One-Pot Sodium Azide-Free Synthesis of Aryl Azides from Anilines

Abstract

This work presents an easy and efficient one-pot protocol for the synthesis of aryl azides without using sodium azide or hydrazine hydrate starting from anilines via aryl hydrazines. This protocol can be applied to anilines bearing groups with donating or withdrawal electronic characteristics.

Keywords:
aryl azides; isopropyl nitrite; diazotization; aryl hydrazines

Introduction

Aryl azides are essential components for several chemical reactions, such as click chemistry,¹-³ aza Wittig reaction,⁴ synthesis of aryl amides,⁵ tetrazole synthesis,⁶ azepine synthesis,⁷,⁸ aziridine synthesis,⁹ total synthesis of natural products,¹⁰ and Staundiger reaction.¹¹,¹² The most used method for its production consists of carrying out the diazotization of anilines followed by a nucleophilic aromatic substitution using sodium azide (Scheme 1).¹³,¹⁴ In certain locations around the world, obtaining sodium azide, even for research, can be a difficult task because of government control due to the explosive potential of this reagent.

Scheme 1
Synthesis of aryl azides found in the literature.

An already explored way to overcome this situation is through the reaction of phenylhydrazine with sodium nitrite, which leads to the production of phenylazide (Scheme 1).¹⁵ A methodology with a similar strategy was also developed by Siddiki et al.¹⁶ using hydrazine hydrate and starting from anilines (Scheme 1). In this methodology, nitrite was responsible for the diazotization of aniline and the in situ production of azide when reacting with hydrazine. However, it is common for hydrazine to also be subject to government control, making it difficult to obtain.

Warmuth and Malkoviec¹⁷ used these methodologies for the synthesis of ¹³C₆-phenilazide starting from ¹³C₆-aniline (Scheme 1). Initially, ¹³C₆-aniline was used to produce ¹³C₆-phenylhydrazine hydrochloride by the classical method through diazotization of aniline and reduction of the diazo group with SnCl₂. Phenyl hydrazine then reacted with sodium nitrite in a two-phase system to produce phenyl azide in 55% yield. Although it has already been shown that azidobenzene can be produced via oxidation of phenylhydrazine, this strategy has not yet been seen in the literature being used to produce substituted aryl azides.

Considering the synthetic importance of aromatic azides and the potential difficulty in obtaining sodium azide for their production, this work carried out the optimization of a one-pot methodology for the synthesis of a series of phenylazides starting from anilines and sodium azide-free.

Results and Discussion

The first attempt to produce phenylazide was carried out with what is already available in the literature: initially, diazotization and reduction of the diazo group were carried out, producing phenylhydrazine¹⁷ and then its reaction was carried out with NaNO₂ in a biphasic system (Scheme 2).¹⁵

Scheme 2
First attempt to synthesize phenylazide.

Attempts were made to reproduce this methodology. Although it was possible to obtain phenylhydrazine in yields consistent with those reported in the literature, it was not possible to obtain phenylazide in yields greater than 20%. Therefore, tests were carried out to optimize this methodology. As phenylhydrazine had been obtained in good yield, the focus of optimization was entirely on the step of converting phenylhydrazine to phenylazide. The tests performed are summarized in Table 1.

Table 1
Reaction conditions for the production of phenylazide

entry	Solvent	R-ONO	Equivalents of R-ONO	Yield / %
1	ethyl ether	NaNO2	2	29
2	none	NaNO2	2	N/R
3	dichloromethane	NaNO2	2	46
4	hexane	NaNO2	2	52
5	hexane	NaNO2	3	50
6	hexane	tButONO	2	44
7	hexane	PentONO	2	30
8	hexane	iPrONO	2	63
9	hexane	iPrONO	3	67

In the first optimization attempt, the entire procedure was performed as in the literature,¹⁵,¹⁷ but in a one-pot manner (entry 1), and there was a slight improvement in the yield for obtaining phenyl azide, from 20 to 29%. Next, the reaction was tested without the use of an organic solvent (entry 2), but curiously, the formation of aromatic azide was not detected. This may be due to the better solubility of organic azides in nonpolar solvents. With this result, all the following procedures were also carried out in a one-pot manner. The solvent exchange was performed to study the impact of solvent polarity on the reaction (entries 1, 3, and 4). The solvent formed a two-phase system in the final stage and the best result was obtained with hexane, without any considerable change using 2 or 3 equivalents of NaNO₂. As the best initial result was obtained with a completely non-polar solvent, tests were not carried out with solvents of higher polarities. Next, a study of the impact of the diazotizing agent used was performed. To this end, the protocol was applied using isopropyl nitrite, t-butyl nitrite, and pentyl nitrite. Among the four nitrites used, isopropyl nitrite (entry 8) was the most prominent, with a 63% yield. As with NaNO₂, the use of 3 equivalents of isopropyl nitrite did not show much difference compared to the use of 2 equivalents.

This methodology was applied to the synthesis of other aromatic azides by varying the substituent attached to the aromatic ring (Table 2).

Table 2
Synthesis of aromatic azides without using sodium azide

Synthesized aryl azide	Yield / %
R = H	63
R = 4-Me	33
R = 4-NO2	45
R = 2-Cl-4-NO2	29
R = 2,5-diCl	22
R = 2,4-diCl	66
R = 4-CF3	58
R = 4-F	50
R = 3-OMe	58
R = 4-Cl	66

Using this protocol, it was possible to obtain azides with yields between 22 and 66%. Plausible mechanism for the oxidation of organic hydrazine to organic azide is described in Scheme 3. Based on this mechanism, it was expected that electron-withdrawing groups in the ring would decrease the nucleophilicity of the hydrazine group. This electron-withdrawing effect translated into a decrease in yields, with the exception of derivatives with a chlorine atom in the para position. In fact, aromatic azides with chlorine atoms in the para position had higher yields than azidobenzene. However, the derivative with R = 2,5 diCl, presenting a chlorine atom in the meta position, had the worst yield in the series. Added to the yield of azide bearing R = 3-OMe, this result may suggest that an inductive electron-withdrawing effect at the meta position is in conflict with the reaction mechanism. In the ortho position, as in R = 2,5-diCl and R = 2-Cl-4-NO₂, without the resonance donating effect in the para position, the chlorine atom could be sterically hindering a nucleophilic attack. The inductive donating effect of R = 4-Me was not enough to increase the nucleophilicity of the hydrazine group. Lower yields were also present with resonance electron-withdrawing groups in the para position.

Scheme 3
Plausible mechanism for the synthesis of organic azides.

Considering the results presented in Table 2, it is clear that this methodology is capable of producing aromatic azides regardless of the electronic nature of the substituent. Interestingly, the reaction worked to produce aromatic azides carrying the nitro group. The chemoselectivity of tin II chloride in reducing the diazo group to hydrazine at the expense of reducing the nitro group to amino is probably due to the low temperature used. It is worth noting that although some derivatives presented low yields, the methodology is still useful if it is impossible to obtain sodium azide to perform the conventional methodology.

Conclusions

It was possible to develop a simple and efficient protocol for the synthesis of aromatic azides without using sodium azide and still maintaining anilines as the starting point for the synthesis.

The currently available methodology for the synthesis of aromatic azides requires the use of reagents controlled by government institutions, such as sodium azide and hydrazine hydrate. This control, although extremely necessary, can make research difficult due to the inaccessibility of reagents. The protocol presented in this work does not use such reagents, as the azido group is formed in situ by the oxidation of the hydrazino group.

This strategy had already been used previously, but had not yet undergone any optimization process. Added to this, the methodology already available required additional isolation steps. The same does not occur in this work, as an optimization was carried out so that the entire process occurs in a one-pot manner and, therefore, only requiring purification at the end of the reaction.

Finally, this strategy had not yet been applied with substituted anilines. In this way, it was possible to demonstrate that this protocol is useful not only for the synthesis of azidobenezene, but of many other substituted aromatic azides.

Experimental

The reagents were purchased from Sigma-Aldrich Brazil and were used without further purification. Column chromatography was performed with silica gel 60 (Merck 70-230 mesh). Analytical thin layer chromatography was performed with silica gel plates (Merck, TLC silica gel 60 F254), and the plots were visualized using UV light. Melting points were obtained on a Fischer-Johns apparatus and were uncorrected. Infrared spectra were measured with KBr pellets on a Thermo-Fischer FTIR Nicolet iS-50 (USA). Nuclear magnetic resonance (NMR) spectra were recorded on a Varian VNMRS 500 MHz (USA) instrument in CDCl₃ solutions. The chemical shift data were reported in units of d (ppm) downfield from solvent and was used as an internal standard; coupling constants (J) are reported in hertz and refer to apparent peak multiplicities.

Organic nitrites were produced from their respective alcohols using a methodology already available in the literature.¹⁸,¹⁹

General procedure for the synthesis of aryl azides

In a 50 mL round-bottom flask equipped with a magnetic stirrer, 1.55 mmol of the desired aniline and 5 mL of a 6 M HCl solution were added. The solution was placed in an ice bath. A solution containing 213 mg (3.1 mmol; 2 eq) of NaNO₂ in 5 mL of water was added to the medium dropwise. Still in an ice bath, the mixture was left to stir for 30 min. 2 mL of a 2 M solution of SnCl₂ in concentrated HCl were added to the medium dropwise. Still in an ice bath, the mixture was left stirring for another 1 h. A solution containing 275 mg (3.1 mmol; 2 eq) of isopropyl nitrite in 10 mL of hexane was added to the medium dropwise. Still in an ice bath, the mixture was left stirring for another 1 h. After the end of the reaction, the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethyl acetate (3 × 50 mL) and the combined organic phases were washed with saturated NaCl solution (3 × 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Aryl azides were purified by silica gel column chromatography using hexane as an eluent.

Azidobenzene

Obtained in 63% as a yellow oil; IR (KBr) ν / cm^-1 2123, 2090, 1593, 1461, 1293, 1279, 745, 685, 668; ¹H NMR (500 MHz, CDCl₃) d 7.37 (t, 2H, J 7.9 Hz), 7.16 (t, 1H, J 7.4 Hz); 7.05 (d, 2H, J 7.7 Hz); ¹³C NMR (125 MHz, CDCl₃) d 119.1, 125.0, 129.9, 140.1.

1-Azido-4-methylbenzene

Obtained in 32% as a yellow oil; IR (KBr) ν / cm^-1 2138, 2101, 1505, 1296, 1114, 808; ¹H NMR (500 MHz, CDCl₃) d 7.16-7.14 (m, 2H), 6.94-6.91 (m, 2H), 2.33 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) d 20.9, 119.0, 130.4, 134.7, 137.3.

1-Azido-4-nitrobenzene

Obtained in 45% as a light-yellow solid; mp 65-67 ºC; IR (KBr) ν / cm^-1 2122, 2085, 1590, 1489, 1287, 844, 746; ¹H NMR (500 MHz, CDCl₃) d 8.24 (d, 2H, J 9.0 Hz); 7.14 (d, 2H, J 9.0 Hz); ¹³C NMR (125 MHz, CDCl₃) d 119.5, 125.7, 144.7, 147.0.

1-Azido-2-chloro-4-nitrobenzene

Obtained in 29% as a yellow solid; mp 65-66 ºC; IR (KBr) ν / cm^-1 2127, 2099, 1513, 1342, 1292, 749; ¹H NMR (500 MHz, CDCl₃) d 8.26 (d, 1H, J 2.5 Hz), 8.18 (dd, 1H, J 8.8, 2.5), 7.30 (d, 1H, J 8.8 Hz); ¹³C NMR (125 MHz, CDCl₃) d 119.6, 123.4, 125.7, 126.5, 144.2, 144.5.

2-Azido-1,4-dichlorobenzene

Obtained in 22% as a light-yellow solid; mp 55-56 °C; IR (KBr) ν / cm^-1 2106, 1472, 1291, 1048, 806; ¹H NMR (500 MHz, CDCl₃) d 7.30 (d, 1H, J 8.6 Hz), 7.16 (d, 1H, J 2.3 Hz), 7.06 (dd, 1H, J 2.3 and 8.6); ¹³C NMR (125 MHz, CDCl₃) d 119.9, 123.6, 125.9, 131.6, 133.6, 138.5.

1-Azido-2,4-dichlorobenzene

Obtained in 66% as a yellow oil; IR (KBr) ν / cm^-1 2113, 2059, 1473, 1302, 797; ¹H NMR (500 MHz, CDCl₃) d 7.39 (d, 1H, J 2.3 Hz); 7.27 (dd, 1H, J 8.6, 2.3 Hz), 7.10 (d, 1H, J 8.6 Hz); ¹³C NMR (125 MHz, CDCl₃) d 120.5, 125.8, 128.2, 130.5, 130.6, 136.1.

1-Azido-4-(trifluoromethyl)benzene

Obtained in 58% as an orange oil; IR (KBr) ν / cm^-1 2124, 2100, 1321, 1304, 1285, 1108, 1063, 836, 534; ¹H NMR (500 MHz, CDCl₃) d 7.61 (d, 2H, J 8,7 Hz), 7.12 (d, 2H, J 8.7); ¹³C NMR (125 MHz, CDCl₃) d 119.3, 124 (q, J 271.1), 127.2 (m), 143.9.

1-Azido-4-fluorobenzene

Obtained in 50% as a yellow oil; IR (KBr) ν / cm^-1 2924, 2113, 1504, 1232, 830; ¹H NMR (500 MHz, CDCl₃) d 7.07 6.97 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) d 116.8 (d, J 23.0 Hz), 120.4 (d, J 8.3 Hz), 135.9, 160.1 (d, J 244.5 Hz).

1-Azido-3-methoxybenzene

Obtained in 58% as a yellow oil; IR (KBr) ν / cm^-1 2103, 1600, 1488, 1225, 1038, 761, ¹H NMR (500 MHz, CDCl₃) d 7.25 (t, 1H, J 8.1 Hz); 6.69 (dd, 1H, J 8.3, 2.4 Hz), 6.65 (dd, 1H, J 8.0, 2.1 Hz); 6.55 (t, 1H, J 2.3); ¹³C NMR (125 MHz, CDCl₃) d 55.4, 105.0, 110.8, 111.4, 130.5, 141.4, 160.9.

1-Azido-4-chlorobenzene

Obtained in 66% as a yellow oil; IR (KBr) ν / cm^-1 2126, 2090, 1485, 1293, 1112, 821, 567, 494; ¹H NMR (500 MHz, CDCl₃) d 7.33-7.30 (m, 2H), 6.97-6.94 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) d 120.4, 130.0, 130.3, 138.8.

Supplementary Information

Supplementary data (Figures S1-S30) are available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

Fellowships granted by CNPq, CAPES and FAPERJ are gratefully acknowledged. FAPERJ: E-26/201.318/2021; FAPERJ: E-26/211.068/2019; CNPq: 306892/2022-7.

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Edited by

• Editor handled this article:
  Brenno A. D. Neto

Publication Dates

• Publication in this collection
  03 Feb 2025
• Date of issue
  2025

History

• Received
  11 Oct 2024
• Accepted
  07 Jan 2025