction of 1a with 2a in DMSO proceeded well in argon atmosphere (Table 1, entry 15). These experiments clearly support the role of DMSO as an oxidant. The reaction of 2a proceeded well with disulfides such as 1,2-bis(1-phenyl-1H-tetrazol-5-yl)disulfane and 1,2-bis(benzo[d]thiazol-2yl)disulfane in the presence of catalytic amount of iodine (10 and 20 mol% of iodine, respectively, Schemes 5c and 5d). 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, the Supporting Information for more details). Similarly, the reaction of (E)-3-(dimethylamino)-1phenylprop-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% (Scheme 5g).


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Scheme 5: Control Experiments



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On the basis of these control experiments and the literature precedence,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-1Htetrazol-5-yl)disulfane (II) reacts with DMS:I2 or I2 to form intermediate that contains S-I bond (III). Further, nucleophillic displacement of iodo group by enaminone forms the product 3a and byproduct HI. Further, iodine is regenerated by the reaction of HI with DMSO and cycle continues (Scheme 6). Scheme 6: A Tentative Reaction Mechanism

Conclusion In conclusion, we have described an iodine catalyzed sulfenylation of enaminones under metalfree reaction conditions using DMSO as an oxidant which shows a broad substrate scope. We believe that this is one of the simplest methodologies that provide a straight forward approach for sulfenylation of heterocyclic thiols, heterocyclic thiones and thiophenol derivatives under CDC 16 ACS Paragon Plus Environment

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conditions. The salient features of the current methodology are; 1) the reaction is performed in the absence of metals; 2) utility of commercially available materials; 3) operational simplicity and short reaction time; 4) inert atmosphere or dry solvent is not required; 5) the reaction is tolerant to a broad range of thiols and thiones with various enaminone derivatives which is most important. EXPERIMENTAL SECTION General Information. NMR spectra were recorded on a 400 MHz spectrometer in CDCl3 or DMSO-d6. Tetramethylsilane (TMS; δ = 0.00 ppm) for 1H NMR in CDCl3, and residual nondeuterated solvent peak (δ = 2.50 ppm) in DMSO-d6, served as an internal standard. The solvent signal (CDCl3, δ = 77.00 ppm; and DMSO-d6, δ = 39.5 ppm) was used as internal standard for 13

C NMR. IR spectra were measured using an FT-IR spectrometer. Mass spectra were obtained

with a Q-TOF Mass Spectrometer (HRMS). Flash column chromatography was carried out by packing glass columns with commercial silica gel 230-400 mesh (commercial suppliers) and thin-layer chromatography was carried out using silica gel GF-254. All catalysts and reagents were procured from commercial suppliers. Dichloroethane solvent was distilled over calcium hydride and stored over molecular sieves and used for all procedures. Other solvents, used for work up and chromatographic procedures were purchased from commercial suppliers and used without any further purification. Experimental Section Typical Experimental Procedure for sulfenylation of enaminones Heterocyclic thiol (0.56 mmol), enaminone (0.62 mmol) were dissolved in DMSO (1 mL) and added iodine (0.17 mmol) (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 17 ACS Paragon Plus Environment


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for 1 h. After the completion of the reaction (monitored by TLC), added water (25 mL) and dilute sodium thiosulphate solution (5 mL) and extract product with ethylacetate (3x20 mL). 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 get 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; Yield 76% (151 mg); Rf (70% EtOAc/hexane) 0.4; 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) m/z: Calcd for C18H17N5OS (M+ + Na) 374.1052; Found 374.1052. (Z)-3-(Dimethylamino)-2-((1-phenyl-1H-tetrazol-5-yl)thio)-1-(p-tolyl)prop-2-en-1-one

(3b).

Pale yellow oily liquid; Yield 68% (140 mg); Rf (70% EtOAc/hexane) 0.4; 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) m/z: Calcd for C19H19N5OS (M+ + Na) 388.1208; Found 388.1207. (Z)-3-(Dimethylamino)-1-(4-methoxyphenyl)-2-((1-phenyl-1H-tetrazol-5-yl)thio)prop-2-en-1one (3c). Yellow viscus liquid; Yield 68% (145 mg); Rf (70% EtOAc/hexane) 0.4; 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


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(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) m/z: Calcd for C19H19N5O2S (M+ + Na) 404.1157; Found 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; Yield 78% (162 mg); Rf (70% EtOAc/hexane) 0.4; 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);

13

C NMR (100

MHz, CDCl3) δ 192.5, 163.6 (d, J = 255), 159.1, 155.7, 136.6 (d, J = 3), 133.8, 130.3 (d, J = 9), 130.0, 129.6, 124.1, 115.0 (d, J =22), 91.1; HRMS (ESI-TOF) m/z: Calcd for C18H16FN5OS (M+ + Na) 392.0957; Found 392.0957. (Z)-1-(3-Chlorophenyl)-3-(dimethylamino)-2-((1-phenyl-1H-tetrazol-5-yl)thio)prop-2-en-1one (3e). Yellow oily liquid; Yield 80% (173 mg); Rf (70% EtOAc/hexane) 0.4; 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) m/z: Calcd for C18H16ClN5OS (M+ + Na) 408.0662; Found (M+ + Na) 408.0663. (Z)-1-(4-Chlorophenyl)-3-(dimethylamino)-2-((1-phenyl-1H-tetrazol-5-yl)thio)prop-2-en-1one (3f). Yellow viscous liquid; Yield 79% (170 mg); Rf (70% EtOAc/hexane) 0.4; 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 MHz, CDCl3) δ 192.6, 159.1, 155.6, 139.0, 135.9, 133.7,



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130.0, 129.6, 129.4, 128.2, 124.1, 91.0; HRMS (ESI-TOF) m/z: Calcd for C18H16ClN5OS (M+ + Na) 408.0662; Found 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); Yield 76% (182 mg); Rf (70% EtOAc/hexane) 0.4; 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 (ESI-TOF) m/z: Calcd for C18H16BrN5OS (M+ + Na) 452.0157; Found 452.0159. (Z)-4-(3-(Dimethylamino)-2-((1-phenyl-1H-tetrazol-5-yl)thio)acryloyl)benzonitrile

(3h).

Yellow oily liquid; Yield 81% (170 mg); Rf (70% EtOAc/hexane) 0.3; 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) m/z: Calcd for C19H16N6OS (M+ + Na) 399.1004; Found 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; Yield 79% (175 mg); Rf (70% EtOAc/hexane) 0.3; 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 (ESITOF) m/z: Calcd for C18H16N6O3S (M+ + Na) 419.0902; Found 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; Yield 81% (180 mg); Rf (70% EtOAc/hexane) 0.3; IR (Neat, cm−1) 3079,


Page 21 of 33

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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) m/z: Calcd for C18H16N6O3S (M+ + Na) 419.0902; Found 419.0902. (Z)-3-(Dimethylamino)-1-(naphthalen-1-yl)-2-((1-phenyl-1H-tetrazol-5-yl)thio)prop-2-en-1one (3k). Yellow oily liquid; Yield 80% (180 mg); Rf (70% EtOAc/hexane) 0.5; 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) m/z: Calcd for C22H19N5OS (M+ + Na) 424.1208; Found 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); Yield 65% (130 mg); Rf (70% EtOAc/hexane) 0.5; IR (KBr, cm−1) 3073, 3003, 2924, 1626, 1576, 1500, 1412; 1H NMR (400 MHz, CDCl3) δ 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) m/z: Calcd for C16H15N5OS2 (M+ + Na) 380.0616; Found 380.0618. (Z)-3-(Dimethylamino)-1-(furan-3-yl)-2-((1-phenyl-1H-tetrazol-5-yl)thio)prop-2-en-1-one (3m). Brown solid (mp. 103-107 °C); Yield 52% (99 mg); Rf (70% EtOAc/hexane) 0.5; 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,



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152.7, 144.5, 133.9, 129.9, 129.6, 124.2, 116.9, 111.4, 90.0; HRMS (ESI-TOF) m/z: Calcd for C16H15N5O2S (M+ + Na) 364.0844; Found 364.0845. (Z)-3-(Dimethylamino)-2-((1-phenyl-1H-tetrazol-5-yl)thio)acrylonitrile (3n). Pale yellow solid (mp. 118-120 °C); Yield 61% (96mg); Rf (50% EtOAc/hexane) 0.2; 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 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) m/z: Calcd for C12H12N6S (M+ + Na) 295.0742; Found 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); Yield 54% (88 mg); Rf (70% EtOAc/hexane) 0.2; 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); 13C 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) m/z: Calcd for C11H12N6O2S (M+ + Na) 315.0640; Found 315.0638. Ethyl (Z)-3-morpholino-2-((1-phenyl-1H-tetrazol-5-yl)thio)acrylate (3p). White solid (mp. 170172 °C); Yield 34% (68 mg); Rf (50% EtOAc/hexane) 0.2; 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) m/z: Calcd for C16H19N5O3S (M+ + Na) 384.1106; Found 384.1107. 5,5-Dimethyl-2-((1-phenyl-1H-tetrazol-5-yl)thio)-3-(phenylamino)cyclohex-2-en-1-one (3q).


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Pale yellow solid (192-194 °C); Yield 82% (180 mg); Rf (50% EtOAc/hexane) 0.2; 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) m/z: Calcd for C21H21N5OS (M+ + Na) 414.1365; Found 414.1366. (Z)-4-(3-(Dimethylamino)-2-(phenylthio)acryloyl)benzonitrile (4a). Yellow solid (mp. 130-133 °C); Yield 67% (103 mg); Rf (50% EtOAc/hexane) 0.2; 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) m/z: Calcd for C18H16N2OS (M+ + Na) 331.0881; Found 331.0878. (Z)-4-(3-(Dimethylamino)-2-(o-tolylthio)acryloyl)benzonitrile (4b). Yellow solid (mp. 115-118 °C); Yield 65% (105mg); Rf (50% EtOAc/hexane) 0.2; 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); 13

C 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) m/z: Calcd for C19H18N2OS (M+ + Na) 345.1038; Found 345.1039. (Z)-4-(3-(Dimethylamino)-2-(p-tolylthio)acryloyl)benzonitrile (4c).8 Yellow solid (mp. 151-154 °C); Yield 68% (110 mg); Rf (50% EtOAc/hexane) 0.2; 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, 23 ACS Paragon Plus Environment


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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) m/z: Calcd for C19H18N2OS (M+ + Na) 345.1038; Found 345.1033. (Z)-4-(3-(Dimethylamino)-2-((2-fluorophenyl)thio)acryloyl)benzonitrile (4d). White solid (mp. 158-160 °C); Yield 66% (107mg); Rf (50% EtOAc/hexane) 0.2; 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); 13

C 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 = 3Hz), 126.2 (d, J = 7Hz), 124.5 (d, J = 3Hz), 118.4, 115.2 (d, J = 21Hz), 112.5, 90.7; HRMS (ESI-TOF) m/z: Calcd for C18H15FN2OS (M+ + Na) 349.0787; Found 349.0786. (Z)-4-(2-((3-Chlorophenyl)thio)-3-(dimethylamino)acryloyl)benzonitrile (4e). Yellow solid (mp. 99-101 °C); Yield 80% (137mg); Rf (50% EtOAc/hexane) 0.2; 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); 13C 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) m/z: Calcd for C18H15ClN2OS (M+ + Na) 365.0491; Found 365.0490. (Z)-4-(2-((4-Chlorophenyl)thio)-3-(dimethylamino)acryloyl)benzonitrile (4f). Yellow solid (mp. 147-150 °C); Yield 73% (125 mg); Rf (50% EtOAc/hexane) 0.2; 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,


Page 25 of 33

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125.9, 118.4, 112.6, 92.5; HRMS (ESI-TOF) m/z: Calcd for C18H15ClN2OS (M+ + Na) 365.0491; Found 365.0490. (Z)-4-(2-((4-Bromophenyl)thio)-3-(dimethylamino)acryloyl)benzonitrile (4g). Pale yellow solid (mp. 132-135 °C); Yield 80% (155 mg); Rf (50% EtOAc/hexane) 0.2; 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) m/z: Calcd for C18H15BrN2OS (M+ + Na) 408.9986; Found 408.9985. (Z)-4-(3-(Dimethylamino)-2-(naphthalen-2-ylthio)acryloyl)benzonitrile (4h). Pale yellow oily liquid; Yield 66% (118 mg); Rf (50% EtOAc/hexane) 0.2; 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) m/z: Calcd for C22H18N2OS (M+ + Na) 381.1038; Found 381.1038. (Z)-3-(Dimethylamino)-2-((1-methyl-1H-tetrazol-5-yl)thio)-1-(4-nitrophenyl)prop-2-en-1-one (4i). Yellow solid (mp. 155-158 °C); Yield 58% (97 mg); Rf (70% EtOAc/hexane) 0.3; 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 (ESI-TOF) m/z: Calcd for C13H14N6O3S (M+ + Na) 357.0746; Found 357.0745.



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(Z)-2-(Benzo[d]thiazol-2-ylthio)-3-(dimethylamino)-1-phenylprop-2-en-1-one

Page 26 of 33

(4j).

Yellow

oily; Yield 54% (92 mg); Rf (70% EtOAc/hexane) 0.4; 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) m/z: Calcd for C18H16N2OS2 (M+ + Na) 363.0602; Found 363.0600. (Z)-4-(2-(Benzo[d]thiazol-2-ylthio)-3-(dimethylamino)acryloyl)benzonitrile (4k). Brown solid (mp. 156-158 °C); Yield 64% (117 mg); Rf (70% EtOAc/hexane) 0.4; 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) m/z: Calcd for C19H15N3OS2 (M+ + Na) 388.0554; Found 388.0553. 3-Amino-2-(Benzo[d]thiazol-2-ylthio)-5,5-dimethylcyclohex-2-en-1-one (4l). Pale yellow solid (mp. 198-200 °C); Yield 82% (125 mg); Rf (70% EtOAc/hexane) 0.2; 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, 31.8, 28.3; HRMS (ESI-TOF) m/z: Calcd for C15H16N2OS2 (M+ + Na) 327.0602; Found 327.0603. (E)-4-Amino-3-((1-phenyl-1H-tetrazol-5-yl)thio)pent-3-en-2-one (5a). White solid (154-156 °C); Yield 81% (112 mg); Rf (30% EtOAc/hexane) 0.2; IR (KBr, cm−1) 3408, 3282, 3130, 2924,


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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) m/z: Calcd for C12H13N5OS (M+ + Na) 298.0739; Found 298.0744. (E)-3-((1-Phenyl-1H-tetrazol-5-yl)thio)-4-(phenylamino)pent-3-en-2-one (5b). White solid (mp. 99-102 °C); Yield 69% (121 mg); Rf (20% EtOAc/hexane) 0.2; 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) m/z: Calcd for C18H17N5OS (M+ + Na) 374.1052; Found 374.1050. Methyl (E)-2-((1-phenyl-1H-tetrazol-5-yl)thio)-3-(phenylamino)but-2-enoate (5c). White solid (mp. 160-163 °C); Yield 45% (83 mg); Rf (20% EtOAc/hexane) 0.2; 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 = 8.0Hz, 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) m/z: Calcd for C18H17N5O2S (M+ + Na) 390.1001; Found 390.1002. (E)-4-Amino-3-(pyridin-2-ylthio)pent-3-en-2-one (5d). Pale yellow solid (mp. 70-72°C); Yield 54% (56 mg); Rf (50% EtOAc/hexane) 0.3; 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,



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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) m/z: Calcd for C10H12N2OS (M+ + Na) 231.0568; Found 231.0569; (E)-4-Amino-3-(pyrimidin-2-ylthio)pent-3-en-2-one (5e). Pale yellow oily liquid; Yield 36% (37 mg); Rf (70% EtOAc/hexane) 0.2; 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) m/z: Calcd for C9H11N3OS (M+ + Na) 232.0521; Found 232.0519. (E)-4-Amino-3-((5-methyl-1,3,4-thiadiazol-2-yl)thio)pent-3-en-2-one (5f). White solid (mp. 170-172 °C); Yield 72% (83 mg); Rf (70% EtOAc/hexane) 0.3; 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) m/z: Calcd for C8H11N3OS2 (M+ + Na) 252.0241; Found 252.0240. (E)-4-Amino-3-(benzo[d]thiazol-2-ylthio)pent-3-en-2-one (5g). Pale yellow oily; Yield 91% (120 mg); Rf (30% EtOAc/hexane) 0.2; 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) m/z: Calcd for C12H12N2OS2 (M+ + Na) 287.0289; Found 287.0289. (E)-4-Amino-3-((5-methoxybenzo[d]thiazol-2-yl)thio)pent-3-en-2-one (5h). Pale brown solid (mp. 191-193 °C); Yield 88% (129 mg); Rf (30% EtOAc/hexane) 0.2; IR (KBr, cm−1) 3275, 28 ACS Paragon Plus Environment

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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 (ESI-TOF) m/z: Calcd for C13H14N2O2S2 (M+ + Na) 317.0394; Found 317.0395. (E)-4-Amino-3-((4-methylthiazol-2-yl)thio)pent-3-en-2-one (5i). Pale yellow oily liquid; Yield 74% (84 mg); Rf (30% EtOAc/hexane) 0.2; 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) m/z: Calcd for C9H12N2OS2 (M+ + Na) 251.0289; Found 251.0291. (E)-4-Amino-3-(benzo[d]oxazol-2-ylthio)pent-3-en-2-one (5j). Brown solid (mp. 150-152°C); Yield 30% (37 mg); Rf (30% EtOAc/hexane) 0.2; 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) m/z: Calcd for C12H12N2O2S (M+ + Na) 271.0517; Found 271.0515. (E)-4-Amino-3-((4-bromophenyl)thio)pent-3-en-2-one (5k). White solid (mp. 164-166 °C); Yield 82% (117 mg); Rf (20% EtOAc/hexane) 0.2; 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) m/z: Calcd for C11H12BrNOS (M+ + Na) 307.9721; Found 307.9719.



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(E)-4-Amino-3-(naphthalen-2-ylthio)pent-3-en-2-one (5l). Pale brown solid (mp. 148-150 °C); Yield 78% (100 mg); Rf (20% EtOAc/hexane) 0.2; 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) m/z: Calcd for C15H15NOS (M+ + Na) 280.0772; Found 280.0774. 1,2-diphenyldisulfane (6).13 White solid (mp. 58-60 °C); Yield 78% (78 mg); Rf (2% EtOAc/hexane) 0.6; 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) m/z: Calcd for C12H10S2 (M+ + Na) 241.0122; Found 241.0120.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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The financial supports from IISc, SERB (NO.SB/S1/OC-56/2013), New Delhi, CSIR (No. 02(0226)15/EMR-II), New Delhi and RL Fine Chem are gratefully acknowledged. YS Thanks CSIR for an SPM fellowship. SUPPORTING INFORMATION: The optimization data, and 1H and

13

C NMR spectral data

of all compounds. REFERENCES AND NOTES (1)

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Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction

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