Fluorinated organic azides – their preparation and synthetic applications

Alkyl azides are widely used in many reactions. Although synthesis of such species is relatively well documented, fluorinated azides, especially with large perfluorinated or highly fluorinated groups


Introduction
The use of organic azides has increased throughout the centuries.They are energy-rich molecules with many synthetic applications.The first organic azide -phenyl azide -was prepared in 1864 by Peter Grieβ. 1,2Many years later, in the 1950s and 1960s azides attracted significant interest as functional groups easily transformable into other functionalities.Not only aryl azides, but also alkyl and acyl azides have been prepared. 3Synthetically, alkyl azides represent an important class of compounds which can be obtained by nucleophilic substitution reactions with heating, 4 phase transfer catalysis, 5 microwave irradiation 6,7 or some mixed procedures.Different azide group sources can be used e.g.trimethylsilyl azide (TMSA), tributyltin azide, (TBSnA), tetrabutylammonium azide (TBAA) and lithium azide (LiN3).][10][11] Nowadays the most common reaction where azides are utilised, is probably 1,3-dipolar cycloaddition, someties referred to as a 'click' reaction.Azides have also been involved in the preparation of new materials with unprecedented properties e.g.membranes, surfactants, liquid crystals and in biomedical applications. 12,13ithin the series of different azides, fluorine-containing azides are of special interest.The reason is that having an azide functionality in a molecule it is relatively simple to introduce flurorinated motif to a parent molecule, changing its properties (e.g.increasing lipophilicity).This is an interesting and common approach in several 'drug delivery systems', employing a 'click' reaction as an efficient synthetic step for the introduction of a fluorinated chain.Fluorinated azides are an excellent tool for the synthesis of fluoroalkylated [1,2,3]triazoles in typical Huisgen cycloadditions. 11,14,15t is well known that the presence of fluorine atoms in a molecule, can unexpectedly change the reactivity of the compound, and may lead to increased biological activity.This is due to the unique properties of the fluorine atom.Fluorine is the element with the highest electronegativity and forms a very strong carbonfluorine bond. 16Fluorine present in the molecule, in most cases causes increased stability.Comparing the steric effects of -CF2-and -CH2-groups, fluorination always increases the steric size of the fluorinated group.The size of a trifluoromethyl group is almost twice that of a methyl group.This effect can be explained by the van der Waals radius of fluorine (1.47 Å) even though it is only 20% larger than hydrogen (1.20 Å).Secondly, the C-F bond length is 1.38 Å compared with common C-H bonds at 1.09 Å.It is worth mentioning that microorganisms or enzymes often do not recognize the difference between analogues with C-F bonds instead of C-H, because the fluorine atom is similar in size to a hydrogen atom. 17,18In fact, the fluorine atoms in fluorinated chains tightly screen a carbon chain, in contrast to hydrogen atoms.As a result, fluorinated compounds have a low surface energy, are more resistant to wetting or hydrolysis and are more slippery. 19All these properties combined, are important factors influencing the application of fluorinated vs non-fluorinated systems.
Organic azides arouse industrial interest as precursors for synthesis of amines or heterocycles such as tetrazoles and triazoles. 20,21As mentioned already, azides are widely used as 'click' chemistry reactants, as scaffolds to introduce some other functions (e.g. in drug delivery systems, surface modification of reactants, etc).Although synthesis of such species is relatively well documented, fluorinated azides, especially with large perfluorinated or highly fluorinated groups, are sometimes tricky to prepare.

Results and Discussion
][24][25] On the other hand, synthesis of analogous azides possessing a long fluorinated chain tends to be more challenging.][28][29][30][31][32][33][34][35][36] In our recent studies, we focused on the long chain compounds which possess a fluorinated alkyl chain and a different -CH2-linkers attached directly to the azido group.Although the preparation of azides is very well documented, there are no much precedences to synthesize fluorinated analogues.By including a short spacer (-CH2-, -CH2CH2-, -CH2CH2CH2-) between the azido group and the perfluorinated chain we can reduce the inductive effect caused by the fluorine substituents in the alkyl chain and increase the reactivity of these compounds in further synthesis. 12,14n this study we have focused on the synthesis of novel compounds, as well as modifications of the experimental procedure to yield the desired fluorinated long chain azides with better efficiency.In some cases we have used different starting materials or modified methodologies to yield corresponding products with better yields.
In 1977 Rondestvedt et al. 28 presented a convenient synthesis of 1H,1H,2H,2H-perfluorooctyl azide 9 by simple reaction of the iodide with sodium azide in moist tert-butanol or isopropanol with satisfying conversions of around 90%. Wu et al. 37 described conversion of fluorinated alcohols into mesylates and their further transformation into corresponding azides by the use of sodium azide and 18-crown-6 ether as a catalyst.Zhu et al. 14 reported the transformation of tosylates in a mixture of DMF and benzene using sodium azide with good (70%) yields.In many cases the reaction between the iodide and sodium azide takes place by heating in MeCN or DMSO as a solvent. 32,38This kind of reaction can be carried out also under microwave irradiation and the reaction time is significantly reduced (e.g. from 24 hours to 1 hour). 15 transformation of an alcohol into its corresponding tosylate or mesylate and subsequent nucleophilic substitution with sodium azide to yield fluoroalkyl azides is one of the methodologies used in the literature.Starting materials, can be obtained from commercially available fluoroalkyl alcohols by reaction with ptoluenesulfonyl chloride or methanesulfonyl chloride, converting the hydroxyl group into a good leaving group.A procedure for preparation of fluoroalkyl tosylates is described by Zhu et al., 14 and we have used an analogous procedure to prepare fluoroalkyl mesylates (Table 1). 24,29,32,34,36,39* Isolated yields.
Several different methodologies for the synthesis of fluorinated tosylates or mesylates have been described, where instead of triethylamine 1a, 24 1b, 32,34 2b, 36 3b, 29 4a 40 other bases were used such as sodium or potassium hydroxide 2a, 24,41 3a, 30,35 5a, 42,43 pyridine 1a, 44 diisopropylamine 4b, 39 DABCO 1a. 45For compound 1b different conditions also used SbCl5. 46The products were obtained within a range of good to excellent yields e.g.: 1a 88%, 45 3a 75% 35 and 3b 51%. 37To our best knowledge, fluorinated mesylate 5b has not been reported.Typically, transformation of a tosylate or mesylate into the corresponding fluoroalkyl azide proceeds in toluene or DMSO as solvent, sometimes with addition of a catalyst such as 18-crown-6 ether. 31,37,47,48Other reports use DMF/benzene as a solvent and simple nucleophilic substitution with sodium azide at elevated temperature. 14We have changed the solvent to hexamethylphosphoramide (HMPA) and used a threefold excess of sodium azide without any extra additives.The reaction mixture was heated in an inert atmosphere in 85 o C or 120 o C for 4.5 hours (Scheme 1).by reaction with triphenylphosphine, imidazole and iodine (Table 3) (Scheme 2). 50,51There are also reports describing preparation of iodides with other methodologies e.g. with P2O5, H3PO4 and KI as a source of iodide anion in an elimination-addition reaction or microwave synthesis with polymer-bound triphenylphosphine and iodine. 22,52 very interesting method has also been described by Badache et al. 23 The reaction of a fluorinated alcohol with diisopropylcarbodiimide yields fluorinated isoureas.Subsequently, the use of hydriodic acid in the next step, afforded fluorinated iodide.the synthetic methodology and characterization of this product is not available in the literature.The synthesis and characterization of azide 16 prepared from iodide 11 is presented in this paper.On the other hand preparation of 1H,1H,2H,2H-perfluorooctyl azide 9 from the corresponding iodide 12 with sodium azide and Aliquat® 336, [55][56][57] in DMF, 14,58 in DMSO 45 or chloride 59 has already been described.
Prepared or purchased iodides were submitted to nucleophilic substitution with sodium azide.The typical procedures used either moist tert-butanol, isopropanol or water as solvent, sometimes with the addition of Aliquat® 336.Reactions were typically performed at elevated temperatures.The synthesis of 1H,1H,2H,2Hperfluorododecyl azide 17 from 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-henicosafluorododecyl iodide 13 proceeded in water at 90-110 °C with addition of Aliquat® 336. 56Reaction time varied from 6 to 12 hours and the reaction yields were very good 87-93%.We decided to extend the reaction time to 17.5 hours but perform the reaction at lower temperature 80 o C. As an additive we used Aliquat® 336 and we changed solvent to a mixture of Et2O and H2O (1:1, v/v).As a result we obtained the desired product 17 in an excellent yield of 97%.The results are summarized in the Table 4.The typical methodology of azide preparation from iodides, described by Riess et al. 60 , using an anhydrous solvent like DMF, without any additives, also allowed us to obtain the desired azides (9, 16, 17), however with significantly lower yields (16, 17) (Table 5).

Conclusion
A short overview of a re-examination of the synthetic methods for azides preparation with different linkers -CH2-and a fluorinated chain has been provided.In summary, a series of highly fluoroalkyl azides were synthesized.The methodologies used were based on the reports available in the literature, however optimized and/or modified by us.All compounds were obtained with good to excellent yields.Further studies and use of prepared compounds as synthetic reagents, e.g. in Husigen cycloaddition reaction, will be reported in due course.All modified procedures for the synthesis of fluorinated compounds (1a-17) and new spectroscopic data are described in Experimental Section.

Experimental Section
General.All chemicals were reagent grade and used as purchased without further purification.Thin-layer chromatography (TLC) was carried out on silica gel plates (Silica gel 60, F254, Merck) with detection by UV light or with a stain solution (10% PPh3 in DCM and 3% ninhydrin in t-BuOH and CH3COOH).Purification was performed with preparative chromatography using normal-phase silica gel (Silica gel 60, 230-400 mesh, Merck).NMR spectra were calibrated using an internal reference: TMS (

General procedure for the synthesis fluorinated tosylates and mesylates (1a-5b).
A solution of TsCl (8.24 mmol, 1 equiv) or MsCl (8.24 mmol, 1 equiv) in DCM (24 mL) was added dropwise to a stirred solution of fluorinated alcohol 1-5 (8.24 mmol, 1 equiv) and Et3N (1.78 mL, 1.55 equiv) at 0 o C.After complete addition (10 min) the reaction mixture was allowed to reach rt and stirring was continued overnight.Then, the reaction mixture was washed with H 2 O (34 mL) and brine (34 mL).The organic layer was dried over Na 2 SO 4 and concentrated to dryness under reduced pressure.The resulting crude product was crystallized from MeOH to afford 1a-5b.

Table 1 .
Preparation of fluorinated tosylates and mesylates from corresponding fluorinated alcohols with ptoluenesulfonyl or methanesulfonyl chloride with triethylamine (Et 3 N) in dichloromethane

Table 3 .
Preparation of fluorinated alkyl iodides from corresponding alcohols

Table 4 .
Preparation of fluorinated azides from iodides

Table 5 .
Synthesis of fluorinated azides from iodides with DMF as solvent