Easy access to synthesize isoquinolines from aryl ketoximes and internal alkynes via Iridium (III)-catalyzed C[sbnd]H/N[sbnd]O bond activation

Article abstract of DOI:10.1016/j.tet.2019.04.039

A highly efficient approach to synthesize isoquinoline derivatives through Iridium(III)-catalyzed cyclization of aryl ketoximes and internal alkynes without oxidant is reported. A broad range isoquinolines are obtained in good to excellent yields and various functional groups are well tolerated.

Full text of DOI:10.1016/j.tet.2019.04.039

Accepted Manuscript
Easy access to synthesize isoquinolines from aryl ketoximes and internal alkynes via
iridium (III)-Catalyzed C -H/N -O bond activation
Wei Lin, Xiu-Xiu Hu, Cang-Wei Zhuang, Ya-Zhen Wang
PII:
S0040-4020(19)30451-X
https://doi.org/10.1016/j.tet.2019.04.039
TET 30284
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 January 2019
Revised Date: 22 March 2019
Accepted Date: 16 April 2019
Please cite this article as: Lin W, Hu X-X, Zhuang C-W, Wang Y-Z, Easy access to synthesize
isoquinolines from aryl ketoximes and internal alkynes via iridium (III)-Catalyzed C -H/N -O bond
activation, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.039.
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ACCEPTED MANUSCRIPT
Easy Access to Synthesize Isoquinolines from Aryl Ketoximes and Internal
Alkynes via Iridium (III)-Catalyzed C-H/N-O Bond Activation
Wei Lin,* Xiu-Xiu Hu, Cang-Wei Zhuang, Ya-Zhen Wang

ACCEPTED MANUSCRIPT
Easy Access to Synthesize Isoquinolines from Aryl Ketoximes and Internal
Alkynes via Iridium (III)-Catalyzed C-H/N-O Bond Activation
Wei Lin,* Xiu-Xiu Hu, Cang-Wei Zhuang, Ya-Zhen Wang
School of Chemistry and Environmental Engineering, Jiangsu University of Technology,
Changzhou 213001, P. R. China.
* Corresponding author. E-mail address: linwei841012@163.com (Wei Lin).
Abstract: A highly efficient approach to synthesize isoquinoline derivatives through
Iridium(III)-catalyzed cyclization of aryl ketoximes and internal alkynes without oxidant is
reported. A broad range isoquinolines are obtained in good to excellent yields and various
functional groups are well tolerated.
Keywords: isoquinoline, synthesis; cyclization, Iridium(III)-catalysis
1. Introduction
Recently, transition-metal-catalyzed directed C−H functionalization has emerged as a
practical approach for organic synthesis, which has been witnessed tremendous progress [1].
Among the most promising activation strategies is to utilize cleverly the proximate effect
by coordination of a directing group in given substrate to the metal center of a catalyst,
which brings regioselective C-H bond activation and functionalization [2].
As well known, isoquinoline framework is an important N-heterocyclic structural
motif, which is found in many naturally occurring compounds that exhibit a variety of
biological activities [3]. And many substituted isoquinolines are also often used in the
synthesis of inhibitors, pharmaceuticals and chiral ligands [4]. In the past decades, various
transition-metal (Rh, Ru, Co) catalyzed annulations by C-H/N-O functionalizations have
been proved elegant methods for the synthesis of isoquinolines (Scheme 1) [5-7]. For
example, Shunsuke Chiba group developed a useful synthetic method for isoquinoline
derivatives from readily available starting materials by using Cu(OAc)2 and [Cp*RhCl2]2
bimetallic relay catalysts in 2011 [8]. An efficient ruthenium-catalyzed redox-neutral
annulations of alkynes different oximes through C-H/N-O functionalization was reported
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by Lutz Ackermann group [9]. Recently, Shigeki Matsunaga group demonstrated one
unique Cp*CoIII catalyst that exhibited high site selectivity and reactivity for the synthesis
of multisubstituted isoquinolines from unsymmetrical O-acyl oximes and terminal as well
as internal alkynes by site-selective C-H bond activation [10]. We hypothesized introducing
a new catalyst to induce the C-H annulation high efficiently, a wider substrate scope and
better functional group tolerance could be observed.
Iridium(III) catalyzed C-H functionalization has achieved significant development,
greatly enriching the type of reaction and the substrate scope [11]. To our knowledge, C-H
annulation to synthesize isoquinoline from ketoxime substrates using Iridium(III) as
catalyst has few reports. Herein, we report the first example of the Ir(III) complex as a
highly efficient catalyst in promoting C-H/N-O annulation of ketoxime with internal
alkynes to build isoquinoline skeleton without using external oxidant (Scheme 1) [12].
Scheme 1. Transition-metal-catalyzed directed C-H/N-O bond activation
2. Results and Discussion
We began our initial study by treating acetophenone oxime 1a with diphenylacetylene
.
2a in the presence of [Cp*IrCl2]2 (2.5 mol%) and Cu(OAc)2 H2O (2 equiv) in DCE at 80 oC
for 24
h
in
a
sealed vial. Unfortunately, only 15%
yield of
1-methyl-3,4-diphenylisoquinoline 3a was detected by GC at the first run (Table 1, entry1).
Screening other solvents, including MeOH, EtOH, TFE and HFIP (Table 1, entries 2-5), led
to the identification of MeOH as the optimal solvent (Table 1, entry 2). We subsequently
tested other base additives such as LiOAc, NaOAc, KOAc and AgOAc. However, none of
them gave better results (Table 1, entries 6-9). Acid additives were also investigated, most
2

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of them displaying positive effect on the product yield (Table 1, entries 10-15). Notably,
PivOH was the best additive, which greatly promoting the annulation reaction and gave
82% yield of product 3a (Table 1, entry 10). Much to our delight, we observed that
lowering the temperature to 60 °C further increased the yield of 3a to 89% (Table 1, entry
.
16). Notably, additional Cu(OAc)2 H2O in the presence of PivOH had not further promoted
the reaction (Table 1, entry 17). Control experiment showed the annulation failed to
proceed in the absence of Ir(III) catalyst, indicating the Iridium could not be replaced in this
transformation (Table 1, entry 18).
Table 1. Optimization of the Reaction Conditionsa
Entry
1
Solvent
DCE
Additive 1
Additive 2
GC-Yieldb
15%
.
Cu(OAc)2 H2O
-
.
2
MeOH
EtOH
Cu(OAc)2 H2O
-
33%
.
3
Cu(OAc)2 H2O
-
<5%
.
4
TFE
Cu(OAc)2 H2O
-
18%
.
5
HFIP
Cu(OAc)2 H2O
-
<5%
6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
LiOAc
-
-
<5%
7
NaOAc
<5%
8
KOAc
-
<5%
9
AgOAc
-
12%
10
11
12
13
14
15
16c
-
-
-
-
-
-
-
PivOH
1-AdCO2H
HOAc
MesCO2H
AgSbF6
AgNTf2
PivOH
82%
69%
63%
65%
41%
10%
89%(86)d
3

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17c
MeOH
MeOH
Cu(OAc)2 H2O
PivOH
90%
0
.
18c,e
-
PivOH
aReaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [Cp*IrCl2]2 (2.5mol%), additive 1
o
b
(0.2 mmol), additive 2 (0.03 mmol), solvent (1 mL), 80 C, 24 h. GC yield of 3a
determined using tridecane as internal standard. c60 oC. dIsolated yield. eNo catalyst.
With the optimized conditions in hand, the scope of aryl ketoximes 1 was examined. As
illustrated in Table 2, a broad range of aryl ketoximes 1 were well tolerated and
corresponding products were obtained in moderate to excellent yields. A variety of
para-substituted substrates 1a-1o was readily converted to annulation products with
internal alkynes, including electron-donating groups and electron-withdrawing groups. To
our delight, even the iodine substitution on the aromatic ring was achieved in 78% yield
without any modifying reaction conditions (3j). When ortho- and meta-substituted
substrates were applied to the method, good yields were observed, such as 3p, 3q, 3r, 3s
and 3t. For unsymmetrically substituted oximes (1s and 1t, except 1u), the Cp*IrIII catalyst
exhibited much site selectivity, both the oximes were converted into the desired products
3s–3t with > 20:1 site selectivity and in 52–87% yield. However, for the substrate 1u, the
less steric functional group results in the poor selectivity at the ortho position, the 1u could
convert into two different products 3u and 3u’, along with 50% and 32% yields respectively.
It was also worth mentioning that heterocyclic substrate 1w also proved to be suitable for
.
the C-H annulation, when employing Cu(OAc)2 H2O as the additive at high temperature.
Furthermore, an oxime-containing bicyclic substrate and sterically more demanding
substituent furnished the assembly of the tricyclic product 3aa in low yield.
Table 2. Substrate Scope of aryl ketoximes
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aReaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Cp*IrCl2]2 (2.5 mol%), PivOH
o
b
o
c
o
d
(0.06 mmol), MeOH (2 mL), 60 C, 24 h. Isolated yield. 100 C. 80 C. [Cp*IrCl2]2
(5mol%). e120 oC. fCu(OAc)2 H2O (0.2 mmol).
.
Table 3. Substrate Scope of internal alkynes a
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3 mol% [Cp*IrCl2]2
.
2 equiv Cu(OAc)2 H2O
N
OH
0.3 equiv PivOH
Ar
N
Ar
Ar
N
+
MeOH, 120 oC, 24 h
Ar
4
2
1a
N
N
OMe
tBu
OMe
4c
tBu
4a
, 65%
4b, 50%
, 61%
N
N
N
Cl
CF3
F
Cl
CF3
F
4d, 53%
4e, 72%
4f, 44%
N
F
N
N
F
F
Br
F
Br
4i, 78%b
4h, 52%b
4g, 41%
N
N
S
S
4j, 47%b
4k, trace
aReaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Cp*IrCl2]2 (3.0 mol%),
.
o
Cu(OAc)2 H2O (0.4 mmol), PivOH (0.06 mmol), MeOH (2 mL), 120 C, 24 h, Isolated
yield. bTFE (2 mL)
Subsequently, different internal alkynes were tested in this Ir(III)-catalyzed protocol,
.
mainly involving aryl and heteroaryl alkynes (Table 3). 2 Equiv Cu(OAc)2 H2O was found
quite necessary to promote the reaction through further modifying the conditions and
.
desired products could be isolated in moderate yields. We speculated that Cu(OAc)2 H2O
play an important role in catalyst regeneration through helping oxidization of the Ir(I) to
Ir(III). Unfortunately, the alkyl-substituted alkyne was found hardly to react with
6

ACCEPTED MANUSCRIPT
acetophenone oxime 1a, just the starting materials remained (4k).
Table 4. Different protecting groups directed C-H annulation a
N
R
standard conditions
N
Ph
Ph
+
Ph
Ph
1a
5
2a
or
3a
OH
OEt
OMe
N
N
N
1a, 86%
5b
5e
, 36%
5a, 43%
NHTs
OPiv
OAc
N
N
N
5c
, 15%
5d
, 37%
, 15%
aReaction conditions: 1a or 5 (0.2 mmol), 2a (0.24 mmol), [Cp*IrCl2]2 (2.5mol%), PivOH
(0.06 mmol), MeOH (2 mL), 60 oC, 24 h, Isolated yield.
Meanwhile, other protecting groups of acetophenone were also examined in the
protocol (Table 4). We were pleased to find that all the annulation could occur with the
assistance of these directing groups, and the desired product could be achieved in low to
moderate yields. Besides, the gram-scale reaction was successfully obtained with 2 mol%
[Cp*IrCl2]2, which highlighted the power of this approach. And the corresponding product
could be coupled with phenylboronic acid, affording 3l in 81% yield (Scheme 2).
Scheme 2. Scaling up and coupling with phenylboronic acid
Based on previous mechanistic study and the recent reports, a plausible mechanism for
the Ir(III)-catalyzed C-H annulation of ketoxime is proposed in Scheme 3 [13]. The
catalytic cycle is likely initiated by the dissociation of the [Cp*IrCl2]2 dimer and the
7

ACCEPTED MANUSCRIPT
exchange of pivaloyl with the coordinated chloro ligand to form a pivaloyl-ligated species.
Then, coordination of the nitrogen atom to the Ir(III) center, followed by arene ortho C-H
cleavage lead to the generation of five-membered Iridiumcycle III. The coordination of the
alkyne π-bond to Iridiumcycle III, followed by insertion of the alkyne, forms the C-C bond
and produces key intermediate V. The subsequent intramolecular annulation and reductive
elimination provides the N-hydroxyisoquinoline cation VI, which could serve as an oxidant
for the regeneration of Ir(III) catalyst for the next cycle and affords the isoquinoline as the
final product.
Scheme 3. Proposed catalytic cycle
3. Conclusion
In summary, we have reported a novel and highly efficient iridium-catalyzed C-H/N-O
Bond of aryl ketoximes with internal alkynes for the synthesis of isoquinolines without
external oxidant. A broad range of aryl ketoximes substituted by various groups could be
well tolerated in this new method, giving the corresponding products in moderate to
excellent yields.
8

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4. Experimental Section
4.1. General
Unless otherwise noted, all reagents were purchased from commercial suppliers and
used without further purification. HRMS analysis was carried out using TOF-MS
instrument with ESI source. 1H NMR and 13C NMR were determined on Varian Invoa-400
MHz spectrometer in CDCl3 solution. J values are in Hz. Chemical shifts are expressed in
ppm downfield from internal standard TMS. Multiplicities are recorded as s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, m = multiplet.
4.2. Characterization data of 3 are represented as follows.
A mixture of compounds 1 or 5 (0.2 mmol), diphenylacetylene 2a (0.24 mmol, 1.2
equiv), [Cp*IrCl2]2 (2.5 mol%), PivOH (0.06 mmol, 0.3 equiv) and MeOH (2 mL) in a 15
mL glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was heated at 60 °C with
vigorous stirring for 24 h. The reaction mixture was cooled to room temperature, diluted
with ethyl acetate, and filtered through Celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel to give the corresponding product 3.
4.2.1. 1-Methyl-3,4-diphenylisoquinoline (3a): Brown solid; 1H NMR (400 MHz, CDCl3) δ
8.21-8.19 (m, 1H), 7.67-7.57 (m, 3H), 7.38-7.17 (m, 10H), 3.08 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 157.3, 149.0, 140.6, 137.1, 135.5, 131.0, 129.8, 129.5, 128.7, 127.7, 127.2,
126.7, 126.5, 126.1, 125.8, 125.7, 125.1, 22.3; HRMS : m/z calcd for C22H17NNa [M+Na]+:
318.1259; Found: 318.1274.
4.2.2. 1,6-Dimethyl-3,4-diphenylisoquinoline (3b): White solid; 1H NMR (400 MHz, CDCl3)
δ 8.09 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.35-7.33 (m, 5H), 7.23-7.16 (m, 5H),
3.04 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 149.1, 140.7, 139.7, 137.3,
135.8, 131.0, 129.8, 128.3, 128.2, 127.7, 127.1, 126.6, 126.4, 125.0, 124.6, 124.1, 22.2,
21.7; HRMS : m/z calcd for C23H20N [M+H]+: 310.1596; Found: 310.1591.
1
4.2.3. 6-Ethyl-1-methyl-3,4-diphenylisoquinoline (3c): White solid; H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.36-7.34 (m, 5H), 7.24-7.17 (m, 5H),
3.05 (s, 3H), 2.76-2.70 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
157.4, 149.6, 146.4, 141.2, 137.8, 136.3, 131.5, 130.3, 128.9, 128.2, 127.6, 127.0, 126.8,
125.6, 124.8, 124.0, 29.4, 22.7, 15.4; HRMS : m/z calcd for C24H22N [M+H]+: 324.1752;
Found: 324.1757.
1
4.2.4. 6-Isopropyl-1-methyl-3,4-diphenylisoquinoline (3d): Brown solid; H NMR (400
MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.58-7.52 (m, 2H), 7.42-7.38 (m, 5H), 7.31-7.23
(m, 5H), 3.11 (s, 3H), 3.06-3.02 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz,
9

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CDCl3) δ 156.9, 150.4, 149.1, 140.8, 137.3, 135.8, 131.0, 129.8, 128.6, 127.7, 127.1, 126.6,
126.3, 125.4, 125.2, 124.5, 122.3, 34.1, 23.2, 22.2; HRMS : m/z calcd for C25H24N [M+H]+:
338.1909; Found: 338.1922.
1
4.2.5. 6-(Tert-butyl)-1-methyl-3,4-diphenylisoquinoline (3e): White solid; H NMR (400
MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.36-7.30 (m, 5H), 7.24-7.15
(m, 5H), 3.04 (s, 3H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.7, 152.5, 149.1,
140.8, 137.3, 135.5, 131.0, 129.8, 128.9, 127.6, 127.1, 126.6, 126.3, 124.9, 124.8, 124.0,
120.8, 34.8, 30.5, 22.1; HRMS : m/z calcd for C26H26N [M+H]+: 352.2065; Found:
352.2055.
4.2.6. 6-Methoxy-1-methyl-3,4-diphenylisoquinoline (3f): White solid; 1H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 9.2 Hz, 1H), 7.36-7.32 (m, 5H), 7.24-7.17 (m, 6H), 6.92-6.91 (m, 1H),
3.73 (s, 3H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 156.5, 149.6, 140.6, 137.6,
137.4, 130.8, 129.8, 128.2, 127.8, 127.1, 127.0, 126.6, 126.4, 121.4, 118.3, 104.0, 54.8,
22.1; HRMS : m/z calcd for C23H20NO [M+H]+: 326.1545; Found: 326.1560.
1
4.2.7. 6-Fluoro-1-methyl-3,4-diphenylisoquinoline (3g): White solid; H NMR (400 MHz,
CDCl3) δ 8.24-8.20 (m, 1H), 7.39-7.32 (m, 6H), 7.27 (dd, J1 = 6.8 Hz, J2 = 2.4 Hz, 1H),
7.22-7.19 (m, 5H), 3.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.0, 161.5, 157.1, 150.0,
140.2, 137.7, 137.6, 136.7, 130.7, 129.8, 128.5, 128.4, 128.2, 128.1, 128.0, 127.0, 126.9,
126.7, 123.0, 116.3, 116.1, 109.5, 109.3, 22.4; HRMS : m/z calcd for C22H17FN [M+H]+:
314.1345; Found: 314.1357.
4.2.8. 6-Chloro-4-(cyclohexa-1,5-dien-1-yl)-1-methyl-3-phenylisoquinoline (3h): White
solid; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.8 Hz, 1H), 7.63-7.62 (m, 1H), 7.53 (dd,
J1 = 8.8 Hz, J1 = 2.0 Hz, 1H), 7.37-7.34 (m, 5H), 7.22-7.18 (m, 5H), 3.06 (s, 3H);13C NMR
(100 MHz, CDCl3) δ 157.2, 150.2, 140.2, 136.7, 136.4, 135.9, 130.8, 129.7, 128.0, 127.9,
127.2, 127.0, 126.9, 126.7, 124.7, 123.9, 22.3; HRMS : m/z calcd for C22H17ClN [M+H]+:
330.1050; Found: 330.1048.
1
4.2.9. 6-Bromo-1-methyl-3,4-diphenylisoquinoline (3i): White solid; H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.8 Hz, 1H), 7.81-7.80 (m, 1H), 7.67 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz,
1H), 7.37-7.34 (m, 5H), 7.22-7.18 (m, 5H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
157.3, 150.1, 140.1, 136.9, 136.3, 130.8, 129.7, 129.5, 128.0, 127.8, 127.2, 127.0, 126.8,
126.7, 124.6, 124.1, 22.2; HRMS : m/z calcd for C22H17BrN [M+H]+: 374.0544; Found:
374.0542.
1
4.2.10. 6-Iodo-1-methyl-3,4-diphenylisoquinoline (3j): Green solid; H NMR (400 MHz,
CDCl3) δ 8.04-8.03 (m, 1H), 7.92-7.84 (m, 2H), 7.38-7.32 (m, 5H), 7.21-7.18 (m, 5H), 3.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9, 150.4, 140.6, 137.5, 136.8, 135.3, 135.1,
131.3, 130.2, 128.4, 128.0, 127.6, 127.4, 127.2, 127.0, 124.8, 97.7, 22.6; HRMS : m/z calcd
for C22H17IN [M+H]+: 422.0406; Found: 422.0398.
1
4.2.11. 1-Methyl-3,4-diphenyl-6-(trifluoromethyl)isoquinoline (3k): White solid; H NMR
(400 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H),
7.39-7.37 (m, 5H), 7.24-7.20 (m, 5H), 3.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4,
150.4, 140.0, 136.0, 135.0, 131.2, 130.9, 130.8, 129.8, 129.2, 128.0, 127.3, 127.2, 126.9,
126.5, 126.4, 124.7, 123.5, 123.4, 122.0, 121.8, 121.7, 22.4; HRMS : m/z calcd for
C23H17F3N [M+H]+: 364.1313; Found: 364.1327.
4.2.12. 1-Methyl-3,4,6-triphenylisoquinoline (3l): White solid; 1H NMR (400 MHz, CDCl3)
10

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δ 8.34-8.32 (m, 1H), 7.92-7.90 (m, 2H), 7.64-7.62 (m, 2H), 7.51-7.38 (m, 8H), 7.34-7.25
(m, 5H), 3.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 149.5, 142.0, 140.6, 140.0,
137.0, 135.9, 131.0, 129.8, 128.9, 128.4, 127.8, 127.5, 127.2, 127.1, 126.7, 126.5, 125.7,
124.7, 123.6, 22.3; HRMS : m/z calcd for C28H22N [M+H]+: 372.1752; Found: 372.1745.
1
4.2.13. 1-Methyl-3,4-diphenylisoquinoline-6-carboxylate (3m): White solid; H NMR (400
MHz, CDCl3) δ 8.41-8.40 (m, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.17 (dd, J1 = 8.8 Hz, J2 = 1.6
Hz, 1H), 7.38-7.34 (m, 5H), 7.24-7.19 (m, 5H), 3.91 (s, 3H), 3.10 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.2, 157.3, 150.0, 140.2, 136.3, 135.0, 130.9, 130.7, 129.8, 129.6, 128.5,
127.9, 127.2, 127.0, 126.7, 125.6, 125.5, 52.0, 22.4; HRMS : m/z calcd for C24H20NO2
[M+H]+: 354.1494; Found: 354.1486
1
4.2.14. 1-Methyl-6-nitro-3,4-diphenylisoquinoline (3n): Brown solid; H NMR (400 MHz,
CDCl3) δ 8.60-8.59 (m, 1H), 8.37-8.31 (m, 2H), 7.41-7.37 (m, 5H), 7.24-7.22 (m, 5H), 3.14
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.6, 151.1, 147.8, 139.5, 135.5, 135.4, 130.7,
130.0, 129.7, 128.3, 127.6, 127.3, 127.2, 127.1, 122.2, 119.4, 22.5; HRMS : m/z calcd for
C22H17N2O2 [M+H]+: 341.1290; Found: 341.1283.
1
4.2.15. N-(1-Methyl-3,4-diphenylisoquinolin-6-yl)acetamide (3o): White solid; H NMR
(400 MHz, CDCl3) δ 8.16 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H), 7.52 (s,
1H), 7.34-7.28 (m, 5H), 7.21-7.16 (m, 5H), 3.02 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.6, 157.3, 140.8, 139.6, 137.5, 137.0, 131.3, 130.2, 128.8, 128.3, 127.6, 127.2,
127.0, 123.4, 120.3, 113.8, 24.6, 22.5; HRMS : m/z calcd for C24H21N2O [M+H]+: 353.1654;
Found: 353.1642.
4.2.16. 8-Fluoro-1-methyl-3,4-diphenylisoquinoline (3p): White solid; 1H NMR (400 MHz,
CDCl3) δ 7.51-7.46 (m, 1H), 7.43-7.41 (m, 1H), 7.37-7.34 (m, 5H), 7.22-7.18 (m, 6H), 3.19
(d, J = 7.6 Hz, 3H); HRMS : m/z calcd for C22H17FN [M+H]+: 314.1345; Found: 314.1355.
1
4.2.17. 1,8-Dimethyl-3,4-diphenylisoquinoline (3q): White solid; H NMR (400 MHz,
CDCl3) δ 7.52-7.49 (m, 1H), 7.40-7.33 (m, 7H), 7.23-7.17 (m, 5H), 3.25 (s, 3H), 3.01 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 157.2, 148.1, 140.4, 137.8, 137.6, 135.5, 131.0, 129.7,
129.6, 129.0, 128.7, 127.7, 127.1, 126.7, 126.6, 126.5, 124.6, 29.5, 25.5; HRMS : m/z calcd
for C23H20N [M+H]+: 310.1596; Found: 310.1588.
1
4.2.18. 8-Methoxy-1-methyl-3,4-diphenylisoquinoline (3r): White solid; H NMR (400
MHz, CDCl3) δ 7.47 (t, J = 8.4 Hz, 1H), 7.40-7.28 (m, 5H), 7.24-7.17 (m, 6H), 6.93 (d, J =
7.6 Hz, 1H), 4.05 (s, 3H), 3.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 157.5, 149.5,
141.0, 138.9, 138.2, 131.4, 130.2, 130.0, 128.4, 128.2, 127.5, 127.0, 126.9, 119.1, 118.4,
105.9, 55.6, 29.3; HRMS : m/z calcd for C23H20NO [M+H]+: 326.1545; Found: 326.1555.
1
4.2.19. 7-Bromo-1-methyl-3,4-diphenylisoquinoline (3s): White solid; H NMR (400 MHz,
CDCl3) δ 8.35-8.34 (m, 1H), 7.64 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz,
1H), 7.37-7.34 (m, 5H), 7.21-7.18 (m, 5H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
156.3, 149.4, 140.1, 136.5, 134.2, 132.8, 130.8, 129.7, 128.6, 127.9, 127.8, 127.4, 127.2,
126.9, 126.8, 126.7, 120.0, 22.2; HRMS : m/z calcd for C22H17BrN [M+H]+: 374.0544;
Found: 374.0528.
1
4.2.20. 1,7-Dimethyl-3,4-diphenylisoquinoline (3t): White solid; H NMR (400 MHz,
CDCl3) δ 7.96 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44-7.41 (m, 1H), 7.37-7.33 (m 5H),
7.23-7.17 (m, 5H), 3.05 (s, 3H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.0, 148.6,
141.1, 137.8, 136.4, 134.2, 132.1, 131.4, 130.3, 129.1, 128.2, 127.6, 127.1, 126.8, 126.4,
11

ACCEPTED MANUSCRIPT
126.1, 124.5, 22.8, 21.9; HRMS : m/z calcd for C23H20N [M+H]+: 310.1596; Found:
310.1601.
1
4.2.21. 7-Methoxy-1-methyl-3,4-diphenylisoquinoline (3u): White solid; H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.24-7.10 (m, 10H), 6.96
(d, J = 7.6 Hz, 1H), 3.41 (s, 3H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 156.9,
151.1, 141.6, 141.4, 130.4, 130.2, 127.9, 127.8, 127.5, 127.3, 127.1, 126.5, 125.6, 118.1,
110.1, 55.6, 23.4; HRMS : m/z calcd for C23H20NO [M+H]+: 326.1545; Found: 326.1556.
1
4.2.21.1. 5-Methoxy-1-methyl-3,4-diphenylisoquinoline (3u’): White solid; H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 9.2 Hz, 1H), 7.40-7.32 (m, 6H), 7.24-7.17 (m, 6H), 3.99 (s,
3H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9, 156.0, 147.7, 141.0, 137.7, 131.4,
130.2, 128.2, 128.0, 127.6, 127.3, 127.1, 126.7, 122.3, 103.5, 55.5, 22.9; HRMS : m/z calcd
for C23H20NO [M+H]+: 326.1545; Found: 326.1553.
1
4.2.22. 1-Methyl-3,4-diphenylbenzo[h]isoquinoline (3v): White solid; H NMR (400 MHz,
CDCl3) δ 8.88 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76-7.69 (m, 2H), 7.65-7.61
(m, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.42-7.31 (m, 5H), 7.24-7.16 (m, 5H), 3.42 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.0, 150.5, 140.2, 137.6, 136.8, 132.5, 131.2, 130.7, 129.8,
129.2, 128.3, 127.8, 127.2, 126.8, 126.7, 126.4, 126.2, 123.8, 123.5, 30.1; HRMS : m/z
calcd for C26H20N [M+H]+: 346.1596; Found: 346.1585.
4.2.23. 7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (3w): Yellow solid; 1H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 5.6 Hz, 1H), 7.37-7.30 (m, 5H), 7.25-7.19 (m, 6H), 2.91 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 151.4, 151.0, 145.7, 140.5, 138.3, 134.2, 130.9, 130.6, 130.3,
128.3, 127.7, 127.2, 127.1, 124.3, 23.7; HRMS : m/z calcd for C20H16NS [M+H]+:
302.1003; Found: 302.1016.
1
4.2.24. 1-Ethyl-3,4-diphenylisoquinoline (3x): White solid; H NMR (400 MHz, CDCl3) δ
8.23-8.20 (m, 1H), 7.64-7.62 (m, 1H), 7.56-7.53 (m, 2H), 7.37-7.29 (m, 5H), 7.22-7.14 (m,
5H), 3.44-3.39 (m, 2H), 1.51 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8,
148.8, 140.7, 137.3 135.9, 130.9, 129.9, 129.2, 128.5, 127.7, 127.1, 126.6, 126.4, 126.0,
125.9, 124.8, 124.7, 28.3, 13.5; HRMS : m/z calcd for C23H20N [M+H]+: 310.1596; Found:
310.1586.
4.2.25. 3,4-Diphenyl-1-propylisoquinoline (3y): White solid; 1H NMR (400 MHz, CDCl3) δ
8.34-8.32 (m, 1H), 7.76-7.74 (m, 1H), 7.68-7.65 (m, 2H), 7.48-7.41 (m, 5H), 7.34-7.25 (m,
5H), 3.50-3.46 (m, 2H), 2.13-2.07 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.8, 148.8, 140.7, 137.3, 135.9, 130.9, 129.9, 129.2, 128.5, 127.7, 127.1, 126.6,
126.4, 125.9, 125.1, 124.8, 37.2, 22.7, 14.1; HRMS : m/z calcd for C24H22N [M+H]+:
324.1752; Found: 324.1759.
1
4.2.26. 1,3,4-Triphenylisoquinoline (3z): White solid; H NMR (400 MHz, CDCl3) δ 8.25
(d, J = 6.4 Hz, 1H), 7.90-7.88 (m, 2H), 7.79 (d, J = 6.4 Hz, 1H), 7.63-7.60 (m, 3H),
7.56-7.51 (m, 4H), 7.45-7.36 (m, 6H), 7.25-7.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
159.9, 149.7, 141.0, 139.9, 137.7, 137.1, 131.5, 130.6, 130.4, 130.1, 129.9, 128.7, 128.5,
128.4, 127.7, 127.6, 127.4, 127.1, 126.7, 126.1, 125.5; HRMS : m/z calcd for C27H20N
[M+H]+: 358.1596; Found: 358.1611.
1
4.2.27. 2,3-Diphenyl-8,9-dihydro-7H-benzo[de]quinolone (3aa): Brown solid; H NMR
(400 MHz, CDCl3) δ 7.49-7.48 (m, 2H), 7.37-7.32 (m, 6H), 7.25-7.17 (m, 5H), 3.39 (t, J =
6.4 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 2.30-2.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
12

ACCEPTED MANUSCRIPT
158.8, 149.0, 140.7, 138.1, 137.4, 135.8, 130.9, 129.8, 129.5, 128.6, 127.7, 127.2, 127.1,
126.6, 126.4, 124.3, 123.4, 123.1, 34.3, 30.3, 23.0; HRMS : m/z calcd for C24H20N [M+H]+:
322.1596; Found: 322.1582.
4.3. Characterization data of 4 are represented as follows.
A mixture of acetophenone oxime 1a (0.2 mmol), diphenylacetylene 2 (0.24 mmol, 1.2
.
equiv), [Cp*IrCl2]2 (3 mol%), PivOH (0.06 mmol, 0.3 equiv), Cu(OAc)2 H2O (0.4 mmol, 2
equiv) and MeOH (2 mL) in a 15 mL glass vial [sealed with poly(tetrafluoroethylene)
(PTFE) cap] was heated at 120 °C with vigorous stirring for 24 h. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The
filtrate was concentrated in vacuo and purified by column chromatography on silica gel to
give the corresponding product 4.
4.3.1. 1-Methyl-3,4-di-p-tolylisoquinoline (4a): White solid; 1H NMR (400 MHz, CDCl3) δ
8.21-8.19 (m, 1H), 7.69-7.67 (m, 1H), 7.60-7.58 (m, 2H), 7.32-7.28 (m, 2H), 7.20-7.13 (m,
4H), 7.04 (d, J = 8.0 Hz, 2H), 3.09 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.4, 149.4, 138.3, 136.6, 136.5, 136.3, 134.7, 131.2, 130.2, 129.7, 129.0, 128.9,
128.4, 126.3, 126.1, 125.5, 22.7, 21.3, 21.2; HRMS : m/z calcd for C24H22N [M+H]+:
324.1752; Found: 324.1762.
1
4.3.2. 3,4-Bis(4-(tert-butyl)phenyl)-1-methylisoquinoline (4b): White solid; H NMR (400
MHz, CDCl3) δ 8.26-8.24 (m, 1H), 7.80-7.76 (m, 1H), 7.65-7.63 (m, 2H), 7.43 (d, J = 8.0
Hz, 2H), 7.35 (t, J = 8.4 Hz, 3H), 7.24-7.21 (m, 3H), 3.14 (s, 3H), 1.42 (s, 9H), 1.33 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 156.9, 149.5, 149.1, 148.9, 137.5, 135.8, 134.1, 130.5,
129.4, 129.3, 128.6, 125.9, 125.8, 125.6, 125.0, 124.5, 124.0, 34.1, 33.9, 30.9, 30.8, 22.2;
HRMS : m/z calcd for C30H34N [M+H]+: 408.2691; Found: 408.2693.
1
4.3.3. 3,4-Bis(4-methoxyphenyl)-1-methylisoquinoline (4c): White solid; H NMR (400
MHz, CDCl3) δ 8.18-8.16 (m, 1H), 7.68-7.66 (m, 1H), 7.58-7.56 (m, 2H), 7.33 (d, J = 8.8
Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.85 (s,
3H), 3.77 (s, 3H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 158.5, 157.4, 149.1,
136.4, 132.4, 131.5, 130.0, 126.2, 126.1, 125.5, 113.8, 113.2, 55.3, 55.2, 22.7; HRMS : m/z
calcd for C24H22NO2 [M+H]+: 356.1651; Found: 356.1646.
4.3.4. 3,4-Bis(4-chlorophenyl)-1-methylisoquinoline (4d): White solid; 1H NMR (400 MHz,
CDCl3) δ 8.22-8.20 (m, 1H), 7.64-7.61 (m, 3H), 7.36 (d, J =8.4 Hz, 2H), 7.29 (d, J =8.4 Hz,
2H), 7.20 (d, J =8.4 Hz, 2H), 7.16 (d, J =8.8 Hz, 2H), 3.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.4, 148.2, 139.2, 135.7, 133.5, 133.3, 132.7, 131.6, 130.3, 128.8, 128.0, 126.9,
126.3, 125.9, 125.7, 22.8; HRMS : m/z calcd for C22H16Cl2N [M+H]+ : 364.0660; Found:
364.0651.
1
4.3.5. 1-Methyl-3,4-bis(4-(trifluoromethyl)phenyl)isoquinoline (4e): White solid; H NMR
(400 MHz, CDCl3) δ 8.21-8.19 (m, 1H), 7.62-7.59 (m, 3H), 7.53-7.50 (m, 1H), 7.45-7.40
(m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.9, 147.8, 141.0, 135.5, 131.7, 130.7, 130.6, 127.4, 126.4, 125.8, 125.5, 125.4, 124.9,
124.8, 22.7; HRMS : m/z calcd for C24H16F6N [M+H]+: 432.1187; Found: 432.1182.
13

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1
4.3.6. 3,4-Bis(4-fluorophenyl)-1-methylisoquinoline (4f): White solid; H NMR (400 MHz,
CDCl3) δ 8.24-8.22 (m, 1H), 7.64-7.63 (m, 3H), 7.36-7.32 (m, 2H), 7.21-7.18 (m, 2H), 7.09
(t, J = 8.8 Hz, 2H), 6.93 (t, J = 8.8 Hz, 2H), 3.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.7, 160.8, 158.1, 136.0, 132.9, 132.8, 132.0, 131.9, 126.8, 125.9, 125.7, 115.6, 115.3,
114.8, 114.6, 22.6; HRMS : m/z calcd for C22H16F2N [M+H]+: 332.1251; Found: 332.1253.
4.3.7. 3,4- Bis(4-bromophenyl)-1-methylisoquinoline (4g): White solid; 1H NMR (400 MHz,
CDCl3) δ 8.22-8.20 (m, 1H), 7.64-7.61 (m, 3H), 7.52 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4
Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 3.07 (s, 3H) ; 13C NMR (100
MHz, CDCl3) δ 158.0, 147.6, 147.5, 135.7, 135.3, 132.6, 132.5, 131.5, 131.3, 130.5, 130.0,
126.6, 125.4, 125.3, 121.2, 22.2; HRMS : m/z calcd for C22H16Br2N [M+H]+: 451.9649;
Found: 451.9629.
4.3.8. 3,4- Bis(3-fluorophenyl)-1-methylisoquinoline (4h): White solid; 1H NMR (400 MHz,
CDCl3) δ 8.23-8.21 (m, 1H), 7.64-7.63 (m, 3H), 7.37-7.32 (m, 1H), 7.19-7.01 (m, 5H),
6.98-6.88 (m, 2H), 3.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 161.0, 158.0, 147.6,
142.4, 139.1, 135.2, 129.9, 129.5, 128.7, 127.7, 126.7, 126.6, 125.8, 125.5, 125.2, 117.9,
117.7, 116.8, 116.5, 114.1, 113.9, 113.6, 22.3; HRMS : m/z calcd for C22H16F2N [M+H]+:
332.1251; Found: 332.1262.
1
4.3.9. 3,4-Bis(2-fluorophenyl)-1-methylisoquinoline (4i): White solid; H NMR (400 MHz,
CDCl3) δ 8.25-8.23 (m, 1H), 7.66-7.63 (m, 2H), 7.57-7.56 (m, 1H), 7.38-7.34 (m, 1H),
7.31-7.28 (m, 1H), 7.23-7.15 (m, 2H), 7.08-7.03 (m, 3H), 6.93-6.88 (m, 1H), 3.09 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.6, 160.9, 159.1, 158.7, 158.4, 146.2, 135.4, 132.7,
131.6, 130.4, 129.8, 129.6, 127.2, 126.5, 125.8, 125.7, 125.4, 123.8, 123.6, 115.5, 115.2,
22.7; HRMS : m/z calcd for C22H16F2N [M+H]+: 332.1251; Found: 332.1265.
1
4.3.10. 1-Methyl-3,4-di(thiophen-2-yl)isoquinoline (4j): Yellow solid; H NMR (400 MHz,
CDCl3) δ 8.06 (d, J =8.0 Hz, 1H), 7.56-7.50 (m, 4H), 7.24-7.23 (m, 1H), 7.21-7.18 (m, 2H),
7.03-7.02 (m, 1H), 6.86-6.84 (m, 1H), 3.01(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0,
137.9, 129.5, 128.2, 127.9, 127.7, 127.6, 127.0, 126.1, 125.8, 125.7, 29.7; HRMS : m/z
calcd for C18H14S2N [M+H]+: 308.0568; Found: 308.0577.
4.4. Scaling Up and and coupling with phenylboronic acid
A mixture of acetophenone oxime 1i (1001.0 mg, 4.70 mmol), diphenylacetylene 2a
(1004.4 mg, 5.64 mmol, 1.2 equiv), [Cp*IrCl2]2 (2 mol%), PivOH (144.0 mg, 1.41 mmol,
0.3 equiv) and MeOH (25 mL) in a 100 mL glass vial [sealed with poly(tetrafluoroethylene)
(PTFE) cap] was heated at 60 °C with vigorous stirring for 24 h. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The
filtrate was concentrated in vacuo and purified by column chromatography on silica gel to
give the desired product 3i in 1.44 g, 82% yield.
A mixture of product 3i (0.2 mmol), phenylboronic acid (0.22 mmol, 1.1 equiv),
Pd(PPh3)2Cl2 (10 mol%), K2CO3 (0.2 mmol, 1 equiv) and 1,4-dioxane (2 mL) in a 15 mL
glass vial [sealed with poly(tetrafluoroethylene) (PTFE) cap] was heated at 90 °C with
14

ACCEPTED MANUSCRIPT
vigorous stirring for 16 h. The reaction mixture was cooled to room temperature, diluted
with ethyl acetate, and filtered through Celite. The filtrate was concentrated in vacuo and
purified by column chromatography on silica gel to give the desired product 3l in 60.1 mg,
81% yield.
Acknowledgements
We acknowledge the financial support from the Foundation of the Natural Science
Foundation of China (No. 21502074), Qing Lan Project of Jiangsu Province and
Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX18-0985)
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