Regioselective Access to 3-Aryl-1-aminoisoquinolines via Nickel(I)-Catalyzed C-C and C-N Cascade Coupling Reactions from the Substituted 2-(Cyanomethyl)benzonitriles

Article abstract of DOI:10.1021/acs.joc.8b01159

A novel and regioselective Ni(I) catalyzed C-C and C-N cascade coupling reactions has been developed. The cascade furnishes atom-economic access to 40 3-aryl-1-aminoisoquinolines. The regioselectivity of C(sp³)-cyano group over C(sp²

Full text of DOI:10.1021/acs.joc.8b01159

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Article
Regio-selective access to 3-Aryl-1-Aminoisoquinolines
via Nickel(I)-catalyzed C-C and C-N cascade coupling
reactions from the substituted 2-(cyanomethyl)benzonitriles.
Xicheng Yang, Haihua Yu, Yulong Xu, and Liming Shao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01159 • Publication Date (Web): 14 Aug 2018
Downloaded from http://pubs.acs.org on August 14, 2018
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Regioꢀselective access to 3ꢀArylꢀ1ꢀAminoisoquinolines via
Nickel(I)ꢀcatalyzed C−C and C−N cascade coupling
reactions from the substituted 2ꢀ(cyanomethyl)benzonitriles.
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⊥
⊥
Xicheng Yang,†, Haihua Yu,†, Yulong Xu,† Liming Shao*,†,‡
†School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hiꢀtech
Park, Pudong, Shanghai 201203, China
‡Shanghai Center for Drug Discovery & Development, 826 Zhangheng Road,
Zhangjiang Hiꢀtech Park, Pudong, Shanghai 201203, China
*Eꢀmail: limingshao@fudan.edu.cn
⊥X.Y and H.Y contributed equally.
Table of Contents/Abstract Graphic:
ABSTRACT: A novel and regioꢀselective Ni(I) catalyzed C−C and C−N cascade
coupling reactions has been developed. The cascade furnishes atomꢀeconomic access
to forty 3ꢀarylꢀ1ꢀaminoisoquinolines. The regioꢀselectivity of C(sp3)ꢀcyano group
over C(sp2)ꢀcyano group was revealed and supported by mechanism studies as well as
the preliminary density functional theory (DFT) calculations.
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INTRODUCTION
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The transitionꢀmetalꢀcatalyzed couplingꢀannulation cascade reactions are fast,
efficient and atomꢀeconomical strategies to access building blocks containing cyclic
or polycyclic skeletons.1 The organonitriles, though lacking electrophilic profile, can
be activated easily by transitionꢀmetals to perform the nucleophilic addition or
Scheme 1. Transitionꢀmetalꢀcatalyzed addition of nitriles and the followꢀup
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annulation cascade reactions
[M]
[M]=Pd,Rh,Ni
O
C
N
Hydrolyze
R1 CN
ArX
Ar
R1
(a)
Ar
R1
X: B(OH)2, I,
COOH, SO2H...
Ar
Ar
(b)
(c)
Ar
[Pd]
CN
FG
Hydrolyze
O
O
ArBXn
FG
N
H
O
R
N
R
[Pd]
R
(d)
(e)
O
[Pd]
[Pd]
ArB(OH)2
N
CN
Ar
Ar
R1
R1
N
R1
R2
N
O
[Pd]
O
N
Ar
R2
N
N
R2
ArB(OH)2
CN
R3
R3
R3
Ar
OTBS
Ar
OTBS
OTBS
CN
Ar
[Ni]
R1
(f)
ArB(OH)2
R1
R1
[Ni]
N
NH2
NH2
This work
N
N
CN
CN
[Ni]
[Ni]
Ar
N
(g)
ArB(OH)2
Ar
C-C Coupling
C-N Coupling
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coupling reactions.2 After the pioneering endeavors of Larock’s group3 and Lu’s
group4, various reports have emerged covering the C−C addition of nitriles catalyzed
by Pd5 and Rh6 whereas only few under the catalysis of the earthꢀabundant Ni7
(Scheme 1a). Moreover, most available nickelꢀcatalyzed addition of nitriles featured
the formation of the hydrolyzed ketone products without tandem transformation
(Scheme 1a). Lu’s group4a and Wu’s group8 developed series palladiumꢀcatalyzed
cascade using the hydrolyzed product ketone as the intermediate (Scheme 1b and 1c).
In a more atomꢀefficient manner to avoid losing the nitrogen atom, Wu’s group9
(Scheme 1d) and our group10 (Scheme 1e) recently disclosed the palladiumꢀcatalyzed
C−C couplings to nitriles followed by sequence reactions to afford isoquinolines and
imidazoles. Using a nickel(I) catalyst, Liu’s group published an intermolecular
cyclization cascade where two C−C coupling reactions were proceeded successively
to alkyne and nitrile (Scheme 1f).11 Unlike the prosperous palladium catalysis, no
nickelꢀcatalyzed cascade reaction starting from the addition of nitriles has yet been
disclosed to the best of our knowledge.
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Herein, we demonstrate the nickel(I)ꢀcatalyzed C−C and C−N cascade coupling
reactions (Scheme 1g). In our cascade reaction, the second cyano group is introduced
to keep all atoms conserved after the cascade. Notably, the C−C coupling step of the
cascade showed regioꢀselectivity on the C(sp3)ꢀcyano group, of which the mechanism
was suggested by model reactions and preliminary DFT studies.
RESULTS AND DISCUSSION
We chose the nickelꢀcatalyzed reaction of 2ꢀ(cyanomethyl) benzonitrile (1a) and
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phenylboronic acid (2a) as a model reaction to investigate the reaction conditions
Table 1. Screening of the reaction conditions for the synthesis of
3ꢀArylꢀ1ꢀAminoisoquinolines
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Entrya
Catalyst
Ligand Additive
Solvent
Yields
(%)b
62
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3
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9
Ni(acac)2
NiCl2
Toluene
Toluene
Toluene
Toluene
DCE
L1
L1
L1
L1
L1
L1
L1
L2
L3
Trace
Trace
48
Pd(acac)2
Pd(OAc)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
44
Dioxane
THF
Trace
Trace
68
Toluene
Toluene
5
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Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Toluene
9
L4
L5
L6
L7
L8
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
64
75
Trace
65
8
12
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22d
23e
24f
25d
26d
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Hacacc
c
Ca(acac)2
17
0
c
Cs2CO3
Cs2CO3
CsF
91
84
82
80
90
64
80
40
0
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
L6
a Standard reaction conditions: 1a (0.5 mmol), 2a (1 mmol, 2 equiv.), Catalyst (0.05
mmol, 10 mol%), ligand (0.05 mmol, 10 mol%), additive (0.1 mmol, 20 mol%) and
b
c
solvent (2.0 mL). 110 °C for 6 h. Isolated yield based on 1a. Additive (0.055
d
mmol, 1.1 equiv.) Ni(acac)2 (0.025 mmol, 5 mol%) and/or L6 (0.025 mmol, 5
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e
f
mol%). Ni(acac)2 (12.5 ꢁmol, 2.5 mol%) and L6 (12.5 ꢁmol, 2.5 mol%).
5
6
7
Ni(acac)2 (0.025 mmol, 5 mol%), L6 (0.025 mmol, 5 mol%) and Cs2CO3 (0.1
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mmol, 10 mol%)
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(Table 1). Using Ni(acac)2 and L1 at 110 °C in toluene, we obtained the desired
product 3a with 62% yield (Entry 1). Replacing Ni(acac)2 with NiCl2 or Pd(acac)2
afforded only trace amount of product (Entry 2ꢀ3). The reaction also worked under the
catalysis of Pd(OAc)2 albeit with a lower yield (Entry 4). Changing the solvent to
DCE gave 3a in the yield of 44% (Entry 5) while the reaction could not work under
dioxane or THF (Entry 6ꢀ7). Next, screening of various bidentate nitrogen ligands
(L2–L8) demonstrated that 4,7ꢀdimethylꢀ1,10ꢀphenanthroline (L6) a superior ligand
with 75% yield (Entry 12). Notably, with ligands containing sp3ꢀnitrogen atoms (L3,
Entry 9), oxygen atom (L4, Entry 10) or steric hindrance group (L7, Entry 13), the
reaction could not work efficiently even with the bidentate nitrogen. Despite the
modest yield, the complete conversion of starting material 1a still could not be
achieved, suggesting that the catalytic cycle was impaired along with the reaction
process. Acetylacetone as well as its anion type were first incorporated with the
assumption of supplementing acac in the cycle. Unfortunately, the yield in both
entries dramatically decreased. (Entry 15ꢀ16). Bases are commonly used to promote
the transmetallation process in coupling reactions. However, stoichiometric amount of
Cs2CO3, a common inorganic strong base, only gave the condensation byꢀproduct
owing to the acidic C(sp3) adjacent to the cyanoꢀgroup (Entry 17). Inspired by Liu’s
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work11, where only catalytic amount of base was applied promoting the formation of
Ni(I)ꢀAr complex, we reduced the amount of Cs2CO3 to 20 mol% giving 3a in an
elevated yield of 91% (Entry 18, vs 75% in Entry 12). Some other lithium salts or
carbonates could also promote the conversion but were slightly inferior to Cs2CO3
(Entry 19ꢀ21). Different equivalents of reagents were further tested where both 5 mol%
loading of the catalyst and the ligand plus 20 mol% Cs2CO3 stood out for comparable
yields of 90% with minimum metal burden (Entry 22ꢀ24). In the absence of the ligand,
the reaction also proceeded to afford 3a in 40% yield (Entry 25). However, no
reaction occurred when there is no catalyst (Entry 26). Regarding the above
optimization studies of reaction conditions, Table 1, Entry 22 was chosen for further
investigation.
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With optimized conditions in hand, we next screened various organoboronic acids
with a reaction partner 1a (Table 2). A wide range of aryl or heteroaryl boronic acids
were well tolerated to synthesize the corresponding 3ꢀArylꢀ1ꢀAminoisoquinolines.
More specifically, the position effect made little contribution to the reaction as the use
of orthoꢀmethyl phenylboronic acid gave a slightly higher yield (3b, 94%) than
metaꢀ(3c, 91%) or paraꢀ(3d, 73%) ones. As the size of the orthoꢀsubstituents
increasing, the yield was getting lower due to the steric effect (3eꢀ3f). As to the
electronic effect of the substituents, the reaction worked well with both
electronꢀdonating and electronꢀwithdrawing groups and a slightly lower yield was
observed with more electronꢀpoor groups (3gꢀ3j). Notably, the Ac group remained
intact and no nickelꢀcatalyzed boron addition to the group was
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Table 2. Scope of boronic acid
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NH2
N
HO
OH
R
Ni(acac)2 (5 mol%)
B
CN
CN
L6 (5 mol%)
+
Cs2CO3 (20 mol%)
Toluene, 6 h, 110 °C
9
1a
R
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2a-2s
3a-3s
NH2
N
NH2
N
NH2
N
NH2
N
CH3
CH3
CH3
CF3
(3c, 91%)
(3d, 73%)
(3a, 90%)
(3b, 94%)
NH2
NH2
NH2
NH2
N
N
N
Et
N
iPr
F
(3g, 55%)
(3h, 46%)
(3e, 68%)
(3f, 54%)
NH2
NH2
N
NH2
N
NH2
N
N
OCH3
F
CF3
O
(3k, 69%)
(3l, 72%)
(3i, 48%)
NH2
(3j, 45%)
NH2
NH2
NH2
N
N
N
N
OCH3
OCH3
Cl
Cl
Cl
Br
(3o, 52%)
(3p, 80%)
(3m, 63%)
(3n, 45%)
NH2
N
NH2
N
NH2
N
O
O
S
(3s, 44%)
(3q, 80%)
(3r, 72%)
Standard reaction conditions: 1a (0.5 mmol), boronic acid (1 mmol, 2.0 equiv.),
Ni(acac)2 (0.025 mmol,5 mol%), L6 (0.025 mmol, 5 mol%), Cs2CO3 (0.1 mmol, 20
mol%) and toluene (2.0 ml) ,110 °C for 6 h; isolated yield based on 1a.
observed (3k). Arylboronic acids bearing methoxy or halogen substituents at the 3ꢀ, 4ꢀ,
or 3,4ꢀ positions afforded the corresponding products in yields of 45%ꢀ80% (3lꢀ3p).
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Fused rings such as 1ꢀnaphthyl and 3,4ꢀmethylenedioxyphenyl as well as heteroaryl
ring like 3ꢀthiophenyl were also successfully transformed under the reaction condition
(3qꢀ3s).
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Furthermore, the scope of the substituted 2ꢀ(cyanomethyl) benzonitrile was
examined (Table 3). Different substitutions on the phenyl ring were incorporated
firstly. Interestingly, unlike the results from arylboronic acids, the reaction worked
equally efficiently on both electronꢀdonating groups (3abꢀ3ac) and
electronꢀwithdrawing group (3ad). The 4ꢀ/5ꢀ halogen substitution of the
2ꢀ(cyanomethyl) benzonitriles gave the corresponding 1ꢀaminoisoquinolines in good
yields ranging from 70% to 85% (3aeꢀ3ag). The 6ꢀClꢀstarting material, with a
potential steric effect on the C(sp2)ꢀcyano group, only afforded 3ah in a 39% yield.
With the 5ꢀClꢀpartener, the reaction operated smoothly utilizing 3,4ꢀdiOMe or 4ꢀF
phenylboronic acid (3ig, 3pg). The incorporation of the 4ꢀphenyl group was also
successful to give the biphenyl product (3ai) with 70% yield. On the other hand,
explorations on the C(sp3)ꢀatom adjacent to the cyano group were also achieved
covering both alkyl and aryl substitutions. Three 4ꢀalkylꢀ3ꢀarylꢀ1ꢀaminoisoquinolines
(3ajꢀ3al) were synthesized, of which the yields decreased with the increased alkyl
dimension. In terms of the aryl substitutions, a variety of groups were also compatible
(3amꢀ3at) while the steric effect (3an) as well as strong electronꢀwithdrawing groups
(3asꢀ3at) slightly influenced the reaction process. Unfortunately, the orthroꢀdimethyl
starting material 1u could not converted to the corresponding product 3au and 90% of
the starting material was recovered. The steric hindrance and the impaired conjugating
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system may contribute to the phenomenon.
Table 3. Scope of 2ꢀ(cyanomethyl)benzonitrile
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NH2
N
Ni(acac)2 (5 mol%)
HO
OH
CN
CN
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B
L6 (5 mol%)
R1
R1
+
Cs2CO3 (20 mol%)
R3
R2
R2
Toluene, 6 h, 110 °C
R3
3ab-3at
3ig,3pg
1b-1u
2a,2i,2p
NH2
NH2
NH2
NH2
H3C
F
N
N
N
N
H3CO
Br
3ab
3ac
3ag
3ad
( ,84%)
(
, 72%)
(
, 76%)
(3ae,85%)
NH2
N
NH2
N
NH2
N
Cl
NH2
Cl
Cl
N
Cl
F
3af
3ah
, 39%)
(
, 78%)
NH2
(
, 70%)
NH2
(
3ig
(
, 63%)
NH2
NH2
Cl
N
CH3
N
N
N
O
O
CH3
CH3
CH3
3pg
(
3ai
3aj
( , 77%)
,70%)
NH2
N
(
, 70%)
NH2
N
(3ak, 60%)
3am
R4=H,
, 81%
NH
N
R4= o-Me, 3an, 68%
R4= m-Me, 3ao, 80%
R4= p-Me,
R4= p-OMe, 3aq, 88%
R4= p-Br, 3ar, 91%
3ap
, 79%
H3C CH3
H3C
CH3
R4
3au
(90% recovery of
0%
3as
R4= p-F,
, 70%
(3al, 42%)
1u
)
R4= p-CF3, 3at, 65%
Standard reaction conditions: 1bꢀ1u (0.5 mmol), boronic acid (1 mmol, 2.0 equiv.),
Ni(acac)2 (0.025 mmol, 5 mol%), L6 (0.025 mmol, 5 mol%), Cs2CO3 (0.1 mmol, 20
mol%) and toluene (2.0 ml), 110 °C for 6 h; isolated yield based on 1bꢀ1u.
Notably, compounds with R4 substitutions (3anꢀ3at) are all new chemical entities.
Comparing with the known methods12, the methodology reported herein gives an
efficient way to afford 3,4ꢀbiarylꢀ1ꢀaminoisoquinolines with less regioselectivity
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problems. Compound 3c, 3eꢀi, 3k, 3nꢀo, 3agꢀ3ai, 3ig, 3pg and 3al are also new
compounds. The skeleton of 3ꢀarylꢀ1ꢀaminoisoquinolines has been found to have
biological activities against cancer13, tumor14, inflammatory15 and Parkinson’s
disease.16 Our method provided a concise approach to the bioactive chemical scaffold,
extending to vision of drug discovery.
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To substantiate the feasibility of this method, we performed the gramꢀscale
synthesis using 1a (1.0 g, 7 mmol), phenylboronic acid (1.7 g, 14 mmol), Ni(acac)2
(90 mg, 0.35 mmol), L6 (0.35 mmol) and Cs2CO3 (1.5 mmol) in toluene for 10 hours.
The product 3a was obtained in 80% yield (Scheme 2a).
To investigate the reaction mechanism, we designed the competing kinetic isotope
effect (KIE) experiment (Scheme 2b). As a result, the KIE effect was not found as the
1
kH/kD ratio was 1:1 between 1a and [d2]ꢀ1a (the KIE was determined by H NMR
spectroscopy by analyzing the ratio of 3a and [d1]ꢀ3a), ruling out the possibility of the
primary KIE effect of the tautomerization step as well as the secondary KIE effect of
the C−C coupling step. Therefore, the C−N coupling step may be the rateꢀdetermining
step of the cascade. Furthermore, the Hammett plots of the R1 (Figure 1A) and R4
substitutions (Figure 1B) were presented. The ρ values of the two plots were less than
zero, but the absolute values were relatively low, indicating that cations or anions
were not existed in the reaction center. In addition, the reaction was not hampered by
the radical scavenger TEMPO, suggesting that the radical species was not involved in
the reaction (Scheme 2c).
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Scheme 2. The gramꢀscale synthesis and mechanism studies.
NH2
N
8
9
Ni(acac)2 (5 mol%)
L6
HO
OH
CN
CN
B
(5 mol%)
+
(a)
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Cs2CO3 (20 mol%)
1a
1 g
3a
80%
Toluene, 10 h, 110 °C
2a
CN
CN
NH2
NH2
Ni(acac)2 (5 mol%)
L6 (5 mol%)
HO
OH
1a
CN
CN
N
B
N
+
(b)
+
Cs2CO3 (20 mol%)
D
Toluene, 10 h, 110 °C
3a
[d1]-3a
D
D
[d2]-1a
/
=
88% kH kD 1:1
NH2
Ni(acac)2 (5 mol%)
HO
OH
N
CN
CN
B
L6 (5 mol%)
(c)
Cs2CO3 (20 mol%)
TEMPO (2 equiv.)
+
3a
88%
1a
2a
Toluene, 10 h, 110 °C
Ni(acac)2 (0.025 mmol)
HO
OH
O
B
CN
L6 (0.025 mmol)
CN
+
+
+
(d)
Cs2CO3 (0.1 mmol)
O
Toluene, 10 min, 110 °C
2a
0.5 mmol
1v
0.5 mmol
1w
0.5 mmol
3av
12%
3aw
20%
CN
CN
Ni(acac)2 (0.025 mmol)
NH
CN
HO
OH
B
L6
(0.025 mmol)
+
+
(e)
NH
Cs2CO3 (0.1 mmol)
Toluene, 10 min, 110 °C
CN
1x
0.5 mmol
2a
0.5 mmol
3ax
7%
3ay
14%
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0.1
0
A
mꢀMe
[CELLRA
7
NGE]
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pꢀCOMe
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ꢀ0.1
ꢀ0.2
ꢀ0.3
ꢀ0.4
p-Me
p-OMe
pꢀF
pꢀBr
pꢀCF3
ꢀ0.4
ꢀ0.2
0
0.2
0.4
0.6
σ
0.08
B
pꢀOMe
pꢀBr
0.04
0
[CELLRA
NGE]
mꢀMe
pꢀF
ꢀ0.04
ꢀ0.08
ꢀ0.12
pꢀMe
pꢀCF3
-0.4
-0.2
0
0.2
0.4
0.6
σ
Figure 1. Hammett plots of the R1 group (A) and the R4 group (B). For A, ρ =
ꢀ0.2309; For B, ρ = ꢀ0.098. The σ value was obtained from Hansch’s review.17
There are two cyano groups in the starting material to compete for the coordination
and the transmetallation in the first step. To understand the preference of the two
cyano groups, we performed the competition reaction of the benzonitrile (1v) and
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benzyl cyanide (1w) under the reaction conditions (Scheme 2d). Quenched at ten
minutes, the hydrolyzed addition product of the C(sp3)ꢀcyano group of 1w was
afforded in a 20% yield (3aw) while addition product of the C(sp2)ꢀcyano group was
obtained in a lower yield of 12% (3av). Furthermore, substrate where the two cyano
groups are spotted in para positions was also tested (Scheme 2e). The reaction
process was stopped at ten minutes and the reaction mixture was purified directly by
column chromatography. Similarly, two cyano groups could both react and the
addition of the C(sp3)ꢀcyano group was the main product (14% for 3ax vs 7% for 3ay).
The above model reactions demonstrated the partial selectivity of the C(sp3)ꢀcyano
group over C(sp2)ꢀcyano group. In our ortho- cyano/cyanomethyl groups system
reported herein, the reaction preference of the C(sp3)ꢀcyano group was much higher.
The preliminary DFT calculations were performed to study the mechanism and
regioselectivity of the cascade (Scheme 3). In accord with the KIE study, the energy
barrier of TS 2 was much higher than TS 1, demonstrating that the CꢀN addition is the
rateꢀdetermining step. The difficulty to rotate bonds and groups to form the
conjugated planar ring may account for the higher energy barrier. The calculated free
energies of TS 1, TS 2 as well as IN 1 – IN 3 were lower than TS 1’, TS 2’ and IN
1’ꢀ IN 3’, respectively, indicating both kinetic and thermodynamic preference for the
C(sp3)ꢀcyano group to perform the C−C and C−N coupling cascade. After analyzing
the structures of the transition states and the intermediates, the steric hindrance
between the two aryl groups was the key factor to the selectivity. In the proposed
rateꢀdetermining step, the dihedral angle of the two aryl groups in TS 2 was 18.32°
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while that of TS 2’ was 65.19° (Figure S1). The steric hindrance increased the
dihedral angle of the two aryl groups with the loss of the conjugate effect, which
contributed to the higher energy.
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Scheme 3. Preliminary DFT results (relative free energies are in Kcal molꢀ1)
Based on the results above, a plausible mechanism was shown in Scheme 4. At the
starting point, a ArNi(I)Ln complex A was formed via the same mechanism in
previous articles.11, 18 Then, the Ni(I) complex A was coordinated to the C(sp3)ꢀcyano
group as a regioselective preference (complex B). After that, the aryl group on the
complex B was inserted into the cyano group to form the Ni(I)ꢀketimine complex C.
The other cyano group, consequently, could undergo the similar
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coordinationꢀinsertion to give the cyclized intermediate E. Subsequent protonation of
E afforded the N−H ketimine F and a nickel(I) salt G. Tautomerization of F
eventually gave the product 3. At the same time, the salt G underwent transmetalation
with ArB(OH)2 to regenerate the nickel(I) complex A again.
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Scheme 4. The proposed mechanism
CONCLUSION
We demonstrate the first nickelꢀcatalyzed cascade coupling reactions starting from the
addition of nitriles. Two cyano groups could undergo C−C and C−N coupling
reactions in sequence in an atomꢀeconomic manner. The mechanism studies as well as
the preliminary DFT studies revealed that the reaction had a priority on the
C(sp3)ꢀcyano group. Further studies will be focused on underlying its detailed
mechanisms and discovering similar reaction types.
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EXPERIMENTAL SECTION
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General Information. All reactions were carried out under an air atmosphere. All
commercially available reagents were used without further purification unless
otherwise stated. UVꢀVisible spectra were collected on a SHIMADZU UVꢀ2550
UVꢀVisible spectrophotometer. Analytical thin layer chromatography (TLC) was
performed using Silica Gel GF254 plates (Rushan Taiyang Desiccant co, .ltd, 0.2 mm
thick). Compounds were purified using column chromatography using the Silica Gel
(Rushan Taiyang Desiccant co, .ltd, 40ꢀ45 ꢁm) . 1H and 13C spectra were recorded on
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1
Varian 400 MHz and Bruker 600 MHz, respectively. Chemical shifts in H NMR
spectra were reported in parts per million (ppm) on the δ scale from an internal
standard of CDCl3(7.26 ppm). Data were reported as follows: chemical shift (δ ppm),
multiplicity (s = singlet, d= doublet, t = triplet, q = quartet, m= multiplet, br = Broad),
coupling constant in hertz (Hz), and integration. Chemical shifts of 13C NMR spectra
were reported in ppm from the central peak of CDCl3 (77.0 ppm) on the δ scale.
ESIꢀHRMS (high resolution mass spectrometry) spectra were obtained on AB SCIEX
TRIPLE TOF 5600+ mass spectrometer. Melting point was performed on WRSꢀ1B
Digital Melting Point Apparatus. All the calculation work was performed on Gaussian
09.19
General procedure for the synthesis of 2ꢀ(cyanomethyl)benzonitrile derivatives
(1bꢀ1h).20 Methyl cyanoacetate (10.0 mmol) was added dropwise to a suspension of
NaH (10.0 mmol) in DMSO at 0 °C. The reaction mixture was stirred at r.t. for 30 min
before the substituted 2ꢀfluoroꢀbenzonitrile (5.0 mmol) in DMSO was added. The
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resulting solution was stirred at 90 overnight and quenched by adding 2 N HCl (20
mL). After extraction with the EtOAc (2 × 30 mL), the combined organic phases were
washed with NaHCO3 (2 × 20 mL), brine (10 mL) and then dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved
in the solution of DMSO/H2O (9/1) and stirred at 110 for 24 hours before quenched
by water. After extraction with the EtOAc (2 × 30 mL), the combined organic phases
were washed with brine (10 mL) and then dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the residue was purified under column
chromatography to afford the desired product.
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2ꢀ(cyanomethyl)ꢀ5ꢀmethylbenzonitrile (1b)21. Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow solid (0.30 g, 38% yield): mp 68.1−71.3 °C.
1H NMR (400 MHz, CDCl3) δ 7.62 – 7.39 (m, 3H), 3.95 (s, 2H), 2.40 (s, 3H). 13C
NMR (151 MHz, CDCl3) δ 139.3, 134.5, 133.5, 130.5, 128.9, 116.7, 116.2, 112.0,
22.2, 20.8.
2ꢀ(cyanomethyl)ꢀ4ꢀmethoxybenzonitrile (1c). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow solid (0.25 g, 29% yield): mp
110.1−112.3 °C. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.7 Hz, 1H), 7.15 (s, 1H),
6.96 (s, 1H), 3.94 (d, J = 24.8 Hz, 5H). 13C NMR (151 MHz, CDCl3) δ 163.5, 135.6,
135.0, 117.0, 116.0, 114.9, 114.4, 103.6, 55.9, 22.7.
2ꢀ(cyanomethyl)ꢀ5ꢀfluorobenzonitrile (1d). Column chromatography: (Petrol
1
ether/ethyl acetate = 20/1). White solid (0.22 g, 28% yield): mp 65.8−67.7 °C. H
NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 8.5, 5.0 Hz, 1H), 7.46 – 7.33 (m, 2H), 3.98 (s,
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2H). 13C NMR (151 MHz, CDCl3) δ 161.7 (d, J = 251.0 Hz), 131.1 (d, J = 8.4 Hz),
129.2 (d, J = 3.5 Hz), 121.3 (d, J = 21.5 Hz), 120.2 (d, J = 24.9 Hz), 115.7, 115.4,
113.7 (d, J = 9.3 Hz), 22.0.
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4ꢀbromoꢀ2ꢀ(cyanomethyl)benzonitrile (1e). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow solid (0.69 g, 62% yield): mp
140.6−144.6 °C. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.3 Hz, 1H), 7.64 (dd, J =
8.3, 1.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 3.98 (s, 2H). 13C NMR (151 MHz, CDCl3)
δ 135.2, 134.2, 132.4, 132.4, 128.9, 115.9, 115.3, 111.0, 22.4.
4ꢀchloroꢀ2ꢀ(cyanomethyl)benzonitrile (1f). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow solid (0.22 g, 25% yield): mp
120.1−122.4 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.58 (m, 2H), 7.49 (d, J = 6.6
Hz, 1H), 4.01 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 140.5, 135.4, 134.3, 129.5,
129.5, 115.8, 115.4, 110.6, 22.5.
5ꢀchloroꢀ2ꢀ(cyanomethyl)benzonitrile (1g). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow solid (0.60 g, 68% yield): mp 66.9−68.2 °C.
1H NMR (400 MHz, CDCl3) δ 7.74 – 7.57 (m, 3H), 3.97 (s, 2H). 13C NMR (151 MHz,
CDCl3) δ 135.1, 134.0, 132.8, 132.0, 130.3, 115.5, 115.3, 113.7, 22.2.
2ꢀchloroꢀ6ꢀ(cyanomethyl)benzonitrile (1h). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). White solid (0.73 g, 83% yield): mp 105.7−108.8 °C. 1H
NMR (400 MHz, CDCl3) δ 7.80 – 7.58 (m, 2H), 7.49 (d, J = 6.6 Hz, 1H), 4.01 (s, 2H).
13C NMR (151 MHz, CDCl3) δ 139.9, 134.8, 133.7, 128.9, 128.8, 115.2, 114.8, 109.9,
21.9.
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Synthesis of 3,6ꢀdiphenylisoquinolinꢀ1ꢀamine (1i)20. The mixture of compound
1e (1.0 mmol), aryl boronic acid (1.6 mmol), Pd(PPh3)4 (0.065 mmol), and K2CO3
(3.6 mmol) in Dioxane/H2O (9:1) was irradiated at 120 °C for 30 min under
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microwave conditions (Sealed tube, the reaction temperature was monitored using
external surface sensor). The reaction mixture was diluted by EtOAc (30 mL) and
washed by saturated NaHCO3 (20 mL), brine (20 mL) and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the residue was
purified under column chromatography (Petrol ether/ethyl acetate = 15/1) to afford
the desired product 1i (0.20 g, 92% yield). Light yellow solid, mp 110.1−113.2 °C. 1H
NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz,
1H), 7.61 (d, J = 7.1 Hz, 2H), 7.55 – 7.39 (m, 3H), 4.06 (s, 2H). 13C NMR (151 MHz,
CDCl3) δ 146.3, 137.7, 133.4, 133.0, 128.7, 128.6, 126.9, 126.8, 126.7, 116.1, 115.4,
109.9, 22.1.
General procedure for the synthesis of 2ꢀ(cyanoalkyl)benzonitrile derivatives
(1jꢀ1l,1u). NaOEt (3.0 mmol; 10.0 equiv for the synthesis of 1u) was added slowly to
the solution of 1a (2.0 mmol) in EtOH at 0 °C and the resulted suspension was stirred
at this temperature for another 30 minutes before adding the alkyl iodine (2.0 mmol ;
10.0 mmol for the synthesis of 1u). The reaction was stirred at 0 °C for 2ꢀ4 hours.
After completing the conversion, the reaction was quenched by 1M NaOH (20 mL),
extracted by EtOAc (2 × 20 mL). The combined organic phases were washed with
brine (10 mL) and then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified under column chromatography to
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afford the desired product.
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2ꢀ(1ꢀcyanoethyl)benzonitrile (1j). Column chromatography: (Petrol ether/ethyl
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acetate = 20/1). Light yellow oil (0.20 g, 64% yield). H NMR (400 MHz, CDCl3) δ
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7.76 – 7.66 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H), 4.33 (q, J = 7.1 Hz, 1H), 1.72 (d, J = 7.2
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 140.7, 133.9, 133.5, 128.8, 127.7, 120.0,
116.6, 111.2, 30.2, 21.3.
2ꢀ(1ꢀcyanopropyl)benzonitrile (1k). Column chromatography: (Petrol ether/ethyl
1
acetate = 20/1). Light yellow oil (0.21 g, 62% yield). H NMR (400 MHz, CDCl3) δ
7.77 – 7.57 (m, 3H), 7.57 – 7.37 (m, 1H), 4.38 – 4.07 (m, 1H), 2.15 – 1.79 (m, 2H),
1.14 (t, J = 7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 139.5, 133.7, 133.4, 128.8,
128.3, 119.3, 116.7, 111.7, 37.5, 29.0, 11.5.
2ꢀ(1ꢀcyanoꢀ2ꢀmethylpropyl)benzonitrile (1l). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow oil (0.11 g, 30% yield). 1H NMR (400 MHz,
CDCl3) δ 7.78 – 7.61 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H), 4.14 (d, J = 5.9 Hz, 1H), 2.26
(dq, J = 13.5, 6.6 Hz, 1H), 1.11 (dd, J = 31.0, 6.7 Hz, 6H). 13C NMR (151 MHz,
CDCl3) δ 138.9, 133.4, 133.4, 128.9, 128.7, 118.4, 116.9, 112.1, 43.5, 33.8, 20.9, 18.5.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C12H13N2, 185.1073; Found 185.1071.
2ꢀ(2ꢀcyanopropanꢀ2ꢀyl)benzonitrile (1u). Column chromatography: (Petrol
ether/ethyl acetate = 20/1). Light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J
= 6.7 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 1.97 (s, 6H). 13C
NMR (151 MHz, CDCl3) δ 142.7, 135.2, 132.9, 127.9, 126.5, 122.2, 117.4, 109.4,
37.4, 26.9.
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General procedure for the synthesis of 2ꢀ(cyanoaryl)benzonitrile derivatives
(1mꢀ1t).22 A solution of substituted phenyl acetonitrile (3.0 mmol) and
2ꢀchlorobenzonitrile (3.3 mmol) in dimethylformamide (1 mL) was added slowly to
the stirring mixture of potassium tertꢀbutoxide (6 mmol) in dimethylformamide (3 mL)
under the ice bath. After stirring for 2 hours, the reaction was quenched by saturated
ammonium chloride (20 mL) and diluted by EtOAc (20 mL). After separation, the
aqueous phase was washed by EtOAc (20 mL). The combined organic phase was
washed by brine and then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified under column chromatography to
afford the desired product.
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2ꢀ(cyano(phenyl)methyl)benzonitrile (1m).22 Column chromatography: (Petrol
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ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.52 g, 90% yield). H NMR (400
MHz, CDCl3) δ 7.76 – 7.64 (m, 3H), 7.51 – 7.32 (m, 6H), 5.57 (s, 1H). 13C NMR (151
MHz, CDCl3) δ 139.5, 134.2, 133.9, 133.6, 129.5, 129.3, 128.9, 128.8, 127.6, 118.3,
116.9, 112.0, 40.9.
2ꢀ(cyano(oꢀtolyl)methyl)benzonitrile (1n). Column chromatography: (Petrol
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ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.54 g, 78% yield). H NMR (400
MHz, CDCl3) δ 7.73 (dd, J = 7.7, 1.2 Hz, 1H), 7.66 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (d,
J = 7.5 Hz, 1H), 7.50 (dd, J = 7.6, 1.1 Hz, 1H), 7.31 – 7.20 (m, 4H), 5.66 (s, 1H), 2.36
(s, 3H). 13C NMR (151 MHz, CDCl3) δ 138.6, 136.2, 133.6, 132.0, 131.4, 129.3,
129.1, 129.0, 128.1, 126.9, 117.8, 116.5, 112.6, 38.0, 19.5. HRMS (ESIꢀTOF) m/z: [M
+ H]+ Calcd for C16H13N2, 233.1073; Found 233.1075.
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2ꢀ(cyano(mꢀtolyl)methyl)benzonitrile (1o). Column chromatography: (Petrol
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ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.45 g, 65% yield). H NMR (400
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1H), 2.35 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 139.6, 139.4, 134.0, 133.9, 133.5,
129.6, 129.3, 129.0, 128.9, 128.2, 124.7, 118.5, 116.9, 111.9, 40.8, 21.4. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C16H13N2, 233.1073; Found 233.1072
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2ꢀ(cyano(pꢀtolyl)methyl)benzonitrile (1p). Column chromatography: (Petrol
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ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.47 g, 67% yield). H NMR (400
MHz, CDCl3) δ 7.70 (dd, J = 17.0, 6.9 Hz, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.29 (t, J =
9.8 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 5.52 (s, 1H), 2.34 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 139.8, 138.9, 133.9, 133.6, 131.3, 130.2, 129.0, 128.8, 127.6, 118.5, 117.0,
111.9, 40.7, 21.1.
2ꢀ(cyano(4ꢀmethoxyphenyl)methyl)benzonitrile (1q). Column chromatography:
1
(Petrol ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.34g, 45% yield). H NMR
(400 MHz, CDCl3) δ 7.76 – 7.57 (m, 3H), 7.46 (s, 1H), 7.32 (d, J = 5.5 Hz, 2H), 6.95
– 6.80 (m, 2H), 5.51 (s, 1H), 3.79 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.8, 139.9,
133.9, 133.6, 128.9, 128.6, 126.2, 118.6, 116.9, 114.8, 111.8, 55.4, 40.2.
2ꢀ((4ꢀbromophenyl)(cyano)methyl)benzonitrile (1r). Column chromatography:
1
(Petrol ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.62g, 70% yield). H NMR
(400 MHz, CDCl3) δ 7.77 – 7.64 (m, 3H), 7.50 (dd, J = 17.2, 8.3 Hz, 3H), 7.29 (t, J =
7.2 Hz, 2H), 5.52 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 138.9, 134.0, 133.7, 133.2,
132.7, 129.3, 128.7, 123.2, 117.8, 116.7, 111.9, 40.4. HRMS (ESIꢀTOF) m/z: [M +
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H]+ Calcd for C15H10BrN2, 297.0022; Found 297.0020.
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2ꢀ(cyano(4ꢀfluorophenyl)methyl)benzonitrile (1s). Column chromatography:
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(Petrol ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.43g, 60% yield). H NMR
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(400 MHz, CDCl3) δ 7.79 – 7.64 (m, 3H), 7.49 (t, J = 7.5 Hz, 1H), 7.40 (dd, J = 8.3,
5.2 Hz, 2H), 7.09 (t, J = 8.3 Hz, 2H), 5.55 (s, 1H). 13C NMR (151 MHz, CDCl3) δ
162.8 (d, J = 249.3 Hz), 139.2, 134.0, 133.7, 130.0 (d, J = 2.7 Hz), 129.6 (d, J = 8.5
Hz), 129.2, 128.7, 118.2, 116.8, 116.5 (d, J = 22.0 Hz), 111.9, 40.3.
2ꢀ(cyano(4ꢀ(trifluoromethyl)phenyl)methyl)benzonitrile
(1t).
Column
chromatography: (Petrol ether/ethyl acetate = 30/1 – 20/1). Colorless oil (0.27g, 32%
1
yield). H NMR (400 MHz, CDCl3) δ 7.78 – 7.63 (m, 5H), 7.62 – 7.43 (m, 3H), 5.63
(s, 1H). 13C NMR (151 MHz, CDCl3) δ 138.5, 138.0, 134.1, 133.8, 131.3 (q, J = 33.1
Hz), 129.5, 128.8, 128.4, 128.2, 126.5 (d, J = 3.3 Hz), 126.2 (d, J = 3.5 Hz), 117.6,
116.7, 112.0, 40.7. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H10F3N2, 309.0610;
Found 309.0613.
Synthesis of 2ꢀ(cyanomethylꢀd2)benzonitrile ([d2]ꢀ1a).23 1a (3.0 mmol) was
dissolved in MeOD (0.6 mL) and then 40% NaOD in D2O was added (17 ꢁL). The
resulting solution was stirred at room temperature for 24 hours. The solvent was
distilled off and the residue was dissolved in MeOD (0.6 mL) and then 40% NaOD in
D2O (17 ꢁL). After 24 hours, the solvent was distilled off and the exchange procedure
was repeated for the third time. The reaction was quenched and neutralized by 20%
DCl in D2O and diluted by anhydrous diethyl ether (5 mL) and D2O (3 mL). After
separation, the aqueous phase was washed by diethyl ether (5 mL). The combined
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organic phase was dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified under column chromatography (Petrol
ether/ethyl acetate = 20/1 – 10/1) to afford [d2]ꢀ1a, light yellow oil (216 mg, 50%
yield). 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.65 (m, 3H), 7.54 – 7.45 (m, 1H).
General procedure for the synthesis of 3ꢀaryllisoquinolinꢀ1ꢀamine derivatives
(3aꢀ3s, 3aaꢀ3at, 3pg, 3ig, [d1]ꢀ3a). The aryl boronic acid (1.0 mmol), Ni(acac)2
(0.025 mmol), ligand (0.025 mmol) and Cs2CO3 (0.1 mmol) were added subsequently
to solution of the substituted 2ꢀ(cyanomethyl)benzonitrile (0.5 mmol) in toluene (2
mL). The reaction mixture was stirred at 110 for 6 hours. After cooling, the mixture
was diluted by EtOAc (20 mL) and H2O (15 mL). After separation, the aqueous phase
was washed by EtOAc (20 mL). The combined organic phase was washed by brine
and then dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was purified under column chromatography to afford the
desired product.
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3ꢀphenylisoquinolinꢀ1ꢀamine (3a)24. Column chromatography: (Petrol ether/ethyl
acetate = 4/1 – 1/1). Light yellow solid (99 mg, 90% yield): mp 91.0−94.3 °C. 1H
NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 8.1, 1.0 Hz, 2H), 7.77 (t, J = 7.3 Hz, 2H),
7.63 – 7.57 (m, 1H), 7.52 – 7.35 (m, 5H), 5.35 (s, 2H). 13C NMR (151 MHz, CDCl3) δ
155.95, 149.53, 139.85, 138.20, 130.23, 128.56, 128.18, 127.52, 126.82, 125.89,
122.59, 116.94, 108.86. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H13N2,
221.1073; Found 221.1071.
3ꢀ(oꢀtolyl)isoquinolinꢀ1ꢀamine (3b)25. Column chromatography: (Petrol ether/ethyl
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acetate = 2/1). Light yellow solid (110 mg, 94% yield): mp 118.3−122.7 °C. 1H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.5
Hz, 1H), 7.54 – 7.43 (m, 2H), 7.31 – 7.22 (m, 3H), 7.11 (s, 1H), 5.36 (s, 2H), 2.40 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 154.8, 150.8, 139.9, 137.2, 135.4, 130.0, 129.8,
129.0, 127.3, 126.7, 125.5, 125.2, 122.1, 115.8, 111.5, 19.8. HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C16H15N2, 235.1230; Found 235.1232.
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3ꢀ(mꢀtolyl)isoquinolinꢀ1ꢀamine (3c). Column chromatography: (Petrol ether/ethyl
acetate = 3/1). Light yellow solid (107 mg, 91% yield): mp 79.2−82.7 °C. 1H NMR
(400 MHz, CDCl3) δ 7.88 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 9.1 Hz, 2H),
7.59 (t, J = 7.5 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.5
Hz, 1H), 5.30 (s, 2H), 2.44 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 155.2, 148.7,
138.9, 137.6, 137.6, 129.8, 128.5, 127.9, 126.9, 125.4, 123.3, 122.1, 116.3, 108.3,
21.0. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H15N2, 235.1230; Found
235.1232.
3ꢀ(pꢀtolyl)isoquinolinꢀ1ꢀamine (3d)25. Column chromatography: (Petrol ether/ethyl
acetate = 2/1). Light yellow solid (85 mg, 73% yield): mp 74.7ꢀ77.9 °C. 1H NMR (400
MHz, CDCl3) δ 7.94 (d, J = 8.1 Hz, 2H), 7.68 (dd, J = 8.1, 4.3 Hz, 2H), 7.53 (t, J =
7.2 Hz, 1H), 7.40 (s, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 5.40 (s,
2H), 2.38 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 155.5, 148.9, 137.7, 137.5, 136.5,
129.6, 128.8, 126.8, 126.2, 125.1, 122.1, 116.3, 107.8, 20.7. HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C16H15N2, 235.1230; Found 235.1231.
3ꢀ(2ꢀethylphenyl)isoquinolinꢀ1ꢀamine (3e). Column chromatography: (Petrol
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ether/ethyl acetate = 2/1). Light yellow oil (84 mg, 68% yield). H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H),
7.44 (dd, J = 27.9, 7.6 Hz, 2H), 7.37 – 7.20 (m, 3H), 7.09 (s, 1H), 5.38 (s, 2H), 2.77
(q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 154.8,
151.7, 146.2, 139.6, 137.2, 129.6, 129.1, 127.6, 126.7, 125.3, 125.0, 124.8, 122.0,
115.8, 111.5, 28.7, 23.6. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H17N2,
249.1386; Found 249.1387.
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3ꢀ(2ꢀisopropylphenyl)isoquinolinꢀ1ꢀamine (3f). Column chromatography: (Petrol
ether/ethyl acetate = 2/1). Light yellow solid (75 mg, 54% yield): mp 105.0−109.3 °C.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62
(t, J = 7.5 Hz, 1H), 7.52 – 7.34 (m, 4H), 7.30 – 7.18 (m, 1H), 7.08 (s, 1H), 5.36 (s,
2H), 3.29 (dt, J = 13.6, 6.7 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H). 13C NMR (151 MHz,
CDCl3) δ 154.9, 151.5, 141.6, 140.0, 137.2, 129.6, 129.2, 128.2, 127.5, 126.7, 125.3,
125.0, 122.0, 115.8, 111.4, 25.6, 15.0. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C18H19N2, 263.1543; Found 263.1545.
3ꢀ(3ꢀfluorophenyl)isoquinolinꢀ1ꢀamine (3g). Column chromatography: (Petrol
ether/ethyl acetate = 12/1 – 3/1). Light yellow solid (66 mg, 55% yield): mp
1
102.0−102.5 °C. H NMR (400 MHz, CDCl3) δ 7.87 – 7.72 (m, 4H), 7.61 (t, J = 7.5
Hz, 1H), 7.50 – 7.34 (m, 3H), 7.05 (t, J = 7.4 Hz, 1H), 5.29 (s, 2H). 13C NMR (151
MHz, CDCl3) δ 163.5, 161.9, 155.3, 147.5, 141.6 (d, J = 7.5 Hz), 137.5, 129.8,129.4
(d, J = 8.1 Hz), 127.0, 125.7, 121.8 (d, J = 54.8 Hz) 116.6, 114.3 (d, J = 21.2 Hz),
113.1 (d, J = 22.5 Hz), 108.5. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H12FN2,
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3ꢀ(3ꢀ(trifluoromethyl)phenyl)isoquinolinꢀ1ꢀamine (3h). Column chromatography:
(Petrol ether/ethyl acetate = 12/1 – 3/1). Light yellow solid (66 mg, 46% yield): mp
94.1−97.5 °C. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H),
7.83 (dd, J = 15.6, 8.3 Hz, 2H), 7.70 – 7.48 (m, 5H), 5.40 (s, 2H). 13C NMR (151
MHz, CDCl3) δ 155.4, 147.0, 139.8, 137.4, 130.3 (q, J = 31.8 Hz), 130.0, 129.3,
128.4, 127.1, 125.9, 124.2 (d, J = 3.3 Hz), 123.1 (d, J = 3.5 Hz), 122.0, 116.6, 108.6.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H12F3N2, 289.0947; Found 289.0945.
3ꢀ(4ꢀfluorophenyl)isoquinolinꢀ1ꢀamine (3i). Column chromatography: (Petrol
ether/ethyl acetate = 12/1). Light yellow solid (57 mg, 48% yield): mp 98.5−103.7 °C.
1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.5, 5.6 Hz, 2H), 7.77 (dd, J = 17.4, 8.2
Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.48 – 7.37 (m, 2H), 7.14 (t, J = 8.7 Hz, 2H), 5.31 (s,
2H). 13C NMR (151 MHz, CDCl3) δ 163.3, 161.7, 155.3, 147.9, 137.6, 135.3, 129.8,
127.9 (d, J = 8.1 Hz) 126.9, 125.4, 122.0, 116.2, 114.9, 114.7, 107.9. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C15H12FN2, 239.0979; Found 239.0980.
3ꢀ(4ꢀ(trifluoromethyl)phenyl)isoquinolinꢀ1ꢀamine (3j)24. Column chromatography:
(Petrol ether/ethyl acetate = 12/1 ꢀ 7/1). Light yellow solid (65 mg, 45% yield): mp
150.9−154.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.4 Hz, 2H), 7.83 – 7.58
(m, 5H), 7.50 (s, 2H), 5.34 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 156.1, 147.9,
143.2, 138.0, 130.5, 130.2 (q, J = 32.1 Hz), 127.7, 127.0, 126.6, 125.5 (d, J = 3.3 Hz)
125.3, 123.5, 122.6, 117.3, 109.6. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C16H12F3N2, 289.0947; Found 289.0945.
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1ꢀ(4ꢀ(1ꢀaminoisoquinolinꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3k). Column chromatography:
(Petrol ether/ethyl acetate = 4/1). Light yellow solid (90 mg, 69% yield): mp
166.5−170.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.1 Hz, 2H), 8.05 (d, J =
8.2 Hz, 2H), 7.82 (dd, J = 17.0, 8.1 Hz, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.53 (dd, J =
16.3, 8.9 Hz, 2H), 5.40 (s, 2H), 2.65 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 198.0,
156.0, 147.8, 144.0, 138.0, 136.6, 130.6, 128.7, 127.8, 126.8, 126.7, 122.7, 117.4,
110.0, 26.7. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H15N2O, 263.1179; Found
263.1189.
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3ꢀ(4ꢀmethoxyphenyl)isoquinolinꢀ1ꢀamine (3l)24. Column chromatography: (Petrol
ether/ethyl acetate = 9/1 – 4/1). Light yellow solid (90 mg, 72% yield): mp
1
137.7−141.2 °C. H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.6 Hz, 2H), 7.76 – 7.66
(m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 – 7.33 (m, 2H), 7.03 – 6.91 (m, 2H), 5.29 (s,
2H), 3.83 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.9, 155.9, 149.3, 138.4, 132.5,
130.2, 128.0, 127.3, 125.5, 122.6, 116.6, 114.0, 107.8, 55.3. HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C16H15N2O, 251.1179; Found 251.1179.
3ꢀ(3ꢀchlorophenyl)isoquinolinꢀ1ꢀamine (3m)25. Column chromatography: (Petrol
ether/ethyl acetate = 10/1). Light yellow solid (80 mg, 63% yield): mp
117.9−121.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H),
7.76 (dd, J = 13.2, 8.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.40 –
7.27 (m, 2H), 5.31 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 155.9, 147.9, 141.7, 138.1,
134.6, 130.4, 129.8, 128.1, 127.6, 127.0, 126.3, 124.8, 122.6, 117.2, 109.1. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C15H12ClN2, 255.0684; Found 255.0683.
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