Gold Catalyzed Photoredox C1-Alkynylation of N-Alkyl-1,2,3,4- tetrahydroisoquinolines by 1-Bromoalkynes with UVA LED Light

Article abstract of DOI:10.1002/adsc.201801289

A synthetic method that combines [Au₂(m-dppm)₂]Cl₂ (dppm=bis(diphenylphosphanyl)methane) and UVA LED (LED=light emitting diode) light (365 nm) to catalyze the regioselective C1-alkynylation of N-alkyl-1,2,3,4-tetrahydroisoquinolines (THIQs) with alkynyl bromides is described. The reaction mechanism was delineated to involve a reductive quench pathway to generate the two posited radical species of the nitrogen-containing heterocycle and organic halide. In contrast, radical formation via an oxidative quench pathway was suggested to be operative in analogous control experiments with a 1-iodoalkyne. The usefulness of this carbon-carbon bond forming strategy was also exemplified by its application to the formal synthesis of the opioid analgesic drug methopholine and synthesis of a protoberberine alkaloid derivative.

Full text of DOI:10.1002/adsc.201801289

Title: Gold Catalyzed Photoredox C1-Alkynylation of N-Alkyl-1,2,3,4-
tetrahydroisoquinolines by 1-Bromoalkynes with Blue LED Light
Authors: Philip Chan, Yichao Zhao, and Jianwen Jin
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801289
Link to VoR: http://dx.doi.org/10.1002/adsc.201801289

10.1002/adsc.201801289
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gold Catalyzed Photoredox C1-Alkynylation of N-Alkyl-1,2,3,4-
tetrahydroisoquinolines by 1-Bromoalkynes with Blue LED
Light
Yichao Zhao,[a] Jianwen Jin,[a] and Philip Wai Hong Chan[a,b]*
a
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
Fax: (+61)–3–9905–4597; e–mail: phil.chan@monash.edu or p.w.h.chan@warwick.ac.uk
Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A synthetic method that combines [Au2(μ-dppm)2]Cl2 (dppm = bis(diphenylphosphanyl)methane) and blue LED
(LED = light emitting diode) light (365 nm) to catalyze the regioselective C1-alkynylation of N-alkyl-1,2,3,4-
tetrahydroisoquinolines (THIQs) with alkynyl bromides is described. The reaction mechanism was delineated to involve a
reductive quench pathway to generate the two posited radical species of the nitrogen-containing heterocycle and organic
halide. In contrast, radical formation via an oxidative quench pathway was suggested to be operative in analogous control
experiments with a 1-iodoalkyne. The usefulness of this carbon-carbon bond forming strategy was also exemplified by its
application to the formal synthesis of the opioid analgesic drug methopholine and synthesis of a protoberberine alkaloid
derivative.
Keywords: alkynylation; gold; homogeneous catalysis; photoredox catalysis; synthetic methods
Introduction
THIQs are a key structural motif found in a wide
variety of bioactive natural products and compounds
of current agrochemical, materials and medicinal
interest.[1–6] The nitrogen-containing heterocycle is
also a versatile building block in organic synthesis
and drug discovery programs. As a consequence, this
has led to a myriad of elegant methods for the
synthesis or functionalization of the N-heterocycle
being developed. An illustrative example of this is the
transition metal-catalyzed C1-alkynylation of THIQs
with terminal alkynes in the presence of an oxidant at
elevated temperatures or photoredox conditions
(Scheme 1a).[3,6] Despite these advances, there
Scheme 1. Transition Metal-Catalyzed C1-Alkynylation of
THIQs by Alkyne Derivatives
remains a continued need to realize new and efficient
catalytic methods for the synthesis and
functionalization of the N-heterocycle from readily
accessible substrates under mild and practical
conditions.
range of organic halides with alkane, alkene and
alkyne substrates.[10,13] The intra- or intermolecular
coupling of the radical species generated in this
manner were subsequently shown to produce a variety
of synthetically valuable targets. To our knowledge,
the analogous Au2(I,I)-catalyzed photoredox reactions
involving radical species III and IV generated from
the respective N-heterocycle and alkynyl halide to
effect C(sp3)–C(sp) bond formation has so far
remained unrealized.[11,14,15] In this regard, we were
A recent notable discovery in homogenous gold
catalysis has been the photoredox cyclization of
alkenyl- and alkynyl-containing alkyl and aryl
bromides with [Au2(μ-dppm)2]Cl2 in the role of the
photosensitizer under blue LED light or sunlight
conditions.[7–12] Following this pioneering work, the
versatility of the readily available and bench-stable
dimeric Au2(I,I) complex was further demonstrated in
a number of studies examining the reactivity of a
1
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10.1002/adsc.201801289
Advanced Synthesis & Catalysis
Table 1. Optimization of the Reaction Conditions.[a]
drawn to the potential radical reaction chemistry of
THIQs 1 with alkynyl bromides 2 (Scheme 1b). In
doing so, we discovered that the two ensuing posited
radical species were likely to be formed through a
reductive quench pathway. Subsequent coupling of
these two in situ formed radical species was then
found to afford the C1-alkynylated THIQ ring system
3. Herein, we report the details of this Au2(I,I)-
X–
t
Yield
catalyzed photoredox chemistry that offers
a
Entry
Solvent
Base
(mol %)
[h] [%][b]
convenient synthetic method for the regioselective
C1-alkynylation of the N-heterocycle in moderate to
excellent product yields. Achieved under blue LED
light and redox neutral conditions at room
temperature, the introduced acetylenic motif provides
a useful handle for further functionalization at a
position that is often occupied by a substituent in a
wide spectrum of THIQ-containing bioactive
compounds. This is demonstrated by its application to
the formal synthesis of the opioid analgesic drug
methopholine and synthesis of a derivative of the
alkaloid protoberberine.[4,5] The proposed radical
formation step is also shown to differ from that
delineated in a previous study and this work exploring
the dimeric Au(I)-mediated reactions of 1-
iodoalkynes, which were found to occur via an
oxidative quench pathway.[10j]
Cl– (1)
Cl– (1)
MeCN
Et3N
16
16
16
16
22
22
22
22
22
42
44
44
44
44
0
1
2
MeCN NaHCO3
0
Cl– (2.5)
Cl– (2.5)
Cl– (2.5)
Cl– (2.5)
Cl– (2.5)
Cl– (2.5)
Cl– (2.5)
Cl– (5)
NTf2– (5) MeCN
OTf2– (5) MeCN
BF4– (5)
SbF6– (5) MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
Na2CO3
K2CO3
47
3
38
4
Na2CO3
NaOAc
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
57
5
62
6
7[d]
8[d]
9[d]
10[e]
11[e]
12[e]
13[e]
14[e]
41
46
DMF
51
MeCN
82[c]
65[c]
62[c]
77[c]
42[c]
MeCN
Results and Discussion
[a] All reactions were performed with 0.2 mmol of 1a, 0.6
mmol of 2a, given catalyst and base (2 equiv) in solvent
(0.5 mL) at room temperature and time stated in the Table.
Our studies began by examining the dimeric gold(I)-
catalyzed
reaction
of
THIQ
1a
by
1
[b] H NMR product yield with CH2Br2 as the internal
(bromoethynyl)benzene 2a with blue LED light at
room temperature to establish the optimum reaction
conditions (Table 1). Initial experiments revealed
treating the N-heterocycle and 3 equiv of the alkynyl
halide with 1 mol % of [Au2(μ-dppm)2]Cl2 and Et3N
or NaHCO3 (2 equiv) in acetonitrile for 16 h led to no
reaction (entries 1 and 2). On the other hand, we were
pleased to find that increasing the loading of the
photosensitizer to 2.5 mol % with Na2CO3 or K2CO3
as the base afforded 3aa in respective yields of 47 and
38% (entries 3 and 4). Slightly higher product yields
of 57 and 62%, respectively, were obtained when the
reaction was allowed to run for 22 h with Na2CO3 or
NaOAc as the base (entries 5 and 6). However,
repeating the reaction with Na2CO3 as the base and
(+)-sodium L-ascorbate (VC-Na, 0.5 equiv) as an
additive in acetonitrile, ethanol or DMF for 22 h were
found to give no improvement in product yields with
3aa being furnished in 41–51% yield (entries 7–9).
Our studies subsequently showed that performing the
reaction of 1a with Na2CO3 in acetonitrile at a catalyst
loading of 5 mol % and 0.25 equiv of the alkynyl
halide for 42 h gave the best result, providing a
product yield of 82% (entry 10). In a final set of
control experiments under these latter conditions, a
standard. [c] Isolated product yield. [d] (+)-Sodium L-
ascorbate (0.5 equiv) was added as an additive. [e]
Reaction was performed with 0.8 mmol of 1a and 0.2
mmol of 2a.
To define the generality of the present photoredox
C1-alkynylation procedure, we next turned our
attention to the C1-alkynylations of a series of THIQs
and acetylenic bromides, and the results are
summarized in Table 2. Overall, the dimeric Au(I)-
catalyzed photoredox reaction conditions were found
to be broad and provided a variety of C1-alkynylated
THIQs 3ab–ma in 19–83% yield from the
corresponding N-heterocycles 1a–m and alkynyl
bromides 2a–l. Reactions of 1a with ethynyl
bromides containing other aryl (2b–g), heteroaryl
(2h,i) or cycloalkyl (2j,k) groups were found to
proceed to give the corresponding C1-alkynylated
THIQs 3ab–ak in 19–83% yield. The C1-
alkynylation of N-heterocycles with a pendant N-
benzyl motif with substituents at various positions of
the phenyl ring (1b–f) or at the benzylic carbon center
(1f) by 2a were also found to be well tolerated,
providing the expected adducts 3ba–fa in 55–89%
yield. Likewise, THIQ substrates in which the N-
benzyl group was replaced with other N-alkyl
moieties, as in 1g–k, were found to have little
influence on the course of the reaction. In these
–
survey of the dimeric Au(I) complex containing NTf2 ,
–
–
OTf–, BF4 , or SbF6 instead of Cl– as the
counteranion led to lower product yields of 42–77%
(entries 11–14).
2
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10.1002/adsc.201801289
Advanced Synthesis & Catalysis
Table 2. C1-Alkynylation of THIQs 1a–n with 2a–l
Catalyzed by [Au2(μ-dppm)2]Cl2 Under Blue LED Light.[a]
with 2a was found to lead to the recovery of the
starting materials. In the above experiments, on the
other hand, no other products arising from the
dehalogenation or alkynylation at the N-alkyl carbon
center of the respective alkynyl halide and N-
1
heterocycle were detected by H NMR measurement
of the crude reaction mixtures.
To further illustrate the synthetic utility of the
present Au2(I,I)-catalyzed photoredox route to C1-
alkynylated THIQs, we applied the new method to the
synthesis of a derivative of the protoberberine
alkaloids.[5] As shown in Scheme 2, treating 3ea to 10
% mol of Pd(Ph3P)4 in DMF and water (1:1 v/v) at
100 °C for 2 h was found to give the nitrogen-
containing tetracyclic adduct 4 in 87% yield.
Scheme 2. Synthesis of the Protoberberine Derivative 4
from 3ea
We next turned our attention to performing a series
of control experiments with the aim of gaining an
insight of the reaction mechanism (Scheme 3). The
initial premise put forward in Scheme 1b reasoned
that C(sp3)–C(sp) bond formation between the N-
heterocycle and alkynyl bromide might occur on
generating the two respective radical species. Our
results for reactions with an electron-withdrawing
group on either substrate, as in 1n and 2e, giving
either no reaction or a low product yield would argue
in favor of the involvement of such radical
intermediates. As shown in Scheme 3a, this argument
was further corroborated by subjecting 1a and 2a to
the Au2(I,I)-catalyzed standard photoredox reaction
[a] All reactions were performed at the 0.2 mmol scale with
5 mol % of [Au2(μ-dppm)2]Cl2 and Na2CO3 (2 equiv) in
acetonitrile (0.5 mL) at room temperature under blue LED
light for 42 h. Values in parenthesis denoted isolated
product yields. [b] Separable mixture of diastereomers in a
ratio of 1.4:1. [c] Inseparable mixture of diastereomers in a
ratio of 1:1.
conditions
and
2
equiv
of
2,2,6,6-
tetramethylpiperdine 1-oxyl (TEMPO). On the basis
1
of H NMR measurements of the crude reaction
mixture, no product formation could be observed and
only the two substrates were found to be present.
Added to this, the role of the dimeric Au(I) complex
and blue LED light in facilitating the radical forming
step could be shown by repeating the control
experiment either in the absence of the light source or
experiments with 2a, the corresponding C1-
alkynylated THIQs 3ga–ka were afforded in 42–68%
yield. The reactions of THIQs containing an electron-
donating (1l,m) or -withdrawing (1n) substituent on
the benzofused ring of the substrate were the only [Au2(μ-dppm)2]Cl2 (Schemes 3b and c). In both
instances, no reaction could be detected by either
instances that were found to give contrasting
outcomes. Reactions of 1l with 2a and 1m with 2l
gave the anticipated C1-alkynylated products 3la and
3ml in 81 and 47% yield, respectively. The assembly
of 3ml is also noteworthy as it is a reported
intermediate in the synthesis of the opioid analgesic
drug methopholine.[4] Its preparation by the present
method thus represents a formal synthesis of the
bioactive compound. However, the reaction of 1n
1
TLC analysis or H NMR measurements. A pathway
involving an iminium salt was next considered but
discounted based on the findings of the following
control experiment. Treatment of the iminium salt 5
with 3 equiv of 2a under the Au2(I,I)-catalyzed
photoredox reaction conditions described in Scheme
3d was observed to result in only the two starting
materials being detected based on 1H NMR
measurements.
3
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10.1002/adsc.201801289
Advanced Synthesis & Catalysis
On the basis of the above results, a tentative
mechanism for the present dimeric Au(I)-catalyzed
photoredox C1-alkynylation of THIQs with alkynyl
bromides under blue LED light is outlined in Scheme
4.[8–10,16] With the reaction of substrates 1a and 2a as a
representative example, this could initially involve the
exciplex species V of the dinuclear gold(I) complex
being generated as it absorbs the blue LED light.[12]
With the metal complex now in the photoexcited
state, this might lead to a single-electron transfer
(SET) from the N-heterocycle to the photosensitizer.
As a result, this delivers the nitrogen-centered THIQ
radical cation species VIa and [AuI–Au0]+ complex
VIIa. With the dimeric metal complex now a
powerful reducing agent, a second SET event might
subsequently occur between it and the alkynyl
bromide. This would give the corresponding alkynyl
radical species IVa as well as lead to the ground state
Au2(I,I) complex being regenerated. Deprotonation of
VIa followed by radical C(sp3)–C(sp) coupling of the
ensuing carbon-centered THIQ radical species IIIa
with IVa would then provide the C1-alkynylated
product 3aa. The origin of the observed product
regioselectivity could be due to the preferential
formation of IIIa over that of VIIIa, the most stable
among other possible cyclic intermediates, which
would lead to products of the type 7aa.
Scheme 3. Control Experiments with 1a, 2a and 5.
As the Au2(I,I)-catalyzed photoredox reactions with
blue LED light or sunlight have been proposed to
proceed via either an oxidative or reductive quench
pathway, a final set of control experiments described
in Table 3 were also examined.[8–10] Under the
standard photoredox reaction conditions with [Au2(μ-
dppm)2]Cl2, the reaction of equimolar amounts 1a
with 2a or four equivalents of the latter were found to
give 3aa along with recovery of the alkynyl bromide
in yields of 31–39% (entries 1 and 2). In contrast to
our earlier findings disclosed in Table 1, entry 10
showing that 3aa could be obtained in 82% when the
molar ratio of 1a:2a = 4:1, this led us to believe that
the present reaction might occur by a reductive
quench pathway. Previously, the alkynylation of
acyclic amines by 1-iodoalkynes was likely to
proceed by an oxidative quench pathway.[10j] This was
further supported by results furnished on repeating
these
reactions
once
more
but
with
(iodoethynyl)benzene 2m in place of 2a (entries 3–5).
In these analogous control experiments, the use of
equimolar amounts 1a and 2m or four equivalents of
either the former or latter were found to afford 3aa
and 6a in respective yields of 11–31 and 11–77%.
Table 3. Control Experiments with 1a, 2a and 2m.[a]
Yield [%][b]
Entry
1a + 2 (equiv)
2a
31
39
-
2m 3aa
6a
-
1a (1) + 2a (1)
1a (1) + 2a (4)
1a (1) + 2m (1)
1a (4) + 2m (1)
1a (1) + 2m (4)
-
-
-
-
-
32
39
11
31
20
1
2
3
4
5
-
16
11
77
-
-
Scheme 4. Proposed Mechanism for the Au2(I,I)-Catalyzed
C1-Alkynylation of THIQs with Alkynyl Bromides Under
Blue LED Light Represented by 1a and 2a via a Reductive
Quench Pathway.
[a] All reactions were performed at the 0.2 mmol scale with
1a and 2a in the ratios stated in the Table, 5 mol % of
[Au2(μ-dppm)2]Cl2 and Na2CO3 (2 equiv) in acetonitrile
(0.5 mL) at room temperature under blue LED light for 42
h. [b] Isolated product yields.
4
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10.1002/adsc.201801289
Advanced Synthesis & Catalysis
bromide and iodide. In reactions with the organic
bromide, the two posited radical species were
suggested to be most likely formed in situ by a
reductive quench pathway. This contrasts to their in
situ generation in the analogous reactions with a 1-
iodoalkyne, which was thought to result from an
oxidative quench pathway.
At this juncture, it is worthy to note that our
findings do not, however, definitively rule out the
possibility of a reaction mechanism in which a
background oxidative quench pathway is also
operative (Scheme 5). There remains the likelihood
that irradiation of the Au2(I,I) complex by blue LED
light might lead to the competitive transfer of an
electron from the resulting photoexcited metal
complex V to the alkynyl bromide. As a consequence,
this triggers fragmentation of the latter to give the
corresponding alkynyl radical species IVa. The [AuI–
AuII]3+ complex IXa also formed during this process
may be reduced by 1a through a SET event. This
would regenerate the ground state Au2(I,I) complex
and produce the nitrogen-centered THIQ radical
cation species VIa. Subsequent deprotonation of this
newly formed species followed by radical C(sp3)–
C(sp) coupling of the ensuing carbon-centered THIQ
radical species IIIa with IVa would then furnish the
C1-alkynylated N-heterocyclic product.
Experimental Section
General Procedure for the Dimeric Gold(I)-Catalyzed
Photoredox C1-Alkynylation of THIQs 1 by Alkynyl
Bromides 2 with Blue LED Light
A 10 mL screw cap reaction tube was charged with THIQ 1
(0.8 mmol), 1-bromoalkyne 2 (0.2 mmol), Na2CO3 (42 mg,
0.4 mmol) and Au2(μ-dppm)2Cl2 (8.5 mg, 0.01 mmol)
followed by the addition of degassed MeCN (0.5 mL). The
reaction was stirred at room temperature under irradiation
of a blue LED light source contained in a glovebox. Upon
completion, the solvent was removed under reduced
pressure and the resulting crude mixture was purified by
flash column chromatography on silica gel (eluent:
petroleum ether:Et2O = 25:1) to afford the C1-alkynylated
product.
2-Benzyl-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3aa)[4b] Pale yellow oil (53 mg,
1
82% yield); H NMR (400 MHz, CDCl3) δ 7.38 (tdd, J =
6.0, 3.2, 1.7 Hz, 4H), 7.29–7.23 (m, 2H), 7.23–7.16 (m,
5H), 7.11–7.01 (m, 3H), 4.71 (s, 1H), 3.91–3.80 (m, 2H),
3.05–2.89 (m, 2H), 2.78–2.66 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 138.4, 135.5, 134.1, 131.8, 129.3, 129.0,
128.3, 128.2, 128.0, 127.8, 127.2, 126.9, 125.8, 123.3, 87.6,
86.8, 59.6, 54.4, 45.8, 29.1.
2-Benzyl-1-(p-tolylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ab) Yellow oil (48 mg, 72%
yield); IR (neat, cm-1): 3061, 3027, 2918, 2824, 1654, 1603,
1508, 1452, 1028, 970, 816, 741, 699; 1H NMR (400 MHz,
CDCl3) δ 7.52–7.48 (m, 2H), 7.40–7.34 (m, 4H), 7.33–7.27
(m, 2H), 7.21–7.10 (m, 5H), 4.81 (s, 1H), 4.01–3.90 (m,
2H), 3.16–2.99 (m, 2H), 2.88–2.78 (m, 2H), 2.36 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 138.5, 138.1, 135.7, 134.1,
131.7, 129.3, 129.0, 129.0, 128.3, 127.9, 127.2, 126.9,
125.8, 120.2, 86.9, 86.8, 59.6, 54.4, 45.8, 29.1, 21.5;
HRMS (ESI) calcd. for C25H24N (M+ + H): 338.1908,
Scheme 5. Proposed Background Oxidative Quench found: 338.1905.
Pathway for the Au2(I,I)-Catalyzed C1-Alkynylation of
THIQs with Alkynyl Bromides Under Blue LED Light
Represented by 1a and 2a.
1-([1,1'-Biphenyl]-4-ylethynyl)-2-benzyl-1,2,3,4-
tetrahydroisoquinoline (3ac) Pale yellow oil (64 mg, 80%
yield); IR (neat, cm-1): 3059, 3027, 2915, 2821, 1654, 1601,
1485, 1451, 1287, 1265, 1126, 1007, 839, 738, 695; H
1
NMR (400 MHz, CDCl3) δ 7.64–7.44 (m, 11H), 7.42–7.29
(m, 5H), 7.24–7.15 (m, 4H), 4.86 (s, 1H), 4.05–3.93 (m,
2H), 3.19–3.01 (m, 2H), 2.95–2.80 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 140.8, 140.4, 138.5, 135.5, 134.1, 132.3,
129.3, 129.1, 128.9, 128.4, 127.9, 127.6, 127.2, 127.1,
127.0, 127.0, 125.9, 122.2, 88.3, 86.7, 59.7, 54.5, 45.8,
29.1; HRMS (ESI) calcd. for C30H26N (M+ + H): 400.2065,
found: 400.2053.
Conclusions
In summary, we have developed an efficient synthetic
method for the regioselective C1-alkynylation of
THIQs that makes use of readily available alkynyl
bromides under dimeric gold(I)-mediated redox
neutral reaction conditions with blue LED light. The
2-Benzyl-1-((4-bromophenyl)ethynyl)-1,2,3,4-
photoredox C(sp3)–C(sp) bond formation reaction tetrahydroisoquinoline (3ad) Pale yellow oil (53 mg, 66%
yield); IR (neat, cm-1): 3061, 3026, 2915, 2821, 1701, 1654,
was shown to be applicable to a wide variety of
substrates to provide access to a privileged scaffold
1
1584, 1484, 1452, 1259, 1069, 1010, 822, 735, 698; H
NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 4H), 7.28–7.22
containing a functional group handle for further
chemical manipulation. This was exemplified by the
formal synthesis of the opioid analgesic drug
methopholine and synthesis of a protoberberine
alkaloid derivative. Our studies also showed the
marked differences in reactivity between an alkynyl
(m, 2H), 7.21–7.17 (m, 2H), 7.17–7.02 (m, 5H), 4.69 (s,
1H), 3.86–3.77 (m, 2H), 3.01–2.88 (m, 2H), 2.77–2.66 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 138.3, 135.2, 134.1,
133.3, 131.5, 129.2, 129.1, 128.4, 128.4, 127.8, 127.3,
127.1, 125.9, 122.3, 122.2, 88.9, 85.8, 59.7, 54.4, 45.8,
29.1; HRMS (ESI) calcd. for C24H21BrN (M+ + H):
402.0857/404.0837, found: 402.0847/404.0837.
5
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10.1002/adsc.201801289
Advanced Synthesis & Catalysis
2-Benzyl-1-((4-(trifluoromethyl)phenyl)ethynyl)-1,2,3,4-
= 13.1 Hz, 1H), 3.73 (d, J = 13.1 Hz, 1H), 2.96–2.83 (m,
tetrahydroisoquinoline (3ae) Yellow oil (15 mg, 19% 2H), 2.74–2.59 (m, 2H), 2.36 (ddd, J = 9.0, 4.5, 1.9 Hz,
yield); IR (neat, cm-1): 3063, 3028, 2920, 2825, 1654, 1614, 1H), 1.74–1.60 (m, 4H), 1.41 (qd, J = 9.2, 4.6 Hz, 3H),
1560, 1495, 1453, 1405, 1321, 1165, 1123, 1066, 1016, 1.25 (ddd, J = 11.4, 7.1, 4.2 Hz, 3H); 13C NMR (100 MHz,
1
841, 744, 730; H NMR (400 MHz, CDCl3) δ 7.47 (s, 4H), CDCl3) δ 138.6, 136.4, 133.9, 129.3, 128.8, 128.2, 127.7,
7.40–7.35 (m, 2H), 7.29–7.20 (m, 3H), 7.16–7.05 (m, 4H), 127.0, 126.6, 125.6, 91.3, 59.5, 54.0, 45.7, 33.1, 32.9, 29.2,
4.73 (s, 1H), 3.91–3.79 (m, 2H), 3.06–2.91 (m, 2H), 2.84– 29.1, 26.0, 24.8.
2.68 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 138.2, 135.0,
134.1, 132.0, 129.7, 129.2 (d, JC-C = 8.0 Hz), 128.4, 127.7,
2-(2-Methylbenzyl)-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ba)[17] Pale yellow oil (51 mg,
127.3, 127.1, 127.0, 125.9, 125.2 (q, JC-F = 3.8 Hz), 122.6,
90.3, 85.6, 77.2, 59.6, 54.3, 45.8, 29.0; HRMS (ESI) calcd.
for C25H21F3N (M+ + H): 392.1626, found: 392.1615.
1
75% yield); H NMR (400 MHz, CDCl3) δ 7.39–7.32 (m,
3H), 7.21–7.14 (m, 4H), 7.12–7.04 (m, 5H), 7.04–7.00 (m,
1H), 4.68 (s, 1H), 3.89–3.75 (m, 2H), 3.05–2.86 (m, 2H),
2.76–2.63 (m, 2H), 2.33 (s, 3H); 13C NMR (100 MHz,
2-Benzyl-1-((2-chlorophenyl)ethynyl)-1,2,3,4-
tetrahydroisoquinoline (3af) Pale yellow oil (49 mg, 57% CDCl3) δ 138.0, 136.4, 135.7, 134.3, 131.8, 130.4, 130.0,
yield); IR (neat, cm-1): 3060, 3025, 2916, 2852, 1735, 1618, 129.0, 128.3, 128.1, 127.9, 127.2, 126.9, 125.8, 125.6,
1
1493, 1472, 1285, 1235, 1127, 1029, 737, 697; H NMR 123.4, 87.9, 86.8, 57.6, 54.5, 45.8, 29.3, 19.4.
(400 MHz, CDCl3) δ 7.42–7.38 (m, 2H), 7.38–7.34 (m, 1H),
7.32–7.28 (m, 1H), 7.28–7.23 (m, 2H), 7.22–7.16 (m, 2H),
2-(4-Methylbenzyl)-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ca)[17] Yellow oil (37 mg, 55%
yield); 1H NMR (400 MHz, CDCl3) δ 7.50–7.46 (m, 2H),
7.41–7.37 (m, 2H), 7.35–7.27 (m, 4H), 7.21–7.13 (m, 5H),
4.82 (s, 1H), 3.98–3.88 (m, 2H), 3.15–3.00 (m, 2H), 2.90–
2.77 (m, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
136.8, 135.6, 135.3, 134.1, 131.8, 129.3, 129.0, 128.2,
128.0, 127.8, 126.9, 125.8, 123.3, 87.6, 86.8, 59.4, 54.3,
45.8, 29.1, 21.2.
7.14–7.02 (m, 5H), 4.75 (s, 1H), 3.90 (s, 2H), 3.10–2.90 (m,
2H), 2.80–2.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
138.4, 135.9, 135.2, 134.2, 133.5, 129.4, 129.2, 129.1,
129.0, 128.3, 127.8, 127.2, 127.0, 126.3, 125.8, 123.2, 93.2,
83.7, 59.6, 54.5, 45.9, 29.1; HRMS (ESI) calcd. for
C24H21ClN (M+ + H): 358.1362, found: 358.1352.
2-Benzyl-1-((3-chlorophenyl)ethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ag)[17] Yellow oil (38 mg, 54%
yield); 1H NMR (400 MHz, CDCl3) δ 7.36 (ddt, J = 8.3, 6.1,
1.7 Hz, 3H), 7.29–7.20 (m, 3H), 7.20–7.02 (m, 7H), 4.70 (s,
1H), 3.88–3.78 (m, 2H), 3.01–2.89 (m, 2H), 2.80–2.65 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 138.3, 135.2, 134.1,
134.1, 131.7, 129.9, 129.5, 129.2, 129.1, 128.4, 128.4,
127.8, 127.3, 127.1, 125.9, 125.0, 89.0, 85.6, 59.7, 54.3,
45.8, 29.1.
2-(3,4-Dimethoxybenzyl)-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3da) Yellow oil (61 mg, 79%
yield); IR (neat, cm-1): 1H NMR (400 MHz, CDCl3) δ 7.38–
7.33 (m, 2H), 7.23–7.16 (m, 4H), 7.11–7.01 (m, 3H), 6.95
(d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.2, 2.0 Hz, 1H), 6.74 (d,
J = 8.1 Hz, 1H), 4.71 (s, 1H), 3.85 (d, J = 6.0 Hz, 1H),
3.84–3.72 (m, 8H), 3.00–2.88 (m, 2H), 2.77–2.66 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 149.0, 148.2, 135.5, 134.1,
131.8, 130.9, 129.0, 128.3, 128.1, 127.8, 127.0, 125.9,
2-Benzyl-1-(thiophen-3-ylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ah) Pale yellow oil (55 mg, 83% 123.3, 121.4, 112.3, 110.9, 87.6, 86.9, 59.4, 55.9, 55.9,
yield); IR (neat, cm-1): 3061, 3025, 2916, 2824, 1709, 1605, 54.4, 45.6, 29.1; HRMS (ESI) calcd. for C22H20NS (M+ +
1
1494, 1452, 1355, 1125, 989, 817, 781, 740, 697; H NMR H): 330.1316, found: 330.1302.
(400 MHz, CDCl3) δ 7.40–7.35 (m, 2H), 7.33 (dd, J = 3.0,
1.2 Hz, 1H), 7.26 (ddt, J = 7.9, 6.4, 1.0 Hz, 2H), 7.22–7.14
2-(2-Bromo-4,5-dimethoxybenzyl)-1-(phenylethynyl)-
(m, 3H), 7.11–7.01 (m, 4H), 4.69 (s, 1H), 3.89–3.78 (m,
1,2,3,4-tetrahydroisoquinoline (3ea) Pale yellow oil (82
2H), 3.03–2.89 (m, 2H), 2.77–2.67 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 138.4, 135.5, 134.1, 130.2, 129.3, 129.0,
128.5, 128.3, 127.8, 127.2, 127.0, 125.9, 125.1, 122.2, 87.1,
81.8, 59.6, 54.5, 45.8, 29.1; HRMS (ESI) calcd. for
C22H20NS (M+ + H): 330.1316, found: 330.1302.
mg, 89% yield); IR (neat, cm-1): 3001, 2931, 2834, 1598,
1502, 1437, 1378, 1252, 1208, 1155, 1027, 959, 800, 736,
1
691. H NMR (400 MHz, CDCl3) δ 7.51–7.43 (m, 2H),
7.38–7.27 (m, 4H), 7.23–7.14 (m, 4H), 7.05 (s, 1H), 4.90 (s,
1H), 4.07–3.95 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.22–
2.92 (m, 2H), 2.87–2.74 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 148.6, 148.5, 135.5, 134.1, 131.8, 129.8, 129.0,
2-Benzyl-1-(pyridin-3-ylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ai) Pale yellow oil (35 mg, 54% 128.2, 128.1, 127.8, 127.0, 125.9, 123.2, 115.5, 114.6,
yield); IR (neat, cm-1): 3026, 2915, 2823, 1726, 1605, 1493, 113.2, 87.8, 86.7, 77.3, 58.5, 56.2, 56.1, 54.9, 45.5, 29.2;
1474, 1452, 1406, 1286, 1186, 1125, 1093, 1023, 803, 737, HRMS (ESI) calcd. for C26H25BrNO2 (M+ + H): 462.1068,
1
699; H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 2.2, 0.9 found: 462.1054.
Hz, 1H), 8.42 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (dt, J = 7.9,
1.9 Hz, 1H), 7.40–7.35 (m, 2H), 7.29–7.23 (m, 2H), 7.23–
2-(1-Phenylethyl)-1-(phenylethynyl)-1,2,3,4-
7.04 (m, 7H), 4.73 (s, 1H), 3.89–3.78 (m, 2H), 3.02–2.90
tetrahydroisoquinoline (3fa) diastereomer 1: Pale yellow
(m, 2H), 2.83–2.67 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 152.5, 148.5, 138.7, 138.2, 135.0, 134.2, 129.2, 129.1,
128.4, 127.7, 127.3, 127.1, 125.9, 122.9, 120.4, 91.2, 83.6,
59.7, 54.3, 45.8, 29.0; HRMS (ESI) calcd. for C23H21N2
(M+ + H): 325.1705, found: 325.1687.
oil (23 mg, 34% yield); IR (neat, cm-1): 3060, 3024, 2970,
2920, 2819, 1598, 1489, 1451, 1369, 1285, 1136, 1028,
1
939, 755, 736, 700; H NMR (400 MHz, CDCl3) δ 7.39–
7.33 (m, 4H), 7.29–7.17 (m, 7H), 7.14–7.08 (m, 2H), 7.07–
7.01 (m, 1H), 5.19 (s, 1H), 3.76 (q, J = 6.5 Hz, 1H), 2.89–
2.70 (m, 2H), 2.70–2.61 (m, 1H), 2.57–2.49 (m, 1H), 1.44
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.1,
2-Benzyl-1-(cyclopropylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3aj)[18] Pale yellow oil (22 mg, 135.8, 134.6, 131.9, 129.1, 128.5, 128.2, 128.1, 128.0,
1
38% yield); H NMR (400 MHz, CDCl3) δ 7.40–7.30 (m, 127.4, 126.9, 126.9, 125.9, 123.3, 87.4, 86.4, 62.0, 52.1,
2H), 7.30–7.14 (m, 3H), 7.13–6.99 (m, 4H), 4.43 (d, J = 43.8, 29.2, 21.8; HRMS (ESI) calcd. for C25H24N (M+ +
1.5 Hz, 1H), 3.83–3.65 (m, 2H), 2.94–2.80 (m, 2H), 2.72– H): 338.1908, found: 338.1905. diastereomer 2: Pale
2.61 (m, 2H), 1.25–1.16 (m, 1H), 0.73–0.53 (m, 4H); 13C yellow oil (16 mg, 24% yield); IR (neat, cm-1): 3061, 3026,
NMR (100 MHz, CDCl3) δ 138.8, 136.5, 134.2, 129.6, 2921, 2825, 1560, 1490, 1370, 1263, 1027, 756, 738, 701;
129.2, 128.6, 128.0, 127.4, 127.0, 126.0, 90.6, 73.4, 59.7, 1H NMR (400 MHz, CDCl3) δ 7.49–7.42 (m, 4H), 7.38–
54.4, 45.9, 29.3, 8.8.
7.28 (m, 5H), 7.18–7.08 (m, 5H), 4.60 (d, J = 1.1 Hz, 1H),
4.09 (q, J = 6.6 Hz, 1H), 3.24–3.02 (m, 3H), 2.94–2.85 (m,
1H), 1.51 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 144.1, 135.9, 134.2, 131.7, 128.8, 128.4, 128.2, 127.9,
127.9, 127.8, 127.7, 127.1, 126.8, 125.7, 123.4, 88.3, 86.8,
60.8, 53.5, 41.6, 29.5, 21.6; HRMS (ESI) calcd. for
C25H24N (M+ + H): 338.1908, found: 338.1900.
2-Benzyl-1-(cyclohexylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ak)[18] Pale yellow oil (19 mg,
1
29% yield); H NMR (400 MHz, CDCl3) δ 7.38–7.34 (m,
2H), 7.28–7.22 (m, 2H), 7.22–7.16 (m, 1H), 7.16–7.11 (m,
1H), 7.07–6.97 (m, 3H), 4.47 (d, J = 1.8 Hz, 1H), 3.83 (d, J
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801289
Advanced Synthesis & Catalysis
1-(Phenylethynyl)-2-(thiophen-2-ylmethyl)-1,2,3,4-
1-((4-Chlorophenyl)ethynyl)-6,7-dimethoxy-2-methyl-
tetrahydroisoquinoline (3ga) Pale yellow oil (40 mg, 61% 1,2,3,4-tetrahydroisoquinoline (3ml)[4b] Yellow oil (32
yield); IR (neat, cm-1): 3061, 3022, 2915, 2820, 1654, 1598, mg, 47% yield); 1H NMR (400 MHz, CDCl3) δ 7.29–7.24
1489, 1442, 1342, 1283, 1123, 1088, 1037, 755, 739, 690; (m, 2H), 7.20–7.15 (m, 2H), 6.74 (s, 1H), 6.52 (s, 1H), 4.53
1H NMR (400 MHz, CDCl3) δ 7.37 (ddt, J = 5.3, 2.6, 1.4 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.93 (ddd, J = 11.2, 8.5,
Hz, 2H), 7.24–7.19 (m, 4H), 7.19–7.16 (m, 1H), 7.11–7.07 4.7 Hz, 1H), 2.87–2.78 (m, 1H), 2.72 (dt, J = 15.3, 4.2 Hz,
(m, 2H), 7.05 (dt, J = 6.0, 2.3 Hz, 1H), 6.99 (dt, J = 3.3, 1.0 1H), 2.66–2.58 (m, 1H), 2.52 (s, 3H); 13C NMR (100 MHz,
Hz, 1H), 6.90 (dd, J = 5.1, 3.4 Hz, 1H), 4.81 (s, 1H), 4.06 CDCl3) δ 148.2, 147.4, 134.1, 133.0, 128.5, 126.8, 125.6,
(qd, J = 13.8, 0.9 Hz, 2H), 3.04–2.90 (m, 2H), 2.87–2.69 121.6, 111.3, 110.3, 88.7, 85.1, 56.5, 56.0, 55.9, 48.7, 43.7,
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.0, 135.3, 28.4.
134.0, 131.8, 129.0, 128.2, 128.1, 127.8, 127.0, 126.5,
126.2, 125.9, 125.2, 123.1, 87.3, 86.9, 54.3, 54.1, 45.7,
Procedure for the Preparation of 13-Benzylidene-10,11-
29.1; HRMS (ESI) calcd. for C22H20NS (M+ + H):
dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-
330.1316, found: 330.1302.
a]isoquinoline (4) from 3ea
2-Methyl-1-(phenylethynyl)-1,2,3,4-
To a solution of 3ea (90 mg, 0.19 mmol) in DMF (6 mL)
tetrahydroisoquinoline (3ha)[4b] Yellow oil (21 mg, 42%
and H2O (2 mL) was added HCO2Na (26 mg, 0.39 mmol).
1
yield); H NMR (400 MHz, CDCl3) δ 7.47–7.41 (m, 2H),
The solution was bubbled with a stream of dry nitrogen gas
7.40–7.34 (m, 1H), 7.29 (tt, J = 3.8, 2.4 Hz, 3H), 7.22–7.17
for 15 min before addition of Pd(PPh3)4 (11 mg, 0.01
(m, 2H), 7.16–7.11 (m, 1H), 4.72 (s, 1H), 3.11–3.01 (m,
mmol). The reaction mixture was heated at 100 ºC in an oil
1H), 2.94 (ddt, J = 21.2, 16.4, 5.4 Hz, 2H), 2.78–2.68 (m,
bath and stirred for 2 h under the nitrogen atmosphere. The
1H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.2,
reaction mixture was diluted with CH2Cl2 (10 mL). The
133.5, 131.8, 128.9, 128.2, 128.1, 127.6, 127.0, 125.9,
organic phase was collected and the aqueous phase was
123.2, 87.5, 86.3, 57.0, 48.7, 43.8, 28.9.
extracted with CH2Cl2 (3 x 10 mL). The combined organic
fractions were washed with brine, dried over anhydrous
2-(2-Methylbutyl)-1-(phenylethynyl)-1,2,3,4-
Na2SO4 and concentrated under reduced pressure. The
tetrahydroisoquinoline (3ia) Yellow oil (35 mg, 68% residue was purified by flash column chromatography on
yield); IR (neat, cm-1): 3226, 2921, 1560, 1406, 1247, 1036, silica gel using eluents (eluent: petroleum ether:EtOAc =
1
896; H NMR (400 MHz, CDCl3) δ 7.35–7.27 (m, 2H), 1:1) to provide the title compound (65 mg, 89% yield) as a
7.26–7.14 (m, 4H), 7.12–7.00 (m, 3H), 4.74 (s, 1H), 2.99– yellow solid; m.p. 190–192°C; IR (neat, cm-1): 2918, 2855,
2.84 (m, 2H), 2.78–2.63 (m, 2H), 2.55 (ddd, J = 19.1, 12.4, 1604, 1510, 1464, 1352, 1259, 1239, 1207, 1148, 1112,
6.7 Hz, 1H), 2.45–2.31 (m, 1H), 1.68–1.57 (m, 1H), 1.45 1022, 830, 744, 696; 1H NMR (400 MHz, CDCl3) δ 7.29 (d,
(dddd, J = 21.0, 13.0, 7.4, 4.9 Hz, 1H), 1.09 (tt, J = 14.1, J = 7.1 Hz, 2H), 7.24–7.01 (m, 9H), 6.33 (s, 1H), 5.23 (s,
7.3 Hz, 1H), 0.85 (ddt, J = 12.7, 7.4, 3.9 Hz, 6H); 13C NMR 1H), 3.88 (s, 3H), 3.79–3.60 (m, 5H), 3.48–3.37 (m, 1H),
(100 MHz, CDCl3) δ 135.9, 135.9, 134.4, 131.7, 129.0, 3.29–3.10 (m, 2H), 2.69 (dd, J = 17.2, 7.7 Hz, 1H); 13C
128.2, 127.9, 127.8, 127.8, 126.8, 125.7, 123.4, 88.1, 88.0, NMR (100 MHz, CDCl3) δ 149.1, 148.0, 137.0, 134.7,
86.1, 62.0, 61.9, 55.5, 54.9, 46.5, 45.9, 32.4, 32.3, 31.5, 134.3, 133.8, 129.0, 128.5, 128.5, 127.6, 127.2, 127.1,
29.2, 29.2, 28.0, 27.6, 18.0, 11.5, 11.3; HRMS (ESI) calcd. 127.0, 126.4, 125.2, 124.7, 108.8, 107.1, 57.8, 56.0, 55.8,
for C22H26N (M+ + H): 304.2065, found: 304.2065.
49.6, 48.0, 22.7; HRMS (ESI) calcd. for C26H25NO2 (M+ +
H): 384.1964, found: 384.1942.
2-Phenethyl-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3ja) Pale yellow oil (36 mg, 53%
yield); IR (neat, cm-1): 3060, 3025, 2922, 2823, 1702, 1648,
Acknowledgements
1
1600, 1489, 1451, 1262, 1095, 1027, 738, 697; H NMR
(400 MHz, CDCl3) δ 7.34–7.28 (m, 2H), 7.27–7.02 (m,
12H), 4.92 (s, 1H), 2.99–2.71 (m, 8H); 13C NMR (100
MHz, CDCl3) δ 140.4, 135.4, 133.9, 131.8, 129.0, 128.9,
128.4, 128.2, 128.1, 127.9, 127.0, 126.1, 125.9, 123.2, 87.1,
86.6, 57.3, 54.6, 46.1, 34.2, 29.0; HRMS (ESI) calcd. for
C25H24N (M+ + H): 338.1908, found: 338.1895.
This work was supported by
a Discovery Project Grant
(DP160101682) from the Australian Research Council.
References
2-Cyclohexyl-1-(phenylethynyl)-1,2,3,4-
[1] Selected reviews: a) M. Chrzanowska, A. Grajewska, M.
D. Rozwadowska, Chem. Rev. 2016, 116, 12369–
12465; b) D. M. Flanigan, F. Romanov-Michailidis, N.
A. White, T. Rovis, Chem. Rev. 2015, 115, 9307–9387;
c) M. Correia-da-Silva, E. Sousa, M. M. Pinto, Med.
Res. Rev. 2014, 34, 223–279; d) Progress in
Heterocyclic Chemistry, (Eds.: G. Gribble, J. Joule),
Elsevier, 2012; e) J. D. Scott, R. M. Williams, Chem.
Rev. 2002, 102, 1669–1730.
tetrahydroisoquinoline (3ka) Yellow oil (35 mg, 55%
yield); IR (neat, cm-1): 3027, 2926, 1560, 1401, 1248, 1030,
739, 691. 1H NMR (400 MHz, CDCl3) δ 7.34–7.30 (m, 2H),
7.26–7.22 (m, 1H), 7.21–7.17 (m, 3H), 7.10–7.07 (m, 2H),
7.06–7.01 (m, 1H), 5.03 (s, 1H), 3.06–2.97 (m, 1H), 2.96–
2.83 (m, 2H), 2.80–2.72 (m, 1H), 2.65 (qd, J = 6.9, 4.3, 3.0
Hz, 1H), 2.18–2.02 (m, 2H), 1.81–1.70 (m, 2H), 1.63–1.54
(m, 1H), 1.30–1.21 (m, 4H), 1.16–1.09 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 136.0, 134.4, 131.7, 128.9, 128.2,
127.9, 127.8, 126.8, 125.8, 123.4, 59.9, 52.3, 42.1, 31.1,
29.5, 29.5, 26.3, 25.7, 25.5; HRMS (ESI) calcd. for
C23H26N (M+ + H): 316.2065, found: 316.2056.
[2] Selected recent examples: a) L. Zeng, B. Huang, Y.
Shen, S. Cui, Org. Lett. 2018, 20, 3460–3464; b) Y.
Zhao, J. Jin, J. W. Boyle, B. R. Lee, D. P. Day, D.
Susanti, G. J. Clarkson, P. W. H. Chan, J. Org. Chem.
2017, 82, 2826–2834; c) H. Zhou, Y. Liu, S. Yang, L.
Zhou, M. Chang, Angew. Chem. Int. Ed. 2017, 56,
2725–2729; d) J. Zhu, H. Tan, L. Yang, Z. Dai, L. Zhu,
H. Ma, Z. Deng, Z. Tian, X. Qu, ACS Catal. 2017, 7,
7003–7007; e) T. B. Nguyen, L. Ermolenko, A. Al-
Mourabit, Chem. Commun. 2016, 52, 4914–4917.
2-Benzyl-6,7-dimethoxy-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (3la)[17] Blue gum (62 mg, 81%
yield); 1H NMR (400 MHz, CDCl3) δ 7.49 (tdd, J = 6.0, 3.1,
1.6 Hz, 4H), 7.41–7.34 (m, 2H), 7.32 (dq, J = 4.8, 2.8 Hz,
4H), 6.77 (s, 1H), 6.63 (s, 1H), 4.72 (s, 1H), 4.00–3.90 (m,
2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.09 (td, J = 10.5, 4.1 Hz,
1H), 2.99 (ddd, J = 16.0, 10.2, 5.7 Hz, 1H), 2.84 (dddd, J =
11.0, 5.5, 2.8, 1.0 Hz, 1H), 2.79–2.69 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 148.2, 147.4, 138.4, 131.8, 129.3,
128.3, 128.3, 128.1, 127.4, 127.2, 126.1, 123.3, 111.4,
110.5, 87.6, 86.8, 59.6, 56.0, 55.9, 53.9, 46.0, 28.7.
7
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Advanced Synthesis & Catalysis
[3] a) T. Huang, X. Liu, J. Lang, J. Xu, L. Lin, X. Feng,
ACS Catal. 2017, 7, 5654–5660; b) I. Perepichka, S.
Kundu, Z. Hearne, C. J. Li, Org. Biomol. Chem. 2015,
13, 447–451; c) S. Sun, C. Li, P. E. Floreancig, H. Lou,
L. Liu, Org. Lett. 2015, 17, 1684–1687; d) M. Rueping,
R. M. Koenigs, K. Poscharny, D. C. Fabry, D. Leonori,
C. Vila, Chem. Eur. J. 2012, 18, 5170–5174; e) J. W.
Tucker, Y. Zhang, T. F. Jamison, C. R. Stephenson,
Angew. Chem. Int. Ed. 2012, 51, 4144–4147; f) D. B.
Freeman, L. Furst, A. G. Condie, C. R. Stephenson,
Org. Lett. 2012, 14, 94–97; g) Z. Li, C. J. Li, Org. Lett.
2004, 6, 4997–4999.
Almendros, E. Busto, C. Lázaro-Milla, J. Org. Chem.
2017, 82, 2177–2186; c) M. Zidan, T. McCallum, L.
Thai-Savarda, L. Barriault, Org. Chem. Front. 2017, 4,
2092–2096; d) J. Xie, J. Li, V. Weingand, M. Rudolph,
A. S. K. Hashmi, Chem. Eur. J. 2016, 22, 12646–
12650; e) T. McCallum, L. Barriault, Chem. Sci. 2016,
7, 4754–4758; f) H. Tran, T. McCallum, M. Morin, L.
Barriault, Org. Lett. 2016, 18, 4308–4311; g) J. Xie, T.
Zhang, F. Chen, N. Mehrkens, F. Rominger, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016,
55, 2934–2938; h) A. Cannillo, T. R. Schwantje, M.
Bégin, F. Barabé, L. Barriault, Org. Lett. 2016, 18,
2592–2595; i) C. D. McTiernan, M. Morin, T.
McCallum, J. C. Scaiano, L. Barriault, Catal. Sci.
Technol. 2016, 6, 201–207; j) J. Xie, S. Shi, T. Zhang,
N. Mehrkens, M. Rudolph, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2015, 54, 6046–6050; k) S. J. Kaldas, A.
Cannillo, T. McCallum, L. Barriault, Org. Lett. 2015,
17, 2864–2866.
[4] a) K. N. Singh, P. Singh, A. Kaur, P. Singh, Synlett
2012, 760–764; b) K. M. Jones, P. Karier, M.
Klussmann, ChemCatChem 2012, 4, 51–54.
[5] a) S. Zhou, R. Tong, Org. Lett. 2017, 19, 1594–1597; b)
E. V. Da-Cunha, I. M. Fechinei, D. N. Guedes, J. M.
Barbosa-Filho, M. S. Da Silva, Alkaloids Chem. Biol.
2005, 62, 1–75.
[11] The
gold-catalyzed
photoredox
α-C(sp3)–H
alkynylation of tertiary aliphatic amines with 1-
iodoalkynes was reported not to be applicable to the
analogous reactions of a N-phenyl protected THIQ, see
Ref [10j].
[6] Selected reviews on photoredox-mediated reactions: a)
N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116,
10075–10166; b) M. H. Shaw, J. Twilton, D. W.
MacMillan, J. Org. Chem. 2016, 81, 6898–6926; c) J. R.
Chen, X. Q. Hu, L. Q. Lu, W. J. Xiao, Acc. Chem. Res.
2016, 49, 1911–1923; d) E. C. Gentry, R. R. Knowles,
Acc. Chem. Res. 2016, 49, 1546–1556; e) C. K. Prier, D.
A. Rankic, D. W. MacMillan, Chem. Rev. 2013, 113,
5322–5363; f) J. W. Tucker, C. R. Stephenson, J. Org.
Chem. 2012, 77, 1617–1622.
[12] a) D. Li, C.-M. Che, H.-L. Kwong, V. W.-W. Yam, J.
Chem. Soc., Dalton Trans. 1992, 3325–3329; b) C.-M.
Che, H.-L. Kwong, K.-C. Poon, V. W.-W. Yam, J.
Chem. Soc., Dalton Trans. 1990, 3215–3219; c) C.-M.
Che, H.-L. Kwong, V. W.-W. Yam, K.-C. Choc, J.
Chem. Soc., Chem. Commun. 1989, 885–886.
[7] Selected reviews on gold catalysis: a) W. Li, J. Zhang,
Chem. Eur. J. 2017, 23, 467–512; b) A. M. Asiri, A. S.
K. Hashmi, Chem. Soc. Rev. 2016, 45, 4471–4503; c) D.
P. Day, P. W. H. Chan, Adv. Synth. Catal. 2016, 358,
1368–1384; d) R. Dorel, A. M. Echavarren, Chem. Rev.
2015, 115, 9028–9072; e) M. Jia, M. Bandini, ACS
Catal. 2015, 5, 1638–1652; f) B. Alcaide, P. Almendros,
Acc. Chem. Res. 2014, 47, 939–952; g) C. Obradors, A.
M. Echavarran, Acc. Chem. Res. 2014, 47, 902–912; h)
[13] Reactions
involving
selective
light-mediated
reductive dehalogenations, see Refs [9], [10j] and: a) C.
Le, T. Q. Chen, T. Liang, P. Zhang, D. W. MacMillan,
Science 2018, 360, 1010–1014; b) K. Shimomaki, K.
Murata, R. Martin, N. Iwasawa, J. Am. Chem. Soc.
2017, 139, 9467–9470; c) III, J. J. Devery, J. D.
Nguyen, C. Dai, C. R. J. Stephenson, ACS Catal. 2016,
6, 5962–5967.
A. S. K. Hashmi, Acc. Chem. Res. 2014, 47, 864–876; i) [14] Selected examples of -aminoalkyl radicals: a) R.
Gold Catalysis: An Homogeneous Approach; F. D.
Toste, V. Michelet, Eds.; Imperial College Press:
London, 2014; j) C. D. Pina, E. Falletta, M. Rossi,
Chem. Soc. Rev. 2012, 41, 350–369; k) N. Krause, C.
Winter, Chem. Rev. 2011, 111, 1994–2009; l) A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2010, 49, 5232–5241;
m) A. Corma, A. Leyva-Pꢀrez, M. J. Sabater, Chem.
Rev. 2011, 111, 1657–1712; n) A. Fürstner, Chem. Soc.
Rev. 2009, 38, 3208–3221; o) A. S. K. Hashmi, Chem.
Rev. 2007, 107, 3180–3211.
Sakamoto, Y. Tomomi, H. Takada, K. Maruoka, Org.
Lett. 2018, 20, 2080–2083; b) W. J. Zhou, G. M. Cao,
G. Shen, X. Y. Zhu, Y. Y. Gui, J. H. Ye, L. Sun, L. L.
Liao, J. Li, D. G. Yu, Angew. Chem. Int. Ed. 2017, 56,
15683–15687; c) J. Xuan, T. T. Zeng, Z. J. Feng, Q. H.
Deng, J. R. Chen, L. Q. Lu, W. J. Xiao, H. Alper,
Angew. Chem. Int. Ed. 2015, 54, 1625–1628; d) Z. Zuo,
D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D.
W. MacMillan, Science 2014, 345, 437–440; e) P.
Kohls, D. Jadhav, G. Pandey, O. Reiser, Org. Lett. 2012,
14, 672–675; f) Y. Miyake, K. Nakajima, Y.
Nishibayashi, J. Am. Chem. Soc. 2012, 134, 3338–3341.
[8] Selected reviews on [Au2(-dppm)2]Cl2 catalysis: a) J.
Xie, H. Jin, A. S. K. Hashmi, Chem. Soc. Rev. 2017, 46,
5193–5203; b) T. McCallum, S. Rohe, L. Barriault, [15] Rare examples of alkynyl radicals: a) K. Ni, L. G.
Synlett 2017, 28, 289–305.
Meng, K. Wang, L. Wang, Org. Lett. 2018, 20, 2245–
2248; b) P. Boutillier, S. Z. Zard, Chem. Commun. 2001,
1304–1305; c) M. S. Robinson, M. L. Polek, V. M.
Bierbaum, C. H. DuPuy, W. C. Lineberger, J. Am.
Chem. Soc. 1995, 117, 6766–6778; d) G. Martelli, P.
Spagnolo, M. Tiecco, J. Chem. Soc. B 1970, 1413–1418.
[9] G. Revol, T. McCallum, M. Morin, F. Gagosz, L.
Barriault, Angew. Chem. Int. Ed. 2013, 52, 13342–
13345.
[10] a) Z.-S. Wang, T.-D. Tan, C.-M. Wang, D.-Q. Yuan, T.
Zhang, P. Zhu, C. Zhu, J.-M. Zhou, L.-W. Ye, Chem.
Commun. 2017, 53, 6848–6851; b) B. Alcaide, P.
8
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Advanced Synthesis & Catalysis
[16] A. S.‐K. Tsang, A. S. K. Hashmi, P. Comba, M. [17] G. Shao, Y. He, Y. Xu, J. Chen, H. Yu, R. Cao, Eur. J.
Kerscher, B. Chan, M. H. Todd, Chem. Eur. J. 2017, 23,
9313–9318.
Org. Chem. 2015, 4615–4619.
[18] Q. H. Zheng, W. Meng, G. J. Jiang, Z. X. Yu, Org.
Lett. 2013, 15, 5928–5931.
9
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Gold Catalyzed Photoredox C1-Alkynylation of N-
Alkyl-1,2,3,4-tetrahydroisoquinolines by 1-
Bromoalkynes with Blue LED Light
Adv. Synth. Catal. 2018, Volume, Page – Page
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