Note Cite This: J. Org. Chem. 2018, 83, 2986−2992
pubs.acs.org/joc
Regioselective Sulfenylation of α′-CH3 or α′-CH2 Groups of α,βUnsaturated Ketones with Heterocyclic Thiols Yogesh Siddaraju and Kandikere Ramaiah Prabhu* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka India S Supporting Information *
ABSTRACT: A rare regioselective sulfenylation of α′-CH3 or α′-CH2 bonds adjacent to α,β-unsaturated ketones using dimethyl sulfoxide as an oxidant and a substoichiometric amount of aq HI as an additive is described. This methodology employs a strong acid such as aq HI or iodine and exhibits a high regioselectivity without undergoing conjugate addition, which is difficult to achieve under the cross dehydrogenative coupling method.
O
unsaturated ketones with heterocyclic thiols using DMSO as an oxidant and a substoichiometric amount of aq HI as an additive. Interestingly, the conjugate product was not observed in these regioselective reactions. Initially, we investigated the reaction of 1-methyl-1Htetrazole-5-thiol (1a) and 5-(E)-4-phenylbut-3-en-2-one (2a) as a model reaction under a variety of reaction conditions (Table 1). Treatment of 1a with 2a, 20 mol % of aq HI 55% as an additive, and 3 equiv of DMSO as an oxidant in DCE as a solvent, furnished the sulfenylated product 3a in 71% yield. In this reaction, a rare regioselective sulfenylation of the α′-CH3 of α,β-unsaturated ketone (1a) occurred in the presence of strong acid HI, and the corresponding conjugate addition product was not observed at all (entry 1, Table 1). Solvents such as toluene, ethyl acetate, and CH3CN resulted in the formation of product 3a in 72, 72, and 28%, respectively (entries 2−4, Table 1, also see the Supporting Information, Table S1, for more details). Use of DMSO as an oxidant as well as a solvent (1 mL) afforded the product 3a in 78% (entry 5). Further screening was performed using DMSO as a solvent (entries 6−14). Using iodine in a substoichiometric amount (20 mol %), the desired product 3a was obtained in 67% (entry 6); the reaction using HBr (55% in water, 20 mol %) did not afford the expected product (entry 7). Increasing or decreasing the equivalent of 1a or 2a or additive aq HI was not helpful (entries 8−12). Reaction in argon balloon proceeded well, forming the product 3a in 77% yield (entry 13). The reaction did not proceed either in the absence of aq HI or in the absence of DMSO (entries 14 and 15). With these screening studies, further investigation was continued using 1a (1 equiv), ketones 2 (2 equiv), and aq HI 20 mol % in DMSO (1 mL) at 80 °C (entry 5). Under the established optimal reaction conditions, the scope and limitation of the reaction were evaluated using a variety of α,β-unsaturated ketones (Scheme 2). First, the influence of
rganosulfur compounds are an important class of compounds that find wide applications in pharmaceutical and material chemistry.1 Recent years have witnessed a significant growth of the oxidative functionalization of carbonyl compounds at the α-position to form C−S bonds using thiol as a coupling partner.2 A number of methods have been developed for α-sulfenylation of ketones under cross dehydrogenative coupling (CDC) methods,1d,2 whereas regioselective sulfenylation at α′-CH3 or α′-CH2 bonds adjacent to a α,β-unsaturated ketones is challenging and rarely addressed under CDC reaction conditions. An additional problem encountered in the sulfenylation of α′-carbon of α,β-unsaturated ketone is the conjugate addition.3−5 Conjugate addition of thiols to α,βunsaturated ketones is usually achieved using iodine,3 acids,4 and metal salts5 (Scheme 1). Among many C−H bond functionalization approaches, CDC reactions are emerging as powerful tools in organic synthesis because they avoid the prefunctionalization of starting substrates and are step- and atom-economical processes.6 Heterocyclic thiols are either easily accessible or readily synthesized precursors for synthesizing a variety of heterocyclic compounds that are present in a variety of synthetic and natural products of medicinal interest.7 Most of the heterocyclic thiols are not bad-smelling and can be used for CDC reactions for the formation of C−S bonds. In recent years, utility of DMSO as an oxidant is increasing as it is stable, readily available, inexpensive, nontoxic, easy to handle, generates ecofriendly byproducts, and affords the corresponding products in excellent yields with high regioselectivity.1,8 In this context, sulfenylation of α,βunsaturated methyl ketone derivatives through C−H functionalization strategy using DMSO as an oxidant provides a useful, green, efficient strategy in organic synthesis. Recently, we reported a metal-free regioselective sulfenylation of α-CH3 group of ketones in the presence of α-CH2- or α-CH-group using CDC strategy.1d In pursuit of our effort on metal-free reactions2e,9 and use of DMSO as an oxidant,1d−f herein we report a convenient and efficient approach for a regioselective sulfenylation of α′-CH3 or α′-CH2 bonds adjacent to a α,β© 2018 American Chemical Society
Received: December 29, 2017 Published: February 1, 2018 2986
DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
Note
The Journal of Organic Chemistry Scheme 1. Sulfenylation of α,β-Unsaturated Ketones
Table 1. Optimization Studiesa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
additive (mol %)
2a (equiv)
aq HI 55% (20) aq HI 55% (20) aq HI 55% (20) aq HI 55% (20) aq HI 55% (20) I2 (20) aq HBr 55% (20) aq HI 55% (20) aq HI 55% (20) aq HI 55% (20) aq HI 55% (30) aq HI 55% (10) aq HI 55% (20) none aq HI 55% (20)
2
oxidant (equiv)
solvent (1 mL)
time (h)
DCE
3
71
isolated yield (%)b
toluene
3
72
EtOAc
3
72
CH3CN
3
28
DMSO
2.5
78
2
DMSO (3) DMSO (3) DMSO (3) DMSO (3) DMSO
2 2
DMSO DMSO
DMSO DMSO
3 3
67 trace
1
DMSO
DMSO
3
55
3
DMSO
DMSO
2
79
4
DMSO
DMSO
2
79
2
DMSO
DMSO
2
77
2
DMSO
DMSO
4
73
2
DMSO
DMSO
2.5
77c
2 2
DMSO none
DMSO none
12 12
nd nd
2 2 2
nitrophenyl)but-3-en-2-one and (E)-4-(4-fluorophenyl)but-3en-2-one underwent a facile sulfenylation, giving the expected products 3g and 3h, respectively, in good yields (64 and 78%, respectively). A slump in the yield was observed in the reaction of 1 with 4-methylpent-3-en-2-one, furnishing the corresponding sulfenylated product 3i in 32%. The scope of the reaction was further extended with α,β-unsaturated ketones that contained naphthalene, furan, and thiophene substitution at the β-position, which furnished the corresponding sulfenylated products 3j, 3k, and 3l in 82, 79, and 72%, respectively (Scheme 2). The reaction of thiol 1 with (E)-1-(o-tolyl)hept-1en-3-one, an α,β-unsaturated ketone that has a long alkyl chain of α′-position, afforded the corresponding sulfenylated product 3m in excellent yield (96%). However, the similar reaction of 1a with but-3-en-2-one did not furnish the corresponding sulfenylated product 3n under the reaction conditions, indicating that the necessity of substitution at the β-position. Compound 3n was not detected due to methyl vinyl ketone being a low boiling compound (81 °C). The reaction of 1phenyl-1H-tetrazole-5-thiol with α,β-unsaturated ketone 2a afforded 3o in good yield (79%), whereas the similar reaction of 2a with pyridine-2-thiol afforded the corresponding sulfenylated 4a in poor yield (14%). The scope of the methodology was further studied using 5methyl-1,3,4-thiadiazole-2-thiol, which is an integral part of a variety of biologically active molecules (Scheme 2).10 Thus, 5methyl-1,3,4-thiadiazole-2-thiol was successfully coupled with (E)-4-phenylbut-3-en-2-one, (E)-4-(3-methoxyphenyl)but-3en-2-one, (E)-4-(4-fluorophenyl)but-3-en-2-one, (E)-4-(furan2-yl)but-3-en-2-one, and (E)-4-(thiophen-2-yl)but-3-en-2-one, obtaining the corresponding sulfenylated products 5a−5e in good yields (Scheme 2). The reaction of 4-phenylbut-3-yn-2one with 1-methyl-1H-tetrazole failed to undergo sulfenylation (5f) under the standard reaction conditions. In this reaction, starting material ketone 4-phenylbut-3-yn-2-one was intact, whereas thiol decomposition was observed. On the basis of this observation, we believe that 4-phenylbut-3-yn-2-one is a less reactive ketone. To understand the reaction pathway, a few experiments were performed, as presented in Scheme 3. The reaction of 1a with 2a in the presence of TEMPO, under the optimal conditions, proceeded well, furnishing the corresponding sulfenylated product 3a in 68%, suggesting the absence of a radical intermediacy in the reaction (Scheme 3a). To evaluate the intermediacy of a disulfide, a reaction of 1,2-bis(1-methyl-1Htetrazol-5-yl)disulfane, 1,2-di(pyridin-2-yl)disulfane, and 1,2bis(benzo[d]thiazol-2-yl)disulfane with (E)-4-phenylbut-3-en2-one with 2a was performed. These reactions proceeded well with a substoichiometric amount of aq HI furnishing the sulfenylated products 3a, 4a, and 6 in 71, 60, and 56%,
a
Reaction conditions: 1a (0.86 mmol), 2a (1.72 mmol), and aq HI 55% (0.17 mmol) in 1 mL of solvent at 80 °C. bIsolated yield. c Reaction under argon atmosphere. nd = not detected.
substituents in the phenyl ring of (E)-4-phenylbut-3-en-2-one on the outcome of the reaction was examined. In these reactions, it was found that the sulfenylation reaction tolerated electron-donating, electron-withdrawing, and halogen groups on the phenyl ring of (E)-4-phenylbut-3-en-2-one under the optimal reaction conditions (3a−3h, Scheme 2). The electronreleasing substituents such as methyl and methoxy groups that resided at different positions on the phenyl ring were found to be compatible and afforded the desired sulfenylated products 3b−3f in good yields (Scheme 2). α,β-Unsaturated arylbutenones that contain electron-withdrawing nitro group and halogen substitution on phenyl ring such as (E)-4-(22987
DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
Note
The Journal of Organic Chemistry Scheme 2. Substrate Scopea
a
Reaction conditions: 1 (0.86 mmol), 2 (1.72 mmol), Aq. HI 55% (0.17 mmol) in 1 mL of DMSO at 80 °C, 2.5 h. Isolated yield. nd = not detected.
respectively (Schemes 3b−d), suggesting that the reaction may proceed through a disulfide intermediate. The reaction of (E)1-iodo-4-phenylbut-3-en-2-one with 1a failed to furnish 3a under the reaction conditions (Scheme 3e), indicating the absence of the iodo-intermediate in the reaction. To confirm the role of DMSO as an oxidant, a reaction of 1a and 2a was performed using 3 equiv of DMSO in solvents such as DCE to find that these reactions proceeded well, furnishing the product 3a in 71% yield (entry 1, Table 1), and the same reaction failed to form 3a in the absence of DMSO (see the Supporting Information, entry 14, Table S1). The reaction of 1a with 2a proceeded well in an argon atmosphere under standard reaction conditions (entry 13, Table 1). These experiments clearly confirm the role of DMSO as an oxidant. However, the reaction of thiol 1a or ketone 2a, independently, under the optimal
reaction conditions resulted in a complete decomposition of these two starting materials (Scheme 3f). The reaction of 1a with 2a in the presence of 20 mol % of HI in DCE, aza-Michael product 7 was observed in 35% isolated yield (Scheme 3g).11 The reason for a rare regioselective sulfenylation of α′-CH3 or α′-CH2 groups of α,β-unsaturated ketones over conjugate addition is due to the presence of DMSO, which is a mild oxidant. Further, DMSO is an efficient oxidant for the regeneration of iodine from hydroiodic acid (HI). Iodine has a low lying σ* orbital as compared to those of other halogens and accepts an electron pair from a heteroatom to act as a Lewis acid and generate hydroiodic acid as a byproduct. Iodine is a strong oxidizing agent for the conversion of thiols to disulfides and S−I intermediate. As a result, formation of 2988
DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
Note
The Journal of Organic Chemistry Scheme 3. Control Experiments
disulfide or S−I intermediate in the reaction mixture acts as an electrophile and inhibits the conjugate addition of ketones. On the basis of these control experiments and literature precedence,1 a tentative mechanism is proposed in Scheme 4. The reaction of 1-methyl-1H-tetrazole-5-thiol (1a) with iodine and DMSO forms the intermediate 1,2-bis(1-methyl-1Htetrazol-5-yl)disulfane (II) and HI as a byproduct. 1,2-Bis(1methyl-1H-tetrazol-5-yl)disulfane (II) reacts further with DMS:I2 or I2, forming the intermediate (III) that contains a S−I bond. Further nucleophilic displacement of iodo group by (E)-4-phenylbuta-1,3-dien-2-ol occurs to form the product 3a and byproduct HI. Further, iodine is regenerated by the reaction of HI with DMSO, and the cycle continues (Scheme 4). In conclusion, we described, for the first time, an interesting regioselective sulfenylation of α′-CH3 or α′-CH2 bonds of α,βunsaturated ketones using cross dehydrogenative coupling under metal-free reaction conditions, employing DMSO as a green oxidant with a a substoichiometric amount of HI as an additive. These mild conditions and simplicity of the procedure provide a valuable method. Current methodology exhibits a broad substrate scope of α,β-unsaturated ketones with heterocyclic thiols with a high regioselectivity without conjugate addition. The salient feature of the current
Scheme 4. Tentative Reaction Mechanism
2989
DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
Note
The Journal of Organic Chemistry
(E)-4-(4-Methoxyphenyl)-1-((1-methyl-1H-tetrazol-5-yl)thio)but3-en-2-one (3e). Yellow solid (mp = 152−154 °C); yield 66% (165 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3766, 3693, 3410, 2924, 2850, 2374, 1716, 1662, 1583; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 16.0 Hz, 1H), 4.63 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.5, 162.2, 153.5, 145.4, 130.5, 126.4, 121.2, 114.5, 55.4, 42.8, 33.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C13H14N4O2SNa 313.0735; found 313.0733. (E)-4-(4-Methoxyphenyl)-3-methyl-1-((1-methyl-1H-tetrazol-5yl)thio)but-3-en-2-one (3f). Pale yellow solid (mp = 77−79 °C); yield 84% (220 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 2955, 2922, 2846, 1649, 1596, 1509, 1453; 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.00−6.95 (m, 2H), 4.91 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 2.13 (d, J = 1.2 Hz, 3H); 13 C{1H}NMR (100 MHz, CDCl3) δ 193.6, 160.4, 153.7, 141.5, 133.3, 132.0, 127.5, 114.0, 55.3, 42.3, 33.4, 13.1; HRMS (ESI-TOF) m/z (M+ + Na) calcd C14H16N4O2SNa 327.0892; found 327.0891. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)-4-(2-nitrophenyl)but-3-en2-one (3g). Yellow solid (mp = 117−119 °C); yield 64% (169 mg); Rf (50% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3423, 2920, 2852, 1685, 1608, 1608, 1566, 1521, 1438; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 16.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.73−7.68 (m, 2H), 7.63− 7.58 (m, 1H), 4.65 (s, 2H), 4.01 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.1, 153.2, 148.2, 140.6, 133.8, 130.9, 130.1, 129.2, 128.1, 125.0, 42.2, 33.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C12H11N5O3SNa 328.0480; found 328.0478. (E)-4-(4-Fluorophenyl)-1-((1-methyl-1H-tetrazol-5-yl)thio)but-3en-2-one (3h). Pale yellow solid (mp = 147−149 °C); yield 78% (186 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3068, 2916, 2371, 1677, 1588, 1506, 1380; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 16.0 Hz, 1H), 7.59−7.55 (m, 2H), 7.13−7.08 (m, 2H), 6.82 (d, J = 16.4 Hz, 1H), 4.62 (s, 2H), 3.99 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.4, 163.7 (d, J = 251 Hz), 153.38, 144.14, 130.6 (d, J = 8 Hz), 130.0 (d, J = 3 Hz), 123.2 (d, J = 2 Hz), 116.3 (d, J = 22 Hz), 42.66, 33.52; HRMS (ESI-TOF) m/z (M + + Na) calcd C12H11FN4OSNa 301.0535; found 301.0535. 4-Methyl-1-((1-methyl-1H-tetrazol-5-yl)thio)pent-3-en-2-one (3i). Yellow viscous solid; yield 32% (59 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3019, 2964, 2916, 1761, 1677, 1609, 1445; 1H NMR (400 MHz, CDCl3) δ 6.24−6.22 (m, 1H), 4.36 (s, 2H), 3.98 (s, 3H), 2.18 (d, J = 1.2 Hz, 3H), 1.96 (d, J = 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.2, 160.3, 153.5, 121.0, 45.1, 33.5, 27.9, 21.2; HRMS (ESI-TOF) m/z (M+ + Na) calcd C8H12N4OSNa 235.0630; found 235.0631. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)-4-(naphthalen-1-yl)but-3en-2-one (3j). Pale yellow solid (mp = 128−130 °C); yield 82% (219 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3037, 2955, 2920, 2851, 2084, 1678, 1598, 1458; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 16.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.60−7.46 (m, 3H), 6.96 (d, J = 15.6 Hz, 1H), 4.67 (s, 2H), 3.97 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.5, 153.4, 142.1, 133.6, 131.5, 130.9, 128.8, 127.2, 126.4, 125.6, 125.5, 125.4, 123.0, 42.8, 33.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C16H14N4OSNa 333.0786; found 333.0789. (E)-4-(Furan-2-yl)-1-((1-methyl-1H-tetrazol-5-yl)thio)but-3-en-2one (3k). Yellow solid (mp = 107−109 °C); yield 79% (170 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3115, 2914, 2852, 2081, 1620, 1466, 1381; 1H NMR (400 MHz, CDCl3) δ 7.54−7.44 (m, 2H), 6.77−6.73 (m, 2H), 6.53−6.51 (m, 1H), 4.56 (d, J = 0.4 Hz, 2H), 3.98 (d, J = 0.8 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.1, 153.3, 150.4, 145.7, 131.0, 120.4, 117.5, 112.8, 42.8, 33.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C10H10N4O2SNa 273.0422; found m/z 273.0420. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)-4-(thiophen-2-yl)but-3-en2-one (3l). Yellow solid (mp = 115−117 °C); yield 72% (164 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3132, 3073, 2957, 2909, 2206, 1671, 1583, 1375; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 16.0, 0.4 Hz, 1H), 7.48−7.46 (m, 1H), 7.37−7.35 (m, 1H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 7.09 (d, J = 15.6 Hz, 1H), 4.58 (s, 2H), 3.98 (s,
methodology is the utility of strong conjugate acceptors such as α,β-unsaturated ketones as nucleophiles, which is a rare phenomenon and is unprecedented.
■
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 13C NMR. IR spectra were measured using an FT-IR spectrometer. Mass spectra were obtained with a QTOF 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, reagents, and reactants were procured from commercial suppliers. Dichloroethane 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. Typical Experimental Procedure for Sulfenylation Reaction. Heterocyclic thiol (0.86 mmol, 1 equiv) and ketone (1.72 mmol, 2 equiv) were dissolved in DMSO (1 mL), and aq HI 55−58% (0.17 mmol, 20 mol %) was added. The reaction mixture was stirred at 80 °C for 2−3 h. After the completion of the reaction (monitored by TLC), water (25 mL) and dilute sodium thiosulfate solution (5 mL) were added and extracted with EtOAc (3 × 20 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 5−30% EtOAc/hexane to get the pure products. Characterization Data. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)4-phenylbut-3-en-2-one (3a). Yellow solid (mp = 94−97 °C); yield 78% (175 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3020, 2959, 2914, 1680, 1601, 1571; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.57−7.54 (m, 2H), 7.42−7.38 (m, 3H), 6.87 (d, J = 16.0 Hz, 1H), 4.62 (s, 2H), 3.95 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 153.4, 145.4, 133.7, 131.1, 129.0, 128.5, 123.5, 42.7, 33.5; HRMS (ESI-TOF) m/z (M+ + H) calcd C12H12N4OSH 261.0810; found 261.0808. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)-4-(o-tolyl)but-3-en-2-one (3b). Pale yellow solid (mp = 103−105 °C); yield 86% (203 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3025, 3025, 2952, 2913, 1677, 1593, 1459, 1379; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 15.6 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.33−7.29 (m, 1H), 7.22 (t, J = 7.2 Hz, 2H), 6.81 (d, J = 16.0 Hz, 1H), 4.61 (s, 2H), 3.98 (s, 3H), 2.45 (s, 3H); 13C{1H} (100 MHz, CDCl3) δ 191.6, 153.3, 142.8, 138.5, 132.6, 131.0, 130.9, 126.5, 126.4, 124.2, 42.8, 33.5, 19.7; HRMS (ESITOF) m/z (M+ + Na) calcd C13H14N4OSNa 297.0786; found 297.0786. (E)-1-((1-Methyl-1H-tetrazol-5-yl)thio)-4-(p-tolyl)but-3-en-2-one (3c). Pale yellow solid (mp = 128−130 °C); yield 76% (180 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3027, 2953, 2920, 2853, 1680, 1594, 1510; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 16.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.82 (d, J = 16.0 Hz, 1H), 4.63 (s, 2H), 3.97 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 153.4, 145.5, 141.9, 131.0, 129.8, 128.6, 122.5, 42.7, 33.5, 21.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C13H14N4OSNa 297.0786; found 297.0784. (E)-4-(3-Methoxyphenyl)-1-((1-methyl-1H-tetrazol-5-yl)thio)but3-en-2-one (3d). Yellow solid (mp = 93−96 °C); yield 84% (210 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3057, 2951, 2906, 2830, 1669, 1601, 1456; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 16.0 Hz, 1H), 7.33−7.29 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.10−7.07 (m, 1H), 6.99−6.96 (m, 1H), 6.85 (d, J = 16.4 Hz, 1H), 4.63 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.5, 159.8, 153.3, 145.3, 135.0, 129.9, 123.7, 121.2, 117.1, 113.2, 55.2, 42.7, 33.4; HRMS (ESI-TOF) m/z (M+ + Na) calcd C13H14N4O2SNa 313.0735; found 313.0735. 2990
DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
Note
The Journal of Organic Chemistry 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.0, 153.3, 139.1, 137.7, 132.8, 130.1, 128.5, 121.9, 42.6, 33.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C10H10N4OS2Na 289.0194; found m/z 289.0190. (E)-4-((1-Methyl-1H-tetrazol-5-yl)thio)-1-(o-tolyl)hept-1-en-3-one (3m). Pale yellow liquid; yield 96% (260 mg); Rf (20% EtOAc/ hexane) 0.2. IR (Neat, cm−1) 3062, 3020, 2961, 2933, 2870, 1686, 1600; 1H NMR (400 MHz, CD2Cl2) δ 8.06 (d, J = 15.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.32−7.27 (m, 1H), 7.24−7.20 (m, 2H), 6.89 (d, J = 15.6 Hz, 1H), 5.03 (t, J = 6.8 Hz, 1H), 3.94 (s, 3H), 2.46 (s, 3H), 2.17−2.07 (m, 1H), 2.02−1.92 (m, 1H), 1.56−1.46 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H}MR (400 MHz, CDCl3) δ 195.3, 153.1, 142.8, 138.7, 132.8, 131.0, 130.8, 126.5, 126.4, 123.9, 55.4, 33.6, 33.5, 20.0, 19.8, 13.7; HRMS (ESI-TOF) m/z (M+ + Na) calcd C16H20N4OSNa 339.1256; found 339.1254. (E)-4-Phenyl-1-((1-phenyl-1H-tetrazol-5-yl)thio)but-3-en-2-one (3o). Pale yellow solid (mp = 94−97 °C); yield 79% (219 mg); Rf (20% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3066, 3014, 2909, 2852, 1642, 1611, 1495; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 16.0 Hz, 1H), 7.63−7.53 (m, 7H), 7.44−7.39 (m, 3H), 6.90 (d, J = 16.4 Hz, 1H), 4.72 (s, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.7, 153.4, 145.4, 133.7, 133.4, 131.2, 130.2, 129.8, 129.0, 128.6, 123.7, 123.6, 42.8; HRMS (ESI-TOF) m/z (M+ + Na) calcd C17H14N4OSNa 345.0786; found 345.0786. (E)-4-Phenyl-1-(pyridin-2-ylthio)but-3-en-2-one (4a). Brown oily liquid; yield 14% (36 mg); Rf (10% EtOAc/hexane) 0.2. IR (Neat, cm−1) 3066, 3014, 2909, 2852, 1642, 1611, 1495; 1H NMR (400 MHz, CDCl3) δ 8.39−8.41 (m, 1H), 7.70 (d, J = 16.4 Hz, 1H), 7.53− 7.46 (m, 3H), 7.38−7.36 (m, 3H), 7.26−7.23 (m, 1H), 7.01−6.96 (m, 2H), 4.28 (s, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 194.4, 156.9, 149.2, 143.7, 136.1, 134.4, 130.5, 128.8, 128.4, 124.1, 122.1, 119.8, 38.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C15H13NOSNa 278.0616; found 278.0616. (E)-1-((5-Methyl-1,3,4-thiadiazol-2-yl)thio)-4-phenylbut-3-en-2one (5a). Brown solid (mp = 80−82 °C); yield 78% (186 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3048, 2923, 2880, 2850, 1680, 1601, 1444; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.57−7.54 (m, 2H), 7.42−7.37 (m, 3H), 6.92 (d, J = 16.4 Hz, 1H), 4.54 (s, 2H), 2.70 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.2, 165.3, 164.0, 144.8, 133.9, 130.9, 128.9, 128.5, 123.7, 42.2, 15.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C13H12N2OS2Na 299.0289; found 299.0289. (E)-4-(3-Methoxyphenyl)-1-((5-methyl-1,3,4-thiadiazol-2-yl)thio)but-3-en-2-one (5b). White solid (mp = 116−118 °C); yield 62% (164 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 2922, 2884, 2833, 1676, 1605, 1492; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 16.4 Hz, 1H), 7.33−7.28 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.07−7.06 (m, 1H), 6.98−6.94 (m, 1H), 6.90 (d, J = 16.4 Hz, 1H), 4.54 (s, 2H), 3.83 (s, 3H), 2.71 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.2, 165.3, 164.0, 159.8, 144.8, 135.3, 129.9, 124.0, 121.2, 116.9, 113.2, 55.2, 42.2, 15.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C14H14N2O2S2Na 329.0394; found 329.0394. (E)-4-(4-Fluorophenyl)-1-((5-methyl-1,3,4-thiadiazol-2-yl)thio)but-3-en-2-one (5c). Pale brown solid (mp = 88−91 °C); yield 62% (158 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3051, 3013, 2930, 2884, 1678, 1596, 1506; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 16.0 Hz, 1H), 7.58−7.54 (m, 2H), 7.09 (t, J = 8.4 Hz, 2H), 6.87 (dd, J = 16.0, 0.4 Hz, 1H), 4.52 (s, 2H), 2.71 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.0, 165.4, 164.1 (d, J = 251 Hz), 163.91 143.41, 130.4 (d, J = 9 Hz), 130.2 (d, J = 4 Hz), 123.4 (d, J = 3 Hz), 116.0(d, J = 22 Hz), 42.1, 15.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C13H11FN2OS2Na 317.0195; found 317.0191. (E)-4-(Furan-2-yl)-1-((5-methyl-1,3,4-thiadiazol-2-yl)thio)but-3en-2-one (5d). Pale yellow solid (mp = 121−123 °C); yield 65% (149 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3096, 2923, 1665, 1585, 1467, 1377; 1H NMR (400 MHz, CDCl3) δ 7.52−7.43 (m, 2H), 6.81 (d, J = 15.6 Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H), 6.50−6.49 (m, 1H), 4.46 (s, 2H), 2.71 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.9, 165.4, 164.0, 150.7, 145.5, 130.6, 120.8, 117.0, 112.7, 42.4, 15.5; HRMS (ESI-TOF) m/z (M+ + Na) calcd C11H10N2O2S2Na 289.0081; found 289.0081.
(E)-1-((5-Methyl-1,3,4-thiadiazol-2-yl)thio)-4-(thiophen-2-yl)but3-en-2-one (5e). Pale brown solid (mp = 113−115 °C); yield 70% (171 mg); Rf (30% EtOAc/hexane) 0.2. IR (KBr, cm−1) 3102, 3052, 2925, 2885, 2116, 2006, 1666, 1589; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 15.6 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.08 (dd, J = 5.2, 3.6 Hz, 1H), 6.71 (d, J = 16.0 Hz, 1H), 4.48 (s, 2H), 2.71 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 191.7, 165.4, 164.0, 139.4, 137.2, 132.5, 129.7, 128.4, 122.3, 42.2, 15.5; HRMS (ESITOF) m/z (M+ + Na) calcd C11H10N2OS3Na 304.9853; found 304.9850. (E)-1-(Benzo[d]thiazol-2-ylthio)-4-phenylbut-3-en-2-one (6). Pale yellow oily liquid; yield 56% (105 mg); Rf (5% EtOAc/hexane) 0.4 (starting material ketone and product appear at same Rf). IR (Neat, cm−1) 3059, 3028, 2911, 1685, 1608, 1574; 1H NMR (400 MHz, CDCl3) δ 7.86−7.84 (m, 1H), 7.76−7.72 (m, 2H), 7.56−7.53 (m, 2H), 7.40−7.37 (m, 4H), 7.31−7.26 (m, 1H), 7.00 (d, J = 16.4 Hz, 1H), 4.53 (s, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.8, 165.1, 152.8, 144.7, 135.5, 134.1, 130.9, 129.0, 128.5, 126.1, 124.4, 123.7, 121.5, 121.1, 41.7; HRMS (ESI-TOF) m/z (M+ + Na) calcd C17H13NOS2Na 334.0336; found 334.0333. 4-(4-Methyl-5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)-4-phenylbutan-2-one (7). Pale yellow solid (mp = 110−112 °C); yield 35% (80 mg); Rf (20% EtOAc/hexane) 0.3. IR (KBr, cm−1) 3062, 3035, 2925, 2262, 2147, 1709, 1601, 1447; 1H NMR (400 MHz, CDCl3) δ 7.41− 7.39 (m, 2H), 7.32−7.27 (m, 3H), 6.26 (dd, J = 9.6, 5.6 Hz, 1H), 3.83−3.75 (m, 4H), 3.31−3.25 (m, 1H), 2.15 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 203.2, 163.9, 136.4, 128.8, 128.7, 127.3, 57.4, 47.1, 34.4, 29.9; HRMS (ESI-TOF) m/z (M+ + Na) calcd C12H14N4OSNa 285.0786; found 285.0788.
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ASSOCIATED CONTENT
S Supporting Information *
This material is available free of charge via the Internet. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03290. 1 H and 13C spectra and spectral data for all compounds (PDF)
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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 This work was supported by SERB (EMR/2016/006358), New-Delhi, CSIR (Grant 02(0226)15/EMRII), New-Delhi, Indian Institute of Science, RL Fine Chem, Bangalore and Synovation Chemicals and Sourcing Pvt Limited, Bangalore. We thank Dr. A. R. Ramesha (RL Fine Chem) for useful discussions. Y.S. thanks CSIR for an SPM fellowship.
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REFERENCES
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DOI: 10.1021/acs.joc.7b03290 J. Org. Chem. 2018, 83, 2986−2992
