Y. Xu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Optimization of reaction conditions.a
Entry
Catalyst
Solvent
Temp
Time
Yieldb
1
2
3
4
5
6
7
8
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
Xylene
DMSO
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
130 °C
Reflux
Reflux
Reflux
12 h
12 h
12 h
8 h
5.4 h
12 h
6 h
6.2 h
9.9 h
12 h
12 h
12 h
12 h
88%
27%
70%
92%
96%
80%
96%
96%
91%
NRc
NRc
47%
63%
Na2CO3 (0.3 eq)
HCl (0.3 eq)
HMDS (0.3 eq)
I C (0.3 eq)e
Imidazole (0.3 eq)
I C (0.2 eq)e
I C (0.1 eq)e
I C (0.05 eq)e
I C (0.1 eq)e
I C (0.1 eq)e
I C (0.1 eq)e
I C (0.1 eq)e
9
10
11d
12d
13d
a
b
c
Reactions were carried out with 2-hydrazinylpyridine (0.1 g, 0.9 mmol, 1 equiv) and DMF (2 mL).
Isolated yield.
No reaction.
DMF (0.46 mL, 6 mmol, 1.2 equiv) and solvent (5 mL).
Imidazolium chloride.
d
e
by the literature reported catalytic effect of imidazolium
hydrochloride in the preparation of 1H-benzo[d]imidazole [16],
the same reagent is added to our system. Gladly, we observed an
improved reaction yield as well as reduced reaction time to 6 h.
Further optimization the amount of imidazolium hydrochloride
confirmed 0.1 equiv catalyst afforded up to 96% cyclization yield
(entry 5–10, Table 1). Alternatively, hexamethyldisilazane (HMDS)
was also investigated to probe its effect on the reaction. The
expected catalytic effect was obvious as demonstrated by 92% yield
(entry 4, Table 1), while longer reaction time compromised HMDS
as the optimal catalyst. Notably, lower reaction temperature from
DMF reflux to 130 °C could not produce any trace amount of pro-
duct formation. Finally, when the reaction was carried out in other
solvents such as toluene, xylene, and DMSO, with 1.2 equiv. of
DMF, zero to low yield were detected (entry 11, 12 and 13, Table 1).
Consequently, our optimized cyclization reaction condition was
using 10 mol % of imidazolium hydrochloride, DMF as reactant
and solvent, at 153 °C close to stoichiometric conversion of 2-
hydrazinylpyridine to 1,2,4-triazolo[4,3-a]pyridine could be
achieved within several hours.
Next, the substitute tolerance on the pyridine ring was investi-
gated. It was delighted to see both electron-withdrawing groups
(3b–3h, Table 2) and electron-donating groups (3i, 3j, 3n, 3o, 3p,
3q, Table 2) were compatible in the above-mentioned condition,
with electron-donating groups being obviously favorable. In the
presence of electron donating groups like methoxy, methyl or phe-
nyl, as illustrated by 3i, 3n 3o and 3p, shorter reaction time (3 h)
and over 94% yield were recorded. By comparison, 3b, 3c, 3d and
3 h with electron-withdrawing groups like halogen or CF3, pro-
longed the reaction time up to 24 h or even longer, and lower
yields (55–79%) were observed. It was noteworthy to mention that
halogen atom like Cl (3b, 3d), Br (3k), and I (3e and 3f) substituted
substrates afforded acceptable yields, which allows subsequent
derivatives to be prepared after the 1,2,4-triazolo[4,3-a]pyridine
being constructed.
We then extended the substrate scope beyond the pyridine ring.
Structurally related pyridazine (3v, Table 2), pyrimidine (3r, 3u,
Table 2), and fused aromatic rings like quinoline (3l, Table 2), iso-
quinoline (3m, Table 2), quinazoline (3t, Table 2) and quinoxaline
(3s, Table 2) were investigated. The synthetic processes for all
these substrates also proceed well, and medium to high reaction
yields were observed.
Having established a robust synthetic condition to construct the
1,2,4-triazolo[3,4-a]pyridine and related derivatives, we next
explored the possibility to replace DMF with other N,N-dimethyl
amide, with the hope to expand the substrate scope on the triazole
ring. N,N-dimethylacetamide (DMA) and N,N-dimethylbenzamide
were selected as representative examples. As shown in Table 3,
acceptable yields from 60% to 91% were obtained for both amides,
although slightly longer reaction time was enforced in order to
observe the substrate total conversion.
To further prove the practical application of this synthetic
method, a gram scale reaction to prepare 1a (1.0 g, 9.16 mmol)
was performed, and we are delighted to observe that 95% yield
(1.05 g, 8.74 mmol) can be achieved without reaction time
compromise.
Significantly, it is worthy to point out that our prepared 1,2,4-
triazolo[3,4-a]pyridine is unsubstituted at the 3-position, while
halogenation of this position could be easily achieved by reactions
with NBS [17] or NCS [18], and the resulting 3-halogenated 1,2,4-
triazolo[3,4-a]pyridine allowed further derivation to afford a broad
scope of products. For example, introduction of cyano group [18],
amination [17] with amine, or Suzuki reaction with organoboron
compound to form the CAC bond [19].
We next extended this annulation method to a [5+1] type reac-
tion, using biguanides and DMF to prepare triazines. Like 1,2,4-tri-
azolo[3,4-a]pyridines, triazine moiety was extensively observed in
a number of biological and pharmaceutical agents [20,21]. Repre-
sentative preparation of triazine routes involve acylation/cycliza-
tion of biguanides with the appropriate esters [22], or transition
Please cite this article as: Y. Xu, B. Shen, L. Liu et al., Metal free [4+1] and [5+1] annulation reactions to prepare heterocycles using DMF and its derivatives