234
L. Fan et al. / Tetrahedron Letters 54 (2013) 231–234
Table 6
well irrespective of the substituents on the a-hydroxyketone sub-
YbCl3-catalyzed one-pot pyrazine formationa
strates (Table 4, entries 1–5). The formation of the corresponding
dihydropyrazined could be realized with other diamines under
the same conditions (Table 4, entries 6–10). Following these con-
siderations, the plausible mechanism is proposed and outlined in
Scheme 2
With dihydropyprazines 3a–3j in hand, we further synthesized
2,3-subsititued piperazines in a one-pot YbCl3-catalyzed reaction
in MeOH. The formation of the dihydropyrazines was followed by
the addition of excess NaBH4 to afford the corresponding pipera-
zine in good yields (Table 5).
R2 NH2
R1
O
R1
R1
N
R2
R3
i. YbCl3, H2O2
ii. KOH
one-pot
+
R3 NH2
R1 OH
N
1
2 a-c
5 a-g
Entry
R1
Ph 1a
4-MeC6H4
1b
R2
R3
Product
Yieldb (%)
1
2
H
H
H
H
5a
5b
85(42c)
83
Finally, we have tested the conversion of the resulting dihydro-
pyrazines 3 to the corresponding pyrazines 5 (Table 6). Upon the
formation of dihydropyrazines 3 (monitored by TLC), a MeOH solu-
tion of KOH was added into the reaction mixture. As expected, the
corresponding pyrazines 5 were obtained with good yields (Table 6,
entries 1–6). Interestingly, even pyrazine with an aliphatic substi-
tuent could be isolated in reasonable yield (Table 6, entry 7)
In conclusion, we developed an efficient synthetic protocol for
the synthesis of dihydropyrazines 3 via YbCl3-catalyzed reaction
3
4
5
4-ClC6H4
1c
4-FC6H4
1e
H
H
H
5c
5d
5e
83
84
81
H
Ph 1a
Me
H
NH2
6
7
Ph 1a
Me 1f
5f
74
50
NH2
2c (1R,2R)
of a-hydroxyketones with ethylenediamine, and obtained dihydro-
NH2
pyrazines 3 with excellent yields. Furthermore, the subsequent
conversion of dihydropyrazines 3 into the corresponding 2,3-
subsitituted piperazines 4 and pyrazines 5 with good yields was
realized in a one-pot reaction under mild conditions.
5g
NH2
2c (1R,2R)
a
Using oxy-1,2-diphenylethanone (1.0 equiv), ethylenediamine (1.5 equiv),
YbCl3 (10 mol %), H2O2 (20 mol %) in EtOH at reflux; after complete consumption to
Acknowledgment
a
-hydroxy ketones, KOH/MeOH (0.4 mol/L) was added.
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 20802052) for financial support.
b
Isolated yield.
c
Reaction yield without any catalyst and additive.
Supplementary data
the air. In order to confirm our conjecture, some parallel experi-
ments were managed and the results are summarized in Table 2.
When the reaction was under nitrogen atmosphere, only a trace
amount of benzyl 1a0 was detected (Table 2, entries 1 and 2). In
Supplementary data associated with this article can be found,
the air, only 28% of
a-hydroxy ketones were converted to benzyl
without catalyst, but when YbCl3 was used, the yield was improved
to 78%. The results proved that oxygen is the oxidant, and YbCl3
plays an important role in this process.
References and notes
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To further improve the yield, some additives were added to the
reaction. It has been found that 5,6-diphenyl-2,3-dihydropyrazine
3a could be obtained in excellent yield in the presence of H2O2
as an additive (Table 3, entry 3). Meanwhile the reaction time
was reduced from 3 to 0.5 h. This reaction also proceeded smoothly
with morpholine and AATEMPOꢀBF4ꢁ, but with relatively lower
yields. With decreasing amounts of YbCl3 and H2O2, the yields de-
creased (Table 3, entries 3–5).
Encouraged by the above mentioned experiments, the synthetic
protocol and scope of this reaction were further explored employ-
ing different kinds of a-hydroxy ketones having electron-rich and
electron-deficient functional groups, and 1.5 equiv of ethylenedi-
amines in the presence of 10 mol % YbCl3 and 20 mol % H2O2. The
results were summarized in Table 4. Clearly, the reaction worked
8. Raw, S. A.; Wilfred, C. D.; Taylor, R. J. Org. Biomol. Chem. 2004, 2, 788–796.
9. Kotharkar, S. A.; Shinde, D. B. Chin. J. Chem. 2007, 25, 105–107.