Tributylstannyl Azide as Efficient Reagent in the Synthesis of Aryl Azides from Aryl Amines

An efficient and straightforward method for one-pot synthesis of aryl azides from the corresponding amines, employing tributylstannyl azide as transfer reagent of N3 group is described. In this procedure diazotization of aryl amines occurs under mild conditions using tert-butyl nitrite (t-BuONO) and p-toluenesulfonic acid (TsOH). A variety of substituted aryl amines, with both electron-withdrawing and electron-donating groups were transformed into aryl azides in good to excellent yields. An important advantage of the present method is that, despite their high toxicity, tin byproducts can be reconverted into the starting tributylstannyl azide by treatment with sodium azide (NaN3) and reused after chromatographic separation of the aryl azide.


Introduction
Over the years, aryl azides have achieved increased importance as valuable synthetic intermediates due to their potential applications in chemistry, biology and materials science.Because of their relatively high stability, these compounds have found industrial use as cross-linkers in photoresistors, for conducting polymers, and for light-induced activation of polymer surfaces. 1More interestingly, aryl azides are well known for their ability as photoaffinity labeling agents for proteins.This function relies on the fact that, upon irradiation an aryl azide expels molecular nitrogen to produce an electron-deficient nitrene species that is capable of inserting into a C-H bond thereby forming a covalent bond between a labelling agent and a protein. 2 In addition, aryl azides are useful synthones in order to obtain various heterocyclic compounds and transition metal complexes, 3 having applications in pharmaceutical, agricultural and materials chemistry. 4 particular, in recent years, these compounds have been popularized in the field of "click chemistry" 5 due to their participation in Cu-(I)-catalyzed Huisgen 1,3dipolar cycloaddition to terminal alkynes (CuAAC), 6 for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.Because of their wide applications in chemical, material and biological sciences, 7 these heterocyclic derivates have increasingly received significant attention.Therefore, given the importance of aryl azides, the development of new methodologies for their synthesis is an area of permanent interest.
Throughout the years, several procedures have been developed for the synthesis of these compounds.Typically, they are prepared from aromatic amines with nitrous acid followed by addition of NaN 3 at low temperature.3a,8 Recently, Das et al. reported the use of t-BuONO in combination with NaN 3 in the synthesis of these compounds. 9Aryl azides have also been synthesized using a combination of aryl amine, TfN 3 , CuSO 4 , and triethylamine; 10 employing stable aryl diazonium silica sulfates 11 or arenediazonium tosylates 12 with NaN 3 in water, and by reaction of [ArN 2 ][BF 4 ] salts immobilized in [BMIM][PF 6 ] ionic liquid with trimethylsilyl azide (TMSN 3 ). 13Furthermore, aryl azides have also been prepared from aromatic amines with t-BuONO, followed by addition of (TMSN 3 ) in acetonitrile under mild conditions. 14Among the several existing methods, we focused our attention on the latter.Although this procedure is highly efficient with excellent yields, the use of TMSN 3 has some downsides; this compound is volatile and hydrolytically unstable resulting in the release of toxic and explosive hydrazoic acid. 14Furthermore, it has a high cost and a tedious synthetic method. 15On the other hand, trialkylstannyl azides, which can also act as transfer reagent of N 3 group, are more stable, more resistant to hydrolysis and are easily obtained by the reaction of the corresponding trialkyltin chloride with sodium azide. 16These properties, together with the importance of aryl azides, encouraged us to initiate a study in order to determine the ability of the tributylstannyl azide as transfer reagent of N 3 group in this transformation.

Results and discussion
Initially, we decided to apply the conditions developed by Moses and coworkers 14 as starting point for our investigation (Table 1, entry 1) and we chose aniline (1a) as a model substrate to optimize the reaction conditions.To our disappointment, after 19 h at room temperature, most of the starting material remained unchanged and we could only observe trace of azidobenzene (4a).Taking into account that the presence of an acidic additive facilitate the diazotization process, 17 we observed that the reaction was significantly improved by adding 1.2 equiv of BF 3 .
OEt 2 (entry 2).Next, we tried to improve the yield of 4a by increasing the amount of tributylstannyl azide to 1.8 equiv.Under these conditions, the desired product was obtained in higher yield (entry 3).
When the reaction was carried out under the initial conditions, in the presence of p-toluenesulfonic acid (TsOH) an increment of the aryl azide yield was achieved (compare entries 2 and 4).Furthermore, we observed that the use of 1.8 equiv. of 3 and TsOH as additive were the optimal conditions, providing the desired product in 96% yield (entry 5).
Next, given the high toxicity of tributylstannyl azide, we tried to avoid the use of large excess of this compound increasing the amount of t-BuONO to 2 equiv.
Unfortunately, under these conditions, 4a was obtained in a lower yield (compare entries 5 and 6).
With the optimized reaction conditions in hand, we explored the reaction scope by testing other aryl amines with different substituents.The results are summarized in Table 2. First, when we carried out the reaction with p-anisidine (1b), after 2 h of stirring at room temperature, the desired product (4b) was obtained in excellent yield (Table 2, entry 1).Taking into account that the optimal reaction conditions required the use of a large excess of the stannylazide and, given the high toxicity of tin compounds, we decided to investigate if tin byproducts generated in this reaction could be reconverted into the starting tributylstannyl azide.In order to accomplish this transformation, after total disappearance of 1b (as indicated by TLC analysis), 1.2 equivalents of sodium azide were added to the mixture and stirring was continued overnight at room temperature (eq 1).
After usual work-up, the 119 Sn-NMR spectrum of the crude mixture showed only one signal at δ=111.09 ppm, which agreed with commercial tributylstannyl azide 119 Sn-NMR spectrum.This confirmed that tin byproducts were completely converted to the starting stannyl azide.Once regenerated, tributylstannyl azide was reused after chromatographic separation of the aryl azide (see Experimental Section).
From Table 2, it is clearly seen that both electron-donating and electronwithdrawing groups on the aromatic ring were suitable for this conversion, giving the corresponding aryl azides in good to excellent yields in 2 -4 hours.

Conclusions
In summary, we have developed a simple, efficient and straightforward method for one-pot diazotization-azidation of aryl amines to produce aryl azides, using tributylstannyl azide as an effective azidating reagent.
The results obtained to date indicate that this procedure allows synthesizing aryl azides with both electron-withdrawing and electron-donating groups, in good to excellent yields, from aryl amines.An important advantage of this protocol over conventional methods is that the azide source can be easily regenerated and reused after chromatographic separation of the aryl azide product.Further expansion of the substrate scope is currently ongoing in our laboratory and the results will be reported in due course.

General experimental methods
Aryl amines, tert-butyl nitrite and p-toluenesulfonic acid were commercially available and used without further purification.Only aniline was distilled under nitrogen before use.Tributylstannyl azide was obtained by the reaction of tributyltin chloride with sodium azide, according to the literature procedures, and used without further purification. 16Acetonitrile was distilled from calcium hydride and dried over molecular sieves prior to use.Reactions were monitored by thin-layer chromatography carried out on silica gel plates (60F-254) and visualized under UV light or using 5% phosphomolybdic acid in ethanol.Flash chromatography was performed over silicagel (0.040-0.063 mm).For infrared analysis a FT-IR spectrophotometer was used and wavenumbers are given in cm -1 .The NMR spectra were recorded on a 300 MHz spectrometer (300.1 MHz for 1 H, 75.5 MHz

Table 1
Optimization of the reaction conditions for diazotization-azidation of aniline.
a Determined by GC for 0.5 mmol scale reaction using o-Cl 2 C 6 H 4 as internal standard.c 19 h, 1a was recovered.