Azides and Triazoles

Introduction
Sulfonamides have many biological activities, i.e. bacteriostatic, diuretic, anti-diabetic or anti-inflammatory. The discovery of an anti-cancer sulfonamide E7010 showed a new potential activity. Molecules containing 1,2,3-triazole group have strong activities too i.e. bactericidal, fungicidal, anti-inflammatory, anti-viral
and anti-neoplastic.

Aim of the study
Aim of the research was to find an effective one-pot, click-chemistry reaction to synthesize quinoline-based compounds with both sulfonamide and triazole groups. Obtained derivatives were to be tested for anti-neoplastic activity.

Material and methods
15 various 4-propargylamino-3-quinolinesulfonamides and 4-amino-3-quinoline-N-propargylsulfonamides were obtained from 4-chloro-3-quinolinesulfonamide chloride. Tested on cancer cell colonies, some of them showed moderate activity. They were used in 5 variants of azide-alkyne 1,3-cycloaddition:
• catalyst-free, solvent: H2O,
• two-phase with phase transfer catalyst (TEBA-Br),
• copper-catalyzed azide-alkyne cycloaddition (CuAAC),
solvents: DMF/H2O or tert-butanol,
• two-step: organic azide sythesis before CuAAC.
The reactions were made with 3 different halides: benzyl, allyl and 3-methyl-2-buten halide. Product structures were determined by 1H NMR and MS.

Results
13 derivatives of 4-amine-(N-4-methyl-1,2,3-triazol-4-yl)-3-quinolinesulfonamides and 4-amine-3-quinoline-N-(4-methyl-1,2,3-triazol-4-yl)sulfonamides were obtained. Benzyl halides yielded 80-90%, 3-methyl-2-buten halides: 70-80%, allyl halides: 40-50%.
Catalyst-free reaction did not occur, due to lack of substrate solubility. Thus it can be applied only for liquids creating water emulsions. Two-phase reaction caused difficulties in product purifying from TEBA-Br remains. Two-step reaction had good yields, but required organic azide synthesis before actual cycloaddition. One-pot CuAAC had good yields and simple ways of product separation: filtration or extraction.

Conclusion
The two last mentioned  methods seem to be most effective and variable in applications. The one-pot CuAAC may be best for chemical and pharmaceutical industry, due to its simplicity and short reaction time (24 to 48h).

Sulfonamides are a huge group of compounds with various biological activities (antihistamine, antibacterial, antiviral and antineoplastic). The discovery of a new sulfonamide marked as E-7010 in 1992, caused increased interest in this chemical group and led to synthesis of many interesting antineoplastic compounds. Some of them are in advanced stage of clinical trials.

In our research over a dozen 4-propargylamino-3-quinolinesulfonamides [2] and 4-amino-3-quinoline-N-propargylsulfonamides [3] were synthesized lately from 4-chloro-3-quinolinesulfonamide chloride.

Sulfonamides [2] and [3] were tested on neoplastic cells, but their activity is relatively low. That is why a one-pot azide-acetylene addition reaction was performed on selected sulfonamides from groups [2] and [3]. The reaction was made in DMF-water solution, in room temperature for 24 hours, with copper(II) ions and ascorbic acid as catalysts. Obtained products were 1,2,3-triazole-substituted compounds, which yielded with 77-90%.

Click chemistry has played a significant role as a rapid and versatile strategy for conjugating two molecular fragments under very mild reaction conditions. Introduction of ferrocene-derived triazole systems using click chemistry has attracted enormous interest in various fields due to its potential applications in electrochemical techniques for detection and sensing. The present discussion focuses on the synthesis of ferrocene-triazole and the im-portance of using a CuAAC reaction for such conjugation. Applications of ferrocene-based click reactions in conjugate chemistry, asymmetric catalysis, medicinal chemistry, host-guest interactions, and materials chemistry have been highlighted.

Due to wide range of biological actions of sulfonamides, quinoline derivatives and 1,2,3-triazoles, as well as presence of this structures in substances bearing anticancer, antibacterial, antitubercular or beta-lactamase inhibiting activities, an effort was made to find an effective, one-pot method for synthesis of derivatives containing those three moieties.

Five "click chemistry" synthesis methods were evaluated:
-single-step CuAAC in DMFaq (A1) and tert-butanol/water (A2),
-single-step PTC method (B),
-two-step method using organic azide (C),
-single-step catalyst free (D).
The substrates were several 4-amino-3-quinolinesulfonamide analogs containing a propargyl group and four different halide types: benzyl bromide and chloride, allyl bromide and 1-bromo-3-methyl-2-buten.

13 new, not published in literature compounds were obtained. They were derivatives of: 4-amino-(N-methyl-1,2,3-triazolyl)-3-quinolinesulfonamides, 4-amino-3-quinoline-N-(4-methyl-1,2,3-triazolyl)sulfonamides and
4-chloro-3-quinoline-N-(methyl-1,2,3-triazolyl)sulfonamides. Yields were between 31 and 99%. Benzyl halide substrates yielded 65-99%, 1-bromo-3-methyl-2-butenu yielded 83-97%, and allyl bromide yielded 31-58%. There was no clear dependence of reaction yields on activity of halide type which was used as substrate.

It was concluded, that best methods for such syntheses are A1, A2, B and C. In most cases the only product was 1,4-disubstituted triazole. Method D has limited significance. For several obtained products a phenomenon similar to polymorphism may occur.

Click chemistry has played a significant role as a rapid and versatile strategy for conjugating two molecular fragments under very mild reaction conditions. Introduction of ferrocene-derived triazole systems using click chemistry has attracted enormous interest in various fields due to its potential applications in electrochemical techniques for detection and sensing. The present discussion focuses on the synthesis of ferrocene-triazole and the im-portance of using a CuAAC reaction for such conjugation. Applications of ferrocene-based click reactions in conjugate chemistry, asymmetric catalysis, medicinal chemistry, host-guest interactions, and materials chemistry have been highlighted.