no trace of 8a was found when resin 3a was cleaved with
TFA. The ratio of 10a and 9a, conveniently monitored by
LC-MS, varied depending on exact cleavage conditions, but
10 was found to be the dominating species in all cases when
intermediates 3a-h were analyzed.
The results of this solid-phase procedure applied to a sparse
matrix of alkyl and aryl substituents at all three sites are
shown in Table 1. Anilines at R1 apparently did not generate
intermediate 2 at room temperature, because only 12h could
be recovered. Only a trace of intermediate 3h was observed
when the reaction was carried out in refluxing THF (data
not shown). At R2 and R3, however, both alkyl- and aryl-
type reactants gave crude 3-alkylamino-1,2,4-triazoles in
good purity (Table 1). All products were characterized by
1
HPLC, LC-MS, and HNMR.18 The typical HPLC chro-
matogram of the 3-alkylamino-1,2,4-triazole products is
depicted in Figure 1.
Our initial test reaction with hydrazine (without the use
of additional base) showed the presence of a significant
amount of uncyclized intermediate 11b (R1 ) 4-MeBn, R2
) 4-MePh, R3 ) H) besides 6b after TFA treatment. This
observation is in contrast with the outcome of the solution-
phase procedure, which gave optimal results at room
temperature. However, full conversion of 3a to 4a (using
methylhydrazine) was achieved at either room temperature
or 50 °C with no appreciable formation of intermediate 11a.
No product was detected using phenylhydrazine at either
room temperature or 50 °C. Importantly, when excess base
was added to the reaction mixture, the desired product was
formed with varying purity. The use of DIPEA gave rise to
a large number of byproducts besides the expected triazole,
and potassium tert-butoxide (solution in THF) furnished the
triazole irreproducibly. Species 10, which can arise from
either hydrolysis of 3 or alkylation of the butoxide anion
with concomitant TFA deprotection of the resultant imidate,
was always present in significant amounts. The apparent
yields with DIPEA and KOtBu were always low probably
because of formation and premature release of the 3-benzo-
triazole substituted 1,2,4-triazoles as observed by Katritzky
in solution.13
Gratifyingly, DBU proved to be superior to all other bases
and furnished the desired products in high purity with good
yields. To establish the extent of benzotriazole-substituted
triazole (7d, route B) formation, 4d (prepared with the
optimized procedure) was subjected to acylation with
4-methoxybenzoyl chloride. Approximately 30% of the
amide formed by the resin-bound amine R1 (5) with
p-methoxybenzoyl chloride was detected. Since 3d is made
with an analogous acylating protocol utilizing p-toluoyl
chloride in the previous step, the presence of the p-
methoxybenzamide derivative must be due to the reaction
route leading to 7. The 70/30 partition is significantly better
than previously observed, and thus the use of DBU in the
corresponding solution-phase reactions13 is expected to
improve purities and yields for 3-aminotriazoles.
Figure 1. Typical HPLC chromatogram of crude 3-alkylamino-
triazoles (6c shown) synthesized according to the procedure in
Scheme 1.
The yields were good for reactions where R3 was a methyl
group and moderate for benzylic or aryl hydrazines, a result
of the formation and premature cleavage of the corresponding
3-benzotriazole-substituted 1,2,4-triazole byproducts (7). A
sharp single peak for the correct ion in two different HPLC
methods confirmed complete regioselectivity for the forma-
1
tion of the aminotriazole products. In addition, HNMR
spectra of purified representative analogues 6a and 6f (and
of all other crude 6 triazoles in Table 1) indicated the
presence of a single isomer as well. Aminotriazoles prepared
regioselectively by the similar solution-phase method have
been shown by X-ray crystallography to be the 3-alkylamino
isomers.13
In conclusion, we demonstrated a method for the solid-
phase synthesis of benzotriazole-1-carboximidamides as well
as N-acyl-benzotriazole-1-carboximidamides and the utility
(18) 1H NMR Data for Compounds in Table 1. 6a: 400 MHz, acetone-
d6 δ 7.72 (d, 2H), 7.43 (d, 2H), 7.31 (d, 2H), 7.17 (d, 2H), 4.43 (s, 2H),
3.94 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H). 6c: 400 MHz, DMSO-d6 δ 7.42
(d, 2H), 7.30-7.08 (m, 11H), 5.12 (s, 2H), 4.14 (s, 2H), 2.36 (s, 3H), 2.25
(s, 3H). 6d: 400 MHz, acetone-d6 δ 7.37 (m, 6H), 7.22 (d, 2H), 7.15 (d,
2H), 7.02 (d, 2H), 4.45 (s, 2H), 3.84 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H). 6e:
400 MHz, acetone-d6 δ 3.85 (s, 3H), 3.20 (m, 1H), 3.02 (d, 2H), 2.05-
1.15 (m, 10H), 0.98 (d, 6H), 0.90 (m, 1H). 6f: 400 MHz, DMSO-d6 δ 7.41
(s, 5H), 5.55 (s, 2H), 3.30 (m, 1H), 3.04 (d, 2H), 1.90-1.60 (m, 6H), 1.43-
1.23 (m, 4H), 0.98 (d, 6H), 0.90 (m, 1H). 6g: 400 MHz, acetone-d6 δ 7.58
(d, 2H), 7.15 (d, 2H), 3.93 (s, 3H), 3.08 (d, 2H), 2.88 (m, 1H), 2.00-1.63
(m, 6H), 1.287 (m, 4H), 0.98 (d, 6H), 0.90 (m, 1H).
(17) StratoSpheres PL-FMP (4-formyl-3-methoxyphenoxymethyl) resin
was used for all solid-phase procedures. Intermediate 3 was prepared as
follows. Resin 1 (0.025 mmol) and Bt1C(dNH)Bt1+Bt1C(dNH)Bt2 (20
mg, 0.075 mmol) in THF (1 mL) was flushed with argon and tumbled
overnight at room temperature. The resin was filtered and washed with
THF (3×) and dichloromethane (3×) to give resin 2. To resin 2 (0.025
mmol) was added dichloromethane (1 mL), DIPEA (44 µL, 0.25 mmol),
and R2COCl (0.125 mmol). The mixture was tumbled overnight at room
temperature. The resin was filtered and washed with dichloromethane (3×),
2-propanol (3×), and dichloromethane (3×) to give resin 3.
Org. Lett., Vol. 4, No. 10, 2002
1753