Efficient conversion of aromatic amines into azides: A one-pot synthesis of triazole linkages

Article abstract of DOI:10.1021/ol070527h

An efficient and improved procedure for the preparation of aromatic azides and their application in the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition ("click reaction") is described. The synthesis of aromatic azides from the corresponding amies i

Full text of DOI:10.1021/ol070527h

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1809-1811
Efficient Conversion of Aromatic
Amines into Azides: A One-Pot
Synthesis of Triazole Linkages
Karine Barral, Adam D. Moorhouse, and John E. Moses*
Department of Pharmaceutical and Biological Chemistry. The School of Pharmacy,
UniVersity of London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom
john.moses@pharmacy.ac.uk
Received March 2, 2007
ABSTRACT
An efficient and improved procedure for the preparation of aromatic azides and their application in the Cu(I)-catalyzed azide−alkyne 1,3-
dipolar cycloaddition (“click reaction”) is described. The synthesis of aromatic azides from the corresponding amines is accomplished under
mild conditions with tert-butyl nitrite and azidotrimethylsilane. 1,4-Disubstituted 1,2,3-triazoles were obtained in excellent yields from a variety
of aromatic amines without the need for isolation of the azide intermediates.
Aromatic azides are versatile intermediates with a diverse
range of applications in organic and bioorganic chemistry,1
with their use as photoaffinity labeling reagents for biomol-
ecules being particularly important.2
ery,6 material science,7 and bioconjugation.8,9 This has
stimulated a demand for readily accessible azide building
blocks, and consequently, a need for reliable and efficient
methods for installing this functional group.
Recently, organic azides have been somewhat popularized
due to their pivitol role in the emerging field of “click
chemistry”,3 and in particular since the discovery of the Cu-
(I)-catalyzed (stepwise) Huisgen4 cycloaddition between
organic azides and terminal alkynes.5
The preparation of alkyl azides is relatively straightfor-
ward,1,10 and can be achieved by simple subsitution using
azide ion and various electrophiles, or by reaction of the
corresponding aliphatic amine with triflyl azide (TfN3).11
A
This powerful and reliable bond-forming process has found
widespread application, e.g., in combinatorial drug discov-
(6) For example see: (a) Moorhouse, A. D.; Santos, A. M.; Gunaratnam,
M.; Moore, M.; Neidle, S.; Moses, J. E. J. Am. Chem. Soc. 2006, 128,
15972-15973. (b) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.;
Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-9589.
(7) For example see: (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker,
C. J.; Scheel, A.; Voit, B.; Pyun, J.; Fre´chet, J. M. J.; Harpless, K. B.;
Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43, 3928-3932. (b) Wu, P.;
Malkoch, M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn, M. G.; Fokin,
V. V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun. 2005, 48, 5775-
5777. (c) Rozkiewicz, D. I.; Jan´czewski, D.; Verboom, W.; Ravoo, B. J.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. 2006, 45, 5292-5296.
(8) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192-3193.
(1) For example see: (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann,
V. Angew. Chem., Int. Ed. 2005, 44, 5188-5240. (b) Scriven, E. F. V.;
Turnbull, K. Chem. ReV. 1988, 88, 297-368.
(2) For reviews on aryl azides as photoaffinity labels and references
therein see: (a) Bayley, H.; Staros, J. V. In Azides and Nitrenes; Scriven,
E. F. V., Ed.; Academic Press: Orlando, FL, 1984; pp 433-490. (b)
Radominska, A.; Drake, R. R. Methods Enzymol. 1994, 230, 330-339. (c)
Fedan, J. S.; Hogaboom, G. K.; O’Donnell, J. P. Biochem. Pharmacol. 1984,
33, 1167-1180.
(3) For recent reviews on click chemistry and references therein see:
(a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004-2021. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today
2003, 8, 1128-1137. (c) Breinbauer, R.; Ko¨hn, M. ChemBioChem 2003,
4, 1147-1149. (d) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur.
J. Org. Chem. 2006, 1, 51-68.
(4) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565-598.
(5) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057-3064. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(9) For example see: (a) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J.
Am. Chem. Soc. 2003, 125, 4686-4687. (b) Speers, A. E.; Cravatt, B. F.
Chem. Biol. 2004, 11, 535-546. (c) Burley, G. A.; Gierlich, J.; Mofid, M.
R.; Nir, H.; Tal, S.; Eichen, Y.; Carell, T. J. Am. Chem. Soc. 2006, 128,
1398-1399.
(10) Sandler, S.; Karo, W. Organic Functional Group Preparations;
Academic Press: New York, 1971; pp 268-284.
(11) For example see: (a) Ruff, J. K. Inorg. Chem. 1965, 4, 567-570.
(b) Cavender, C. J.; Shiner, V. J. J. Org. Chem. 1972, 37, 3567-3569. (c)
Eaton, P. E.; Fisher, A. M.; Hormann, R. E. Synlett 1990, 737-738.
10.1021/ol070527h CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/29/2007

recent modification of the latter method, popularized by
Wong,12 has found numerous applications,13 due to the high
yields and relatively mild conditions of the adapted proce-
dure. However, the synthesis of aryl azides relies upon a
more limited selection of transformations.1b They are com-
monly prepared from the corresponding amines via their
diazonium salts,14 which may sometimes be problematic with
respect to the presence of incompatible functional groups.
Alternative methods have been investigated, for example,
reactions of organometallic aryls (derived from the corre-
sponding aryl halide) with p-tosyl azide.15 More recently,
Liu and Tor have applied Wong’s (TfN3) methodology
toward the efficient preparation of aryl azides.16 Although
powerful, this procedure presents some drawbacks. First,
toxic and potentially explosive NaN3, and the highly reactive
Tf2O are used in excess. Second, TfN3 has been reported to
be explosive when not in solvent, thus presenting further
potential hazards.17 Recently, Das et al. reported the use of
tert-butyl nitrite (t-BuONO) in combination with NaN3 in
the synthesis of aromatic azides.18 This procedure requires
a large excess of reagents (12 equiv of t-BuONO, 3 equiv
of NaN3), which is undesirable considering the hazards
associated with NaN3.
equiv) and TMSN3 (1.2 equiv) at 0 °C, with warming to
room temperature.20 The reaction proceeds smoothly and
rapidly to afford azidobenzene 1 in 93% isolated yield.20
To explore the scope of this reaction, a range of aromatic
amines (2-18) were reacted under the optimized conditions.
Table 1 summarizes the results. Simple anilines containing
inert substituents reacted smoothly to afford the desired
product in high yield (e.g., entry 2). Electron-rich (e.g.,
entries 5 and 6) as well as sterically demanding (e.g., entry
3) anilines also react effectively. In contrast to the related
TfN3 procedure,16 anilines substituted with strong electron-
withdrawing groups react rapidly and with high yields (e.g.,
entries 7, 9, and 10). Interestingly, several aminobenzoic acid
derivatives afforded the desired azides in good yields and
did not require purification (e.g., entries 12-18) (Table 1
and the Supporting Information).
Although organic azides are stable against most reaction
conditions, compounds of low molecular weight tend to be
explosive and are difficult to handle.1 Thus, in the context
of the “click reaction”, procedures which generate azides in
situ, followed by azide-alkyne cycloaddition have become
an attractive option.21
We considered whether our described procedure could be
adapted toward a convenient one-pot synthesis of triazole
linked structures starting from aromatic amines, thus avoiding
the isolation of the azide intermediates. The key to this
procedure was the generation of Cu(I) required for the azide-
alkyne cycloaddition, which was achieved by adding Cu(II)
and a reducing agent after complete diazo transfer.5b
The reaction conditions for a sequential one-pot procedure
were optimized by using aniline as the chosen substrate
(Scheme 2).22 First, the azide transfer was performed as
In this contribution, we disclose a less hazardous and
practical synthesis of aromatic azides from their correspond-
ing amines using stable and non-explosive reagents: tert-
butyl nitrite (t-BuONO) and azidotrimethylsilane (TMSN3).19
Mild reaction conditions and very high yields make this
transformation an attractive option for the straightforward
preparation of numerous aromatic azides.
Scheme 1
Scheme 2
In a typical reaction (Scheme 1), aniline was dissolved in
acetonitrile and reacted in the presence of t-BuONO (1.5
outlined above. After complete consumption of starting
material (TLC), catalytic amount sof CuSO4 (7 mol %),
(12) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6032.
(13) For example see: (a) Ding, Y.; Swayze, E. E.; Hofstadler, S. A.;
Griffey, R. H. Tetrahedron Lett. 2000, 41, 4049-4052. (b) Greenberg, W.
A.; Priestley, E. S.; Sears, P. S.; Alper, P. B.; Rosenbohm, C.; Hendrix,
M.; Hung, S.-C.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 6527-6541.
(14) For a review see: Biffin, M. E. C.; Miller, J.; Paul, D. B. In The
Chemistry of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp
147-176. See also: (b) Takahashi, M.; Suga, D. Synthesis 1998, 7, 986-
990.
(20) Aniline (200 mg, 2.14 mmol) was dissolved in CH3CN (4 mL) in
a 25 mL round-bottomed flask and cooled to 0°C in an ice bath. To this
stirred mixture was added t-BuONO (331 mg, 380 µL, 3.21 mmol) followed
by TMSN3 (300 mg, 340 µL, 2.56 mmol) dropwise. The resulting solution
was stirred at room temperature for 1 h. The reaction mixture was
concentrated under vacuum and the crude product was purified by silica
gel chromatography (hexane) to give the product, 1, as a pale yellow oil
(236 mg, 93%). IR (film) 3062.99, 2124.35, 2093.43, 1593.63, 1491.52,
(15) For example see: (a) Smith, P. A. S.; Rowe, C. D.; Bruner, L. B.
J. Org. Chem. 1969, 34, 3430-3433. (b) Gavenonis, J.; Tilley, T. D.
Organometallics 2002, 21, 5549-5563.
1
1294.58 cm-1. H NMR (CDCl3, 400 MHz) δ 6.96 (dd, J ) 7.6 and 0.7
Hz, 2H), 7.06 (td, J ) 7.6 and 0.7 Hz, 1H), 7.27 (t, J ) 7.6 Hz, 2H). 13C
NMR (CDCl3, 100 MHz) δ 119.0, 124. 9, 129.8, 140. 0. EA calcd for
C6H5N3: C, 60.50; H, 4.23; N, 35.27. Found: C, 60.48; H, 4.27; N, 35.25.
(21) For example see: (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett.
2007, 9, 1-4. (b) Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. Tetrahedron
Lett. 2006, 47, 2383-2385. (c) Yan, R.-B.; Yang, F.; Wu, Y.; Zhang, L.-
H.; Ye, X.-S. Tetrahedron Lett. 2005, 46, 8993-8995. (d) Chittaboina, S.;
Xie, F.; Wang, Q. Tetrahedron Lett. 2005, 46, 2331-2336. (e) Feldman,
A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897-3899. (f)
Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org. Lett.
2004, 6, 4223-4225.
(16) Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571-2572.
(17) Zaloom, J.; Roberts, D. C. J. Org. Chem. 1981, 46, 5173-5176.
(18) Das, J.; Patil, S. N.; Awasthi, R.; Narasimhulu, C. P.; Trehan, S.
Synthesis 2005, 11, 1801-1806.
(19) This combination of reagents has been previously used in large
excess in the synthesis of 2-azidodeoxyadenosine, see: (a) Higashiya, S.;
Kaibara, C.; Fukuoka, K.; Suda, F.; Ishikawa, M.; Yoshida, M.; Hata, T.
Bioorg. Med. Chem. Lett. 1996, 6, 39-42. (b) Wada, T.; Mochizuki, A.;
Higashiya, S.; Tsuruoka, H.; Kawahara, S.-I.; Ishikawa, M.; Sekine, M.
Tetrahedron Lett. 2001, 42, 9215-9219.
1810
Org. Lett., Vol. 9, No. 9, 2007

Table 1. ArN3 Prepared from ArNH2
entrya
R1
R2
R3
R4
R5
reaction time (h)
yield (%)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
CtCH
OCH3
H
H
H
H
H
H
H
CH3
Cl
H
H
H
H
CH-(CH3)2
H
H
H
OCH3
NO2
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
1
1
1
1
2
2
2
2
2
1
2
2
2
2
2
2
2
96
95
84
88
83
76
90
95
96
74
81
83
78
67
65
78
90
CH2-CH3
H
H
H
H
H
H
H
OH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
CH2-CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C(O)CH3
CtN
NO2
H
H
H
I
H
OCH3
H
OCH3
NO2
a See the Supporting Information for procedures and spectral data.
sodium ascorbate (0.2 equiv), and phenylacetylene (1 equiv)
were added directly at room temperature without any workup
procedure. The 1,2,3-triazole product, 19, was obtained in
high yield within a reasonable reaction time.
To investigate the scope of this one-pot protocol, a
selection of aromatic amines were employed using this
methodology (Table 2). In each case, the triazole products
20-23 were isolated in very good yields.22
azides, under very mild conditions, has been described. This
procedure offers advantages over current methodologies in
terms of safety, ease of execution, and efficiency. Moreover,
an efficient one-pot “click-reaction” has been described,
which enabled access to 1,2,3-triazoles without the need to
isolate the corresponding aromatic azide. This procedure
should prove especially useful when unstable low molecular
weight and polyvalent aromatic azides are needed.
In summary, a simple and highly efficient procedure for
the conversion of aromatic amines into their corresponding
Acknowledgment. We thank the EPSRC and AICR for
funding, our colleagues at The School of Pharmacy, Caterina
Lombardo for assistance in synthesis, and Kersti Karu and
Sibylle Heidelberger for providing analytical services.
Table 2. One-Pot Synthesis of 1,2,3-Triazoles from Aromatic
Amines
Supporting Information Available: Detailed experi-
mental procedures for all compounds, and spectral data for
new compounds 13, 14, 16, and 20-23. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL070527H
(22) For example: Aniline (50 mg, 0.54 mmol) was dissolved in CH3-
CN (2 mL) in a 25 mL round-bottomed flask and cooled to 0°C in an ice
bath. To this stirred mixture was added t-BuONO (83 mg, 96 µL, 0.81
mmol) followed by TMSN3 (75 mg, 86 µL, 0.65 mmol) dropwise. The
resulting solution was stirred at room temperature for 2 h. Phenylacetylene
(55 mg, 60 µL, 0.54 mmol), an aq solution (0.2 mL) of CuSO4 (9 mg,
0.027 mmol), and sodium ascorbate (24 mg, 0.108 mmol) were then added
and the reaction was stirred overnight at room temperature. Most of the
solvent was evaporated and the product was then precipitated with methanol
to give the product, 19, as an off-white solid (104 mg, 88%). IR (film)
3062.99, 2372.93, 1597.92, 1502.89, 1480.90 cm-1. 1H NMR (CDCl3, 400
MHz) δ 7.03 (m, 1H), 7.39 (m, 3H), 7.48 (t, J ) 7.6 Hz, 2H), 7.73 (d, J
) 8.0 Hz, 2H), 7.85 (d, J ) 8.0 Hz, 2H), 8.12 (s, 1H). 13C NMR (CDCl3,
100 MHz) δ 117.6, 120.6, 125.9, 128.5, 128.8, 128.9, 129.8, 130.3, 137.1,
148.5. HRMS [ES+] calcd for C14H11N3 222.1031 [M + H]+, found
222.1029. EA calcd for C14H11N3: C, 76.00; H, 5.01; N, 18.99. Found: C,
75.82; H, 4.91; N, 18.72.
a See the Supporting Information for procedures and spectral data.
Org. Lett., Vol. 9, No. 9, 2007
1811