Abstract
A green method has been developed for the synthesis of N-arylsulfonylhydrazones via a simple grindstone procedure. By grinding mixtures of benzensulfonyl hydrazides and a series of aryl aldehydes or ketones in the mortar using L-tyrosine as catalyst, 24 N-arylsulfonylhydrazones were synthesized in a few minutes with high yield. All compounds were screened for their antibacterial activities. Most of them exhibit some antibacterial activities especially for 3d, 3l and 3v showing high activity against Staphylococcus aureus and Escherichia coli.
Introduction
Grindstone chemistry can be regarded as the most efficient and green chemistry technology, and its traditional instrument—the mortar and pestle—was used in the stone age [1]. The first application of this technique was preparation of foods, then its application extended to preparation of minerals, medicines and other types of materials. In 1893, Ling et al. first used the grindstone method to synthesize the derivatives of quinhydrone [2]. Up to now, it has been demonstrated that more and more types of synthesis such as Reformatsky reaction [3], Aldol condensation [4], Dieckmann condensation [5], Knevenagel condensation [6], Sonogashira reaction [7] and other reactions [8,9] can be performed competently by the grindstone technique. Compared to a traditional organic reaction, the grindstone method often is more efficient than solution-based methods and in some cases even more selective [10]. Furthermore, it also has many advantages, such as mainly mild conditions, reduced pollution, short reaction time, low costs, effective reproducibility and simplicity in process and handling [11, 12, 13, 14]. Thus, the grindstone chemistry gained ever-widening attention in greener organic transformations during the past decades.
N-arylsulfonylhydrazones, a branch of acylhydrazones, serve a key role in medicinal chemistry. They display various biological activities, including anti-tumor [15], antibacterial [16], antiviral [17], anti-inflammatory [18] and as novel inhibitors of IMP-1[19] or carbonic anhydrase [20]. In 2007, the N-arylsulfonylhydrazone derivative (E)-N’-(1-(6-bromo-2-methylimidazo[1,2-a]pyridin-3-yl) ethylidene)-N,2-dimethyl-5-nitrobenzenesulfonohydrazide was reported as a novel p110α inhibitor[21]. In 2014, Çevrimli et al. synthesized a new compound, 2-hydroxy-1-naphthaldehydeethanesulfonylhydrazone, exhibiting excellent antibacterial activities [22]. The synthesis of N-arylsulfonylhydrazones is similar with that of N-acylhydrazones. It is carried out by reacting arylsulfonylhydrazines with aryl/alkyl aldehydes or ketones under reflux, in presence of Brønsted-Lowry acid catalysts and in protic polar solvents. The process takes from few minutes to several hours. However, these conditions inevitably can produce waste liquid pollution with poor stereoselectivity because a mixture of E/Z diastereomers is often formed. Herein, we report a new grindstone method to synthesize N-arylsulfonylhydrazones using tyrosine as catalyst with no environmental pollution and high stereoselectivity (Scheme 1).
Synthesis of N-arylsulfonylhydrazones by grindstone method.
Results and discussion
Chemistry
Initially, according to Pinheiro [23], benzenesulfonyl hydrazine 1a (1mmol) and 2-cyclohexenone 2a (1mmol) were ground together in the mortar using 50ul AcOH as catalyst. After 12 minutes, the color of benzenesulfonyl hydrazide gradually changed from light yellow to white, indicating the completion of reaction. The arylsulfonylhydrazone 3a was isolated (52%) and characterized by NMR and MS (Table 1, entry 1). In order to improve the yield, other catalysts such as CeCl3·7H2O and K10 montmorillonite were tested to get 3a in 41% and 58% (Table 1, entry 2 and 3). Tyrosine as efficient, bifunctional, and ecofriendly catalyst can catalyze the knoevenagel condensation in high yield [24]. Inspired by this paper, tyrosine was used and obtained 3a the highest yield ultimately (Table 1, entry 4). Reduction in the amount of L-tyrosine to 10 mol% (Table 1, entry 5) did not show any decrease in the yield and response time. However, the yield was reduced to 50% when the amount of L-tyrosine was cut to 5 mol% and the reaction time was up to 15 minutes, compared to 6 minutes at 10 mol% (Table 1, entry 6). Considering the atom economy of reaction and the yield of 3a, 10 mol% L-tyrosine was chosen as the appropriate catalyst for this reaction (Table 1, entry 5).
Optimization of catalyst type and dosage.a
| Entry | Catalyst | Catalyst load (mol%) | Time (min) | Yieldb(%) |
|---|---|---|---|---|
| 1 | AcOH | 50ul | 12 | 52 |
| 2 | CeCl3·7H2O | 15% | 10 | 41 |
| 3 | K10 mont. | 15% | 10 | 58 |
| 4 | L-Tyrosine | 15% | 6 | 66 |
| 5 | L-Tyrosine | 10% | 6 | 66 |
| 6 | L-Tyrosine | 5% | 15 | 50 |
aA mixture of 1a (1mmol) and 2a (1mmol) ground in the mortar at room temperature.
bIsolated yield.
Having obtained the optimized reaction conditions, we investigated the generality of these reaction conditions by extending to a variety of phenyl ring substituted arylsulfonyl hydrazine 1 and ketone or aldehyde derivatives 2. Thus, grinding 1a with 2-cyclohexenone 2a or 2-cyclopentenone 2b in the mortar at room temperature for 6 minutes, gave yield of 66% of 3a and 62% of 3b respectively (Table 2, entry 1 and 2). Similarly, treatment of 2-hydroxyacetophenone 2c and acetophenone 2d, gave a higher yield of 3c 73% and 3d 78% in a shorter time (Table 2, entry 3 and 4). The similar result occurred from 3e to 3l (Table 2, entry 5-12), reacting with the same arylsulfonyl hydrazine 1b or 1c, acetophenone 2d can produce the highest yield (Table 2, entry 8 and 12), followed by 2c (Table 2, entry 7 and 11), 2a (Table 2, entry 5 and 9) and 2b (Table 2, entry 6 and 10). The results showed that electronic factors and steric resistance play as major factors in these reactions. The benzene ring of aryl ketones, equivalent to an electron withdrawing group (EWG), can enhance the formation of a carbocation on the carbonyl group, and further improve the yield of reaction. On the contrary, the electron donating effect of 2-cyclohexenone and 2-cyclopentenone obviously decrease the yield. The steric hindrance of 2-hydroxyacetophenone 2c may impede the approach of the NH2 group of the hydrazine to the carbocation on the carbonyl group, which generates a lower yield than acetophenone 2d. However, the electronic donating group (EDG) at substituent R on the benzenesulfonyl hydrazine cannot cause a significant difference to the yield of 3, compared to the substrates bearing an electronic withdrawing group (EWG) at R (Table 2, entry 5-12). The main reason is the electronic factors of substituent R have no obvious influence on the nucleophilicity of the NH2 group of the hydrazine.
Synthesis of N-arylsulfonylhydrazones 3a-3l.a
| Entry | R | 1 | 2 | 3 | Time (min) | Yieldb (%) |
|---|---|---|---|---|---|---|
| 1 | H | 1a | 2a | 3a | 6 | 66 |
| 2 | H | 1a | 2b | 3b | 6 | 62 |
| 3 | H | 1a | 2c | 3c | 4 | 73 |
| 4 | H | 1a | 2d | 3d | 4 | 78 |
| 5 | OCH3 | 1b | 2a | 3e | 6 | 75 |
| 6 | OCH3 | 1b | 2b | 3f | 6 | 72 |
| 7 | OCH3 | 1b | 2c | 3g | 4 | 81 |
| 8 | OCH3 | 1b | 2d | 3h | 2 | 92 |
| 9 | Cl | 1c | 2a | 3i | 5 | 78 |
| 10 | Cl | 1c | 2b | 3j | 5 | 73 |
| 11 | Cl | 1c | 2c | 3k | 4 | 81 |
| 12 | Cl | 1c | 2d | 3l | 2 | 84 |
aA mixture of 1 (1 mmol) and 2a-2d (1 mmol) ground in the mortar at room temperature using 10% of L-tyrosine as catalyst.
bIsolated yield.
As shown in Table 3, aryl aldehydes produce a much higher yield with benzosulfonyl hydrazine because of the their increased reactivity compared to aryl ketones. Different substituents of EDG and EWG attached to the aromatic ring of aryl aldehydes can also lead to a similar result to the one observed with aryl ketones. When benzaldehydes bearing EDG hydroxy are submitted to the grindstone chemistry condensation, easily formatting a carbocation on the carbonyl group, all reactions lead to a higher yield (Table 3, entry 2, 6 and 10). On the other hand, aldehydes bearing EWG chloro- have exhibited a lower yield (Table 3, entry 3, 7 and 11). The reactivity of furfural 2h is weaker than benzaldehyde leading to the lower yield (Table 3, entry 4, 8 and 12). As described above, for aldehydes or ketones, the ease of formation of the carbonyl carbocation depends upon the nature of the substituents present in the aromatic ring. Electron-donating groups favors its formation, whereas electron-withdrawing substituents exert the opposite effect. Finally, an interesting phenomenon we observed was when furfural 2h, reacted with p-methoxybenzenesulfonyl hydrazine 1b, the product 3t was obtained as a mixture of E/Z diastereomers in a ratio of 1:1. With benzenesulfonyl hydrazine 1a, the ratio is 2:1. Meanwhile the E-isomer can be isolated from the tautomer by recrystallization. However, reacting with p-chlorobenzenesulfonyl hydrazine 1c, the product 3x was only the E-isomer was confirmed by 1H-NMR.
Synthesis of N-arylsulfonylhydrazones 3m-3x.a
| Entry | R | 1 | 2 | 3 | Time (min) | Yieldb (%) |
|---|---|---|---|---|---|---|
| 1 | H | 1a | 2e | 3m | 4 | 82 |
| 2 | H | 1a | 2f | 3n | 2 | 87 |
| 3 | H | 1a | 2g | 3o | 5 | 78 |
| 4 | H | 1a | 2h | 3p | 6 | 67 |
| 5 | OCH3 | 1b | 2e | 3q | 4 | 91 |
| 6 | OCH3 | 1b | 2f | 3r | 2 | 96 |
| 7 | OCH3 | 1b | 2g | 3s | 4 | 85 |
| 8 | OCH3 | 1b | 2h | 3t | 6 | 78 |
| 9 | Cl | 1c | 2e | 3u | 4 | 88 |
| 10 | Cl | 1c | 2f | 3v | 2 | 94 |
| 11 | Cl | 1c | 2g | 3w | 4 | 83 |
| 12 | Cl | 1c | 2h | 3x | 6 | 66 |
aA mixture of 1 (1mmol) and 2e-2h (1mmol) ground in the mortar at room temperature using 10% of L-tyrosine as catalyst.
bIsolated yield.
A plausible mechanism for the formation N-arylsulfonylhydrazones is depicted in Scheme 2 [24]. L-tyrosine, in its zwitterionic form (B), abstracts a proton from the NH2 group of the benzenesulfonyl hydrazine (1) forming the negative ion of hydrazide (11) which then attacks the protonated benzaldehyde (21) forming the corresponding intermediate (22) that loses the water to form the end product 3.
Plausible mechanism for the formation of N-arylsulfonylhydrazones.
Antibacterial activity
All compounds were screened for their antibacterial activities in vitro by broth microdilution method [25] and the minimum inhibitory concentration (MIC) values are presented in Table 4. The antimicrobial drug penicillin was used as reference drug. The results in Table 4 revealed that when the substituent R1 is OCH3, the antibacterial activities of N-arysulfonylhydrazones were relatively weak (compound 3e, 3f, 3g, 3q, 3r, 3s). Conversely, electron withdrawing group chloro- can increase the antibacterial activity (compound 3i, 3k, 3l, 3u, 3v, 3w, 3x). R2 has a large influence on the antibacterial activities of N-arysulfonylhydrazones compounds. Furaldehyde and acetophenone can enhance the antibacterial activities. Especially for acetophenone, where the MIC of the compounds was found to be the same as that of penicillin against Staphylococcus aureus (3d, 3h, 3l). For p-chlorobenzaldehyde, the spatial stereo conformation of compounds was changed which may reduce the antibacterial activity.
In vitro antibacterial activity of N-arysulfonylhydrazones compounds.
| Compounds | Minimum inhibitory concentration (ug/mL)a | |
|---|---|---|
| Escherichia coli. | Staphylococcus aureus | |
| Penicillin | 15.6 | 62.5 |
| 3a | 62.5 | 125 |
| 3b | 125 | 125 |
| 3c | 125 | 125 |
| 3d | 62.5 | 62.5 |
| 3e | 125 | 125 |
| 3f | 125 | 125 |
| 3g | 125 | 125 |
| 3h | 125 | 62.5 |
| 3i | 62.5 | 125 |
| 3j | 125 | >125 |
| 3k | 62.5 | 125 |
| 3l | 62.5 | 62.5 |
| 3m | 62.5 | 125 |
| 3n | 125 | 62.5 |
| 3o | 125 | 125 |
| 3p | 62.5 | 125 |
| 3q | 125 | >125 |
| 3r | 125 | >125 |
| 3s | >125 | 125 |
| 3t | 62.5 | 125 |
| 3u | 62.5 | 125 |
| 3v | 62.5 | 62.5 |
| 3w | 125 | 62.5 |
| 3x | 62.5 | 125 |
aResults were determined by the broth microdilution method.
Conclusions
In summary, we have described the preparation of N-arylsulfonylhydrazones by condensation reaction in solvent free conditions under the grindstone method at room temperature using L-tyrosine as an efficient catalyst. Electronic factors and steric resistance of aryl aldehydes and ketones play key roles in these reactions, which influence the formation of the carbonyl carbocation on carbonyl group, then determine the ease of the reaction. This strategy is useful and attractive for the preparation of N-arylsulfonylhydrazones. Antimicrobial screening studies were also performed. The results show that some of the compounds exhibited a good antibacterial activity especially for Staphylococcus aureus.
Acknowledgements
This research was supported by the National Natural Science Foundation of China (No: 21576220) and the Key Laboratory Project of Shaanxi education department (No: 17JS085).
References
[1] Laszlo, T. The historical development of mechano-chemistry. Chem. Soc. Rev. 2013, 427649-7659.Search in Google Scholar
[2] Ling, A. R.; Baker, J. L. Derivatives of quinhydrone. J. Chem. Soc., Trans. 1893, 63:1314-1327.10.1039/CT8936301314Search in Google Scholar
[3] Tanaka, K.; Kishigami, S.; Toda, F. Reformatsky and Luche reaction in the absence of solvent. J. Org. Chem. 1991, 56: 4333–4334.10.1021/jo00013a055Search in Google Scholar
[4] Toda, F.; Tanaka, K.; Hamai, K. Aldol condensations in theabsence of solvent: acceleration of the reaction and enhancement of the stereoselectivity. J. Chem. Soc., Perkin Trans. 1 1990, 3207–3209.10.1039/p19900003207Search in Google Scholar
[5] Toda, F.; Suzuki, T.; Higa, S. Solvent-free Dieckmanncondensation reactions of diethyl adipate and pimelate. J. Chem. Soc., Perkin Trans 1 1998, 3521–3522.10.1039/a805884iSearch in Google Scholar
[6] Ren, Z.; Cao, W.; Tong, W. The Knoevenagel condensationreaction of aromatic aldehydes with malononitrile by grinding inthe absence of solvents and catalysts. Synth. Commun. 2002, 32: 3475–3479.10.1081/SCC-120014780Search in Google Scholar
[7] Thorwirth, R.; Stolle, A.; Ondruschka, B. Fast copper-, ligand- and solvent-free Sonogashira coupling in a ball mill. Green Chem. 2010, 12: 985-991.10.1039/c000674bSearch in Google Scholar
[8] Szuppa, T.; Stolle, A.; Ondruschka, B.; Hopfe, W. Solvent-free dehydrogenation of γ-terpinene in a ball mill: investigation of reaction parameters. Green Chem. 2010, 12: 1288-1294.10.1039/c002819cSearch in Google Scholar
[9] Thorwirth, R.; Stolle, A. Solvent-free synthesis of enamines from alkyl esters of propiolic or but-2-yne dicarboxylic acid in a ball mill. Synlett. 2011, 15: 2200-2202.10.1002/chin.201205060Search in Google Scholar
[10] Abdel Hameed, A. M. Rapid synthesis of 1,6-naphthyridines by grindstone chemistry. Environ. Chem. Lett. 2015, 13: 125-129.10.1007/s10311-015-0494-6Search in Google Scholar
[11] Kaupp, G.; Schmeyers, J.; Boy, J. Waste-free solid-state syntheses with quantitative yield. Chemosphere 2001, 43: 55-61.10.1016/S0045-6535(00)00324-6Search in Google Scholar
[12] Kummar, A.; Sharma, S. A grinding-induced catalyst-and solvent-free synthesis of highly functionalized 1,4-dihydropyridines via a domino multicomponent reaction. Green Chem. 2011, 13: 2017-2020.10.1039/c1gc15223hSearch in Google Scholar
[13] Li, D. P.; Zhang, G. L.; An, L. T.; Zou, J. P.; Zhang, W. Solvent- and catalyst-free synthesis of 2,3-dihydro-1H-benzo[d]imidazoles. Green Chem. 2011, 13: 594-597.10.1039/c0gc00572jSearch in Google Scholar
[14] Baig, R. B. N.; Varma, R. S. Alternative energy input: mechanochemical, microware and ultrasound-assisted organic synthesis. Chem. Soc. Rev. 2012, 41: 1559-1584.10.1039/C1CS15204ASearch in Google Scholar
[15] May Jr, J. A.; Sartorelli, A. Antineoplastic properties of arylsulfonylhydrazones of 3-formypyridazine 2-oxide and 4-formylpyrimidine 3-oxide. J. Med. Chem.1978, 21: 1333-1335.10.1021/jm00210a036Search in Google Scholar PubMed
[16] Zimmer, H.; Benjamin, B. H.; Gerlach, E. H.; Fry, K.; Pronay, A. C.; Schmank, H. Synthesis and antibacterial activity of some 4-substituted benzenesulfonylhydrazones. J. Org. Chem. 1959, 24: 1667-1675.10.1021/jo01093a010Search in Google Scholar
[17] Dawood, K. M.; Abdel-Gawad, H.; Mohamed, H. A.; Badria, F. A. Synthesis, anti-HSV-1, and cytotoxic activities of some newpyrazole- and isoxazole-based heterocycles. Med. Chem. Res. 2011, 20: 912-919.10.1007/s00044-010-9420-4Search in Google Scholar
[18] Maia, R. C.; Silva, L. L.; Mazzeu, E. F.; Fumian, M. M.; Rezende, C. M.; Doriguetto, A. C.; Correa, R. S.; Miranda, A. L. P.; Barreiro, E. J.; Fraga, C. A. M. Synthesis and analgesic profile of conformationally constrainedN-acylhydrazone analogues: Discovery of novel N-arylideneaminoquinazolin-4(3H)-one compounds derived from natural safrole. Bioorg. Med. Chem. 2009, 17: 6517-6525.10.1016/j.bmc.2009.08.009Search in Google Scholar PubMed
[19] Stefan, S.; Evanoff, D. P.; Marrone, L.; Clarke, A. J.; Viswanatha, T.; Dmitrienko, G. I. N-arysulfonyhydrazones as inhibitors of IMP-1 metallo-β-lactamase. Antimicrob. Agents Chemother. 2002, 46: 2450-2457.10.1128/AAC.46.8.2450-2457.2002Search in Google Scholar PubMed PubMed Central
[20] Supuran, C. T.; Scozzafava, A.; Casini, A. Carbonic anhydrase inhibitors. Med. Res. Rev. 2003, 23: 146-189.10.1002/med.10025Search in Google Scholar PubMed
[21] Hayakawa, M.; Kawaguchi, K.I.; Kaizawa, H.; Koizumi, T.; Ohish,i T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S. I.; Raynaud, F. I.; Parker, P.; Workman, P.; Waterfield, M. D. Synthesis and biological evaluation of sulfonylhydrazonesubstituted imidazo[1,2-a]pyridines as novel PI3 kinase p110a inhibitors. Bioorg. Med. Chem. 2007, 15: 5837-5844.10.1016/j.bmc.2007.05.070Search in Google Scholar PubMed
[22] Gündu, A. B.; Özmen, Ümmühan, Ö. Ö.; Çevrimli, B. S.; Mamas, S.; Çete, S. Synthesis, characterization, electrochemical behavior, and antimicrobial activities of aromatic/heteroaromatic sulfonylhydrazone derivatives. Med Chem Res 2014, 23:3255–3268.10.1007/s00044-013-0907-7Search in Google Scholar
[23] Pinheiro, S. M.; dos Santos Filho, J. M. Stereoselective, solvent free, highly efficient synthesis of aldo- and keto-N-acylhydrazones applying grindstone chemistry. Green Chem. 2017, 19: 2212-2224.10.1039/C7GC00730BSearch in Google Scholar
[24] Thirupathi, G.; Venkatanarayana, M.; Dubey, P. K.; Bharathi Kumari, Y. L-Tyrosine as an eco-friendly and efficient catalyst for knoevenagel condensation of arylaldehydes with meldrum’s acid in solvent-free condition under grindstone method. Org. Chem. Int. 2012, article id: 191584, 4 pages.10.1155/2012/191584Search in Google Scholar
[25] Natanael, D. S.; Ricardo, A. M. S.; Mariana, C. F. S.; Marcelo, M.; Fernando, R. C.; Ohara, A.; Elizabeth, I. F. New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors. Bioorg. Med. Chem. Lett. 2016, 26; 3988-3933.10.1016/j.bmcl.2016.06.089Search in Google Scholar PubMed
© 2019 Qian Yang et al., published by De Gruyter
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