Applications of solid supported azide anion: A one-pot, two-step preparation of functionalized 1,2,3-triazoles

Article abstract of DOI:10.1016/S0040-4039(03)00180-1

Functionalized 1,2,3-triazoles were prepared in a one-pot, two-step synthesis from alkyl halides and alkynes using a polymer supported azide. Two different base resins were examined. The chemistry is suitable for the preparation of combinatorial libraries.

Full text of DOI:10.1016/S0040-4039(03)00180-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2153–2155
Applications of solid supported azide anion: a one-pot, two-step
preparation of functionalized 1,2,3-triazoles
Benjamin E. Blass,a,* Keith R. Coburn,a Amy L. Faulkner,a William L. Seibela and Anil Srivastavab
aProcter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
bChembiotek Research International, Salt Lake, Block BN, /Sector V, Kolkata 700091, India
Received 19 July 2002; accepted 16 January 2003
Abstract—Functionalized 1,2,3-triazoles were prepared in a one-pot, two-step synthesis from alkyl halides and alkynes using a
polymer supported azide. Two different base resins were examined. The chemistry is suitable for the preparation of combinatorial
libraries. © 2003 Published by Elsevier Science Ltd.
Over the past several years, the field of combinatorial
chemistry has established itself as a valuable tool for
drug discovery.1 The synthesis of vast libraries based on
heterocyclic scaffolds, including imidazoles, benzodi-
azepines, diketopiperazines, oxazolidinones, and
quinolones have been reported. As part of our ongoing
efforts to develop novel scaffolds for the preparation of
combinatorial libraries, we have been investigating the
preparation of functionalized 1,2,3-triazoles. Members
of this class of compounds have been identified as
adenosine antagonists, oxalic acid antagonists, metallo-
protease inhibitors, antibacterials, b-lactamase ini-
a-bromo acid (4) and modification to the resin bound
azide (5) was followed by cycloaddition with a suitable
alkyne to produce a resin bound triazole acid. Removal
from the resin was then accomplished using standard
conditions (Scheme 2).4
While both of these methods are effective for the pro-
duction of functionalized triazoles, they both are lim-
ited by the required incorporation of a ‘carboxyl’
functionality to serve as the point of attachment for the
resin. We felt that in order to increase the breadth of
accessible library members of the triazole series, the
presence of a required resin linker would need to be
eliminated. Thus, we have developed a two-step prepa-
ration of substituted 1,2,3-triazoles based on the appli-
cation of both resin bound reagent and cycloaddition
chemistry. In this case, the use of a resin supported
azide allows the use of an excess of this sometimes
volatile reagent without requiring an aqueous work up
to remove the excess azide. Simple filtration of the
reaction removes the excess azide, and the next step can
be performed without purification. Conversion of the
alkyl bromide (6) to the necessary azide (7) can be
hibitors, antivirals and anticonvulsants.2
A brief
literature search identified two solid-phase syntheses of
this class of compounds The first method employs
functionalized, solid supported, b-ketoamides (1).
Enamine formation (2), followed by ring closure with
tosyl azide and TFA induced resin cleavage produced
the desired 1,2,3-triazoles (3, Scheme 1).3
The second method, which has been recently disclosed,
is an alternative solid phase method for the preparation
of 1,2,3-triazoles from readily available bromo acids,
alkynes, and Wang resin. Initial resin loading of an
Scheme 1.
Keywords: solid supported azide; 1,2,3-triazoles; 2+3 cycloaddition.
* Corresponding author. Fax: 513-622-3797; e-mail: blass.be@pg.com
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00180-1

2154
B. E. Blass et al. / Tetrahedron Letters 44 (2003) 2153–2155
Scheme 2.
Table 1. Azide preparation and 2+3 cycloaddition with methyl propiolate

B. E. Blass et al. / Tetrahedron Letters 44 (2003) 2153–2155
2155
Scheme 3.
accomplished with either Amberlite azide ion exchange
resin5 or the more conventional Merrifield resin sup-
ported tetra-alkyl ammonium azide (prepared from the
commercially available polymer supported bromide)6 in
DMA over 72 hours. Removal of the resin by filtration
and then heating the reaction to 80°C in the presence of
1.0 equiv. of methyl propiolate provided the desired
1,2,3-triazole (8) via a 2+3 cycloaddition reaction
(Scheme 3). The products could then be isolated by
simple evaporation of the solvents.7 It is interesting to
note that the while benzyl chloride provide the desired
product in both reasonable yield and purity, the less
reactive b-chlorophenetole did not provide detectable
levels of the desired product. This is in direct contrast
to b-bromophenetole, suggesting that alkyl chlorides
that do not contain an additional activating feature are
not reactive enough under the conditions examined. An
examination of alternative solvents, such as EtOAc,
THF, DMF and 1,4-dioxane, demonstrated that the
reaction did occur, but the best results were obtained
with DMA. Both of the azide resins provided the
desired 1,2,3-traizoles in reasonable yields and purity,
but the Merrifield resin bound azide showed superior
swelling properties which may make it useful for addi-
tional chemistry that is not compatible with the Amber-
lite resin.
Riviere, M. E.; Karolchyk, M. A. Epilepsy Res. 2001, 43,
115–124.
3. Dorwald, F. Z., WO 9740025.
4. Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Hunn, C. L.;
Natchus, M. G.; Parker, M. S.; Portlock, D. E.; Tullis, J.
S.; Wood, R. Tetrahedron Lett. 2002, 43, 4059–4061.
5. Hassner, A.; Stern, M. Angew. Chem., Int. Ed. Engl. 1986,
25, 478.
6. Merrifield resin supported ammonium azide is prepared
from the commercially available polymer supported bro-
mide (3.5 mmol Br/g) as follows: 5.0 g of polymer sup-
ported bromide is suspended in 30 ml of DMA and 5.7 g
of NaN3 (5 equiv.) is added. After 48 h, the reaction is
filtered, washed with methanol, and dried to a solid with
IR showing a significant signal for azide at 2002 cm−1
.
7. Typical experimental procedure: To a suspension of azide
bound resin (250 mg) in DMA (6 ml) is added a halide (50
mg). The mixture is then agitated for 72 h at room
temperature. After the completion of the reaction (TLC),
the resin is filtered off. To the solution is then added
methyl propiolate (1 equiv.) and the reaction is stirred
overnight at 80°C. The solvent is then evaporated and the
desired product is isolated by reverse phase HPLC on a
C18 symmetry column (20×100 mm; 5 mm) using a linear
gradient from 100% water to 100% acetonitrile (0.02%
TFA in both solvents) over 15 min (20 ml/min flow rate).
Spectral data for Table 1: Entry 1 (1H NMR, 300 MHz,
CD3OD): l 3.30 (m, 2H), 3.75 (s, 3H), 4.50 (t, J=6.50 Hz,
2H), 7.09–7.20 (m, 5H), 8.33 (s, 1H). (M+H) 264. Entry 2
(1H NMR, 300 MHz, CD3OD): l 1.01 (d, J=4.0 Hz, 6H),
1.87 (q, J=7.0 Hz, 2H), 2.10 (m, 1H), 3.72 (m, 2H), 3.94
(s, 3H), 8.59 (s, 1H). (M+H) 198. Entry 3 and 4 (1H NMR,
300 MHz, CD3OD): l 3.90 (s, 3H), 5.66 (s, 2H), 7.31 (brs,
5H), 8.54 (s, 1H). (M+H) 218. Entry 5 (1H NMR, 300
MHz, CD3OD): l 1.69 (m, 2H), 2.02 (m, 2H), 2.49 (t,
J=7.30 Hz, 2H), 3.73 (s, 3H), 3.82 (s, 3H), 4.39 (t, J=7.00
Hz, 2H), 8.46 (s, 1H). (M+H) 242. Entry 6 (1H NMR, 300
MHz, CD3OD): l 1.77 (d, J=7.18 Hz, 3H), 3.77 (s, 3H),
5.46 (m, 1H), 6.98 (t, J=3.20 Hz, 1H), 7.34 (t, J=7.50 Hz,
2H), 7.66 (d, J=8.50 Hz, 2H), 8.77 (s, 1H). (M+H) 275.
Entry 7 (1H NMR, 300 MHz, CD3OD): l 3.84 (s, 3H),
3.70 (m, 2H), 4.40 (t, J=5.0 Hz, 2H), 6.82–6.89 (m, 3H),
7.17 (t, J=5.30 Hz, 2H), 8.55 (s, 1H). (M+H) 247. Entry 9
(1H NMR, 300 MHz, CD3OD): l 2.20 (m, 2H), 3.72 (t,
J=7.50 Hz, 2H), 3.93 (s, 3H), 7.06 (m, 1H), 7.40 (d,
J=8.0 Hz, 2H), 7.58 (m, 2H), 8.25 (s, 1H). (M+H) 271.
Entry 10 (1H NMR, 300 MHz, CD3OD): l 1.97 (s, 6H),
3.79 (s, 3H), 4.30 (m, 2H), 5.36 (m, 1H), 8.33 (s, 1H).
(M+H) 196. Entry 11 (1H NMR, 300 MHz, CD3OD): l
1.15 (m, 6H), 3.61 (m, 4H), 3.80 (s, 3H), 3.94 (m, 2H), 4.58
(m, 2H), 8.50 (s, 1H). (M+H) 292. Entry 12 (1H NMR, 300
MHz, CD3OD): l 1.30–1.46 (m, 11H), 1.88 (m, 2H), 3.83
(s, 3H), 4.38 (t, J=7.50 Hz, 2H), 8.38 (s, 1H). (M+H) 238.
In summary, we have developed a simple, two step
method for the preparation of libraries of functional-
ized 1,2,3-triazoles using a solid phase reagent. The
products are obtained in reasonable yields and purity.
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