Improved simplicity and practicability in copper-catalyzed alkynylation of tetrahydroisoquinoline

Article abstract of DOI:10.1007/s00706-016-1877-5

Abstract: Alkynylation reactions of N-protected tetrahydroisoquinolines have been performed using several different protocols of cross dehydrogenative coupling. Initially, a CuCl-catalyzed method was investigated, which worked well with three different N-

Full text of DOI:10.1007/s00706-016-1877-5

Monatsh Chem
DOI 10.1007/s00706-016-1877-5
ORIGINAL PAPER
Improved simplicity and practicability in copper-catalyzed
alkynylation of tetrahydroisoquinoline
1
1
Birgit Groll Patricia Schaaf1 Michael Schnurch
¨
•
•
¨
Received: 6 October 2016 / Accepted: 13 November 2016
Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Alkynylation reactions of N-protected tetrahy-
droisoquinolines have been performed using several
different protocols of cross dehydrogenative coupling.
Initially, a CuCl-catalyzed method was investigated, which
worked well with three different N-protecting groups,
namely phenyl, PMP, and benzyl and t-BuOOH as oxidant
in acetonitrile as solvent. The peroxide could then be
replaced by simple air and acetonitrile for water, leading to
an overall very environmentally friendly protocol. Finally,
a decarboxylative alkynylation protocol starting from
alkynoic acids was also developed using again air as oxi-
dant. This avoids the use of gaseous alkynes in the
introduction of short-chained alkyne substituents.
Introduction
The formation of carbon–carbon bonds is key to the assem-
bling of complex organic molecules. Hence, the development
ofefficient methods to make thesebonds is aninfinite research
area. The field of metal catalysis was able to contribute sig-
nificantly to this area in the last few decades. The first
transformations to come into mind are arguably the famous
cross-coupling reactions [1, 2]; however, in more recent times
significantcompetitioncamefromthefieldofmetal-catalyzed
C–H activation chemistry [3–9], where the C–H bond is
exploited as functional group, replacing either the organo-
metal or the halide part of a classical cross-coupling reaction.
Even moredesirable wouldbemethods, which takeadvantage
of a C–H bond in both coupling partners for C–C bond-
forming processes, leading formally only to an equivalent of
H2 as waste. One such method has gained prominence under
the time of cross-dehydrogenative coupling (CDC) [10–12].
One substrate which plays a predominant role in CDC reac-
tions is tetrahydroisoquinolines (TIQ). N-Substituted TIQs
have been applied in a number of transformations to introduce
various substituents to C1 (Fig. 1) [13–20].
Graphical abstract
The reported protocols have several common features:
(1) the TIQ nitrogen carries a protecting group, mostly
phenyl; (2) an external oxidant is required (mostly t-
BuOOH); (3) the reactions are either carried out neat or in
organic solvents (whereas ‘‘neat’’ reactions typically use a
t-BuOOH solution in decane as oxidant).
Keywords Alkynes Á Catalysis Á Cross dehydrogenative
coupling Á Oxidative coupling Á Copper catalysis
Even though these are not severe limitations, it leaves
room for improvement. A cleavable N-protecting group
would definitely be an advantage since it would allow more
flexible further elaboration of the CDC products. Replacing
t-BuOOH by a more benign oxidant (ideally air) and the
typically applied organic solvents by water would further
improve the practicability of this approach.
& Michael Schnu¨rch
michael.schnuerch@tuwien.ac.at
1
Institute of Applied Synthetic Chemistry, TU Wien,
Getreidemarkt 9/163, 1060 Vienna, Austria
123

¨
B. Groll et al.
Fig. 1 Reported CDC reactions on N-substituted TIQs
isolated yield and 63% ee for the preparation of 2 starting
from N-phenyl-TIQ (1) using phenylacetylene as coupling
partner. Typically, the alkyne was used as limiting reagent
with 2 equivalents of 1 as coupling partner. In our case, we
were not focused on enantioselective reactions, but on
improving the practicability of the protocol. Hence, we
started with a screening to test whether CuOTf would also
be the best metal source if the main focus lies on yield
rather than ee. Using again 1 as substrate and pheny-
lacetylene as alkyne, we screened for the ideal combination
of catalyst, temperature, and solvent. Reactions were car-
ried out with CuBr, CuCl, CuCN, Cu(NO3)2Á3H2O,
(CuOTf)2 toluene complex, and Fe(NO3)2Á9H2O as cata-
lysts, at 50 and 100 °C, and in THF, acetonitrile,
dichloromethane, or neat. Fe(NO3)2Á9H2O was included as
potential catalyst since we successfully applied it in
indolation reactions of tetrahydroisoquinolines derivatives
[19, 20]. Parameters and yields of successful experiments
are listed in Table 1. It has to be mentioned that in all those
experiments, a 2:1 ratio between 1 and phenylacetylene
was used. This is necessary since oxidation in position 1 of
TIQ is a common side reaction which cannot be suppressed
completely. Hence, the alkyne is used as the limiting
reagent.
Scheme 1
As test reaction, we identified the CuOTf-catalyzed
alkynylation originally published by the group of Li
(Scheme 1) [21]. In this paper, even an enantioselective
CDC reaction was disclosed taking advantage of chiral
PyBOX-type ligands. It can be considered as a typical CDC
example which uses commonly applied t-BuOOH as oxi-
dant in THS as solvent.
Within this contribution, we report our efforts to
develop this transformation toward a more environmentally
benign alkynylation method for various TIQs.
Results and discussion
Based on the original report by the group of Li (Scheme 1)
[21], we started optimizing the protocol. Li optimized his
procedure toward maximum ee and in this regard he
identified CuOTf as an ideal metal source giving 67%
It can be seen that in most cases, moderate to high yields
were obtained with copper catalysts, the exception being
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
Table 1 Parameter screening in the alkynylation of 1 with phenylacetylene
Entry
Catalyst
T/°C
Solvent
Yield 2/%a
1
(CuOTf)2 toluene complex
(CuOTf)2 toluene complex
(CuOTf)2 toluene complex
(CuOTf)2 toluene complex
(CuOTf)2 toluene complex
(CuOTf)2 toluene complex
CuBr
50
50
THF
55
75
26
33
n.c.
n.c.
66
53
55
51
100
59
80
61
67
48
72
37
70
86
67
65
58
60
45
n.c.
n.c.
2
MeCN
Neat
3
50
4
50
DCM
Neat
5
100
100
50
6
MeCN
Neat
7
8
CuBr
50
DCM
MeCN
THF
9
CuBr
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
CuBr
50
CuBr
100
100
50
Neat
CuBr
MeCN
Neat
Cu(NO3)2Á3H2O
Cu(NO3)2Á3H2O
Cu(NO3)2Á3H2O
Cu(NO3)2Á3H2O
Cu(NO3)2Á3H2O
Cu(NO3)2Á3H2O
CuCl
50
MeCN
DCM
THF
50
50
100
100
50
Neat
MeCN
THF
CuCl
50
MeCN
Neat
CuCl
50
CuCl
50
DCM
Neat
CuCl
100
100
50
CuCl
MeCN
MeCN
MeCN
Neat
CuCN
Fe(NO3)2Á9H2O
Fe(NO3)2Á9H2O
50
100
Standard screening conditions: 0.4 mmol 1, 0.2 mmol phenylacetylene, 0.22 mmol t-BuOOH (*5.5 M solution in decane), 10 mol% catalyst,
and 1 cm3 solvent, argon atmosphere
a
Isolated yield
the (CuOTf)2-catalyzed reactions at 100 °C, where no
conversion could be detected. Also, Fe(NO3)2Á9H2O gave
no conversion at all. The solvent THF was identified as an
ideal solvent to obtain high ee in the original publication of
Li [21]. In our screening, the best yields were obtained
either under neat conditions or using acetonitrile as solvent,
depending on the copper catalyst. (CuOTf)2 toluene com-
plex and CuCl gave the best yield in acetonitrile, whereas
CuBr and Cu(NO3)2Á3H2O gave better results under neat
conditions. It has to be mentioned that ‘‘neat’’ means no
addition of additional solvent, but the oxidant in the
screening is provided as 5.5 M solution in decane.
The two best performing protocols were then used in a
second screening in which the N-protecting group was var-
ied. In most literature examples of cross-dehydrogenative
coupling reactions, a phenyl group is attached to the TIQ
nitrogen [13–18, 21]. This has to be considered as a perma-
nent group. Cleavage of an N-phenyl group has been
reported, but not on a TIQ substrate and only under very
harsh conditions (100 equiv of Li/NH3/THF/40 °C, 3 h)
123

¨
B. Groll et al.
Table 2 Protecting group
screening
Entry
1
Substrate
PG
CuBr, neat, 100 °C CuCl, MeCN, 50 °C
3
n.c.
traces
2
4
n.c.
n.c.
CH3
Boc
3
4
5
6
~50
n.c.
n.c.
n.c.
5
6
7
8
7
8
<10
n.c.
n.c.
n.c.
n.c.
n.c.
n.c.
n.c.
Acetyl
Pivaloyl
9
10
H
9
11
12
n.c.
21a
n.c.
42a
10
a
GC yield with internal standard
[22]. We could show that Boc can be used instead in the CDC
reaction of TIQ and indoles [19, 20]. Hence, we tested
whether also in the alkynylation protocol, other N-protecting
groups can be applied. The two best conditions identified in
Table 1 were used on different substrates (Table 2).
pursued. In the case of the Boc-protected substrate 7,
product formation was very low—beyond 10%—according
1
to GC–MS and crude H NMR. In case of PMP-protected
substrate 12, the conversion remained low with 21%. In
case of CuCl in acetonitrile at 50 °C, 12 gave a more
promising conversion of 42% (entry 10). Trace amounts of
product were detected for the benzyl-protecting group
(entry 1, substrate 3) and in all other cases no conversion
was detected.
In the case of CuBr as catalyst, at 100 °C and no
additional solvent, product formation was observed for the
methyl-, Boc-, and PMP-protecting groups (see Table 2,
entries 3, 5 and 10, substrates 5, 7, and 12). Although the
yield was around 50% according to GC–MS for 2-methyl-
1,2,3,4-tetrahydroisoquinoline (5), the alkynylation product
could not be isolated due to purification difficulties even
though several attempts were undertaken. Since the methyl
group cannot be cleaved either, this was not further
Next, the substrate scope was investigated. It was
decided to use the CuCl protocol since handling of the
reactions was simpler in the presence of solvent. Addi-
tionally, the PMP group gave better results in the initial
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
Table 3 Substrate scope
investigations of alkyne
coupling partners
Entry
1
Product
R1
R2
Yield /%a
86
2
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13f
67
49
93
42
77
57
42
14a
9
14b
14c
14d
14e
14f
71
61
10
11
12
13
14
25
93
52
14g
n.c.
Standard conditions: 0.4 mmol 1, 0.2 mmol alkyne, 0.22 mmol t-BuOOH
(*5.5 M solution in decane), 10 mol% CuCl, 1 cm3 MeCN, argon atmosphere
a
Isolated yield
123

¨
B. Groll et al.
in which both alkyne groups carry a TIQ residue. With
5-chloropent-1-yne, a similar but less pronounced trend
was observed, with substrate 1 giving 77% yield and sub-
strate 12, 52%. More severe was the difference for
3-ethynylthiophene, which only gave the product in the
reaction with 1 (Table 3, entry 7, 57%), but no conversion
with the PMP starting material 12 (Table 3, entry 14).
Finally, ethynylcyclopropane gave the highest yield in an
alkynylation reaction with the PMP substrate 12 (Table 3,
entry 13, 93%) and a significantly lower yield with the
phenyl substrate 1 (Table 3, entry 6, 42%).
Table 4 Substrate scope investigations of alkyne coupling partners
Entry
1
Product
R1
Yield /%a
traces
15a
The same set of alkynes was then also reacted with the
benzyl-protected substrate 3, even though only traces of the
product were detected in the reaction with phenylacetylene.
It was found that the other p-system containing alkynes
were equally inefficient (Table 4, entries 1, 4, and 7), but
aliphatic alkynes indeed gave product formation (Table 4,
entries 2, 3, 5, and 6). However, yields remained moderate
to low, with the best result for ethynylcyclopropane, which
gave 53% yield of 15e (Table 4, entry 5).
2
3
4
5
15b
15c
15d
15e
30
40
n.c.
53
Since our overall goal was to develop a more convenient
protocol, we wanted to test whether the so far applied
oxidant could be substituted for a cheaper, more readily
available one. Before screening for other oxidants, we
tested the role of the oxidant by applying various amounts
of Cu(I) and Cu(II) with or without external oxidant. As
test reaction, again the alkynylation of 1 with phenyl-
acetylene was used (Table 5).
6
7
15f
48
15g
n.c.
Standard conditions: 0.4 mmol 1, 0.2 mmol alkyne, 0.22 mmol t-
BuOOH (*5.5 M solution in decane), 10 mol% CuCl, 1 cm3 MeCN,
and argon atmosphere
Traces of alkynylation product were detected via GC–
MS in the presence of 5 mol% of copper(II) source
(Table 5, entry 4) without t-BuOOH. When carrying out
the reaction with 1 equivalent of copper(II) source
(Table 5, entry 6), 35% of product 2 was detected after 2 d.
No product was found to be formed with 5 mol% of cop-
per(I) source and without t-BuOOH (Table 5, entry 2). In
the presence of t-BuOOH, the reactions worked both with
catalytic amounts (5 mol%) of copper(I) or copper(II)
sources (Table 5, entries 1 and 3). These findings indicate
that Cu(II) is the species which is needed for the alkyny-
lation process and that it is reduced during the alkynylation
reaction. Since the reaction works without t-BuOOH but
with quantitative amount of Cu(II), the only role of t-
BuOOH is to oxidize the copper source back to oxidation
state II after the alkynylation step. Next, different oxidants
were tested in our protocol (Table 6).
a
Isolated yield
screening and should be included in the substrate scope
investigations.
Two alkyne coupling partners, namely phenylacetylene
and 1-octyne, were the same as in the report by Li [21], so we
can compare the yield between the two protocols. Otherwise,
we tried to focus on alkynes which were not applied by
previous reports. For phenylacetylene, we received 86% for
the phenyl and 42% yield for the PMP-protecting group
´
(Table 3, entries 1 and 8). This compares favorably to Lis
protocol in case of the phenyl PG where Li obtained 67% of
2, but is unfavorable in case of the PMP group where Li
obtained 59% yield of 14a. In case of 1-octyne, it is just the
other way round; our protocol gave higher yield for PMP
(61% of 14c vs. 48%), but lower for the phenyl PG (49% of
13b vs 65%) (Table 3, entries 3 and 10).
Use of hydrogen peroxide did not lead to product for-
mation, but decomposition of the substrate to several
unidentifiable side products was observed (Table 6, entry
2). Performing the reactions under oxygen atmosphere led
to almost quantitative formation of the desired alkynylation
product 2 and formation of approximately 30% of oxidized
product 16, due to the excess of starting material (Table 6,
entry 3). When carrying out the reactions under air
For the other alkynes, 1-heptyne gave similar yields for
both protecting groups (entries 2 and 9). For 1,7-octadiyne,
an excellent yield of 93% was obtained for the phenyl PG
and a low yield of 25% for the PMP group (Table 3, entries
4 and 11). Interestingly, only one of the terminal alkyne
groups reacted in both cases and no products were detected
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
Table 5 Role of oxidant
It can be seen that for all applied alkynes, excellent
yields were obtained using this environmentally absolutely
benign protocol. For phenylacetylene (Table 7, entry 1),
1-hexyne (entry 2), 1-octyne (entry 3), and 5-chloropent-1-
yne (entry 6) yields greater than 90% were isolated. The
drawback is the limited compatibility with other N-pro-
tecting groups. Interestingly, neither with the PMP-
protected substrate 12 nor the benzyl-protected starting
material 3, significant conversions were detected in any
example.
Entry
Catalyst
Loading
t-BuOOH
Yield/%a
1
2
3
4
5
6
a
CuCl
CuCl
CuCl2
CuCl2
CuCl
CuCl2
5 mol%
5 mol%
5 mol%
5 mol%
1 equiv.
1 equiv.
Yes
No
Yes
No
No
No
90
–
78
Traces
–
35
GC yield with dodecane as internal standard
All our protocols disclosed here have one additional
limitation. The alkyne scope is limited to non-volatile
liquid or solid alkyne sources. To introduce also short-
chained aliphatic alkynes, which are typically gaseous at
room temperature, we recently disclosed a decarboxylative
protocol, also taking advantage of copper catalysis [26].
Since the decarboxylative reaction (Scheme 2) worked
well with the t-BuOOH/Ar/MeCN protocol, further
experiments were carried out with the water/air protocol
(see Scheme 2).
atmosphere, only 20% of relative product formation was
observed (Table 6, entry 4), either due to bad circulation in
a closed vial with an air balloon or due to evaporation of
the solvent and alkyne source when carrying out the
reaction in an open vial. Performing the reactions under
pressure (5 bar), almost quantitative conversion to 2 was
observed (Table 6, entry 5), with only negligible amounts
of 16 being observed. This is one rare example where air
can be used as sole oxidant in a CDC reaction [23–25].
Since the reaction worked well in acetonitrile, we
wanted to take it one step further toward an environmen-
tally benign protocol by substituting acetonitrile by a green
solvent, ideally water. To our delight, the reaction worked
with identical efficiency also in water, even at shorter
reaction time of 24 h and lower catalyst loading of
5 mol%! Additionally, a 1:1 ratio between 1 and alkyne
source could be used instead of the formerly applied ratio
of 2:1. Table 7 summarizes the results.
Yet, only traces of product 17 could be detected via
GC–MS. Assuming that the decarboxylation process
does not tolerate water as a solvent, reactions were
carried out in MeCN, leading to higher conversion, but
with no reproducible yields due to the instability of
the pressure vial sealing in the presence of MeCN and
high pressure. Further reactions were carried out in
different water/MeCN mixtures, as listed below in
Table 8.
When the typical ratio of TIQ substrate:alkyne source of
2:1 was used, only traces of product 17 were formed
Table 6 Oxidant screening
Entry
Oxidant
P/bar
Yield 2/%a
16
1
2
3
t-BuOOH
H2O2
O2
1
1
1
90
–
Traces
–
95
0.3
equiv.
4
5
a
Air
Air
1
5
20
93
Traces
Traces
GC yield with dodecane as internal standard
123

¨
B. Groll et al.
Table 7 CDC alkynylation in water using air as oxidant
Table 8 Solvent screening for decarboxylative coupling in aqueous
media
Entry
Ratio H2O/MeCN
Ratio TIQ/alkyne
Yield 17/%
1
2
3
4
5
6
7
8
a
100:0
99:1
2:1
2:1
2:1
2:1
1:1
1:1
1:1
1:1
Traces
Traces
Traces
Traces
Traces
5a
90:10
50:50
100:0
99:1
Entry
1
Product
R1
Yield /%a
97
2
90:10
50:50
50b
80b
2
3
4
5
13a
13b
13c
13d
93
91
88
GC yield with dodecane as internal standard
Isolated yield
b
Conclusion
Summarizing, three different alkynylation methods were
established on N-phenyl, N-PMP, and N-benzyl-1,2,3,4-te-
trahydroisoquinoline. First, the parameters of Li’s protocol
[21] were changed to a different solvent (MeCN) and catalyst
(CuCl). Under these conditions, it was possible to introduce
different alkynes to N-phenyl-, N-PMP-, and also N-benzyl-
TIQ substrates 1, 3, and 12 in moderate to high yields.
Second, in the search for a greener process, it was
possible to change the reaction conditions to water as
solvent and air as oxidant (instead of MeCN and t-
BuOOH). The water protocol was shown to be only
applicable to N-phenyl-TIQ 2, leading to higher yields
under greener conditions than with the original procedure
in MeCN.
78
6
7
13e
13f
95
71
Standard conditions: 0.4 mmol 1, 0.4 mmol alkyne, air (4–5 bar),
5 mol% CuCl, and 1 cm3 H2O
a
Isolated yield
Scheme 2
Third, to introduce also shorter alkynes and terminal
alkynes to the C1-position, a decarboxylative protocol was
developed, using alkynoic acids as alkyne sources, air as
oxidant, and water/MeCN as the solvent mixture.
Experimental
Unless otherwise noted, chemicals were purchased from
commercial suppliers and used without further purification.
Flash column chromatography was performed on silica gel
60 from Merck (40–63 lm), whereas separations were
carried out using a Bu¨chi SepacoreTM MPLC system. For
TLC, aluminum-coated silica gel was used and signals
were visualized with UV light (254 nm). GC–MS runs
were performed on a Thermo Finnigan Focus GC/DSQ II
using a standard capillary column BGB 5 (30 m 9
0.32 mm ID) and the following settings were used as
standard: injection: 1 mm3 (hot needle-technique), split-
injection (split-ratio: 1:8); flow: 2 cm3/min helium; injector
block temperature: 250 °C; MS-transferline temperature:
independent of the solvent composition (Table 8, entries
1–4). However, when changing to a 1:1 ratio, the situation
changed and at a water/MeCN ratio of 50:50, an isolated
yield of 80% could be achieved (Table 8, entry 8). Ratios
with higher MeCN content resulted in decomposition of the
sealing.
Using 1 as substrate, excellent results were obtained
for the two longest chained alkynoic acids (Table 9,
entries 4 and 5), which gave almost quantitative yield.
Also propynoic acid gave a good yield of 17 of 80%
(Table 9, entry 1). Butynoic acid and pentynoic acid gave
only a mediocre yield of 18 and 19, respectively (Table 9,
entries 2 and 3).
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
General Procedure B
Table 9 Decarboxylative coupling in aqueous media
To a mixture of 4 mg copper(I) chloride (0.04 mmol, 0.1
equiv.) and the corresponding 1,2,3,4-tetrahydroisoquino-
line (0.4 mmol, 1.0 equiv.) in 1 cm3 water in a pressure
vial, the alkyne (0.4 mmol, 1.0 equiv.) was added. The vial
was quickly filled with air to a pressure of 4–5 bar. The
reaction mixture was then stirred at 50 °C for 24 h. After
cooling down to room temperature, the reaction mixture
was extracted 39 with 2 cm3 EtOAc, the organic phases
were combined, the solvent was evaporated, and the resi-
due was purified by column chromatography or preparative
TLC.
Entry
Product
R1
Yield/
a
%
1
2
3
4
5
17
18
H
80
32
47
95
98
CH3
19
C2H5
n-C3H7
n-C5H11
20
13a
General Procedure C
Standard conditions: 1 (0.4 mmol), alkynoic acid (0.4 mmol), CuCl
(0.04 mmol), water:MeCN (1:1, 1 cm3), air, 50 °C, 24 h
To a mixture of 4 mg copper(I) chloride (0.04 mmol, 0.1
equiv.), 83.7 mg 2-phenyl-1,2,3,4-tetrahydroisoquinoline
(0.4 mmol, 1.0 equiv.) in 1 cm3 of a 1:1 mixture of water
and MeCN in a pressure vial, alkynoic acid (0.4 mmol, 1.0
equiv.) was added. The vial was quickly filled with air to a
pressure of 4–5 bar. The reaction mixture was then stirred
at 50 °C for 24 h. After cooling down to room temperature,
the solvent was evaporated and the residue was purified by
column chromatography or preparative TLC.
a
Isolated yield
280 °C. HR-MS was carried out by E. Rosenberg at the
Vienna University of Technology, Institute for Chemical
Technologies and Analytics. All samples were analyzed by
LC–IT-TOF-MS in only positive ion detection mode upon
recording of MS and MS/MS spectra. For the evaluation in
the following, only positive ionization spectra were used
(where the quasi-molecular ion is the one of [M?H]?), and
further data or information were not taken into considera-
tion. Melting points were determined using a Kofler-type
N-Phenyl-1,2,3,4-tetrahydroisoquinoline (1)
Copper(I) iodide (39.8 mg, 0.21 mmol, 0.1 equiv.) and
887.3 mg potassium phosphate (4.18 mmol, 2.09 equiv.)
were weighed in a round flask which was evacuated and
back filled with nitrogen three times. 2-Propanol (2 cm3),
0.23 cm3 ethylene glycol, 426.4 mg iodobenzene
(0.23 cm3, 2.09 mmol, 1.05 equiv.) and 0.27 g 1,2,3,4-
tetrahydroisoquinoline (0.26 cm3, 2.0 mmol, 1 equiv.)
were added via micro syringe at room temperature. The
reaction mixture was heated to 85–90 °C, stirred for 24 h
and then allowed to cool to room temperature. Diethyl
ether (5 cm3) and 5 cm3 water were then added to the
reaction mixture. The organic layer was extracted by
diethyl ether (2 9 20 cm3). The combined organic phases
were washed with brine and dried over magnesium sulfate.
The solvent was removed in vacuo and the crude mixture
purified by column chromatography on silica gel (PE:E-
tOAc = 20:1) to give 83% (0.347 g, 1.66 mmol) of 1 as a
beige solid. M.p.: 43–46 °C (lit. m.p.: 45–46 °C [27]);
Rf = 0.69 (PE:EtOAc = 10:1).
1
Leica Galen III micro hot stage microscope. H NMR and
13C NMR spectra were recorded on a Bruker AC 200
(200 MHz) or on a Bruker Avance UltraShield 400
(400 MHz) spectrometer. Chemical shifts are reported as
ppm downfield from TMS (tetramethylsilane) as internal
standard with multiplicity, number of protons, allocation,
and coupling constant(s) in Hertz.
General Procedure A
A mixture of 2 mg copper(I) chloride (0.02 mmol, 0.1
equiv.) and the corresponding 1,2,3,4-tetrahydroisoquino-
line (0.4 mmol, 2.0 equiv.) in 1 cm3 MeCN was flushed
with Ar for about 2 min and then 0.04 cm3 tert-butyl
hydroperoxide (5.5 M in decane) was dropped into the
mixture via syringe at room temperature, followed by the
alkyne (0.2 mmol, 1.0 equiv.). The reaction temperature
was raised to 50 °C and the mixture was stirred at this
temperature for 2 days and then cooled to room tempera-
ture. The resulting suspension was diluted with diethyl
ether or dichloromethane and filtered through a little
amount of silica gel in a frit. The solvent was evaporated
and the residue was purified by column chromatography or
preparative TLC.
2-Phenyl-1-phenylethynyl-1,2,3,4-tetrahydroisoquinoline
(2)
It was prepared according to the General Procedure A
(86%, 53 mg, 0.17 mmol) and
B (97%, 120 mg,
0.38 mmol). The product was isolated by column chro-
matography (PE:DCM = 10:3) as a light yellow oil. NMR
data were in agreement with the literature [21].
123

¨
B. Groll et al.
N-Benzyl-1,2,3,4-tetrahydroisoquinoline (3)
subjected to flash column chromatography using gradient
elution with PE:EtOAc (100:0–40:60) to afford the desired
product 6 in 64% (670 mg, 3.19 mmol) as a pale yellow
solid. M.p.: 39–42 °C; Rf = 0.65 (PE:EtOAC = 10:1);
NMR data were in agreement with the literature [31].
To an argon-degassed solution of 2.66 g THIQ (2.53 cm3,
20 mmol, 1.0 equiv.) and 6.07 g TEA (8.4 cm3, 60 mmol,
3.0 equiv.) in 50 cm3 dry DCM, 5.13 g benzyl bromide
(3.4 cm3, 30 mmol, 1.5 equiv.) was added at 0 °C. After
10 min, the reaction mixture was warmed to r.t. and stirred
under argon for 5 h. The reaction mixture was quenched
with aqueous saturated sodium carbonate solution, and
extracted three times with EtOAc. The collected organic
layers were washed twice with brine, dried over sodium
sulfate, filtered, and evaporated. The crude product was
purified via column chromatography (PE:CHCl3 = 3:1) to
give 82% (3.68 g, 16.5 mmol) of 3 as a pale yellow solid.
M.p.: 35–37 °C (lit. m.p.: 35–36 °C [28]); TLC: Rf = 0.36
(PE:CHCl3 = 3:1).
N-Boc-1,2,3,4-tetrahydroisoquinoline (7)
To an argon-degassed solution of 2.66 g 1,2,3,4-tetrahy-
droisoquinoline (2.53 cm3, 20.0 mmol, 1.0 equiv.) and
6.07 g TEA (8.37 cm3, 60.0 mmol, 3.0 equiv.) in 45 cm3
dry DCM, a solution of 4.80 g Boc2O (5.05 cm3,
22.0 mmol, 1.1 equiv.) in 5 cm3 DCM was added
dropwise. The reaction was stirred under argon atmosphere
at r.t. for 15 h. Then, the solvent was evaporated in vacuo,
and the residue directly subjected to flash column chro-
matography using gradient elution with PE:Et2O
(100:0–40:60) to afford the desired product 7 in 99%
(4.60 g, 19.7 mmol) as a colorless solid. M.p.: 27–35 °C;
TLC: Rf = 0.79 (PE:Et2O = 5:1); NMR data were in
agreement with the literature [32].
N-(4-Methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline
hydrochloride (4)
To an argon-degassed solution of 1.33 g 1,2,3,4-tetrahy-
droisoquinoline (1.27 cm3, 10 mmol, 1.0 equiv.) and
3.04 g TEA (4.2 cm3, 30 mmol, 3.0 equiv.) in 15 cm3
dry DCM, 2.35 g 4-methoxybenzylchloride (2.03 cm3,
15 mmol, 1.5 equiv.) was added at 0 °C. After 10 min,
the reaction mixture was warmed to r.t. and stirred under
argon for 12 h. The reaction mixture was diluted with
aqueous 2 M HCl and extracted three times with EtOAc.
The collected organic layers were washed twice with brine,
dried over sodium sulfate, filtered, and evaporated. The
crude product was triturated in hot EtOAc, cooled down to
-20 °C, and the colorless precipitate collected by filtration
to give 86% (2.50 g, 8.63 mmol) of 4 after drying as
colorless solid. M.p.: 210–212 °C (lit. m.p.: 211 °C [29]);
TLC: Rf = 0.55 (PE:EtOAc = 3:1).
N-Acetyl-1,2,3,4-tetrahydroisoquinoline (8)
A 50 cm3 flask was loaded with 1.51 g 1,2,3,4-tetrahy-
droisoquinoline (1.44 cm3, 11.3 mmol, 1.0 equiv.) and
1.19 g acetic acid anhydride (1.10 cm3, 11.3 mmol, 1.0
equiv.). The mixture was heated to 100 °C for 3 h. After 1 h
another equivalent of acetic acid anhydride was added to the
reaction. The reaction mixture was cooled to r.t. and diluted
with 200 cm3 DCM. The organic layer was washed twice
with 2 M aqueous NaOH to get rid of excess acetic acid,
washed twice with brine, dried over sodium sulfate, filtered,
and evaporated. The crude product was subjected to flash
column chromatography using gradient elution with PE:E-
tOAc (100:0–50:50) to afford the desired product 8 in 75%
(1.49 g, 8.50 mmol) as pale yellow crystals. M.p.: 44–46 °C
(lit. m.p.: 45–46 °C [33]); Rf = 0.29 (PE:EtOAc = 10:1).
N-Methyl-1,2,3,4-tetrahydroisoquinoline (5)
1,2,3,4-THIQ (1.332 g, 10 mmol) was added, under cool-
ing, to 2.302 g formic acid (50 mmol) and 0.751 g
formaldehyde (25 mmol). The reaction mixture was
refluxed overnight, diluted with 2 M hydrochloric acid,
and then extracted with EtOAc. This solution was neutral-
ized with brine and dried with sodium sulfate. The EtOAc
was vaporized and the crude mixture separated via column
chromatography (PE:EtOAc = 20:1) to give 87% (1.28 g,
N-Pivaloyl-1,2,3,4-tetrahydroisoquinoline (9)
To an argon-degassed solution of 2.66 g 1,2,3,4-tetrahy-
droisoquinoline (2.53 cm3, 20.0 mmol, 1.0 equiv.) and
6.07 g TEA (8.37 cm3, 60.0 mmol, 3.0 equiv.) in 50 cm3
dry DCM, 3.61 g pivaloyl chloride (3.68 cm3, 30.0 mmol,
1.5 equiv.) was added slowly at 0 °C. Then, the reaction
mixture was warmed to r.t. and stirred at r.t. under argon
for 2 h. The reaction mixture was cooled to 0 °C, diluted
with aqueous 2 N HCl, and extracted three times with
Et2O. The collected organic layers were washed twice with
2 N NaOH, and once with brine, dried over sodium sulfate,
filtered, and evaporated. The crude product was subjected
to flash column chromatography using gradient elution
with PE:Et2O (100:0–40:60) to afford the desired product 9
in 86% (3.75 g, 17.3 mmol) as a pale yellow solid. M.p.:
63–65 °C (lit. m.p.: 67–69 °C [34]); Rf = 0.47
(PE:EtOAc = 5:1).
8.7 mmol) of 5 as a yellow oil. Rf = 0.70 (PE:
EtOAc = 10:1); NMR data were in agreement with the
literature [30].
N-(Pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (6)
1,2,3,4-Tetrahydroisoquinoline
(666 mg,
0.63 cm3,
5.00 mmol, 1.0 equiv.) and 510 mg 2-fluoropyridine
(0.45 cm3, 5.05 mmol, 1.05 equiv.) were placed in a
screw-capped glass vial at r.t., heated to 120 °C, and stirred
for 15 h. Completion of the reaction was monitored by
TLC, the reaction mixture cooled to r.t., and directly
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
N-Benzoyl-1,2,3,4-tetrahydroisoquinoline (10)
C5), 128.6 (d, C8), 128.9 (d, C30), 133.8 (s, C8a), 135.9 (s,
C4a), 149.2 (s, C10) ppm; HR-MS: m/z calculated [M?H]?
304.2060, found 304.2064.
Benzoyl chloride (4.22 g, 30.0 mmol, 1.5 equiv.), was
added slowly to a solution of 2.66 g THIQ (2.53 cm3,
20.0 mmol, 1.0 equiv.) and 6.07 g TEA (8.37 cm3,
60.0 mmol, 3.0 equiv.) in 50 cm3 dry DCM at 0 °C. The
reaction mixture was warmed to r.t. after completion of the
addition and stirred at r.t. under argon for 15 h. Then, the
reaction mixture was cooled to 0 °C, diluted with aqueous
2 N HCl, and extracted three times with Et2O. The
collected organic layers were washed twice with 2 N
NaOH, and once with brine, dried over sodium sulfate,
filtered, and evaporated. The crude product was subjected
to flash column chromatography using gradient elution
with PE:Et2O (100:0–40:60) to afford the desired product
10 in 98% (4.67 g, 19.7 mmol) as a pale yellow solid.
M.p.: 125–127 °C (lit. m.p.: 127–129 °C [34]); Rf = 0.24
(PE:EtOAc = 5:1).
1-(Oct-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(13b, C23H27N)
It was prepared according to General Procedure A (49%,
31 mg, 0.1 mmol) and B (91%, 116 mg, 0.36 mmol). The
product was isolated by column chromatography (PE/
DCM) as a light yellow oil. Rf = 0.62 (PE:EtOAc = 20:1);
NMR data were in agreement with the literature [21].
1-(Octa-1,7-diyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (13c, C23H23N)
It was prepared according to General Procedure A (93%,
58 mg, 0.19 mmol) and B (88%, 110 mg, 0.34 mmol). The
product was isolated by column chromatography (PE/
DCM) as a light yellow oil. Rf = 0.47 (PE:EtOAc = 20:1);
1H NMR (200 MHz, CDCl3): d = 1.45–1.68 (m, 4H, H200,
H300), 1.99 (s, 1H, H600), 2.09-2.31 (m, 4H, H100, H400),
2.99–3.27 (m, 2H, H4), 3.55–3.83 (m, 2H, H3), 5.50 (s, 1H,
H1), 6.88–7.46 (m, 9H, H5-H8, H20, H30) ppm; 13C NMR
(50 MHz, CDCl3): d = 18.2 (t, C400), 18.6 (t, C100), 27.6 (t,
C300), 27.8 (t, C200), 29.1 (t, C4), 43.4 (t, C3), 52.2 (d, C1),
68.7 (d, C600), 79.9 (s, C alkyne), 84.9 (s, C alkyne, C500),
117.0 (d, C20), 119.9 (d, C40), 126.5 (d, C7), 127.3 (d, C6),
127.6 (d, C5), 129.2 (d, C8), 129.4 (d, C30), 134.4 (s, C4a),
136.3 (s, C8a), 150.0 (s, C10) ppm; HR-MS: m/z calculated
[M?H]? 314.1903, found 314.1900.
N-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(12)
Copper(I) iodide (39.8 mg, 0.21 mmol, 0.1 equiv.), 887.3 mg
potassium phosphate (4.18 mmol, 2.09 equiv.), and 489.1 mg
4-iodoanisole (2.09 mmol, 1.05 equiv.) were put into a round
flask which was evacuated and back filled with nitrogen three
times. 2-Propanol (2 cm3), 0.23 cm3 ethylene glycol, and
0.27 g 1,2,3,4-tetrahydroisoquinoline (0.26 cm3, 2.0 mmol,
1.0 equiv.) were added via Hamilton syringe at room
temperature. The reaction mixture was heated to 85–90 °C,
stirred for 24 h, and then allowed to cool to room temperature.
Diethyl ether (5 cm3) and 5 cm3 water were then added to the
reaction mixture. The organic layer was extracted by diethyl
ether (2 9 20 cm3). The combined organic phases were
washed with brine and dried over magnesium sulfate. The
solvent was removed in vacuo and the product purified by
column chromatography on silica gel (PE:EtOAc = 20:1) to
give 79% (0.38 g, 1.58 mmol) of 12 as a colorless solid. M.p.:
89–91 °C; TLC: Rf = 0.56 (PE:EtOAc = 5:1); NMR data
were in agreement with the literature [35].
1-(Cyclopropylethynyl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (13d, C20H19N)
It was prepared according to General Procedure A (42%,
23 mg, 0.08 mmol) and B (78%, 86 mg, 0.32 mmol). The
product was isolated by column chromatography (PE/
DCM) as a light yellow oil. Rf = 0.55 (PE:EtOAc = 20:1);
NMR data were in agreement with the literature [36].
1-(5-Chloropent-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahy-
droisoquinoline (13e, C20H20ClN)
1-(Hept-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquino-
line (13a, C22H25N)
It was prepared according to General Procedure A (77%,
46 mg, 0.15 mmol) and B (95%, 118 mg, 0.38 mmol). The
product was isolated by column chromatography (PE/DCM)
asa light yellow oil. Rf = 0.45(PE:EtOAc = 20:1);1H NMR
It was prepared according to the General Procedure A (67%,
41 mg, 0.13 mmol), B (93%, 116 mg, 0.36 mmol), and C
(98%, 118 mg, 0.40 mmol). The product was isolated by
column chromatography (PE/DCM) as a light yellow oil.
Rf = 0.57 (PE:EtOAc = 20:1); 1H NMR (200 MHz,
CDCl3): d = 0.78–1.02 (m, 3H, H500), 1.22–1.56 (m, 6H,
H200-H400), 1.99 (t, 2H, H100), 2.86–3.27 (m, 2H, H4),
3.51–3.87 (m, 2H, H3), 5.45 (s, 1H, H1), 6.90 (m, 1H,
H40), 7.02–7.48 (m, 8H, H5–H8, H20, H30) ppm; 13C NMR
(50 MHz, APT, CDCl3): d = 13.9 (q, C500), 17.9 (t, C100),
21.6 (t, C400), 27.9 (t, C200), 28.2 (t, C4), 30.2 (t, C300), 42.0 (t,
C3), 50.5 (d, C1), 79.9 (s, C alkyne), 84.5 (s, C alkyne), 116.1
(d, C20), 118.9 (d, C40), 125.9 (d, C7), 126.9 (d, C6), 127.4 (d,
3
(200 MHz, CDCl3): d = 1.83 (qui, J = 6.5 Hz, 2H, H200),
2.31 (dt, 3J = 6.7 Hz, 4J = 2.1 Hz, 2H, H300), 2.87–3.23 (m,
2H, H4), 3.38–3.79 (m, 4H, H3, H200) 5.46 (s, 1H, H1), 6.9 (dt,
3J = 7.2 Hz, 4J = 1.0 Hz, 1H, H40), 7.08 (dd, 3J = 8.7 Hz,
4J = 1.0 Hz, 2H, H20), 7.16-7.40 (m, 6H, H5–H8, H30) ppm;
13C NMR (50 MHz, CDCl3): d = 16.4 (t, C300), 29.1 (t, C4),
31.5 (t, C200), 43.2 (t, C100), 43.7 (t, C3), 52.2 (d, C1), 80.5 (s,
CA1), 83.2 (s, CA2), 116.9 (d, C20), 119.8 (d, C40), 126.4 (d,
C7), 127.3 (d, C6), 127.5 (d, C5), 129.1 (d, C8), 129.3 (d, C30),
134.3 (s, C8a), 135.9 (s, C4a), 149.9 (s, C10) ppm; HR-MS: m/
z calculated [M?H]? 310.1357, found 310.1347.
123

¨
B. Groll et al.
2-Phenyl-1-(thiophen-3-ylethynyl)-1,2,3,4-tetrahydroiso-
quinoline (13f, C21H17NS)
(PE:EtOAc = 20:1); NMR data were in agreement with
the literature [21].
It was prepared according to General Procedure A (57%,
36 mg, 0.11 mmol) and B (71%, 90 mg, 0.28 mmol). The
product was isolated by column chromatography (PE/
DCM) as a light yellow oil. Rf = 0.49 (PE:EtOAc = 20:1);
1H NMR (200 MHz, CDCl3): d = 2.92–3.28 (m, 2H, H4),
3.55–3.87 (m, 2H, H3), 5.66 (s, 1H, H1), 6.84–7.48 (m,
12H, H5-H8, H20-H40, H200, H300, H400) ppm; 13C NMR
(50 MHz, CDCl3): d = 29.2 (t, C4), 43.7 (t, C3), 52.5 (d,
C1), 80.11 (s, C alkyne), 88.42 (s, C alkyne), 116.9 (d,
C20), 119.9 (d, C40), 122.3 (d, C200), 125.3 (s, C100), 126.6
(d, C7), 127.5 (d, C6), 127.7 (d, C5), 128.9 (d, C300), 129.2
(d, C8), 129.4 (d, C30), 130.3 (d, C400), 134.7 (s, C4a),
135.6 (s, C8a), 149.8 (d, C40) ppm; HR-MS: m/z calculated
[M?H]? 316.1154, found 316.1143.
1-(Octa-1,7-diyn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-te-
trahydroisoquinoline (14d, C24H25NO)
Prepared according to General Procedure A (25%, 17 mg,
0.05 mmol). The product was isolated by preparative TLC
(CHCl3) as
a
light yellow oil. Rf = 0.30 (PE:E-
1H
NMR (200 MHz, CDCl3):
tOAc = 20:1);
d = 1.48–1.57 (m, 4H, Alkyl-CH2), 1.99–2.02 (m, 1H,
alkyne-CH), 2.13–2.29 (m, 4H, alkyl-CH2), 2.88–3.30 (m,
2H, TIQ-CH2), 3.52–3.65 (m, 2H, TIQ-CH2), 3.88 (s, 3H,
OCH3), 5.38 (s, 1H, TIQ-CH), 6.91–7.40 (m, 8H, Ar–CH)
ppm; 13C NMR (50 MHz, CDCl3): d = 18.2 (t, C400), 18.6
(t, C100), 27.6 (t, C300), 27.9 (t, C200), 29.3 (t, C4), 44.3 (t,
C3), 54.1 (q, OCH3), 55.9 (d, C1), 56.3 (OCH3), 68.7 (C1),
79.7 (s, CA1), 84.6 (d, C600), 85.5 (s, CA2), 94.8 (s, C500),
114.6 (d, C20), 118.4, 120.3 (d, C30), 126.3 (d, C7), 127.2
(d, C6), 127.7 (d, C5), 129.3 (d, C8), 132.6, 134.1 (s, C4a),
136.4 (s, C8a), 144.6 (s, C10), 154.3 (s, C40) ppm; HR-MS:
m/z calculated [M?H]? 344.2009, found 344.2006.
1-(2-Phenylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droisoquinoline (14a)
It was prepared according to General Procedure A (42%,
29 mg, 0.08 mmol). The product was isolated by column
chromatography (PE/DCM) as a light yellow oil. Rf = 0.30
(PE:EtOAc = 20:1); NMR data were in agreement with
the literature [21].
1-(Cyclopropylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-te-
trahydroisoquinoline (14e, C21H21NO)
It was prepared according to General Procedure A (93%,
56 mg, 0.19 mmol). The product was isolated by prepar-
1-(Hept-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droisoquinoline (14b, C23H27NO)
ative TLC (CHCl3) as
a
yellow oil. Rf = 0.31
It was prepared according to General Procedure A (75%,
50 mg, 0.15 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as an orange oil. Rf = 0.31
(PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3):
d = 0.83 (t, 3J = 6.4 Hz, 3J = 6.4 Hz, 3H, H500),
(PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3):
d = 0.49–0.76 (m, 4H, H200), 1.09–1.26 (m, 1H, C100),
2.84–3.23 (m, 2H, H4), 3.45–3.68 (m, 2H, H3), 3.83 (s, 3H,
3
OCH3), 5.33 (s, 1H, H1), 6.91 (d, J = 9.1 Hz, 2H, H30),
7.08 (d, 3J = 9.1 Hz, 2H, H20), 7.14–7.35 (m, 4H, H5–H8)
ppm; 13C NMR (50 MHz, CDCl3): d = 0.0 (d, C100), 8.6 (t,
C200), 29.2 (t, C4), 44.3 (t, C3), 54.0 (q, OCH3), 55.9 (d,
C1), 74.3 (s, C alkyne), 89.3 (s, C alkyne), 114.5 (d, C20),
120.3 (d, C30), 126.3 (d, C7), 127.2 (d, C6), 127.7 (d, C5),
129.3 (d, C8), 134.1 (s, C4a), 136.4 (s, C8a), 144.5 (s, C10),
154.3 (s, C40) ppm; HR-MS: m/z calculated [M?H]?
304.1696, found 304.1694.
3
1.11–1.45 (m, CH2, 6H, H200–H400), 2.07(dt, J = 6.8 Hz,
3J = 6.9 Hz, 4J = 1.9 Hz, 2H, H100), 2.87 (td,
3J = 16.3 Hz, 4J = 3.5 Hz, 4J = 3.5 Hz, 1H, H4), 3.09
3
4
4
(ddd, J = 16.5 Hz, J = 9.7 Hz, J = 6.8 Hz, 1H, H4),
3.45–3.58 (m, 2H, H3), 3.77 (s, 3H, OCH3), 5.28 (s, 1H,
3
3
H1), 6.86 (d, J = 9.1 Hz, 2H, H30), 7.04 (d, J = 9.1 Hz,
2H, H20), 7.10–7.30 (m, 4H, H5–H8) ppm; 13C NMR
(50 MHz, APT, CDCl3): d = 14.0 (q, C500), 18.7 (t, C100),
22.2 (t, C200), 28.4 (t, C400), 29.0 (t, C4), 30.9 (t, C300), 44.0
(t, C3), 53.8 (q, OCH3), 55.5 (d, C1), 78.9 (s, C alkyne),
86.0 (s, C alkyne), 114.3 (d, C20), 120.0 (d, C30), 126.0 (d,
C7), 126.9 (d, C6), 127.4 (d, C5), 129.0 (d, C8), 133.8 (s,
C4a), 136.3 (s, C8a), 144.3 (s, C10), 154.0 (s, C40) ppm;
HR-MS: m/z calculated [M?H]? 334.2165, found
334.2162.
1-(5-Chloropent-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (14f, C20H20ClN)
It was prepared according to General Procedure A (52%,
32 mg, 0.10 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as a light yellow oil. Rf = 0.28
(PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3):
d = 1.72–1.88 (m, 2H, H200), 2.21–2.35 (m, 2H, H300),
2.81–3.23 (m, 2H, H4), 3.34–3.59 (m, 4H, H3, H100), 3.80
(s, 3H, OCH3), 5.32 (s, 1H, H1), 6.89 (d, 3J = 9.1 Hz, 2H,
1-(Oct-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahy-
droisoquinoline (14c)
3
H30), 7.05 (d, J = 9.1 Hz, 2H, H20), 7.12–7.34 (m, 4H,
It was prepared according to General Procedure A (61%,
42 mg, 0.12 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as a light yellow oil. Rf = 0.35
H5–H8) ppm; 13C NMR (50 MHz, CDCl3): d = 16.5 (t,
C300), 29.3 (t, C4), 31.7 (t, C200), 43.8 (t, C100), 44.3 (t, C3),
54.3 (q, OCH3), 55.9 (d, C1), 77.8 (s, C alkyne), 80.4 (s, C
123

Improved simplicity and practicability in copper-catalyzed alkynylation of…
4
alkyne), 114.7 (d, C20), 120.4 (d, C30), 126.4 (d, C7), 127.3
(d, C6), 127.7 (d, C5), 129.3 (d, C8), 134.1 (s, C4a), 136.0
(s, C8a), 154.6 (s, C40) ppm; HR-MS: m/z calculated
[M?H]? 340.1463, found 340.1456.
3J = 6.8 Hz, J = 2.0 Hz, 2H, H300), 2.68–2.86 (m, 2H,
H4), 2.88–3.01 (m, 2H, H3), 3.67 (t, 3J = 6.4 Hz, 2H,
H100), 3.80 (d, 3J = 13.2 Hz, 1H, Ph-CH2), 3.90 (d,
3J = 13.2 Hz, 1H, Ph-CH2), 4.57 (s, 1H, H1), 7.05–7.49
(m, 9H, H5–H8, H20–H40) ppm; 13C NMR (50 MHz,
CDCl3): d = 16.5 (t, C300), 31.8 (t, C200), 43.9 (t, C100), 45.8
(t, C3), 54.2 (t, Ph-CH2), 59.7 (d, C1), 79.3 (s, C alkyne),
85.2 (s, C alkyne), 125.9 (d, C7), 127.0 (d, C40), 127.3 (d,
C6), 127.8 (d, C5), 128.5 (d, C30), 129.2 (d, C8), 129.4 (d,
C20), 134.1 (s, C4a), 136.2 (s, C8a), 138.5 (s, C10) ppm;
HR-MS: m/z calculated [M?H]? 324.1514, found
324.1504.
1-(Hept-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(15b, C23H27N)
It was prepared according to General Procedure A (30%,
19 mg, 0.06 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as a light yellow oil. Rf = 0.65
(PE:CHCl3 = 3:2); 1H NMR (200 MHz, CDCl3):
d = 0.92 (t, 3H, H500), 1.29–1.62 (m, 6H, H200–H400),
2.17–2.30 (m, 2H, H100), 2.70–3.08 (m, 4H, H4, H3), 3.86
3
4
(dt, J = 17 Hz, J = 7.8 Hz, 2H, Ph-CH2), 4.56 (s, 1H,
H1), 7.05–7.50 (m, 9H, H5–H8, H20–H40) ppm; 13C NMR
(50 MHz, CDCl3): d = 14.2 (q, C500), 18.9 (t, C100), 22.3 (t,
C400), 28.8 (t, C200), 29.1 (t, C4), 31.2 (t, C300), 45.7 (t, C3),
54.2 (t, Ph-CH2), 59.6 (d, C1), 78.0 (s, C alkyne), 87.3 (s, C
alkyne), 125.8 (d, C7), 126.8 (d, C40), 127.2 (d, C6), 127.8
(d, C5), 128.4 (d, C30), 129.0 (d, C8), 129.4 (d, C20), 133.9
(s, C4a), 136.4 (s, C8a), 138.6 (s, C10) ppm; HR-MS: m/
z calculated [M?H]? 318.2216, found 318.2206.
1-Ethynyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(17, C17H15N)
It was prepared according to General Procedure C (80%,
75 mg, 0.32 mmol). The product was purified via prepar-
ative TLC (PE:CHCl3 = 3:1) as a colorless oil. Rf = 0.70
1
(CHCl3); H NMR (200 MHz, CDCl3): d = 2.33 (d, 1H,
HA2), 3.00 (m, 2H, H4), 3.59 (m, 2H, H3), 5.48 (s, 1H,
H1), 6.91 (t, 3J = 7.2 Hz, 1H, H40), 7.03–7.42 (m, 8H, H5-
H8, H20, H30) ppm; 13C NMR (50 MHz, CDCl3):
d = 29.13 (t, C4), 43.42 (t, C3), 51.85 (d, C1), 73.07 (d,
C alkyne), 83.18 (s, C alkyne), 116.87 (d, C20), 120.13 (d,
C40), 126.66 (d, C7), 127.56 (d, C6), 127.73 (d, C5), 129.31
(d, C8), 129.51 (d, C30), 134.59 (s, C4a), 135.16 (s, C8a),
149.61 (s, C10) ppm; HR-MS: m/z calculated [M?H]?
234.1277, found 234.1271.
1-(Oct-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(15c)
It was prepared according to General Procedure A (40%,
27 mg, 0.08 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as
a
yellow oil. Rf = 0.62
(PE:CHCl3 = 3:2); NMR data were in agreement with
the literature [37].
1-(Propyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(18, C18H17N)
1-(Cyclopropylethynyl)-2-benzyl-1,2,3,4-tetrahydroiso-
quinoline (15e, C21H21N)
It was prepared according to General Procedure C (32%,
32 mg, 0.13 mmol). The product was purified via prepar-
ative TLC (PE:CHCl3 = 3:1) as a light yellow oil.
Rf = 0.18 (PE:CHCl3 = 4:1); 1H NMR (200 MHz,
DMSO-d6): d = 1.77 (s, 3H, H100), 2.90–3.22 (m, 2H,
H4), 3.52–3.75 (m, 2H, H3), 5.42 (s, 1H, H1), 6.79–7.50
(m, 9H, H5–H8, H20–H40) ppm; 13C NMR (50 MHz,
DMSO-d6): d = 2.8 (q, C100), 27.6 (t, C4), 41.6 (t, C3),
49.7 (d, C1), 78.4 (s, C alkyne), 79.7 (s, Calkyne), 115.3 (d,
C20), 118.2 (d, C40), 125.5 (d, C7), 126.5 (d, C6), 126.9 (d,
C5), 128.2 (d, C8), 128.5 (d, C30), 133.4 (s, C4a), 135.4 (s,
C8a), 148.5 (s, C10) ppm; HR-MS: m/z calculated [M?H]?
248.1434, found 248.1422.
It was prepared according to General Procedure A (53%,
30 mg, 0.11 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as a light orange oil. Rf = 0.45
(PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3):
d = 0.60–0.88 (m, 4H, H200), 1.19–1.31 (m, 1H, H100),
2.62–3.09 (m, 4H, H4, H3), 3.68–3.96 (m, 2H, Ph-CH2),
4.54 (s, 1H, H1), 7.01–7.56 (m, 9H, H5–H8, H20–H40)
ppm; 13C NMR (50 MHz, CDCl3): d = 0.0 (d, C100), 8.8 (t,
C200), 29.3 (t, C4), 45.9 (t, C3), 54.4 (t, Ph-CH2), 59.7 (d,
C1), 73.4 (s, C alkyne), 90.6 (s, C alkyne), 126.0 (d, C7),
127.0 (d, C40), 127.40 (d, C6), 128.0 (d, C5), 128.6 (d,
C30), 129.2 (d, C8), 129.6 (d, C20), 134.2 (s, C4a), 136.4 (s,
C8a), 138.8 (s, C10) ppm; HR-MS: m/z calculated [M?H]?
288.1747, found 288.1738.
1-(Butyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(19, C19H19N)
It was prepared according to General Procedure C (47%,
49 mg, 0.19 mmol). The product was purified via prepar-
ative TLC (PE:CHCl3 = 3:1) as an orange oil. Rf = 0.22
(PE:CHCl3 = 4:1); 1H NMR (200 MHz, CDCl3): d = 1.10
(t, 3J = 7.5 Hz, 3H, H200), 2.91 (dq, 3J = 7.4 Hz,
4J = 1.8 Hz, 2H, H100), 2.92–3.28 (m, 2H, H4),
3.60–3.86 (m, 2H, H3), 5.48 (s, 1H, H1), 6.94 (t,
1-(5-Chloropent-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroiso-
quinoline (15f, C21H22ClN)
It was prepared according to General Procedure A (48%,
31 mg, 0.10 mmol). The product was isolated by prepar-
ative TLC (CHCl3) as a light yellow oil. Rf = 0.4
(PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3):
d = 1.98 (qui, 3J = 6.6 Hz, 2H, H200), 2.46 (dt,
123

¨
B. Groll et al.
3J = 7.2 Hz, 1H, H40), 7.09–7.44 (m, 8H) ppm; 13C NMR
(50 MHz, CDCl3): d = 12.81 (q, C200), 14.29 (t, C100),
29.13 (t, C4), 43.52 (t, C3), 51.94 (d, C1), 78.71 (s, C
alkyne), 86.86 (s, C alkyne), 116.76 (d, C20), 119.57 (d,
C40), 126.46 (d, C7), 127.29 (d, C6), 127.60 (d, C5), 129.15
(d, C8), 129.36 (d, C30), 134.52 (s, C4a), 136.54 (s, C8a),
149.88 (s, C10) ppm; HR-MS: m/z calculated [M?H]?
262.1590, found 262.1584.
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(PE:CHCl3 = 4:1); NMR data were in agreement with the
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Acknowledgements Open access funding provided by TU Wien
(TUW). We acknowledge the Austrian Science Foundation (FWF,
Project P21202-N17) for financial support of this work.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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