Direct oxidative C-H alkynylation of: N -carbamoyl tetrahydroisoquinolines and dihydroisoquinolines

Article abstract of DOI:10.1039/c8ob00373d

An efficient oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by a TEMPO oxoammonium salt has been established. A variety of electronically varied N-carbamoyl tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild metal-free conditions. Dihydroisoquinolines were also suitable components for the reaction. The synthetic applicability of the method for facile access to structurally diverse bioactive molecules was further demonstrated.

Full text of DOI:10.1039/c8ob00373d

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Paper
Direct Oxidative C–H Alkynylation of N-Carbamoyl
Tetrahydroisoquinolines and Dihydroisoquinolines†
Lei Chen,‡a,b Chuanxi Sun,‡a Guidong Feng,‡a Min Cao,b,c Shu-lei Zhao,*c Jun Yan,a Ren-zhong Wan,*a
and Lei Liu*b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient oxidative C–H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by TEMPO
oxoammonium salt has been established. A variety of electronically varied N-carbamoyl
tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild
10 metal-free conditions. Dihydroisoquinolines were also suitable components for the reaction. The synthetic
applicability of the method in facile access to structurally diverse bioactive molecules were further
demonstrated.
Introduction
Naturally occurring alkaloids and synthetic molecules containing
15 α-substituted tetrahydroisoquinoline skeletons have exhibited a
wide range of pharmaceutical activities.1 For example, noscapine,
50
primarily mediated by its σ-receptor agonist activity, is known for
its antitussive effects, and reported to have promising effects in
the treatment of several cancers and hypoxic ischemia in stroke
20 patients.2 Emetine, isolated from ipecac root, is a drug used as
both
an anti-protozoal and
to
induce vomiting.3
55
Tetrahydropalmatine, isolated from Corydalis, has been identified
to possess significant analgesic effects and have therapeutic
potential for heart disease and liver damage.4 The clinical
25 application of these drugs is limited by harsh side effects, such as
devastating cytotoxicity, and drug resistance. Moreover, their
preparation typically suffers from ponderous multiple steps
predominantly due to the complicated α-substituent patterns.
Therefore, discovering novel tetrahydroisoquinoline classes
30 bearing simplified α-substituent patterns that target alternative
binding sites would be in high demand in medicinal chemistry. In
the context, Waldmann identified a noscapine-inspired anti-
cancer agent tetrahydroisoquinoline A that is more potent than
noscapine against HeLa cells for antimitotic action, and inhibition
35 of tubulin assembly in vitro and in cells.5 Recently, our group
found that tetrahydroisoquinoline B can markedly inhibit A549
cell proliferation mediated by G0/G1 phase arrest and cell
apoptosis. In both molecules A and B, arylalkynyl moieties at the
α-position proved to be crucial to the promising anti-cancer
60 Figure 1. Bioactive α-substituted tetrahydroisoquinolines
multitude of readily available alkyne building blocks through the
structural-core diversification strategy represents an ideal strategy
to rapidly provide the access to such libraries with significant
functional diversity.7,8
65
During the past decades, the direct oxidative C–H
alkynylation of tetrahydroisoquinoline skeletons has received
much attentions.9 In these studies, an N-aryl protecting group was
always required to weaken the target C−H bond and stabilize the
resulting iminium intermediate, thus allowing the initial C−H
70 cleavage to be effectively harmonized with subsequent
alkynylation process.10,11 However, the incompatibility of the
alkyne functionality with the oxidation condition for aryl
protecting group removal makes the methods inapplicable to the
access to the scaffold A or B-based library.12 Alternatively, the
75 groups of Yu and Ma reported respectively an innovative CuI-
catalyzed A3 reaction of tetrahydroisoquinolines, aldehydes, and
terminal alkynes, facilely furnishing diverse N-benzyl protected
α-alkynylated moieties.13 The benzyl group is typically removed
40 activity.6
Further
optimization
of
such
α-alkynyl
tetrahydroisoquinoline for anti-cancer drug discovery would
highly dependent on access to a high-quality, mother molecule-
like library. Therefore,
a general and predictable C–H
functionalization of tetrahydroisoquinoline scaffold with a
45
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under a hydrogenation condition, and therefore the α-alkyne
motif would similarly not be tolerated. On the other hand, the
direct oxidative C–H alkynylation of more challenging N-
carbamoyl tetrahydroisoquinolines with markedly increased
oxidation potentials would be a good solution to the expected
library construction because acyl protecting groups could be
readily cleaved under either acidic or basic condition. While
oxidative C–H alkylation,14 arylation, and alkenylation15 of N-
carbamoyl tetrahydroisoquinolines have been established,
View Article Online
DOI: 10.1039/C8OB00373D
5
10 efficient C–H alkynylation with diverse alkyne functionalities
remains elusive. We disclosed a mild Ph3CClO4 mediated C–H
functionalization of N-carbamoyl tetrahydroisoquinolines with
alkynyl potassium trifluoroborates (7 examples).16 However, the
strong acidity of trityl cation (Ph3C+) and potential explosion
15 property of perchlorate salt make the method less practicality.
Herein, we report a practical TEMPO+BF4 -mediated oxidative
‐
C–H functionalization of N-carbamoyl tetrahydroisoquinolines
with a broad range of alkyne potassium trifluoroborates, allowing
for the rapid access to a library of the heterocycles bearing
20 diverse alkyne substituent patterns at the α-position.
45
Results and discussion
Initially, the oxidative C–H alkynylation of N-Cbz protected
tetrahydroisoquinolines 1a with alkynyl potassium trifluoroborate
2a was selected for optimization (Table 1). Several common
25 oxidants for N-Ar tetrahydroisoquinoline oxidations, including
DDQ, TBHP, PhI(OAc)2, and Na2S2O8, failed to promote the
coupling (entry 1, Table 1). Next, a variety of TEMPO
oxoammonium salts were evaluated (entries 2-6, Table 1). The
counterion of the oxidant proved to be crucial for the coupling,
Scheme 1. Oxidative C–H alkynylation of N-Cbz tetrahydroisoquinolines.
‐
30 and TEMPO+BF4 afforded the best yield of 96% (entry 6, Table
next investigated (Scheme 1). The reaction efficiency was found
to be unsusceptible to the electronic properties of aryl acetylenes,
1).17 N-Boc substrate was also well tolerated, though N-acyl one
50 and electron-withdrawing halides (3b-3d), and trifluoromethyl
(3e), together with electron-donating moieties (3f-3h) were well
tolerated in 90-96% yield. Diverse substituent patterns of aryl
acetylenes, including meta- (3i and 3j) and ortho- (3k), were
was futile (entries 7 and 8, Table 1).
Table 1. Reaction condition optimization.a
35
55
60
65
70
Entry
R/1
Oxidant
oxidant
Yieldb (%)
1c
2
3
4
5
6
7
8
OBn/1a
OBn/1a
OBn/1a
OBn/1a
OBn/1a
OBn/1a
OtBu/1a
Me/1c
< 5
66
60
55
82
96
92
< 5
TEMPO+OTf-
TEMPO+PF6
-
TEMPO+SbCl6
-
TEMPO+ClO4
-
TEMPO+BF4
-
TEMPO+BF4
-
TEMPO+BF4
-
a General conditions: 1 (0.1 mmol), 2a (0.15 mmol), and oxidant (0.11
40 mmol) in CH2Cl2 (1.0 mL) at rt for 1 h. Isolated yield. DDQ, TBHP,
PhI(OAc)2, and Na2S2O8 as oxidant.
b
c
The scope of the oxidative C–H alkynylation of
tetrahydroisoquinoline 1a with diverse alkyne components was
75 Scheme 2. The scope of tetrahydroisoquinolines.
2
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Organic & Biomolecular Chemistry
compatible with the coupling. Heteroaryl acetylene (3l) was also
ion 11 underwent subsequent alkynylation with potassium
suitable components for the reaction. Besides arylacetylene
partners, alkylacetylenes were also well tolerated in high
efficiency (3m-3p). The mild oxidation condition exhibits
excellent functional group compatibility, with halogens and
benzyl ether well-tolerated for further manipulations.
The scope with respect to tetrahydroisoquinolines was further
studied (Scheme 2). Diverse electron-donating (4a-4f) and -
withdrawing groups (4g and 4h) on either C6 or C7 position of
trifluoroborates 2 delivering expected 13.20
View Article Online
DOI: 10.1039/C8OB00373D
hydride abstraction
NCbz
+
+
F
NCbz
N
N
O
10
5
60
H
OH
12
11
1a
F
F
R
B
2
10 tetrahydroisoquinoline skeletions were well compatible with the
oxidative C–H alkynylation process, furnishing the desired
products 5a-5h in excellent yields. Substrate 4i bearing a
substituent at C8 position delivered a slightly dropped yield of
82%, which might be ascribed to the increased steric bulk of the
15 electrophile.
65
NCbz
H
13
Scheme 4. A proposed mechanism.
Conclusions
70 In summary, a direct and efficient oxidative C–H alkynylation of
N-carbamoyl tetrahydroisoquinolines mediated by TEMPO+BF4
-
is described. The reaction exhibits an excellent functional group
tolerance, with a variety of electronically varied N-carbamoyl
tetrahydroisoquinolines and
a range of alkynyl potassium
20
75 trifluoroborates well tolerated. Dihydroisoquinolines were also
suitable components for the reaction. The N-carbamoyl group can
be facilely removed under mild conditions with alkyne moiety
intact, thus allowing for the rapid access to structurally diverse
bioactive molecules and a library of tetrahydroisoquinolines
80 bearing diverse α-alkyne substituent patterns for subsequent lead
optimization.
25
Experimental
30
Proton (1H NMR) and carbon (13C NMR) nuclear magnetic
resonance spectra were recorded at 500 MHz and 125 MHz,
85 respectively. The chemical shifts are given in parts per million
(ppm) on the delta (δ) scale. The solvent peak was used as a
Scheme 3. Synthetic applications.
We then explored the synthetic utilities of the method
(Scheme 3). Under standard conditions, dihydroisoquinoline 6
participated in the C–H alkynylation reaction smoothly, providing
35 the expected 7 in 91% yield (eq 1, Scheme 3). In light of the
variety of existing approaches that utilize the enamine moiety in 7
1
reference value, for H NMR: CDCl3 = 7.27 ppm, for 13C NMR:
CDCl3 = 77.23 ppm. Analytical TLC was performed on precoated
silica gel GF254 plates. HRMS were carried out using an
90 Orbitrap analyzer.
as
a reactive handle for further manipulation, such as
cycloadditions, alkylations, oxidations, and reductions, the
efficient oxidative C–H alkynylation of N-carbamoyl
40 dihydroisoquinolines should provide opportunities to develop a
structurally and stereochemically diverse library of
General procedure for the oxidative C–H alkynylation of N-
Carbamoyl tetrahydroisoquinolines
To a solution of N-Cbz tetrahydroisoquinolines 1a (0.1 mmol, 1.0
95 eq) in CH2Cl2 (1.0 mL) was added potassium trifluoroborates 2a
(0.15 mmol, 1.5 eq) and TEMPO+BF4 (0.11 mmol, 1.1 eq)
-
tetrahydroisoquinoline-based
through
diversity-oriented
synthesis.18 The N-carbamoyl moiety can be facilely removed
under acid condition with the alkyne motif intact, as
45 demonstrated by the preparation of anticancer agent 8 (eq 2,
Scheme 3). Finally, the synthesis of analgesic drug Methopholine
was perfomed through the hydrogenation of alkynylated 5c
followed by an established methylation process (eq 3, Scheme
successively at rt. The mixture was stirred at that temperature
under N2 atmosphere until all the 1a disappeared monitored by
TLC. The volatiles were removed under reduced pressure and the
100 residue was purified by flash chromatography on silica gel using
EtOAc/petroleum ether (5:95) as eluent to give the desired
product.
3).19
-
50
The mechanism for TEMPO+BF4 mediated oxidative C–H
alkynylation was studied (Scheme 4). The coupling was not
influenced by adding stoichiometric radical inhibitors 2,6-di-tert-
butyl-4-methylphenol or TEMPO, suggesting that radical-
involved process might not be viable. Therefore, we envisioned
Characterization data for the products in Scheme 1
105 Benzyl
1-(phenylethynyl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3a)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3a as a light yellow oil (35.2 mg,
55 that tetrahydroisoquinoline 1a might undergo
a hydride
-
abstraction by TEMPO+BF4 , and the generated N-acyliminium
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1
96% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.45–
125.3, 125.3, 125.2, 123.0, 91.1, 82.2, 67.8, 47.5, 39.1, 28.6;
7.29 (m, 8H), 7.27–7.18 (m, 5H), 7.16–7.09 (m, 1H), 6.33–6.06 60 HRMS (EI) m/z [M + H]+calculated for C26H21F3NO2: 436.1519,
View Article Online
DOI: 10.1039/C8OB00373D
(m, 1H), 5.41–5.12 (m, 2H), 4.43–4.08 (m, 1H), 3.76–3.40 (m,
1H), 3.11–2.67 (m, 2H); 13C NMR (126 MHz, CDCl3, rotamers
seen) δ 154.9, 136.6, 133.9, 131.8, 129.1, 128.8, 128.5, 128.3,
128.2, 128.0, 127.9, 127.5, 127.4, 126.6, 122.7, 88.4, 83.3, 67.5,
found 436.1503.
Benzyl
1-((4-methoxyphenyl)ethynyl)-3,4-
5
dihydroisoquinoline-2(1H)-carboxylate (3f)
It was prepared following the general procedure and purified by
47.4, 39.1, 38.8, 28.4; HRMS (EI) m/z [M + H]+calculated for 65 flash chromatography on silica gel using ethyl acetate/petroleum
C25H22NO2: 368.1645, found 368.1631.
Benzyl 1-((4-fluorophenyl)ethynyl)-3,4-dihydroisoquinoline-
ether (5:95) as eluent to afford 3f as a light yellow oil (38.1 mg,
96% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.46–
1
10 2(1H)-carboxylate (3b)
It was prepared following the general procedure and purified by
7.28 (m, 8H), 7.25–7.19 (m, 2H), 7.15 (s, 1H), 6.80 (s, 1H), 6.78
(s, 1H), 6.29–6.09 (m, 1H), 5.37–5.15 (m, 2H), 4.41–4.14 (m,
flash chromatography on silica gel using ethyl acetate/petroleum 70 1H), 3.77 (s, 3H), 3.66–3.44 (m, 1H), 3.07–2.94 (m, 1H), 2.89–
ether (5:95) as eluent to afford 3b as a light yellow oil (35.4 mg,
92% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.46–
15 7.32 (m, 8H), 7.28–7.23 (m, 2H), 7.20–7.16 (m, 1H), 7.01–6.95
(m, 2H), 6.40–5.96 (m, 1H), 5.38–5.20 (m, 2H), 4.49–4.12 (m,
1H), 3.79–3.45 (m, 1H), 3.06–2.86 (m, 2H); 13C NMR (126 MHz, 75 found 398.1730.
2.79 (m, 1H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ
159.7, 155.1, 136.8, 133.4, 129.2, 128.7, 128.2, 128.0, 127.7,
127.4, 126.7, 114.9, 113.9, 87.1, 83.4, 67.6, 55.4, 47.6, 38.9, 28.6;
HRMS (EI) m/z [M + H]+calculated for C26H24NO3: 398.1751,
1
CDCl3, rotamers seen) δ 163.7, 161.7, 155.1, 137.0, 136.8, 133.9,
133.9, 129.8, 129.3, 128.7, 128.3, 128.2, 128.1, 127.7, 127.6,
20 126.8, 126.7, 126.5, 119.0, 115.7, 115.6, 88.3, 82.4, 67.7, 47.5,
39.4, 28.6; HRMS (EI) m/z [M + H]+calculated for C25H21FNO2:
386.1551, found 386.1566.
Benzyl
1-(benzo[d][1,3]dioxol-5-ylethynyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate (3g)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
80 ether (5:95) as eluent to afford 3g as a light yellow oil (38.6 mg,
1
Benzyl 1-((4-chlorophenyl)ethynyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (3c)
94% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.51–
7.30 (m, 6H), 7.29–7.23 (m, 2H), 7.23–7.10 (m, 2H), 6.93–6.80
(m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.30–6.04 (m, 1H), 5.96 (s, 2H),
5.41–5.16 (m, 2H), 4.40–4.15 (m, 1H), 3.79–3.42 (m, 1H), 3.08–
25 It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3c as a light yellow oil (37.3 mg, 85 2.80 (m, 2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ
1
93% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47–
7.33 (m, 7H), 7.29–7.16 (m, 6H), 6.32–6.06 (m, 1H), 5.39–5.17
30 (m, 2H), 4.39–4.16 (m, 1H), 3.77–3.44 (m, 1H), 3.05–2.81 (m,
2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 155.1, 136.7,
155.2, 148.1, 147.5, 136.8, 134.1, 129.3, 128.8, 128.7, 128.3,
128.1, 127.7, 127.5, 126.8, 126.6, 126.5, 116.2, 112.0, 108.5,
101.5, 86.9, 83.4, 67.7, 47.6, 39.0, 28.7; HRMS (EI) m/z [M +
H]+calculated for C26H22NO4: 412.1543, found 412.1530.
134.2, 131.9, 130.1, 129.6, 129.4, 128.8, 128.8, 128.3, 128.2, 90 Benzyl
1-([1,1'-biphenyl]-4-ylethynyl)-3,4-
127.7, 127.7, 126.9, 89.8, 82.1, 67.8, 47.5, 39.3, 28.6; HRMS (EI)
m/z [M + H]+calculated for C25H21ClNO2: 402.1255, found
35 402.1263.
Benzyl 1-((4-bromophenyl)ethynyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (3d)
dihydroisoquinoline-2(1H)-carboxylate (3h)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3h as a light yellow oil (42.1 mg,
1
95 95% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.61–
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
40 ether (5:95) as eluent to afford 3d as a light yellow oil (42.4 mg,
7.51 (m, 4H), 7.50–7.32 (m, 11H), 7.28–7.24 (m, 2H), 7.22–7.16
(m, 1H), 6.36–6.12 (m, 1H), 5.42–5.18 (m, 2H), 4.44–4.19 (m,
1H), 3.79–3.47 (m, 1H), 3.10–2.82 (m, 2H); 13C NMR (126 MHz,
CDCl3, rotamers seen) δ 155.2, 141.2, 140.5, 136.8, 133.3, 132.7,
1
95% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47–
7.31 (m, 8H), 7.27–7.13 (m, 5H), 6.29–6.08 (m, 1H), 5.40–5.15 100 132.4, 131.2, 129.0, 128.7, 128.3, 128.1, 127.8, 127.7, 127.6,
(m, 2H), 4.42–4.17 (m, 1H), 3.6–3.42 (m, 1H), 3.08–2.80 (m, 2H);
13C NMR (126 MHz, CDCl3, rotamers seen) δ 155.1, 136.8,
45 133.4, 131.6, 129.3, 128.7 , 128.3, 128.2, 128.1, 127.6, 126.8,
126.6, 126.4, 122.8, 121.8, 89.7, 82.4, 67.7, 47.6, 39.5, 28.6;
127.3, 127.2, 127.0, 126.8, 89.2, 83.4, 67.7, 47.7, 39.0, 28.7;
HRMS (EI) m/z [M + H]+calculated for C31H26NO2: 444.1958,
found 444.1966.
Benzyl 1-((3-fluorophenyl)ethynyl)-3,4-dihydroisoquinoline-
HRMS (EI) m/z [M + H]+calculated for C25H21BrNO2: 446.0750, 105 2(1H)-carboxylate (3i)
found 446.0759.
It was prepared following the general procedure and purified by
Benzyl
1-((4-(trifluoromethyl)phenyl)ethynyl)-3,4-
flash chromatography on silica gel using ethyl acetate/petroleum
50 dihydroisoquinoline-2(1H)-carboxylate (3e)
It was prepared following the general procedure and purified by
ether (5:95) as eluent to afford 3i as a light yellow oil (35.1 mg,
91% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.48–
1
flash chromatography on silica gel using ethyl acetate/petroleum 110 7.32 (m, 6H), 7.27–6.99 (m, 7H), 6.32–6.07 (m, 1H), 5.41–5.15
ether (5:95) as eluent to afford 3e as a light yellow oil (39.1 mg,
90% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.56–
55 7.32 (m, 10H), 7.28–7.16 (m, 3H), 6.34–6.09 (m, 1H), 5.42–5.16
(m, 2H), 4.43–4.18 (m, 1H), 3.67–3.41 (m, 1H), 3.09–2.82 (m,
2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 155.2, 136.7, 115 116.0, 115.8, 89.5, 82.3, 82.3, 67.7, 47.5, 39.1, 28.6; HRMS (EI)
132.3, 129.4, 128.8, 128.3, 128.2, 127.8, 127.6, 126.9, 126.7,
(m, 2H), 4.44–4.14 (m, 1H), 3.81–3.41 (m, 1H), 3.08–2.81 (m,
2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 163.4, 161.5,
155.1, 136.7, 134.1, 130.0, 129.9, 129.3, 128.7, 128.3, 128.1,
127.9, 127.7, 127.7, 126.9, 126.7, 126.5, 124.7, 118.9, 118.7,
1
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m/z [M + H]+calculated for C25H21FNO2: 386.1551, found
386.1559.
Benzyl
Benzyl
carboxylate (3n)
1-((3-methoxyphenyl)ethynyl)-3,4- 60 It was prepared following the general procedure and purified by
1-(oct-1-yn-1-yl)-3,4-dihydroisoquinoline-2(1H)-
View Article Online
DOI: 10.1039/C8OB00373D
dihydroisoquinoline-2(1H)-carboxylate (3j)
flash chromatography on silica gel using ethyl acetate/petroleum
5
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3n as a colorless oil (33.0 mg,
88% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.46–
1
ether (5:95) as eluent to afford 3j as a light yellow oil (36.9mg,
93% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47– 65 (m, 2H), 4.36–4.13 (m, 1H), 3.60–3.36 (m, 1H), 3.06–2.78 (m,
7.28 (m, 6H), 7.25–7.11 (m, 3H), 6.09–5.86 (m, 1H), 5.35–5.16
1
7.33 (m, 6H), 7.27–7.16 (m, 4H),7.02 –6.83 (m, 3H), 6.32–6.11
2H), 2.16 (td, J = 7.1, 1.8 Hz, 2H), 1.52–1.45 (m, 2H), 1.36–1.24
(m, 6H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3,
rotamers seen) δ 155.1, 136.9, 134.9, 133.9, 129.2, 128.7, 128.2,
128.0, 127.6, 127.3, 126.6, 84.3, 79.4, 67.5, 47.2, 38.7, 31.4, 28.7,
10 (m, 1H), 5.38–5.19 (m, 2H), 4.46–4.15 (m, 1H), 3.79 (s, 3H),
3.70–3.43 (m, 1H), 3.01 (s, 1H), 2.93–2.81 (m, 1H); 13C NMR
(126 MHz, CDCl3, rotamers seen) δ 159.4, 155.1, 136.8, 129.4,
129.3, 128.7, 128.2, 128.1, 127.7, 127.6, 126.8, 124.6, 123.9, 70 28.7, 22.7, 18.9, 14.2; HRMS (EI) m/z [M + H]+ calculated for
116.7, 115.2, 88.3, 83.4, 67.7, 55.5, 47.6, 39.3, 28.6; HRMS (EI)
C25H30NO3: 376.2271, found 376.2250.
15 m/z [M
398.1743.
Benzyl
+
H]+calculated for C26H24NO3: 398.1751, found
Benzyl
1-(dec-1-yn-1-yl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3o)
1-(o-tolylethynyl)-3,4-dihydroisoquinoline-2(1H)-
It was prepared following the general procedure and purified by
75 flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3o as a colorless oil (35.1 mg,
carboxylate (3k)
It was prepared following the general procedure and purified by
20 flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 3k as a light yellow oil (34.3 mg,
1
87% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47–
7.28 (m, 6H), 7.26–7.11 (m, 3H), 6.10–5.89 (m, 1H), 5.35–5.17
(m, 2H), 4.39–4.12 (m, 1H), 3.59–3.37 (m, 1H), 3.05–2.76 (m,
1
90% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.49–
7.29 (m, 7H), 7.26–7.24 (m, 1H), 7.24–7.13 (m, 4H), 7.14–7.07 80 2H), 2.21–2.13 (m, 2H), 1.53–1.45 (m, 2H), 1.36–1.26 (m, 10H),
(m, 1H), 6.39–6.12 (m, 1H), 5.39–5.18 (m, 2H), 4.45–4.17 (m,
25 1H), 3.79–3.45 (m, 1H), 3.11–2.93 (m, 1H), 2.93–2.80 (m, 1H),
2.33 (s, 3H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 155.2,
136.9, 136.4, 132.1, 129.1, 128.7, 128.5, 128.5, 128.4, 128.2,
0.92 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3, rotamers
seen) δ 155.1, 136.9, 134.9, 133.8, 129.1, 128.6, 128.1, 128.0,
127.5, 127.2, 126.6, 84.2, 79.4, 67.5, 47.2, 38.7, 32.0, 29.3, 29.2,
29.0, 28.7, 28.6, 22.8, 18.9, 14.3; HRMS (EI) m/z [M + H]+
128.1, 128.1, 127.5, 123.0, 88.7, 83.4, 67.6, 47.6, 39.2, 28.3, 21.3; 85 calculated for C27H34NO3: 404.2584, found 404.2596.
HRMS (EI) m/z [M + H]+calculated for C26H24NO2: 382.1802,
Benzyl
1-(4-(benzyloxy)but-1-yn-1-yl)-3,4-
30 found 382.1790.
dihydroisoquinoline-2(1H)-carboxylate (3p)
Benzyl
2(1H)-carboxylate (3l)
1-(thiophen-2-ylethynyl)-3,4-dihydroisoquinoline-
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
It was prepared following the general procedure and purified by 90 ether (5:95) as eluent to afford 3p as a colorless oil (36.2 mg,
1
flash chromatography on silica gel using ethyl acetate/petroleum
85% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47–
7.31 (m, 11H), 7.27–7.13 (m, 3H), 6.14–5.90 (m, 1H), 5.40–5.15
(m, 2H), 4.55 (s, 2H), 4.40–4.13 (m, 1H), 3.69–3.40 (m, 3H),
3.07–2.79 (m, 2H), 2.61–2.46 (m, 2H); 13C NMR (126 MHz,
35 ether (10:90) as eluent to afford 3l as a light yellow oil (34.7 mg,
93% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.57–
7.28 (m, 6H), 7.27–7.13 (m, 5H), 6.97–6.90 (m, 1H), 6.35–6.08
1
(m, 1H), 5.42–5.12 (m, 2H), 4.42–4.16 (m, 1H), 3.77–3.41 (m, 95 CDCl3, rotamers seen) δ 155.0, 138.3, 136.8, 135.0, 134.5, 133.8,
1H), 3.11–2.76 (m, 2H)；13C NMR (126 MHz, CDCl3, rotamers
40 seen) δ 155.1, 136.8, 132.6, 128.8, 128.3, 128.1, 127.7, 127.8,
127.3, 127.0, 126.9, 126.7, 92.4, 76.8, 67.8, 47.8, 39.1, 28.6;
HRMS (EI) m/z [M + H]+calculated for C23H20NO2S: 374.1209,
found 374.1197.
133.7, 129.2, 128.6, 128.5, 128.2, 128.0, 127.8, 127.8, 127.7,
127.5, 127.3, 126.6, 80.7, 80.4, 73.0, 68.5, 67.5, 47.1, 38.7, 28.5,
20.4; HRMS (EI) m/z [M + H]+ calculated for C28H28NO3:
426.2064, found 426.2051.
100
Benzyl
1-(hex-1-yn-1-yl)-3,4-dihydroisoquinoline-2(1H)-
Characterization data for the products in Scheme 2
45 carboxylate (3m)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
Benzyl
6,7-dimethoxy-1-(phenylethynyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate (5a)
ether (5:95) as eluent to afford 3m as a colorless oil (31.6 mg, 105 It was prepared following the general procedure and purified by
1
91% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.47–
50 7.29 (m, 6H), 7.26–7.13 (m, 3H), 6.14–5.85 (m, 1H), 5.40–5.16
(m, 2H), 4.40–4.12 (m, 1H), 3.65–3.35 (m, 1H), 3.08–2.75 (m,
2H), 2.24–2.12 (m, 2H), 1.52–1.43(m, 2H), 1.43–1.33 (m, 2H),
flash chromatography on silica gel using ethyl acetate/petroleum
ether (10:90) as eluent to afford 5a as a light yellow oil (40.1 mg,
1
94% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.46–
7.34 (m, 7H), 7.32–7.27 (m, 3H), 6.85 (s, 1H), 6.63 (s, 1H), 6.24–
0.95–0.87 (m, 3H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 110 5.95 (m, 1H), 5.37–5.18 (m, 2H), 4.45–4.19 (m, 1H), 3.90–3.87
155.1, 136.9, 134.9, 133.8, 129.1, 128.6, 128.1, 128.0, 127.5,
55 127.2, 126.6, 84.2, 79.4, 67.5, 47.2, 38.7, 32.0, 29.3, 29.2, 29.0,
28.7, 28.6, 22.8, 18.9, 14.3; HRMS (EI) m/z calcd for C23H25NO2
[M + H]+ 348.1958, found 348.1941.
(m, 6H), 3.76–3.44 (m, 1H), 2.99–2.70 (m, 2H); 13C NMR (126
MHz, CDCl3, rotamers seen) δ 155.1, 148.6, 148.1, 147.9, 136.8,
132.0, 128.7, 128.5, 128.4, 128.2, 128.1, 127.2, 126.1, 125.8,
122.9, 111.6, 110.2, 88.6, 83.4, 67.7, 56.3, 56.1, 56.1, 47.3, 38.9,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00 00
–
| 5

Organic & Biomolecular Chemistry
Page 6 of 9
28.2; HRMS (EI) m/z [M + H]+ calculated for C27H26NO4:
428.1856, found 428.1840.
It was prepared following the general procedure and purified by
60 flash chromatography on silica gel using ethyl acetate/petroleum
View Article Online
Benzyl
6,7-dimethoxy-1-((4-methoxyphenyl)ethynyl)-3,4-
ether (25:95) as eluent to afford 5f as a light yellow oil (34.7 mg,
DOI: 10.1039/C8OB00373D
91% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.48–
1
dihydroisoquinoline-2(1H)-carboxylate (5b)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
5
7.26 (m, 10H), 7.18 (s, 1H), 7.05 (s, 2H), 6.28–6.04 (m, 1H),
5.39–5.15 (m, 2H), 4.40–4.14 (m, 1H), 3.67–3.43 (m, 1H), 2.95
ether (15:85) as eluent to afford 5b as a light yellow oil (43.9 mg, 65 (s, 1H), 2.89–2.77 (m, 1H), 2.35 (s, 3H); 13C NMR (126 MHz,
1
96% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.49–
7.29 (m, 7H), 6.84 (s, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 6.62 (s, 1H),
CDCl3, rotamers seen) δ 155.2, 136.9, 136.4, 132.1, 129.1, 128.7,
128.5, 128.5, 128.4, 128.2, 128.1, 128.1, 127.5, 123.0, 88.7, 83.4,
67.6, 47.6, 39.2, 28.3, 21.3; HRMS (EI) m/z [M + H]+ calculated
for C26H24NO2: 382.1802, found 382.1991.
10 6.21–5.99 (m, 1H), 5.39–5.13 (m, 2H), 4.41–4.19 (m, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.62–3.39 (m, 1H), 3.01–2.84
(m, 1H), 2.77–2.69 (m, 1H); 13C NMR (126 MHz, CDCl3, 70 Benzyl 7-chloro-1-(phenylethynyl)-3,4-dihydroisoquinoline-
rotamers seen) δ 159.8, 155.1, 148.5, 148.1, 136.9, 133.5, 128.7,
128.2, 128.1, 115.0, 114.0, 111.6, 110.3, 87.2, 83.3, 67.6, 56.3,
15 56.1, 55.5, 47.3, 38.9, 28.2; HRMS (EI) m/z [M + H]+ calculated
for C28H28NO5: 458.1962, found 459.1981.
2(1H)-carboxylate (5g)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 5g as a light yellow oil (36.6 mg,
1
Benzyl
1-((4-chlorophenyl)ethynyl)-6,7-dimethoxy-3,4- 75 91% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.48–
dihydroisoquinoline-2(1H)-carboxylate (5c)
It was prepared following the general procedure and purified by
20 flash chromatography on silica gel using ethyl acetate/petroleum
7.27 (m, 11H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 7.13–7.07 (m, 1H),
6.31–6.04 (m, 1H), 5.43–5.16 (m, 2H), 4.45–4.16 (m, 1H), 3.65–
3.40 (m, 1H), 3.05–2.76 (m, 2H); 13C NMR (126 MHz, CDCl3,
rotamers seen) δ 155.0, 136.7, 132.4, 132.0, 130.6, 128.7, 128.7,
ether (5:95) as eluent to afford 5c as a light yellow oil (43.0 mg,
1
92% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.51– 80 128.4, 128.3, 128.1, 127.8, 127.6, 122.6, 87.7, 84.1, 67.8, 47.3,
7.28 (m, 9H), 6.86 (s, 1H), 6.67 (s, 1H), 6.30–6.03 (m, 1H), 5.48–
5.15 (m, 2H), 4.51–4.23 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.66–
25 3.42 (m, 1H), 3.07–2.70 (m, 2H); 13C NMR (126 MHz, CDCl3,
rotamers seen) δ 155.0, 148.4, 147.9, 147.8, 147.7, 136.6, 131.8,
38.8, 28.1; HRMS (EI) m/z [M + H]+ calculated for C25H21ClNO2:
402.1255, found 402.1259.
Benzyl 7-bromo-1-(phenylethynyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (5h)
128.5, 128.3, 128.2, 128.1, 127.9, 125.5, 122.8, 111.4, 110.0, 85 It was prepared following the general procedure and purified by
88.5, 83.3, 67.5, 56.1, 56.0, 56.0, 56.0, 47.1, 38.8, 28.1; HRMS
(EI) m/z calcd for C27H25ClNO4[M + H]+ 462.1467, found
30 462.1475.
flash chromatography on silica gel using ethyl acetate/petroleum
ether (5:95) as eluent to afford 5h as a light yellow oil (40.1 mg,
90% yield). 1H NMR (500 MHz, CDCl3, rotamers seen) δ 7.52 (s,
1H), 7.50–7.26 (m, 11H), 7.04 (d, J = 7.9 Hz, 1H), 6.29–6.05 (m,
90 1H), 5.42–5.13 (m, 2H), 4.43–4.16 (m, 1H), 3.65–3.41 (m, 1H),
3.03–2.73 (m, 2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ
155.0, 136.6, 132.1, 131.0, 130.7, 130.5, 128.8, 128.7, 128.4,
128.3, 128.2, 122.6, 120.2, 87.7, 84.1, 67.8, 47.2, 38.7, 28.2;
HRMS (EI) m/z [M + H]+ calculated for C25H21BrNO2: 446.0750,
tert-Butyl
6,7-dimethoxy-1-(phenylethynyl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate (5d)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
35 ether (2:98) as eluent to afford 5d as a light yellow oil (36.5 mg,
1
93% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.48–
7.39 (m, 2H), 7.39–7.25 (m, 3H), 6.88 (s, 1H), 6.66 (s, 1H), 6.26– 95 found 446.0763.
5.90 (m, 1H), 4.41–4.10 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.60–
3.31 (m, 1H), 3.04–2.61 (m, 2H), 1.57 (s, 9H); 13C NMR (126
40 MHz, CDCl3, rotamers seen) δ 152.9, 146.9, 146.4, 130.4, 126.8,
124.7, 121.5, 110.0, 108.7, 87.5, 81.3, 79.0, 54.8, 54.6, 45.9, 36.6,
Benzyl 8-chloro-1-(phenylethynyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (5i)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
27.1, 26.8; HRMS (EI) m/z calcd for C24H28NO4 [M + H]+ 100 ether (5:95) as eluent to afford 5i as a light yellow oil (33.0 mg,
1
394.2013, found 394.2022.
82% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.46–
7.29 (m, 12H), 7.23–7.18 (m, 1H), 6.35–6.09 (m, 1H), 5.41–5.13
(m, 2H), 4.54–4.28 (m, 1H), 3.73–3.38 (m, 1H), 3.14–2.79 (m,
2H); 13C NMR (126 MHz, CDCl3, rotamers seen) δ 155.0, 147.1,
Benzyl
5-(phenylethynyl)-7,8-dihydro-[1,3]dioxolo[4,5-
45 g]isoquinoline-6(5H)-carboxylate (5e)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum 105 136.6, 132.0, 128.8, 128.7, 128.4, 128.3, 128.3, 128.1, 128.1,
ether (6:94) as eluent to afford 5e as a light yellow oil (38.2 mg,
93% yield). H NMR (500 MHz, CDCl3, rotamers seen) δ 7.49–
50 7.26 (m, 10H), 6.83 (s, 1H), 6.61 (s, 1H), 6.22–5.97 (m, 1H),
5.98–5.90 (m, 2H), 5.40–5.17 (m, 2H), 4.36–4.14 (m, 1H), 3.64–
3.40 (m, 1H), 2.91 (s, 1H), 2.80–2.69 (m, 1H); 13C NMR (126 110 Characterization data for the products in Scheme 3
127.6, 127.4, 126.2, 122.6, 87.8, 84.3, 67.8, 47.4, 38.6, 26.7;
HRMS (EI) m/z [M + H]+ calculated for C25H21ClNO2: 402.1255,
found 402.1278.
1
MHz, CDCl3, rotamers seen) δ 155.1, 147.22, 146.6, 136.8,
132.0, 128.7, 128.5, 128.4, 128.2, 128.1, 127.5, 122.9, 108.8,
55 107.4, 101.2, 88.4, 83.5, 67.7, 47.6, 39.0, 28.7; HRMS (EI) m/z
calcd for C26H22NO4 [M + H]+ 412.1543, found 412.1556.
Benzyl 7-methyl-1-(phenylethynyl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (5f)
Benzyl 1-(phenylethynyl)isoquinoline-2(1H)-carboxylate (7)
It was prepared following the general procedure and purified by
flash chromatography on silica gel using ethyl acetate/petroleum
115 ether (5:95) as eluent to afford 7 as a light yellow oil (33.2 mg,
1
91% yield). H NMR (500 MHz, CDCl3) δ 7.51–7.32 (m, 7H),
6
|
Journal Name, [year], [ovl], 00 00
–
This journal is © The Royal Society of Chemistry [year]

Page 7 of 9
Organic & Biomolecular Chemistry
Heidelberg, New York, Tokyo, 1985, p. 213; (d) J. P. Michael, Nat.
Prod. Rep. 2008, 25, 166.
7.28–7.21 (m, 6H), 7.15–6.89 (m, 2H), 6.48–6.31 (m, 1H), 6.06–
5.92 (m, 1H), 5.49–5.16 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
155.2, 136.9, 136.4, 132.1, 129.1, 128.7, 128.5, 128.5, 128.4,
128.2, 128.1, 128.1, 127.5, 123.0, 88.7, 83.4, 67.6, 47.6, 39.2,
28.3, 21.3; HRMS (EI) m/z [M + H]+ calculated for C25H20NO2:
366.1489, found 366.1496.
60
View Article Online
2
3
J. Kamei, Pulm Pharmacol 1996, 9, 349.
DOI: 10.1039/C8OB00373D
J. H. Kim, E. B. Cho, J. Lee, O. Jung, B. J. Ryu, S. H. Kim, J. Y.
Cho, C. Ryou, S. Y. Lee, Chem.-Biol. Interact. 2015, 242, 25.
L. Wu, H. Ling, L. Li, L. Jiang, M. He, J. Pharm. Pharmacol. 2007,
59, 695.
5
4
5
6
65
6,7-Dimethoxy-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (8)
1H NMR (500 MHz, CDCl3) δ 7.43–7.41 (m, 2H), 7.30–7.27 (m,
10 3H), 6.88 (s, 1H), 6.60 (s, 1H), 5.05 (s, 1H), 3.87 (s, 3H), 3.86 (s,
3H), 3.45–3.37 (m, 1H), 3.14–3.06 (m, 1H), 2.78 (t, J = 5.8 Hz,
2H); 13C NMR (126 MHz, CDCl3) δ 148.2, 147.5, 131.9, 128.4,
128.3, 127.4, 126.5 123.2, 111.7, 110.1, 90.9, 83.4, 56.1, 56.0,
49.1, 41.4, 28.7; HRMS (EI) m/z [M + H]+ calculated for
15 C19H20NO2: 294.1489, found 294.1501.
T. J. Zimmermann, S. Roy, N. E. Martinez, S. Ziegler, C. Hedberg,
H. Waldmann, ChemBioChem 2013, 14, 295.
X. Sun, M. Liu, L. Gao, Y. Mao, D. Zhao, J. Zhuang, L. Liu, Eur. J.
Med. Chem. DOI:10.1016/j.ejmech.2018.03.017.
(a) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40; (b) B. M. Trost, Acc. Chem. Res. 2002, 35,
695.
M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46.
(a) C.-J. Li, Z. Li, Pure Appl. Chem. 2006, 78, 935; (b) S.
Murahashi, D. Zhang, Chem. Soc. Rev. 2008, 37, 1490; (c) C. J. Li,
Acc. Chem. Res. 2009, 42, 335; (d) R. Giri, B. F. Shi, K. M. Engle,
N. Maguel, J. Q. Yu, Chem. Soc. Rev. 2009, 38, 3242; (e) C.
Scheuermann, Chem.―Asian J. 2010, 5, 436; (f) M. Klussmann, D.
Sureshkumar, Synthesis 2011, 353; (g) C. Liu, H. Zhang, W. Shi, A.
Lei, Chem. Rev. 2011, 111, 1780; (h) C. L. Sun, B. J. Li, Z. J. Shi,
Chem. Rev. 2011, 111, 1293; (i) C. Zhang, C. Tang, N. Jiao, Chem.
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Chang, Chem. Soc. Rev. 2011, 40, 5068; (k) J. Le Bras, J. Muzart,
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70 7
8
9
75
1-(4-Chlorophenethyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (9)
A mixture of 5c (100 mg, 0.19 mmol) and Pd/C (20 mg) in
MeOH (10 mL) was stirred vigorously at room temperature for 5
20 h. The heterogeneous mixture was filtered through a short Celite
pad, and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography eluting with 1%
80
1
MeOH in CH2Cl2 to afford 9 as colorless oil (58.7 mg, 93%). H
85
NMR (500 MHz, CDCl3) δ 7.27–7.25 (m, 2H), 7.18 (d, J = 8.2
25 Hz, 2H), 6.59 (s, 1H), 6.55 (s, 1H), 4.07–3.98 (m, 1H), 3.86 (s,
3H), 3.84 (s, 3H), 3.34–3.25 (m, 1H), 3.11–3.02 (m, 1H), 2.88–
2.70 (m, 4H), 2.17–2.03 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
147.9, 147.7, 140.8, 131.8, 130.1, 130.0, 128.7, 127.1, 112.1,
109.3, 56.3, 56.1, 55.1, 41.0, 38.1, 31.8, 29.0; these data are
30 consistent with reported literature values.19
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Acknowledgements
95
We gratefully acknowledge the National Science Foundation of
China (21472112 and 21722204), Fok Ying Tung Education
Foundation (151035), and the Fundamental Research Funds of
35 Shandong University (2015JC035).
100
105
110
115
120
Notes and references
a
College of Animal Science and Veterinary Medicine, Shandong
Agricultural University, Taian 271018, China
E-mail: wrzh63@163.com
b
40 School of Chemistry and Chemical Engineering, Shandong University,
Jinan 250100, China
E-mail: leiliu@sdu.edu.cn
c
Department of Gastroenterology, Shandong Provincial Hospital
Affiliated to Shandong University, 324 Jingwu Weiqi Rd, Jinan 250021,
45 China
E-mail: wenzhu24@126.com
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
50 10.1039/b000000x/
‡ These authors contributed equally to this work
1
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Organic & Biomolecular Chemistry
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB00373D
An efficient oxidative C–H alkynylation of N-carbamoyl tetrahydroisoquinolines and
dihydroisoquinolines is described.