Scheme 1
Wang resin and its preliminary use in the synthesis of a
variety of trisubstituted 1,2,4-triazoles.
(i) neat hydrazine hydrate (99%) at room temperature, (ii)
hydrazine hydrate (99%) in dioxane (15% v/v) or (iii) glycol
(1:1) at 90 °C, (iv) hydrazine hydrate (99%) in DMF (1:1)
at room temperature. Of all the conditions tried, hydrazine
hydrate (99%) in 2-methoxyethanol (1:1) at 90 °C gave the
best result in terms of yield (>95%), purity (93-97%), and
reproducibility. The reaction is usually complete after 3 days;
however, we obtained almost the same results for the 7 day
reaction, which demonstrates that the reaction products are
stable on the resin under these conditions.
Synthesis of 1,2,4-Triazole Linker on Wang Resin.
Several synthetic routes for the preparation of 1,2,4-triazoles
6
in the solution phase are documented. Considering the
relatively milder reaction conditions and greater availability
6
b
of starting materials, we utilized Meckler et al.’s method
as a three-step procedure (Scheme 1). Acid-labile Wang resin
was selected as the solid support. After each step, the product
was cleaved from the resin and analyzed by HPLC, GCMS,
or NMR to determine the reaction process.7
Resin 3 was reacted with benzamidine, using sodium
methoxide as catalyst in 2-methoxyethanol at 100 °C to
produce triazole resin 4a. Samples of the resin were
frequently cleaved, and the resulting mixture was analyzed
by HPLC (comparing to authentic sample made via solution-
Resin 2 was easily prepared from Wang resin and methyl
p-hydroxybenzoate (1), via a Mitsunobu reaction (Scheme
8
1
), in quantitative yield and 100% purity (according to GC
analysis of the mixture after cleavage). Both diisopropyl
azodicarboxylate (DIAD) and diethyl azodicarboxylate
6
b
phase chemistry ) and LC/MS (ESI). It was found that
adding 4 Å molecular sieves as a water scavenger facilitates
(
DEAD) were used successfully in this reaction.
1
0
Conversion of ester resin 2 into acyl hydrazide resin 39
the cyclization process. Under these conditions, the ex-
pected triazole 5a was obtained in a quantitative overall mass
yield of product mixture based on the original loading of
the Wang resin, in 85% purity. We also found that the use
of freshly made acyl hydrazide resin 2 (less than 2 days old)
gave much better results than using resin stored for a longer
time (about 2 weeks). In a similar manner, 3-nitrobenz-
amidine was treated with acyl hydrazide resin 3 to give
was attempted under various reaction conditions, including
(5) While this paper was in the internal review process, our group and
others prepared benzotriazole on solid support, as well as the solid-phase
synthesis of 3-thio-1,2,4-triazoles, see: (a) Katritzky, A. R.; Belyakov, S.
A.; Tymoshenko, D. O. J. Comb. Chem. 1999, 1, 173. (b) Schiemann, K.;
Showalter, H. D. H. J. Org. Chem. 1999, 64, 4972. (c) Paio, A.; Zaramella,
A.; Ferritto, R.; Conti, N.; Marchioro, C.; Seneci, P. J. Comb. Chem. 1999,
1
, 317. (d) Wilson, M. W.; Hernandez, A. S.; Calvet, A. P.; Hodges, J. C.
Mol. DiVersity 1998, 3, 95.
6) (a) Temple, C., Jr. The Chemistry of Heterocyclic Compounds, Vol.
7; Montgomery, J. A., Ed.; 1981; p 41. (b) Francis, J. E.; Gorczyca, L.
(
(10) Preparation of Triazole Resin 5a. (i) Twenty bags of Wang resin
(loading 0.86 mmol/g, 100 mg/bag) were suspended in N-methylmorpholine
(NMM, 160 mL). Methyl p-hydroxybenzoate (40 mmol) was added and
dissolved in NMM, followed by Ph3P (40 mmol) and DIAD (40 mmol) at
0 °C. After the mixture was shaked at room temperature for 24 h, the tea
bags were washed with DMF (2 × 50 mL), MeOH (50 mL), DMF (50
mL), MeOH (50 mL), CH2Cl2 (50 mL), MeOH (50 mL), and CH2Cl2 (2 ×
50 mL) and dried under vacuum to give ester resin 2. (ii) Ten bags of resin
2 and NH2NH2‚H2O (99%, 30 mL) in 2-methoxyethanol (30 mL) were
stirred at 90 °C for 3 days. The resin was then washed with MeOH (2 ×
50 mL), CH2Cl2 (50 mL), MeOH (50 mL), and CH2Cl2 (2 × 50 mL) and
dried under vacuum to afford acyl hydrazide resin 3. (iii) Ten bags of resin
3 were added to a solution of benzamidine (40 mmol) in 2-methoxyethanol
(80 mL), followed by 4 Å molecular sieves (7 g). The tea bags were heated
at 100 °C for 7 days, washed as for resin 2, and dried to give triazole resin
4a.
3
A.; Mazzeuga, G. C.; Meckler, H. Tetrahedron Lett. 1987, 28, 5133. (c)
Kosmrlj, J.; Kocevar, M.; Polanc, S. Synlett 1996, 652.
(7) Resin cleavage conditions: 20% TFA/CH2Cl2 (v/v) at room tem-
perature for 30 min. HPLC conditions: reverse phase column (ODS-3);
UV detector at 210 nm. Mobile phase: 70% CH3CN-30% H2O-0.1%
TFA.
(8) (a) Hughes, D. L. Org. React. 1992, 42, 355. (b) Richter, L. S.; Gadek,
T. R. Tetrahedron Lett. 1994, 35, 4705. (c) Rano, T. A.; Chapman, K. T.
Tetrahedron Lett. 1995, 36, 3789. (d) Krchnak, V.; Flegelova, Z.; Weichsel,
A. S.; Lebl, M. Tetrahedron Lett. 1995, 36, 6193.
(9) An alternative route for the synthesis of resin 3 was also tried.
However, the Mitsunobu reaction between Wang resin and 4-hydroxyben-
zoic hydrazide in DMSO/NMM gave a complex mixture, according to
HPLC analysis.
1190
Org. Lett., Vol. 1, No. 8, 1999