Azidation of aryl halides promoted by EDTA

1 Introduction

Aryl azides are widely used in bioactive molecules as synthetic targets due to their extensive usages [1]. Such compounds can act as exceptional platforms for diverse functional group incorporation; the azido functionality leads to the insertion of many different heteroatoms; therefore their usefulness as photoaffinity probes can be explained [3]. These compounds can also be useful in photoresistors [4], polymers with conducting ability [4], and light-rendered energizing polymers [6]. Therefore, gaining an efficient procedure for such structural motifs is extremely favorable.

Up to now, a few synthetic routs have been demonstrated for construction of aryl azides. The classical route to diazotization of aromatic amines and subsequent reaction with azide ions [7]. Controlling reaction condition is very difficult when two or more amino groups exist as substituents in aromatic rings. Another method is the S_NAr reation between NaN₃ activated aryl chlorides and fluorides [8]. But it must be mentioned that such methods cannot be suitable when electron-donating groups are on the aromatic motifs. Aryl boronic acids are able to turn into aryl azides [9]. Nevertheless, such method is outdated because of low accessibility to derivatives of these acids. Therefore, coupling of NaN₃ and aryl halides is preferable. It also should be said that in such cross-coupling reaction bewildering arrays of reports can be obtained according to obtaining aryl azides or aryl amines as products.

Ma and Zhu reported synthesis of aryl/vinyl azides by applying cross-coupling reaction between NaN3 and vinyl/aryl halides under catalysis through CuI/L-proline in 7EtOH/3H2O [10]. Fast method for production of aryl azides from the corresponding aryl halides was reported by Liang and co-workers. They used microwave conditions and also a mixture of CuI and an expensive diamine as catalytic system [11]. Haloarene amination was studied by applying excess NaN₃. Using CuI/DMEDA as catalyst under reported condition lead to not forming of azides[12]. Thatcher reported the solvent switching from 7EtOH/3H₂O to DMSO/2EtOH along with the use of excess amount of NaN₃, stoichiometric amount of base and CuI/L-proline can be lead to producing aryl amines as exclusive products in lieu of relevant aryl azides. Thatcher and co-workers deduced that synthesis of aryl amines is because of the lack of aryl azides stabilities at increased temperatures [13]. Lately, Helquist published Cu-mediated replacement of halides with a large amount NaN₃ for synthesis of aryl amines and also showed that Cu₂O/DMEDA catalytic system improves efficiency of the transformation [14]. The confusing variety of published results along with the changing in type of products which depend on several factors such as solvents and ligands in Niknam and Hajipor group, encouraged us to publish number of promising articles in this field [15, 16].

In an attempt to selective synthesis of aryl azides, we use simple and cheaper [CuI/EDTA]^–3 as catalytic system to facilitate azide-halide cross-coupling. It should be noted that the price of EDTA is at least 1/500 of previously reported DMEDA. Only aryl azides (not aryl amines) can be formed as a single product.

2 Results and discussion

Here, linkage of NaN₃ with aryl halides has been performed using [CuI/EDTA]^–3 as a catalytic system. For optimizing condition, we performed testing different variables applying 2 mmol NaN₃ and 1 mmol 4-bromoanisole as model substrates. p-bromoanisole was selected as a representative material due to the small amount of conversion which was obtained for p-methoxyaniline (46%) according to the Helquist conditions. It was found that by employing 10 mol% CuI, 20 mol% EDTA, 1 eq NaOH in mixed solvent (7EtOH/3H₂O) corresponding azides were obtained after 2 h with 40% yield (Table 1, Entry 1). Various bases were used such as NaOH, Na₂CO₃, K₃PO₄, KOH, K₂CO₃ (Table 1, Entries 1–5). Performed experiments showed that K₂CO₃ gave higher yieds than the other mentioned bases (Table 1, Entry 5). To figure the function of catalyst, cross-coupling was performed without catalyst and reaction was failed to give any product under such condition (Table 1, Entry 6). By applying higher amounts of catalyst (15 mol% and 20 mol%), there was no difference in conversion (Table 1, Entries 7-8), so, 10 mol% CuI was selected as an optimized condition. It should be regarded that lowering catalyst quantity from 10 mol% to 5 mol% lead to the decreasing in the yields of products (Table 1, Entry 9). We used some higher amounts of EDTA (30 mol%) and under such condition, conversion was increased from 45% to 50% (Table 1, Entry 10). Similar procedures was performed at various time intervals: 2 h, 4 h, 6 h, 8 h, 10 h (Table 1, Entries 10–14). Increasing the time up to 6h was led to an increase in the percentage of conversion (Table 1, Entry 12). Then, we selected lower temperatures to do this reaction but no products were achieved between 50°C–60°C (Table 1, Entry 15). Then, various solvents were considered for screening process. Applying various solvents such as EtOH, EG (ethylene glycol), DMSO, H₂O and mixed solvents such as 7EtOH/3H₂O, 7EtOH/3EG, 7EG/3H₂O (Table 1, Entries 12, 16–21) showed that 7EtOH/3H₂O had better yields than other solvents (Table 1, Entry 12).

For investigation of generality and scope of the method, reaction of different aryl iodides and bromides with NaN₃ were explored (see Table 2). So, the best obtained condition showed that (Table 1, Entry 12) aryl azides were solely obtained as product and formation of aryl amines was failed. Most of the performed cross-couplings gave good yields of aryl azide derivatives in air atmosphere and without any need for microwave condition except in the cases of aryl halides possess potent electron accepting group in the para position (Table 2, Entries 7-8) or potent electron donating group of aromatic scaffold (Table 2, Entries 11-12). A closer look at the Table 2 shows that the reaction of m-nitro and m-acetyl aryl halides gave modest yields of products (Table 2, Entries 6 and). Surprisingly, product has not been obtained under the optimum condition when p-bromoaniline and p-iodoaniline were used as starting materials (Table 2, Entries 11-12). Also, it should be regarded that such cross-coupling reaction can be good for aryl bromides and iodides, but in the case of aryl chlorides no product has been achieved (Table 2, Entry 15).

A possible mechanism for aryl halide is outlined in Scheme 1. We believe that a copper(I)/copper(III) catalytic system is in place. coordination of the aryl halide to [EDTA–Cu]^–3 and oxidation by oxygen gives a copper(III) intermediate 2. The transmetalation of 2 with the sodium azide gives 3, which undergoes reductive elimination to give product 4, and also provides the copper(I)-bound catalyst 1. Coordination of the aryl halide and oxidation by oxygen leads to regeneration of the copper(III) intermediate 2.

OPEN IN VIEWER

Scheme 1

Possible mechanism for aryl halide by the [EDTA–Cu]^–3 catalyst.

A flask containing a magnet was filled with 1 mmol aryl halide, 2 mmol sodium azide, 3 mL mixtures of 7EtOH/3H₂O, 10 mol% CuI and 30 mol% EDTA. This mixture was stirred at 100 °C and promotion of reaction was followed using thin layer chromatography. Then, the cooled solution was diluted by adding H₂O and EtOAc. Organic layer was separated with EtOAc, repeatedly. Drying combined organic layers was performed with CaCl₂ and then removal of solvent was done under decreased pressure to achieve product. In some cases, it was required to separate extracted compounds with column chromatography. All compounds are known and were characterized by comparison of their IR and ¹H-NMR spectroscopic data with reported values [17–21].

Supplementary information

Experimental data associated with this article can be found in the online version, at supplementary material section.