Journal of Current Scientific Research

Journal of Current Scientific Research

Journal of Current Scientific Research

Current Issue Volume No: 1 Issue No: 3

Short Communication Open Access Available online freely Peer Reviewed Citation

A One-Pot Synthesis of Sulfonyl Amidinesvia Three-Component Reaction Under Mild and Solvent-Free Conditions

Chiaa Adiche 1,   Douniazad El Abed 1  

1Laboratory of Fine Chemistry (L.F.C), Chemistry Department, Faculty of Exact and Applied Sciences University of Oran 1 Ahmed BenBella BP 1524 El M’naouer Oran 31000 Algeria.

Abstract

A convenient one-pot synthetic protocol for the preparation of sulfonyl amidines has been developed. The procedure combines three-component reaction of sulfonyl azide, methyl propiolate and secondary cyclic amine coupling in one sequence without any solvent or catalyst and at room temperature. The reaction proceeds smoothly and a variety of desired sulfonyl amidines were obtained in moderate to good yields. This protocol has synthetic advantages in terms of low environmental impact and very short reaction time.

Author Contributions
Received 05 Apr 2021; Accepted 28 May 2021; Published 17 Dec 2021;

Academic Editor: Shailendra Dwivedi, University of Oklahoma | ou · Department of Obstetrics and Gynecology.

Checked for plagiarism: Yes

Review by: Single-blind

Copyright ©  2021 Chiaa Adiche, et al.

License
Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests

The authors have declared that no competing interests exist.

Citation:

Chiaa Adiche, Douniazad El Abed (2021) A One-Pot Synthesis of Sulfonyl Amidinesvia Three-Component Reaction Under Mild and Solvent-Free Conditions. Journal of Current Scientific Research - 1(3):1-12. https://doi.org/10.14302/issn.2766-8681.jcsr-21-3805

Download as RIS, BibTeX, Text (Include abstract )

DOI 10.14302/issn.2766-8681.jcsr-21-3805

Introduction

Multicomponent reactions (MCRs) are a powerful tool for the synthesis of complex molecules with broad structural diversity in a single operation.1 These reactions combine at least three or more reactants in a one-pot reaction to form a new product that incorporates structural features of each reagent.2 Compared to conventional multistep organic syntheses, this strategy offers several other advantages besides atom economy, such as higher overall yields, shorter reaction times, environmentally benign milder reactions, and easiness of procedure.3MCRs have played a central role in the development of modern synthetic methodology for biologically active compounds, bioactive heterocycles and natural products.4Heterocyclic compounds constitute the largest and most varied family of organic compounds significant to almost all aspects of modern organic chemistry, medicinal chemistry, and biochemistry.5Amidines,the dinitrogen analogs of carboxylic acids, are widely used in medicinal chemistry,6coordination chemistry,7and synthetic chemistry.8They are important units in chemistry for the synthesis of various diversified nitrogen heterocycles9e.g.,pyrroles,10triazoles,11pyridines,12pyrimidines,13thiadiazines14and triazines.15In addition, these compounds are found in numerous natural bioactive products and are identified as important pharmacophores.16

Indeed, a broad range of nitrogen compounds containing an amidine moiety have interesting biological properties, such as anti-inflammatory, 17antiparasitic,18antiplatelet,19antimalarial,20anticancer17,21and antimicrobial activities,22etc. The sulfonyl amidine units also show broad-spectrum biological activities. In order to illustrate the importance of the sulfonyl amidine motifs in the field of pharmaceutical chemistry, a few examples of molecules with biological and therapeutic activities (antitumor,23antiproliferative,24antibacterial,25and antiresorptive 26) incorporating them have been selected in figure 1.

Figure 1.Selected examples for bioactive sulfonylamidines
Selected examples for bioactive sulfonylamidines

There are several strategies described in the literature for the synthesis of amidines.27The most common method is based on the simple functional group transformation from some precursors such as nitriles, 28amides.29 Other methods for their preparation include the reduction of amidoxime,30the cycloaddition-decarboxylation of isocyanates and nitrones.31Also, they were prepared by the reductive functionalization of carboxamides (via enamines) into sulfonylformamidines.32 Furthermore, they are prepared using the 1,3-dipolar cycloaddition reaction between the enaminoesters and sulfonyl azides,33 etc. Recently, numerous methods for the synthesis of sulfonyl amidines have been reported.34Among various MCRs developed, the Cu-catalyzed three-component coupling reactions of a terminal alkyne, a sulfonyl azide and with a third component, like amine, alcohol or water are one of the most powerful strategies for forming sulfonyl amidines, N-sulfonylimidates, and sulfonamides, respectively.35A highly efficient copper-catalyzed one-pot synthesis of N-sulfonyl amidines has been described by Chang and co-workers via the coupling of a sulfonyl azide, an alkyne and an amine.35,36Many other copper catalyzed three-component reaction, involving a sulfonyl azide, an alkyne and an amine, are performed under widely differing conditions have been reported by Wang’s group37 and others.38However, these approaches to synthesize sulfonyl amidines suffered from some disadvantages including stepwise synthesis, harsh reaction conditions, long reaction times and requirement of inert atmosphere, the use of catalyst or expensive reagents and hazardous organic solvents.

Therefore, the development of a mild, simple, fast and novel method with attractive features such as easily accessible starting materials, mild reaction conditions, and non-toxic side products to generate structural diversity sulfonyl amidines is still desirable because of their biological significance. As a continuation of our interest in developing new green synthetic methods of sulfonyl amidines,39 herein we report a facile, rapid and practical synthesis of sulfonyl amidines, potentially bioactive, via a MCR performed in air, coupling of arenesulfonylazides with methyl propiolate and secondary cyclic amines using solvent-free conditions and without requiring any catalyst or additive.

Experimental

All reagents and solvents were purchased from commercial suppliers and were used without further purification. Melting points were determined with a Kofler apparatus and they are uncorrected. 1H (300 MHz) and 13C (75 MHz), NMR spectra were recorded using a Bruker AC300 spectrometer using CDCl3.Infrared spectra (IR) were taken on a Nicolet IRFT IR 200 spectrometer, and were obtained as solids in KBr. Peaks are reported in cm-1. High-resolution mass spectra (MS) were obtained at 2.8kV electrospray voltage, 20 V voltage orifice, and flow of nebulizing gas (nitrogen): 100 L/h.

Atmospheric pressure ionization (API) and electrospray (ESI) mass spectra were recorded on a SYNAPTG2 HDMS spectrometer (Waters). Elemental analyses were performed by apparatus CHNS.

General Procedure for Preparing Sulfonyl Azides:

The sulfonyl azides1 were prepared according to the procedure of the literature40which was modified as follows: sulfonyl chloride (30 mmol) in acetone (25 mL) was added drop wise to a solution of sodium azide (33 mmol) in 10mL of ethanol (96%) at room temperature. Upon addition the solution turns an orange color with NaCl precipitate was seen. After stirring for 15 hours the precipitate was filtered off and the solvent was evaporated. The residue was taken up with water and extracted with 25 mL dichloromethane. The organic layer was dried over anhydrous MgSO4, filtered and the solvent was evaporated under reduced pressure to give the desired sulfonyl azide.

General Procedure for Synthesis of Sulfonyl Amidines under Mild and Solvent-free Conditions:

Sulfonylazide1 (1 mmol,1 equiv.), methyl propiolate (1 mmol,1 equiv.) and amine 2 (1 mmol,1 equiv.) was successively added to a flask at room temperature, after that a precipitate was formed,a pure product was obtained by recrystallization in EtOH followed by simple filtration.

Results and Discussion

Sulfonyl amidines 3-5 are obtained by a direct three-component reaction of arenesulfonylazide, methyl propiolate with secondary cyclic amines (Scheme 1).

Scheme 1.One pot synthesis of sulfonylamidines 3-5
One pot synthesis of sulfonylamidines 3-5

The structure of synthesized sulfonyl amidines 3-5 was confirmed mainly by a combination of the usual spectroscopic methods (IR, 1H, 13C, DEPT NMR) elemental analysis, and the mass spectra which gave good agreement with the proposed structures.

The reaction conditions for a sequential one-pot procedure were optimized using different solvents, as illustrated in Table 1.

Table 1. Optimization of the reaction conditions for the three-component reactions of tosylazide1a, methyl propiolate and morpholine2a.



• aReaction conditions: tosylazide1a (1 mmol, 1 equiv.), methyl propiolate (1 mmol, 1 equiv.), and morpholine2a (1 mmol, 1 equiv.), bIsolated yield after recrystallization in ethanol followed by simple filtration.

Preliminary experiments were carried out with tosylazide 1a, methyl propiolate and morpholine 2a. The reactions were performed in various solvents. As can be seen from Table 1, THF, CH2Cl2, methanol and toluene afforded low yields (Table 1, entries 1, 3, 5 and 7), where as the solvents H2O, CHCl3, and DMSO achieved moderate yield (Table 1, entries 2, 6 and 8). The reaction accomplished in ether leads to a good yield (Table 1, entry 4). However, the best yield was obtained in the absence of the solvent (Table 1, entry 9).

To extend the general applicability and the reactivity of this three-component reaction, several substituted sulfonyl azides 1 bearing electron-donating and electron-withdrawing groups, were reacted with methyl propiolate and secondary cyclic amines (morpholine, piperidine and pyrrolidine) under the optimized conditions in the absence of solvent and without any catalyst, the results are given in Table 2, Table 3, Table 4

Arenesulfonylazides were successfully employed as efficient reacting partners in three-component coupling with methyl propiolate and morpholine to afford the corresponding sulfonyl amidines (3a-l) which were produced with yields varying from 22 to 89%, spontaneously. The reactions proceeded very efficiently, and led to the formation of the corresponding sulfonyl amidines 3a, 3d and 3e in good yields (Table 2, entries 1, 4 and 5) as 89, 84 and 88%, respectively. However, a drastic decrease in yield (32 and 29%) was observed with the benzene sulfonyl azide and the para-ethylbenzenesulfonylazide (Table 2, entries 2 and 3). On the other hand, the electron with-drawing para-nitro was found to be more reactive than the ortho-nitro and the meta-nitrobenzenesulfonylazides (Table 2, entries 5-7) with 88, 41 and 54%, respectively. The reaction was also compatible with the presence of the halogen groups. Thus, the bromo and iodo groups led to the desired products 3j, and 3k with better yields compared to the fluoro and chloro groups which led to the compounds 3h and 3i (Table 2, entries 8-11) with 72 , 64, 22 and 42%, respectively. It is noted that the disulfonylamidine3l was obtained with a yield of 66% (Table 2, entry 12).

Table 2. Sulfonyl amidines3 prepared from methyl propiolate, arenesulfonylazides and morpholinea



• aReaction conditions: arenesulfonylazide1 (1 mmol, 1 equiv.), methyl propiolate (1 mmol, 1 equiv.), and morpholine2a (1 mmol, 1 equiv.), bIsolated yield after recrystallization in ethanol followed by simple filtration, cBenzene-1,3-disulfonyl azide (1 mmol, 1 equiv.), methyl propiolate (2 mmol, 2 equiv.), and morpholine2a (2 mmol, 2 equiv.).

In addition, the system was applied to other amines. The results obtained for the synthesis of sulfonyl amidines (4a-i) from piperidine are given in the Table 3.

Using piperidine as nucleophilic partner, we evaluated the ability to perform the three-component reaction. This reaction sequence generated the corresponding sulfonyl amidines (4a-i) with yields ranging from 11 to 81%. The best yield was obtained from the para-nitro benzenesulfonylazide. Indeed, the para-nitro benzenesulfonylazide has a decisive influence on the successful formation of 4c (Table 3, entry 3) as 81%. The ortho-nitro and the meta-nitro benzenesulfonylazide were also examined as electron with-drawing source and gave the targeted products 4d and 4e in moderate yields (Table 3, entries 4 and 5) as 51 and 44%. The presence of either electron-donating groups (Me) or (2,4,6-triisopropyl) on benzenesulfonylazide provides almost similar yields (Table 3, entries 1 and 2) around 40%. The arenesulfonylazides containing a halogen group reacted with piperidine and methyl propiolate were unsuccessful. The corresponding products 4f-h were obtained in weak yields (Table 1, entries 6-8), with 14, 13 and 11% yields, respectively. The benzene-1,3-disulfonylazide give low yield of the desired product 4i (Table 3, entry 9) with a 28% yield.

Difference in reactivity was also observed when pyrrolidine was used. The results obtained for the synthesis of sulfonyl amidines (5a-j) are shown in the Table 4.

Table 3. Sulfonyl amidines4 prepared from methyl propiolate, arenesulfonylazides and piperidinea



• aReaction conditions: arenesulfonylazide1 (1 mmol, 1 equiv.), methyl propiolate (1 mmol, 1 equiv.), and piperidine 2b (1 mmol, 1 equiv.), bIsolated yield after recrystallization in ethanol followed by simple filtration, cBenzene-1,3-disulfonyl azide(1 mmol, 1 equiv.), methyl propiolate (2 mmol, 2 equiv.), and piperidine 2b (2 mmol, 2 equiv.)
Table 4. Sulfonyl amidines5 prepared from methyl propiolate, arenesulfonylazides and pyrrolidinea



• aReaction conditions: arenesulfonylazide1 (1 mmol, 1 equiv.), methyl propiolate (1 mmol, 1 equiv.), and pyrrolidine 2c (1 mmol, 1 equiv.), bIsolated yield after recrystallization in ethanol, followed by simple filtration. cBenzene-1,3-disulfonyl azide(1 mmol, 1 equiv.), methyl propiolate (2 mmol, 2 equiv.), and pyrrolidine2c (2 mmol, 2 equiv.)

Next, we performed to prepare sulfonyl amidines by way of the pyrrolidine according to the same sequence and under the same conditions as the previous reactions. This reaction produces the corresponding sulfonyl amidines 5a-j with yields ranging from 10 to 51%. When the reaction was run with the tosylazide and benzenesulfonylazide the sulfonyl amidines 5a and 5b were isolated in only 15 and 10%, respectively (Table 4, entries 1 and 2). In other hand, the 2,4,6-triisopropyl, bulky and strongly electron-withdrawing group, showed low reactivity leading to relatively moderate yield of 44% for the sulfonyl amidine 5c (Table 4, entry 3). It is note that substitution of the benzenesulfonylazide by nitro group in the ortho or meta position on the phenyl ring provided the desired sulfonyl amidines 5d and 5e in moderate yields (Table 4, entries 4 and 5) as 43%. Also, the benzene-1,3-disulfonyl azide give the disulfonyl amidine 5i with an average yield of 51% (Table 4, entry 10). However, when the electron donor substituent has been used such as halogen groups (fluoro, chloro, bromo and iodo) low yields were obtained ranging from 22-33% in this case (Table 4, entries 6-9).

On the basis of our experimental results, together studies in literature 41, a possible reaction mechanism for the formation of sulfonyl amidines is proposed in Scheme 2.

Scheme 2.Proposed mechanism for the synthesis of compounds 3-5.
Proposed mechanism for the synthesis of compounds 3-5.

First the secondary cyclic amine reacts with methyl propiolate through a hydroamination reaction to afford corresponding enamine. Then, the formed enamine reacts with arenesulfonylazide to yield the unstable D21,2,3-triazolineintermediate which then release one molecule of methyl diazoacetate to provide the expected sulfonyl amidines 3-5. It should be noted that the nature of substituents of arenesulfonylazides and the cyclic secondary amine structure has a great influence on the yield of the reaction.

Conclusion

In conclusion, we have developed a fast, efficient, easy, and practical three-component reaction of arenesulfonylazides, methyl propiolate and secondary cyclic amines to produce sulfonyl amidines. The reactions were performed without any solvent or catalyst, at room temperature, very short reaction time and with moderate to good yields. Compared to previously other reported synthesis of sulfonyl amidines, this protocol is highlighted by its simplicity, atom economical nature and green operational method.

Acknowledgements

The authors cordially thank Professor J.-M Pons (Institut des Sciences Moléculaires de Marseille (ism2) of Aix-Marseille University, Faculty of Sciences) for centesimal analysis and the mass spectra.

References

  1. 1.Zhu J, Wang Q, Wang M-X. (2014) . Eds.Multicomponent Reactions in Organic Synthesis;Wiley-VCH Verlag GmbH: , Weinheim, Germany .
  1. 2.Zhu J, Bienaymé H. (2005) Multicoponent reactions”, eds, Wiley-VCH. , Weinhein Germany
  1. 3.Andrade CKZ, Dar A R. (2016) . Tetrahedron.72: 7375
  1. 4.Ameta K L, Dandia A. (2017) Multicomponent Reactions: Synthesis of Bioactive Heterocycles.
  1. 5.Mishra B B, Kumar D, Mishra A, Mohapatra P P, Tiwari V K. (2012) . Advances in Heterocyclic Chemistry.107: 4 .
  1. 6.J V Greenhill, Lue P, Prog.. Med. Chem.30(1993)203;
  1. 7.Barker J, Kilner M, Coord.. Chem. Rev.133(1994)219;
  1. 8.Boyd G V. (1991) Reactions and synthetic uses of amidines”In The Chemistry of Amidines. , New York,2: 367.
  1. 9.Aly A A, Ahmed M, Nour-El-Din A M. (2008) . Arkivoc.153
  1. 10.Ito K, Kizuka Y, Ihara S. (2006) . Heterocyclic Chem.43: 1217.
  1. 11.Sudheendran K, Schmidt D, Frey W, Conrad J, Beifus U. (2014) . , Tetrahedron 70, 1635.
  1. 12.Guo W. (2016) . , Chinese Chem. Lett 27, 47.
  1. 13.Bellur E, Langer P. (2006) . , Tetrahedron 62, 5426.
  1. 14.Hajri A, Abderrahim R. (2011) . , Phosphorus, Sulfur, Silicon, Relat. Elem.186: 520.
  1. 15.Zhang J, Zheng T, Zhang J. (2020) . , Eur. J. Org. Chem.21: 860.
  1. 16.Kumamoto T. (2009) . Amidines and Guanidines in Natural Products and Medicines” In “Superbases for OrganicSynthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts” ed. by I. Ishikawa , West Sussex, UK 295.
  1. 17.Sondhi S M, Dinodia M.A Kumar. (2006).Bioorg. Med. Chem.14: 4657
  1. 18.FE Goda Barghash, Eisa H M, Wenzler T, Brun R, Liu Y et al. (2010) . , Bioorg. Med. Chem.18: 557.
  1. 19.Sielecki T M, Liu J, Mousa S A, Racanelli A L, Hausner E A.. RR Wexler and RE Olson. (2001).Bioorg.Med. Chem. Lett.11: 2202.
  1. 20.Calas M, Ouattara M, Piquert G, Ziora Z, Bordat Y et al.. (2007).J Med. Chem.50: 6307
  1. 21.Racane L, Kralj M, Šuman L, Stojkovic R, Tralic-Kulenovic V et al. (2010) . , Bioorg. Med 18, 1038.
  1. 22.Turan Z G, Sivaci D M, Kaplancikli Z A.A Ozdemir. (2002).Il Farmaco,57(2002) 569;
  1. 23.Song Z L, Chen H L, Y H Wang, Goto M, Gao W J et al.. (2015).Bioorg. Med.Chem. Lett.25: 2690
  1. 24.Krstulović L, Saftić D, Ismaili H, Bajić M, Glavaš-Obrovac L et al.. (2017).Croat. Chem. Acta,90: 625
  1. 25.L P Graham, D P Patrick, ChimiePharmaceutique. (2003) . , Paris, de Boeck, 355
  1. 26.S Chang Baek, Kim S H. (2011) . , Bioorg. Med. Chem. Lett.21: 727.
  1. 27.Dekorver K A, Johnson W L, Zhang Y, Hsung R P, J Deng HDai et al. (2011) . 76, 5092.
  1. 28.Volkova K A, Albanov A I. (2006) . , Russ. J. Org. Chem.42: 1730.
  1. 29.Das V K, Thakur A J. (2013) . Tetrahedron Lett.54: 4164.
  1. 30.Yang H J, Sun W H, Li Z L, Ma Z. (2002) . , Chinese Chem.Lett 13, 3.
  1. 31.Wu Y, Chen X, Zhang M M. (2020) . Synthesis.52: 1773.
  1. 32.Trillo P, Slagbrand T, Tinnis F, Adolfsson H. (2017) . Chemistry Open.6: 484.
  1. 33.Wan X Zhengand JP. (2019) . , Adv. Synth. Catal 361, 5690.
  1. 34.Chin.. , J. Org. Chem 40(2020), 1891.
  1. 35.Bae I, Han H, Chang S. (2005) . , J Am Chem Soc. 127: 2038
  1. 36.Kim J Y, Kim S H, Chang S. (2008) . Tetrahedron Lett.49: 1745.
  1. 37.Cui S L, Wang J, Wang Y G. (2007) . Org. Lett.9: 5023.
  1. 38.Whiting M, Fokin. (2006) . , Chem. Int. Ed 45, 3157.
  1. 39.Adiche C, Hamadouche M, D El Abed. (2016) . , Heterocycles 92, 1614.
  1. 40.Ruppel J V, Kamble R M, Zhang X P. (2007) . , Lett 9, 4889.
  1. 41.S Torabi BKaboudin, Kazemi F, Aoyama H. (2020) . Adv.10: 26701.