Study on the iodine-catalyzed reaction of 3-aminopyrazine-2-carbohydrazide and 2-(arylethynyl)benzaldehydes

Article abstract of DOI:10.1016/j.tet.2018.02.007

At 60 °C in DMSO, the iodine-catalyzed reaction of 3-aminopyrazine-2-carbohydrazide and 2-(arylethynyl)benzaldehydes led hydrazones. Increasing the reaction temperature to 100 °C, the amino and amido still indicated inactive, only the imine took part in the addition of acetylene bond to give 2-arylisoquinolines in high yields with the cleavage of N-N bond unexpectedly under metal-free conditions.

Full text of DOI:10.1016/j.tet.2018.02.007

Accepted Manuscript
Study on the iodine-catalyzed reaction of 3-Aminopyrazine-2-carbohydrazide and 2-
(Arylethynyl)benzaldehydes
Wan-Chen Pan, Jian-Quan Liu, Xiang-Shan Wang
PII:
S0040-4020(18)30132-7
10.1016/j.tet.2018.02.007
TET 29278
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 November 2017
Revised Date: 29 January 2018
Accepted Date: 2 February 2018
Please cite this article as: Pan W-C, Liu J-Q, Wang X-S, Study on the iodine-catalyzed reaction of 3-
Aminopyrazine-2-carbohydrazide and 2-(Arylethynyl)benzaldehydes, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.02.007.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Study on the Iodine-Catalyzed Reaction of 3-Aminopyrazine-2-carbohydrazide
and 2-(Arylethynyl)benzaldehydes
Wan-Chen Pan, Jian-Quan Liu, Xiang-Shan Wang*
At 60 °C in DMSO, the iodine-catalyzed reaction of 3-aminopyrazine-2-carbohydrazide and
2-(arylethynyl)benzaldehydes lead hydrazones. Increasing the reaction temperature to 100 °C, the
amino and amido still indicated inactive, only the imine took part in the addition of acetylene bond
to give 2-arylisoquinolines in high yields with the cleavage of N-N bond unexpectedly under
metal-free conditions.

ACCEPTED MANUSCRIPT
Study on the Iodine-Catalyzed Reaction of 3-Aminopyrazine-2-carbohydrazide
and 2-(Arylethynyl)benzaldehydes
Wan-Chen Pan, Jian-Quan Liu, Xiang-Shan Wang*
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China
xswang1974@yahoo.com
Abstract: At 60 °C in DMSO, the iodine-catalyzed reaction of 3-aminopyrazine-2-carbohydrazide
and 2-(arylethynyl)benzaldehydes lead hydrazones. Increasing the reaction temperature to 100 °C,
the amino and amido still indicated inactive, only the imine took part in the addition of acetylene
bond to give 2-arylisoquinolines in high yields with the cleavage of N-N bond unexpectedly under
metal-free conditions.
Keywords: 3-aminopyrazine-2-carbohydrazide, 2-(arylethynyl)benzaldehyde, 2-arylisoquinoline,
iodine, metal-free
1. Introduction
Isoquinoline is a very useful heterocyclic skeleton, and the derivatives of which
possess various kinds of pharmacological and biological activities, such as
anti-telomerase,1 anti-tobacco mosaic virus,2 antibacterial,3 and anti-muscle atrophy
activities.4 Roxadustat (FG-4592; Figure 1, left)5 is a well-known drug based on
isoquinoline moiety, and it is an anti-anemic drug which is already used in the phase
III clinical trials. Another medicine is the famous Papaverine6 (Figure 1, right) which
is also a polysubstituted isoquinoline. It is an opium alkaloid and antispasmodic
medication which is used in the treatment of visceral spasm and vasospasm. In view
of their biological applications, numerous novel procedures have been reported to
synthesize structurally diversified isoquinoline derivatives in recent years.7
Of which, utilization of 2-(arylethynyl)benzaldehyde as a reactant is a very
efficient method to construct 2-substituted isoquinolines. The nitrogen sources
1

ACCEPTED MANUSCRIPT
involve NH4OAc,8 NH4HCO3,9 amidine,10 urea,11 hydrazine,12 NH3,13 amine14 and
hydroxylamine.15 However, the catalyst of transition metal salt is essential to this
conversion because it is always used to activate carbon-carbon triple bond, such as
Cu(I),10 Cu(II)11 and Yb(III),16 especially for Ag(I).8,9,12,14,15 Therefore, searching for a
novel procedure under metal-free conditions is still necessary.
Figure 1. The drugs containing isoquinoline moiety
Scheme 1. Our approach to 2-arylisoquinolines
Iodine is a mild Lewis acid which has been used to promote a lot of organic
reactions.17 In our recent study, it was submitted to catalyze the reaction of
3-aminopyrazine-2-carbohydrazide (1) and 2-(arylethynyl)benzaldehydes (2) in the air.
Our intention was to build the fused tetracyclic 5-arylidene-5,6-dihydro-8H-
phthalazino[1,2-b]pteridin-8-ones using three amino groups in the reactant of 1.
However, the amino on pyrazine and the amido group all showed chemical inertness,
only the third hydrazine amino group took part in the reaction. It was found that only
hydrazones were obtained at 60 °C, while at 100 °C, the subsequent cyclization and
2

ACCEPTED MANUSCRIPT
cleavage of N-N bond took place to give 2-arylisoquinolines losing a molecule of
3-amino-N-hydroxypyrazine-2-carboxamide unexpectedly (Scheme 1).
As our continuous research on the construction of heterocycles catalyzed by
iodine,18 we would like to report the synthesis of 2-arylisoquinoline from an
iodine-catalyzed reaction of 3-aminopyrazine-2-carbohydrazide and 2-(arylethynyl)
benzaldehydes under metal-free conditions.
2. Results and discussion
Scheme 2. The iodine-catalyzed reaction to hydrazone at 60 °C
As shown in Scheme 1 and 2, in our initial assumption, we planned to build
phthalazino[1,2-b]pteridin-8-one skeleton promoted by iodine. However, a new
compound was obtained at 60°C in the presence of 5 mol% iodine, and twelve protons
(see SI) were observed in its 1H NMR when 2-(phenylethynyl)benzaldehyde (2a, R1 =
R2 = H) was submitted to react with 1 in DMSO. Two peaks arriving (see SI) at 86.2
and 95.1 indicated that the triple bond did not attend the reaction initially. According
to the NMR data, 5H-pyrazino[2,3-e][1,2,4]triazepin-5-one (3′) was thought to be the
cyclation and oxidation product. Subsequently, various kinds of 2 (Table 1) were
3

ACCEPTED MANUSCRIPT
tested to react with 1, and all gave the similar products 3a-m in high yields under the
optimized reaction conditions. In our continuous study, a single crystal of 3e was
obtained in CHCl3 solution, and the X-ray diffraction analysis (Figure 2) confirmed
that it was the hydrazone (3e) that was 3-amino-N'-(5-fluoro-2-(phenylethynyl)
benzylidene)pyrazine-2-carbohydrazide.
Figure 2. The crystal structure of 3e
Table 1. The synthetic results for the products 3
Entry
1
R1
H
R2
H
Products
3a
Yields (%)
95
97
93
97
92
93
90
91
92
85
89
88
87
2
4-Cl
H
3b
3c
3
4-F
H
4
5-Cl
H
3d
3e
5
5-F
H
6
5-OCH3
4,5-(OCH3)2
2-Thieny
H
H
3f
7
H
3g
8
H
3h
3i
9
3-Cl
4-Cl
3-F
4-Cl
4-n-Pr
10
11
12
13
H
3j
4-Cl
3k
3l
4,5-(OCH3)2
4,5-(OCH3)2
3m
Reaction condition: 1 (77 mg, 0.5 mmol), 2 (0.5 mmol), iodine (7 mg), DMSO (5.0 mL), 60
°C.
4

ACCEPTED MANUSCRIPT
In order to promote one of the following reactions: (1) the addition of amino and
imine; (2) the coupling between amido and triple bond of carbon; (3) the addition of
imine and acetylenic bond, we subsequently changed the reaction temperature,
catalyst dosage and solvents in our lab (Table 2). It was found that the third addition
of imine and acetylenic bond gradually took place when the reaction increased to 100
°C giving isoquinoline derivatives. Furthermore, the highest yield reached 91% using
10 mol% iodine as a catalyst (Table 2) in the solvent of DMSO.
Table 2. The screening of reaction conditions from 1 to 4
Entry
T/°C
70
Cat./mol% Solvent
Yields (%)
1
2
5
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Dioxane
Toluene
Xylene
DMF
-
Trace
78
80
3
100
110
100
100
100
100
100
100
5
4
5
76
5
10
15
10
10
10
10
91
6
90
7
86
8
78
9
76
10
87
Reaction condition: 1 (77 mg, 0.5 mmol), 2a (103 mg, 0.5 mmol), solvent (5.0 mL).
With the optimized reaction conditions in hand, we next investigated the substrate
scope of the I2-catalyzed reaction by varying 2-(arylethynyl)benzaldehydes (Table 3).
In general, the reactants 2 with both electron-donating (e.g., H, Ph or Me) and
-withdrawing groups (e.g., Cl, F or Br) all reacted smoothly with 1 to give
2-arylisoquinolines in good to excellent yields (4a-4q, Table 3, 85-93%). It was
worthy to be noted that 2-(phenylethynyl)thiophene-3-carbaldehyde (2k) also
underwent the same reaction to lead 6-phenylthieno[3,2-c]pyridine (4k) in 88% yield.
However, we failed to give non-substituted isoquinoline (4r) when
2-ethynylbenzaldehyde (2r) was used as a reactant to react with 1 under the same
reaction conditions.
5

ACCEPTED MANUSCRIPT
Table 3. The structurally diversified isoquinoline products 4
O
CHO
N
R2
I2, 100 oC
DMSO
R1
NHNH2
R1
+
N
N
NH2
R2
4
1
2
Cl
F
N
N
N
N
Cl
4d, 91%
4a, 91%
4b, 93%
4c, 90%
N
N
N
N
H3CO
O2N
F
F
4g, 85%
4f, 93%
4j, 89%
4h, 91%
4e, 91%
Ph
S
O
O
MeO
MeO
Cl
N
N
N
N
4l, 90%
4i, 89%
4k, 88%
Et
Pr
Cl
N
N
N
N
4m, 86%
4n, 89%
4r, 0%
4o, 88%
4p, 90%
OCH3
N
N
4q, 92%
Reaction condition: 1 (77 mg, 0.5 mmol), 2 (0.5 mmol), DMSO (5.0 mL), I2 (13 mg, 0.05 mmol),
100 °C.
According to the literature12 and the structure of 4a, we believe that the iodine
activates the acetylenic bond first as a Lewis acid followed by the imine addition to
the activated triple bond to produce ylide 6. In the following step, the nitrogen anion
undergoes a protonation from water to yield intermediate 7. Finally, the key cleavage
of N-N bond occurs to give final product 4a, losing a molecule of
3-amino-N-hydroxypyrazine-2-carboxamide (8). The possible reaction mechanism is
outlined in Scheme 3 as follows (using 4a as a model).
6

ACCEPTED MANUSCRIPT
Ph
O
Ph
O
N
N
NH2
N
N
N
N
I2
N
H
NH2
H
+
O
- H2O
NH2
H
3a
1
2a
I2
Ph
Ph
O
O
N
N
N
N
N
I2
H2O
N
N
H
- OH
N
NH2
NH2
6
5
Ph
O
O
Ph
N
N
OH
N
N
N
N
N
N-N bond
cleavage
+
H
H
N
NH2
NH2
4a
OH
7
8
Scheme 3. The possible reaction mechanism
In order to acquire more insight to the reaction mechanism, one of the
intermediate products 6 (R1 = 6-F, R2 = Ph) could be isolated in 32% yield by column
chromatography when the reaction (Scheme 4) was stopped at about half time (3 h).
To our delight, the 3-amino-N-hydroxypyrazine-2-carboxamide (8) was also obtained
(52% yield) successfully in the filtrate which was extracted by ethyl acetate.
Scheme 4. The controlled reaction to 6
3. Conclusion
In conclusion, we found
a
temperature-controlled reaction of
3-aminopyrazine-2-carbohydrazide and 2-(arylethynyl)benzaldehydes catalyzed by
7

ACCEPTED MANUSCRIPT
iodine. It only gave hydrazones at 60 °C while the amino on pyrazine and amido
groups did not participate in this reaction. With the increase of temperature (100 °C)
and catalyst dosage (10 mol%), the imine group indicated higher reactivity to provide
2-arylisoquinoline derivatives with satisfied yields.
4. Experimental Section
Melting points were determined in open capillaries and are uncorrected. IR
1
spectra were recorded on a Tensor 27 spectrometer in KBr pellet. H NMR spectra
were obtained from a solution in DMSO-d6 with Me4Si as internal standard using a
Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-micro-
TOF-Q-MS analyzer. All the starting materials were purchased from Beijing
InnoChem Science & Technology Co., Ltd except for 2-(arylethynyl)benzaldehydes
which were prepared from the reaction of substituted 2-bromobenzoaldehydes and
arynes according to the literature.19
4.1 General procedure for the syntheses of (E)-3-amino-N'-(2-(arylethynyl)
benzylidene)pyrazine-2-carbohydrazides 3
3-Aminopyrazine-2-carbohydrazide (77 mg, 0.5 mmol) 2-(arylethynyl)benz-
aldehydes (0.5 mmol), iodine (7 mg, 0.025 mmol), and DMSO (5.0 mL) was added into
a dry 25 mL flask. The reaction mixture was stirred at 60 °C for 2-6 h until all the 1
was consumed which was monitored by TLC. Water (about 50 mL) was added to the
cool mixture, and the pale yellow precipitate formed immediately. The crude product
was obtained by filtration and purified by recrystallization from EtOH to give 3.
3-Amino-N'-(2-(phenylethynyl)benzylidene)pyrazine-2-carbohydrazide (3a):
1
M.p. 160 161 °C; H NMR (CDCl3, 400 MHz): δH 5.78 (brs., 2H, NH2), 7.38~7.42
(m, 5H, ArH), 7.56~7.58 (m, 1H, ArH), 7.60~7.62 (m, 2H, ArH), 7.85 (d, J = 1.6 Hz,
8

ACCEPTED MANUSCRIPT
1H, ArH), 8.22 (d, J = 2.0 Hz, 1H, ArH), 8.28~8.30 (m, 1H, ArH), 8.75 (s, 1H, CH),
13
10.88 (s, 1H, NH). C NMR (CDCl3, 100 MHz): δC 86.2, 95.1, 122.8, 123.5, 125.3,
126.1, 128.5, 128.7, 128.8, 130.2, 131.7, 132.7, 134.4, 146.5, 147.5, 155.4, 162.0. IR
(KBr):
ν 3397, 3313, 2975, 1691, 1666, 1603, 1529, 1478, 1438, 1390, 1350, 1294,
1249, 1150, 1034, 945, 922, 828 cm-1. HRMS (ESI, m/z): Calcd for C20H14N5O [M -
H]- 340.1204, found 340.1183.
3-Amino-N'-(4-chloro-2-(phenylethynyl)benzylidene)pyrazine-2-carbohydra
1
zide (3b): M.p. 216 217 °C; H NMR (CDCl3, 400 MHz): δH 5.73 (brs., 2H, NH2),
7.36 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H, ArH), 7.41~7.43 (m, 3H, ArH), 7.56~7.60 (m,
3H, ArH), 7.85 (d, J = 1.6 Hz, 1H, ArH), 8.21~8.23 (m, 2H, ArH), 8.68 (s, 1H, CH),
13
10.89 (s, 1H, NH). C NMR (CDCl3, 100 MHz): δC 84.9, 96.1, 122.2, 124.8, 125.1,
127.4, 128.6, 129.1, 129.2, 131.70, 131.72, 132.2, 132.9, 136.0, 145.3, 147.6, 155.4,
162.0. IR (KBr):
ν 3371, 3166, 3135, 1663, 1618, 1581, 1498, 1453, 1420, 1361,
1321, 1278, 1226, 1166, 1029, 950, 825, 691 cm-1. HRMS (ESI, m/z): Calcd for
C20H13ClN5O [M - H]- 374.0814, found 374.0838.
3-Amino-N'-(4-fluoro-2-(phenylethynyl)benzylidene)pyrazine-2-carbohydra
1
zide (3c): M.p. 189 190 °C; H NMR (CDCl3, 400 MHz): δH 5.68 (brs., 2H, NH2),
7.09~7.14 (m, 1H, ArH), 7.24~7.27 (m, 1H, ArH), 7.41~7.44 (m, 3H, ArH), 7.58~7.62
(m, 2H, ArH), 7.85 (d, J = 2.4 Hz, 1H, ArH), 8.23 (d, J = 2.0 Hz, 1H, ArH), 8.27~8.30
(m, 1H, ArH), 8.70 (s, 1H, CH), 10.87 (s, 1H, NH). IR (KBr):
ν 3400, 3362, 3143,
2972, 1655, 1618, 1513, 1476, 1381, 1289, 1241, 1209, 1132, 1048, 1037, 941, 863,
805 cm-1. HRMS (ESI, m/z): Calcd for C20H13FN5O [M - H]- 358.1109, found
358.1102.
9

ACCEPTED MANUSCRIPT
3-Amino-N'-(5-chloro-2-(phenylethynyl)benzylidene)pyrazine-2-carbohydra
1
zide (3d): M.p. 198 199 °C; H NMR (CDCl3, 400 MHz): δH 5.70 (brs., 2H, NH2),
7.34~7.36 (m, 1H, ArH), 7.40~7.42 (m, 3H, ArH), 7.49 (d, J = 8.4 Hz, 1H, ArH),
7.58~7.61 (m, 2H, ArH), 7.85 (d, J = 2.0 Hz, 1H, ArH), 8.24 (d, J = 2.4 Hz, 1H, ArH),
8.28 (d, J = 2.4 Hz, 1H, ArH), 8.69 (s, 1H, CH), 10.92 (s, 1H, NH). 13C NMR (CDCl3,
100 MHz): δC 85.3, 95.9, 121.7, 122.4, 125.0, 125.9, 128.6, 129.0, 130.3, 131.66,
131.71, 133.8, 135.1, 135.9, 145.1, 147.7, 155.4, 162.0. IR (KBr):
ν 3386, 3312,
3153, 2993, 1690, 1630, 1557, 1505, 1434, 1376, 1304, 1252, 1214, 1172, 1136,
1093, 1036, 1009, 997, 836, 806, 580 cm-1. HRMS (ESI, m/z): Calcd for
C20H13ClN5O [M - H]- 374.0814, found 374.0844.
3-Amino-N'-(5-fluoro-2-(phenylethynyl)benzylidene)pyrazine-2-carbohydra
1
zide (3e): M.p. 183 184 °C; H NMR (CDCl3, 400 MHz): δH 5.70 (brs., 2H, NH2),
7.08~7.12 (m, 1H, ArH), 7.40~7.42 (m, 3H, ArH), 7.53~7.60 (m, 3H, ArH), 7.85 (d, J
= 1.6 Hz, 1H, ArH), 7.98 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 8.23 (d, J = 1.2 Hz,
1H, ArH), 8.71 (s, 1H, CH), 10.92 (s, 1H, NH). IR (KBr):
ν 3400, 3260, 2958, 2930,
1665, 1612, 1586, 1502, 1439, 1408, 1337, 1247, 1215, 1143, 1094, 1004, 936, 883,
810, 758, 685 cm-1. HRMS (ESI, m/z): Calcd for C20H13FN5O [M - H]- 358.1109,
found 358.1101.
3-Amino-N'-(5-methoxy-2-(phenylethynyl)benzylidene)pyrazine-2-carbohyd
1
razide (3f): M.p. 248 249 °C; H NMR (CDCl3, 400 MHz): δH 3.91 (s, 3H, OCH3),
5.82 (brs., 2H, NH2), 6.96 (dd, J = 8.8 Hz, J’ = 2.4 Hz, 1H, ArH), 7.38~7.41 (m, 3H,
ArH), 7.48 (d, J = 8.8 Hz, 1H, ArH), 7.57~7.59 (m, 2H, ArH), 7.75 (d, J = 2.4 Hz, 1H,
ArH), 7.85 (d, J = 1.6 Hz, 1H, ArH), 8.23 (d, J = 2.0 Hz, 1H, ArH), 8.74 (s, 1H, CH),
13
10.90 (s, 1H, NH). C NMR (CDCl3, 100 MHz): δC 55.7, 86.3, 93.8, 108.7, 116.2,
118.6, 123.1, 125.2, 128.47, 128.51, 131.5, 131.7, 134.0, 135.8, 146.7, 147.6, 155.4,
10

ACCEPTED MANUSCRIPT
159.8, 162.0. IR (KBr):
ν 3391, 3266, 3148, 3072, 1691, 1627, 1604, 1574, 1556,
1527, 1487, 1429, 1353, 1276, 1138, 1081, 949, 795, 678 cm-1. HRMS (ESI, m/z):
Calcd for C21H16N5O2 [M - H]- 370.1309, found 370.1306.
3-Amino-N'-(4,5-dimethoxy-2-(phenylethynyl)benzylidene)pyrazine-2-carbo
1
hydrazide (3g): M.p. 204 205 °C; H NMR (CDCl3, 400 MHz): δH 3.95 (s, 3H,
OCH3), 4.01 (s, 3H, OCH3), 5.84 (brs., 2H, NH2), 7.01 (s, 1H, ArH), 7.40~7.41 (m,
3H, ArH), 7.59~7.61 (m, 2H, ArH), 7.72 (s, 1H, ArH), 7.85 (d, J = 2.4 Hz, 1H, ArH),
8.22 (d, J = 2.4 Hz, 1H, ArH), 8.68 (s, 1H, CH), 10.82 (s, 1H, NH). 13C NMR (CDCl3,
100 MHz): δC 56.1, 56.3, 86.3, 93.9, 107.5, 114.0, 117.0, 122.9, 125.3, 128.1, 128.5,
128.6, 131.6, 131.7, 146.9, 147.4, 149.9, 150.9, 155.4, 161.8. IR (KBr):
ν 3414, 3312,
3258, 3190, 3143, 1677, 1650, 1641, 1613, 1530, 1505, 1492, 1468, 1434, 1421,
1351, 1259, 1236, 1200, 1155, 1130, 1083, 1001, 982, 929, 880, 750, 687 cm-1.
HRMS (ESI, m/z): Calcd for C22H18N5O3 [M - H]- 400.1415, found 400.1440.
3-Amino-N'-((3-(phenylethynyl)thiophen-2-yl)methylene)pyrazine-2-carboh
1
ydrazide (3h): M.p. 213 214 °C; H NMR (CDCl3, 400 MHz): δH 5.76 (brs., 2H,
NH2), 7.13~7.14 (m, 1H, ArH), 7.36~7.40 (m, 4H, ArH), 7.56~7.59 (m, 2H, ArH),
7.82~7.83 (m, 1H, ArH), 8.21~8.22 (m, 1H, ArH), 8.66 (s, 1H, CH), 10.82 (s, 1H,
13
NH). C NMR (CDCl3, 100 MHz): δC 82.6, 94.7, 122.6, 124.9, 125.2, 128.3, 128.5,
128.8, 130.3, 131.6, 140.3, 142.1, 147.5, 155.4, 161.7. IR (KBr):
ν 3478, 3400, 3251,
2360, 2342, 1656, 1652, 1606, 1562, 1515, 1490, 1470, 1434, 1397, 1359, 1237,
1209, 1090, 1065, 1035, 1014, 940, 849, 830, 757 cm-1. HRMS (ESI, m/z): Calcd for
C18H12N5OS [M - H]- 346.0768, found 346.0782.
3-Amino-N'-(2-((3-chlorophenyl)ethynyl)benzylidene)pyrazine-2-carbohydr
1
azide (3i): M.p. 195 196 °C; H NMR (CDCl3, 400 MHz): δH 5.91 (brs., 2H, NH2),
11

ACCEPTED MANUSCRIPT
7.32~7.62 (m, 7H, ArH), 7.86 (d, J = 2.4 Hz, 1H, ArH), 8.23 (d, J = 2.4 Hz, 1H, ArH),
8.27~8.29 (m, 7H, ArH), 8.76 (s, 1H, CH), 10.89 (s, 1H, NH). IR (KBr):
ν 3432,
3337, 3292, 1624, 1592, 1558, 1505, 1466, 1444, 1357, 1212, 1147, 1089, 1003, 954,
891, 777, 752, 675 cm-1. HRMS (ESI, m/z): Calcd for C20H13ClN5O [M - H]-
374.0814, found 374.0837.
3-Amino-N'-(2-((4-chlorophenyl)ethynyl)benzylidene)pyrazine-2-carbohydr
1
azide (3j): M.p. 212 213 °C; H NMR (CDCl3, 400 MHz): δH 5.72 (brs., 2H, NH2),
7.37~7.42 (m, 4H, ArH), 7.52~7.57 (m, 3H, ArH), 7.85 (d, J = 2.4 Hz, 1H, ArH), 8.23
(d, J = 2.4 Hz, 1H, ArH), 8.27~8.29 (m, 1H, ArH), 8.73 (s, 1H, CH), 10.88 (s, 1H,
NH). 13C NMR (CDCl3, 100 MHz): δC 87.2, 93.9, 121.2, 123.1, 125.2, 126.2, 128.86,
128.92, 130.2, 131.7, 132.7, 132.9, 134.4, 134.9, 146.3, 147.6, 155.4, 162.0. IR
(KBr):
ν 3400, 3333, 3295, 3195, 3156, 1664, 1628, 1598, 1584, 1549, 1524, 1502,
1468, 1441, 1360, 1290, 1246, 1208, 1143, 1102, 1081, 1001, 953, 876, 823, 750, 687
cm-1. HRMS (ESI, m/z): Calcd for C20H13ClN5O [M - H]- 374.0814, found 374.0839.
3-Amino-N'-(4-chloro-2-((3-fluorophenyl)ethynyl)benzylidene)pyrazine-2-car
bohydrazide (3k): M.p. 194 195 °C; 1H NMR (CDCl3, 400 MHz): δH 5.80 (brs., 2H,
NH2), 7.09~7.14 (m, 1H, ArH), 7.30 (dd, J = 8.8 Hz, J’ = 2.4 Hz, 1H, ArH), 7.35~7.39
(m, 3H, ArH), 7.49 (d, J = 8.4 Hz, 1H, ArH), 7.86 (d, J = 2.0 Hz, 1H, ArH), 8.24 (d, J
= 2.4 Hz, 1H, ArH), 8.28 (d, J = 2.0 Hz, 1H, ArH), 8.69 (s, 1H, CH), 10.93 (s, 1H,
NH). IR (KBr):
ν 3478, 3350, 3226, 3102, 1651, 1600, 1546, 1527, 1510, 1454, 1431,
1327, 1284, 1236, 1202, 1145, 1066, 1027, 945, 932, 861, 837, 810, 753, 738, 692
cm-1. HRMS (ESI, m/z): Calcd for C20H12ClFN5O [M - H]- 392.0720, found 392.0714.
3-Amino-N'-(2-((4-chlorophenyl)ethynyl)-4,5-dimethoxybenzylidene)pyrazin
e-2-carbohydrazide (3l): M.p. 212 213 °C; 1H NMR (CDCl3, 400 MHz): δH 3.94 (s,
12

ACCEPTED MANUSCRIPT
3H, OCH3), 4.01 (s, 3H, OCH3), 5.92 (brs., 2H, NH2), 6.99 (s, 1H, ArH), 7.36~7.38
(m, 2H, ArH), 7.51~7.53 (m, 2H, ArH), 7.72 (s, 1H, ArH), 7.84 (d, J = 2.0 Hz, 1H,
13
ArH), 8.22 (d, J = 2.4 Hz, 1H, ArH), 8.66 (s, 1H, CH), 10.84 (s, 1H, NH). C NMR
(CDCl3, 100 MHz): δC 56.1, 56.3, 87.3, 92.7, 107.5, 114.0, 116.5, 121.4, 125.3, 128.3,
128.9, 131.7, 132.8, 134.7, 146.7, 147.5, 150.1, 150.9, 155.4, 161.9. IR (KBr):
ν
3460, 3408, 1687, 1592, 1556, 1506, 1467, 1450, 1438, 1409, 1377, 1335, 1250,
1215, 1171, 1141, 1094, 1070, 1002, 938, 856, 756 cm-1. HRMS (ESI, m/z): Calcd for
C22H17ClN5O3 [M - H]- 434.1025, found 434.1014.
3-Amino-N'-(4,5-dimethoxy-2-((4-propylphenyl)ethynyl)benzylidene)pyrazi
ne-2-carbohydrazide (3m): M.p. 193 194 °C; 1H NMR (CDCl3, 400 MHz): δH 0.96
(t, J = 7.2 Hz, 3H, CH3), 1.66~1.70 (m, 2H, CH2), 2.63 (t, J = 7.2 Hz, 2H, CH2), 3.94
(s, 3H, OCH3), 4.01 (s, 3H, OCH3), 5.88 (brs., 2H, NH2), 7.00 (s, 1H, ArH), 7.20~7.22
(m, 2H, ArH), 7.49~7.51 (m, 2H, ArH), 7.70 (s, 1H, ArH), 7.84 (d, J = 2.4 Hz, 1H,
13
ArH), 8.21 (d, J = 2.4 Hz, 1H, ArH), 8.68 (s, 1H, CH), 10.82 (s, 1H, NH). C NMR
(CDCl3, 100 MHz): δC 13.8, 24.4, 38.0, 56.1, 56.3, 85.6, 94.1, 107.4, 114.0, 117.2,
120.0, 125.3, 128.0, 128.7, 131.5, 131.7, 143.7, 147.0, 147.4, 149.8, 150.9, 155.4,
161.8. IR (KBr):
ν 3400, 3343, 3197, 1659, 1651, 1608, 1548, 1531, 1504, 1494,
1462, 1441, 1408, 1360, 1237, 1202, 1145, 1108, 1083, 949, 754, 688 cm-1. HRMS
(ESI, m/z): Calcd for C25H24N5O3 [M - H]- 442.1884, found 442.1889.
4.3 General procedure for the syntheses of 2-arylisoquinoline derivatives 4
3-Aminopyrazine-2-carbohydrazide (1, 77 mg, 0.5 mmol) 2-(arylethynyl)
benzaldehydes 2 (0.5 mmol), iodine (13 mg, 0.05 mmol), and DMSO (5.0 mL) was
added into a dry 25 mL flask. The reaction mixture was stirred at 100 °C for 4-10 h
until all the 1 and intermediate product hydrazone were consumed which was
monitored by TLC. The separation and purification of the products 4 were the same to
13

ACCEPTED MANUSCRIPT
those of 3. In the process of 4a, the filtrate was extracted with ethyl acetate (30 mL ×
3). The organic layer was combined and dried by anhydrous Na2SO4. The ethyl
acetate was recovered by rotary evaporation, and the residue was purified by column
chromatography using ethyl acetate and petroleum ether (2:1) as an eluant to give
3-amino-N-hydroxypyrazine-2-carboxamide (8) in 52% yield.
1
3-Phenylisoquinoline (4a): M.p. 104 105 °C (Lit.20 103~104 °C); H NMR
(CDCl3, 400 MHz): δH 7.39~7.44 (m, 1H, ArH), 7.49~7.59 (m, 3H, ArH), 7.66~7.70
(m, 1H, ArH), 7.86 (d, J = 8.0 Hz, 1H, ArH), 7.98 (d, J = 8.4 Hz, 1H, ArH), 8.06 (s,
1H, ArH), 8.11~8.14 (m, 2H, ArH), 9.33 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz):
δC 116.5, 126.9, 127.0, 127.1, 127.6, 127.8, 128.5, 128.8, 130.5, 136.7, 139.6, 151.3,
152.4. IR (KBr):
ν 2912, 1625, 1585, 1562, 1515, 1489, 1332, 1279, 1196, 1139,
1131, 1035, 960, 944, 884, 742, 713, 680 cm-1. HRMS (APCI, m/z): Calcd for
C15H12N [M + H]+ 206.0964, found 206.0973.
3-Amino-N-hydroxypyrazine-2-carboxamide (8): M.p. 198-200 °C (Lit.21 196
1
°C), H NMR (DMSO-d6, 400 MHz): δH 7.42 (brs, 3H, NH2 + OH), 7.76 (d, J = 2.4
Hz, 1H, ArH), 8.17 (d, J = 2.4 Hz, 1H, ArH), 9.43 (brs, 1H, NH). 13C NMR
(DMSO-d6, 100 MHz): δC 126.3, 131.3, 146.8, 155.1, 163.6.
1
6-Chloro-3-phenylisoquinoline (4b): M.p. 143 144 °C (Lit.22 140~141 °C); H
NMR (CDCl3, 400 MHz): δH 7.41~7.45 (m, 1H, ArH), 7.50~7.54 (m, 3H, ArH),
7.84(d, J = 2.0 Hz, 1H, ArH), 7.92(d, J = 8.8 Hz, 1H, ArH), 7.96 (s, 1H, ArH),
13
8.09~8.12 (m, 2H, ArH), 9.30 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 115.5,
125.7, 125.9, 127.1, 128.1, 128.9, 129.2, 136.8, 137.4, 139.1, 152.2, 152.4. IR (KBr):
ν
3058, 2924, 1597, 1563, 1479, 1451, 1383, 1271, 1071, 1020, 966, 944, 896, 817,
14

ACCEPTED MANUSCRIPT
760, 690, 677 cm-1. HRMS (APCI, m/z): Calcd for C15H11ClN [M + H]+ 240.0575,
found 240.0585.
1
6-Fluoro-3-phenylisoquinoline (4c): M.p. 110 111 °C (Lit.23 108~110 °C); H
NMR (CDCl3, 400 MHz): δH 7.31~7.36 (m, 1H, ArH), 7.41~7.53 (m, 4H, ArH),
7.97~8.01 (m, 2H, ArH), 8.09~8.12 (m, 2H, ArH), 9.30 (s, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 110.2 (d, J(F-C) = 20.8 Hz), 116.0 (d, J(F-C) = 5.4 Hz), 117.6 (d,
J(F-C) = 25.6 Hz), 124.9, 127.1, 128.8, 128.9, 130.6(d, J(F-C) = 9.9 Hz), 138.1 (d, J(F-C)
=
10.5 Hz), 139.2, 152.06, 152.14, 163.4 (d, J(F-C) = 250.8 Hz). IR (KBr): 3049, 3030,
ν
1625, 1162, 1585, 1562, 1515, 1488, 1372, 1332, 1279, 1212, 1184, 1139, 1131, 1111,
1035, 1015, 960, 944, 884, 742, 713 cm-1. HRMS (APCI, m/z): Calcd for C15H11FN
[M + H]+ 224.0870, found 224.0886.
1
7-Chloro-3-phenylisoquinoline (4d): M.p. 106 107 °C (Lit.22 108~110 °C); H
NMR (CDCl3, 400 MHz): δH 7.44~7.47 (m, 1H, ArH), 7.52~7.56 (m, 2H, ArH), 7.65
(dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H, ArH), 7.84 (d, J = 8.8 Hz, 1H, ArH), 7.99 (s, 1H,
ArH), 8.07 (s, 1H, ArH), 8.13~8.15 (m, 2H, ArH), 9.29 (s, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 116.1, 126.3, 127.0, 128.1, 128.6, 128.8, 128.9, 131.6, 132.5,
134.9, 139.2, 151.4, 151.7. IR (KBr):
ν 3057, 3028, 1583, 1569, 1497, 1448, 1348,
1274, 1212, 1078, 947, 921, 882, 814, 782, 761, 689 cm-1. HRMS (APCI, m/z): Calcd
for C15H11ClN [M + H]+ 240.0575, found 240.0585.
1
7-Fluoro-3-phenylisoquinoline (4e): M.p. 108 109 °C (Lit.24 136~138 °C); H
NMR (CDCl3, 400 MHz): δH 7.40~7.44 (m, 1H, ArH), 7.45~7.53 (m, 3H, ArH), 7.59
(dd, J = 8.8 Hz, J’ = 2.4 Hz, 1H, ArH), 7.88 (dd, J = 9.2 Hz, J’ = 5.2 Hz, 1H, ArH),
8.05 (s, 1H, ArH), 8.09~8.12 (m, 2H, ArH), 9.29 (s, 1H, ArH). 13C NMR (CDCl3, 100
MHz): δC 110.6 (d, J(F-C) = 20.5 Hz), 116.3 (d, J(F-C) = 1.5 Hz), 121.2 (d, J(F-C) = 25.5
15

ACCEPTED MANUSCRIPT
Hz), 126.9, 128.2 (d, J(F-C) = 8.3 Hz), 128.6, 128.8, 129.6 (d, J(F-C) = 8.4 Hz), 133.7 (d,
J(F-C) = 0.5 Hz), 139.3, 151.0 (d, J(F-C) = 2.8 Hz), 151.6 (d, J(F-C) = 5.5 Hz), 160.8 (d,
J(F-C) = 247.8 Hz). IR (KBr):
ν 3056, 3045, 1574, 1500, 1492, 1452, 1389, 1358,
1280, 1223, 1181, 1138, 1020, 966, 909, 859, 814, 780, 767, 690 cm-1. HRMS (APCI,
m/z): Calcd for C15H11FN [M + H]+ 224.0870, found 224.0888.
1
7-Nitro-3-phenylisoquinoline (4f): M.p. 106 107 °C (Lit.23 105~107 °C); H
NMR (CDCl3, 400 MHz): δH 7.46~7.56 (m, 3H, ArH), 8.01 (d, J = 8.8 Hz, 1H, ArH),
8.16~8.18 (m, 3H, ArH), 8.45 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H, ArH), 8.95 (d, J = 2.0
Hz, 1H, ArH), 9.52 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 116.4, 126.9,
127.3, 127.6, 127.8, 128.2, 128.9, 130.7, 134.6, 136.6, 138.0, 150.0, 152.5. IR (KBr):
ν
3085, 2919, 1628, 1589, 1519, 1484, 1444, 1400, 1343, 1275, 1214, 1085, 959, 924,
830, 822, 789, 786, 765, 691 cm-1. HRMS (APCI, m/z): Calcd for C15H11N2O2 [M +
H]+ 251.0815, found 251.0822.
7-Methoxy-3-phenylisoquinoline (4g): M.p. 164 165 °C (Lit.25 158~159 °C);
1H NMR (CDCl3, 400 MHz): δH 3.96 (s, 3H, OCH3), 7.24~7.26 (m, 1H, ArH), 7.35
(dd, J = 8.8 Hz, J’ = 2.8 Hz, 1H, ArH), 7.37~7.42 (m, 1H, ArH), 7.48~7.52 (m, 2H,
ArH), 7.77 (d, J = 8.8 Hz, 1H, ArH), 8.00 (s, 1H, ArH), 8.09~8.11 (m, 2H, ArH), 9.24
(s, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 55.5, 104.7, 116.4, 123.8, 126.7,
128.2, 128.5, 128.8, 128.9, 132.3, 139.7, 149.7, 150.9, 158.4. IR (KBr):
ν 2997, 2967,
1622, 1590, 1492, 1410, 1388, 1359, 1269, 1235, 1202, 1159, 1025, 957, 910, 880,
846, 826, 797, 695 cm-1. HRMS (APCI, m/z): Calcd for C16H14NO [M + H]+
236.1070, found 236.1074.
1
8-Fluoro-3-phenylisoquinoline (4h): M.p. 99 100 °C (Lit.26 99~100 °C); H
NMR (CDCl3, 400 MHz): δH 7.45~7.49 (m, 2H, ArH), 7.57~7.61 (m, 1H, ArH),
16

ACCEPTED MANUSCRIPT
7.68~7.72 (m, 1H, ArH), 7.86 (d, J = 8.4 Hz, 1H, ArH), 7.98 (d, J = 8.4 Hz, 1H, ArH),
8.03 (s, 1H, ArH), 8.05~8.08 (m, 2H, ArH), 9.31 (s, 1H, ArH). 13C NMR (CDCl3, 100
MHz): δC 110.8 (d, J(F-C) = 19.0 Hz), 115.8 (d, J(F-C) = 2.9 Hz), 118.1 (d, J(F-C) = 15.5
Hz), 122.8 (d, J(F-C) = 4.3 Hz), 127.1, 128.8, 130.8 (d, J(F-C) = 8.5 Hz), 138.1 (d, J(F-C)
= 3.6 Hz), 139.2, 146.2 (d, J(F-C) = 4.6 Hz), 152.3 (d, J(F-C) = 0.9 Hz), 159.3 (d, J(F-C)
=
254.7 Hz). IR (KBr): 3057, 2954, 2924, 1625, 1561, 1492, 1458, 1438, 1402, 1329,
ν
1277, 1216, 1200, 1141, 1090, 1010, 961, 942, 886, 833, 750, 738, 714, 655 cm-1.
HRMS (APCI, m/z): Calcd for C15H11FN [M + H]+ 224.0870, found 224.0885.
6,7-Dimethoxy-3-phenylisoquinoline (4i): M.p. 127 128 °C (Lit.24 129~131 °C); 1H
NMR (CDCl3, 400 MHz): δH 4.04 (s, 6H, 2OCH3), 7.12 (s, 1H, ArH), 7.22 (s, 1H,
ArH), 7.38~7.41 (m, 1H, ArH), 7.47~7.51 (m, 2H, ArH), 7.93 (s, 1H, ArH), 8.07~8.09
(m, 2H, ArH), 9.12 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 56.08, 56.11,
105.0, 105.3, 115.5, 123.8, 126.8, 128.2, 128.7, 133.3, 133.9, 149.8, 150.28, 150.30,
153.2. IR (KBr):
ν 2995, 1621, 1594, 1577, 1505, 1477, 1363, 1270, 1241, 1148,
1024, 1005, 834, 845, 752, 689, 652 cm-1. HRMS (APCI, m/z): Calcd for C17H16NO2
[M + H]+ 266.1176, found 266.1167.
7-Phenyl-[1,3]dioxolo[4,5-g]isoquinoline (4j): M.p. 135 136 °C (Lit.24
135~137 °C); 1H NMR (CDCl3, 400 MHz): δH 6.10 (s, 2H, OCH2), 7.12 (s, 1H, ArH),
7.21 (s, 1H, ArH), 7.37~7.41 (m, 1H, ArH), 7.47~7.51 (m, 2H, ArH), 7.90 (s, 1H,
13
ArH), 8.06~8.08 (m, 2H, ArH), 9.06 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC
101.6, 102.8, 103.1, 116.3, 125.0, 126.8, 128.3, 128.7, 135.1, 139.7, 148.3, 150.2,
150.6, 151.1. IR (KBr):
ν 2955, 2900, 1600, 1483, 1459, 1441, 1262, 1233, 1159,
1088, 1048, 963, 921, 885, 851, 778, 755, 705 cm-1. HRMS (APCI, m/z): Calcd for
C16H12NO2 [M + H]+ 250.0863, found 250.0878.
17

ACCEPTED MANUSCRIPT
1
6-Phenylthieno[3,2-c]pyridine (4k): M.p. 73 74°C; H NMR (CDCl3, 400
MHz): δH 7.39~7.43 (m, 2H, ArH), 7.48~7.51 (m, 2H, ArH), 7.72 (d, J = 5.2 Hz, 1H,
ArH), 8.04~8.07 (m, 2H, ArH), 8.12 (d, J = 0.8 Hz, 1H, ArH), 9.22 (s, 1H, ArH). 13C
NMR (CDCl3, 100 MHz): δC 114.5, 123.3, 127.0, 128.5, 128.8, 132.4, 135.1, 139.7,
144.3, 146.0, 151.9. IR (KBr):
ν 3080, 3052, 1585, 1532, 1476, 1435, 1393, 1296,
1238, 1188, 1178, 1074, 1033, 1016, 898, 869, 760, 689, 645 cm-1. HRMS (APCI,
m/z): Calcd for C13H10NS [M + H]+ 212.0528, found 212.0548.
3-(3-Chlorophenyl)isoquinoline (4l): M.p. 103 104 °C (Lit.22 99~100 °C); 1H NMR
(CDCl3, 400 MHz): δH 7.37~7.45 (m, 2H, ArH), 7.59~7.63 (m, 1H, ArH), 7.69~7.73
(m, 1H, ArH), 7.88 (d, J = 8.0 Hz, 1H, ArH), 7.99~8.01 (m, 2H, ArH), 8.05 (s, 1H,
13
ArH), 8.14~8.15 (m, 1H, ArH), 9.33 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC
116.8, 125.0, 127.0, 127.1, 127.4, 127.6, 128.0, 128.5, 130.0, 130.7, 134.9, 136.5,
141.4, 149.7, 152.5. IR (KBr):
ν 2955, 2923, 1589, 1564, 1490, 1485, 1472, 1443,
1410, 1386, 1323, 1281, 1214, 1202, 1141, 1091, 1079, 1038, 996, 961, 798, 748,
696, 673 cm-1. HRMS (APCI, m/z): Calcd for C15H11ClN [M + H]+ 240.0575, found
240.0578.
1
3-(4-Chlorophenyl)isoquinoline (4m): M.p. 141 143 °C (Lit.22 140 142); H NMR
(CDCl3, 400 MHz): δH 7.18~7.22 (m, 1H, ArH), 7.41~7.46 (m, 1H, ArH), 7.50~7.54
(m, 2H, ArH), 7.59~7.66 (m, 2H, ArH), 8.06 (s, 1H, ArH), 8.11~8.14 (m, 2H, ArH),
9.61 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 116.4, 126.9, 127.3, 127.6, 127.8,
128.2, 128.9, 130.7, 134.6, 136.6, 138.0, 150.1, 152.5. IR (KBr):
ν 2955, 2924, 1564,
1484, 1443, 1410, 1339, 1323, 1281, 1213, 1202, 1141, 1091, 1079, 1037, 1015, 961,
943, 898, 877, 854, 798, 748, 696, 673 cm-1. HRMS (APCI, m/z): Calcd for
C15H11ClN [M + H]+ 240.0575, found 240.0595.
18

ACCEPTED MANUSCRIPT
1
3-(p-Tolyl)isoquinoline (4n): M.p. 97 98 °C (Lit.22 94~96 °C); H NMR
(CDCl3, 400 MHz): δH 2.42 (s, 3H, CH3), 7.30~7.32 (m, 2H, ArH), 7.53~7.57 (m, 1H,
ArH), 7.65~7.69 (m, 1H, ArH), 7.84 (d, J = 8.4 Hz, 1H, ArH), 7.96 (dd, J = 8.0 Hz, J’
13
= 0.4 Hz, 1H, ArH), 8.01~8.04 (m, 3H, ArH), 9.32 (s, 1H, ArH). C NMR (CDCl3,
100 MHz): δC 21.3, 116.0, 126.8, 127.5, 127.6, 129.5, 130.4, 136.7, 136.8, 138.4,
151.3, 152.3. IR (KBr):
ν 3061, 1636, 1591, 1574, 1450, 1434, 1351, 1280, 1256,
1218, 1194, 1083, 1049, 1030, 905, 894, 866, 795, 778, 689, 677 cm-1. HRMS (APCI,
m/z): Calcd for C16H14N [M + H]+ 220.1121, found 220.1131.
3-(4-Ethylphenyl)isoquinoline (4o): M.p. 89 90 °C (Lit.27 85~87 °C); 1H NMR
(CDCl3, 400 MHz): δH 1.29 (t, J = 7.6 Hz, 3H, CH3), 2.72 (q, J = 7.6 Hz, 2H, OCH2),
7.33~7.35 (m, 2H, ArH), 7.53~7.57 (m, 1H, ArH), 7.65~7.68 (m, 1H, ArH), 7.84 (d, J
= 8.0 Hz, 1H, ArH), 7.96 (d, J = 8.4 Hz, 1H, ArH), 8.03~8.06 (m, 3H, ArH), 9.32 (s,
1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 15.6, 28.7, 116.0, 126.9, 127.0, 127.6,
127.7, 128.3, 130.4, 136.7, 137.1, 144.8, 151.4, 152.3. IR (KBr):
ν 2961, 2927, 1743,
1623, 1611, 1584, 1510, 1485, 1445, 1436, 1279, 1186, 1141, 1016, 965, 941, 888,
759 cm-1. HRMS (APCI, m/z): Calcd for C17H16N [M + H]+ 234.1277, found
234.1290.
1
3-(4-n-Propylphenyl)isoquinoline (4p): M.p. 68 69 °C; H NMR (CDCl3, 400
MHz): δH 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.66~1.75 (m, 2H, CH2), 2.66 (t, J = 7.2 Hz,
2H, CH2), 7.31~7.33 (m, 2H, ArH), 7.54~7.58 (m, 1H, ArH), 7.66~7.70 (m, 1H, ArH),
7.86 (d, J = 8.0 Hz, 1H, ArH), 7.98 (d, J = 8.0 Hz, 1H, ArH), 8.03~8.05 (m, 3H, ArH),
13
9.32 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 13.9, 24.5, 37.8, 116.1, 126.9,
127.57, 127.64, 129.0, 130.5, 136.7, 137.0, 143.3, 151.4, 152.3. IR (KBr):
ν 3000,
2955, 1742, 1624, 1588, 1565, 1511, 1488, 1447, 1438, 1376, 1329, 1280, 1208,
19

ACCEPTED MANUSCRIPT
1195, 1142, 1133, 1017, 962, 941, 887, 839, 806, 748, 683 cm-1. HRMS (APCI, m/z):
Calcd for C18H18N [M + H]+ 248.1434, found 248.1442.
3-(4-Methoxyphenyl)isoquinoline (4q): M.p. 105 106 °C (Lit.25 102~103 °C);
1H NMR (CDCl3, 400 MHz): δH 3.88 (s, 3H, OCH3), 7.03~7.05 (m, 2H, ArH),
7.53~7.56 (m, 1H, ArH), 7.65~7.68 (m, 1H, ArH), 7.83 (d, J = 8.4 Hz, 1H, ArH),
7.95~7.98 (m, 2H, ArH), 8.07~8.09 (m, 2H, ArH), 9.30 (s, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 55.4, 114.2, 115.4, 126.7, 126.8, 127.4, 127.6, 128.2, 130.5,
132.3, 136.8, 151.1, 152.3, 160.1. IR (KBr):
ν 3059, 2963, 1740, 1625, 1514, 1491,
1455, 1442, 1345, 1282, 1271, 1196, 1174, 1111, 1039, 1024, 961, 943, 881, 830, 818,
747, 725, 679 cm-1. HRMS (APCI, m/z): Calcd for C16H14NO [M + H]+ 236.1070,
found 236.1068.
4.4 General procedure for the syntheses of ylide 6
3-Aminopyrazine-2-carbohydrazide (1, 77 mg, 0.5 mmol) 4-fluoro-2-(phenyl
ethynyl)benzaldehyde (2c, 112 mg, 0.5 mmol), iodine (13 mg, 0.05 mmol), and DMSO
(5.0 mL) was added into a dry 25 mL flask. The reaction mixture was stirred at 100
°C for 3 h. The cooled mixture was poured into 100 mL water which was extracted
with ethyl acetate (50 mL × 3). The organic layer was combined and dried by
anhydrous Na2SO4. The ethyl acetate was recovered by rotary evaporation, and the
residue was purified by column chromatography using ethyl acetate and petroleum
ether (1:1) as an eluant to give 4c, 6 in 48% and 32% yields, respectively.
(3-Aminopyrazine-2-carbonyl)(6-fluoro-3-phenylisoquinolin-2-ium-2-yl)amide
1
(6): M.p. 245~246 °C; H NMR (DMSO-d6, 400 MHz): δH 7.15 (s, 2H, NH2),
7.44~7.46 (m, 3H, ArH), 7.64~7.71 (m, 3H, ArH), 7.91 (s, 2H, ArH), 8.10 (d, J = 9.2
Hz, 1H, ArH), 8.50~8.54 (m, 2H, ArH), 9.87 (s, 1H, ArH). 13C NMR (DMSO-d6, 100
20

ACCEPTED MANUSCRIPT
MHz): δC 111.5 (d, J(F-C) = 22.0 Hz), 121.5 (d, J(F-C) = 27.1 Hz), 125.0, 126.1 (d, J(F-C)
= 5.3 Hz), 128.6, 129.1, 129.8, 130.3, 131.5, 132.0, 133.1 (d, J(F-C) = 9.8 Hz), 137.7
(d, J(F-C) = 9.5 Hz), 146.6, 148.8, 155.3, 165.4 (d, J(F-C) = 253.8 Hz), 167.4, 169.7.
HRMS (APCI, m/z): Calcd for C20H15FN5O [M + H]+ 360.1255, found 360.1248.
Acknowledgements
This work was financially supported by NSFC of China (No. 21702078), the NSF of
Jiangsu Province (No. BK20170231 and 17KJA150003), the Priority Academic
Program Development of Jiangsu Higher education Institutions and TAPP.
References
1. Noureini SK, Esmaeili H, Abachi F, Khiali S, Islam B, Kuta M, Saboury AA,
Hoffmann M, Sponer J, Parkinson G, Haider S, Biochim Biophys Acta.
2017;1861:2020-2030.
2. Zhou L, Liu LX, Yang GR, Xing HH, Ma HY, Yang Y, Wang YD, Zhou K, Dong W,
Zhou M, Ye YQ, Hu QF. Chem Nat Compd. 2017;53:508-511.
3. Panchaud P, Bruyère T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M,
Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G.
J Math Chem. 2017;60:3755-3775.
4. Lee HJ, Tuong LT, Jeong JH, Lee SJ, Bae GU, Ryu JH. Bioorg Med Chem Lett.
2017;27:1401-1404.
5. Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K,
Daniel TM, Leong R, Poole L, Zhong M, Saikali KG, Franco M, Hemmerich S, Poney
KH, Neff TB. J Am Soc Nephrol. 2016;27:1225-1233.
6. Ricci JA, Koolen PG, Shah J, Tobias AM, Lee BT, Lin SJ. Plast Reconst Surg.
2016;138:401e-408e.
7. (a) Chrzanowska M, Grajewska A, Rozwadowska MD. Chem Rev.
2016;116:12369-12465. (b) He R, Huang Z-T, Zheng Q-Y, Wang C. Tetrahedron Lett.
2014;55:5705-5713. (c) Majumdar KC, Ponra S. J Indian Chem Soc. 2013;
90:1599-1616. (d) Alvarez M, Joule JA. Sci Synth. 2005;15:661-838. (e) Gong S-S, Xi
W-L, Ding Z-H, Sun H-Y. J Org Chem. 2017;82:7643-7647. (f) Hu K, Qi L-J, Yu S-L,
Cheng T-X, Wang X-D, Li Z-J, Xia Y-Z, Chen J-X, Wu H-Y. Green Chem.
21

ACCEPTED MANUSCRIPT
2017;9:1740-1750. (g) Siddaraju Y, Prabhu KR. Tetrahedron. 2016;72:959-967. (h)
He R-Y, Huang Z-T, Zheng Q-Y, Wang C-Y. Tetrahedron Lett. 2014;55:705-5713. (i)
Magnus P, Matthews KS. Tetrahedron. 2012;68:6343-6360. (j) Pilgrim BS, Gatland
AE, Esteves CH, McTernan CT, Jones G, Tatton MR, Procopiou PA, Donohoe TJ. Org
Biomol Chem. 2016;14:1065-1090.
8. Domaradzki ME, Long L, She Z, Liu X, Zhang G, Chen Y. J Org Chem.
2015;80:11360-11368.
9. Zhao YH, Luo MJ, Li YB, Liu X, Tang ZL, Deng KQ, Zhao G. Chin J Chem.
2016;34:857-860.
10. Shekarrao K, Kaishap PP, Gogoi S, Boruah RC. RSC Adv. 2014;4:14013-14023.
11. Ju J, Hua R. Curr Org Chem. 2013;10:328-332.
12. Zhao YH, Li Y, Luo M, Tang Z, Deng K. Synlett. 2016;27:2597-2600.
13. Alfonsi M, Acqua MD, Facoetti D, Arcadi A, Abbiati G, Rossi E. J Org Chem.
2010;2009:2852-2862.
14. Jeganathan M, Pitchumani K. RSC Adv. 2014;4:38491-38497.
15. Gao H-Y, Zhang J-L. Adv Synth Catal. 2009;351:85-88.
16. Yao B, Deng C-L, Liu Y, Tang R-Y, Zhang X-G, Li J-H. Chem Commun.
2015;51:4097-4100.
17. (a) Wang Q-D, Yang J-M, Fang D, Ren J-M, Zeng B-B. Tetrahedron Lett.
2017;58:2877-2880. (b) Tiwari AR, Bhanage BM. Asian J Org Chem.
2017;6:831-836. (c) Siddaraju Y, Prabhu KR. Org Biomol Chem. 2017;15:5191-5196.
(d) Zhang H-W, Muniz K. ACS Catal. 2017;7:4122-4125. (e) Lu L, Zhang M-M,
Jiang H, Wang X-S. Tetrahedron Lett. 2013;54:757-760.
18. (a) Zhang W-T, Qiang W-W, Yao C-S, Wang X-S. Tetrahedron.
2016;72:2178-2185. (b) Feng B-B, Lu L, Li C, Wang X-S. Org Biomol Chem.
2016;14:2774-2779. (c) Jin R-Z, Zhang W-T, Zhou Y-J, Wang X-S. Tetrahedron Lett.
2016;57:2515-2519.
19. Sonogashira K, Tohda Y, Hagihara N. Tetrahedron Lett. 1975;16:4467-4470.
20. Domaradzki ME, Long YH, She ZG, Liu XC, Zhang G, Chen Y. J Org Chem.
2015;80:11360-11368.
21. Wright WB, Smith JM. J Am Chem Soc. 1955;77:3926-3927.
22. Niu YN, Yan ZY, Gao G-, Wang HL, Shu XZ, Ji KG, Liang YM. J Org Chem.
2009;74:2893-2896.
23. Dhara S, Singha R, Nuree Y, Ray JK. Tetrahedron Lett. 2014;55:795-798.
22

ACCEPTED MANUSCRIPT
24. Ghavtadze N, Froehlich R, Wuerthwein EU. Eur J Org Chem. 2010;(9):
1787-1797.
25. Yang D-Q, Burugupalli S, Daniel D, Chen Y. J Org Chem. 2012;77:4466-4472.
26. Song J, Chen WB, Zhao YJ, Li CL, Liang G, Huang LH. RSC Adv.
2016;6:54984-54992.
27. Kumar S, Saunthwal RK, Aggarwal T, Kotla SR, Verma AK. Org Biomol Chem.
2016;14:9063-9071.
23