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DOI: 10.1055/s-0040-1719935
α-Sulfenylation between 4-Hydroxydithiocoumarin and 1,3-Dicarbonyl Compounds: A Key Precursor for the Synthesis of New Pyrazole Derivatives
A. T. K. is highly indebted to the Department of Science and Technology, Ministry of Science and Technology (SERB), New Delhi for the financial support (research project Grant No.: CRG/2018/002120/OC). Ms. Santa Mondal is grateful to Indian Institute of Technology Guwahati (IIT Guwahati) for her research fellowship. The authors are also thankful to Ministry of Human Resource Development for 500 MHz NMR facility in the department (MHRD, Grant No. F. No. 5-5/2014-TS-VII). We duly acknowledge the Department of Science and Technology, Ministry of Science and Technology, New Delhi for providing 500 MHz NMR facility under the DST-FIST program (Sanction No. SR/FST/CS-II/2017/23C), and North East Centre for Biological Sciences and Healthcare Engineering, IIT Guwahati (Sanction No. BT/COE/34/SP28408/2018) for 400 MHz NMR facility.
Abstract
An efficient synthetic protocol for the α-sulfenylation of 1,3-dicarbonyl compounds is reported through a cross dehydrogenative coupling reaction with 4-hydroxydithiocoumarins in the presence of 10 mol% KI and 1 equiv. TBHP in toluene under reflux conditions. Some of the products are utilized for the synthesis of substituted new pyrazole derivatives on reaction with phenylhydrazine in ethanol at room temperature. In addition, α-benzylation is also achieved on treatment with benzyl bromide using K2CO3/CH3CN under mild conditions. The salient features of the present protocol are good yields, mild reaction conditions, shorter reaction time, no byproducts were formed (sulfoxide/sulfone), and no deacylation occurs during the process. In the present protocol, 4-hydroxydithiocoumarin is converted into a suitable electrophile through a radical substitution pathway, which undergoes ultimately C–S bond formation with 1,3-dicarbonyl compounds by a nucleophilic substitution reaction.
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Key words
4-hydroxydithiocoumarin - 1,3-dicarbonyl compounds - α-thio-carbonyl compounds - cross dehydrogenative coupling reaction - pyrazole - α,α-disubstituted 1,3-dicarbonyl compoundsOrganosulfur compounds are important intermediates in different chemical syntheses and they have gained a lot of attention in natural and non-natural product synthesis.[1] The organosulfur compounds, used as medicines with the C–S linkage, exhibit antiviral, antibacterial, antiallergic, and antimalarial activities.[2] As a matter of fact, organic chemists have given much attention to developing newer processes for C–S bond formation reactions. 1,3-Dicarbonyl compounds are valuable starting materials for the synthesis of pyrazoles,[3] oxazoles,[4] and other pharmaceutically[5] significant heterocyclic compounds, and they are also are an integral part of many naturally occurring compounds.[6] The achievement of heteroatom substitution of the methylene site of 1,3-dicarbonyl compounds is still an attraction among the scientific community. In this context, α-thio-carbonyl compounds, which have emerged as building blocks in organic synthesis,[7] medicines, and agrochemicals,[8] deserve special consideration. Some of the most effective molecules containing α-thio-carbonyl compounds, such as malathion, gliotoxin, and 2-[(2-methylphenyl)thio]indane-1,3-dione, are well known.[9]
Numerous methods have been developed for the sulfenylation of 1,3-dicarbonyl compounds with thiols using prefunctionalization of 1,3-dicarbonyl compounds.[10] Prabhu et al. reported the synthesis of α-thio-carbonyl compounds from exocyclic sulfur-containing benzoxazole and 1,3-dicarbonyl compounds in the presence of K2S2O8 and aq. HClO4 at room temperature.[11] Zeng et al. reported the synthesis of α-thio-β-dicarbonyl compounds using Cs2CO3 starting from a thiol and active methylene compounds.[12]
It is challenging to accomplish C–H/S–H oxidative coupling reactions of thiols with 1,3-dicarbonyl compounds due to: (i) products might be subsequently oxidized to produce sulfoxides or sulfones; (ii) metal catalysts with high coordination to sulfur atoms are typically poisoned for this process; (iii) deacylation can occur when disulfide or its equivalent is employed in a process;[13] and (iv) requirement of inert atmosphere[14] and longer reaction times.[15] Only a few examples of α-thio-carbonyl compounds being synthesized in one step using 1,3-dicarbonyl compounds and thiophenols as starting materials have been published due to these limitations. Since 1,3-dicarbonyl compounds and thiophenols are both nucleophiles, one of them must be converted into the respective electrophile before a C–S bond can be generated, hence typical α-thio-carbonyl syntheses are strenuous and laborious. Exploring how to synthesize α-thio-carbonyl compounds from thiophenols directly and 1,3-dicarbonyl compounds is fascinating and challenging.
Recently our group has shown the reactivity behavior of 4-hydroxydithiocoumarin for the synthesis of numerous new compounds, which has been reviewed recently.[16] From the reactivity pattern of 4-hydroxydithiocoumarin, it was noted that it could generate one of intermediate as a thiol (2-mercapto-4H-thiochromen-4-one)[17] in the reaction medium. The thiol form of 4-hydroxydithiocoumarin acts as a nucleophile, and 1,3-dicarbonyl compounds are also nucleophiles. The cross-coupling reaction between two nucleophiles is a challenging task and using these α-thio-carbonyl compound derivatives, we can synthesize a new class of pyrazole derivatives.
Herein, we report the synthesis of α-thio-carbonyl compounds from 4-hydroxydithiocoumarins and 1,3-dicarbonyl compounds using 10 mol% KI and 1 equivalent of TBHP in toluene at 110 °C as shown in Scheme [1].
We have synthesized various 4-hydroxydithiocoumarin derivatives from 2′-chloroacetophenone and carbon disulfide in the presence of sodium hydride for our present study.[17] 4-Hydroxydithiocoumarin (1a) and acetylacetone (2a) were used as the model substrates to find suitable reaction conditions (Table [1]). We began our experiment with 4-hydroxydithiocoumarin and acetylacetone in DMSO at room temperature and 70 °C in the presence of 10 mol% I2 and 1 equiv. of TBHP, no reaction occurred, and the starting materials were recovered (Table [1], entries 1 and 2). Delightfully, product 3a was observed when we performed the reaction with 10 mol% I2 and 1 equiv. of TBHP at 100 °C (Table [1], entry 3). The structure of product 3a was characterized by using IR, 1H NMR, 13C NMR spectra, and HRMS. Furthermore, the reactions were executed with 10 mol% I2 in DMSO by varying oxidants like DTBP, and K2S2O8 at 100 °C (entry 4 and 5), but the yields were not improved. During the catalyst screening, we also used Bu4NI or KI in the presence of TBHP in DMSO at 100 °C (entries 6 and 7) but the yields also did not improve to those expected. Moreover, we examined the reaction in the presence of 10 mol% KI and 1 equiv. of TBHP by varying the solvent to DMF, methanol, CH3CN, 1,4-dioxane, and toluene (entries 8–12). We obtained the best yield in toluene under reflux conditions. Finally, we have executed the reactions in toluene with increased catalyst loading (entries 13 and 14) and TBHP (entries 15 and 16). We concluded from all these observations that the best reaction conditions to obtain the desired product in maximum yield are 10 mol% KI, 1 equiv. TBHP in toluene at 110 °C (Table [1], entry 12).
a Reaction conditions: 4-hydroxydithiocoumarin (0.25 mmol), acetylacetone (0.25 mmol), KI (10 mol%), TBHP (1 equiv.), solvent (1 mL).
b Isolated yield.
c Room temperature.
d 70 °C temperature.
e 100 °C temperature.
f Reflux conditions.
Using these optimized reaction conditions, we examined the substrate scope of this transformation with respect to acetylacetone (2a) and the successful results are summarized in Scheme [2]. Initially, various 4-hydroxydithiocoumarins were investigated. The substrates having a substituent such as -Cl, -F, -CF3 in the 4-hydroxydithiocoumarin moiety may be easily converted into the corresponding products 3b–f in moderate to good yields. To study the substrate scope of the reaction, we have performed the reaction of various 4-hydroxydithiocoumarins 1 with 1-phenylbutane-1,3-dione (2b). When 1-phenylbutane-1,3-dione (2b) was employed, the reaction also proceeded smoothly to afford the products regardless of the nature of the substituent present on the 4-hydroxydithiocoumarin nucleus to give 3g–l in 80–84% yield, respectively. Interestingly, the reaction also proceeded well with a β-keto ester such as methyl acetoacetate (2c). The reaction of methyl acetoacetate (2c) and various 4-hydroxydithiocoumarin derivatives also provided the expected products 3m–q in 76–85% yield. Next, we have examined whether the present protocol can be extended to heterocyclic acetylacetone or not. Unfortunately, no desired product was obtained other than starting materials when the reaction was carried out with 2-furoylacetone.
The possible mechanism for the formation of product 2 is illustrated in Scheme [3]. Initially, TBHP produces a tert-butoxy radical and hypoiodous acid when it reacts with iodide. After that, the tert-butoxy radical reacts with TBHP to form the tert-butylperoxy radical.[18] Furthermore, tert-butoxy radicals or tert-butylperoxy radicals can abstract hydrogen from 4-hydroxydithiocoumarin 1 to generate radical intermediate A,[19] which could also exist either as B or C.[17] Pathway I: either radical intermediate C dimerizes to produce intermediate E, which is then converted into product 3, or Pathway II: the intermediate C combines with an iodide radical to produce intermediate D,[20] which is then converted into product 3 after nucleophilic substitution. After then, the iodide ion is oxidized to iodine.
The control experiments (Scheme [4]) were carried out to confirm whether the reaction is going through the radical pathway or not. When two reactions were carried out with the radical inhibitors BHT and TEMPO, the yield of the product 3a was reduced significantly, i.e., 30% and 10%, respectively, compared to yield 78%. We may predict a radical pathway favors the reaction based on these two observations.
In addition, to demonstrate the utility of this reaction, the active methine carbon of the sulfenylation product, 3a, was used as a nucleophile with an electrophilic reagent such as benzyl bromide to yield the corresponding quaternary carbon-containing products in good yield (5a, 78%) (Scheme [5]).
Some of pyrazole derivatives are well-known as drugs and they exhibit a wide range of biological activities in the literature.[21] By assuming these activities, we tried to explore a new class of pyrazole derivative having 4-hydroxydithiocoumarin skeleton, which might possesses better biological activity.
With this goal in mind, the products 3a–c were converted into the pyrazole derivative 7a–c by reacting with phenylhydrazine (Scheme [5]).
In conclusion, we have demonstrated the synthesis of a new class of α-thio-carbonyl derivatives via cross dehydrogenative coupling (CDC) reaction between 4-hydroxydithiocoumarin and 1,3-dicarbonyl compounds by employing 10 mol% KI and TBHP, which is a highly practical and efficient approach. This observation is the first example of the CDC reaction of 4-hydroxydithiocoumarin with 1,3-dicarbonyl compounds that we are aware of it. The current strategy should be applied to the design of product libraries with a wide range of features. The reaction is notable for its high yields, mild reaction conditions, and shorter reaction time. Specifically, these α-thio-carbonyl compounds can be explored further for the synthesis of pyrazoles, and quaternary carbon-containing α,α-disubstituted β-diketones. This reaction has potential since it forms an asymmetric quaternary carbon core, which can be used to build enantioselective procedures. Our laboratory is now conducting additional research in this area.
1H and 13C NMR spectra were recorded on 600 MHz, 500 MHz and 400 MHz spectrometers, TMS as an internal reference. IR spectra were recorded in KBr. HRMS spectra were recorded using ESI mode.
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4-Hydroxydithiocoumarin Derivatives 1a–f; General Procedure
A wide variety of 4-hydroxydithiocoumarins were prepared by following the previously reported procedure.[17]
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α-Thio-carbonyl Compounds 3a–q; General Procedure
To a 10-mL round-bottom flask was added a mixture of 4-hydroxydithiocoumarin 1 (0.25 mmol) and 1,3-dicarbonyl compound 2 (0.25 mmol) in toluene (1 mL) then TBHP (1 equiv.) and KI (10 mol%) were added successively. The mixture refluxed in a preheated oil bath with constant stirring monitoring by TLC. When the reaction was complete, the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd Na2SO4) and then concentrated using a rotary evaporator. The residue was purified by column chromatography (silica gel 60–120 mesh, EtOAc/hexane 1.5:8.5) to give 3a–q.
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2-((2-Hydroxy-4-oxopent-2-en-3-yl)thio)-4H-thiochromen-4-one (3a)
Brown solid; yield: 57 mg (78%); mp 150–151 °C.
IR (KBr): 3291, 1720, 1688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 17.51 (s, 1 H), 8.46 (s, 1 H), 7.58 (d, J = 1.9 Hz, 1 H), 7.52 (s, 2 H), 6.92 (s, 1 H), 2.41 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 198.9, 178.7, 155.8, 137.0, 131.6, 130.7, 128.9, 128.1, 126.0, 120.4, 98.3, 24.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H13O3S2: 293.0301; found: 293.0302.
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6-Chloro-2-((2-hydroxy-4-oxopent-2-en-3-yl)thio)-4H-thiochromen-4-one (3b)
Brown liquid; yield: 61 mg (75%).
IR (KBr): 3302, 1722, 1679 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.49 (s, 1 H), 8.44 (s, 1 H), 7.54 (dd, J = 8.5, 2.1 Hz, 1 H), 7.45 (d, J = 8.6 Hz, 1 H), 6.92 (s, 1 H), 2.40 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 199.0, 177.4, 156.4, 135.1, 134.7, 132.0, 131.9, 128.6, 127.4, 120.2, 98.1, 24.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClO3S2: 326.9911; found: 326.9911.
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7-Chloro-2-((2-hydroxy-4-oxopent-2-en-3-yl)thio)-4H-thiochromen-4-one (3c)
Brown liquid; yield: 61 mg (76%).
IR (KBr): 3285, 1718, 1684 cm–1.
1H NMR (400 MHz, CDCl3): δ = 17.51 (s, 1 H), 8.39 (d, J = 8.6 Hz, 1 H), 7.52 (d, J = 2.1 Hz, 1 H), 7.48–7.45 (m, 1 H), 6.90 (s, 1 H), 2.41 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 199.0, 177.8, 155.7, 138.4, 138.3, 130.5, 129.1, 128.8, 125.4, 120.5, 98.1, 24.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClO3S2: 326.9911; found: 326.9920.
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5-Chloro-2-((2-hydroxy-4-oxopent-2-en-3-yl)thio)-4H-thiochromen-4-one (3d)
Brown liquid; yield: 58 mg (72%).
IR (KBr): 3289, 1716, 1683 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.46 (s, 1 H), 7.49 (t, J = 4.5 Hz, 1 H), 7.40 (d, J = 4.8 Hz, 2 H), 6.83 (s, 1 H), 2.40 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 198.9, 178.1, 152.4, 139.9, 136.5, 131.9, 130.9, 127.5, 125.1, 122.0, 98.1, 24.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClO3S2: 326.9911; found: 326.9915.
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2-((2-Hydroxy-4-oxopent-2-en-3-yl)thio)-6-(trifluoromethyl)-4H-thiochromen-4-one (3e)
Yellow solid; yield: 70 mg (78%); mp 173–174 °C.
IR (KBr): 3301, 1724, 1687 cm–1.
1H NMR (400 MHz, CDCl3): δ = 17.54 (s, 1 H), 8.74 (d, J = 2.1 Hz, 1 H), 7.79 (dd, J = 8.4, 2.1 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.96 (s, 1 H), 2.41 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 199.0, 177.5, 156.5, 140.4, 131.7, 130.9, 130.5 (q, J = 33.4 Hz), 127.7 (q, J = 3.3 Hz), 126.9, 126.3 (q, J = 4.0 Hz), 123.5 (q, J = 270.7 Hz), 120.5, 119.4, 97.9, 24.6.
19F NMR (377 MHz, CDCl3): δ = –62.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H12F3O3S2: 361.0174; found: 361.0173.
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7-Fluoro-2-((2-hydroxy-4-oxopent-2-en-3-yl)thio)-4H-thiochromen-4-one (3f)
Brown liquid; yield: 54 mg (70%).
IR (KBr): 3287, 1720, 1683 cm–1.
1H NMR (600 MHz, CDCl3): δ = 17.50 (s, 1 H), 8.48 (dd, J = 8.6, 5.9 Hz, 1 H), 7.23–7.20 (m, 2 H), 6.89 (s, 1 H), 2.41 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 199.0, 177.7, 164.0 (d, J = 255.1 Hz), 155.6, 139.0 (d, J = 9.5 Hz), 131.9 (d, J = 9.7 Hz), 127.3 (d, J = 2.5 Hz), 120.4, 116.6 (d, J = 22.1 Hz), 112.1 (d, J = 24.7 Hz), 98.0, 24.6.
19F NMR (377 MHz, CDCl3): δ = –105.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H12FO3S2: 311.0206; found: 311.0210.
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2-((3-Hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-4H-thiochromen-4-one (3g)
Brown liquid; yield: 71 mg (80%).
IR (KBr): 3305, 1726, 1680 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.93 (s, 1 H), 8.45 (dd, J = 8.3, 1.5 Hz, 1 H), 7.68–7.66 (m, 2 H), 7.59–7.56 (m, 1 H), 7.52–7.50 (m, 2 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 2 H), 6.87 (s, 1 H), 2.52 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.4, 192.8, 178.6, 156.6, 137.0, 135.1, 131.9, 131.6, 130.7, 128.9, 128.5, 128.2, 128.1, 126.0, 120.3, 97.5, 25.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H15O3S2: 355.0457; found: 355.0465.
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6-Chloro-2-((3-hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-4H-thiochromen-4-one (3h)
Brown liquid; yield: 79 mg (82%).
IR (KBr): 3306, 1727, 1685 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.93 (s, 1 H), 8.42 (d, J = 2.4 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.53 (dd, J = 8.6, 2.4 Hz, 1 H), 7.46 (dd, J = 11.6, 8.2 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 6.86 (s, 1 H), 2.52 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.3, 193.0, 177.4, 157.1, 135.1, 135.1, 134.7, 131.9, 131.9, 128.5, 128.5, 128.2, 127.4, 120.0, 97.3, 25.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClO3S2: 389.0067; found: 389.0066.
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7-Chloro-2-((3-hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-4H-thiochromen-4-one (3i)
Brown liquid; yield: 74 mg (77%).
IR (KBr): 3300, 1724, 1688 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.92 (s, 1 H), 8.36 (d, J = 8.6 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 2 H), 7.51–7.50 (m, 1 H), 7.48–7.44 (m, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 6.83 (s, 1 H), 2.52 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.3, 193.0, 177.7, 156.4, 138.3, 138.3, 135.1, 131.9, 130.4, 129.1, 128.7, 128.5, 128.2, 125.4, 120.4, 97.3, 25.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClO3S2: 389.0067; found: 389.0065.
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5-Chloro-2-((3-hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-4H-thiochromen-4-one (3j)
Brown liquid; yield: 77 mg (80%).
IR (KBr): 3292, 1728, 1678 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.90 (s, 1 H), 7.66 (d, J = 7.9 Hz, 2 H), 7.48–7.47 (m, 2 H), 7.41–7.39 (m, 4 H), 6.77 (s, 1 H), 2.52 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.3, 192.9, 178.0, 153.2, 139.9, 136.5, 135.1, 131.9, 131.9, 130.9, 128.5, 128.2, 127.5, 125.1, 121.8, 97.3, 25.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClO3S2: 389.0067; found: 389.0064.
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2-((3-Hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-6-(trifluoromethyl)-4H-thiochromen-4-one (3k)
Brown liquid; yield: 88 mg (84%).
IR (KBr): 3304, 1725, 1676 cm–1.
1H NMR (400 MHz, CDCl3): δ = 17.98 (s, 1 H), 8.72 (s, 1 H), 7.78 (d, J = 6.4 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 3 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 2 H), 6.90 (s, 1 H), 2.53 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.3, 193.1, 177.4, 157.2, 140.4, 135.0, 132.0, 130.9, 130.5 (q, J = 33.4 Hz), 128.5, 128.2, 127.6 (q, J = 3.5 Hz), 126.9, 126.3 (q, J = 4.0 Hz), 123.5 (q, J = 270.8 Hz), 120.3, 97.1, 25.6.
19F NMR (471 MHz, CDCl3): δ = –62.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H14F3O3S2: 423.0331; found: 423.0335.
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7-Fluoro-2-((3-hydroxy-1-oxo-1-phenylbut-2-en-2-yl)thio)-4H-thiochromen-4-one (3l)
Brown liquid; yield: 76 mg (82%).
IR (KBr): 3298, 1723, 1682 cm–1.
1H NMR (500 MHz, CDCl3): δ = 17.95 (s, 1 H), 8.46 (dd, J = 9.7, 5.8 Hz, 1 H), 7.66 (d, J = 7.0 Hz, 2 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2 H), 7.23–7.21 (m, 2 H), 6.83 (s, 1 H), 2.52 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 202.4, 192.9, 177.6, 164.0 (d, J = 254.9 Hz), 156.2, 139.0 (d, J = 9.6 Hz), 135.0, 131.9, 131.9 (d, J = 9.6 Hz), 128.5, 128.2, 127.3 (d, J = 2.4 Hz), 120.2, 116.5 (d, J = 22.0 Hz), 112.1 (d, J = 24.7 Hz), 97.3, 25.6.
19F NMR (471 MHz, CDCl3): δ = –105.7.
HRMS (ESI): m/z [M + H]+ calcd for C19H14FO3S2: 373.0363; found: 373.0362.
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Methyl 3-Hydroxy-2-((4-oxo-4H-thiochromen-2-yl)thio)but-2-enoate (3m)
Brown solid; yield: 58 mg (76%); mp 160–165 °C.
IR (KBr): 3292, 1791, 1674 cm–1.
1H NMR (500 MHz, CDCl3): δ = 14.03 (s, 1 H), 8.48–8.46 (m, 1 H), 7.58–7.55 (m, 1 H), 7.52–7.49 (m, 2 H), 6.90 (s, 1 H), 3.82 (s, 3 H), 2.40 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 187.6, 172.5, 137.3, 131.5, 130.8, 128.9, 127.9, 125.9, 120.5, 88.6, 53.2, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H13O4S2: 309.0250; found: 309.0251.
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Methyl 2-((6-Chloro-4-oxo-4H-thiochromen-2-yl)thio)-3-hydroxybut-2-enoate (3n)
Brown solid; yield: 70 mg (83%); mp 177–178 °C.
IR (KBr): 3295, 1723, 1687 cm–1.
1H NMR (500 MHz, CDCl3): δ = 14.04 (s, 1 H), 8.44 (d, J = 2.4 Hz, 1 H), 7.52 (dd, J = 8.6, 2.4 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 6.90 (s, 1 H), 3.82 (s, 3 H), 2.39 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 187.7, 177.6, 172.4, 156.8, 135.4, 134.5, 132.0, 131.8, 128.5, 127.3, 120.2, 88.3, 53.2, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClO4S2: 342.9860; found: 342.9857.
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Methyl 2-((7-Chloro-4-oxo-4H-thiochromen-2-yl)thio)-3-hydroxybut-2-enoate (3o)
Light brown solid; yield: 67 mg (79%); mp 180–182 °C.
IR (KBr): 3297, 1727, 1682 cm–1.
1H NMR (500 MHz, CDCl3): δ = 14.04 (s, 1 H), 8.38 (d, J = 8.6 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.44 (dd, J = 8.6, 2.0 Hz, 1 H), 6.87 (s, 1 H), 3.82 (s, 3 H), 2.39 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 187.7, 177.9, 172.4, 156.1, 138.6, 138.2, 130.4, 129.2, 128.5, 125.3, 120.5, 88.3, 53.2, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H12ClO4S2: 342.9860; found: 342.9866.
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Methyl 3-Hydroxy-2-((4-oxo-6-(trifluoromethyl)-4H-thiochromen-2-yl)thio)-but-2-enoate (3p)
Light brown solid; yield: 80 mg (85%); mp 211–212 °C.
IR (KBr): 3304, 1725, 1677 cm–1.
1H NMR (500 MHz, CDCl3): δ = 14.06 (s, 1 H), 8.73 (s, 1 H), 7.77 (dd, J = 8.5, 2.1 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 6.93 (s, 1 H), 3.82 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 187.8, 177.6, 172.3, 157.0, 140.8, 131.6, 130.5 (q, J = 33.2 Hz), 127.5 (q, J = 3.5 Hz), 126.8, 126.2 (q, J = 4.1 Hz), 123.4 (q, J = 270.8 Hz), 120.4, 88.1, 53.2, 21.2.
19F NMR (471 MHz, CDCl3): δ = –62.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H12F3O4S2: 377.0124; found: 377.0135.
#
Methyl 2-((7-Fluoro-4-oxo-4H-thiochromen-2-yl)thio)-3-hydroxybut-2-enoate (3q)
Light brown solid; yield: 66 mg (81%); mp 190–191 °C.
IR (KBr): 3297, 1723, 1689 cm–1.
1H NMR (500 MHz, CDCl3): δ = 14.04 (s, 1 H), 8.47 (dd, J = 9.6, 6.0 Hz, 1 H), 7.20 (t, J = 8.6 Hz, 2 H), 6.86 (s, 1 H), 3.82 (s, 3 H), 2.39 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 187.7, 177.8, 172.4, 164.0 (d, J = 254.8 Hz), 155.8, 139.3 (d, J = 9.3 Hz), 131.8 (d, J = 9.6 Hz), 127.4, 120.4, 116.3 (d, J = 22.1 Hz), 111.9 (d, J = 24.6 Hz), 88.3, 53.2, 21.3.
19F NMR (377 MHz, CDCl3): δ = –106.0.
HRMS (ESI): m/z [M + H]+ calcd for C14H12FO4S2: 327.0156; found: 327.0157.
#
3-Benzyl-3-((4-oxo-4H-thiochromen-2-yl)thio)pentane-2,4-dione (5a)
In a 25-mL round-bottomed flask, a mixture of α-thio-carbonyl compound 3a (0.5 mmol), benzyl bromide (4; 1.5 mmol), and K2CO3 (1.5 mmol) in CH3CN (2 mL) was stirred at r.t. with monitoring by TLC. When the starting material had been consumed, the CH3CN was removed on a rotatory evaporator. The crude residue was extracted with EtOAc (2 × 10 mL) and the combined extracts were dried (anhyd Na2SO4). Finally, the organic layer was concentrated using a rotatory evaporator and the crude residue was purified column chromatography (silica gel) to give a brown liquid; yield: 74 mg (78%).
IR (KBr): 2895, 1722, 1682 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.47 (d, J = 7.9 Hz, 1 H), 7.63–7.60 (m, 1 H), 7.54 (t, J = 8.2 Hz, 2 H), 7.31–7.27 (m, 5 H), 7.10 (s, 1 H), 3.61 (s, 2 H), 2.27 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 200.2, 179.5, 145.1, 139.0, 134.3, 133.8, 132.1, 130.8, 130.0, 129.0, 128.7, 128.4, 127.7, 125.8, 80.2, 38.2, 27.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H19O3S2: 383.0770; found: 383.0769.
#
Pyrazole Derivatives 7; General Procedure
To a 25 mL round-bottomed flask was added α-thio-carbonyl compound 3a (0.5 mmol) and phenylhydrazine (6; 1.5 mmol) in EtOH (2 mL) and the mixture was stirred at r.t. When the reaction was complete (TLC monitoring), the EtOH was removed on a rotatory evaporator. Finally, the crude residue was purified using column chromatography (silica gel); no work-up procedure was required.
#
2-((3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)thio)-4H-thiochromen-4-one (7a)
Dark brown liquid; yield: 65 mg (72%).
IR (KBr): 1721, 1682 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.45 (dd, J = 8.0, 1.6 Hz, 1 H), 7.56–7.52 (m, 2 H), 7.50 (d, J = 2.4 Hz, 4 H), 7.49–7.43 (m, 2 H), 6.90 (s, 1 H), 2.39 (s, 3 H), 2.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 178.8, 156.9, 153.7, 145.7, 139.5, 137.5, 131.4, 130.7, 129.4, 128.8, 128.5, 127.8, 125.9, 125.0, 120.6, 101.6, 12.2, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2OS2: 365.0777; found: 365.0783.
#
7-Chloro-2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)thio)-4H-thiochromen-4-one (7b)
Brown liquid; yield: 74 mg (75%).
IR (KBr): 1723, 1685 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 8.6 Hz, 1 H), 7.51 (dd, J = 13.6, 6.7 Hz, 4 H), 7.47–7.42 (m, 3 H), 6.87 (s, 1 H), 2.39 (s, 3 H), 2.35 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.9, 156.9, 153.6, 145.7, 139.4, 138.8, 138.1, 130.4, 129.4, 129.1, 128.5, 128.5, 125.2, 125.0, 120.6, 101.3, 12.2, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H16ClN2OS2: 399.0387; found: 399.0389.
#
2-((3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)thio)-7-fluoro-4H-thiochromen-4-one (7c)
Brown liquid; yield: 67 mg (70%).
IR (KBr): 1723, 1685 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.47 (dd, J = 8.9, 5.9 Hz, 1 H), 7.54–7.47 (m, 4 H), 7.46–7.42 (m, 1 H), 7.22–7.14 (m, 2 H), 6.87 (s, 1 H), 2.39 (s, 3 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.9, 165.2, 162.7, 156.8, 153.6, 145.7, 139.6, 139.5, 139.3, 131.8, 131.8, 129.4, 128.5, 127.3, 127.2, 125.0, 120.8, 120.5, 116.4, 116.2, 115.4, 112.0, 111.8, 101.3, 12.2, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H16FN2OS2: 383.0683; found: 383.0689.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgement
We are thankful to the Department of Chemistry for providing instrumental facilities. We are highly indebted to SAIF, IIT Patna for providing HRMS facilities.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1719935.
- Supporting Information
-
References
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Corresponding Author
Publication History
Received: 07 March 2022
Accepted after revision: 07 June 2022
Article published online:
05 July 2022
© 2022. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1a Miękus N, Marszałek K, Podlacha M, Iqbal A, Puchalski C, Świergiel AH. Molecules 2020; 25: 3804
- 1b Wang N, Saidhareddy P, Jiang X. Nat. Prod. Rep. 2020; 37: 246
- 2a Rouf R, Uddin SJ, Sarker DK, Islam MT, Ali ES, Shilpi JA, Nahar L, Tiralongo E, Sarker SD. Trends Food Sci. Technol. 2020; 104: 219
- 2b Sorlozano-Puerto A, Albertuz-Crespo M, Lopez-Machado I, Gil-Martinez L, Ariza-Romero JJ, Maroto-Tello A, Baños-Arjona A, Gutierrez-Fernandez J. Pharmaceuticals 2021; 14 (21) 1
- 2c Unangst PC, Connor DT, Stabler SR, Weikert RJ, Carethers ME, Kennedy JA, Thueson DO, Chestnut JC, Adolphson RL, Conroy MC. J. Med. Chem. 1989; 32: 1360
- 3a Chauhan M, Kumar R. Bioorg. Med. Chem. 2013; 21: 5657
- 3b Kumar V, Kaur K, Gupta GK, Sharma AK. Eur. J. Med. Chem. 2013; 69: 735
- 3c Deng X, Mani NS. Org. Lett. 2008; 10: 1307
- 3d Fustero S, Román R, Sanz-Cervera JF, Simón-Fuentes A, Cuñat AC, Villanova S, Murguía M. J. Org. Chem. 2008; 73: 3523
- 3e Gerstenberger BS, Rauckhorst MR, Starr JT. Org. Lett. 2009; 11: 2097
- 4a Wan C, Zhang J, Wang S, Fan J, Wang Z. Org. Lett. 2010; 12: 2338
- 4b Turchi IJ, Dewar MJ. S. Chem. Rev. 1975; 75: 389
- 4c Turchi IJ. Ind. Eng. Chem. Prod. Res. Dev. 1981; 20: 32
- 5 Kljun J, Turel I. Eur. J. Inorg. Chem. 2017; 1655
- 6a Christoffers J, Baro A, Werner T. Adv. Synth. Catal. 2004; 346: 143
- 6b Schröder P, Bauer JO, Strohmann C, Kumar K, Waldmann H. J. Org. Chem. 2016; 81: 10242
- 7a Gao W.-C, Zhao J.-J, Hu F, Chang H.-H, Li X, Wei W.-L. RSC Adv. 2015; 5: 25222
- 7b Pan X.-J, Gao J, Yuan G.-Q. Tetrahedron 2015; 71: 5525
- 7c Mulina OM, Pirgach DA, Nikishin GI, Terent’ev AO. Eur. J. Org. Chem. 2019; 4179
- 7d Gao W.-C, Tian J, Shang Y.-Z, Jiang X. Chem. Sci. 2020; 11: 3903
- 8 Jeschke P. Pest Manage. Sci. 2016; 72: 210
- 9a McDougall JK. Arch. Gesamte Virusforsch. 1969; 27: 255
- 9b Giles D, Prakash MS, Ramseshu KV. Cent. Eur. J. Chem. 2007; 4: 428
- 10a Yoshida Z, Ogoshi H, Tokumitsu T. Tetrahedron 1970; 26: 2987
- 10b Rashid MA, Reinke H, Langer P. Tetrahedron Lett. 2007; 48: 2321
- 11 Varun BV, Gadde K, Prabhu KR. Org. Lett. 2015; 17: 2944
- 12 Chen Q, Wang X, Wen C, Huang Y, Yan X, Zeng J. RSC Adv. 2017; 7: 39758
- 13 Zou L.-H, Priebbenow DL, Wang L, Mottweiler J, Bolm C. Adv. Synth. Catal. 2013; 355: 2558
- 14 Cao H, Yuan J, Liu C, Hu X, Lei A. RSC Adv. 2015; 5: 41493
- 15 Jiang Y, Zou J.-X, Huang L.-T, Peng X, Deng J.-D, Zhu L.-Q, Yang Y.-H, Feng Y.-Y, Zhang X.-Y, Wang Z. Org. Biomol. Chem. 2018; 16: 1641
- 16 Belal Md, Mondal S, Yashmin S, Khan AT. Org. Biomol. Chem. 2022; 20: 715
- 17 Anderson-McKay JE, Liepa AJ. Aust. J. Chem. 1987; 40: 1179
- 18 Wang H, Chen C, Liu W, Zhu Z. Beilstein J. Org. Chem. 2017; 13: 2023
- 19 Aruri H, Singh U, Kumar S, Kushwaha M, Gupta AP, Vishwakarma RA, Pal Singh P. Org. Lett. 2016; 18: 3638
- 20 Mahato K, Arora N, Bagdi PR, Gattu R, Ghosh SS, Khan AT. Chem. Commun. 2018; 54: 1513
- 21 Naim MJ, Alam O, Nawaz F, Alam MJ, Alam P. J. Pharm. BioAllied Sci. 2016; 8: 2
