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N. Yu. Gorobets et al. / Tetrahedron Letters 51 (2010) 2095–2098
determined based on the differences in NOESY correlations of the
methyl group at position 13. In the case of the compound 7c, cor-
relations were observed with the protons of the aryl ring, while for
7b such correlations are absent (Fig. 2, see Supplementary data for
details).
Next we investigated the application of different carbonyl com-
pounds. Thus, 16 h of stirring of an equimolar mixture of salicylic
aldehyde and 3-amino-1,2,4-triazole with 1.1 equiv of ethyl aceto-
acetate in the presence of 0.1 equiv of HCl (solution in dioxane) in
absolute ethanol resulted in the formation of dihydroxy derivative
10a (Fig. 2) that was isolated in a yield of 67% after precipitation
(conditions (a) of Scheme 2 were applied). In this case absolute
ethanol was used instead of methanol to avoid transesterification.
The relative configuration at the stereocenters was assigned by
NMR as being 5R,6S,7S. Compound 10a was observed to slowly un-
dergo isomerization into diastereoisomer 10b (5R,6R,7S) in DMSO-
d6 solution during NMR-measurement.9
When 3-acetyl-dihydrofuran-2(3H)-one was used in this Bigi-
nelli-like multicomponent reaction (MeOH, 0.1 equiv of HCl,
40 °C, 16 h) a regio- and stereoselective formation of the spiro-
pyrimidine 11 was observed which could be isolated in 71% yield.9
In summary, we can conclude that for the investigated exam-
ples the 3-amino-1,2,4-triazole behaves differently compared to
other aminoazoles in the Biginelli-like multicomponent reaction.
The aldehyde component reacted with the exocyclic aminogroup
of the 3-amino-1,2,4-triazole instead of the endocyclic nitrogen
of the triazole ring. Optimized reaction conditions were obtained
under conventional and microwave heating using salicylic alde-
hydes. An efficient microwave-assisted procedure was developed
to generate the corresponding oxygen-bridged compounds.
Scheme 2. Products formed depending on the applied conditions: (a) MeOH, HCl
(4 N in dioxane), 40 °C, 16 h; (b) EtOH, HCl (4 N in dioxane), MW 150 °C, 30 min.
(structure as depicted in Scheme 2) was obtained in a low yield of
25% next to the imine 4 (Fig. 1) as the major side compound, while
under microwave irradiation at a ceiling temperature of 170 °C for
30 min the oxygen-bridged compound 6a (structure as depicted in
Scheme 2) was formed in 29% yield. Clearly, in both cases, the alde-
hyde component reacted with the exocyclic aminogroup of the 3-
amino-1,2,4-triazole instead of the endocyclic nitrogen of the tria-
zole ring (Scheme 2). Also when preformed imine 4 (Fig. 1) was
used as the starting material, the same reaction pattern was ob-
served. Intrigued by this observation we tried to optimize the reac-
tion conditions (Table 1). To exclude water from the reaction
mixture a dioxane solution of HCl was used (4 N) while the reac-
tion was performed in methanol at 40 °C for 16 h. A moderate yield
of 60% was obtained for compound 5 when 0.1 equiv of HCl was
used (Table 1). As recorded in our preliminary experiments, oxygen
bridge formation requires higher temperatures, and therefore the
synthesis of 6a was optimized using microwave irradiation. The
reaction was performed in ethanol with 0.3 equiv of HCl (4 N in
dioxane) and upon microwave irradiation at a ceiling temperature
of 150 °C and a maximum power of 300 W for 30 min to yield the
desired compound 6a in 47 % yield (Scheme 2). Interestingly when
water compatible Lewis acids8, for example, Yb(OTf)3 and Sc(OTf)3
(1.0–15 mol %) were used, lower yields were obtained. The scope
and limitations of the optimized microwave-assisted protocol were
further evaluated for the synthesis of oxygen-bridged compounds
2. Experimental section
2.1. Synthesis of (5R,7S)-5-(2-hydroxyphenyl)-7-methyl-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-7-ol (5)
Scheme 2, Reaction conditions (a): To a mixture of salicylic
aldehyde (15 mmol), 3-amino-1,2,4-triazole (15 mmol), and ace-
tone (45 mmol, 3.3 mL) in MeOH (15 mL) in a sealed round-bot-
tomed flask, HCl (1.5 mmol, 0.38 mL, 4 N solution in dioxane)
was added. The mixture was stirred at 40 °C for 16 h, then cooled
to room temperature, and the precipitate was filtered off, washed
with MeOH (5 mL) and ether (3 Â 5 mL), and dried. The compound
was obtained in 60% yield. The compounds 10a and 11 were
6b–g applying
a number of commercially available salicylic
aldehydes (Table 2). Yields ranging between 33% and 51% were
obtained upon precipitation next to an array of unidentified side
compounds being present in the mother liquor. Under similar reac-
tion conditions butan-2-one afforded a mixture of three isomers
7a–c obtained in 42 % yield in a ratio 3:3:1 for 7a:7b:7c, as was
established by LC/MS (Fig. 2). These compounds could be separated
by preparative HPLC. With 3-methylbutan-2-one and 4-methyl-
acetophenone the corresponding bridged compounds 8 and 9 were
formed, although they were isolated upon precipitation in rather
poor yields of 25% and 21%, respectively, due to incomplete
reaction and imine formation.
Table 2
Microwave-assisted synthesis of oxygen-bridged heterocycles 6a–g
8
R
The structures of compounds 5 and 6c were proven via single
crystal X-ray diffraction study, clearly showing that for compound
5 the aromatic ring and the methyl group are cis-orientated
(Fig. 3). The structures of the diastereoisomers 7b and 7c were
9
7
6a-g
10
11
13
6
O
12
HN
5
1N
2
N
Table 1
Me
Variation of the catalyst amounts in the synthesis of 5 and 6b under conditions (a)
and (s) correspondingly
N
3
Product
R
Isolated yield (%)
Reaction conditions (a)
Reaction conditions (b)
6a
6b
6c
6d
6e
6f
H
47
47
51
33
50
49
50
Entry HCl in dioxane (4 N
solution) (equiv)
Yield Entry HCl in dioxane (4 N
Yield
(%)
7-MeO
7-EtO
8-MeO
9-Me
9-Cl
(%)
solution) (equiv)
1
2
3
4
0.05
0.1
0.3
55
60
47
23
1
2
3
4
0.1
0.3
0.5
1.0
41
47
34
0
0.5
6g
9-Br
Gorobets, Nikolay Yu.
