A heterogeneous gold(I)-catalyzed cascade annulation of aldehydes with propargylamine leading to 3-substituted 2,5-dimethylpyrazines

Article abstract of DOI:10.1016/j.jorganchem.2017.07.012

A heterogeneous gold(I)-catalyzed cascade annulation reaction of aldehydes with propargylamine was achieved in 1,2-dichloroethane at 40 °C by using an MCM-41-immobilized phosphine gold(I) complex[MCM-41-PPh₃-AuNTf₂] as catalyst, yielding a variety of 3-substituted 2,5-dimethylpyrazines in good to excellent yields. The new heterogeneous gold(I) catalyst can easily be prepared via a simple procedure from commercially readily available reagents, and recovered by filtration of the reaction solution and recycled at least eight times without significant loss of activity.

Full text of DOI:10.1016/j.jorganchem.2017.07.012

Accepted Manuscript
A heterogeneous gold(I)-catalyzed cascade annulation of aldehydes with
propargylamine leading to 3-substituted 2,5-dimethylpyrazines
Quan Nie, Fang Yao, Feiyan Yi, Mingzhong Cai
PII:
S0022-328X(17)30441-2
10.1016/j.jorganchem.2017.07.012
JOM 20026
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 21 May 2017
Revised Date: 8 July 2017
Accepted Date: 10 July 2017
Please cite this article as: Q. Nie, F. Yao, F. Yi, M. Cai, A heterogeneous gold(I)-catalyzed cascade
annulation of aldehydes with propargylamine leading to 3-substituted 2,5-dimethylpyrazines, Journal of
Organometallic Chemistry (2017), doi: 10.1016/j.jorganchem.2017.07.012.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A heterogeneous gold(I)-catalyzed cascade annulation of
aldehydes with propargylamine leading to 3-substituted 2,5-
dimethylpyrazines
Quan Nie, Fang Yao, Feiyan Yi, Mingzhong Cai*
A novel, efficient and practical heterogeneous gold(I)-catalyzed cascade annulation
reaction of propargylamine with aldehydes for the synthesis of 3-substituted 2,5-
dimethylpyrazines has been described.

ACCEPTED MANUSCRIPT
A heterogeneous gold(I)-catalyzed cascade annulation of
aldehydes with propargylamine leading to 3-substituted
2,5-dimethylpyrazines
Quan Nie,a Fang Yao,b Feiyan Yi,a Mingzhong Cai a*
a Key Laboratory of Functional Small Organic Molecule, Ministry of Education and
College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang
330022, P. R. China
b College of Chemical and Material Engineering, Quzhou University, Quzhou 324000,
P. R. China
ABSTRACT
A heterogeneous gold(I)-catalyzed cascade annulation reaction of aldehydes with
propargylamine was achieved in 1,2-dichloroethane at 40 °C by using an MCM-41-
immobilized phosphine gold(I) complex[MCM-41-PPh3-AuNTf2] as catalyst, yielding
a variety of 3-substituted 2,5-dimethylpyrazines in good to excellent yields. The new
heterogeneous gold(I) catalyst can easily be prepared via a simple procedure from
commercially readily available reagents, and recovered by filtration of the reaction
solution and recycled at least eight times without significant loss of activity.
Keywords: Gold; Pyrazine; Cascade annulation; MCM-41; Heterogeneous catalysis
1. Introduction
Pyrazines are an important class of N-heterocycles found in a number of bioactive
natural products and therapeutic agents and have important applications in the field of
medicine as antibacterial, antiviral, antituberculotic, and anti-inflammatory agents and
as kinase inhibitors [1-3]. Besides, pyrazine compounds are of considerable interest in
the cosmetics and food industries as flavoring agents [4-6] and have also attracted
*Corresponding author. Fax: +86 791 88120388.
1
E-mail address: caimzhong@163.com (M. Cai).

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attention in material sciences [7-9]. Despite their broad utility, only a limited number
of synthetic methods are described for the preparation of multisubstituted pyrazines
[10-15]. Traditional methods for the generation of alkylpyrazines through conden-
sation of vicinal diamines with α-diketones followed by dehydrogenation [16-18] or
autocondensation of α-amino carbonyl compounds [19] are showing the lack of
regioselectivity as a major impediment. In addition to these methods, pyrazines have
been prepared by some modified approaches such as oxidative addition of amino
alcohols to epoxides [20], reaction of α-azido ketones with α-amino methoximes [21],
1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes [22], N–H insertion of
α-amino acid-derived primary amides with α-keto carbenoids followed by cyclization
[23], and opening of 2H-azirines and dimerization [24]. The functionalization of a
preformed pyrazine nucleus or cyclohexane derivatives having two nitrogen atoms at
1,4-position has proved to be a useful alternative for the synthesis of a wide range of
pyrazines [25-28]. Recently, rhodium and ruthenium-catalyzed synthesis of pyrazines
has also been reported [29-33]. However, most of these methods suffer from some
drawbacks such as low yields, rigorous conditions, not readily available starting
materials, limited substrate scope, difficulties of preparing unsymmetrical substituted
pyrazines and the use of expensive metal catalysts. Hence, development of new
methodologies for the synthesis of pyrazines from simple, readily available starting
materials under mild conditions still represents a continuing challenge.
Homogeneous gold catalysis has received much attention and cationic gold(I)
complexes have evolved as mild Lewis acid catalysts for organic transformations
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requiring the activation of π bonds in the past two decades [34-38]. Recently,
gold-catalyzed construction of heterocyclic compounds has attracted great interest due
to their high efficiency and mild reaction conditions [39-48]. Recycling of homoge-
neous catalysts is a task of great economic and environmental importance in chemical
and pharmaceutical industries, especially when expensive and/or toxic heavy metal
complexes are employed [49]. The heterogenization of the existing homogeneous
catalysts appears to be a logical solution to these problems [50-53]. There has been
considerable interest in the development of heterogeneous catalytic systems that can
be easily recycled whilst maintaining the inherent activity of the catalytic center. The
discovery of mesoporous MCM-41 materials has provided a new possible candidate
for an ideal support to immobilize homogeneous catalysts and given an enormous
stimulus to research in heterogeneous transition-metal catalysis [54-56]. To date, some
functionalized MCM-41-immobilized palladium [57-59], rhodium [60], molybdenum
[61], gold [62-64] and copper [65,66] complexes have been successfully used as
potentially green and sustainable catalysts in organic synthesis. However, to the best
of our knowledge, no example of a heterogeneous gold-catalyzed synthesis of pyra-
zines has been reported until now. But there has been a report on the homogeneous
synthesis of pyrazines [67]. In continuing our efforts to develop greener synthetic
pathways for organic transformations [59,65,66], herein we wish to report the pre-
paration of an MCM-41-immobilized phosphine gold(I) complex [MCM-41-PPh3-
AuNTf2] and its successful application to the cascade annulation of aldehydes with
propargylamine leading to 3-substituted 2,5-dimethylpyrazines. The new hetero-
3

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geneous gold(I) complex shows high catalytic activity in the reaction under mild
reaction conditions and can easily be recovered by a simple filtration of the reaction
solution, and recycled at least eight times without significant loss of activity.
2. Experimental
2.1. General remarks
All chemicals were reagent grade and used as purchased. The mesoporous material
MCM-41 [54] and 1-(4-(diphenylphosphino)phenyl)-3-(3-(triethoxysilyl)propyl)urea
[68] were prepared according to literature methods. The products were purified by
flash chromatography on silica gel. A mixture of light petroleum ether (30-60 °C) and
ethyl acetate was generally used as eluent. All products were characterized by
1
comparison of their spectra and physical data with authentic samples. H NMR
spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer with TMS as
an internal standard in CDCl3 as solvent. 13C NMR spectra were recorded on a Bruker
Avance 400 (100 MHz) spectrometer in CDCl3 as solvent. HRMS spectra were
recorded on a Finnigan MAT8430 spectrometer. X-ray diffraction (XRD) measure-
ments were carried out at room temperature using an X-ray powder diffractmeter.
X-ray energy dispersive spectroscopy (EDS) was performed using a microscope.
2.2. Preparation of MCM-41-PPh3-AuNTf2 complex
1-(4-(Diphenylphosphino)phenyl)-3-(3-(triethoxysilyl)propyl)urea (0.525g, 1 mmol)
was added to a suspension of 2.0 g of the MCM-41 in 100 mL of dry toluene. The
mixture was stirred at 100 °C for 24 h under Ar. Then the solid was filtered, washed
4

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with CHCl3 (2 × 20 mL), and dried in vacuum at 150 °C for 5 h. The dried white solid
was then soaked in a solution of 2.5 g of Me3SiCl in 80 mL of dry toluene at room
temperature under stirring for 24 h. The solid product was filtered, washed with
acetone (3 × 20 mL), and dried in vacuum at 120 °C for 5 h to obtain 2.359 g of
hybrid material MCM-41-PPh3. The phosphine content was found to be 0.37 mmol g-1
by elemental analysis.
In a small Schlenk tube, 1.00 g of the above-functionalized MCM-41 (MCM-41-
PPh3) was mixed with Me2SAuCl (83 mg, 0.28 mmol) in 30 mL of dry CH2Cl2. The
mixture was stirred at room temperature for 8 h under an argon atmosphere. The
precipitate was filtered off, washed with CH2Cl2 and then treated with AgNTf2 (107
mg, 0.28 mmol) in CH2Cl2 (30 mL) at room temperature for 0.5 h. The solid product
was filtered, washed with NH3·H2O (2 × 10 mL), distilled water and EtOH, and dried
under vacuum to give 1.042 g of a gray gold complex (MCM-41-PPh3-AuNTf2). The
gold content was found to be 0.26 mmol g-1 by ICP-AES.
2.3. General procedure for the heterogeneous gold(I)-catalyzed cascade annulation
reaction of aldehydes with propargylamine
To a resealable Schlenk tube was added MCM-41-PPh3-AuNTf2 (192 mg, 0.05
mmol). The reaction tube was evacuated and back-filled with argon and this
evacuation/back-fill procedure was repeated one additional time. Aldehyde (1.0
mmol), propargylamine (4.0 mmol), water (5.0 mmol), and DCE (4 mL) were then
added under a stream of argon. The reaction tube was quickly sealed and the mixture
was stirred at 40 °C until disappearance of the starting material (TLC, typically 48 h).
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After being cooled to room temperature, the reaction mixture was diluted with ethyl
acetate (20 mL) and filtered. The catalyst was washed with ethyl acetate (2 × 5 mL)
and diethyl ether (2 × 5 mL), and reused in the next run. The filtrate was concentrated
under reduced pressure and the residue was purified by flash chromatography
(petroleum ether/ethyl acetate mixtures) to afford the corresponding product.
2.3.1. 2-((3,6-Dimethylpyrazin-2-yl)methyl)-1H-indole, 2a [44]
Orange oil. 1H NMR (400 MHz, CDCl3): δ = 8.68 (br, 1H), 8.24 (s, 1H), 7.52 (d, J
= 7.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.13-7.04 (m, 2H), 6.32 (s, 1H), 4.26 (s, 2H), 2.58
13
(s, 3H), 2.54 (s, 3H); C NMR (100 MHz, CDCl3): δ = 151.1, 150.3, 149.2, 141.9,
136.4, 134.5, 128.4, 121.5, 120.0, 119.7, 110.6, 101.0, 34.1, 21.3, 21.1.
2.3.2. 3-((3,6-Dimethylpyrazin-2-yl)methyl)-1H-indole, 2b
1
Orange oil. IR (neat): νmax/cm-1 3152, 2933, 1578, 1450, 1419, 765; H NMR (400
MHz, CDCl3): δ = 8.49 (br, 1H), 8.19 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.26-7.23 (m,
1H), 7.17-7.07 (m, 2H), 6.74 (t, J = 1.2 Hz, 1H), 4.26 (s, 2H), 2.51 (s, 3H), 2.48 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 153.4, 150.2, 149.4, 141.2, 136.4, 127.4,
+
122.3, 122.1, 119.4, 119.2, 112.4, 111.2, 32.2, 21.3, 21.1. HRMS calcd for C15H15N3
[M+]: 237.1266, found 237.1262.
2.3.3. 7-((3,6-Dimethylpyrazin-2-yl)methyl)-1H-indole, 2c [44]
Pale yellow solid, m.p.: 110-111 °C. 1H NMR (400 MHz, CDCl3): δ = 9.98 (br, 1H),
8.18 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.23-7.21 (m, 1H), 7.15-7.13 (m, 1H),
7.08-7.04 (m, 1H), 6.52-6.50 (m, 1H), 4.34 (s, 2H), 2.64 (s, 3H), 2.56 (s, 3H); 13C
6

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NMR (100 MHz, CDCl3): δ = 151.9, 149.8, 149.4, 141.5, 135.9, 128.3, 124.3, 122.4,
120.0, 119.8, 119.7, 102.5, 39.7, 21.5, 21.1.
2.3.4. 3-((3,6-Dimethylpyrazin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine, 2d [44]
1
Orange solid, m.p.: 187-188 °C. H NMR (400 MHz, CDCl3): δ = 11.58 (br, 1H),
8.29 (dd, J = 4.8, 1.6 Hz, 1H), 8.22 (s, 1H), 7.97 (dd, J = 7.8, 1.4 Hz, 1H), 7.06-7.03
13
(m, 2H), 4.26 (s, 2H), 2.54 (s, 3H), 2.50 (s, 3H); C NMR (100 MHz, CDCl3): δ =
152.8, 150.2, 149.2, 149.1, 142.5, 141.4, 127.9, 123.1, 120.2, 115.3, 110.6, 32.4, 21.3,
21.1.
2.3.5. 2-(Benzo[b]thiophen-2-ylmethyl)-2,5-dimethylpyrazine, 2e [44]
1
Yellow oil. H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1H), 7.74-7.71 (m, 1H),
7.65-7.63 (m, 1H), 7.29-7.23 (m, 2H), 6.96 (s, 1H), 4.40 (s, 2H), 2.56 (s, 3H), 2.55 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 151.5, 150.6, 149.2, 142.0, 141.5, 139.8,
139.7, 124.2, 123.8, 123.0, 122.1, 121.9, 37.0, 21.3, 21.1.
2.3.6. 3-(Benzo[b]thiophen-3-ylmethyl)-2,5-dimethylpyrazine, 2f
1
Yellow oil. IR (neat): νmax/cm-1 3056, 2920, 1456, 1371, 1360, 1120, 757, 725; H
NMR (400 MHz, CDCl3): δ = 8.25 (s, 1H), 7.92-7.84 (m, 2H), 7.42-7.34 (m, 2H),
6.83 (s, 1H), 4.34 (s, 2H), 2.54 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
= 151.8, 150.4, 149.5, 141.7, 140.4, 138.8, 132.5, 124.4, 124.1, 122.9, 122.8, 122.0,
35.3, 21.3, 21.1. HRMS calcd for C15H14N2S + [M+]: 254.0878, found 254.0881.
2.3.7. 2,5-Dimethyl-3-(thiophen-3-ylmethyl)pyrazine, 2g [69]
1
Orange oil. H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1H), 7.16-7.14 (m, 1H),
6.92-6.90 (m, 1H), 6.79-6.77 (m, 1H), 4.32 (s, 2H), 2.53 (s, 6H); 13C NMR (100 MHz,
7

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CDCl3): δ = 152.1, 150.4, 149.0, 141.8, 140.4, 126.8, 125.4, 124.3, 36.1, 21.3, 21.1.
2.3.8. 3-(3,5-Dimethoxybenzyl)-2,5-dimethylpyrazine, 2h [44]
Orange oil. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 6.32-6.30 (m, 3H), 4.10
(s, 2H), 3.74 (s, 6H), 2.53 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
160.9, 152.7, 150.2, 149.5, 141.5, 140.3, 107.0, 98.2, 55.3, 41.9, 21.4, 21.1.
2.3.9. 3-(Benzo[d][1,3]dioxol-5-ylmethyl)-2,5-dimethylpyrazine, 2i [44]
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H),
13
6.68-6.63 (m, 2H), 5.91 (s, 2H), 4.07 (s, 2H), 2.53 (s, 3H), 2.45 (s, 3H); C NMR
(100 MHz, CDCl3): δ = 153.0, 150.2, 149.3, 147.8, 146.2, 141.4, 131.7, 121.6, 109.1,
108.2, 100.9, 41.3, 21.4, 21.1.
2.3.10. 3-(3-Methoxybenzyl)-2,5-dimethylpyrazine, 2j
1
Orange oil. IR (neat): νmax/cm-1 2925, 1740, 1597, 1448, 1259, 1150, 770; H NMR
(400 MHz, CDCl3): δ = 8.21 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.76-6.73 (m, 3H), 4.14
(s, 2H), 3.76 (s, 3H), 2.53 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
159.7, 152.8, 150.2, 149.4, 141.5, 139.6, 129.5, 121.1, 114.7, 111.6, 55.2, 41.7, 21.4,
21.1. HRMS calcd for C14H16N2O+ [M+]: 228.1263, found 228.1268.
2.3.11. 3-(4-Methoxybenzyl)-2,5-dimethylpyrazine, 2k [70]
Orange oil. 1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1H), 7.09 (d, J = 8.8 Hz,2H),
13
6.82-6.79 (m, 2H), 4.10 (s, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H); C NMR
(100 MHz, CDCl3): δ = 158.2, 153.3, 150.2, 149.3, 141.3, 130.0, 129.6, 114.0, 55.2,
40.8, 21.4, 21.1.
2.3.12. 3-(4-(Allyloxy)benzyl)-2,5-dimethylpyrazine, 2l
8

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1
Yellow oil. IR (neat): νmax/cm-1 2923, 1613, 1509, 1243, 1122, 1000, 795; H NMR
(400 MHz, CDCl3): δ = 8.20 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H),
6.07-5.99 (m, 1H), 5.41-5.36 (m, 1H), 5.27-5.24 (m, 1H), 4.50-4.48 (m, 2H), 4.09 (s,
2H), 2.52 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 157.3, 153.3, 150.2,
149.3, 141.3, 133.4, 130.2, 129.6, 117.6, 114.8, 68.8, 40.9, 21.4, 21.1. HRMS calcd
for C16H18N2O+ [M+]: 254.1419, found 254.1418.
2.3.13. 3-(2,4-Dimethoxybenzyl)-2,5-dimethylpyrazine, 2m [44]
Orange oil. 1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H),
6.47-6.45 (m, 1H), 6.36 (dd, J = 8.4, 2.4 Hz, 1H), 4.07 (s, 2H), 3.81 (s, 3H), 3.77 (s,
3H), 2.50 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 159.6, 157.9, 153.6,
150.0, 149.6, 141.0, 129.9, 119.2, 104.1, 98.5, 55.4, 55.3, 34.4, 21.1.
2.3.14. 2-((3,6-Dimethylpyrazin-2-yl)methyl)phenol, 2n [44]
Pale yellow solid, m.p.: 116-117 °C. 1H NMR (400 MHz, CDCl3): δ = 10.39 (s, 1H),
8.24 (s, 1H), 7.20-7.14 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H),
4.10 (s, 2H), 2.70 (s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 156.6,
152.7, 149.0, 148.7, 142.2, 130.3, 128.9, 124.4, 120.2, 118.4, 37.2, 21.4, 20.5.
2.3.15. 3-(2-Methoxybenzyl)-2,5-dimethylpyrazine, 2o
1
Orange oil. IR (neat): νmax/cm-1 2925, 1597, 1483, 1245, 1131, 1032, 750; H NMR
(400 MHz, CDCl3): δ = 8.19 (s, 1H), 7.22-7.16 (m, 1H), 6.88-6.80 (m, 3H), 4.15 (s,
2H), 3.84 (s, 3H), 2.50 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 157.0,
153.3, 150.1, 149.6, 141.1, 129.5, 127.6, 126.7, 120.5, 110.2, 55.4, 35.0, 21.2, 21.1.
HRMS calcd for C14H16N2O+ [M+]: 228.1263, found 228.1259.
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2.3.16. 3-(2-(Allyloxy)benzyl)-2,5-dimethylpyrazine, 2p [44]
1
Yellow oil. H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1H), 7.19-7.15 (m, 1H),
6.90-6.82 (m, 3H), 6.07-5.98 (m, 1H), 5.41-5.37 (m, 1H), 5.28-5.25 (m, 1H),
4.56-4.55 (m, 2H), 4.19 (s, 2H), 2.50 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 156.1, 153.3, 150.1, 149.6, 141.1, 133.4, 129.7, 127.5, 127.0, 120.7,
117.2, 111.6, 68.9, 35.2, 21.2, 21.1.
2.3.17. 2,5-Dimethyl-3-(4-methylbenzyl)pyrazine, 2q [70]
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1H), 7.09-7.04 (m, 4H), 4.12
(s, 2H), 2.53 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
153.2, 150.2, 149.3, 141.3, 136.0, 134.9, 129.2, 128.5, 41.3, 21.4, 21.1, 21.0.
2.3.18. 3-(4-Fluorobenzyl)-2,5-dimethylpyrazine, 2r [70]
1
Orange oil. H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1H), 7.15-7.11 (m, 2H),
6.99-6.93 (m, 2H), 4.13 (s, 2H), 2.53 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 161.6 (d, 1JC-F = 243.1Hz), 152.8, 150.3, 149.2, 141.5, 133.6 (d, 4JC-F =
3.2 Hz), 130.0 (d, 3JC-F = 7.9 Hz), 115.3 (d, 2JC-F = 21.2 Hz), 40.8, 21.3, 21.1.
2.3.19. 3-(4-Chlorobenzyl)-2,5-dimethylpyrazine, 2s [70]
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1H), 7.26-7.22 (m, 2H), 7.11
(d, J = 8.4 Hz, 2H), 4.12 (s, 2H), 2.53 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 152.5, 150.4, 149.2, 141.6, 136.5, 132.4, 130.0, 128.7, 40.9, 21.4, 21.1.
2.3.20. 3-(4-Bromobenzyl)-2,5-dimethylpyrazine, 2t [44]
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H),
7.05 (d, J = 8.4 Hz, 2H), 4.10 (s, 2H), 2.52 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz,
10

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CDCl3): δ = 152.4, 150.4, 149.2, 141.6, 137.0, 131.6, 130.4, 120.4, 41.0, 21.3, 21.1.
2.3.21. 3-(Cyclohexylmethyl)-2,5-dimethylpyrazine, 2u
Pale yellow oil. IR (neat): νmax/cm-1 2925, 2850, 1733, 1451, 1371, 1283, 1171, 896;
1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1H), 2.66 (d, J = 7.2 Hz, 2H), 2.52 (s, 3H),
2.49 (s, 3H), 1.84-1.76 (m, 1H), 1.72-1.62 (m, 5H), 1.27-1.17 (m, 3H), 1.10-0.99 (m,
13
2H); C NMR (100 MHz, CDCl3): δ = 154.1, 150.0, 148.9, 140.6, 42.4, 38.2, 33.3,
+
26.4, 26.3, 21.5, 21.1. HRMS calcd for C13H20N2 [M+]: 204.1626, found 204.1628.
2.3.22. 3-Cinnamyl-2,5-dimethylpyrazine, 2v [44]
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 7.34-7.26 (m, 5H), 6.45
(d, J = 16.0 Hz, 1H), 6.36 (dt, J = 16.0, 6.4 Hz, 1H), 3.73 (d, J = 6.4 Hz, 2H), 2.56 (s,
3H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 152.4, 150.4, 149.1, 141.3, 137.2,
131.9, 128.5, 127.3, 126.2, 125.9, 39.2, 21.2, 21.1.
3. Results and discussion
3.1. Synthesis and characterization of MCM-41-PPh3-AuNTf2 complex
The MCM-41-immobilized phosphine gold(I) complex [MCM-41-PPh3-AuNTf2]
was synthesized according to the procedure presented in Scheme 1. Firstly, the meso-
porous MCM-41 was condensed with 1-(4-(diphenylphosphino)phenyl)-3-(3-(trietho-
xysilyl)propyl)urea in toluene at 100 °C for 24 h, followed by the silylation with
Me3SiCl in toluene at room temperature for 24 h to generate triphenylphosphine-
functionalized MCM-41 (MCM-41-PPh3). The latter was reacted with Me2SAuCl in
dichloromethane (DCM) at room temperature for 8 h, and then treated with AgNTf2 in
11

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DCM at room temperature for 0.5 h to afford the MCM-41-immobilized phosphine
gold(I) complex [MCM-41-PPh3-AuNTf2] as a gray powder, the gold content of the
complex was found to be 0.26 mmol g-1 according to the ICP-AES measurements.
The small angle X-ray powder diffraction (XRD) patterns of the parent MCM-41
and the MCM-41-PPh3-AuNTf2 complex are illustrated in Figure 1. Small angle
X-ray diffraction of the parent MCM-41 gave three peaks corresponding to hexa-
gonally ordered mesoporous phases [54]. For the MCM-41-PPh3-AuNTf2, the (100)
reflection of the parent MCM-41 with decreased intensity was remained after func-
tionalization, while the (110) and (200) reflections became weak and diffuse, which
may be mainly due to contrast matching between the silicate framework and organic
moieties which are located inside the channels of MCM-41. These results indicate that
the structure of the mesoporous MCM-41 remains unchanged through the grafting
procedure and the formation of the catalyst has taken place preferentially inside the
pore system of MCM-41. The energy dispersive X-ray spectroscopy (EDS) shows the
elements present in the material. EDS analysis of fresh MCM-41-PPh3-AuNTf2
complex indicates the presence of Si, O, C, N, P, S, F and Au elements (Figure 2).
3.2. Heterogeneous gold(I)-catalyzed cascade annulation reaction of aldehydes with
propargylamine
The MCM-41-PPh3-AuNTf2 complex was then used as catalyst for the cascade
annulation reaction of aldehydes with propargylamine. Initial experiments with indole
-2-carbaldehyde (1a) and propargylamine were performed to optimize the reaction
conditions, and the results are summarized in Table 1. At first, the temperature effect
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was examined by using 5 mol% of MCM-41-PPh3-AuNTf2 as catalyst in 1,2-dichloro-
ethane (DCE) (entries 1-4). It is evident that the yield of the desired product 2a
increased with the increase in temperature and the reaction at 40 ºC gave the best
result (entry 3). However, further raising the temperature to 50 ºC resulted in a lower
yield of 71% (entry 4). The addition of 3 Ǻ molecular sieves (MS) to the reaction
mixture decreased the yield obviously and the reaction did not go to completion,
which indicating the importance of adventitious water for efficient formation of 2a
(entry 5). To our delight, the addition of 5 equiv. of H2O to the reaction under
otherwise identical conditions could accelerate the conversion and retain the excellent
yield (entry 6). Our next studies focused on the effect of solvent on the model reaction
and a significant solvent effect was observed (entries 6-11). Among the solvents
examined, toluene, DMSO and DCM also gave good yields (entries 7-9) and DCE
was the best choice (entry 6), while THF and MeCN were substantially less efficient
(entries 10 and 11). Reducing the amount of the catalyst to 2.5 mol% resulted in a
lower yield and a long reaction time was required (entry 12). Increasing the amount of
the catalyst could shorten the reaction time, but did not improve the yield further
(entry 13). Thus, the optimized reaction conditions for this transformation are the
MCM-41-PPh3-AuNTf2 (5 mol%) in DCE at 40 ºC in the presence of 5 equiv. of H2O
under Ar for 48 h (entry 6).
With the optimized conditions in hand, we then investigated the scope and limita-
tion of this heterogeneous gold(I)-catalyzed cascade annulation reaction using a range
of aldehydes as the substrates (Scheme 2) and the results are summarized in Table 2.
13

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As shown in Table 2, the annulation reactions of N-heterocyclic aldehydes such as
indole-3-carbaldehyde (1b), indole-7-carbaldehyde (1c) and 1H-pyrrolo[2,3-b]pyri-
dine-3-carbaldehyde (1d) with propargylamine proceeded smoothly under the
optimized conditions to afford the desired pyrazines 2b-2d in 82-92% yields.
Benzo[b]thiophene-2-carbaldehyde (1e), benzo[b]thiophene-3-carbaldehyde (1f) and
thiophene-3-carbaldehyde (1g) proved to be also good substrates and generated the
corresponding pyrazines 2e-2g in 72-90% yields. Substituted benzaldehydes 1h-1t
could undergo the cascade annulation reaction with propargylamine effectively to
afford the corresponding pyrazines 2h-2t in good to excellent yields. The electronic
nature of substituents on the benzene ring did not have a strong influence on the
heterogeneous gold(I)-catalyzed cascade annulation reaction, and both electron-
donating and electron-withdrawing groups were tolerated well. Also, no significant
steric effect was observed when meta-methoxybenzaldehyde (1j), para-methoxy-
benzaldehyde (1k), and ortho-methoxybenzaldehyde (1o) were used as substrates, and
the ortho-substituted benzaldehydes 1m-1p could afford the desired pyrazines 2m-2p
in high yields. It is noteworthy that under the optimized conditions, C–X bond (X = F,
Cl, Br) remained intact, and the obtained 3-(4-halophenylmethyl)-2,5-dimethyl-
pyrazines 2r-2t could be easily transferred into their new derivatives by C–X bond
activation and its coupling reaction. In addition, we also examined this heterogeneous
gold(I)-catalyzed annulation reaction employing aliphatic aldehydes, unfortunately,
only cyclohexanecarbaldehyde (1u) was found to be suitable substrate and afforded
the desired product 2u in 67% yield, while other aliphatic aldehydes such as heptanal
14

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and phenylacetaldehyde did not work. Interestingly, cinnamaldehyde (1v) also gave
the expected product 2v in a moderate yield.
To determine whether the observed catalysis was due to the heterogeneous catalyst
MCM-41-PPh3-AuNTf2 or to a leached gold species in solution, we performed the hot
filtration test [71]. We focused on the tandem annulation reaction of indole-2-carb-
aldehyde (1a) with propargylamine. We filtered off the MCM-41-PPh3-AuNTf2 com-
plex after 36 h of reaction time and allowed the filtrate to react further. The catalyst
filtration was performed at the reaction temperature (40 °C) in order to avoid possible
recoordination or precipitation of soluble gold upon cooling. We found that, after this
hot filtration, no further reaction was observed, indicating that leached gold species
from the catalyst (if any) are not responsible for the observed activity. It was also
confirmed by ICP-AES analysis that no gold species could be detected in the filtrate.
These results suggest that the gold(I) complex remains on the MCM-41 support
during the reaction and the observed catalysis was intrinsically heterogeneous.
A possible mechanism for this heterogeneous gold(I)-catalyzed cascade annulation
reaction of aldehydes 1 with propargylamine is outlined in Scheme 3 [72]. Firstly,
coordination of the MCM-41-PPh3-AuNTf2 catalyst to alkyne moiety in the imine
derived from aldehyde 1 and propargylamine and subsequent hydroamination reaction
with propargylamine generates an MCM-41-immobilized vinylgold cation interme-
diate A [73]. Then, intermediate A undergoes protonolysis of the Au–C bond via a
1,3-proton shift, followed by recoordination of the gold(I) catalyst to the triple bond
of the imine to give an MCM-41-anchored phosphine-Au(I) alkyne complex inter-
15

ACCEPTED MANUSCRIPT
mediate B, which experiences an intramolecular nucleophilic addition of the imine to
the activated-alkyne moiety to form an MCM-41-immobilized vinylgold cation inter-
mediate C. Such not symmetry-allowed shifts and long distance shifts of protons in
gold catalysis have been shown to be mediated by small water clusters as proton
shuttles [74]. This could explain the beneficial effect of the added five equivalents of
water. The new cationic intermediate C readily releases the aldehyde by hydrolysis,
followed by protonolysis of the Au–C bond leading to the formation of 2,5-dimethy-
lenepiperazine D with concurrent regeneration of the gold(I) catalyst. The latter inter-
mediate D readily isomerizes to its more stable 2,5-dimethyl-1,4-dihydropyrazine
isomer E. Then, an intermolecular enamine addition of intermediate E to the gold(I)-
activated aldehyde occurs to produce intermediate F, which undergoes 1,5-proton-
migration and release of the gold(I) catalyst, subsequent dehydration to afford the
2-alkylidene-3,6-dimethyl-1,2-dihydropyrazine intermediate G. The last step of the
transformation involves the isomerization by aromatization of intermediate G to the
final pyrazine 2.
3.3. Recycling of the catalyst
For a heterogeneous precious metal catalyst, it is important to examine its ease of
separation, stability and reusability. The MCM-41-PPh3-AuNTf2 catalyst can be easily
separated and recovered by a simple filtration of the reaction solution. We next
examined the recycling of the catalyst by using the cascade annulation reaction of
indole-2-carbaldehyde (1a) with propargylamine. After completion of the reaction, the
16

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catalyst was recovered by simple filtration and washed with ethyl acetate and diethyl
ether. After being air-dried, it can be reused directly without further purification. The
highest turnover numbers obtained in gold-catalyzed reactions of alkynes with nucleo-
philes were reported by Hashmi group [75-77]. The recovered gold catalyst was used
in the next run, and almost the same yield of 2a was observed for 8 consecutive cycles
(Figure 3). In addition, gold leaching in the heterogeneous catalyst was also deter-
mined by ICP-AES analysis on the recovered catalyst after eight consecutive runs,
which revealing almost the same gold content as the fresh one.
4. Conclusion
In summary, heterogenized homogeneous catalyst based on gold has been success-
fully developed for the cascade annulation reaction of propargylamine with aldehydes.
It is demonstrated that such a heterogenized phosphine-gold(I) complex performs
efficiently as a recyclable heterogeneous catalytic system for a one-pot construction of
diverse 3-substituted 2,5-dimethylpyrazines. The reaction was applicable to a wide
range of aromatic aldehydes and heterocyclic aldehydes with high functional group
tolerance. This heterogeneous gold(I)-catalyzed cascade annulation reaction has some
attractive advantages such as readily accessible starting materials, mild reaction
conditions, good yields, and excellent recyclability of the gold(I) catalyst, providing a
simple, practical and environmentally friendly method for the synthesis of pyrazine
derivatives.
17

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Acknowledgements
We thank the National Natural Science Foundation of China (No. 21462021), the
Natural Science Foundation of Jiangxi Province of China (No. 20161BAB203086)
and Key Laboratory of Functional Small Organic Molecule, Ministry of Education
(No. KLFS-KF-201409) for financial support.
References
[1] P.B. Miniyar, P.R. Murumkar, P.S. Patil, M.A. Barmade, K.G. Bothara,
Mini-Rev. Med. Chem. 13 (2013) 1607-1625.
[2] G. Roymahapatra, S.M. Mandal, W.F. Porto, T. Samanta, S .Giri, J. Dinda, O.L.
Franco, P.K. Chattaraj, Curr. Med. Chem. 19 (2012) 4184-4193.
[3] M. Dolezal, J. Zitko, Expert Opin. Ther. Patents. 25 (2015) 33-47.
[4] M.S. Allen, M.J. Lacey, S.J. Boyd, J. Agric. Food Chem. 43 (1995) 769-772.
[5] A. Adams, N. de Kimpe, Food Chem. 115 (2009) 1417-1423.
[6] D.P. De Schutter, D. Saison, F. Delvaux, G. Derdelinckx, J.-M. Rock, H. Neven,
F.R. Devaux, J. Agric. Food Chem. 56 (2008) 246-254.
[7] R. Mondal, S. Ko, Z. Bao, J. Mater. Chem. 20 (2010) 10568-10576.
[8] M. Wriedt, I. Jess, C. Nather, Eur. J. Inorg. Chem. (2009) 363-372.
[9] H.-Y. Liu, H. Wu, J.-F. Ma, J. Yang, Y.-Y. Liu, Dalton Trans. 38 (2009)
7957-7961.
[10] A. Ohta, R. Itoh, Y. Kaneko, H. Koike, K. Yuasa, Heterocycles 29 (1989)
939-942.
[11] G. Buchi, J. Galindo, J. Org. Chem. 56 (1991) 2605-2611.
[12] C.H. Heathcock, S.C. Smith, J. Org. Chem. 59 (1994) 6828-6839.
[13] M. Drogemuller, T. Flessner, R. Jautelat, U. Scholz, E. Winterfeldt, Eur. J. Org.
Chem. (1998) 2811-2817.
[14] T.A. Elmaaty, L.W. Castle, Org. Lett. 7 (2005) 5529-5532.
[15] V.P. Mehta, A. Sharma, K.V. Hecke, L.V. Meervelt, E.V. der Eycken, J. Org.
Chem. 73 (2008) 2382-2387.
18

ACCEPTED MANUSCRIPT
[16] A. Ohta, S. Masano, S. Iwakura, A. Tamura, H. Watahiki, M. Tsutsui, Y. Akita,
T. Watanabe, T. Kurihara, J. Heterocycl. Chem. 19 (1982) 465-473.
[17] D.D. Kenning, K.A. Mitchell, T.R. Calhoun, M.R. Funfar, D.J. Sattler, S.C.
Rasmussen, J. Org. Chem. 67 (2002) 9073-9076.
[18] K.K.D.R. Viswanadham, M. Prathap Reddy, P. Sathyanarayana, O. Ravi, R.
Kant, S.R. Bathula, Chem. Commun. 50 (2014) 13517-13520.
[19] S. Albrecht, M. Al-Lakkis-Wehbe, A. Orsini, A. Defoin, P. Pale, E. Salomon, C.
Tarnus, J.-M. Weibel, Bioorg. Med. Chem. 19 (2011) 1434-1442.
[20] D.F. Taber, P.W. DeMatteo, K.V. Taluskie, J. Org. Chem. 72 (2007) 1492-1494.
[21] C. Guo, S. Bhandaru, P.L. Fuchs, J. Am. Chem. Soc. 118 (1996) 10672-10673.
[22] D. Aparicio, O.A. Attanasi, P. Filippone, R. Ignacio, S. Lillini, F. Mantellini, F.
Palacios, J.M. de los Santos, J. Org. Chem. 71 (2006) 5897-5905.
[23] H. Matsushita, S.-H. Lee, K. Yoshida, B. Clapham, G. Koch, J. Zimmermann,
K.D. Janda, Org. Lett. 6 (2004) 4627-4630.
[24] F. Palacios, A.M.O. de Retana, J. Gil, R.L. de Munain, Org. Lett. 4 (2002)
2405-2408.
[25] V.P. Mehta, S.G. Modha, E.V. Van der EYcken, J. Org. Chem. 75 (2010)
976-979.
[26] M. Mosrin, T. Bresser, P. Knochel, Org. Lett. 11 (2009) 3406-3409.
[27] F. Buron, N. Ple, A. Turck, G. Queguiner, J. Org. Chem. 70 (2005) 2616-2621.
[28] W. Liu, D.S. Wise, L.B. Townsend, J. Org. Chem. 66 (2001) 4783-4787.
[29] T. Ryu, Y. Baek, P.H. Lee, J. Org. Chem. 80 (2015) 2376-2383.
[30] N.V. Rostovskii, J.O. Ruvinskaya, M.S. Novikov, A.F. Khlebnikov, I.A.
Smetanin, A.V. Agafonova, J. Org. Chem. 82 (2017) 256-268.
[31] B. Gnanaprakasam, E. Balaraman, Y. Ben-David, D. Milstein, Angew. Chem.
Int. Ed. 50 (2011) 12240-12244.
[32] D. Srimani, Y. Ben-David, D. Milstein, Angew. Chem. Int. Ed. 52 (2013)
4012-4016.
[33] P. Ganji, P.W.N.M. van Leeuwen, J. Org. Chem. 82 (2017) 1768-1774.
[34] Modern Gold Catalyzed Synthesis; A.S.K. Hashmi, F.D. Toste, Eds.; Wiley-
19

ACCEPTED MANUSCRIPT
VCH: Weinheim, 2012.
[35] A. Corma, A. Leyva-Perez, M.J. Sabater, Chem. Rev. 111 (2011) 1657-1712.
[36] R. Dorel, A.M. Echavarren, Chem. Rev. 115 (2015) 9028-9072.
[37] D.B. Huple, S. Ghorpade, R.-S. Liu, Adv. Synth. Catal. 358 (2016) 1348-1367.
[38] D. Pflasterer, A.S.K. Hashmi, Chem. Soc. Rev. 45 (2016) 1331-1367.
[39] Y. Liu, F. Song, Z. Song, M. Liu, B. Yan, Org. Lett. 7 (2005) 5409-5412.
[40] Y. Liu, F. Song, S. Guo, J. Am. Chem. Soc. 128 (2006) 11332-11333.
[41] A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180-3211.
[42] A.S.K. Hashmi, M. Buhrle, Aldrichimica Acta 43 (2010) 27-33.
[43] S.N. Karad, R.-S. Liu, Angew. Chem. Int. Ed. 53 (2014) 9072-9076.
[44] B. Alcaide, P. Almendros, J.M. Alonso, I. Fernandez, G. Gomez-Campillos,
M.R. Torres, Chem. Commun. 50 (2014) 4567-4570.
[45] X. Li, M. Chen, X. Xie, N. Sun, S. Li, Y. Liu, Org. Lett. 17 (2015) 2984-2987.
[46] Y. Matuda, S. Naoe, S. Oishi, N. Fujii, H. Ohno, Chem. Eur. J. 21 (2015)
1463-1472.
[47] V.V. Pagar, A.M. Jadhav, R.-S. Liu, J. Am. Chem. Soc. 133 (2011) 20728-
20731.
[48] X. Li, X. Xie, Y. Liu, J. Org. Chem. 81 (2016) 3688-3694.
[49] D.J. Cole-Hamilton, Science 299 (2003) 1702-1706.
[50] N.T.S. Phan, M.V.D. Sluys, C.W. Jones, Adv. Synth. Catal. 348 (2006)
609-679.
[51] R. Akiyama, S. Kobayashi, Chem. Rev. 109 (2009) 594-642.
[52] M.J. Climent, A. Corma, S. Iborra, Chem. Rev. 111 (2011) 1072-1133.
[53] S. Tsupova, A. Cadu, S.A.C. Carabineiro, M. Rudolph, A.S.K. Hashmi, J. Catal.
350 (2017) 97-102.
[54] C.T. Kresge, M.E. Leonowicz, W.J. Roth, J.C. Vartuli, J.S. Beck, Nature 359
(1992) 710-712.
[55] W. Zhou, J.M. Thomas, D.S. Shephard, B.F.G. Johnson, D. Ozkaya, T.
Maschmeyer, R.G. Bell, Q. Ge, Science 280 (1998) 705-708.
[56] R.M. Martin-Aranda, J. Cejka, Top. Catal. 53 (2010) 141-153.
20

ACCEPTED MANUSCRIPT
[57] P.C. Mehnert, D.W. Weaver, J.Y. Ying, J. Am. Chem. Soc. 120 (1998)
12289-12296.
[58] K. Mukhopadhyay, B.R. Sarkar, R.V. Chaudhari, J. Am. Chem. Soc. 124 (2002)
9692-9693.
[59] W. Hao, H. Liu, L. Yin, M. Cai, J. Org. Chem. 81 (2016) 4244-4251.
[60] S.-G. Shyu, S.-W. Cheng, D.-L. Tzou, Chem. Commun. (1999) 2337-2338.
[61] M. Jia, A. Seifert, W.R. Thiel, Chem. Mater. 15 (2003) 2174-2180.
[62] C. Gonzalez-Arellano, A. Corma, M. Iglesias, F. Sanchez, Adv. Synth. Catal.
346 (2004) 1758-1764.
[63] A. Corma, E. Gutierrez-Puebla, M. Iglesias, A. Monge, S. Perez-Ferreras, F.
Sanchez, Adv. Synth. Catal. 348 (2006) 1899-1907.
[64] G. Villaverde, A. Corma, M. Iglesias, F. Sanchez, ACS Catal. 2 (2012) 399-406.
[65] H. Zhao, W. He, R. Yao, M. Cai, Adv. Synth. Catal. 356 (2014) 3092-3098.
[66] H. Zhao, W. He, L. Wei, M. Cai, Catal. Sci. Technol. 6 (2016) 1488-1495.
[67] S. Shi, T. Wang, W. Yang, M. Rudolph, A.S.K. Hashmi, Chem. Eur. J. 19 (2013)
6576-6580.
[68] E. Lindner, T. Salesch, S. Brugger, F. Hoehn, P. Wegner, H.A. Mayer, J.
Organomet. Chem. 641 (2002) 165-172.
[69] T. Noel, A.J. Musacchio, Org. Lett. 13 (2011) 5180-5183.
[70] J. Su, H. Liu, R. Hua, Int. J. Mol. Sci. 16 (2015) 3599-3608.
[71] H.E.B. Lempers, R.A. Sheldon, J. Catal. 175 (1998) 62-69.
[72] A.S.K. Hashmi, Angew. Chem. Int. Ed. 49 (2010) 5232-5241.
[73] A.S.K. Hashmi, A.M. Schuster, F. Rominger, Angew. Chem. Int. Ed. 48 (2009)
8247-8249.
[74] C.M. Krauter, A.S.K. Hashmi, M. Pernpointner, ChemCatChem 2 (2010)
1226-1230.
[75] M.C. Blanco Jaimes, F. Rominger, M.M. Pereira, R.M.B. Carrilho, S.A.C.
Carabineiro, A.S.K. Hashmi, Chem. Commun. 50 (2014) 4937-4940.
[76] M.C. Blanco Jaimes, C.R.N. Bohling, J.M. Serrano-Becerra, A.S.K. Hashmi,
Angew. Chem. Int. Ed. 52 (2013) 7963-7966.
21

ACCEPTED MANUSCRIPT
[77] A.S.K. Hashmi, Science 338 (2012) 1434-1434.
Table 1 Optimization of the reaction conditions.a
Entry Solvent
Additive
Temp. (ºC)
Time (h)
72
Yieldb(%)
45
1
2
DCE
–
25
30
40
50
40
DCE
–
72
62
3
DCE
–
72
93
4
DCE
–
60
71
5
DCE
3 Ǻ MS
72
68
6
DCE
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
H2O (5 equiv) 40
48
94
7
Toluene
DMSO
DCM
THF
48
69
8
48
78
9
48
75
10
11
12c
13d
72
23
MeCN
DCE
72
18
72
61
DCE
30
94
a All reactions were performed using indole-2-carbaldehyde 1a (1.0 mmol), propargylamine (4.0
b
mmol), MCM-41-PPh3-AuNTf2 (5 mol%) in solvent (4 mL) under Ar. Isolated yield based on
c
d
indole-2-carbaldehyde 1a used. 2.5 mol% of MCM-41-PPh3-AuNTf2 was used. 10 mol% of
MCM-41-PPh3-AuNTf2 was used.
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Table 2 Annulation of aldehydes with propargylamine catalyzed by MCM-41-PPh3-
AuNTf2.a,b
N
N
N
N
N
H
N
N
N
N
N
N
N
N
N
N
S
H
H
H
2e, 80%
2d, 84%
2c, 82%
2a, 94%
2b, 92%
N
N
N
N
N
N
N
N
N
N
O
N
S
S
O
O
O
O
2g, 72%
2f, 90%
2j, 76%
2h, 92%
2i, 81%
N
N
N
N
N
N
N
N
N
O
O
O
O
O
OH
2n, 93%
2k, 79%
2l, 82%
2o, 83%
2m, 81%
N
N
N
N
N
N
N
N
N
N
O
F
Br
Cl
2r, 70%
2s, 72%
2t, 74%
2q, 70%
2p, 86%
N
N
N
N
2u, 67%
2v, 55%
a All reactions were performed using aldehyde 1 (1.0 mmol), propargylamine (4.0 mmol), H2O (5
mmol), MCM-41-PPh3-AuNTf2 (5 mol%) in DCE (4 mL) under Ar for 48 h. b Isolated yield based
on aldehyde 1 used.
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Scheme 1. Preparation of MCM-41-PPh3-AuNTf2 complex
Scheme 2. Heterogeneous gold(I)-catalyzed one-pot protocol for the synthesis of
pyrazines from aldehydes and propargylamine.
24

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Scheme 3. A possible mechanism for this Au-catalyzed formation of pyrazines.
(100)
1
(110)
4
2
(200)
2
3
5
6
7
8
2θ (degrees)
Fig. 1. XRD patterns of the parent MCM-41 (1) and MCM-41-PPh3-AuNTf2 (2).
25

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Fig. 2. Energy dispersive spectra (EDS) of MCM-41-PPh3-AuNTf2.
100
80
60
40
20
0
1
2
3
4
5
6
7
8
Reused times
Fig. 3. Recycle of the MCM-41-PPh3-AuNTf2 catalyst
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Research Highlights
► The new MCM-41-PPh3-AuNTf2 complex can be easily prepared by a simple
procedure.
► Heterogeneous Au-catalyzed annulation of RCHO with propargylamine is first
reported.
► The reaction generates 3-substituted 2,5-dimethylpyrazines in high yields.
► The Au(I) catalyst can be recycled for 8 times without significant loss of activity.
► Our catalytic system provides a new and practical route to pyrazine derivatives.