Preparation of aryl azides from aromatic amines in N-methyl-2-pyrrolidonium bisulfate

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Preparation of Aryl Azides from Aromatic
Amines in N-Methyl-2-Pyrrolidonium
Bisulfate
Abdol Reza Hajipour a b & Fatemeh Mohammadsaleh a
a Pharmaceutical Research Laboratory, Department of Chemistry ,
Isfahan University of Technology , Isfahan, 84156, Iran
b Department of Pharmacology, University of Wisconsin Medical
School , 1300 University Avenue , Madison, WI, USA 53706-1532
Published online: 06 Oct 2011.
To cite this article: Abdol Reza Hajipour & Fatemeh Mohammadsaleh (2011) Preparation of
Aryl Azides from Aromatic Amines in N-Methyl-2-Pyrrolidonium Bisulfate, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 43:5, 451-455, DOI:
10.1080/00304948.2011.613695
To link to this article: http://dx.doi.org/10.1080/00304948.2011.613695
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Organic Preparations and Procedures International, 43:451–455, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.613695
Preparation of Aryl Azides from Aromatic Amines
in N-Methyl-2-Pyrrolidonium Bisulfate
Abdol Reza Hajipour1,2 and Fatemeh Mohammadsaleh1
1Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology Isfahan 84156, Iran
2Department of Pharmacology, University of Wisconsin Medical School,
1300 University Avenue, Madison, WI, USA 53706-1532
Azides are useful intermediates for the synthesis of organic and bioorganic compounds.1–6
Azidonucleosides have attracted tremendous interest for the treatment of AIDS.7 In ad-
dition, due to their relatively high stability, aromatic azides have found biological8,9 and
industrial use as photoaffinity labels,10,11 as cross-linkers in photoresistors,12 for conducting
polymer films,13 and for light-induced activation of polymer surfaces.14 Aromatic azides
are generally prepared by treatment of diazonium salts with sodium azide, the most com-
monly used azide source. Aromatic diazonium salts are important intermediates not only in
classical organic synthesis but also in the preparation of organic compounds such as organic
nano-compounds and in the grafting of organic molecules onto metallic or non-metallic
surfaces.15–18 Therefore, the devel-opment of safe and mild conditions for the preparation
of azides is a useful area of investigation.
The most commonly used procedure for the process of diazotization–azidation is
usually carried out in two steps; diazotization of the amine with sodium nitrite at low
temperatures in hydrochloric or sulfuric acid, and subsequent treatment with azide ion.19
Usually this method must be carried out below 10◦C to prevent phenol formation as a
by-product in aqueous media. In continuation of our effort to develop efficient methods
in organic synthesis,20–24 we recently reported one-pot methods for azidation of aromatic
compounds25 by a diazotization-azidation sequence. In the present work, we have developed
an efficient and simple method for the diazotization and azidation of aromatic amines using
the acidic ionic liquid N-methyl-2-pyrrolidonium bisulfate ([H-NMP]HSO4) as solvent and
a novel proton source for the diazotization process at room temperature.
The diazotization of various aryl amines was easily carried out by grinding of the
appropriate aromatic amine, NaNO2 and acidic ionic liquid in the presence of a little water
at room temperature. The mild reaction conditions, simple work-up and high yields led us
to choose this method for the preparation of numerous aromatic azides (Scheme 1).
Received March 21, 2011; in final form May 6, 2011.
Address correspondence to Abdol Reza Hajipour, Pharmaceutical Research Laboratory, Depart-
ment of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran. E-mail: haji@cc.iut.ac.ir
451

452
Hajipour and Mohammadsaleh
Me
H
N
O
HSO4
1.
Ar NH2
Ar N3
2. NaNO2 , r.t
3. NaN3
Scheme 1
The ionic liquid [H-NMP]HSO4, was synthesized by reaction of 1-methylpyrrolidin-
2-one with H2SO4 in a 1:1 molar ratio. Although the Bro¨nsted acidity is one of the key
properties of Bro¨nsted acidic ILs, very little research has been conducted into this field.26
Different techniques have been employed to measure the acidity of these ionic liquids.27–29
The pKa value of [H-NMP]HSO4 was determined by titration with NaOH. Despite the
presence of two acidic protons in the structure of the ionic liquid, only one deprotonation
step appeared on the pH-metric titration diagram and a pKa value of 1.65 was obtained.
The acidic protons appears as a single signal in the 1H NMR (500 MHz, DMSO) spectrum
of the ionic liquid. Based on these results, it seems that there is a very rapid exchange
between these protons.
This acidic ionic liquid was employed successfully for the synthesis of various aryl
diazonium salts starting from the corresponding aryl amines. The prepared aryl diazonium
salts were transformed in high yields to aryl azides in the presence of azide ion (Table 1).
Table 1
a,b
Synthesis of Aryl Azides from Aromatic Amines using [H-NMP]HSO4
Entry
Substrate
Product
Yield
(%)
bp./mp (lit.)
(◦C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4-HO2CC6H4NH2
4-O2NC6H4NH2
2-O2NC6H4NH2
4-NCC6H4NH2
3-O2NC6H4NH2
4-IC6H4NH2
4-HO2CC6H4N3
4-O2NC6H4N3
2-O2NC6H4N3
4-NCC6H4N3
3-O2NC6H4N3
4-IC6H4N3
97
91
90
85
84
86
78
80
95
64
60
96
94
92
188–190 (190)30
70–72 (70-71)31
52–53 (51-53)32
60–62 (56-59)33
59–60 (55-56) 34
oil33
4-BrC6H4NH2
4-BrC6H4N3
Oil (20)35
4-MeCOC6H4NH2
4-PhCOC6H4NH2
2,3-(Me)2C6H4NH2
2-HO2CC6H4NH2
H2NC6H4SO2C6H4NH2 N3C6H4SO2C6H4N3
H2NC6H4OC6H4NH2
C6H5NH2
4-MeCOC6H4N3
4-PhCOC6H4N3
2,3-(Me)2C6H4N3
2-HO2CC6H4N3
40–41 (40-45)33
70–72 (70-71)31
Oil35
145–147 (147–148)36
153–154 (154–155)37
70–72 (67–68)37
53–54 (53–54.5)38
N3C6H4OC6H4N3
C6H5N3
aThe yields refer to the isolated pure products.
bThe products were characterized from their spectral (IR, 1H NMR).

Preparation of Aryl Azides from Aromatic Amines
453
The reactions were accomplished at room temperature in an aqueous medium and in
the air without phenol formation as a by-product. Attempts to prepare the diazide from
4-aminoaniline were unsuccessful; however in the cases of bis-(p-aminophenyl)sulfone
and bis-(p-aminopheny)ether, it was possible to produce the bis azides (Table 1, Entries 12
and 13) in high yields. The optimal molar ratio for amine/sodium nitrite/[H-NMP]HSO4
and NaN3 was found to be 1:2.5:4:2.5 and for the diamines the ratio was 1:5:8:5. The most
important advantages of this diazotization-azidation method are simplicity, short reaction
times, straightforward work-up, high yields and production of pure azide without further
purification.
The stability of the intermediate aryldiazonium salts prepared using [H-NMP]HSO4
was studied and it was found that keeping the aryldiazonium salts at room temperature for
more than 1 hr, led to lower yields of aryl azides; however, storage of these compounds at
0◦C temperature for longer period (up to 7 days) did not lower the overall yields.
We observed that all the aryldiazonium obtained employing this procedure were safe
and non-explosive, this may be because the reactivity of these aryldiazonium salts decreases
whentheyaregenerateinionicliquids. Therefore, ourdiazotization-azidationmethodissafe
and grinding of these aryldiazonium salts in a mortar is not hazardous under our laboratory
conditions. In contrast to traditional methods, the diazotization-azidation reaction rate
increases using this procedure because these aryldiazonium salts are more stable, however,
we recommend carrying the reaction under hood. To evaluate the method and its safety, we
scaled up the preparation of phenyl azide from aniline to 100 mmol without any explosion
or decreased yield.
In conclusion, we have developed an efficient and simple method for the diazotization
and azidation of aromatic amines using the acidic ionic liquid [H-NMP]HSO4 as a novel
proton source for the diazotization process at room temperature. The resulting diazonium
salts are relatively stable and react rapidly with sodium azide to produce aryl azides in
high yields. The diazonium salts prepared may be kept at 0◦C for several days without
decomposition.
Experimental Section
All chemical reagents were purchased from Merck and were used without purification.
1H-NMR spectra were recorded on a Bruker 500 spectrometer using TMS as an internal
standard in CDCl3 and FT-IR spectra were obtained as KBr pellets on a JASCO 680-PLUS
spectrophotometer. UV spectra were obtained by a JASCO V-570 UV spectrophotometer.
Melting points were determined with a Gallenkamp melting apparatus and are uncorrected.
Preparation of Acidic ([H-NMP]HSO4)
In a 25-mL round bottom flask a mixture containing 0.97 ml (10 mmol) of 1-methyl-2-
pyrrolidone in dichloromethane (15 ml) was cooled in ice with stirring. Then 0.53 ml of
sulfuric acid (10 mmol) was added dropwise to the reaction mixture within 10 min and
the mixture was stirred for 4 h at room temperature. The dichloromethane was removed
under reduced pressure using a rotary evaporator and the product was dried at 70◦C under
vacuum for 1 h to afford the product as an oil in quantitative yields. 1H NMR (500 MHz,

454
Hajipour and Mohammadsaleh
DMSO): δ 1.86 (m, 2H, CH2), 2.16 (t, 2H, CH2), 2.65 (s, 3H, CH3), 3.27 (t, 2H, CH2), 9.15
(s, H). 13C NMR (500 MHz, D2O): δ 22.22 (CH2), 35.09 (CH2), 42.10–43.51 (CH2, CH3),
180 (C O) ppm. FT-IR: 2300–3600, 1660, 1509, 1302, 1114, 962, 610 cm−1
.
Determination of pKa of the Acidic Ionic Liquid
A 0.1 mol L−1 solution of N-methyl-2-pyrrolidonium bisulfate [H-NMP]HSO4 was pre-
pared in a volumetric flask, then was titrated with aqueous NaOH solution (0.05 mol L−1).
The pH of the solution was measured using a calibrated glass electrode on pH meter at
25◦C. The pKa value was calculated from the pH/ V graph.
General Procedure for the Preparation of Aryl Azides
An aromatic amine (1 mmol) was ground in a mortar with 2 ml of water and the acidic
ionic liquid (4 mmol, 0.79 g) for 1 min. Then NaNO2 (2.5 mmol, 0.175 g), was added and
the mixture was ground for 15–20 min with periodic grinding using a pestle. Then, NaN3
(2.5 mmol, 0.163 g) was added to the diazonium salt, and grinding continued for 5–10 min
until gas evolution was completely stopped. The azidation reaction began immediately after
NaN3 addition, and the reaction mixture volume increased due to the evolution of nitrogen
gas. The product paste was treated with water and the precipitated aryl azide products
were collected and dried. The liquid azides were extracted with petroleum ether (3 ×
20 mL). The solid aryl azides were washed with 10% HCl solution to produce the pure
azides without further purification. The grinding of aryl azides using this procedure is safe
and all of the reactions were carried out under fume hood.
Acknowledgments
We gratefully acknowledge the funding support received for this project from the Isfa-
han University of Technology (IUT), IR Iran. Further financial support from Center of
Excellence in Sensor Research (IUT) is gratefully acknowledged.
References
1. B. Stefan and B. Klaus, Organic Azides: Syntheses and Applications, John Wiley & Sons, New
York, 2010.
2. Wu Xinghua and Hu Longqin, J. Org. Chem., 72, 765 (2007).
3. S. Revital and R. Shlomo, Org. Lett., 7, 2177 (2005).
4. E. F. V. Scriven and K. Turnbull, Chem. Rev., 88, 297 (1988).
5. B. E. Blass, K. R. Coburn, A. L. Faulkner, W. L. Seibel and A. Srivastava, Tetrahedron Lett., 44,
2153 (2003).
6. Z.-X. Wang and Z.-G. Zhao, J. Heterocycl. Chem., 44, 89 (2007).
7. T. S. Lin and W. H. Prusoff, J. Med. Chem., 21, 109 (1978).
8. R. A. Abramovitch and B. A. Davis, Chem. Rev., 64, 149 (1964).

Preparation of Aryl Azides from Aromatic Amines
9. G. B. Schuster and M. S. Platz, 18, 69 (1992).
455
10. S. X. Cai, D. J. Glenn, K. R. Gee, M. D. Yan, R. E. Cotter, N. L. Reddy, E. Weber and J. F. W.
Keana, Bioconjugate Chem., 4, 545 (1993).
11. M. S. Platz, Photochem. Photobiol., 65, 193 (1997).
12. S. X. Cai, D. J. Glenn, M. Kanskar, M. N. Wybourne and J. F. W. Keana, Chem. Mater., 6, 1822
(1994).
13. E. W. Meijer, S. Nijhuis and F. C. B. M. Vroonhoven, J. Am. Chem. Soc. 110, 7209 (1988).
14. P. Nahar, N. M. Wali and R. P. Gandhi, Anal. Biochem. 294, 148 (2001).
15. A. Roglans, A. Pla-Quintana and M. Moreno-Manas, Chem. Rev., 106, 4622 (2006).
16. H. Zollinger, in The Chemistry of Amino, Nitroso, Nitro and Related Groups, S. Patai, Ed.; Wiley
& Sons: New York, 1996.
17. T. I. Godovikova, O. A. Rakitin and L. I. Khmelnitskii, Russ. Chem. Rev., 52, 440 (1983).
18. A. A. Rostami and M. T. McDermott, J. Surf. Sci. Nanotech., 4, 419 (2006).
19. B. S. Furniss, A. J. Hannaford, P. W. G. Smith and A. R. Tatchell, Vogel’s Textbook of Chem.
Practical Organic Chemistry, Fifth Ed., John Wiley & Sons, New York, 1989.
20. S. Mallakpour, A. R. Hajipour and K. Faghihi, Polymer Int., 49, 1383 (2000).
21. A. R. Hajipour, F. Rafiee and A. E. Ruoho, Synlett, 1118 (2007).
22. A. R. Hajipour, G. Azizi and A. E. Ruoho, Synlett, 1974 (2009).
23. A. R. Hajipour, L. Khazdooz and A. E. Ruoho, J. Chin. Chem. Soc., 56, 398 (2009); Chem.
Abstr., 151, 550259 (2009).
24. A. R. Hajipour, Y. Ghayeb, N. Sheikhan and A. E. Ruoho, Synlett, 741 (2010).
25. A. Zarei, A.R. Hajipour, L. Khazdooz and H. Aghaei, Tetrahedron Lett., 50, 4443 (2009).
26. T. L. Greaves and C. J. Drummond, Chem. Rev., 108, 206 (2008).
27. Z. Fei, D. Zhao, T. J. Geldbach, R. Scopelliti and P. Dyson, Chem. Eur. J., 10, 4886 (2004).
28. S. A. Siddiqui, T. M. Potewar, R. J. Lahoti and K. V. Srinivasan, Synthesis, 2849 (2006).
29. S. Palimkar, S. S. Siddiqui, T. Daniel, R. J. Lahoti and K. V. Srinivasan, J. Org. Chem., 68, 9371
(2003).
30. J. H. Boyer, J. Org. Chem., 23, 127 (1958).
31. T. Keumi, T, Umeda, Y. Inouf and H. Kitajima, Bull. Chem. Soc. Jpn, 62 (1989)
32. P. A. S. Smith, Org. Synth., 31, 14 (1951).
33. K. D. Grimes, A. Gupte, and C. C. Aldrich, Synthesis, 1441 (2010).
34. A. Hubbad, J. Org. Chem., 73, 316 (2008).
35. J. Zhao and Z. Qing., Bioorg. Med. Chem. Lett., 20, 6222 (2010).
36. S. S. More, D. Shanmaghapriya, Y. Lingam and N. B. Pater, Synth. Commun., 39, 2058 (2009).
37. J. R. Thomas, Y. Liu and P. J. Hergenrother, J. Am. Chem. Soc., 127, 12434 (2005).
38. J. H. Boyer and L. R. Morgan Jr., J. Org. Chem., 24, 561 (1959).