Microwave-assisted one-pot synthesis of isoquinolines, furopyridines, and thienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminal acetylenes and ammonium acetate

Article abstract of DOI:10.1021/jo300494a

A palladium-catalyzed microwave-assisted one-pot reaction for the synthesis of isoquinolines is developed. The reaction is carried out by sequential coupling-imination-annulation reactions of ortho-bromoarylaldehydes and terminal alkynes with ammonium acetate, and a variety of substituted isoquinolines, furopyridines, and thienopyridines is prepared in moderate to excellent yields (up to 86%).

Full text of DOI:10.1021/jo300494a

Note
pubs.acs.org/joc
Microwave-Assisted One-Pot Synthesis of Isoquinolines,
Furopyridines, and Thienopyridines by Palladium-Catalyzed
Sequential Coupling−Imination−Annulation of 2-
Bromoarylaldehydes with Terminal Acetylenes and Ammonium
Acetate
Dingqiao Yang, Satvika Burugupalli, David Daniel, and Yu Chen*
Department of Chemistry and Biochemistry, Queens College and the Graduate Center of the City University of New York, Flushing,
New York 11367, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed microwave-assisted one-
pot reaction for the synthesis of isoquinolines is developed.
The reaction is carried out by sequential coupling−imination−
annulation reactions of ortho-bromoarylaldehydes and terminal
alkynes with ammonium acetate, and a variety of substituted
isoquinolines, furopyridines, and thienopyridines is prepared in
moderate to excellent yields (up to 86%).
he synthesis of isoquinolines has attracted considerable
attention from the organic synthetic community due to
terminal acetylenes. A synthesis of 1,2-dihydroisoquinolin-1-
ylphosphonates was reported by Wu via a tandem four-
component reaction,7 and a three-component cascade reaction
for the synthesis of isoquinolines was reported by Abbiati in
which aqueous ammonia was used as the reagent for the
imination step.8 In the latter case, only low to moderate
chemical yields were obtained, with this methodology failing for
linear aliphatic alkynes.
T
the wide range of biological activities exhibited by isoquinoline
derivatives.1 Of the numerous synthetic methods developed to
construct the isoquinoline core structure, the late transition
metal catalyzed isoquinoline synthesis plays a particularly
significant role.2 This is because these reactions usually require
milder reaction conditions, compared to the classical synthetic
methods, such as the Pictet−Spengler reaction, Pomeranz−
Fritsch reaction, and Bischler−Napieralski reaction, which
generally incorporate strong acidic conditions.3 Among the
late transition metal catalyzed syntheses of isoquinolines, the
palladium catalyzed protocols have received the most attention
due to the significant role palladium plays in carbon−carbon
bond coupling4 and annulation reactions of alkynes.5 The
reported palladium catalyzed isoquinoline synthesis generally
starts from the tert-butyl imine of either 2-halo benzaldehyde or
2-alkynyl benzaldehyde, which are prepared from tert-butyl
amine and the corresponding 2-halo benzaldehydes or 2-alkynyl
benzaldehydes.2a−c,l,n,o
Ammonium acetate (NH4OAc), a known ammonia source,9
has only been employed once in the isoquinoline synthesis,
specifically in its reaction with 2-(1,1-difluoroalkenyl)-
benzaldehyde.10 Only two isoquinoline derivatives were
prepared by this method. Our interest in the late transition
metal catalyzed annulation reaction has promoted our
exploration of ammonium acetate as the ammonia source for
the imination step in the palladium-catalyzed one-pot synthesis
of isoquinolines.
The microwave enhanced one-pot reaction has been
highlighted recently.11 Microwave technology has been well-
recognized to enhance chemical reactions and to generate clean
and high-yielding chemical transformations. We hereby report a
microwave-assisted one-pot reaction protocol to isoquinilones
from commercially available 2-bromoarylaldehydes, terminal
acetylenes, and ammonium acetate. No copper catalyst is
involved in the current method, which is different from the
previous palladium-catalyzed one-pot synthetic protocols for
isoquinoline synthesis.7,8
The concept of pot economy has been highlighted recently.6
By combining a sequence of chemical transformations in a
single reaction vessel, chemists are able to complete a multistep
synthesis without the need for product isolation and
purification between each successive synthetic step, thus
avoiding a lengthy separation process of the intermediate
chemical compounds and the generation of excess waste.
However, the palladium-catalyzed one-pot synthesis of
isoquinolines from commercially available starting materials
still remains scarce. To the best of our knowledge, there are
only two examples involving palladium-catalyzed one-pot
synthesis of isoquinolines or 1,2-dihydroisoquinolines starting
directly from commercially available 2-bromoarylaldehydes and
Our initial study focused on the reaction of 2-bromobenzal-
dehyde, 4-methoxyphenyl acetylene, and ammonium acetate
Received: March 6, 2012
Published: April 11, 2012
© 2012 American Chemical Society
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Note
a
Table 1. Optimization of Reaction Conditions for the One-Pot Isoquinoline Synthesis
b
entry
catalyst
base
solvent
ammonium salt (equiv)
% yield
c
1
PdCl2(PPh3)2 (2 mol %)/CuI (4 mol %)
PdCl2(PPh3)2 (2 mol %)/CuI (4 mol %)
Pd(OAc)2 (2 mol %) PPh3 (4 mol %)/CuI (4 mol %)
Pd(PPh3)4 (2 mol %)/CuI (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (1 mol %)/PPh3 (2 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Pd(OAc)2 (2 mol %)/PPh3 (4 mol %)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
Et3N (1.0 mL)
K3PO4 (5 equiv)
Cs2CO3 (5 equiv)
DIPEA (5 equiv)
KOAc (5 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
KOAc (2 equiv)
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (5)
NH4OAc (2)
NH4OAc (2)
NH4OAc (2)
(NH4)2CO3 (2)
NH4HCO3 (2)
HCO2NH4 (2)
NH4OAc (2)
37
62
53
66
72
41
62
36
42
49
60
83
82
67
79
50
43
63
60
2
3
4
5
6
7
8
9
10
11
12
13
14
d
15
16
17
18
e
19
a
Representative procedure: 2-bromobenzaldehyde (1a, 1 equiv, 0.5 mmol), 4-methoxyphenyl acetylene (2a, 1.1 equiv, 0.55 mmol), catalyst, base,
and solvent (2 mL) were mixed in a 5 mL microwave vial. The vial was flushed with nitrogen and sealed with an aluminum/Teflon crimp top. The
reaction mixture was stirred at 80 °C under microwave (300 W) irradiation for 1 h. After cooling to room temperature, ammonium salt was added to
b
the microwave vial, and the reaction mixture was stirred at 150 °C under microwave irradiation for 2 h. Isolated yields after column
c
chromatography. 2-Bromobenzaldehyde (1a, 1 equiv, 0.5 mmol), 4-methoxyphenyl acetylene (2a, 1.1 equiv, 0.55 mmol), PdCl2(PPh3)2 (2 mol %),
CuI (4 mol %), Et3N (1.0 mL), NH4OAc (5 equiv, 2.5 mmol), and DMF (2 mL) were mixed in a 5 mL microwave vial. The vial was flushed with
nitrogen and sealed with an aluminum/Teflon crimp top. The reaction mixture was stirred at 150 °C under microwave (300 W) irradiation for 3 h.
d
e
The second step of the reaction was heated to 120 °C by microwave irradiation. The reaction was carried out with an oil bath heating (step 1, 80
°C; step 2, 150 °C).
using the standard Sonogashira coupling condition. In the
presence of 2 mol % of PdCl2(PPh3)2 and 4 mol % of CuI, the
one-pot reaction was completed in 3 h using DMF as the
solvent and microwave irradiation as the heating source. By
initially adding NH4OAc to the reaction mixture, we effectively
rendered the reaction a one-step process affording the desired
product 3a in a moderate 37% yield (Table 1, entry 1). After
several trials, we found that by carrying out the one-pot
reaction in two sequential steps, we were able to increase our
yield of the desired product 3a to 62% (Table 1, entry 2).
Therefore, we added NH4OAc to the reaction mixture after the
palladium-catalyzed coupling was completed. As shown by
TLC, there was no 2-bromobenzaldehyde remaining. After
trying several palladium and copper catalyst systems (Table 1,
entries 2−4), we found that in the absence of copper catalyst
the combination of 2 mol % of Pd(OAC)2 and 4 mol % of PPh3
gave the best yield (72%) (Table 1, entry 5). Other solvents
such as DMSO, CH3CN, and toluene were found to be inferior
to DMF (Table 1, entries 6−8). Among the inorganic and
organic bases investigated (Table 1, entries 9−11), KOAc
showed superior effect, affording the desired product 3a in an
83% yield (Table 1, entry 12). The loading of KOAc and
NH4OAc could be both reduced from 5 to 2 equiv with a
similar chemical yield (Table 1, entry 13). Changing the
conditions to a lower reaction temperature (120 °C) resulted in
a slightly lower chemical yield (79%) (Table 1, entry 15).
Similarly, when the catalyst loading was reduced to 1 mol % of
Pd(OAc)2 and 2 mol % of PPh3, the chemical yield decreased
as well (Table 1, entry 14). Other ammonium salts were also
investigated, including (NH4)2CO3, NH4HCO3, and
HCO2NH4 (Table 1, entries 16−18), all showing inferior
results to NH4OAc. When the reaction was carried out with oil
bath heating (step 1, 80 °C; step 2, 150 °C), only a 60% yield
of 3a was obtained within the same reaction time parameters
(Table 1, entry 19).
This one-pot reaction protocol has proved to be a very
general route for an array of isoquinolines (Table 2). A wide
variety of 2-bromobenzaldehydes has been studied in this
reaction, in which both electron-donating substituents (Table 2,
entries 3, 4, and 7) and electron-withdrawing substituents
(Table 2, entry 5) are found to be compatible. Additionally,
both the aryl and alkyl acetylenes are found to be compatible in
this reaction as well. In particular, the linear alkyl acetylenes all
gave good to excellent yields (Table 2, entries 2, 5, and 13).
This is due to the development of a reaction pathway meant to
circumvent the problem arising from the use of aqueous
ammonia solution as the ammonia source, as had been done in
previous studies.8 A 75% yield is obtained when the sterically
demanding 2-methoxyphenyl acetylene is used (Table 2, entry
8). However, only a moderate yield (38%) is obtained when the
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Note
a
Table 2. Preparation of Isoquinolines/Furopyridines/Thienopyridines by Microwave-Assisted One-Pot Reactions
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Note
Table 2. continued
a
Representative procedure: 2-bromoarylaldehyde (1, 1 equiv, 0.5 mmol), a terminal acetylene (2, 1.1 equiv, 0.55 mmol), Pd(OAc)2 (2.25 mg, 2 mol
%, 0.01 mmol), PPh3 (5.25 mg, 4 mol %, 0.02 mmol), KOAc (98 mg, 2 equiv, 1 mmol), and DMF (2 mL) were mixed in a 5 mL microwave vial. The
vial was flushed with nitrogen and sealed with an aluminum/Teflon crimp top. The reaction mixture was stirred at 80 °C under microwave (300 W)
irradiation for 1 h. After cooling to room temperature, NH4OAc (77 mg, 2 equiv, 1 mmol) was added to the microwave vial, and the reaction mixture
b
was stirred at 150 °C under microwave irradiation for 2 h. Isolated yields after column chromatography.
sterically more demanding 3,3-dimethylbut-1-yne is used
(Table 2, entry 23). Besides 2-bromobenzaldehydes, 3-
bromofuran-2-carbaldehydes and 3-bromothiophene-2-carbal-
dehydes have been successfully employed in the current
synthetic protocol, leading to furopyridines (Table 2, entries
9 and 20) and thienopyridines (Table 2, entries 10−11 and
21−22), respectively. Trimethylsilyl acetylene fails in the
current isoquinoline synthetic protocol, and no useful product
is obtained from the reaction mixture (Table 2, entry 24).
Our effort to expand the current protocol from 2-
bromoarylaldehydes to 2′-bromoarylketones has met very
limited success. Under the optimal reaction conditions for 2-
bromoarylaldehydes, no desired 1-substituted isoquinolines
were obtained from 2′-bromoarylketones. Only very moderate
chemical yields were obtained when 2′-iodoarylketones were
employed instead of 2′-bromoarylketones. In the best case
scenario, an 18% yield is obtained for compound 3y (Table 3,
cially available 2-bromoarylaldehydes, terminal acetylenes, and
NH4OAc. Ammonium acetate is used as the imination reagent
and gives superior results to its aqueous ammonia counterpart.
No copper catalyst is necessary in the current reaction protocol.
The preparation of an isoquinoline derivative library using the
current protocol is underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. All microwave irradiation reactions were
carried out on a Biotage-EXP Microwave synthesis system, operating
at a frequency of 2450 MHz with continuous irradiation power from 0
to 300 W. All reactions were carried out in 5 mL oven-dried Biotage
microwave vials sealed with an aluminum/Teflon crimp top, which can
be exposed to a maximum of 250 °C and 20 bar internal pressure. The
reaction temperature was measured by an IR sensor on the outer
surface of the process vial. All commercially available chemicals were
used as received without further purification. All H and 13C NMR
1
spectra were recorded at 500 and 125 MHz respectively, using CDCl3
or DMSO-d6 as a solvent. The chemical shifts of all 1H and 13C NMR
spectra are referenced to the residual signal of CDCl3 (δ 7.26 ppm for
Table 3. Preparation of Isoquinolines by Microwave-Assisted
a
One-Pot Reactions from 1-(2-Iodophenyl) Ethanone
1
the H NMR spectra and δ 77.23 ppm for the 13C NMR spectra) or
DMSO-d6 (δ 2.54 ppm for the 1H NMR spectra and δ 40.45 ppm for
the 13C NMR spectra). The high resolution mass spectra were
recorded on a double focusing magnetic sector mass spectrometer
using electrospray ionization. The melting points are uncorrected.
General Procedure for the Preparation of Isoquinolines/
Furopyridines/Thienopyridines. The 2-bromoarylaldehyde (1, 1
equiv, 0.5 mmol), a terminal acetylene (2, 1.1 equiv, 0.55 mmol),
Pd(OAc)2 (2.25 mg, 2 mol %, 0.01 mmol), PPh3 (5.25 mg, 4 mol %,
0.02 mmol), KOAc (98 mg, 2 equiv, 1 mmol), and DMF (2 mL) were
mixed in a 5 mL microwave vial. The vial was flushed with nitrogen
and sealed with an aluminum/Teflon crimp top. The reaction mixture
was stirred at 80 °C under microwave (300 W) irradiation for 1 h until
the disappearance of the starting material as monitored by thin layer
chromatography. After cooling to room temperature, NH4OAc (77
mg, 2 equiv, 1 mmol) was added to the microwave vial, and the
reaction mixture was stirred at 150 °C under microwave irradiation for
2 h until the disappearance of the starting material as monitored by
thin layer chromatography. The reaction mixture was diluted with
saturated brine (20 mL) and extracted with diethyl ether (3 × 10 mL).
The organic layers were combined and washed with water (10 mL) to
remove any remaining DMF and then dried over anhydrous MgSO4.
The solvent was removed under vacuum, and the residue was purified
by flash column chromatography on silica gel using ethyl acetate/
hexanes as the eluent to afford the desired product 3.
a
Representative procedure: 1-(2-iodophenyl) ethanone (1, 1 equiv,
0.5 mmol), a terminal acetylene (2, 1.1 equiv, 0.55 mmol), Pd(OAc)2
(2.25 mg, 2 mol %, 0.01 mmol), PPh3 (5.25 mg, 4 mol %, 0.02 mmol),
KOAc (98 mg, 2 equiv, 1 mmol), and DMF (2 mL) were mixed in a 5
mL microwave vial. The vial was flushed with nitrogen and sealed with
an aluminum/Teflon crimp top. The reaction mixture was stirred at 80
°C under microwave (300 W) irradiation for 1 h. After cooling to
room temperature, NH4OAc (77 mg, 2 equiv, 1 mmol) was added to
the microwave vial, and the reaction mixture was stirred at 150 °C
3-(4-Methoxyphenyl)isoquinoline (3a). The compound was
1
obtained as a beige solid (96 mg, 82% yield): mp 102−103 °C; H
NMR (500 MHz, CDCl3) δ 9.33 (s, 1H), 7.80−8.20 (m, 2H), 7.78 (s,
1
1H), 7.57−7.69 (m, 4H), 7.06−7.40 (m, 2H), 3.90 (s, 3H). The H
b
NMR spectral data are in good agreement with the literature data.8
under microwave irradiation for 2 h. Isolated yields after column
chromatography.
3-Tridecylisoquinoline (3b). The compound was obtained as a
1
yellow oil (120 mg, 77% yield): H NMR (500 MHz, CDCl3) δ 9.20
(s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.63 (t, J =
7.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.45 (s, 1H), 2.92 (t, J = 7.6 Hz,
2H), 1.77−1.83 (m, 2H), 1.31−1.41 (m, 4H), 1.23−1.31 (m, 16H),
0.87 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 156.1, 152.2,
136.7, 130.3, 127.6, 127.2, 126.4, 126.2,118.1, 38.4,32.1, 30.2, 30.0,
29.9, 29.8, 29.7, 29.6, 29.5, 22.9, 14.3; IR (KBr) 2918, 2847, 1629,
1592, 1580, 1468, 965, 884, 759, 743, 719, 667 cm−1; HRMS (EI)
calcd for C22H33N 311.2613, found 311.2615.
entry 1). This one-pot reaction presumably takes place by a Pd-
catalyzed coupling reaction between a 2-bromoarylaldehyde
and a terminal acetylene, followed by imination and intra-
molecular annulation reactions.
In conclusion, a palladium-catalyzed microwave assisted one-
pot reaction for the synthesis of isoquinoline, furopyridine, and
thienopyridine derivatives has been developed from commer-
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Note
3-(Cyclohex-1-en-1-yl)-7-methoxyisoquinoline (3c). The com-
pound was obtained as a white solid (95 mg, 79% yield): mp 116−
117 °C; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 7.66 (d, J = 8.9
Hz, 1H), 7.53 (s, 1H), 7.28 (dd, J = 8.9, 2.6 Hz, 1H), 7.18 (d, J = 2.5
Hz, 1H), 6.93−6.94 (m, 1H), 3.93 (s, 3H), 2.54−2.58 (m, 2H), 2.29−
2.33 (m, 2H), 1.82−1.87 (m, 2H), 1.68−1.73 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 158.0, 151.1, 150.3, 135.8, 132.3, 128.6, 128.5,
127.4, 123.5, 114.2, 104.9, 35.6, 26.3, 26.1, 23.1, 22.4; IR (KBr) 2932,
2857, 1651, 1578, 1559, 1540, 1508, 1489, 1456, 1225, 1159, 1026,
889, 856, 668 cm−1; HRMS (EI) calcd for C16H17NO 239.1310, found
239.1311.
6,7-Dimethoxy-3-(thiophen-3-yl)isoquinoline (3d). The com-
pound was obtained as a beige solid (104 mg, 77% yield): mp 134−
136 °C; 1H NMR (500 MHz, CDCl3) δ 9.01 (s, 1H), 7.93 (dd, J = 2.8,
0.9 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J = 5.0, 0.8 Hz, 1H), 7.39 (dd, J =
5.0, 3.1 Hz, 1H), 7.13 (s, 1H), 7.01 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 153.2, 150.1, 149.1, 146.6, 142.6,
133.3, 126.3, 126.1, 123.7, 122.4, 115.0, 105.4, 104.8, 56.2, 56.1; IR
(KBr) 3106, 3092, 2989, 2962, 2938, 2829, 1622, 1593, 1577, 1499,
1459, 1423,1340, 1295, 1247, 1232, 1198, 1151, 1007, 895, 870, 843,
796, 760, 675 cm−1; HRMS (EI) calcd for C15H13NO2 S 271.0667,
found 271.0665.
1314, 1284, 1247, 1228, 1023, 878, 843, 818, 780 cm−1; HRMS (EI)
calcd for C14H11NO2 225.0790, found 225.0786.
5-(2-Methoxyphenyl)thieno[2,3-c]pyridine (3j). The compound
was obtained as a yellow solid (66 mg, 55% yield): mp 95−97 °C; 1H
NMR (500 MHz, CDCl3) δ 9.25 (s, 1H), 8.22 (d, J = 0.9 Hz, 1H),
7.84 (dd, J = 7.6, 1.8 Hz, 1H), 7.69 (d, J = 5.4 Hz, 1H), 7.36−7.40 (m,
2H), 7.11 (dt, J = 7.4, 1.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 3.88 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 157.0, 149.9, 145.4, 144.2,
134.8, 132.2, 131.6, 129.6, 129.3, 123.5, 121.2, 119.1, 111.5, 55.8; IR
(KBr) 3103, 3005, 2969, 2943, 2839, 1494, 1439, 1235, 1023, 900,
875, 822, 779 cm−1; HRMS (EI) calcd for C14H11NOS 241.0561,
found 241.0559.
5-(Thiophen-3-yl)thieno[2,3-c]pyridine (3k). The compound was
1
obtained as a beige solid (79 mg, 73% yield): mp 120−122 °C; H
NMR (500 MHz, CDCl3) δ 9.14 (t, J = 0.7 Hz, 1H), 7.98 (d, J = 1.0
Hz, 1H), 7.94 (dd, J = 3.0, 1.3 Hz, 1H), 7.70 (dd, J = 5.0, 1.3 Hz, 1H),
7.67 (d, J = 5.4 Hz, 1H), 7.41 (dd, J = 5.0, 3.0 Hz, 1H), 7.35 (dd, J =
5.4, 0.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 148.0, 146.0, 144.4,
142.4, 134.8, 132.6, 126.4, 126.3, 123.3, 122.9, 114.1; IR (KBr) 3095,
3041, 1587, 1446, 1294, 1182, 1031, 860, 798, 764, 665 cm−1; HRMS
(EI) calcd for C11H7NS2 217.0020, found 217.0020.
3-(4-Methoxyphenyl)isoquinolin-7-ol (3l). The compound was
obtained as a light brown oil (84 mg, 67% yield): 1H NMR (500 MHz,
DMSO-d6) δ 10.29 (s, 1H), 9.23 (s, 1H), 8.25 (s, 1H), 7.90−7.95 (m,
2H), 7.38−7.43 (m, 2H), 7.34 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 0.8 Hz,
1H), 7.11 (t, J = 0.8 Hz, 1H), 3.87 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 157.7, 157.3, 151.0, 146.6, 131.7, 131.0, 130.2, 129.8,
129.6, 129.5, 124.4, 121.6, 121.5, 112.8, 108.7, 56.6; IR (KBr) 3423,
3065, 3003, 2957, 2934, 2834, 1574, 1559, 1540, 1504, 1489, 1457,
1241, 1158, 1025, 827, 752, 667 cm−1; HRMS (EI) calcd for
C16H13NO2 251.0946, found 251.0945.
4-(6-Fluoroisoquinolin-3-yl)butanenitrile (3e). The compound was
1
obtained as a yellow oil (92 mg, 86% yield): H NMR (500 MHz,
CDCl3) δ 9.14 (s, 1H), 7.92−7.95 (m, 1H), 7.46 (s, 1H), 7.28−7.35
(m, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.16−2.22
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.5 (d, JC−F = 251.6 Hz),
153.9, 152.3, 138.0 (d, JC−F = 10.6 Hz), 130.7 (d, JC−F = 9.8 Hz),
124.6, 119.7, 118.6 (d, JC−F = 5.3 Hz), 117.6 (d, JC−F = 25.7 Hz), 109.7
(d, JC−F = 20.9 Hz), 36.4, 25.2, 16.7; IR (KBr) 3084, 3066, 2958, 2911,
2253, 2242, 1633, 1495, 1207, 895, 818, 711, 672 cm−1; HRMS (EI)
calcd for C13H11FN2 214.0906, found 214.0905.
6-Fluoro-3-(2-methoxyphenyl)isoquinoline (3f). The compound
was obtained as a yellow oil (82 mg, 65% yield): 1H NMR (500 MHz,
CDCl3) δ 9.31 (s, 1H), 8.17 (s, 1H), 7.98 (dd, J = 9.0, 5.6 Hz, 1H),
7.92 (dd, J = 7.6, 1.8 Hz, 1H), 7.46 (dd, J = 9.5, 2.3 Hz, 1H), 7.38−
7.41 (m, 1H), 7.33 (dt, J = 8.8, 2.4 Hz, 1H), 7.13 (dt, J = 7.5, 1.0 Hz,
1H), 7.05 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 163.4 (d, JC−F = 252.1 Hz), 157.2, 151.7, 150.2, 137.7 (d,
JC−F = 10.4 Hz), 131.6, 130.6 (d, JC−F = 9.7 Hz), 129.9, 128.9, 124.7,
121.2, 120.8 (d, JC−F = 5.3 Hz), 117.7 (d, JC−F = 25.8 Hz), 111.6, 110.4
(d, JC−F = 20.9 Hz), 55.8; IR (KBr) 3007, 2975, 1630, 1496, 1243,
1027, 887, 748 cm−1; HRMS (EI) calcd for C16H12FNO 253.0903,
found 253.0901.
7-(Thiophen-3-yl)-[1,3]dioxolo[4,5-g]isoquinoline (3g). The com-
pound was obtained as a beige solid (103 mg, 81% yield): mp 146−
147 °C; 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H), 7.93 (dd, J = 3.0,
1.3 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J = 5.0, 1.1 Hz, 1H), 7.40 (dd, J =
5.0, 3.1 Hz, 1H), 7.16 (s, 1H), 7.05 (s, 1H), 6.07 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 151.3, 150.3, 148.3, 147.0, 142.4, 135.2, 126.4,
126.2, 125.0, 122.7, 116.0, 103.4, 102.8, 101.8; IR (KBr) 3106, 3091,
2910, 1598, 1479, 1455, 1231, 1031, 958, 934, 866, 854 cm−1; HRMS
(EI) calcd for C14H9NO2S 255.0354, found 255.0354.
4-(Isoquinolin-3-yl)butanenitrile (3m). The compound was
1
obtained as a white solid (81 mg, 83% yield): mp 99−101 °C; H
NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H),
7.77 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.4 Hz,
1H), 7.53 (s, 1H), 3.09 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.1 Hz, 2H),
2.19−2.25 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 152.7, 152.5,
136.4, 130.6, 127.6, 127.4, 126.9, 126.2, 119.7, 118.9, 36.3, 25.2, 16.6;
IR (KBr) 2972, 2948, 2935, 2882, 2853, 2242, 1559, 1541, 1507, 1458,
892, 761, 666 cm−1; HRMS (EI) calcd for C13H12N2 196.1000, found
196.1000.
7-Methoxy-3-(thiophen-3-yl)isoquinoline (3n). The compound
was obtained as a beige solid (99 mg, 82% yield): mp 154−155 °C;
1H NMR (500 MHz, CDCl3) δ 9.15 (s, 1H), 7.96 (dd, J = 3.1, 1.2 Hz,
1H), 7.84 (s, 1H), 7.71 (t, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H),
7.41 (dd, J = 5.1, 3.1 Hz, 1H), 7.32 (dd, J = 9.0, 2.5 Hz, 1H), 7.19 (d, J
= 2.5 Hz, 1H), 3.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4,
151.1, 146.1, 142.5, 132.3, 128.8, 128.4, 126.4, 126.1, 124.0, 122.5,
116.0, 104.9, 55.6; IR (KBr) 3119, 3101, 3007, 2967, 2937, 1587,
1490, 1236, 1208, 1155, 1025, 879, 824, 798, 697 cm−1; HRMS (EI)
calcd for C14H11NOS 241.0561, found 241.0557.
7-Methoxy-3-phenylisoquinoline (3o). The compound was
1
obtained as a white solid (92 mg, 78% yield): mp 158−159 °C; H
NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.09−8.11 (m, 2H), 7.99 (s,
1H), 7.76 (d, J = 9.0 Hz, 1H), 7.49−7.52 (m, 2H), 7.38−7.42 (m,
1H), 7.34 (dd, J = 8.9, 2.5 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 3.95 (S,
3H); 13C NMR (125 MHz, CDCl3) δ 158.5, 151.1, 149.8, 139.9,
132.4, 129.0, 128.9, 128.6, 128.4, 126.9, 123.9, 116.6, 104.8, 55.6; IR
(KBr) 3065, 3057, 2997, 1557, 1540, 1489, 1457, 1387, 1360, 1235,
1203, 1159, 1027, 880, 847, 760, 694 cm−1; HRMS (EI) calcd for
C16H13NO 235.0997, found 235.0992.
7-(2-Methoxyphenyl)-[1,3]dioxolo[4,5-g]isoquinoline (3h). The
compound was obtained as a white solid (105 mg, 75% yield): mp
1
121−122 °C; H NMR (500 MHz, CDCl3) δ 9.08 (s, 1H), 8.03 (s,
1H), 7.85 (dd, J = 7.6, 1.8 Hz, 1H), 7.35−7.38 (m, 1H), 7.20 (s, 1H),
7.08−7.12 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.10 (s, 2H), 3.89 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 157.1, 151.0, 150.0, 148.8,
148.4, 134.7, 131.5, 129.5, 129.4, 124.8, 121.2, 121.1, 111.5, 103.2,
103.1, 101.7, 55.9; IR (KBr) 3002, 2909, 1597, 1494, 1463, 1450,
1250, 1224, 1040, 1026, 959, 899, 839, 756, 668 cm−1; HRMS (EI)
calcd for C17H13NO3 279.0895, found 279.0896.
3-(Cyclohex-1-en-1-yl)-6,7-dimethoxyisoquinoline (3p). The com-
pound was obtained as a yellow solid (100 mg, 74% yield): mp 143−
1
145 °C; H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.46 (s, 1H),
5-(4-Methoxyphenyl)furo[2,3-c]pyridine (3i). The compound was
1
7.14 (s, 1H), 7.01 (s, 1H), 6.89−6.91 (m, 1H), 3.99(s, 6H), 2.53−2.56
(m, 2H), 2.27−2.31 (m, 2H), 1.80−1.85 (m, 2H), 1.67−1.72 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 153.0, 151.7, 149.9, 149.2, 135.9,
133.3, 127.4, 123.5, 113.5, 105.5, 105.0, 56.2, 56.1, 26.3, 26.1, 23.1,
22.4; IR (KBr) 2993, 2929, 2862, 2823,1505, 1457, 1247, 1152, 1005
cm−1; HRMS (EI) calcd for C17H19NO2 269.1416, found 269.1415.
obtained as a yellow solid (72 mg, 64% yield): mp 128−130 °C; H
NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H),
7.88 (s, 1H), 7.74 (t, J = 1.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.82 (s,
1H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.0, 151.5,
151.2, 148.6, 135.2, 133.3, 132.8, 128.4, 114.3, 112.2, 106.5, 55.5; IR
(KBr) 3146, 3116, 2965, 2935, 2840, 1607, 1570, 1517, 1457, 1430,
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Note
6-Fluoro-3-tridecylisoquinoline (3q). The compound was obtained
as a beige solid (112 mg, 68% yield): mp 60−61 °C; H NMR (500
1H), 7.66 (dt, J = 7.0, 1.0 Hz, 1H), 7.57 (dt, J = 7.0, 1.2 Hz, 1H),
7.35−7.39 (m, 1H), 7.12 (dt, J = 7.5, 1.0 Hz, 1H), 7.04 (d, J = 8.2 Hz,
1H), 3.89 (s, 3H), 3.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
158.2, 157.3, 148.1, 136.4, 131.6, 130.0, 129.6, 129.5, 127.9, 126.9,
126.4, 125.9, 121.3, 120.1, 111.6, 55.9, 22.8; IR (KBr) 3007, 2935,
2836, 1557, 1539, 1490, 1458, 1435, 1267, 1238, 1025, 753, 668 cm−1;
HRMS (EI) calcd for C17H15NO 249.1154, found 249.1150.
1
MHz, CDCl3) δ 9.16 (s, 1H), 7.92 (dd, J = 8.9, 5.6 Hz, 1H), 7.41 (s,
1H), 7.33 (dt, J = 9.6, 1.7 Hz, 1H), 7.27 (dt, J = 8.7, 2.2 Hz, 1H), 2.91
(t, J = 7.8 Hz, 2H), 1.77−1.81 (m, 2H), 1.32−1.40 (m, 4H), 1.25−
1.31 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 163.5 (d, JC−F = 251.5 Hz), 157.0, 151.9, 138.2 (d, JC−F = 10.4 Hz),
130.7 (d, JC−F = 10.0 Hz), 124.5, 117.8 (d, JC−F = 5.3 Hz), 117.1 (d,
JC−F = 25.6 Hz), 109.6 (d, JC−F = 20.8 Hz), 38.3, 32.1, 30.2, 29.89,
29.86, 29.8, 29.7, 29.63, 29.57, 22.9, 14.4; IR (KBr) 2955, 2919, 2849,
1637, 1494, 1471, 1465, 1209, 1143, 891, 820, 809 cm−1; HRMS (EI)
calcd for C22H32FN 329.2519, found 329.2519.
3-(4-Methoxyphenyl)-1-methylisoquinoline (3z). The compound
was prepared using the general procedure except that 1-(2-
iodophenyl) ethanone was used instead of 2-bromoarylaldehyde.
The compound was obtained as a beige solid (20 mg, 16% yield): mp
1
54−56 °C; H NMR (500 MHz, CDCl3) δ 8.08−8.12 (m, 3H), 7.84
(s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63−7.66 (m, 1H), 7.52−7.55 (m,
1H), 7.02−7.04 (m, 2H), 3.88 (s, 3H), 3.03 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 160.2, 158.6, 149.9, 137.1, 132.7, 130.2, 128.4, 127.7,
126.6, 126.4, 125.8, 114.33, 114.30, 55.6, 22.9; IR (KBr) 3073, 3057,
2994, 2959, 2917, 2836, 1607, 1514, 1250, 1176, 1028, 841, 668 cm−1;
HRMS (EI) calcd for C17H15NO 249.1154, found 249.1155.
7-(Cyclohex-1-en-1-yl)-[1,3]dioxolo[4,5-g]isoquinoline (3r). The
compound was obtained as a yellow solid (98 mg, 77% yield): mp
1
119−121 °C; H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 7.42 (s,
1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.87−6.89 (m, 1H), 3.04 (s, 2H),
2.51−2.54 (m, 2H), 2.26−2.31 (m, 2H), 1.79−1.84 (m, 2H), 1.66−
1.71 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 152.0, 150.9, 149.5,
147.9, 135.8, 135.0, 127.6, 124.7, 114.3, 103.3, 102.8, 101.6, 26.3, 26.1,
23.1, 22.4; IR (KBr) 2931, 2923, 2863, 2818, 1591, 1476, 1452, 1223,
1039, 947, 858 cm−1; HRMS (EI) calcd for C16H15NO2 253.1103,
found 253.1101.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for the new compounds.
7-Phenyl-[1,3]dioxolo[4,5-g]isoquinoline (3s). The compound was
1
obtained as a beige solid (93 mg, 75% yield): mp 112−114 °C; H
This material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.03 (dd, J = 8.5, 1.4 Hz,
2H), 7.87 (s, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.35(t, J = 7.3 Hz, 1H),
7.17 (s, 1H), 7.08 (s, 1H), 6.06 (s, 2H); 13C NMR (125 MHz, CDCl3)
δ 151.2, 150.6, 150.2, 148.4, 139.7, 135.1, 128.8, 128.9, 126.9, 125.1,
116.5, 103.2, 102.9, 101.7; IR (KBr) 3057, 3035, 2900, 1483, 1459,
1233, 1047, 963, 885, 756, 691 cm−1; HRMS (EI) calcd for
C16H11NO2 249.0790, found 249.0789.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yu.chen1@qc.cuny.edu.
Notes
5-(Thiophen-3-yl)furo[2,3-c]pyridine (3t). The compound was
1
The authors declare no competing financial interest.
obtained as a white solid (54 mg, 54% yield): mp 120−122 °C; H
NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 7.85−7.86 (m, 2H), 7.75 (d,
J = 2.1 Hz, 1H), 7.67 (dd, J = 5.0, 1.1 Hz, 1H), 7.40 (dd, J = 5.0, 3.1
Hz, 1H), 6.82 (d, J = 1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
151.5, 148.7, 147.5, 142.6, 135.1, 133.5, 126.5, 126.4, 122.6, 112.6,
106.4; IR (KBr) 3118, 3103, 1558, 1540, 1521, 1506, 1458, 1230,
1119, 1029, 874, 855, 794, 777, 677 cm−1; HRMS (EI) calcd for
C11H7NOS 201.0248, found 201.0248.
5-(4-Methoxyphenyl)thieno[2,3-c]pyridine (3u). The compound
was obtained as a yellow solid (80 mg, 66% yield): mp 107−108 °C;
1H NMR (500 MHz, CDCl3) δ 9.18 (s, 1H), 8.03 (d, J = 0.8 Hz, 1H),
7.99−8.02 (m, 2H), 7.67 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 5.4 Hz, 1H),
7.00−7.03 (m, 2H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
160.2, 151.7, 146.2, 144.3, 134.6, 132.5, 128.3, 123.4, 114.3, 113.7,
55.5; IR (KBr) 3102, 3081, 3000, 2964, 2933, 2909, 2836, 1603, 1586,
1506, 1417, 1281, 1184, 1035, 1017, 837, 816, 769, 647 cm−1; HRMS
(EI) calcd for C14H11NOS 241.0561, found 241.0559.
ACKNOWLEDGMENTS
■
The work was supported by Queens College, City University of
New York. We thank the Queens College Undergraduate
Research and Mentoring Education (UR/ME) program and the
Queens College Research Enhancement Award for their
financial support. We thank Dr. Cliff Soll at Hunter College
for recording the mass spectra, Prof. William Hersh for helpful
discussions, and Mr. Abraham Perl for his help during the
preparation of the manuscript.
REFERENCES
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1
as a yellow solid (53 mg, 50% yield): mp 78−79 °C; H NMR (500
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2H), 7.70 (d, J = 5.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.2
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(s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.63 (dt, J =
7.6, 0.9 Hz, 1H), 7.61 (s, 1H), 7.52 (dt, J = 7.5, 0.8 Hz, 1H), 1.47 (s,
1
9H). The H NMR spectral data are in good agreement with the
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3-(2-Methoxyphenyl)-1-methylisoquinoline (3y). The compound
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iodophenyl) ethanone was used instead of 2-bromoarylaldehyde.
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1
90−91 °C; H NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 8.5, 0.4 Hz,
1H), 8.05 (s, 1H), 7.93 (dd, J = 7.6, 1.8 Hz, 1H), 7.84 (d, J = 8.2 Hz,
4471
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