Letter Cite This: Org. Lett. 2017, 19, 6748−6751
pubs.acs.org/OrgLett
Synthesis of N,S‑Heterocycles and Dithiocarbamates by the Reaction of Dithiocarbamic Acids and S‑Alkyl Dithiocarbamates with Nitroepoxides Azim Ziyaei Halimehjani* and Yazdanbakhsh Lotfi Nosood Faculty of Chemistry, Kharazmi University, 49 Mofateh Street, Tehran 15719-14911, Iran S Supporting Information *
ABSTRACT: A facile and efficient procedure for the synthesis of substituted thiazole-2(3H)-thiones and thiazolidine-2-thiones by the reaction of primary amines, carbon disulfide, and nitroepoxides is described. By using secondary amines in this protocol, the corresponding dithiocarbamate-substituted phenyl-2-propanones were prepared in excellent yields. In addition, substituted thiazoles and 1-(alkylthio)-1phenylpropan-2-ones were prepared in reactions of S-alkyl dithiocarbamates and nitroepoxides.
N
significant biological activities as anticancer,15 antibacterial,16 antidiabetic,17 and antifungal agents.18 Given the abovementioned features, the development of novel processes for the synthesis of various categories of N,S-heterocyclic compounds is always in demand. In continuation of our interest toward the synthesis of novel dithiocarbamates and their applications as intermediates for the synthesis of novel biologically active compounds,12f,13b−f we herein report the reaction of in situ generated dithiocarbamic acids with nitroepoxides, for the first time, for the synthesis of thiazole-2(3H)-thiones, thiazolidine-2-thiones, and dithiocarbamate-substituted phenyl-2-propanones. Additionally, the reactions of S-alkyl dithiocarbamates with nitroepoxides for the synthesis of 2-(alkylsulfanyl)thiazoles and 1-(alkylthio)-1phenylpropan-2-ones have been investigated (routes 1−5, Scheme 1). Initially, we investigated a one-pot, three-component reaction of butylamine, carbon disulfide, and nitroepoxide 1a. We observed that by mixing butyl amine (1 equiv) and carbon disulfide (2 equiv) in THF at room temperature for 15 min, followed by the addition of nitroepoxide 1a (1 equiv) and further stirring at room temperature for 2 h, the product 3butyl-4-methyl-5-phenylthiazole-2(3H)-thione (2a) was obtained in 68% isolated yield. The replacement of THF with other organic solvents provided unsatisfactory yields of 2a. Changing stoichiometry to 1.5 equiv of butylamine afforded 2a in 79% yield. A further increase of the amount of amine did not lead better product yield.
itroepoxides have attracted the broad attention of synthetic chemists in recent years due to their interesting and unique reactivity in organic transformations. These versatile small molecules can be considered as synthons of vicinal double electrophilic compounds such as α-diones and αhaloketones.1 α-Nitroepoxides can be easily prepared by epoxidation of nitroalkenes with H2O2/NaOH.2 Nitroepoxides have been applied in the synthesis of very important heterocycles such as 1,3-thiazoles,3 quinoxalines,4,5 pyrazines,5 and imidazoles.6,7 Recently, Gonzalez and co-workers reported a stereoselective synthesis of morpholines and benzoxazines in a two-step sequence by the reaction of nitroepoxides with Nmethylethanolamines and N-methyl-2-hydroxyanilines, respectively.8 Yu et al. developed an efficient method for the synthesis of 2-aminothiazoles via the reaction of nitroepoxides with thioureas under mild conditions.9 Very recently, the same group reported the synthesis of pyrroles by a one-pot, threecomponent reaction of nitroepoxides, primary amines, and dialkyl acetylenedicarboxylate under catalyst-free conditions.10 Dithiocarbamates are very valuable compounds due to their potential as versatile building blocks for the synthesis of biologically active compounds, and they are widely utilized in agriculture and medicinal chemistry.11 Furthermore, dithiocarbamates are very useful intermediates in synthetic organic chemistry.12 Dithiocarbamic acids act as efficient nucleophiles toward various electrophiles, especially when they are derived from primary amines and carbon disulfide, and can react both with sulfur and nitrogen atoms.13 N,S-Heterocycles including thiazoles, thiazole-2(3H)-thiones, and thiazolidine-2-thiones are very important subunits in the structure of many complex natural products and pharmaceuticals.14 Compounds containing these heterocycles have shown © 2017 American Chemical Society
Received: November 11, 2017 Published: December 6, 2017 6748
DOI: 10.1021/acs.orglett.7b03501 Org. Lett. 2017, 19, 6748−6751
Letter
Organic Letters Scheme 2. Synthesis of Thiazolidine-2-thionesa,b
Scheme 1. Reaction of Dithiocarbamic Acids and S-Alkyl Dithiocarbamates with Nitroepoxides
a
Reaction conditions: amine (1.5 equiv), CS2 (2 equiv), nitroepoxide (0.5 mmol, 1 equiv), water (3 mL), rt, 2 h. bIsolated yield.
Under optimized reaction conditions, different primary amines and nitroepoxides 1a−d were applied to investigate the scope of the process (Table 1). High to excellent yields
performing the reactions in the presence of PTSA (10 mol %) in water, the dehydration step was accelerated and the corresponding thiazole-2(3H)-thiones 2 were obtained. Encouraged by the work of Tsogoeva et al.,3,19 we also examined a one-pot, two-step procedure for the synthesis of thiazole-2(3H)-thione 2a using nitrostyrene 4 (Scheme 3). We
Table 1. Diversity in the Synthesis of Thiazole-2(3H)thionesa
Scheme 3. One-Pot, Two-Step Process for the Synthesis of Thiazole-2(3H)-thione 2a from Nitrostyrene 4
entry
R
1, R′
2 (yield %)b
1 2 3 4 5 6 7 8 9 10 11 12
n-butyl n-propyl methyl isobutyl allyl n-propyl n-propyl n-butyl isobutyl n-propyl n-butyl isobutyl
1a, H 1a, H 1a, H 1a, H 1a, H 1b, 3-OCH3 1c, 3-NO2 1c, 3-NO2 1c, 3-NO2 1d, 4-Cl 1d, 4-Cl 1d, 4-Cl
2a (79) 2b (76) 2c (88) 2d (77) 2e (74) 2f (68) 2g (84) 2h (82) 2i (87) 2j (83) 2k (90) 2l (85)
concluded that the in situ oxidation of 4 with tert-butyl hydroperoxide (TBHP) in the presence of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), followed by addition of carbon disulfide and n-butylamine, afforded the product 2c in good yield. Furthermore, we expanded the utility of this protocol using secondary amines. We observed that while dithiocarbamic acids derived from secondary amines are good sulfur mononucleophiles toward nitroepoxides, the reaction stops at the dithiocarbamate stage. Thus, various dithiocarbamate-substituted phenyl 2-propanones were synthesized via a one-pot, three-component reaction of secondary amines, CS2, and nitroepoxides in water for 2 h. The generality of the reaction was extended using various secondary amines and nitroepoxides (1a−d). The corresponding racemic carbamodithioates (5a−i) were prepared in high to excellent yields (Scheme 4). tertButylamine reacted similarly to the secondary amines to afford the corresponding dithiocarbamate 5j in high yields. Next, the reactions of S-alkyl dithiocarbamates with nitroepoxides for the synthesis of 2-(alkylsulfanyl)thiazoles were studied. The reaction of S-isopenthyl dithiocarbamate 6a (1 equiv) with nitroepoxide 1a (1 equiv) was considered as a model reaction for optimization of reaction conditions (Table 2). We found that by mixing an equal molar amount of the starting materials in various organic solvents such as THF, CH2Cl2, ethanol, and water at room temperature for 1 h, low yields of 7a were obtained (Table 2, entries 1−4). By
a Reaction conditions: amine (1.5 equiv), CS2 (2 equiv), nitroepoxide (0.5 mmol, 1 equiv), THF, rt, 2 h. bIsolated yield.
(68−90%) of products were obtained. The results show that higher yields can be achieved using nitroepoxides containing an electron-withdrawing group on the phenyl ring. The reaction cascade starts by the addition of amine to CS2 to give the corresponding dithiocarbamic acid, followed by epoxide ring opening with the sulfur of the dithiocarbamate, intramolecular hemiaminalization, and finally dehydration. By using water as solvent in this protocol, thiazolidine-2thiones 3a−d were obtained as a mixture of diastereomers in high yields (Scheme 2). It shows that in the presence of water at room temperature the dehydration step did not proceed. We confirmed that by heating the reaction mixtures to 50 °C or 6749
DOI: 10.1021/acs.orglett.7b03501 Org. Lett. 2017, 19, 6748−6751
Letter
Organic Letters
under solvent-free conditions at 60 °C for 1 h was considered optimal reaction conditions for further derivatization. Using the optimized reaction conditions, the reaction scope was investigated using various S-alkyl dithiocarbamates 6a−g and nitroepoxides 1a−d (Table 3). The desired products 7a−o
Scheme 4. Synthesis of Dithiocarbamate-Substituted Phenyl 2-Propanonesa
Table 3. Diversity in the Synthesis of 2(Alkylsulfanyl)thiazolesa
a
Reaction conditions: secondary amine (1.5 equiv), CS2 (2 equiv), nitroepoxide (0.5 mmol, 1 equiv), H2O, rt, 2 h. bIsolated yield.
a
6a (equiv)
solvent
temp (°C)
yielda (%)
1 2 3 4 5 6 7 8 9 10
1 1 1 1 1 1.2 1.5 1.2 1.2 1.2
THF CH2Cl2 EtOH H2O THF THF THF neat neat neat
rt rt rt rt reflux reflux reflux 80 60 50
22 18 15 trace 34 39 38 83 84 78
1, R′
6, R
7
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1a, H 1a, H 1a, H 1a, H 1a, H 1b, 3-OCH3 1b, 3-OCH3 1b, 3-OCH3 1b, 3-OCH3 1c, 3-NO2 1c, 3-NO2 1d, 4-Cl 1d, 4-Cl 1d, 4-Cl 1d, 4-Cl
6a, isopentyl 6b, n-butyl 6c, n-hexyl 6d, n-octyl 6e, sec-butyl 6a, isopentyl 6b, n-butyl 6c, n-hexyl 6f, butyl propanoate 6e, sec-butyl 6g, benzyl 6a, isopentyl 6b, n-butyl 6c, n-hexyl 6g, benzyl
7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o
84 86 83 78 85 87 84 76 79 89 87 91 93 88 81
a
Reaction conditions: S-alkyl dithiocarbamate (1.2 equiv), nitroepoxide (0.5 mmol, 1 equiv), solvent-free, 60 °C, 1 h. bIsolated yield.
Table 2. Optimization of the Reaction of S-Alkyl Dithiocarbamate 6a with Nitroepoxide 1a
entry
entry
were obtained in high to excellent yields. The 13C NMR spectra clearly confirmed the product structure; the chemical shift for C-2 of the thiazole ring was assigned to approximately 162 ppm, while the C-4 and C-5 of the thiazole ring appeared around 148 and 132 ppm, respectively.20 Interestingly, when the reaction of S-alkyldithiocarbamates 6 with nitroepoxides was carried out in the presence of 1 equiv of DBU in THF, the corresponding reacemic 1-(alkylsulfanyl)-1phenylpropan-2-ones were obtained in excellent yields. The reaction may proceed via the decomposition of S-alkyldithiocarbamate in the presence of DBU to furnish the alkylthiol group, followed by epoxide ring opening and elimination of the nitro group (Scheme 5). Scheme 5. Synthesis of 1-(Alkylsulfanyl)-1-phenylpropan-2ones 8 from Nitroepoxide 1a and S-Alkyldithiocarbamates 6
Isolated yield.
performing the reaction in refluxing THF for 1 h, the yield was improved to 34% (Table 2, entry 5). Although a higher yield (39%) (Table 2, entry 6) of 7a was achieved by increasing the amount of 6a to 1.2 equiv, further increasing the amount of 6a to 1.5 equiv did not improve the yield (Table 2, entry 7). Performing the model reaction in neat conditions at different temperatures revealed that the best yield was obtained at 60 °C (84%) (Table 2, entries 8−10). In summary, stirring S-alkyl dithiocarbamate 6a (1.2 equiv) and nitroepoxide 1a (1 equiv)
In summary, we have developed several efficient and highly practical methods for the synthesis of various categories of N,Sheterocycles including thiazole-2(3H)-thiones (12 new compounds), thiazolidine-2-thiones (four new compounds), and 2(alkylsulfanyl)thiazoles (15 new compounds) from nitroepoxides and in situ generated dithiocarbamic acids or S-alkyl dithiocarbamates. In addition, a facile and green process for the 6750
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E. J. Angew. Chem., Int. Ed. 2007, 46, 5377−5380. (h) McMaster, C.; Bream, R. N.; Grainger, R. S. Org. Biomol. Chem. 2012, 10, 4752− 4758. (13) (a) D'hooghe, M.; De Kimpe, N. Tetrahedron 2006, 62, 513. (b) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem. 2006, 71, 3634. (c) Ziyaei Halimehjani, A.; Marjani, K.; Ashouri, A. Green Chem. 2010, 12, 1306. (d) Ziyaei Halimehjani, A.; Hajilou Shayegan, M.; Shakouri Poshteh, S.; Amani, V.; Notash, B.; Hashemi, M. M. Tetrahedron Lett. 2015, 56, 7124. (e) Ziyaei Halimehjani, A.; Hosseinkhany, S. Synthesis 2015, 47, 3147. (f) Ziyaei Halimehjani, A.; Hajiloo Shayegan, M.; Hashemi, M. M.; Notash, B. Org. Lett. 2012, 14, 3838−3841. (14) (a) Kalgutkar, A. S.; Crews, B. C.; Marnett, L. J. Biochemistry 1996, 35, 9076. (b) Dondoni, A. Org. Biomol. Chem. 2010, 8, 3366. (c) Jain, A. K.; Vaidya, A.; Ravichandran, V.; Kashaw, S. K.; Agrawal, R. K. Bioorg. Med. Chem. 2012, 20, 3378. (15) Havrylyuk, D.; Mosula, L.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Eur. J. Med. Chem. 2010, 45, 5012. (16) Soltero-Higgin, M.; Carlson, E. E.; Phillips, J. H.; Kiessling, L. L. J. Am. Chem. Soc. 2004, 126, 10532. (17) Ohishi, Y.; Mukai, T.; Nagahara, M.; Yajima, M.; Kajikawa, N.; Miyahara, K.; Takano, T. T. Chem. Pharm. Bull. 1990, 38, 1911. (18) Kavitha, C. V.; Basappa, S.; Swamy, S. N.; Mantelingu, K.; Doreswamy, S.; Sridhar, M. A.; Prasad, J. S.; Rangappa, K. S. Bioorg. Med. Chem. 2006, 14, 2290. (19) Wei, S.; Wieß, K. M.; Tsogoeva, S. B. Synthesis 2012, 44, 3441. (20) Ziyaei Halimehjani, A.; Hasani, L.; Alaei, M. A.; Saidi, M. R. Tetrahedron Lett. 2016, 57, 883. (b) Zhao, D.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Tetrahedron 2016, 72, 5285.
synthesis of novel dithiocarbamate-substituted phenyl-2-propanones (10 compounds) was developed by the reaction of secondary amines, CS2, and nitroepoxides in water. Furthermore, 1-(alkylsulfanyl)-1-phenyl-2-propanones were obtained in the reaction of S-alkyldithiocarbamates with nitroepoxides in the presence of DBU. The presented reactions are characterized by the use of mild reaction conditions, short reaction times, and good to excellent product yields.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03501. Experimental procedures, product characterization, and NMR spectra for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Azim Ziyaei Halimehjani: 0000-0002-0348-8959 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the faculty of chemistry of Kharazmi University for supporting this work. REFERENCES
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DOI: 10.1021/acs.orglett.7b03501 Org. Lett. 2017, 19, 6748−6751
