Synthesis of 1-aminoisoquinolines by gold(III)-mediated domino reactions from 2-alkynylbenzamides and ammonium acetate

Article abstract of DOI:10.1021/jo302794z

A facile synthetic route toward pharmaceutically interesting 1-aminoisoquinoline derivatives by gold(III)-mediated domino reactions is described. This synthetic protocol starts from readily available 2-alkynylbenzamides and ammonium acetate and takes plac

Full text of DOI:10.1021/jo302794z

Article
pubs.acs.org/joc
Synthesis of 1‑Aminoisoquinolines by Gold(III)-Mediated Domino
Reactions from 2‑Alkynylbenzamides and Ammonium Acetate
Yuhua Long, Zhigang She, Xiaochen Liu, and Yu Chen*
Department of Chemistry and Biochemistry, Queens College and the Graduate Center of the City University of New York, 65-30
Kissena Boulevard, Flushing, New York 11367, United States
S
* Supporting Information
ABSTRACT: A facile synthetic route toward pharmaceutically
interesting 1-aminoisoquinoline derivatives by gold(III)-medi-
ated domino reactions is described. This synthetic protocol starts
from readily available 2-alkynylbenzamides and ammonium
acetate and takes place under mild reaction conditions
compatible with a variety of functional groups. A plausible
mechanism for the domino process is proposed, supported by the
reaction of a possible intermediate, N-(3-phenyl-1H-isochromen-
1-ylidene)propan-1-amine.
carbon−carbon bonds. It is especially useful for activating
carbon−carbon triple bonds during nucleophilic additions.10
Gold-catalyzed intramolecular nucleophilic cyclizations have
attracted particular interest due to their potential use in the
synthesis of a wide variety of carbo- and heterocyclic
compounds.10,11
Building on our previous success using ammonium acetate
(NH4OAc) in the synthesis of isoquinolines12 and continuing
our interest in developing new synthetic methods for the
synthesis of biologically important molecules employing late-
transition-metal catalysts,12,13 we hereby report a facile
synthesis of 1-aminoisoquinolines by gold(III)-mediated
domino reactions from 2-alkynylbenzamides and ammonium
acetate (Scheme 1, path b).
INTRODUCTION
■
The synthesis of 1-aminoisoquinolines has recently attracted
considerable attention from medicinal chemists due to the wide
range of biological activities exhibited by their derivatives.
These derivatives consist of known antitumor agents1 and
inhibitors of factor Xa,2 thrombin,3 and rho kinase-I.4 They also
display antimalarial activity5 and are used for the treatment of
diseases associated with inappropriate alk5.6 While there is a
high demand for 1-aminoisoquinoline derivatives in high-
throughput drug screening, there are relatively few synthetic
routes toward these compounds.
The most common method currently used by medicinal
chemists to prepare 1-aminoisoquinolines involves the direct
installation of an amino group in the 1-position of an existing
isoquinoline by nucleophilic aromatic substitution (Scheme 1,
path a).1−6 One drawback to this method is that it involves
harsh reaction conditions, including the use of strong bases,
high reaction temperatures, or high pressure in the preparation
of either the final products or the starting materials. Recently,
Li et al. reported a synthetic pathway for the production of N-
substituted 1-aminoisoquinolines through the Rh-catalyzed
oxidative coupling of N-aryl- and N-alkylbenzamidines.7
Additionally, a silver-catalyzed synthesis of 1-aminoisoquino-
lines from 2-alkynylbenzaldoximes has been reported by Wu et
al.8 It is important to note that, although both of these methods
can be used to synthesize secondary amines, it is necessary to
remove their alkyl and aryl groups in order to convert them
into their more biologically important primary amine counter-
parts. Swager et al. have briefly reported the synthesis of 1-
aminoisoquinolines by reacting isobenzopyrylium salts with
anhydrous ammonia. However, only a few 1-aminoisoquino-
lines, formed in only moderate chemical yields, have been
reported using this method.9
RESULTS AND DISCUSSION
■
The 2-alkynylbenzamide starting materials 3 were prepared by
Sonogashira coupling14 of 2-bromobenzamides (2) with
terminal alkynes, except for compounds 3g,i,j,l (Scheme 2).
2-Ethynylbenzamide (3l) was prepared from compound 3k via
a cesium fluoride mediated desilylation reaction. Compounds
3g,i,j were prepared by Sonogashira coupling of 3l with aryl
iodides. 2-Bromobenzamides 2 were either commercially
available or prepared from the corresponding 2-bromobenzoic
acids 1 or 2-bromobenzoyl chloride, as shown in Scheme 2.
Our initial study focused on the reaction of the model
substrate 3a with 3 equiv of NH4OAc in acetonitrile (CH3CN)
at 85 °C. In the absence of a catalyst, none of the desired 1-
aminoisoquinoline 4a was obtained after 20 h (Table 1, entry
1). In addition, no cyclization was observed in the presence of a
Brønsted acid catalyst such as trifluoromethanesulfonic acid
(TfOH) (Table 1, entry 2). Although no desired 1-amino-
Gold, a soft Lewis acid with distinct carbophilic character, has
been widely used in the catalysis of reactions of multiple
Received: December 23, 2012
Published: February 25, 2013
© 2013 American Chemical Society
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Scheme 1. Synthetic Routes toward 1-Aminoisoquinolines
Scheme 2. Preparation of 2-Alkynylbenzamides (3)
Table 1. Optimization of Reaction Conditions for the 1-
Aminoisoquinoline Synthesis
isoquinoline 4a was obtained when a Lewis acid catalyst such as
CuI or PtCl2 was used (Table 1, entries 3 and 4), a moderate
50% chemical yield was obtained when a palladium(II) catalyst,
Pd(O2CCF3)2, was employed (Table 1, entry 5). While Au(I)
catalysts such as Au(Ph3P)Cl only showed moderate catalytic
activity (Table 1, entry 6), a 61% yield was obtained when the
relatively more Lewis acidic Au(III) catalyst NaAuCl4·2H2O
was used (Table 1, entry 7). The desired product 4a was
obtained in 54% yield when AgSbF6 was employed as the
catalyst (Table 1, entry 9). The chemical yields of 4a were
enhanced to more than 70% when the catalyst loading of either
NaAuCl4·2H2O or AgSbF6 was increased to 12 mol % (Table 1,
entries 8 and 10). Further exploration showed that the yield of
4a was significantly increased when AgSbF6 was used as a
cocatalyst with NaAuCl4·2H2O, leading to a 92% yield (Table
1, entry 11).15 Other solvents, such as 1,2-dichloroethane
(DCE), 1,2-dimethoxyethane (DME), and tetrahydrofuran
(THF), all showed inferior results in comparison with
CH3CN, and only low to moderate yields were obtained
(Table 1, entries 12−14). Reducing the loading of NH4OAc to
2 equiv resulted in a lower yield (Table 1, entry 15). The
reaction parameters were then changed, by reducing the
temperature to 50 °C. This resulted in a yield of only 35%
(Table 1, entry 16). When the amount of gold catalyst was
reduced to 3 mol %, a 45% yield was obtained (Table 1, entry
17). Taking these results into account, the conditions listed in
entry 11 in Table 1 were chosen as the optimal reaction
conditions.
a
b
entry
catalyst (amt (mol %))
TfOH (6)
solvent
yield (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
0
0
2
3
CuI (6)
0
4
PtCl2 (6)
0
5
Pd(O2CCF3)2 (6)
50
28
61
72
54
73
92
11
34
28
85
35
45
6
Au(Ph3P)Cl (6)
7
NaAuCl4·2H2O (6)
NaAuCl4·2H2O (12)
AgSbF6 (6)
8
9
10
11
12
13
14
AgSbF6 (12)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (3/3)
DME
THF
c
15
d
CH3CN
CH3CN
CH3CN
16
17
a
General procedure: In a 4 dram vial were added the catalyst,
NH4OAc (69.3 mg, 0.9 mmol), 3a (66.3 mg, 0.3 mmol), and solvent
b
A variety of 2-alkynylbenzamides, including those with aryl,
heteroaryl, alkenyl, and alkyl groups at the distal position of the
alkyne triple bond, were then subjected to these reaction
conditions and found to be compatible (Table 2, entries 1−10).
(3 mL). The reaction mixture was stirred at 85 °C for 20 h. Isolated
c
yields after column chromatography. Two equivalents of NH4OAc
d
was added. The reaction mixture was heated at 50 °C for 20 h.
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a
Table 2. Gold(III)-Mediated Synthesis of 1-Aminoisoquinolines
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Table 2. continued
a
b
c
See the Experimental Section for the general procedure. Isolated yields after column chromatography. The starting material 3g (40%) was
d
e
recovered from the reaction mixture. The starting material 3v (12%) was recovered from the reaction mixture. The starting material 3w (82%) was
recovered from the reaction mixture.
Scheme 3. Plausible Mechanism for Gold(III)-Mediated Synthesis of 1-Aminoisoquinolines (4) from 2-Alkynylbenzamides (3)
Although a sterically hindered alkyl group, tert-butyl, is well
accommodated at the distal position of the alkyne triple bond,
leading to an excellent 85% yield (Table 2, entry 6), a slower
reaction was observed when a sterically hindered naphthyl
group was introduced at the same position of the alkyne triple
bond. In the latter case, only a moderate 51% yield was
obtained after 20 h, along with 40% recovery of the starting
material 3g (Table 2, entry 7). While it was found that both
electron-donating and electron-withdrawing groups were
tolerated in the 2-alkynylbenzamide substrates, excellent
chemical yields were only obtained when electron-donating
groups were present (Table 2, entries 8, 13, 14, and 16−19).
Only moderate chemical yields were obtained in the presence
of strong electron-withdrawing groups (Table 2, entries 9 and
10). The current synthetic method is not applicable to either
trimethylsilyl (TMS)-protected alkynes or terminal alkynes, as
only an unidentifiable mixture was obtained under these
reaction conditions (Table 2, entries 11 and 12). In addition to
primary amides, the reactivities of secondary and tertiary
amides have also been investigated in this reaction. While
secondary amides with an aliphatic substituent on the nitrogen
atom reacted appreciably (Table 2, entries 20 and 21), a low
yield of the desired product 4v was obtained, when an aryl
substituent was present on the nitrogen atom (Table 2, entry
22). For each of the secondary amides, the side product 1-
aminoisoquinoline 4a was also observed (Table 2, entries 20−
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Scheme 4. Preparation and Gold(III)-Mediated Reaction of N-(3-Phenyl-1H-isochromen-1-ylidene)propan-1-amine (17a)
22). In contrast, none of the desired cyclization product 4w was
obtained when the tert-amide 3w was subjected to these
reaction conditions. Instead, the side product 4a was obtained
in 9% yield, along with the starting material 3w recovered in
82% yield (Table 2, entry 23).
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in sealed 4
dram vials unless otherwise indicated. 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. The microwave irradiation
reactions were carried out in 20 mL oven-dried Biotage microwave
vials sealed with an aluminum/Teflon crimp cap, which can be
exposed to a maximum of 250 °C and 20 bar internal pressure. An IR
sensor was used to measure the reaction temperatures of the
microwave irradiation reactions by measuring the temperature of the
outer surface of the process vials. All commercially available chemicals
were used as received without further purification unless otherwise
noted. All products were purified by flash column chromatography on
The current reaction presumably takes place by the Au(III)-
catalyzed intramolecular 6-endo-dig cyclization of the 2-
alkynylbenzamide 3 to the organogold intermediate 5, which
is converted to the isobenzopyrylium salt 6 after protonation.
The nucleophilic addition of ammonia to isobenzopyrylium salt
6 leads to the isochromene intermediate 7. After deprotonation
of the ammonium nitrogen atom and protonation of the oxygen
atom in isochromene 7, isochromenylium 8 forms. The
carbon−oxygen bond in 8 dissociates to form enol 9, which
subsequently converts to 10 after deprotonation and
tautomerizes to ketone 11. Intramolecular nucleophilic addition
of the amino group to the ketone carbonyl group forms
intermediate 12. After subsequent dehydration and aromatiza-
tion, the final product, 1-aminoisoquinoline 4, is formed
(Scheme 3). In the case when secondary and tertiary amides are
employed, ammonia can substitute the primary or secondary
amines in intermediate 9 through a sequential nucleophilic
addition and elimination process, leading to intermediate 16.
The latter then undergoes a reaction mechanism similar to that
for intermediate 9 to form a primary isoquinolin-1-amine. It is
worth noting that the isobenzopyrylium salt 6 has a pair of
resonance structures, 6A,B. Deprotonation of the resonance
structure 6B could then give 1H-isochromen-1-imine 17.
A possible intermediate, N-(3-phenyl-1H-isochromen-1-
ylidene)propan-1-amine (17a), was therefore prepared from
benzamide 3t, according to a literature procedure (Scheme
4).16 Compound 17a was subjected to our optimal reaction
conditions. After 20 h, 1-aminoisoquinolines 4t,a were isolated
from the reaction mixture in 75% and 15% yields, respectively.
These results are comparable to the data shown in entry 20 of
Table 2, providing evidence supporting the formation of
isobenzopyrylium 6 in our proposed mechanism.
silica gel (230−400 mesh) unless otherwise noted. All H and 13C
NMR spectra were recorded at 500 and 125 MHz, respectively, using
1
1
CDCl3 or DMSO-d6 as the solvent. The chemical shifts of all H and
13C NMR spectra are referenced to the residual signal of CDCl3 (δ
7.26 ppm for the 1H NMR spectra and δ 77.23 ppm for the 13C NMR
1
spectra) or DMSO-d6 (δ 2.54 ppm for the H 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.
Synthesis of 2-Bromobenzamides (2a,b) from 2-Bromoben-
zoic Acids (1). A mixture of the appropriate benzoic acid (1, 12.0
mmol) and thionyl chloride (25 mL) was refluxed at 70 °C in a 50 mL
round-bottomed flask equipped with a water condenser and a drying
tube (filled with Drierite) for 20 h. The thionyl chloride was removed
using a rotary evaporator under reduced pressure (20 mmHg). The
residue was then dissolved in aqueous NH4OH solution (25 mL, 5.0 N
solution in water) and stirred for 1 h at room temperature. The
reaction mixture was filtered, and the residue was dried under high-
vacuum conditions to afford the desired amide.
2-Bromo-5-methylbenzamide (2a). This compound was obtained
as a white solid (2.20 g, 86% yield): mp 195.8−196.7 °C; H NMR
(500 MHz, CDCl3) δ 7.47−7.49 (m, 2H), 7.11 (dd, J = 8.2, 2.1 Hz,
1H), 6.10 (s, 1H), 6.10 (s, 1H), 2.34 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.5, 138.0, 136.2, 133.5, 132.8, 130.9, 115.9, 21.0; IR
(CHCl3, cm−1) ν 3359, 3177, 1647; HRMS (ESI) calcd for
C8H9BrNO (M + H)+ 213.9862, found 213.9861.
1
2-Bromo-5-fluorobenzamide (2b). This compound was obtained
as a white solid (1.80 g, 69% yield): mp 150.9−151.5 °C; H NMR
1
CONCLUSION
(500 MHz, CDCl3) δ 7.57−7.60 (m, 1H), 7.40 (dd, J = 8.5, 3.1 Hz
1H), 7.03−7.07 (m, 1H), 6.18 (s, 2H); 13C NMR (125 MHz, CDCl3)
δ 168.0, 161.9 (d, JC−F = 247.8 Hz), 138.3 (d, JC−F = 6.8 Hz), 135.4 (d,
JC−F = 7.6 Hz), 119.4 (d, JC−F = 22.3 Hz), 117.6 (d, JC−F = 24.4 Hz),
113.6 (d, JC−F = 3.3 Hz); IR (CHCl3, cm−1) ν 3356, 3177, 1643;
HRMS (ESI) calcd for C7H6BrFNO (M + H)+ 217.9611, found
217.9611.
■
The synthesis of pharmaceutically interesting 1-aminoisoquino-
lines by gold(III)-mediated domino reactions is described. This
synthetic route starts from readily available 2-alkynylbenza-
mides and ammonium acetate and takes place under mild
reaction conditions. A variety of functional groups are
compatible with the reaction conditions. A broad range of 2-
alkynylbenzamides has been examined, leading to 1-amino-
isoquinolines in moderate to excellent chemical yields. We
expect that this facile synthetic route will soon find applications
in high-throughput drug screening. The further exploration of
new synthetic methods for biologically interesting heterocyclic
and carbocyclic compounds by gold-mediated intramolecular
cyclization is underway in our laboratory.
Synthesis of N-Substituted 2-Bromobenzamides (2c−f) from
2-Bromobenzoyl Chloride. The appropriate amine (5 mL) was
added dropwise to 2-bromobenzoyl chloride (1.10 g, 5.0 mmol) at 0
°C. After the addition of amine, the reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was then poured into
30 mL of ethyl acetate and washed with saturated aqueous NaHCO3
solution (30 mL) and brine (20 mL). The organic layer was dried over
anhydrous MgSO4 and concentrated using a rotary evaporator under
reduced pressure (20 mmHg). This resulted in the formation of a
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solid, which was then dried under high-vacuum conditions to afford
the desired amide.
(s, 1H), 5.96 (s, 1H), 2.17−2.23 (m, 4H), 1.62−1.72 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 168.2, 137.3, 133.9, 133.6, 131.2, 130.6,
128.5, 120.9, 120.2, 98.2, 85.5, 29.0, 26.0, 22.3, 21.5; IR (CHCl3,
cm−1) ν 3382, 3179, 1657; HRMS (ESI) calcd for C15H16NO (M +
H)+ 226.1226, found 226.1226.
2-Bromo-N-propylbenzamide (2c). This compound was obtained
as a white solid (1.10 g, 91% yield): mp 83.5−84.8 °C; 1H NMR (500
MHz, CDCl3) δ 7.58 (dd, J = 8.0, 0.9 Hz, 1H), 7.53 (dd, J = 7.7, 1.7
Hz, 1H), 7.36 (dt, J = 7.5, 1.1 Hz, 1H), 7.26 (dt, J = 8.1, 1.8 Hz, 1H),
5.98 (s, 1H), 3.42−3.46 (m, 2H), 1.64−1.69 (m, 2H), 1.02 (t, J = 7.4
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 167.8, 138.2, 133.5, 131.3,
129.7, 127.7, 119.3, 42.0, 22.9, 11.7; IR (CHCl3, cm−1) ν 3276, 1638;
HRMS (ESI) calcd for C10H13BrNO (M + H)+ 242.0175, found
242.0177.
2-(5-Cyanopent-1-yn-1-yl)benzamide (3d). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (279.8 mg, 44% yield): mp 108.6−
1
109.4 °C; H NMR (500 MHz, CDCl3) δ 7.96−7.98 (m, 1H), 7.48−
7.50 (m, 1H), 7.38−7.44 (m, 2H), 7.15 (s, 1H), 6.44 (s, 1H), 2.68 (t, J
= 6.8 Hz, 2H), 2.58 (t, J = 7.1 Hz, 2H), 1.96−2.01 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 168.9, 135.2, 133.9, 131.1, 129.9, 128.7, 120.4,
119.2, 93.9, 81.2, 24.4, 18.9, 16.5; IR (CHCl3, cm−1) ν 3348, 3192,
2247, 1667; HRMS (ESI) calcd for C13H13N2O (M + H)+ 213.1022,
found 213.1025.
2-Bromo-N-butylbenzamide (2d). This compound was obtained as
1
a white solid (1.27 g, 99% yield): mp 90.8−91.4 °C; H NMR (500
MHz, CDCl3) δ 7.58 (dd, J = 8.0, 0.8 Hz, 1H), 7.52 (dd, J = 7.6, 1.7
Hz, 1H), 7.35 (dt, J = 7.5, 0.9 Hz, 1H), 7.26 (dt, J = 7.8, 1.7 Hz, 1H),
5.99 (s, 1H), 3.44−3.48 (m, 2H), 1.59−1.65 (m, 2H), 1.42−1.46 (m,
2H), 0.97 (t, J = 7.3 Hz, 3H). The 1H NMR spectral data are in good
agreement with the literature data.17
2-(Pentadec-1-yn-1-yl)benzamide (3e). Eluent of column chroma-
tography: hexanes/ethyl acetate 3/1. This compound was obtained as
1
a light yellow solid (461.4 mg, 47% yield): mp 85.3−86.2 °C; H
2-Bromo-N-phenylbenzamide (2e). This compound was obtained
NMR (500 MHz, CDCl3) δ 8.12−8.14 (m, 1H), 7.72 (s, 1H), 7.49−
7.50 (m, 1H), 7.38−7.44 (m, 2H), 6.03 (s, 1H), 2.49 (t, J = 7.2 Hz,
2H), 1.60−1.65 (m, 2H), 1.42−1.47 (m, 2H), 1.26−1.33 (m, 18H),
0.88 (t, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 168.3, 134.0,
131.2, 130.5, 128.3, 121.2, 98.2, 79.9, 32.1, 29.89, 29.86, 29.84, 29.7,
29.6, 29.3, 29.2, 28.6, 22.9, 19.8, 14.4 (fewer 13C signals were observed
due to signal overlapping); IR (CHCl3, cm−1) ν 3370, 3172, 1646;
HRMS (ESI) calcd for C22H34NO (M + H)+ 328.2635, found
328.2635.
1
as a yellow solid (1.30 g, 94% yield): mp 119.1−120.0 °C; H NMR
(500 MHz, CDCl3) δ 7.73 (s, 1H), 7.62−7.65 (m, 4H), 7.37−7.42 (m,
1
3H), 7.30−7.34 (m, 1H), 7.16−7.19 (m, 1H). The H NMR spectral
data are in good agreement with the literature data.17
(2-Bromophenyl)(piperidin-1-yl)methanone (2f). This compound
was obtained as a yellow oil (1.29 g, 96% yield): 1H NMR (500 MHz,
CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.33 (dt, J = 7.4, 1.0 Hz, 1H),
7.20−7.23 (m, 2H), 3.68−3.80 (m, 2H), 3.11−3.23 (m, 2H), 1.60−
1.71 (m, 5H), 1.42−1.46 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
167.7, 138.7, 132.9, 130.2, 127.8, 127.7, 119.3, 48.0, 42.7, 26.4, 25.6,
24.7; IR (CHCl3, cm−1) ν 1635; HRMS (ESI) calcd for C12H15BrNO
(M + H)+ 268.0332, found 268.0334.
2-(3,3-Dimethylbut-1-yn-1-yl)benzamide (3f). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a white solid (319.6 mg, 53% yield): mp 96.4−96.8 °C; 1H
NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 7.2, 2.5 Hz, 1H), 7.69 (s,
1H), 7.45−7.47 (m, 1H), 7.35−7.41 (m, 2H), 6.68 (s, 1H), 1.33 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 168.6, 134.1, 133.7, 131.0,
130.4, 128.2, 120.9, 105.6, 78.5, 30.7, 28.5; IR (CHCl3, cm−1) ν 3439,
3179, 1670; HRMS (ESI) calcd for C13H16NO (M + H)+ 202.1226,
found 202.1230.
Synthesis of 2-Alkynylbenzamides 3 from 2-Bromobenza-
mides 2 and Terminal Alkynes. The following 2-alkynylbenzamides
3 were prepared via Sonogashira coupling reactions18 of the
corresponding 2-bromobenzamides 2 with terminal alkynes using
microwave irradiation. An oven-dried 20 mL microwave vial was
charged with a 2-bromobenzamide 2 (3.0 mmol), a terminal alkyne
(3.3 mmol), Pd(PPh3)2Cl2 (42.1 mg, 0.06 mmol), CuI (11.4 mg, 0.06
mmol), Et3N (14 mL), and DMF (2 mL). The vial was flushed with
nitrogen and sealed with an aluminum/Teflon crimp cap. The reaction
mixture was stirred at 120 °C while undergoing microwave (300 W)
irradiation for 3 h. This continued until the starting material
disappeared, as monitored by thin-layer chromatography. The reaction
mixture was diluted with ethyl acetate (50 mL) and washed with brine
(30 mL). The aqueous phase was extracted with ethyl acetate twice (2
× 20 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated using a rotary evaporator under reduced
pressure (20 mmHg). The residue was then purified by flash column
chromatography on silica gel (eluent: hexanes/ethyl acetate).
2-(Phenylethynyl)benzamide (3a). Eluent of column chromatog-
raphy: hexanes/ethyl acetate 3/1. This compound was obtained as a
2-((4-Methoxyphenyl)ethynyl)benzamide (3h). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (466.9 mg, 62% yield): mp 123.7−
1
124.0 °C; H NMR (500 MHz, CDCl3) δ 8.12 (dd, J = 7.7, 1.4 Hz,
1H), 7.60 (dd, J = 7.6, 1.4 Hz, 1H), 7.55 (s, 1H), 7.41−7.48 (m, 4H),
1
6.89 (d, J = 8.9 Hz, 2H), 6.30 (s, 1H), 3.83 (s, 3H). The H NMR
spectral data are in good agreement with the literature data.19
2-((Trimethylsilyl)ethynyl)benzamide (3k). Eluent of column
chromatography: hexanes/ethyl acetate 4/1. This compound was
obtained as a yellow solid (319.4 mg, 49% yield): mp 82.0−83.4 °C;
1H NMR (500 MHz, CDCl3) δ 8.15−8.17 (m, 1H), 7.76 (s, 1H),
7.55−7.58 (m, 1H), 7.43−7.47 (m, 2H), 5.82 (s, 1H), 0.28 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 168.2, 134.7, 134.1, 131.1, 130.6,
129.3, 120.1, 104.0, 102.3, −0.2; IR (CHCl3, cm−1) ν 3444, 3180,
1656; HRMS (ESI) calcd for C12H16NOSi (M + H)+ 218.0996, found
218.1001.
1
white solid (437.6 mg, 66% yield): mp 146.4−147.5 °C; H NMR
(500 MHz, CDCl3) δ 8.13 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.2 Hz,
1H), 7.53−7.55 (m, 2H), 7.46−7.49 (m, 3H), 7.39−7.40 (m, 3H),
5-Methoxy-2-(phenylethynyl)benzamide (3m). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (369.1 mg, 49% yield): mp 162.5−
1
6.14 (s, 1H). The H NMR spectral data are in good agreement with
the literature data.19
1
163.5 °C; H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 2.7 Hz, 1H),
2-(Thiophen-3-ylethynyl)benzamide (3b). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (524.4 mg, 77% yield): mp 111.7−
7.64 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.50−7.52 (m, 2H), 7.36−7.39
(m, 3H), 7.02 (dd, J = 8.5, 2.8 Hz, 1H), 6.42 (s, 1H), 3.88 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 168.2, 160.1, 136.1, 135.2, 131.6, 129.1,
128.8, 122.5, 118.5, 114.5, 112.4, 94.7, 87.9, 55.8; IR (CHCl3, cm−1) ν
3383, 3186, 1648; HRMS (ESI) calcd for C16H14NO2 (M + H)+
252.1019, found 252.1021.
1
112.2 °C; H NMR (500 MHz, CDCl3) δ 8.12 (dd, J = 6.7, 1.0 Hz,
1H), 7.59−7.63 (m, 2H), 7.44−7.50 (m, 2H), 7.42 (s, 1H), 7.36−7.37
(m, 1H), 7.21 (d, J = 5.0 Hz, 1H), 5.90 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 168.5, 134.6, 133.6, 131.2, 130.5, 129.9, 129.7, 129.0, 126.2,
121.2, 120.3, 91.2, 87.4; IR (CHCl3, cm−1) ν 3368, 3183, 1640; HRMS
(ESI) calcd for C13H10NOS (M + H)+ 228.0478, found 228.0480.
2-(Cyclohex-1-en-1-ylethynyl)benzamide (3c). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a dark yellow solid (364.5 mg, 54% yield): mp 134.0−
5-Methyl-2-(phenylethynyl)benzamide (3n). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (324.4 mg, 46% yield): mp 168.3−
1
169.0 °C; H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 0.6 Hz, 1H),
7.52−7.54 (m, 4H), 7.38−7.39 (m, 3H), 7.30 (dd, J = 7.8, 1.2 Hz,
1H), 6.19 (s, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
168.6, 139.6, 134.3, 133.7, 132.1, 131.7, 131.1, 129.3, 128.8, 122.4,
1
135.2 °C; H NMR (500 MHz, CDCl3) δ 8.13 (dd, J = 7.5, 1.1 Hz,
1H), 7.60 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.39−7.45 (m, 2H), 6.28
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113.3, 95.3, 88.0, 21.6; IR (CHCl3, cm−1) ν 3367, 3182, 1651; HRMS
(ESI) calcd for C16H14NO (M + H)+ 236.1070, found 236.1070.
5-Fluoro-2-(phenylethynyl)benzamide (3o). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a white solid (358.6 mg, 50% yield): mp 160.3−161.2 °C;
1H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 9.7, 2.8 Hz, 1H), 7.63
(dd, J = 8.5, 5.4 Hz, 1H), 7.58 (s, 1H), 7.52−7.54 (m, 2H), 7.39−7.41
(m, 3H), 7.20 (dt, J = 8.3, 2.8 Hz, 1H), 6.07 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 167.0, 162.7 (d, JC−F = 251.0 Hz), 137.0 (d, JC−F = 7.1
Hz), 135.8 (d, JC−F = 8.0 Hz), 131.7, 129.6, 128.9, 122.0, 118.8 (d, JC−F
= 22.0 Hz), 117.7 (d, JC−F = 24.2 Hz), 116.5 (d, JC−F = 3.5 Hz), 95.8,
86.8; IR (CHCl3, cm−1) ν 3364, 3177, 1649; HRMS (ESI) calcd for
C15H11FNO (M + H)+ 240.0819, found 240.0823.
5-Methoxy-2-(pentadec-1-yn-1-yl)benzamide (3p). Eluent of
column chromatography: hexanes/ethyl acetate 3/1. This compound
was obtained as a white solid (482.6 mg, 45% yield): mp 80.9−82.1
°C; 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.69 (d, J = 2.8 Hz,
1H), 7.41 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.9 Hz, 1H), 6.01 (s,
1H), 3.86 (s, 3H), 2.46 (t, J = 7.2 Hz, 2H), 1.60−1.63 (m, 2H), 1.42−
1.45 (m, 2H), 1.26 (s, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 168.0, 159.4, 135.4, 135.3, 118.6, 114.2, 113.4, 96.6,
79.7, 55.7, 32.1, 30.0, 29.9, 29.8, 29.7, 29.5, 29.3, 29.2, 28.7, 22.9, 19.8,
14.3 (fewer 13C signals were observed due to signal overlapping); IR
(CHCl3, cm−1) ν 3375, 3172, 1600; HRMS (ESI) calcd for
C23H36NO2 (M + H)+ 358.2741, found 358.2740.
5-Methyl-2-(pentadec-1-yn-1-yl)benzamide (3q). Eluent of col-
umn chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a light yellow solid (464.0 mg, 45% yield): mp 98.1−98.5
°C; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 1.1 Hz, 1H), 7.76 (s,
1H), 7.38 (d, J = 7.9 Hz, 1H), 7.23 (dd, J = 7.7, 1.3 Hz, 1H), 5.82 (s,
1H), 2.47 (t, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.59−1.65 (m, 2H), 1.41−
1.47 (m, 2H), 1.26−1.34 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 168.4, 138.6, 133.9, 133.6, 132.1, 131.1,
118.2, 97.3, 80.0, 32.1, 29.89, 29.87, 29.85, 29.7, 29.6, 29.3, 29.2, 28.7,
22.9, 21.5, 19.8, 14.4 (fewer 13C signals were observed due to signal
overlapping); IR (CHCl3, cm−1) ν 3368, 3178, 1648; HRMS (ESI)
calcd for C23H36NO (M + H)+ 342.2791, found 342.2793.
2-((4-Methoxyphenyl)ethynyl)-5-methylbenzamide (3r). Eluent of
column chromatography: hexanes/ethyl acetate 3/1. This compound
was obtained as a white solid (532.7 mg, 67% yield): mp 159.0−160.1
°C; 1H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.59 (s, 1H), 7.45−
7.51 (m, 3H), 7.29 (dd, J = 9.0, 1.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H),
5.87 (s, 1H), 3.85 (s, 3H), 2.42 (s. 3H); 13C NMR (125 MHz, CDCl3)
δ 168.7, 160.3, 139.1, 134.0, 133.5, 133.2, 132.1, 131.1, 117.7, 114.4,
95.5, 86.8, 55.5, 21.5 (fewer 13C signals were observed due to signal
overlapping); IR (CHCl3, cm−1) ν 3354, 3178, 1645; HRMS (ESI)
calcd for C17H16NO2 (M + H)+ 266.1176, found 266.1178.
1H), 7.52−7.54 (m, 2H), 7.43−7.46 (m, 2H), 7.39−7.40 (m, 3H),
7.34 (s, 1H), 3.49−3.53 (m, 2H), 1.55−1.59 (m, 2H), 1.35−1.42 (m,
2H), 0.85 (t, J = 7.3 Hz, 3H). The 1H NMR spectral data are in good
agreement with the literature data.20
N-Phenyl-2-(phenylethynyl)benzamide (3v). Eluent of column
chromatography: hexanes/ethyl acetate 5/1. This compound was
obtained as a white solid (383.5 mg, 43% yield): mp 155.9−156.5 °C;
1H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 8.14−8.16 (m, 1H), 7.67
(d, J = 7.8 Hz, 3H), 7.49−7.52 (m, 4H), 7.33−7.40 (m, 5H), 7.14 (t, J
= 7.4 Hz, 1H). The 1H NMR spectral data are in good agreement with
the literature data.16
(2-(Phenylethynyl)phenyl)(piperidin-1-yl)methanone (3w). Eluent
of column chromatography: hexanes/ethyl acetate 5/1. This
1
compound was obtained as a yellow oil (390.7 mg, 45% yield): H
NMR (500 MHz, CDCl3) δ 7.54−7.56 (m, 1H), 7.47−7.49 (m, 2H),
7.31−7.38 (m, 6H), 3.77−3.79 (m, 2H), 3.19−3.30 (m, 2H), 1.62−
1.67 (m, 5H), 1.41−1.47 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
168.5, 139.7, 132.1, 131.5, 128.7, 128.6, 128.4, 126.3, 122.9, 120.0,
92.7, 87.0, 48.1, 42.6, 26.4, 25.7, 24.5 (fewer 13C signals were observed
due to signal overlapping); IR (CHCl3, cm−1) ν 1632; HRMS (ESI)
calcd for C20H20NO (M + H)+ 290.1539, found 290.1540.
Synthesis of 2-Ethynylbenzamide (3l). A 50 mL round-
bottomed flask was charged with 2-((trimethylsilyl)ethynyl)benzamide
(3k; 1.087 g, 5.0 mmol), CsF (1.139 g, 7.5 mmol), and methanol (25
mL). The reaction mixture was stirred overnight at room temperature
until the starting material disappeared, as monitored by thin-layer
chromatography. Methanol was removed using a rotary evaporator
under reduced pressure. The residue was dissolved in ethyl acetate (50
mL) and washed with brine (30 mL). The aqueous phase was
extracted with ethyl acetate (20 mL). The combined organic layers
were dried over anhydrous MgSO4 and concentrated using a rotary
evaporator under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl acetate 4/
1), to afford a light yellow solid (688.8 mg, 95% yield): mp 117.3−
1
118.2 °C; H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.9 Hz, 1H),
7.61 (d, J = 7.4 Hz, 1H), 7.45−7.50 (m, 2H), 7.36 (s, 1H), 5.95 (s,
1H), 3.53 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 168.3, 135.5,
134.5, 131.2, 130.3, 129.6, 119.1, 84.2, 82.5; IR (CHCl3, cm−1) ν 3296,
3179, 1646; HRMS (ESI) calcd for C9H8NO (M + H)+ 146.0600,
found 146.0601.
Synthesis of 2-Alkynylbenzamides (3g,i,j) from 2-Ethynyl-
benzamide (3l) and Aryl Iodides. A 4 dram vial was charged with
2-ethynylbenzamide (3l; 145.2 mg, 1.0 mmol), an aryl iodide (1.0
mmol), Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol), CuI (3.8 mg, 0.02
mmol), Et3N (5 mL), and DMF (1 mL). The vial was flushed with
nitrogen. The reaction mixture was stirred at 80 °C for 6 h until the
starting material disappeared, as monitored by thin-layer chromatog-
raphy. The reaction mixture was diluted with ethyl acetate (30 mL)
and washed with brine (20 mL). The aqueous phase was extracted
with ethyl acetate (20 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated using a rotary evaporator
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent: hexanes/ethyl acetate).
2-(Naphthalen-1-ylethynyl)benzamide (3g). Eluent of column
chromatography: hexanes/ethyl acetate 3/1. This compound was
obtained as a white solid (214.3 mg, 79% yield): mp 169.8−170.8 °C;
1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 8.4 Hz, 1H), 8.13 (dd, J =
5-Fluoro-2-((4-methoxyphenyl)ethynyl)benzamide (3s). Eluent of
column chromatography: hexanes/ethyl acetate 3/1. This compound
was obtained as a light yellow solid (363.6 mg, 45% yield): mp 164.7−
1
165.3 °C; H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 9.7, 2.7 Hz,
1H), 7.67 (s, 1H), 7.59−7.61 (m, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.19
(dt, J = 8.0, 2.8 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.05 (s, 1H), 3.85
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.8, 162.5 (d, JC−F = 249.4
Hz), 160.6, 136.6 (d, JC−F = 7.1 Hz), 135.7 (d, JC−F = 7.8 Hz), 133.2,
118.8 (d, JC−F = 22.2 Hz), 117.8 (d, JC−F = 24.3 Hz), 116.8 (d, JC−F
=
3.6 Hz), 114.5, 113.9, 96.1, 85.8, 55.6; IR (CHCl3, cm−1) ν 3372,
3190, 1651; HRMS (ESI) calcd for C16H13FNO2 (M + H)+ 270.0925,
found 270.0926.
7.6, 1.4 Hz, 1H), 7.89 (t, J = 6.6 Hz, 2H), 7.76 (dt, J = 8.3, 1.1 Hz,
2H), 7.62 (dt, J = 6.9, 1.2 Hz, 1H), 7.48−7.58 (m, 5H), 6.26 (s, 1H).
2-(Phenylethynyl)-N-propylbenzamide (3t). Eluent of column
chromatography: hexanes/ethyl acetate 5/1. This compound was
obtained as a white solid (426.5 mg, 54% yield): mp 97.8−98.5 °C; 1H
NMR (500 MHz, CDCl3) δ 8.05−8.07 (m, 1H), 7.60−7.62 (m, 1H),
7.52−7.54 (m, 2H), 7.44−7.46 (m, 2H), 7.39−7.41 (m, 4H), 3.46−
1
The H NMR spectral data are in good agreement with the literature
data.19
2-((4-(Trifluoromethyl)phenyl)ethynyl)benzamide (3i). Eluent of
column chromatography: hexanes/ethyl acetate 3/1. This compound
was obtained as a light yellow solid (199.6 mg, 69% yield): mp 145.8−
1
3.50 (m, 2H), 1.61−1.65 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). The H
NMR spectral data are in good agreement with the literature data.16
N-Butyl-2-(phenylethynyl)benzamide (3u). Eluent of column
chromatography: hexanes/ethyl acetate 5/1. This compound was
obtained as a white solid (491.0 mg, 59% yield): mp 121.7−122.7 °C;
1H NMR (500 MHz, CDCl3) δ 8.05−8.07 (m, 1H), 7.59−7.61 (m,
1
146.3 °C; H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 9.0 Hz, 1H),
7.63 (t, J = 9.4 Hz, 5H), 7.47−7.52 (m, 2H), 7.14 (s, 1H), 6.64 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 168.8, 135.5, 133.8, 132.0, 130.9
(q, JC−F = 32.5 Hz), 131.2, 130.1, 129.5, 126.1, 125.7 (q, JC−F = 32.5
Hz), 123.9 (q, JC−F = 270.7 Hz), 119.7, 94.0, 89.8; IR (CHCl3, cm−1) ν
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3362, 3191, 1655; HRMS (ESI) calcd for C16H11F3NO (M + H)+
290.0787, found 290.0787.
(s, 2H), 2.70 (t, J = 7.7 Hz, 2H), 1.72−1.75 (m, 4H), 1.25−1.38 (m,
18H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.8,
154.1, 138.3, 130.3, 126.9, 125.4, 122.7, 116.4, 110.1, 38.2, 32.1, 29.93,
29.91, 29.90, 29.87, 29.84, 29.80, 29.7, 29.6, 22.9, 14.4 (fewer 13C
signals were observed due to signal overlapping); IR (CHCl3, cm−1) ν
3301, 3115; HRMS (ESI) calcd for C22H35N2 (M + H)+ 327.2795,
found 327.2794.
Methyl 4-((2-Carbamoylphenyl)ethynyl)benzoate (3j). Eluent of
column chromatography: hexanes/ethyl acetate 3/1. This compound
was obtained as a white solid (226.2 mg, 81% yield): mp 194.4−194.9
°C; 1H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J = 8.4 Hz, 2H), 7.94
(s, 1H), 7.67−7.69 (m, 3H), 7.64 (s, 1H), 7.59−7.61 (m, 1H), 7.52−
7.55 (m, 2H), 3.91 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 170.0,
166.6, 140.7, 133.7, 132.6, 130.7, 130.4, 130.3, 130.1, 128.7, 128.3,
120.2, 92.6, 92.1, 53.4; IR (CHCl3, cm−1) ν 3353, 3186, 1724, 1652;
HRMS (ESI) calcd for C17H14NO3 (M + H)+ 280.0968, found
280.0971.
General Procedure for Gold-Catalyzed Synthesis of 1-
Aminoisoquinolines (4). A 4 dram vial was charged with
NaAuCl4·2H2O (7.2 mg, 0.018 mmol), AgSbF6 (6.2 mg, 0.018
mmol), NH4OAc (69.3 mg, 0.9 mmol), 2-alkynylbenzamide 3 (0.3
mmol), and acetonitrile (3 mL). The reaction mixture was stirred at 85
°C for 20 h. After it was cooled to room temperature, the resulting
mixture was diluted with 15 mL of ethyl acetate and washed with brine
(15 mL). The aqueous phase was extracted with ethyl acetate (2 × 10
mL). The combined organic layers were dried over anhydrous MgSO4
and concentrated using a rotary evaporator under reduced pressure.
The residue was purified by flash column chromatography on silica gel
(eluent: hexanes/ethyl acetate) to afford the corresponding 1-
aminoisoquinoline product.
3-(tert-Butyl)isoquinolin-1-amine (4f). Eluent of column chroma-
tography: hexanes/ethyl acetate 2/1. This compound was obtained as
a yellow oil (51.0 mg, 85% yield): 1H NMR (500 MHz, CDCl3) δ 7.75
(d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.55−7.58 (m, 1H),
7.39−7.42 (m, 1H), 7.02 (s, 1H), 5.13 (s, 2H), 1.39 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 161.6, 155.2, 138.3, 129.9, 127.4, 125.4, 122.6,
116.3, 106.5, 36.9, 30.2; IR (CHCl3, cm−1) ν 3383, 3217; HRMS
(ESI) calcd for C13H17N2 (M + H)+ 201.1386, found 201.1389.
3-(Naphthalen-1-yl)isoquinolin-1-amine (4g). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a light yellow solid (41.4 mg, 51% yield): mp 168.3−168.9
°C; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 7.91 (t, J
= 7.0 Hz, 2 H), 7.83 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.66
(m, 2H), 7.45−7.58 (m, 4H), 7.31 (s, 1H), 5.37 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 155.9, 151.2, 139.1, 138.1, 134.1, 131.1, 130.6,
128.5, 128.4, 127.6, 127.4, 126.37, 126.35, 126.3, 125.9, 125.5, 122.8,
116.8, 113.5; IR (CHCl3, cm−1) ν 3306, 3174; HRMS (ESI) calcd for
C19H15N2 (M + H)+ 271.1230, found 271.1233.
3-(4-Methoxyphenyl)isoquinolin-1-amine (4h). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a white solid (72.1 mg, 96% yield): mp 137.4−138.4 °C;
1H NMR (500 MHz, CDCl3) δ 8.00−8.03 (m, 2H), 7.77 (d, J = 8.6
Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.60 (dt, J = 8.1, 1.0 Hz, 1H), 7.41−
7.44 (m, 2H), 7.01−6.98 (m, 2H), 5.24 (s, 2H), 3.86 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 160.0, 156.0, 149.5, 138.5, 132.7, 130.4,
128.2, 127.6, 125.7, 122.8, 116.8, 114.1, 108.0, 55.5; IR (CHCl3, cm−1)
ν 3289, 3130; HRMS (ESI) calcd for C16H15N2O (M + H)+ 251.1179,
found 251.1183.
3-Phenylisoquinolin-1-amine (4a). Eluent of column chromatog-
raphy: hexanes/ethyl acetate 2/1. This compound was obtained as a
1
light yellow solid (60.8 mg, 92% yield): mp 91.0−92.2 °C; H NMR
(500 MHz, CDCl3) δ 8.07 (d, J = 7.3 Hz, 2H), 7.77 (t, J = 9.0 Hz,
2H), 7.61 (m, 1H), 7.45−7.49 (m, 4H), 7.39 (d, J = 7.6 Hz, 1H), 5.30
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 156.1, 149.6, 139.9, 138.4,
130.5, 128.8, 128.4, 127.8, 127.0, 126.2, 122.8, 117.1, 109.1; IR
(CHCl3, cm−1) ν 3347, 3205; HRMS (ESI) calcd for C15H13N2 (M +
H)+ 221.1073, found 221.1076.
3-(Thiophen-3-yl)isoquinolin-1-amine (4b). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a brown solid (64.5 mg, 95% yield): mp 108.6−109.2 °C;
1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H),
7.72 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.60 (t, J = 7.5 Hz,
1H), 7.43 (t, J = 7.5 Hz, 1H), 7.37−7.39 (m, 2H) 5.27 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 156.1, 145.8, 142.7, 138.4, 130.5, 127.6,
126.2, 126.1, 125.9, 123.0, 122.8, 117.1, 108.5; IR (CHCl3, cm−1) ν
3384, 3187; HRMS (ESI) calcd for C13H11N2S (M + H)+ 227.0637,
found 227.0638.
3-(4-(Trifluoromethyl)phenyl)isoquinolin-1-amine (4i). Eluent of
column chromatography: hexanes/ethyl acetate 2/1. This compound
was obtained as a light yellow solid (32.9 mg, 38% yield): mp 135.9−
1
137.1 °C; H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.2 Hz, 2H),
7.78−7.82 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H),
7.52 (t, J = 7.3 Hz, 2H), 5.28 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
156.2, 148.1, 143.4, 138.2, 130.7, 130.1 (q, JC−F = 32.2 Hz), 127.9,
127.2, 126.7, 125.7 (q, JC−F = 3.8 Hz), 123.6 (q, JC−F = 184.4 Hz),
122.8, 117.5, 109.8; IR (CHCl3, cm−1) ν 3314, 3111; HRMS (ESI)
calcd for C16H12F3N2 (M + H)+ 289.0947, found 289.0949.
3-(Cyclohex-1-en-1-yl)isoquinolin-1-amine (4c). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a light yellow oil (54.0 mg, 80% yield): H NMR (500
Methyl 4-(1-Aminoisoquinolin-3-yl)benzoate (4j). Eluent of
column chromatography: hexanes/ethyl acetate 2/1. This compound
was obtained as a light yellow solid (45.1 mg, 54% yield): mp 175.2−
1
MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H),
7.54 (dt, J = 7.0, 0.9 Hz, 1H), 7.37 (dt, J = 8.1, 1.1 Hz, 1H), 7.04 (s,
1H), 6.94−6.96 (m, 1H), 5.15 (s, 2H), 2.51−2.54 (m, 2H), 2.28−2.31
(m, 2H), 1.79−1.84 (m, 2H), 1.67−1.71 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 155.2, 150.6, 138.3, 135.7, 130.1, 127.7, 127.5, 125.5,
122.7, 117.2, 107.0, 26.1, 26.0, 23.1, 22.4; IR (CHCl3, cm−1) ν 3378,
3213, 1621; HRMS (ESI) calcd for C15H17N2 (M + H)+ 225.1386,
found 225.1388.
1
176.0 °C; H NMR (500 MHz, CDCl3) δ 8.12−8.16 (m, 4H), 7.79−
7.83 (m, 2H), 7.65 (dt, J = 7.0, 0.9 Hz, 1H), 7.57 (s, 1H), 7.50−7.53
(m, 1H), 5.29 (s, 2H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
167.3, 156.2, 148.4, 144.3, 138.2, 130.7, 130.1, 129.7, 128.0, 126.8,
126.7, 122.8, 117.5, 110.1, 52.4; IR (CHCl3, cm−1) ν 3375, 3220,
1716; HRMS (ESI) calcd for C17H15N2O2 (M + H)+ 279.1128, found
279.1130.
4-(1-Aminoisoquinolin-3-yl)butanenitrile (4d). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a white solid (55.8 mg, 88% yield): mp 106.2−107.2 °C;
1H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 8.3 Hz, 1H), 7.63 (d, J
= 7.7 Hz, 1H), 7.58 (dt, J = 8.0, 0.9 Hz, 1H), 7.40 (dt, J = 8.1, 1.2 Hz,
1H), 6.84 (s, 2H), 6.77 (s, 1H), 2.68 (t, J = 7.3 Hz, 2H), 2.50−2.52
(m, 2H), 1.96−2.00 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ
158.1, 152.8, 138.6, 130.9, 127.0, 125.7, 124.9, 121.7, 117.0, 108.4,
37.0, 25.7, 16.9; IR (CHCl3, cm−1) ν 3365, 3180, 2361; HRMS (ESI)
calcd for C13H14N3 (M + H)+ 212.1182, found 212.1185.
7-Methoxy-3-phenylisoquinolin-1-amine (4m). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a beige solid (56.0 mg, 74% yield): mp 126.1−126.8 °C;
1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.68 (d, J =
8.9 Hz, 1H), 7.45−7.47 (m, 3H), 7.34−7.37 (m, 1H), 7.29 (d, J = 8.7
Hz, 1H), 7.05 (s, 1H), 5.25 (s, 2H), 3.91 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 158.0, 155.2, 147.4, 139.9, 133.5, 129.3, 128.8, 128.1,
126.8, 122.5, 117.9, 109.2, 101.9, 55.7; IR (CHCl3, cm−1) ν 3373,
3201; HRMS (ESI) calcd for C16H15N2O (M + H)+ 251.1179, found
251.1182.
3-Tridecylisoquinolin-1-amine (4e). Eluent of column chromatog-
7-Methyl-3-phenylisoquinolin-1-amine (4n). Eluent of column
raphy: hexanes/ethyl acetate 2/1. This compound was obtained as a
chromatography: hexanes/ethyl acetate 2/1. This compound was
1
1
yellow solid (93.2 mg, 95% yield): mp 87.2−87.6 °C; H NMR (500
obtained as a light yellow oil (57.0 mg, 80% yield): H NMR (500
MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H),
7.58 (dt, J = 6.9, 0.8 Hz, 1H), 7.40−7.43 (m, 1H), 6.88 (s, 1H), 5.13
MHz, CDCl3) δ 8.04−8.06 (m, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.57 (d,
J = 0.4 Hz, 1H), 7.45−7.48 (m, 4H), 7.35−7.39 (m, 1H), 5.23 (s, 2H),
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2.52 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.6, 148.8, 140.1,
136.4, 136.0, 132.5, 128.7, 128.2, 127.6, 126.9, 122.0, 113.2, 109.0,
22.1; IR (CHCl3, cm−1) ν 3315, 3178; HRMS (ESI) calcd for
C16H15N2 (M + H)+ 235.1230, found 235.1232.
7-Fluoro-3-phenylisoquinolin-1-amine (4o). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
obtained as a yellow solid (61.0 mg, 85% yield): mp 112.8−113.6 °C;
1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J = 8.0, 0.5 Hz, 2H), 7.76−
7.79 (m, 1H), 7.37−7.50 (m, 6H), 5.13 (s, 2H); 13C NMR (125 MHz,
CDCl3) δ 160.6 (d, JC−F = 248.4 Hz), 155.6 (d, JC−F = 4.9 Hz), 149.2
(d, JC−F = 2.7 Hz), 139.7, 135.4, 130.2 (d, JC−F = 8.0 Hz), 128.8, 128.5,
126.9, 120.6 (d, JC−F = 24.7 Hz), 117.5 (d, JC−F = 7.2 Hz), 108.8, 107.1
(d, JC−F = 21.5 Hz); IR (CHCl3, cm−1) ν 3378, 3197; HRMS (ESI)
calcd for C15H12FN2 (M + H)+ 239.0979, found 239.0981.
MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 8.0 Hz, 2H), 7.58
(t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.39−7.45 (m, 3H), 5.26
(s, 1H), 3.77−3.81 (m, 2H), 1.77−1.83 (m, 2H), 1.52−1.59 (m, 2H),
1.05 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.9, 149.1,
140.4, 138.1, 129.8, 128.6, 128.2, 127.8, 126.8, 125.6, 121.4, 117.5,
106.6, 41.7, 32.0, 20.7, 14.3; IR (CHCl3, cm−1) ν 3452; HRMS (ESI)
calcd for C19H21N2 (M + H)+ 277.1699, found 277.1699.
N,3-Diphenylisoquinolin-1-amine (4v). Eluent of column chroma-
tography: hexanes/ethyl acetate 5/1. This compound was obtained as
a brown solid (19.0 mg, 21% yield): mp 89.2−90.1 °C; 1H NMR (500
MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H),
7.87 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.64−7.67 (m, 2H),
7.54 (dt, J = 8.2, 1.1 Hz, 1H) 7.49 (t, J = 7.9 Hz, 2H), 7.37−7.43 (m,
3H), 7.24 (s, 1H), 7.09 (t, J = 7.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 151.7, 149.0, 140.7, 139.9, 138.5, 130.2, 129.1, 128.8, 128.5,
128.2, 126.9, 126.5, 122.6, 121.5, 120.0, 118.1, 109.4; IR (CHCl3,
cm−1) ν 3446; HRMS (ESI) calcd for C21H17N2 (M + H)+ 297.1386,
found 297.1390.
7-Methoxy-3-tridecylisoquinolin-1-amine (4p). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
1
obtained as a light yellow oil (90.9 mg, 85% yield): H NMR (500
MHz, CDCl3) δ 7.54 (d, J = 9.1 Hz, 1H), 7.29−7.27 (m, 2H), 6.78 (s,
1H), 6.21 (s, 2H), 3.92 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 1.74−1.70
(m, 2H), 1.24−1.36 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 157.9, 154.9, 133.2, 128.4, 123.5, 117.2, 109.7,
102.6, 56.0, 36.6, 32.1, 29.89, 29.86, 29.80, 29.7, 29.62, 29.57, 22.9,
14.3 (fewer 13C signals were observed due to signal overlapping); IR
(CHCl3, cm−1) ν 3335, 3149; HRMS (ESI) calcd for C23H37N2O (M
+ H)+ 357.2900, found 357.2902.
Synthesis of N-(3-Phenyl-1H-isochromen-1-ylidene)propan-
1-amine (17a). Eluent of column chromatography: hexanes/ethyl
acetate 5/1. This compound was synthesized from 2-(phenylethynyl)-
N-propylbenzamide (3t) on a 0.5 mmol scale according to a procedure
in the literature.16 The compound was obtained as a colorless oil (56.7
1
mg, 43% yield): H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 7.9 Hz,
1H), 7.80 (dd, J = 8.4, 0.8 Hz, 2H), 7.45−7.48 (m, 3H), 7.40−7.42
(m, 1H), 7.33 (dt, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.63
(s, 1H), 3.62 (t, J = 7.1 Hz, 2H), 1.77−1.81 (m, 2H), 1.08 (t, J = 7.4
7-Methyl-3-tridecylisoquinolin-1-amine (4q). Eluent of column
chromatography: hexanes/ethyl acetate 2/1. This compound was
1
1
Hz, 3H). The H NMR spectral data are in good agreement with the
obtained as a light yellow oil (91.5 mg, 90% yield): H NMR (500
literature data.16
MHz, CDCl3) δ 7.52−7.54 (m, 2H), 7.40 (dd, J = 8.4, 1.4 Hz, 1H),
6.84 (s, 1H), 5.17 (s, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.49 (s, 3H), 1.70−
1.76 (m, 2H), 1.25−1.37 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 155.4, 153.1, 136.4, 135.1, 132.3, 126.7,
121.9, 116.5, 109.9, 38.1, 32.1, 29.93, 29.90, 29.89, 29.87, 29.83, 29.80,
29.7, 29.6, 22.9, 22.0, 14.4 (fewer 13C signals were observed due to
signal overlapping); IR (CHCl3, cm−1) ν 3303, 3128; HRMS (ESI)
calcd for C23H37N2 (M + H)+ 341.2951, found 341.2951.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra for the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
3-(4-Methoxyphenyl)-7-methylisoquinolin-1-amine (4r). Eluent
of column chromatography: hexanes/ethyl acetate 2/1. This
compound was obtained as a green solid (74.9 mg, 94% yield): mp
166.9−167.8 °C; 1H NMR (500 MHz, CDCl3) δ 8.00−8.01 (m, 2H),
7.63 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.42 (dd, J = 8.3, 1.3 Hz, 1H),
7.38 (s, 1H), 6.98−7.01 (m, 2H), 5.25 (s, 2H), 3.86 (s, 3H), 2.49 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 159.9, 155.6, 148.5, 136.6,
135.6, 132.7, 132.4, 128.1, 127.4, 122.0, 116.9, 114.1, 107.9, 55.5, 22.0;
IR (CHCl3, cm−1) ν 3354, 3170; HRMS (ESI) calcd for C17H17N2O
(M + H)+ 265.1335, found 265.1337.
AUTHOR INFORMATION
Corresponding Author
*E-mail for Y.C.: yu.chen1@qc.cuny.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Queens College Research Enhancement Award
(2011) and the CUNY Collaborative Incentive Research Grant
(Round 18) for their financial support and Dr. Cliff Soll at
Hunter College for recording the mass spectra for all of the new
compounds. Y.L. thanks South China Normal University for
partial financial support.
7-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-amine (4s). Eluent of
column chromatography: hexanes/ethyl acetate 2/1. This compound
was obtained as a yellow solid (76.5 mg, 95% yield): mp 180.5−181.4
1
°C; H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H), 7.76−
7.73 (m, 1H), 7.42−7.37 (m, 3H), 7.00 (d, J = 8.3 Hz, 2H), 5.11 (s,
2H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.3 (d, JC−F
=
245.5 Hz), 160.1, 155.5 (d, JC−F = 4.8 Hz), 149.0, 135.5, 132.4, 130.1
(d, JC−F = 8.3 Hz), 128.1, 120.5 (d, JC−F = 24.4 Hz), 117.2 (d, JC−F
=
REFERENCES
■
7.1 Hz), 114.2, 107.7, 107.1 (d, JC−F = 21.4 Hz), 55.6; IR (CHCl3,
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269.1085, found 269.1086.
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1
obtained as a light yellow oil (61.4 mg, 74% yield): H NMR (500
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