Base promoted synthesis of 3-benzyl-2,5-diarylpyrazines from arylaldehydes and α-amino ketones

Article abstract of DOI:10.1080/00397911.2020.1725973

A novel approach to 3-benzyl-2,5-diarylpyrazine derivatives from α-amino ketones hydrochloride and arylaldehydes in the presence of Na₂CO₃ has been developed. In contrast with the classic synthetic methods of pyrazines, this protocol does not need additional oxidants and is more friendly to environment.

Full text of DOI:10.1080/00397911.2020.1725973

Synthetic Communications
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Base promoted synthesis of 3-benzyl-2,5-
diarylpyrazines from arylaldehydes and α-amino
ketones
Chao Wang
To cite this article: Chao Wang (2020): Base promoted synthesis of 3-benzyl-2,5-
diarylpyrazines from arylaldehydes and α-amino ketones, Synthetic Communications, DOI:
10.1080/00397911.2020.1725973
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https://doi.org/10.1080/00397911.2020.1725973
Base promoted synthesis of 3-benzyl-2,5-diarylpyrazines
from arylaldehydes and a-amino ketones
Chao Wang
School of Chemistry and Chemical Engineering, Shaanxi Xueqian Normal University, Xi’an, Shaanxi,
P. R. China
ABSTRACT
ARTICLE HISTORY
Received 25 September 2019
A novel approach to 3-benzyl-2,5-diarylpyrazine derivatives from
a-amino ketones hydrochloride and arylaldehydes in the presence of
Na2CO3 has been developed. In contrast with the classic synthetic
methods of pyrazines, this protocol does not need additional oxi-
dants and is more friendly to environment.
KEYWORDS
a-amino ketones; 3-Benzyl-
2,5-diarylpyrazines; hetero-
cycles; condensation
GRAPHICAL ABSTRACT
Introduction
Pyrazines are found in many new drugs, active pharmaceutical ingredients and fine
chemicals. There are many compounds containing pyrazines which present cytostatic,
antifungal, analgesic and antitumor properties.[1] Pyrazine derivatives widely exist in fla-
vorings and alarm pheromones (Fig. 1).[2] In addition, pyrazine derivatives can be used
as fluorescent glomerular filtration rate (GFR) tracer agents.[3] Therefore, the develop-
ment of new methods to synthesize pyrazines attracts lots of attention.
To date, there are many useful approaches for accessing pyrazines in the literature, which
include condensation of a-oximido carbonyl compounds with allylamines followed by elec-
trocyclization,[4] 1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes,[5] reductive con-
densation of a-nitro ketones with a-amino ketones using electron transfer reagent,[6] NꢀH
insertion of a-amino acid amides with a-diazo-b-ketoesters followed by cyclization,[7]
opening of epoxides with 1,2-amino alcohols and Swern oxidation,[8] Ru-catalyzed
CONTACT Chao Wang
wchoa@163.com
School of Chemistry and Chemical Engineering, Shaanxi Xueqian Normal
University, Shenhe 2nd Road, Chang’an District, Xi’an 710100, P. R. China
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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Figure 1. Bioactive compounds containing pyrazine nucleus.
Scheme 1. Classic method to synthesize pyrazines from a-amino ketones and this work.
dehydrogenative self-coupling of b-amino alcohols,[9] opening of 2H-azirines or oximes fol-
lowed by dimerization,[10] Rh-catalyzed reaction of 2H-azirines with N-sulfonyl 1,2,3-tria-
zoles,[11] the reaction of a-diazo oxime ethers with 2H-azirines via electrocyclization of 1,4-
diazahexatrienes.[12] An alternative approach involving functionalization of a preformed pyr-
azine nucleus or pyrazinones has also been developed.[13]
One of the classic methods to access diarylated pyrazines involves self-condensation prod-
uct of a-amino ketones followed by oxidation with additional oxidants (Scheme 1, Eq. (1)).
In 1979, Flament’s group reported a protocol to construct trisubstituted pyrazines from

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Table 1. Reaction optimizationa.
Entry
1a (equiv.)
2a (equiv.)
Base (equiv.)
NaHCO3 (2)
Solvent
Temp (oC)
Yield (%)b
1
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
DMF
DMF
80
80
80
80
80
80
80
90
100
110
100
100
100
100
100
100
100
100
100
100
100
100
31
10
24
14
12
11
11
43
66
64
71
80
81
85
83
77
88
46
45
74
75
67
2c
3
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (3)
NaHCO3 (3.2)
NaHCO3 (3.5)
NaHCO3 (3.7)
NaHCO3 (4)
KHCO3 (3.7)
Na2CO3 (3.7)
K2CO3 (3.7)
Cs2CO3 (3.7)
AcONa (3.7)
Et3N (3.7)
CH3CN
1,4-Dioxane
Toluene
THF
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DCE
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2
2
2.2
2.5
2.7
3
2.7
2.7
2.7
2.7
2.7
2.7
2.7
DIPEA (3.7)
aA mixture of 2-aminoacetophenone hydrochloride 1a, 4-methoxybenzaldehyde 2a (0.5 mmol), base and solvent
(0.5 mL) was stirred at 80–110 ꢁC under Ar atomsphere. bIsolated yield. cThe reaction was conducted under oxy-
gen atmosphere.
1-aminoacetone hydrochloride and aldehydes, but only three pyrazine derivatives were pre-
pared.[14] Herein, we described our extensive study of this method to prepare 2,3,5-trisubsti-
tuted pyrazines use arylaldehydes and a-amino ketones upon oxygen-free condition
(Scheme 1, Eq. (2)).
Results and discussion
We commenced our studies with 2-aminoacetophenone hydrochloride (1a), 4-methoxyben-
zaldehyde (2a) as the model substrates with NaHCO3 as the base under Ar atmosphere in
0.5 mL DMF at 80ꢁC (Table 1, entry 1). Delightedly, the desired product 3aa was obtained
in 31% yield. However, when the reaction was conducted in the presence of O2, the product
3aa was decreased to 10% (Table 1, entry 2). We thought that it might be that the self-
condensation product 4 is readily converted to 5 with O2. Next, we started to optimize reac-
tion conditions including solvent, temperature, ratio of reactants, and base. DMF was the
best one among the solvents examined (Table 1, entries 3–7). Raising temperature could
increase the yield, but increasing temperature did not obviously result in higher yield when
temperature is above 100 ꢁC (Table 1, entries 8–10). After choosing a better solvent and

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Table 2. Synthesis of 2,3,5-trisubstituted pyrazines.a
aA mixture of 1 (1.35 mmol), aldehyde 2 (0.5 mmol), Na2CO3 (1.85 mmol), and DMF (0.5 mL) was stirred at 100 ꢁC
under Ar atomsphere. bThe yield is reported by Flament.[14
]
temperature, we proposed that increasing the amount of base may be helpful to improve the
yield. To our delight, the result was in accordance with our expectation and the yield was
improved to 71% (Table 1, entry 11). When the ratio of 1a:2a:NaHCO3 was adjusted to
2.7:1:3.7, the yield was better than the others (Table 1, entries 11–15). Finally, a number of

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Figure 2. X-ray ORTEP diagram for compound 3ab.
bases were also tested and revealed that Na2CO3 was the best choice (Table 1, entries
16–22). Thus, we chose conditions of entry 17 as the optimal conditions.
With the optimal reaction conditions in hand, we then screened the substrate scope
as well as the functional group compatibility. It was found that the substitution effect of
electron-donating group had little influence on the yield (Table 2, 3aa–3ag). When pol-
ysubstituted aldehyde was employed as the reactant, the reaction also proceed smoothly
to obtain the corresponding products (3ab) in 70% yield. Structure of 3ab was con-
firmed by X-ray crystallography (Fig. 2).
When a variety of heterocyclic aldehydes were chosen as the reactants, the reaction
also afforded the corresponding product with good yields (3ah–3al). It was worth not-
ing that the indole-3-carboxaldehyde could not completely be transform into the corre-
sponding product (3ak). The 4-Cl substituted aldehyde gave the best yield among the
para, meta, ortho substituted aldehydes (3am–3ao). It indicated that the steric hindrance
might exist in the reaction. Benzaldehydes with various of electron-withdrawing groups
afforded corresponding products smoothly (3ap–3au). We also extended the 1a to ali-
phatic aminoacetone hydrochloride derivatives under our optimized conditions, the cor-
responding product was obtained in 82% yield (3bd), while the previous yield reported
by Flament was only 37%.[14] When we used substituted 2-aminoacetophenone hydro-
chloride, the corresponding product was obtained in 63% yield (3cm).
A plausible mechanism was proposed by taking the formation of 3ad as an example
shown in Scheme 2. Firstly, the self-condensation of 1a afforded dihydropyrazine 4.
Under Ar atmosphere, the compound 4 condensated with PhCHO 2d in the presence
of Na2CO3 to afford the intermediate 6, which dehydrated to afford the intermediate 7.
Finally, 7 undergoes tautomerization to the product 3ad. Beyond that, dihydropyrazine
4 was dehydrogenated to afford the 2,5-diphenylpyrazine 5 under O2.

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Scheme 2. Proposed reaction mechanism.
Conclusion
In summary, we have systematically studied a novel approach to construct 3-benzyl-2,5-
diarylpyrazine derivatives using arylaldehydes and a-amino ketones as the starting mate-
rials. The present method is enhanced in terms of yield, reaction time and making a
complementary to the chemistry of a-amino ketones. In contrast to the classic synthetic
method of pyrazines, the present method does not need additional oxidants and is more
friendly to environment.
Experimental
General experimental procedure
A mixture of a-amino ketone 1 (1.35 mmol), aldehyde 2 (0.5 mmol), and Na2CO3
(1.0 mmol) was placed in a 10 mL Schlenk tube in DMF (0.5 mL) and stirred at 100 ꢁC
under argon. When the starting materials were consumed completely as monitored by
TLC, the reaction mixture was isolated by silica gel column chromatography to give
1
product. The identity and purity of the product was confirmed by H and 13C NMR
spectroscopic analysis.
3-(4-methoxybenzyl)-2,5-diphenylpyrazine (3aa): mp 143–144 ꢁC. 1H NMR
(400 MHz; CDCl3) d 3.75 (s, 3H), 4.24 (s, 2H), 6.78 (d, J ¼ 8.4 Hz, 2H), 7.08 (d,
J ¼ 8.4 Hz, 2H), 7.45–7.53 (m, 8H), 8.09–8.10 (m, 2H), 8.94 (s, 1H); 13C NMR
(100 MHz; CDCl3) d 40.2, 55.2, 113.7, 126.9,128.4, 128.6, 129.0, 129.1, 129.6, 129.8,
131.1, 136.4, 138.5, 138.6, 150.0, 152.2, 152.9, 158.1.ESI-MS m/z (relative intensity, %):
353.2 (M þ H). HRMS (ESI) Calcd. for C24H20N2O þ Hþ 353.1648, Found 353.1642.
Pyrazines 3aa–3an and 3cm are new compounds, while derivatives 3bd has been
described in the literature.[14] See the Supplementary Information for the characteriza-
tion data of products 3aa–3an and 3cm.
Funding
This work was supported by the Talent Introduction Research Project of Shaanxi Xueqian
Normal University [2017DS03], the Science Foundation of Shaanxi Xueqian Normal
University [2018YBKJ33].

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