A Short Approach to N -Aryl-1,2,3,4-tetrahydroisoquinolines from N -(2-Bromobenzyl)anilines via a Reductive Amination/Palladium-Catalyzed Ethoxyvinylation/Reductive N -Alkylation Sequence

Article abstract of DOI:10.1055/s-0040-1706002

N -Aryl-1,2,3,4-tetrahydroisoquinolines are obtained via a convenient and short protocol with a broad range of substituents on both aromatic rings and high functional group tolerance. Starting from readily available ortho -brominated aromatic aldehydes and primary aromatic amines, condensation of these building blocks under reductive conditions gives N -aryl 2-bromobenzylamines. The C-3/C-4-unit of the tetrahydroisoquinoline is introduced using commercially available 2-ethoxyvinyl pinacolboronate under Suzuki conditions. Finally, the obtained crude ortho -ethoxyvinyl benzylamines are cyclized via an intramolecular reductive amination using the combination of triethylsilane/TFA to give the desired N -aryl-1,2,3,4-tetrahydroisoquinolines.

Full text of DOI:10.1055/s-0040-1706002

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–L
paper
A
en
C. Glas et al.
Paper
Synthesis
A Short Approach to N-Aryl-1,2,3,4-tetrahydroisoquinolines from
N-(2-Bromobenzyl)anilines via a Reductive Amination/Palladium-
Catalyzed Ethoxyvinylation/Reductive N-Alkylation Sequence
Carina Glas
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AcOH (cat.), MeOH
then NaCNBH3
Ricky Wirawan
Franz Bracher*
(1)
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(1) reductive amination
(2a) Suzuki coupling
(2b) reductive N-alkylation
H2N-Ar
Department of Pharmacy – Center for Drug Research,
Ludwig-Maximilians University Munich, Butenandtstr.
5-13, 81377 Munich, Germany
Ar
CHO
N
(2b)
Br
R
R
TFA
Franz.Bracher@cup.uni-muenchen.de
13 examples
Et3SiH
DCM
OEt
(2a)
up to 55% overall
yield over 3 steps in 2
working operations
Pd(PPh3)4
Cs2CO3
1,4-dioxane/H2O
eFDrMeapnaaizClrotBFmrrraeencnshzpt.eBoorrnfadPcihnaegrrmA@ucatuchypo.–urnCie-nmtuerenfocrhDenru.dgeResearch, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377 Munich, Germany
(RO)2B
Received: 20.10.2020
Accepted after revision: 30.11.2020
Published online: 07.01.2021
tively.2e Further, N-aryl-1,2,3,4-tetrahydroisoquinolines
have been described as ligands for estrogen receptors,3a G-
protein coupled receptors,3b and serotonin transporters.3c
Whereas common 1-substituted 1,2,3,4-tetrahydroiso-
quinolines are readily available starting from arylethyl-
amines through established cyclization reactions (Pictet–
Spengler, Bischler–Napieralski, followed by reduction)4 or
through controlled reduction of fully aromatic isoquino-
lines,5 to date, there are only a limited number of published
synthetic routes to N-aryl-1,2,3,4-tetrahydroisoquinolines.
These include mainly N-arylations of 1,2,3,4-tetrahydroiso-
quinolines utilizing aryl bromides or iodides under palladi-
um (Buchwald–Hartwig reaction)6a,b or copper catalysis
(Ullmann reaction);6c alternatively, arylboronic acids or tri-
fluoroborates were coupled under copper catalysis.6d Tran-
sition-metal-free N-arylations can be achieved with reac-
tive aryl halides2b or by using in situ prepared arynes6e
(with associated regioselectivity issues). Other procedures
involving the de novo construction of the 1,2,3,4-tetrahy-
droisoquinoline ring system via incorporation of primary
aromatic amines are less convenient as they require either
hazardous (ortho-halomethyl-arylethyl halides)7 or poorly
accessible (benzo-anellated dihydropyrans)7b,c starting
materials (Figure 1). A Pomeranz–Fritsch-type cyclization
of N-aryl-N-benzylaminoacetaldehyde acetals to 4-hy-
droxy-N-aryl-1,2,3,4-tetrahydroisoquinolines is hampered
by the strongly acidic conditions required and the forma-
tion of diverse side products.8
DOI: 10.1055/s-0040-1706002; Art ID: ss-2020-z0544-op
Abstract N-Aryl-1,2,3,4-tetrahydroisoquinolines are obtained via a
convenient and short protocol with a broad range of substituents on
both aromatic rings and high functional group tolerance. Starting from
readily available ortho-brominated aromatic aldehydes and primary aro-
matic amines, condensation of these building blocks under reductive
conditions gives N-aryl 2-bromobenzylamines. The C-3/C-4-unit of the
tetrahydroisoquinoline is introduced using commercially available 2-
ethoxyvinyl pinacolboronate under Suzuki conditions. Finally, the ob-
tained crude ortho-ethoxyvinyl benzylamines are cyclized via an intra-
molecular reductive amination using the combination of triethylsi-
lane/TFA to give the desired N-aryl-1,2,3,4-tetrahydroisoquinolines.
Key words N-aryl-1,2,3,4-tetrahydroisoquinolines, reductive cycliza-
tion, Pd-catalyzed ethoxyvinylation, reductive N-alkylation, cross-cou-
pling
The isoquinoline ring system is an important structural
motif in bioactive heterocycles. Due to its biosynthetic ori-
gin from amino acid derived arylethylamine precursors, 1-
substituted 1,2,3,4-tetrahydroisoquinolines (especially 1-
benzyl derivatives) are a dominant structural element in
isoquinolines obtained from natural sources, and com-
pounds of this chemotype show a wide spectrum of biolog-
ical activity.1
In contrast, N-aryl-1,2,3,4-tetrahydroisoquinolines are
rather underexplored. Diverse biological activities have
been reported for this chemotype, mostly in patents, e.g.,
the inhibition of enzymes such as cathepsin B and calpain-
2,2a tumor-relevant NADPH quinone oxidoreductase and E.
coli nitroreductase,2b blocking of P-gp efflux pumps in tu-
mor cells,2c and modulation of potassium and sodium chan-
nels leading to antiepileptic2d and analgesic effects, respec-
Consequently, the development of convenient ap-
proaches to N-aryl-1,2,3,4-tetrahydroisoquinolines is still a
promising task. In continuation of our research on bioactive
isoquinolines9 we were interested in the synthesis of N-
aryl-1,2,3,4-tetrahydroisoquinolines as rigid analogues of
steroids3a and azobenzenes.10
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Glas et al.
Paper
Synthesis
We performed our pilot experiment with 2-bromo-
benzaldehyde (1) and aniline (2) (Scheme 1; reactions are
depicted with optimized conditions). For the first step, the
intermolecular reductive amination, we employed standard
conditions utilizing NaCNBH3 as the reducing agent and ob-
tained N-phenyl 2-bromobenzylamine (3a) in quantitative
yield. For the subsequent de novo construction of the N-
aryl-1,2,3,4-tetrahydroisoquinoline ring system, we investi-
gated different conditions in order to optimize the yield and
to reduce waste, purification efforts and workload (Table 1
and Scheme 1).
Published approaches:
1. N-Arylation of tetrahydroisoquinolines
+ Ar-Br/Ar-I, cat. Pd or Cu
NH
+ reactive Ar-Hal and base
+ Ar-B(OH)2 or Ar-BF3K, cat. Cu
+ aryne
R
2. Construction of the isoquinoline ring system
Hal
O
H2N-Ar
or
+
Hal
(1)
R
R
New approach:
(1) reductive
amination
H2N-Ar
First, the Suzuki reaction was performed according to
Ar
CHO
(2a)
Br
N
(2b)
(2a) Suzuki
coupling
an established protocol from our previous work9b,11 using 2-
OEt
(2b) reductive
N-alkylation
ethoxyvinyl
pinacolboronate,
tetrakis(triphenylphos-
R
R
phine)palladium(0) and cesium carbonate (Scheme 1). The
formation of enol ether 4a could be monitored by TLC. We
decided not to purify the intermediate ortho-ethoxyvinyl
benzylamine 4a, but only isolated the crude organic materi-
al after aqueous work-up and then re-dissolved it in di-
chloromethane (DCM), an established solvent for silane/TFA
reductions. For the reductive cyclization of crude 4a we ex-
amined procedures derived from similar N-arylethylation
reactions,12a,13 as shown in Table 1.
(RO)2B
Figure 1 Published approaches to N-aryl-1,2,3,4-tetrahydroisoquino-
lines and the retrosynthetic concept of the new approach reported
herein
In order to achieve a short approach to the target N-
aryl-1,2,3,4-tetrahydroisoquinolines and related ring sys-
tems with maximum variability in both aromatic rings, we
have developed a novel modular method starting from or-
tho-brominated aromatic aldehydes and primary aromatic
amines (Figure 1). Both of these building blocks are readily
available with a broad variety of additional substituents on
the rings. Condensation of these building blocks under re-
ductive conditions would give N-aryl 2-bromobenzyl-
amines. The missing C-3/C-4-unit of the isoquinoline was to
be introduced using commercially available 2-ethoxyvinyl
pinacolboronate under Suzuki conditions.9b,11 Finally, the
obtained ortho-ethoxyvinyl N-arylbenzylamine would un-
dergo an intramolecular reductive amination using the
combination of triethylsilane/trifluoroacetic acid (TFA) to
give the desired N-aryl-1,2,3,4-tetrahydroisoquinolines.
Similar N-arylethylations of aromatic amines using enol
ethers have recently been performed in our group for the
synthesis of arylethylated anilines and N-heterocycles.12 In
a similar manner, benzodiazepines were obtained by intra-
molecular reductive amination with acetals,13 and intermo-
lecular N-alkylations using silane/TFA reagents were ac-
complished with acetals14a and free aldehydes.14b
Table 1 The Reaction Conditions Explored for the Reductive Cycliza-
tion
Entry Conditions for the cyclization of crude enol
Yield of 5a
ether 4a
112a
213
3
Et3SiH (10 equiv), TFA (10 equiv), dry DCM,
0 °C, 3.5 h
30% over 2 steps
34% over 2 steps
Et3SiH (2.5 equiv), TFA (13 equiv), dry DCM,
rt, 2.5 h
pure 4a, Et3SiH (2.5 equiv), TFA (13 equiv),
dry DCM, rt, 2.5 h
41% over 1 step
(21% over 2 steps)
4
one-pot, Et3SiH (10 equiv), TFA (13 equiv),
0 °C to rt, 72 h
6% over 2 steps
6% over 2 steps
59b
Et3SiH (0 equiv), TFA (13 equiv), dry DCM,
0 °C, 3.5 h
We first followed the protocol of Vögerl et al.12a and
used 10 equivalents of triethylsilane at 0 °C (Table 1, entry
1). The desired N-aryl-1,2,3,4-tetrahydroisoquinoline 5a
O
B
1) aniline (2)
AcOH (cat.), MeOH
rt, 16 h
2) NaCNBH3, MeOH
rt, 3 h
O
EtO
Pd(PPh3)4, Cs2CO3
1,4-dioxane/H2O
75 °C, 19 h
TFA, Et3SiH
DCM
O
rt, 3 h
N
H
H
N
N
quant.
H
34%
over 2 steps
Br
Br
3a
OEt
1
4a
5a
Scheme 1 A pilot experiment using 2-bromobenzaldehyde (1) and aniline (2) for the new synthetic approach to N-aryl-1,2,3,4-tetrahydroisoquinolines
(illustrated with optimized conditions)
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

C
C. Glas et al.
Paper
Synthesis
was formed within 3.5 hours in 30% yield, however, a labo-
rious purification by repeated flash column chromatogra-
phy (FCC) was required due to the necessity to remove ex-
cess triethylsilane. To minimize the purification efforts, we
explored the conditions described by Popp et al.13 (Table 1,
entry 2). Here, only 2.5 equivalents of triethylsilane were
used, and the reaction was performed at room temperature.
TLC monitoring indicated full consumption of the starting
material after 2.5 hours, and product 5a was obtained in a
slightly increased yield of 34% after only one round of FCC.
To investigate a possible negative impact of residual re-
agents or impurities from the Suzuki reaction, we purified
enol ether 4a by FCC (50% yield) and then performed the cy-
clization reaction (Table 1, entry 3) according to the condi-
tions in entry 2. In this case product 5a was obtained in 41%
yield (21% over 2 steps), leading us to the conclusion that
purification of 4a was not necessary and rather causes a de-
crease in the overall yield of 5a.
In another experiment we omitted the solvent change
and directly added, in a one-pot procedure, the required re-
agents for the cyclization (triethylsilane/TFA) into the reac-
tion mixture of the Suzuki coupling (Table 1, entry 4; fol-
lowing the conditions in entry 1). The reaction was stopped
after 72 hours as formation of the cyclized product 5a was
not clearly visible by TLC. Nevertheless, after FCC, product
5a was isolated in a very poor yield of 6%.
The underlying mechanism of the cyclization reaction
using triethylsilane/TFA involves -protonation of the
ethoxyvinyl moiety in 4a giving a carbenium-oxonium ion,
a subsequent intramolecular cyclization leading to forma-
tion of a C–N bond with the (necessarily unprotonated)
amino group, and finally O-protonation, elimination of
amine
1)
O
H2N
R
B
O
EtO
AcOH (cat.), MeOH
TFA
rt, 16 h
2) NaCNBH3, MeOH
rt, 3 h
Pd(PPh3)4, Cs2CO3
1,4-dioxane/H2O
75°C, 19 h
Et3SiH
DCM
rt, 2–4 h
O
N
H
R
(Het)Ar
H
N
N
R
(Het)Ar
R
(Het)Ar
(Het)Ar
H
Br
Br
3b–m
OEt
aldehyde
5b–m
5b–m (yield
5b–m (yield
Aldehyde
Amine
3b–m (yield)
3b (85%)
Aldehyde
O
Amine
3b–m (yield)
over 2 steps)
over 2 steps)
O
S
2
2
5b (48%)
5c (49%)
H
2
3h (88%)
3i (92%)
5h (38%)
5i (0%)
H
H
O
Br
O
Br
O
O
3c (74%)
3d (78%)
2
H
Br
O
N
Br
H2N
O
O
2
2
5d (55%)
5e (29%)
H
H
1
3j (74%)
5j (55%)
O
Br
O
H2N
1
1
3k (65%)
3l (48%)
5k (70%)
5l (0%)
OEt
3e (89%)
O
O
Br
O
H2N
OH
HO
O
H
H
2
2
3f (92%)
3g (88%)
5f (56%)
5g (63%)
H2N
1
1
3m (76%)
3n (47%)
5m (69%)
5n (24%)
Br
O
Cl
O2N
H2N
N
Br
Scheme 2 Scope and limitations of the newly developed synthetic approach towards N-aryl-1,2,3,4-tetrahydroisoquinolines
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

D
C. Glas et al.
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Synthesis
ethanol, and hydride transfer from triethylsilane to the re-
sulting iminium ion. This prompted us to examine whether
we would obtain the 3,4-dehydro analogue of 5a, an N-aryl-
1,2-dihydroisoquinoline, when only TFA, but no triethylsi-
lane was used (Table 1, entry 5; following conditions pub-
lished for the synthesis of 1-oxo-1,2-dihydroisoquinolines
by Schütz et al.9b). Thus crude enol ether 4a was treated
with only TFA at 0 °C, and after 3.5 hours, enol ether 4a was
completely consumed. The only product we could isolate
from the product mixture in pure form was, surprisingly, N-
aryl-1,2,3,4-tetrahydroisoquinoline 5a in a poor yield of 6%
over both steps.
With optimized cyclization conditions in hand, we next
applied our newly developed approach for the synthesis of
N-aryl-1,2,3,4-tetrahydroisoquinolines and related hetero-
cycles starting from differently substituted ortho-brominat-
ed aromatic aldehydes and primary aromatic amines
(Scheme 2).
Overall, this method enabled us to synthesize a variety
of N-aryl-1,2,3,4-tetrahydroisoquinolines with yields rang-
ing from 24–70% over two steps starting from the corre-
sponding N-aryl 2-bromobenzylamines. As shown in
Scheme 2 there was a noticeable difference in the yield of
the final products depending on the substitution pattern of
the starting material. It is important to note that during
their investigation on the scope and limitations of the Suzu-
ki–Miyaura coupling, Buchwald et al. came to the conclu-
sion that differently substituted aryl bromides did not af-
fect the yield significantly when coupled with alkenyl bo-
ronic acids.15 Therefore, the herein observed differences
supposedly occur mainly during the final cyclization step.
During this work, we observed an increase in the yield
of the final products when anilines with electron-with-
drawing substituents were used. Product 5k, carrying an
ester group, and halogenated product 5m were obtained in
70% and 69% yields over two steps, being twice as high
compared to that of product 5a derived from unsubstituted
aniline (34% yield over two steps). A similar trend was ob-
served with products derived from 4-methoxyaniline (5j,
yield 55%) and methoxylated benzaldehydes (5b, 5c, 5d,
yields 48–55%), compared to product 5g derived from a ni-
trobenzaldehyde (yield 63%).
Using our approach even products 5e and 5f bearing a
free phenolic group could be obtained. Tetrahydroisoquino-
line 5f bearing the phenolic group at a remote position was
isolated in a good yield of 56% over two steps. In contrast,
phenolic product 5e was only generated in 29% yield. In this
case the intermediate enol ether probably underwent, in
part, a competing reaction with the hydroxy group at the
other ortho-position with cyclization to a benzofuran deriv-
ative. A comparable cyclization under acidic conditions has
been published by Sakamoto et al.16
O
O
O
1)
O
O
7
H2N
O
AcOH (cat.), MeOH
rt, 16 h
O
H
H
N
O
N
H
2) NaCNBH3, MeOH
rt, 4 h
Br
H
O
N
O
O
Br
96%
O
O
6
3o
O
B
O
O
O
EtO
O
O
Pd(PPh3)4, Cs2CO3
THF/H2O
TFA, Et3SiH
DCM
O
O
75 °C, 19 h
rt, 2.5 h
N
N
H
H
H
O
N
O
N
O
O
O
O
OEt
OH
O
OH
KOH
H2O/THF
rt, 1.5 h
N
60%
over 3 steps
H
HO
N
O
O
5o
Scheme 3 Application of the method toward the rigidized azobenzene analogue N-aryl-1,2,3,4-tetrahydroisoquinoline 5o
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

E
C. Glas et al.
Paper
Synthesis
However, our newly developed method is not limited to
bromobenzaldehydes and anilines as starting materials and
was successfully applied utilizing heteroaromatic com-
pounds. Intermediates 3h (derived from a brominated thio-
phenecarbaldehyde) and 3n (derived from 2-aminopyri-
dine) gave the expected cyclization products 5h and 5n in
38% and 24% yields, respectively, over two steps. In contrast,
2-bromonicotinaldehyde-derived amine 3i underwent the
Suzuki coupling, but did not result in the desired cyclized 6-
phenyl-5,6,7,8-tetrahydro[1,6]naphthyridine (5i) using the
standard conditions. The unsuccessful formation of the N-
aryltetrahydroisoquinoline derivative here, and the poor
yield of N-pyridyl-1,2,3,4-tetrahydroisoquinoline (5n),
might in part be due to counter-productive protonation of
the pyridine-containing intermediates by TFA during the
cyclization step.
In conclusion, we have developed a convenient and
short protocol for the synthesis of N-aryl-1,2,3,4-tetrahy-
droisoquinolines and related heterocyclic ring systems pos-
sessing a wide range of substituents on both aromatic rings,
whilst demonstrating high functional group tolerance.
Starting from readily available ortho-brominated aromatic
aldehydes and primary aromatic amines, the application of
reductive conditions allows condensation of these building
blocks to give N-aryl 2-bromobenzylamines. Commercially
available 2-ethoxyvinyl pinacolboronate is then employed
under Suzuki conditions to introduce the C-3/C-4-unit of
the tetrahydroisoquinoline. Finally, the obtained ortho-
ethoxyvinyl benzylamines undergo cyclization via an intra-
molecular reductive amination using triethylsilane/TFA to
give the desired N-aryl-1,2,3,4-tetrahydroisoquinolines.
Notwithstanding that the Suzuki reaction and final cycliza-
tion gave only moderate to good yields over two steps, this
protocol is more effective than previous approaches to the
target chemotype, due to the good availability of the build-
ing blocks and the very small number of steps.
In previous work in this field,12a,13,17 we found that N-
arylethylations utilizing enol ethers and the triethylsi-
lane/TFA reagent mixture were limited to nitrogen com-
pounds of low to very low basicity, like anilines, carbazoles,
indoles and phenothiazines. Aliphatic amines, however, are
protonated by TFA and hence are prevented from nucleop-
hilic attack at the protonated enol ether, leading to failure of
the reaction. This finding was again confirmed in this work
during examination of the intermolecular reductive amina-
tion with N-cyclohexyl-2-bromobenzylamine (3l).
The successful Suzuki coupling could again be con-
firmed by TLC and mass spectrometry, but as expected,
subsequent cyclization did not result in the desired N-cy-
clohexyl-1,2,3,4-tetrahydroisoquinoline (5l), and only un-
identifiable side products were observed.
During these studies on the scope and limitations of our
method, we observed that some of the compounds were
air-sensitive and experienced oxidative degradation. There-
fore, the final N-aryl-1,2,3,4-tetrahydroisoquinolines
should be stored under inert gas after their preparation.
In the course of a project aimed at the synthesis of N-
aryl-1,2,3,4-tetrahydroisoquinolines as rigidized analogues
of bioactive azobenzenes,10 we applied our new approach
to the synthesis of analogue 5o, starting from known ace-
tonide-protected 5-aminosalicylic acid 718 and amide-sub-
stituted 2-bromobenzaldehyde 6 (obtained from the corre-
sponding carboxylic acid and -alanine ethyl ester under
standard amidation conditions), introducing two more
functional groups for the analysis of the scope and limita-
tions of the novel cyclization method (Scheme 3). The inter-
molecular reductive amination yielded 3o in 96% yield. The
Suzuki reaction, cyclization and subsequent alkaline depro-
tection generated target compound 5o in 60% yield over 3
steps, once again confirming the beneficial effects of elec-
tron-withdrawing substituents on the yield of the cycliza-
tion. Unfortunately, this product was not stable and had to
be analyzed and, if desired, tested shortly after preparation.
Further, compared to previous methods, this protocol
yields products of predictable structure; the formation of
regioisomeric products is excluded due to the utilization of
ortho-brominated aromatic aldehydes. In summary, this
methodology opens a novel and straightforward access to
N-aryl-1,2,3,4-tetrahydroisoquinolines and represents an
attractive alternative to previous approaches.
(E)-2-Ethoxyvinylboronic acid pinacol ester was purchased from
Sigma Aldrich. All solvents were purchased from commercial sources
and used without further purification. Solvents were dried, if neces-
sary, according to standard methods and stored over activated molec-
ular sieves under a nitrogen atmosphere. Standard vacuum-line tech-
niques were used and glassware was flame-dried prior to use. Organic
solvents were dried during workup using phase separation paper. Re-
actions were monitored via thin-layer chromatography (TLC) using
POLYGRAM SIL G/UV254 polyester sheets coated with 0.2 mm silica gel
(Macherey-Nagel). Plates were visualized using UV light (254 nm or
365 nm) or by staining with 1% aq KMnO4 or CAM (ceric ammonium
molybdate). Monitoring was also performed by mass spectrometry
using an atmospheric pressure solids analysis probe (ASAP) with at-
mospheric pressure chemical ionization (APCI) on an expression
LCMS device (Advion, Ithaca, USA). Products were purified by flash
column chromatography (normal-phase silica gel chromatography)
using SiO2 60 (0.040–0.063 mm, 230–400 mesh ASTM) from Merck.
Melting points were measured with a Büchi Schmelzpunktapparatur
B-540 and are reported in °C. Infrared spectra were recorded from
4000 to 650 cm–1 on a PERKIN ELMER Spectrum BX-59343 FT-IR in-
strument. A Smiths Detection DuraSamp IR II Diamond ATR sensor
was used for detection. The absorption bands are reported in wave-
numbers (cm–1). NMR spectra (1H NMR, 13C NMR, DEPT, COSY, HSQC,
HMBC) were recorded using Avance III HD 400 MHz Bruker BioSpin
and Avance III HD 500 MHz Bruker BioSpin spectrometers (1H NMR:
400 MHz and 500 MHz, 13C NMR: 101 MHz and 126 MHz) and the
deuterated solvent stated. Chemical shifts () are quoted in parts per
million (ppm) and are referenced to the residual solvent peak. Multi-
plicities are denoted as s (singlet), d (doublet), t (triplet), q (quartet)
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

F
C. Glas et al.
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Synthesis
and derivatives thereof. Coupling constants J are given in Hz. High-
resolution mass spectrometry (HRMS) was performed using a Jeol
MStation 700 or JMS GCmate II Jeol instrument for electron impact
ionization (EI). A Thermo Finnigan LTQ was used for electrospray ion-
ization (ESI).
HRMS (ESI): m/z [M + H]+ calcd for C13H13BrN+: 262.0226; found:
262.0227.
The analytical data are in accordance with those published in the lit-
erature.19
(E)-N-[2-(2-Ethoxyvinyl)benzyl]aniline (4a)
Reductive Amination; General Procedure A
Under a nitrogen atmosphere, compound 3a (131 mg, 0.500 mmol),
Pd(PPh3)4 (57.8 mg, 0.0500 mmol, 10 mol%) and (E)-2-ethoxyvinylbo-
ronic acid pinacol ester (212 L, 1.00 mmol) were dissolved in de-
gassed 1,4-dioxane (3.0 mL) and stirred for 10 min at rt. Under a ni-
trogen atmosphere, cesium carbonate (815 mg, 2.50 mmol) was dis-
solved in degassed water (1.0 mL) and added to the reaction mixture.
Stirring was then continued at 75 °C for 19 h. The reaction mixture
was allowed to cool to room temperature and sat. aq ammonium
chloride solution (10.0 mL) was added. The organic material was ex-
tracted with EtOAc (3 × 15.0 mL) and the combined organic phases
were dried using phase separation paper. The solvent was removed in
vacuo and the crude product was purified by FCC (hexanes/EtOAc,
95:5) to give product 4a (63.4 mg, 0.250 mmol, 50%) as a yellow oil.
The appropriate 2-bromobenzaldehyde (1.2 equiv) and aniline (1.0
equiv) were dissolved in MeOH to a concentration of 0.15 M (with re-
spect to the aniline). A catalytic amount of acetic acid was added, and
the reaction mixture stirred at room temperature for 16 h. Sodium
cyanoborohydride (3.0 equiv) was added in portions at room tem-
perature. After stirring for an additional 2.5–3 h (TLC monitoring),
water was added and the mixture extracted with ethyl acetate (× 3).
The combined organic phase was dried using phase separation paper
and the solvent was evaporated in vacuo. The crude product was puri-
fied by flash column chromatography (FCC) using the indicated elu-
ent.
Suzuki–Miyaura Coupling and Subsequent Cyclization; General
Procedure B
Rf = 0.48 (hexanes/EtOAc, 95:5).
IR (ATR): 3430, 3061, 2976, 1631, 1599, 1507, 1327, 1158, 930, 747,
The appropriate N-(2-bromobenzyl)aniline (1.0 equiv), Pd(PPh3)4 (0.1
equiv) and (E)-2-ethoxyvinylboronic acid pinacol ester (2.0 equiv)
were dissolved in degassed 1,4-dioxane to a concentration of 0.15 M
(with respect to the aniline) under a nitrogen atmosphere. The result-
ing mixture was then stirred for 10 min at room temperature. Cesium
carbonate (5.0 equiv) was dissolved in degassed water to a concentra-
tion of 0.5 M (with respect to the aniline) under a nitrogen atmo-
sphere and added to the reaction mixture. Stirring was continued at
75 °C for 16–19 h, after which the reaction mixture was allowed to
cool to room temperature and sat. aq ammonium chloride solution
was added. The organic material was extracted with EtOAc (× 3) and
the combined organic phases were dried using phase separation pa-
per. The solvent was removed in vacuo. The crude product was dis-
solved in dry DCM to a concentration of 0.33 M (with respect to the
aniline) under a nitrogen atmosphere. Trifluoroacetic acid (13 equiv)
and triethylsilane (2.5 equiv) were added under a nitrogen atmo-
sphere at room temperature in rapid succession. After completion of
the reaction (2.5–4.5 h; TLC monitoring), 2 M NaOH was added and
the mixture was extracted with DCM (× 3). The combined organic ex-
tracts were dried using phase separation paper. The solvent was re-
moved in vacuo and the crude product purified by FCC using the indi-
cated eluent.
691 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.34 (ddd, J = 9.3, 7.6, 1.4 Hz, 2 H, 3′-H
and 6′-H), 7.25–7.21 (m, 1 H, 4′-H), 7.22–7.18 (m, 2 H, 3-H and 5-H),
7.16 (td, J = 7.5, 1.4 Hz, 1 H, 5′-H), 6.89 (d, J = 12.8 Hz, 1 H, 2′′-H), 6.73
(tt, J = 7.3, 1.1 Hz, 1 H, 4-H), 6.67–6.63 (m, 2 H, 2-H and 6-H), 6.05 (d,
J = 12.8 Hz, 1 H, 1′′-H), 4.28 (s, 2 H, 1′-CH2), 3.85 (q, J = 7.0 Hz, 2 H,
CH2CH3), 1.31 (t, J = 7.0 Hz, 3 H, CH2CH3).
13C NMR (101 MHz, CDCl3):  = 149.4 (C-2′′), 148.4 (C-1), 135.6 (C-2′),
135.3 (C-1′), 129.4 (C-3 and C-5), 129.2 (C-6′), 127.9 (C-4′), 126.3 (C-
5′), 125.5 (C-3′), 117.6 (C-4), 112.9 (C-2 and C-6), 103.0 (C-1′′), 65.8
(CH2CH3), 46.9 (1′-CH2), 14.9 (CH2CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO+: 254.1539; found:
254.1536.
2-Phenyl-1,2,3,4-tetrahydroisoquinoline (5a)
Prepared according to General Procedure B from N-(2-bromoben-
zyl)aniline (3a) (131 mg, 0.500 mmol) and (E)-2-ethoxyvinylboronic
acid pinacol ester (212 L, 1.00 mmol). The crude product was puri-
fied by FCC (hexanes/EtOAc, 95:5) to give product 5a (35.6 mg, 0.169
mmol, 34%) as a dark yellow-orange oily solid.
Rf = 0.38 (hexanes/EtOAc, 95:5).
N-(2-Bromobenzyl)aniline (3a)
IR (ATR): 3023, 2922, 2821, 1661, 1598, 1498, 1460, 1387, 1293, 1212,
Prepared according to General Procedure A but with 2.0 equivalents of
2-bromobenzaldehyde (1) (1.85 g, 10.0 mmol) and aniline (2) (456
L, 5.00 mmol). The crude product was purified by FCC (hexanes/EtO-
Ac, 95:5) to give product 3a (1.31 g, 5.00 mmol, quant.) as a white sol-
id.
1151, 1112, 1034, 989, 935, 741, 690 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.32–7.27 (m, 2 H, 3′-H and 5′-H),
7.21–7.15 (m, 4 H, 5-H, 6-H, 7-H and 8-H), 7.01–6.97 (m, 2 H, 2′-H
and 6′-H), 6.84 (tt, J = 7.3, 1.1 Hz, 1 H, 4′-H), 4.42 (s, 2 H, 1-H), 3.57 (t,
J = 5.8 Hz, 2 H, 3-H), 3.00 (t, J = 5.9 Hz, 2 H, 4-H).
Rf = 0.25 (hexanes/EtOAc, 95:5); mp 40–42 °C.
13C NMR (126 MHz, CDCl3):  = 150.7 (C-1′), 135.0 (C-4a or C-8a),
134.6 (C-4a or C-8a), 129.3 (C-3′ and C-5′), 128.7 (C-5), 126.7 (C-8),
126.5 (C-6 or C-7), 126.2 (C-6 or C-7), 118.8 (C-4′), 115.3 (C-2′ and C-
6′), 50.9 (C-1), 46.7 (C-3), 29.3 (C-4).
HRMS (ESI): m/z [M – H]– calcd for C15H14N–: 208.1126; found:
208.1120.
IR (ATR): 3381, 3049, 2837, 1601, 1504, 1464, 1433, 1319, 1253, 1178,
1100, 1067, 1043, 1023, 991, 748, 691, 658 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.56 (dd, J = 7.9, 1.3 Hz, 1 H, 3′-H), 7.47
(dd, J = 7.7, 1.7 Hz, 1 H, 6′-H), 7.29–7.23 (m, 1 H, 5'-H), 7.22–7.16 (m, 2
H, 2-H and 6-H), 7.13 (td, J = 7.6, 1.8 Hz, 1 H, 4′-H), 6.82–6.76 (m, 1 H,
4-H), 6.73–6.67 (m, 2 H, 3-H and 5-H), 4.43 (s, 2 H, 1′-CH2).
13C NMR (101 MHz, CDCl3):  = 146.4 (C-1), 137.4 (C-1′), 133.0 (C-3′),
129.7 (C-6′), 129.5 (C-2 and C-6), 129.1 (C-4′), 127.7 (C-5′), 123.7 (C-
2′), 119.1 (C-4), 114.3 (C-3 and C-5), 49.2 (1′-CH2).
The analytical data are in accordance with those published in the lit-
erature.6c
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

G
C. Glas et al.
Paper
Synthesis
N-(2-Bromo-4-methoxybenzyl)aniline (3b)
HRMS (EI): m/z [M]•+ calcd for C14H14BrNO•+: 291.0253; found:
291.0253.
Prepared according to General Procedure A from 2-bromo-4-me-
thoxybenzaldehyde (129 mg, 0.600 mmol) and aniline (2) (45.6 L,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
95:5) to give product 3b (123 mg, 0.422 mmol, 85%) as a pale yellow
solid.
7-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5c)
Prepared according to General Procedure B from N-(2-bromo-5-me-
thoxybenzyl)aniline (3c) (73.0 mg, 0.250 mmol) and (E)-2-ethoxyvin-
ylboronic acid pinacol ester (106 L, 0.500 mmol). The crude product
was purified by FCC (hexanes/EtOAc, 95:5) to give product 5c (29.0
mg, 0.121 mmol, 49%) as a colorless oil.
Rf = 0.25 (hexanes/EtOAc, 95:5); mp 69–73 °C.
IR (ATR): 3439, 3062, 2937, 2832, 1601, 1567, 1507, 1486, 1456, 1435,
1319, 1270, 1229, 1176, 1028, 988, 879, 809, 749, 688 cm–1
.
Rf = 0.27 (hexanes/EtOAc, 95:5).
1H NMR (400 MHz, CDCl3):  = 7.37 (d, J = 8.5 Hz, 1 H, 6′-H), 7.22–7.15
(m, 2 H, 3-H and 5-H), 7.11 (d, J = 2.6 Hz, 1 H, 3′-H), 6.83–6.77 (m, 2 H,
4-H and 5′-H), 6.72 (d, J = 7.7 Hz, 2 H, 2-H and 6-H), 4.37 (s, 2 H, 1′-
CH2), 3.78 (s, 3 H, 4′-OCH3).
13C NMR (101 MHz, CDCl3):  = 159.6 (C-4′), 146.2 (C-1), 130.6 (C-6′),
129.5 (C-3 and C-5), 129.1 (C-1′), 124.1 (C-2′), 119.4 (C-4 and C-5′),
118.3 (C-3′), 114.6 (C-2 or C-6), 113.7 (C-2 or C-6), 55.7 (4′-OCH3),
48.8 (1′-CH2).
IR (ATR): 3023, 2907, 2832, 1598, 1501, 1461, 1382, 1319, 1253, 1234,
1147, 1119, 1038, 932, 813, 748, 691 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.33–7.27 (m, 2 H, 3′-H and 5′-H), 7.08
(d, J = 8.3 Hz, 1 H, 5-H), 6.99 (dd, J = 8.8, 1.1 Hz, 2 H, 2′-H and 6′-H),
6.87–6.81 (m, 1 H, 4′-H), 6.76 (dd, J = 8.4, 2.7 Hz, 1 H, 6-H), 6.71 (d, J =
2.7 Hz, 1 H, 8-H), 4.39 (s, 2 H, 1-H), 3.81 (s, 3 H, 7-OCH3), 3.56 (t, J =
5.8 Hz, 2 H, 3-H), 2.92 (t, J = 5.8 Hz, 2 H, 4-H).
13C NMR (101 MHz, CDCl3):  = 158.0 (C-7), 150.7 (C-1′), 135.7 (C-8a),
129.6 (C-5), 129.3 (C-3′ and C-5′), 127.1 (C-4a), 118.8 (C-4′), 115.4 (C-
2′ and C-6′), 112.7 (C-6), 111.4 (C-8), 55.5 (7-OCH3), 51.1 (C-1), 47.0
(C-3), 28.3 (C-4).
HRMS (EI): m/z [M – H]• calcd for C16H16NO•: 238.1232; found:
238.1226.
HRMS (EI): m/z [M]•+ calcd for C14H14BrNO•+: 291.0253; found:
291.0253.
6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5b)
Prepared according to General Procedure B from N-(2-bromo-4-me-
thoxybenzyl)aniline (3b) (73.0 mg, 0.250 mmol) and (E)-2-ethoxyvi-
nylboronic acid pinacol ester (106 L, 0.500 mmol). The crude prod-
uct was purified by FCC (hexanes/EtOAc, 92:8) to give product 5b
(28.6 mg, 0.120 mmol, 48%) as a yellow solid.
The analytical data are in accordance with those published in the lit-
erature.20
Rf = 0.32 (hexanes/EtOAc, 92:8); mp 39–44 °C.
N-(2-Bromo-4,5-dimethoxybenzyl)aniline (3d)
Prepared according to General Procedure A from 2-bromo-4,5-dime-
thoxybenzaldehyde (147 mg, 0.600 mmol) and aniline (2) (45.6 L,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
80:20) to give product 3d (126 mg, 0.392 mmol, 78%) as a yellow sol-
id.
IR (ATR): 3060, 2933, 2833, 1731, 1597, 1504, 1460, 1388, 1331, 1275,
1227, 1194, 1152, 1032, 913, 849, 805, 751, 690 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.32–7.27 (m, 2 H, 3′-H and 5′-H), 7.08
(d, J = 8.4 Hz, 1 H, 8-H), 7.01 (d, J = 8.0 Hz, 2 H, 2′-H and 6′-H), 6.85 (t,
J = 6.9 Hz, 1 H, 4′-H), 6.77 (dd, J = 8.4, 2.7 Hz, 1 H, 7-H), 6.70 (d, J = 2.6
Hz, 1 H, 5-H), 4.37 (s, 2 H, 1-H), 3.80 (s, 3 H, 6-OCH3), 3.56 (t, J = 5.9
Hz, 2 H, 3-H), 2.97 (t, J = 5.9 Hz, 2 H, 4-H).
13C NMR (126 MHz, CDCl3):  = 158.2 (C-6), 150.7 (C-1′), 136.2 (C-4a),
129.3 (C-3′ and C-5′), 127.6 (C-8), 126.8 (C-8a), 118.8 (C-4′), 115.3 (C-
2′ and C-6′), 113.3 (C-5), 112.5 (C-7), 55.4 (6-OCH3), 50.4 (C-1), 46.6
(C-3), 29.5 (C-4).
Rf = 0.36 (hexanes/EtOAc, 80:20); mp 81–83 °C.
IR (ATR): 3378, 2929, 2837, 1600, 1499, 1434, 1388, 1312, 1255, 1223,
1164, 1099, 1027, 958, 851, 797, 754, 694 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.21–7.16 (m, 2 H, 3-H and 5-H), 7.04
(s, 1 H, 3′-H), 6.97 (s, 1 H, 6′-H), 6.78–6.73 (m, 1 H, 4-H), 6.68–6.63 (m,
2 H, 2-H and 6-H), 4.33 (s, 2 H, 1′-CH2), 3.87 (s, 3 H, 4′-OCH3 or 5′-
OCH3), 3.79 (s, 3 H, 4′-OCH3 or 5′-OCH3).
HRMS (EI): m/z [M – H]• calcd for C16H16NO•: 238.1232; found:
13C NMR (126 MHz, CDCl3):  = 148.8 (C-4′ or C-5′), 148.7 (C-4′ or C-
5′), 147.7 (C-1), 130.2 (C-1′), 129.4 (C-3 and C-5), 118.4 (C-4), 115.7
(C-3′), 113.5 (C-2 and C-6), 113.3 (C-2′), 112.4 (C-6′), 56.4 (4′-OCH3 or
5′-OCH3), 56.2 (4′-OCH3 or 5′-OCH3), 48.7 (1′-CH2).
HRMS (EI): m/z [M]•+ calcd for C15H16BrNO2•+: 321.0359; found:
321.0358.
238.1227.
N-(2-Bromo-5-methoxybenzyl)aniline (3c)
Prepared according to General Procedure A from 2-bromo-5-me-
thoxybenzaldehyde (129 mg, 0.600 mmol) and aniline (2) (45.6 L,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
95:5) to give product 3c (108 mg, 0.370 mmol, 74%) as a yellow oil.
The analytical data are in accordance with those published in the lit-
erature.21
Rf = 0.33 (hexanes/EtOAc, 95:5).
IR (ATR): 3418, 3048, 3003, 2932, 2836, 1600, 1504, 1466, 1432, 1294,
1265, 1240, 1159, 1053, 1015, 868, 803, 747, 691, 600 cm–1
.
6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5d)
1H NMR (400 MHz, CDCl3):  = 7.43 (d, J = 8.8 Hz, 1 H, 3′-H), 7.22–7.16
(m, 2 H, 3-H and 5-H), 7.05 (d, J = 2.9 Hz, 1 H, 6′-H), 6.78 (t, J = 7.4 Hz,
1 H, 4-H), 6.73–6.66 (m, 3 H, 2-H, 6-H and 4′-H), 4.38 (s, 2 H, 1′-CH2),
3.74 (s, 3 H, 5′-OCH3).
13C NMR (101 MHz, CDCl3):  = 159.4 (C-5′), 146.6 (C-1), 138.6 (C-1′),
133.5 (C-3′), 129.5 (C-3 and C-5), 119.1 (C-4), 115.3 (C-6′), 114.7 (C-
4′), 114.2 (C-2 and C-6), 113.8 (C-2′), 55.6 (5′-OCH3), 49.3 (1′-CH2).
Prepared according to General Procedure B from N-(2-bromo-4,5-di-
methoxybenzyl)aniline (3d) (80.6 mg, 0.250 mmol) and (E)-2-
ethoxyvinylboronic acid pinacol ester (106 L, 0.500 mmol). The
crude product was purified by FCC (hexanes/EtOAc, 75:25) to give
product 5d (36.7 mg, 0.136 mmol, 55%) as a yellow solid.
Rf = 0.45 (hexanes/EtOAc, 75:25); mp 86–90 °C.
IR (ATR): 2920, 2805, 2684, 1599, 1516, 1462, 1450, 1377, 1252, 1209,
1114, 1025, 979, 932, 855, 825, 750, 731, 693 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

H
C. Glas et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.33–7.27 (m, 2 H, 3′-H and 5′-H), 7.03
(d, J = 7.9 Hz, 2 H, 2′-H and 6′-H), 6.87 (t, J = 7.6 Hz, 1 H, 4′-H), 6.65 (s,
1 H, 5-H or 8-H), 6.65 (s, 1 H, 5-H or 8-H), 4.35 (s, 2 H, 1-H), 3.88 (s, 3
H, 6-OCH3 or 7-OCH3), 3.87 (s, 3 H, 6-OCH3 or 7-OCH3), 3.56 (t, J = 5.8
Hz, 2 H, 3-H), 2.91 (t, J = 5.8 Hz, 2 H, 4-H).
13C NMR (101 MHz, CDCl3):  = 149.6 (C-1′), 147.9 (C-6 or C-7), 147.8
(C-6 or C-7), 129.4 (C-3′ and C-5′), 126.5 (C-4a and C-8a), 122.2 (C-4′),
115.9 (C-2′ and C-6′), 111.5 (C-5), 109.5 (C-8), 56.13 (6-OCH3 or 7-
OCH3), 56.08 (6-OCH3 or 7-OCH3), 51.0 (C-1), 47.3 (C-3), 28.3 (C-4).
4-Bromo-2-methoxy-5-[(phenylamino)methyl]phenol (3f)
Prepared according to General Procedure A from 2-bromo-5-hydroxy-
4-methoxybenzaldehyde (139 mg, 0.600 mmol) and aniline (2) (45.6
L, 0.500 mmol). The crude product was purified by FCC (DCM/hex-
anes, 0:100 to 70:30) to give product 3f (141 mg, 0.458 mmol, 92%) as
a brownish solid.
Rf = 0.20 (DCM/hexanes, 70:30); mp 62–63 °C.
IR (ATR): 3475, 2922, 1602, 1497, 1434, 1328, 1269, 1197, 1146, 1034,
861, 822, 797, 745, 692 cm–1
.
•
HRMS (EI): m/z [M – H]• calcd for C17H18NO2 : 268.1338; found:
1H NMR (400 MHz, CDCl3):  = 7.21–7.15 (m, 2 H, 3′-H and 5′-H), 7.05
(s, 1 H, 6-H), 7.02 (s, 1 H, 3-H), 6.77 (tt, J = 7.2, 0.8 Hz, 1 H, 4′-H), 6.71–
6.66 (m, 2 H, 2′-H and 6′-H), 4.31 (s, 2 H, CH2), 3.87 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3):  = 146.62 (C-2), 146.56 (C-1′), 145.3 (C-
1), 130.4 (C-5), 129.4 (C-3′ and C-5′), 118.9 (C-4′), 115.7 (C-6), 115.2
(C-3), 114.1 (C-2′ and C-6′), 112.5 (C-4), 56.4 (OCH3), 48.7 (CH2).
268.1332.
The analytical data are in accordance with those published in the lit-
erature.22
2-Bromo-6-methoxy-3-[(phenylamino)methyl]phenol (3e)
Prepared according to General Procedure A from 2-bromo-3-hydroxy-
4-methoxybenzaldehyde (139 mg, 0.600 mmol) and aniline (2) (45.6
L, 0.500 mmol). The crude product was purified by FCC (DCM/hex-
anes, 0:100 to 65:35) to give product 3e (137 mg, 0.445 mmol, 89%)
as a beige solid.
HRMS (EI): m/z [M]•+ calcd for C14H14BrNO2•+: 307.0202; found:
307.0200.
6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-7-ol (5f)
Prepared according to General Procedure B from 4-bromo-2-me-
thoxy-5-[(phenylamino)methyl]phenol (3f) (77.0 mg, 0.376 mmol)
and (E)-2-ethoxyvinylboronic acid pinacol ester (106 L, 0.500
mmol). The crude product was purified by FCC (DCM/hexanes, 0:100
to 70:30) to give product 5f (36.0 mg, 0.141 mmol, 56%) as a brownish
solid.
Rf = 0.23 (DCM/hexanes, 65:35); mp 86–88 °C.
IR (ATR): 3424, 2840, 1599, 1487, 1435, 1332, 1276, 1232, 1193, 1139,
1030, 987, 947, 810, 741, 689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.21–7.15 (m, 2 H, 3′-H and 5′-H), 6.98
(d, J = 8.4 Hz, 1 H, 4-H), 6.79–6.74 (m, 2 H, 4′-H and 5-H), 6.68 (d, J =
7.8 Hz, 2 H, 2′-H and 6′-H), 4.38 (s, 2 H, CH2), 3.88 (s, 3 H, OCH3).
Rf = 0.26 (DCM/hexanes, 70:30); mp 96–97 °C.
13C NMR (101 MHz, CDCl3):  = 146.8 (C-1′), 146.5 (C-6), 143.4 (C-1),
130.4 (C-3), 129.4 (C-3′ and C-5′), 120.3 (C-4), 118.8 (C-4′), 114.0 (C-2
and C-6), 109.8 (C-2), 109.6 (C-5), 56.5 (OCH3), 48.8 (CH2).
HRMS (EI): m/z [M]•+ calcd for C14H14BrNO2•+: 307.0202; found:
307.0201.
IR (ATR): 3231, 2942, 2825, 1595, 1529, 1501, 1458, 1376, 1274, 1219,
1203, 1110, 1025, 924, 857, 828, 758, 684 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.32–7.27 (m, 2 H, 3′-H and 5′-H), 7.02
(d, J = 8.1 Hz, 2 H, 2′-H and 6′-H), 6.86 (t, J = 6.8 Hz, 1 H, 4′-H), 6.72 (s,
1 H, 8-H), 6.62 (s, 1 H, 5-H), 5.54 (s, 1 H, OH), 4.32 (s, 2 H, 1-H), 3.87 (s,
3 H, OCH3), 3.55 (t, J = 5.9 Hz, 2 H, 3-H), 2.90 (t, J = 5.9 Hz, 2 H, 4-H).
6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-5-ol (5e)
13C NMR (101 MHz, CDCl3):  = 150.5 (C-1′), 145.2 (C-6), 144.0 (C-7),
129.2 (C-3′ and C-5′), 127.0 (C-4a or C-8a), 126.1 (C-4a or C-8a), 118.8
(C-4′), 115.4 (C-2′ and C-6′), 112.2 (C-8), 110.6 (C-5), 56.0 (OCH3), 50.4
(C-1), 46.9 (C-3), 28.6 (C-4).
Prepared according to General Procedure B from 2-bromo-6-me-
thoxy-3-[(phenylamino)methyl]phenol (3e) (116 mg, 0.376 mmol)
and (E)-2-ethoxyvinylboronic acid pinacol ester (159 L, 0.753
mmol). The crude product was purified by FCC (DCM/hexanes, 0:100
to 70:30) to give product 5e (28.0 mg, 0.110 mmol, 29%) as a yellow
solid.
•+
HRMS (EI): m/z [M]•+ calcd for C16H17NO2
: 255.1254; found:
255.1248.
Rf = 0.26 (DCM/hexanes, 70:30); mp 84–86 °C.
N-(2-Bromo-5-nitrobenzyl)aniline (3g)
IR (ATR): 3457, 2923, 2839, 1598, 1500, 1445, 1392, 1342, 1281, 1228,
Prepared according to General Procedure A from 2-bromo-5-nitro-
benzaldehyde (138 mg, 0.600 mmol) and aniline (2) (45.6 L, 0.500
mmol). The crude product was purified by FCC (hexanes/EtOAc,
80:20) to give product 3g (135 mg, 0.440 mmol, 88%) as a yellow sol-
id.
1196, 1090, 1043, 1006, 875, 793, 747, 689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.32–7.27 (m, 2 H, 3′-H and 5′-H), 7.03
(d, J = 8.1 Hz, 2 H, 2′-H and 6′-H), 6.86 (t, J = 7.3 Hz, 1 H, 4′-H), 6.75 (d,
J = 8.3 Hz, 1 H, 7-H), 6.68 (d, J = 8.3 Hz, 1 H, 8-H), 5.70 (s, 1 H, OH), 4.36
(s, 2 H, 9-H), 3.88 (s, 3 H, OCH3), 3.57 (t, J = 6.0 Hz, 2 H, 3-H), 2.95 (t, J =
6.0 Hz, 2 H, 4-H).
13C NMR (101 MHz, CDCl3):  = 144.6 (C-6), 143.0 (C-5), 129.3 (C-3′
and C-5′), 127.9 (C-8a), 121.5 (C-4a), 119.4 (C-4′), 117.3 (C-8), 116.1
(C-2′ and C-6′), 108.8 (C-7), 56.3 (C-OCH3), 50.9 (C-9), 47.0 (C-3), 22.9
(C-4); [C-1′ not visible].
Rf = 0.50 (hexanes/EtOAc, 80:20); mp 123–128 °C.
IR (ATR): 3398, 3089, 2929, 2857, 1602, 1573, 1525, 1493, 1340, 1270,
1239, 1108, 1027, 987, 917, 872, 806, 749, 737, 692 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.28 (d, J = 2.8 Hz, 1 H, 6′-H), 7.99 (dd,
J = 8.7, 2.8 Hz, 1 H, 4′-H), 7.76 (d, J = 8.6 Hz, 1 H, 3′-H), 7.22–7.14 (m, 2
H, 3-H and 5-H), 6.80–6.73 (m, 1 H, 4-H), 6.61–6.56 (m, 2 H, 2-H and
6-H), 4.48 (s, 2 H, 1′-CH2).
13C NMR (101 MHz, CDCl3):  = 147.8 (C-5′), 147.0 (C-1), 141.0 (C-1′),
133.9 (C-3′), 130.1 (C-2′), 129.6 (C-3 and C-5), 123.7 (C-6′), 123.4 (C-
4′), 118.7 (C-4), 113.1 (C-2 and C-6), 48.5 (1′-CH2).
•+
HRMS (EI): m/z [M]•+ calcd for C16H17NO2
: 255.1254; found:
255.1260.
HRMS (EI): m/z [M]•+ calcd for C13H11BrN2O2•+: 305.9998; found:
305.9999.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

I
C. Glas et al.
Paper
Synthesis
7-Nitro-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5g)
13C NMR (126 MHz, CDCl3):  = 150.6 (C-1′), 134.3 (C-3a), 132.9 (C-
7a), 129.4 (C-3′ and C-5′), 127.2 (C-3), 122.7 (C-2), 119.6 (C-4′), 116.4
(C-2′ and C-6′), 48.3 (C-7), 47.6 (C-5), 25.5 (C-4).
Prepared according to General Procedure B from N-(2-bromo-5-nitro-
benzyl)aniline (3g) (76.8 mg, 0.250 mmol) and (E)-2-ethoxyvinylbo-
ronic acid pinacol ester (106 L, 0.500 mmol). The crude product was
purified by FCC (hexanes/EtOAc, 85:15) to give product 5g (39.9 mg,
0.157 mmol, 63%) as an orange solid.
HRMS (EI): m/z [M]•+ calcd for C13H13NS•+: 215.0763; found: 215.0763.
N-[(2-Bromopyridin-3-yl)methyl]aniline (3i)
Rf = 0.50 (hexanes/EtOAc, 85:15); mp 66–70 °C.
Prepared according to General Procedure A from 2-bromo-3-pyridin-
ecarboxaldehyde (112 mg, 0.600 mmol) and aniline (2) (45.6 L,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
85:15) to give product 3i (121 mg, 0.460 mmol, 92%) as a beige solid.
IR (ATR): 2920, 2846, 2774, 1599, 1514, 1493, 1460, 1378, 1340, 1262,
1194, 1086, 931, 891, 813, 756, 733, 695 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.07–8.02 (m, 2 H, 6-H and 8-H), 7.34–
7.28 (m, 3 H, 3′-H, 5′-H and 5-H), 7.02–6.98 (m, 2 H, 2′-H and 6′-H),
6.89 (tt, J = 7.3, 1.1 Hz, 1 H, 4′-H), 4.48 (s, 2 H, 1-H), 3.61 (t, J = 5.8 Hz,
2 H, 3-H), 3.08 (t, J = 5.8 Hz, 2 H, 4-H).
Rf = 0.26 (hexanes/EtOAc, 85:15); mp 107–109 °C.
IR (ATR): 3295, 2921, 1600, 1560, 1531, 1496, 1398, 1324, 1276, 1254,
1178, 1051, 987, 860, 800, 745, 689 cm–1
.
13C NMR (101 MHz, CDCl3):  = 150.1 (C-1′), 146.5 (C-7), 142.8 (C-4a),
136.2 (C-8a), 129.8 (C-5), 129.5 (C-3′ and C-5′), 121.9 (C-6 or C-8),
121.5 (C-6 or C-8), 119.8 (C-4′), 115.9 (C-2′ and C-6′), 51.0 (C-1), 46.6
(C-3), 29.3 (C-4).
1H NMR (500 MHz, CDCl3):  = 8.27 (dt, J = 4.7, 1.3 Hz, 1 H, 6′-H), 7.69
(ddt, J = 7.6, 1.9, 0.9 Hz, 1 H, 4′-H), 7.22 (dd, J = 7.6, 4.7 Hz, 1 H, 5′-H),
7.20–7.15 (m, 2 H, 3-H and 5-H), 6.75 (tt, J = 7.3, 1.1 Hz, 1 H, 4-H),
6.59–6.55 (m, 2 H, 2-H and 6-H), 4.41 (d, J = 4.6 Hz, 2 H, 3′-CH2), 4.29
(s, 1 H, NH).
•
HRMS (EI): m/z [M – H]• calcd for C15H13NO2 : 253.0977; found:
13C NMR (126 MHz, CDCl3):  = 148.7 (C-6′), 147.2 (C-1), 142.8 (C-2′),
137.2 (C-4′), 135.8 (C-3′), 129.6 (C-3 and C-5), 123.2 (C-5′), 118.4 (C-
4), 113.1 (C-2 and C-6), 47.5 (3′-CH2).
253.0971.
The analytical data are in accordance with those published in the lit-
erature.23
•+
HRMS (EI): m/z [M]•+ calcd for C12H11BrN2
: 262.0100; found:
N-[(3-Bromothiophen-2-yl)methyl]aniline (3h)
262.0101.
Prepared according to General Procedure A from 3-bromothiophene-
2-carboxaldehyde (115 mg, 0.600 mmol) and aniline (2) (45.6 L,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
95:5) to give product 3h (117 mg, 0.438 mmol, 88%) as a yellow liq-
uid.
The analytical data are in accordance with those published in the lit-
erature.24
N-(2-Bromobenzyl)-4-methoxyaniline (3j)
Prepared according to General Procedure A from 2-bromobenzalde-
hyde (1) (111 mg, 0.600 mmol) and p-anisidine (62.2 mg, 0.500
mmol). The crude product was purified by FCC (hexanes/EtOAc,
90:10) to give product 3j (108 mg, 0.369 mmol, 74%) as a dark yellow
liquid.
Rf = 0.47 (hexanes/EtOAc, 95:5).
IR (ATR): 3410, 1600, 1501, 1312, 1259, 1180, 1152, 1095, 1067, 923,
869, 748, 690 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.22–7.17 (m, 3 H, 3-H, 5-H and 5′-H),
6.96 (d, J = 5.3 Hz, 1 H, 4′-H), 6.76 (tt, J = 7.4, 1.1 Hz, 1 H, 4-H), 6.70–
6.66 (m, 2 H, 2-H and 6-H), 4.48 (d, J = 5.0 Hz, 2 H, 2′-CH2), 4.14 (s, 1 H,
NH).
Rf = 0.39 (hexanes/EtOAc, 90:10).
IR (ATR): 3419, 3059, 2995, 2931, 2831, 1618, 1568, 1509, 1464, 1440,
1357, 1232, 1178, 1123, 1082, 1025, 818, 749, 660 cm–1
.
13C NMR (126 MHz, CDCl3):  = 147.4 (C-1), 138.0 (C-2′), 130.2 (C-4′),
129.4 (C-3 and C-5), 124.8 (C-5′), 118.6 (C-4), 113.5 (C-2 and C-6),
108.6 (C-3′), 43.1 (2′-CH2).
1H NMR (400 MHz, CDCl3):  = 7.56 (dd, J = 8.0, 1.3 Hz, 1 H, 3′-H),
7.46–7.42 (m, 1 H, 6′-H), 7.29–7.23 (m, 1 H, 5′-H), 7.15–7.10 (m, 1 H,
4′-H), 6.80–6.60 (m, 4 H, 2-H, 3-H, 5-H and 6-H), 4.38 (s, 2 H, 1′-CH2),
3.74 (s, 3 H, 4-OCH3).
HRMS (EI): m/z [M]•+ calcd for C11H10BrNS•+: 266.9712; found:
13C NMR (101 MHz, CDCl3):  = 153.0 (C-4), 141.1 (C-1), 138.0 (C-1′),
132.9 (C-3′), 129.7 (C-6′), 128.9 (C-4′), 127.7 (C-5′), 123.6 (C-2′), 115.1
(C-2 and C-6 or C-3 and C-5), 115.0 (C-2 and C-6 or C-3 and C-5), 55.9
(4-OCH3), 49.8 (1′-CH2).
HRMS (EI): m/z [M]•+ calcd for C14H14BrNO•+: 291.0253; found:
291.0253.
266.9712.
6-Phenyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (5h)
Prepared according to General Procedure B from N-[(3-bromothio-
phen-2-yl)methyl]aniline (3h) (53.6 mg, 0.200 mmol) and (E)-2-
ethoxyvinylboronic acid pinacol ester (84.7 L, 0.400 mmol). The
crude product was purified by FCC (hexanes/EtOAc, 95:5) to give
product 5h (16.4 mg, 0.0762 mmol, 38%) as a yellow oil.
The analytical data are in accordance with those published in the lit-
erature.25
Rf = 0.26 (DCM/hexanes, 25:75).
IR (ATR): 3318, 2920, 1598, 1497, 1381, 1317, 1244, 1228, 1183, 1127,
2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (5j)
994, 886, 750, 690 cm–1
.
Prepared according to General Procedure B from N-(2-bromobenzyl)-
4-methoxyaniline (3j) (51.0 mg, 0.175 mmol) and (E)-2-ethoxyvinyl-
boronic acid pinacol ester (74.2 L, 0.350 mmol). The crude product
was purified by FCC (hexanes/EtOAc, 85:15) to give product 5j (22.9
mg, 95.7 mol, 55%) as a brown solid.
1H NMR (500 MHz, CDCl3):  = 7.30–7.25 (m, 2 H, 3′-H and 5′-H), 7.14
(dt, J = 5.0, 0.8 Hz, 1 H, 2-H), 7.02–6.98 (m, 2 H, 2′-H and 6′-H), 6.86
(tt, J = 7.3, 1.1 Hz, 1 H, 4′-H), 6.81 (d, J = 5.0 Hz, 1 H, 3-H), 4.47–4.45
(m, 2 H, 7-H), 3.62 (t, J = 5.7 Hz, 2 H, 5-H), 2.82 (tt, J = 5.8, 1.7 Hz, 2 H,
4-H).
Rf = 0.58 (hexanes/EtOAc, 85:15); mp 80–84 °C.
IR (ATR): 2920, 2808, 1509, 1459, 1442, 1385, 1272, 1240, 1206, 1188,
1151, 1111, 1035, 930, 822, 800, 754, 720, 701 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

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C. Glas et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.21–7.11 (m, 4 H, 5-H, 6-H, 7-H and 8-
H), 7.05–6.98 (m, 2 H, 2′-H and 6′-H), 6.90–6.85 (m, 2 H, 3′-H and 5′-
H), 4.31 (s, 2 H, 1-H), 3.78 (s, 3 H, 4′-OCH3), 3.46 (t, J = 5.9 Hz, 2 H, 3-
H), 3.00 (t, J = 5.9 Hz, 2 H, 4-H).
The analytical data are in accordance with those published in the lit-
erature.27
N-(2-Bromobenzyl)cyclohexanamine (3l)
13C NMR (101 MHz, CDCl3):  = 153.6 (C-4′), 145.5 (C-1′), 134.8 (C-4a
or C-8a), 134.7 (C-4a or C-8a), 128.8 (C-5), 126.7 (C-6 or C-7 or C-8),
126.4 (C-6 or C-7 or C-8), 126.0 (C-6 or C-7 or C-8), 118.2 (C-2′ and C-
6′), 114.7 (C-3′ and C-5′), 55.8 (4′-OCH3), 52.8 (C-1), 48.6 (C-3), 29.2
(C-4).
Prepared according to General Procedure A from 2-bromobenzalde-
hyde (1) (111 mg, 0.600 mmol) and cyclohexylamine (57.8 L, 0.500
mmol). The crude product was purified by FCC (hexanes/EtOAc +
Et3N, 90:10 + 1) to give product 3l (64.0 mg, 0.239 mmol, 48%) as a
colorless oil.
HRMS (EI): m/z [M – H]• calcd for C16H16NO•: 238.1232; found:
Rf = 0.30 (hexanes/EtOAc, 90:10 + Et3N).
238.1226.
IR (ATR): 2923, 2851, 1462, 1440, 1347, 1259, 1124, 1024, 888, 746,
656 cm–1
.
The analytical data are in accordance with those published in the lit-
erature.6c
1H NMR (500 MHz, CDCl3):  = 7.53 (dd, J = 7.9, 1.3 Hz, 1 H, 3′-H), 7.40
(dd, J = 7.6, 1.8 Hz, 1 H, 6′-H), 7.27 (td, J = 7.5, 1.1 Hz, 1 H, 5′-H), 7.11
(td, J = 7.7, 1.8 Hz, 1 H, 4′-H), 3.88 (s, 2 H, 1′-CH2), 2.46 (tt, J = 10.3, 3.7
Hz, 1 H, 1-H), 1.96–1.90 (m, 2 H, 2-H and/or 6-H), 1.77–1.71 (m, 2 H,
3-H and/or 5-H), 1.64–1.58 (m, 1 H, 4-H), 1.31–1.20 (m, 2 H, 2-H
and/or 6-H), 1.20–1.10 (m, 3 H, 4-H and 3-H and/or 5-H).
13C NMR (126 MHz, CDCl3):  = 140.0 (C-1′), 132.9 (C-3′), 130.5 (C-6′),
128.6 (C-4′), 127.6 (C-5′), 124.1 (C-2′), 56.2 (C-1), 51.1 (1′-CH2), 33.7
(C-2 and C-6), 26.3 (C-4), 25.2 (C-3 and C-5).
Ethyl 4-[(2-Bromobenzyl)amino]benzoate (3k)
Prepared according to General Procedure A from 2-bromobenzalde-
hyde (1) (111 mg, 0.600 mmol) and ethyl-4-aminobenzoate (82.6 mg,
0.500 mmol). The crude product was purified by FCC (hexanes/EtOAc,
75:25) to give product 3k (108 mg, 0.323 mmol, 65%) as a white solid.
Rf = 0.47 (hexanes/EtOAc, 75:25); mp 117–120 °C.
IR (ATR): 3374, 2928, 1722, 1672, 1598, 1530, 1439, 1336, 1268, 1173,
1106, 1023, 839, 770, 752, 700 cm–1
.
HRMS (EI): m/z [M]•+ calcd for C13H18BrN•+: 267.0617; found:
267.0617.
1H NMR (400 MHz, CDCl3):  = 7.91–7.85 (m, 2 H, 2-H and 6-H), 7.57
(dd, J = 7.9, 1.3 Hz, 1 H, 3′-H), 7.41 (d, J = 7.5 Hz, 1 H, 6′-H), 7.29–7.23
(m, 1 H, 5′-H), 7.15 (td, J = 7.6, 1.7 Hz, 1 H, 4′-H), 6.67 (d, J = 8.3 Hz, 2
H, 3-H and 5-H), 4.49 (s, 2 H, 1′-CH2), 4.31 (q, J = 7.1 Hz, 2 H, 7-H), 1.35
(t, J = 7.1 Hz, 3 H, 8-H).
The analytical data are in accordance with those published in the lit-
erature.28
N-(2-Bromobenzyl)-4-chloroaniline (3m)
13C NMR (101 MHz, CDCl3):  = 166.8 (1-COOEt), 150.6 (C-4), 136.9
(C-1′), 133.1 (C-3′), 131.6 (C-2 and C-6), 129.4 (C-6′), 129.3 (C-4′),
127.8 (C-5′), 123.6 (C-2′), 120.3 (C-1), 112.7 (C-3 and C-5), 60.5 (C-7),
48.4 (1′-CH2), 14.6 (C-8).
Prepared according to General Procedure A from 2-bromobenzalde-
hyde (1) (111 mg, 0.600 mmol) and 4-chloroaniline (65.1 mg, 0.500
mmol). The crude product was purified by FCC (hexanes/EtOAc, 95:5)
to give product 3m (112 mg, 0.379 mmol, 76%) as a pale yellow oil.
HRMS (EI): m/z [M]•+ calcd for C16H16BrNO2•+: 333.0359; found:
Rf = 0.33 (hexanes/EtOAc, 95:5).
333.0358.
IR (ATR): 3430, 2923, 2852, 1599, 1497, 1464, 1440, 1319, 1264, 1177,
1095, 1024, 812, 747 cm–1
.
The analytical data are in accordance with those published in the lit-
erature.26
1H NMR (500 MHz, CDCl3):  = 7.57 (dd, J = 7.9, 1.2 Hz, 1 H, 3′-H), 7.36
(dq, J = 7.7, 0.8 Hz, 1 H, 6′-H), 7.26 (td, J = 7.5, 1.3 Hz, 1 H, 5′-H), 7.18–
7.13 (m, 1 H, 4′-H), 7.13–7.09 (m, 2 H, 3-H and 5-H), 6.55–6.51 (m, 2
H, 2-H and 6-H), 4.38 (d, J = 5.7 Hz, 2 H, 1′-CH2), 4.22 (t, J = 5.0 Hz, 1 H,
NH).
13C NMR (126 MHz, CDCl3):  = 146.4 (C-1), 137.8 (C-1′), 133.1 (C-3′),
129.3 (C-3 and C-5), 129.2 (C-6′), 129.0 (C-4′), 127.7 (C-5′), 123.4 (C-
2′), 122.5 (C-4), 114.2 (C-2 and C-6), 48.6 (1′-CH2).
Ethyl 4-[3,4-Dihydroisoquinolin-2(1H)-yl]benzoate (5k)
Prepared according to General Procedure B from ethyl 4-[(2-bromo-
benzyl)amino]benzoate (3k) (83.6 mg, 0.250 mmol) and (E)-2-
ethoxyvinylboronic acid pinacol ester (106 L, 0.500 mmol). The
crude product was purified by FCC (hexanes/EtOAc, 85:15) to give
product 5k (49.1 mg, 0.175 mmol, 70%) as an off-white solid.
Rf = 0.32 (hexanes/EtOAc, 95:5); mp 49–51 °C.
HRMS (EI): m/z [M]•+ calcd for C13H11BrClN•+: 294.9758; found:
IR (ATR): 2977, 2850, 1695, 1604, 1519, 1390, 1362, 1277, 1228, 1181,
294.9758.
1102, 1024, 926, 827, 767, 741, 698 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.98–7.94 (m, 2 H, 2-H and 6-H), 7.24–
7.16 (m, 4 H, 5′-H, 6′-H, 7′-H and 8′-H), 6.91–6.85 (m, 2 H, 3-H and 5-
H), 4.52 (s, 2 H, 1′-H), 4.33 (q, J = 7.1 Hz, 2 H, 7-H), 3.66 (t, J = 5.9 Hz, 2
H, 3′-H), 3.00 (t, J = 5.9 Hz, 2 H, 4′-H), 1.38 (t, J = 7.1 Hz, 3 H, 8-H).
13C NMR (126 MHz, CDCl3):  = 167.0 (1-COOEt), 153.1 (C-4), 135.2 (C-
8′a), 134.0 (C-4′a), 131.4 (C-2 and C-6), 128.4 (C-5′), 126.9 (C-6′ or C-
7′ or C-8′), 126.7 (C-6′ or C-7′ or C-8′), 126.5 (C-6′ or C-7′ or C-8′),
118.9 (C-1), 112.3 (C-3 and C-5), 60.4 (C-7), 49.3 (C-1′), 45.0 (C-3′),
29.2 (C-4′), 14.6 (C-8).
2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (5m)
Prepared according to General Procedure B from N-(2-bromobenzyl)-
4-chloroaniline (3m) (59.3 mg, 0.200 mmol) and (E)-2-ethoxyvinyl-
boronic acid pinacol ester (84.7 L, 0.400 mmol). The crude product
was purified by FCC (hexanes/EtOAc, 98:2) to give product 5m (33.6
mg, 0.138 mmol, 69%) as a beige solid.
Rf = 0.36 (hexanes/EtOAc, 98:2); mp 59–62 °C.
IR (ATR): 3316, 2915, 2842, 1595, 1494, 1459, 1430, 1384, 1341, 1300,
1224, 1156, 1093, 928, 806, 738, 720 cm–1
.
•
HRMS (EI): m/z [M – H]• calcd for C18H18NO2 : 280.1338; found:
280.1332.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

K
C. Glas et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.24–7.21 (m, 2 H, 3′-H and 5′-H),
7.21–7.14 (m, 4 H, 5-H, 6-H, 7-H and 8-H), 6.90–6.87 (m, 2 H, 2′-H
and 6′-H), 4.38 (s, 2 H, 1-H), 3.53 (t, J = 5.9 Hz, 2 H, 3-H), 2.98 (t, J = 5.9
Hz, 2 H, 4-H).
13C NMR (126 MHz, CDCl3):  = 149.2 (C-1′), 134.8 (C-4a), 134.2 (C-
8a), 129.2 (C-3′ and C-5′), 128.7 (C-5), 126.7 (C-6 or C-7 or C-8), 126.6
(C-6 or C-7 or C-8), 126.3 (C-6 or C-7 or C-8), 123.5 (C-4′), 116.3 (C-2′
and C-6′), 50.8 (C-1), 46.7 (C-3), 29.1 (C-4).
Ethyl 3-(3-Bromo-4-{[(2,2-dimethyl-4-oxo-4H-benzo[d][1,3]diox-
in-6-yl)amino]methyl}benzamido)propanoate (3o)
Prepared according to General Procedure A (but with 1.5 equivalents
of the aldehyde) from ethyl 3-(3-bromo-4-formylbenzamido)propa-
noate (6) (200 mg, 0.609 mmol) and 6-amino-2,2-dimethyl-4H-ben-
zo[d][1,3]dioxin-4-one (7) (78.5 mg, 0.406 mmol). The product 3o
(196 mg, 0.389 mmol, 96%) was obtained without further purification
as a yellow oily solid.
HRMS (EI): m/z [M – H]• calcd for C15H13ClN•: 242.0737; found:
Rf = 0.34 (hexanes/EtOAc, 50:50).
242.0730.
IR (ATR): 3369, 2989, 2938, 2322, 2178, 1715, 1648, 1536, 1495, 1378,
1295, 1278, 1196, 1126, 1051, 1035, 980, 934, 826 cm–1
.
The analytical data are in accordance with those published in the lit-
erature.29
1H NMR (400 MHz, DMSO-d6):  = 8.64 (t, J = 5.5 Hz, 1 H, CONH), 8.06
(d, J = 1.7 Hz, 1 H, 2′-H), 7.78 (dd, J = 8.0, 1.7 Hz, 1 H, 6′-H), 7.45 (d, J =
8.0 Hz, 1 H, 5′-H), 6.93 (dd, J = 8.9, 2.8 Hz, 1 H, 7′′-H), 6.89 (d, J = 8.7
Hz, 1 H, 8′′-H), 6.86 (d, J = 2.7 Hz, 1 H, 5′′-H), 6.53 (t, J = 6.0 Hz, 1 H,
CH2NH), 4.33 (d, J = 5.9 Hz, 2 H, CH2NH), 4.06 (q, J = 7.1 Hz, 2 H,
CH2CH3), 3.47 (td, J = 6.7, 5.4 Hz, 2 H, 3-H), 2.56 (t, J = 6.9 Hz, 2 H, 2-H),
1.62 [s, 6 H, C(CH3)2], 1.17 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (126 MHz, DMSO-d6):  = 171.2 (C-1), 164.6 (CONH), 160.7
(C-4′′), 146.7 (C-8a′′), 143.9 (C-6′′), 141.2 (C-4′), 134.8 (C-1′), 131.1 (C-
2′), 128.6 (C-5′), 126.6 (C-6′), 122.4 (C-3′), 121.8 (C-7′′), 117.9 (C-8′′),
113.5 (C-4a′′), 109.3 (C-5′′), 105.9 (C-2′′), 59.9 (CH2CH3), 47.1
(CH2NH), 35.6 (C-3), 33.6 (C-2), 25.2 [C(CH3)2], 14.1 (CH2CH3).
N-(2-Bromobenzyl)pyridin-2-amine (3n)
Prepared according to General Procedure A from 2-bromobenzalde-
hyde (1) (111 mg, 0.600 mmol) and 2-aminopyridine (47.1 mg, 0.500
mmol). The crude product was purified by FCC (hexanes/EtOAc +
Et3N, 90:10 + 1) to give product 3n (62.0 mg, 0.236 mmol, 47%) as a
yellow solid.
Rf = 0.25 (hexanes/EtOAc + Et3N, 90:10 + 1); mp 109–112 °C.
IR (ATR): 3235, 3020, 1600, 1580, 1537, 1448, 1425, 1331, 1277, 1152,
1023, 767, 750 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.11 (ddd, J = 5.1, 1.9, 0.9 Hz, 1 H, 6-H),
7.56 (dd, J = 7.9, 1.2 Hz, 1 H, 3′-H), 7.45–7.39 (m, 1 H, 6′-H), 7.40 (ddd,
J = 8.7, 7.1, 1.9 Hz, 1 H, 4-H), 7.28–7.24 (m, 1 H, 5′-H), 7.15–7.10 (m, 1
H, 4′-H), 6.60 (ddd, J = 7.1, 5.0, 1.0 Hz, 1 H, 5-H), 6.36 (dt, J = 8.3, 0.9
Hz, 1 H, 3-H), 5.06–5.00 (m, 1 H, NH), 4.59 (d, J = 6.3 Hz, 2 H, 1′-CH2).
HRMS (ESI): m/z [M – H]– calcd for C23H24BrN2O6–: 503.0823; found:
503.0827.
5-{6-[(2-Carboxyethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-
yl}-2-hydroxybenzoic Acid (5o)
13C NMR (126 MHz, CDCl3):  = 158.5 (C-2), 148.3 (C-6), 138.2 (C-1′),
137.7 (C-4), 132.9 (C-3′), 129.4 (C-6′), 128.9 (C-4′), 127.7 (C-5′), 123.6
(C-2′), 113.5 (C-5), 107.0 (C-3), 46.6 (1′-CH2).
•+
Prepared according to General Procedure B from ethyl 3-(3-bromo-4-
{[(2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-6-yl)amino]meth-
yl}benzamido)propanoate (3o) (150 mg, 0.208 mmol) and (E)-2-
ethoxyvinylboronic acid pinacol ester (88.0 L, 0.416 mmol).
HRMS (EI): m/z [M]•+ calcd for C12H11BrN2
: 262.0100; found:
262.0100.
Without purification, the crude cyclized product (0.208 mmol) was
then dissolved in THF (1.4 mL) followed by the addition of a solution
of KOH (58.3 mg, 1.04 mmol) in water (1.4 mL). The reaction mixture
was stirred at room temperature for 1.5 h. Then water (10 mL) was
added and the mixture acidified to pH 1 using 2 N aq HCl. The organic
material was extracted with EtOAc (3 × 15 mL). The combined organic
layers were extracted with 0.5 M aq NaOH (3 × 15 mL). The aqueous
phase was then again acidified to pH 1 using 2 M aq HCl and extract-
ed with EtOAc (3 × 15 mL). The combined organic layers were dried
using phase separating paper and the solvents were removed in vac-
uo. The crude product was purified by FCC (MeOH/DCM + AcOH, 5:95
+ 1) and dried under high vacuum to give 5o (47.9 mg, 0.125 mmol,
60% over 3 steps) as a yellow-brown oily solid.
2-(Pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (5n)
Prepared according to General Procedure B from N-(2-bromoben-
zyl)pyridin-2-amine (3n) (52.6 mg, 0.200 mmol) and (E)-2-ethoxyvi-
nylboronic acid pinacol ester (84.7 L, 0.400 mmol). The crude prod-
uct was purified by FCC (hexanes/EtOAc + Et3N, 90:10 + 1) to give
product 5n (10.1 mg, 0.0480 mmol, 24%) as an off-white oily solid.
Rf = 0.40 (hexanes/EtOAc + Et3N, 95:5 + 1).
IR (ATR): 3006, 2922, 2837, 1666, 1592, 1562, 1480, 1435, 1387, 1312,
1299, 1228, 1157, 978, 937, 764, 741 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.22 (ddd, J = 5.0, 2.0, 0.9 Hz, 1 H, 6′-H),
7.50 (ddd, J = 8.9, 7.1, 2.0 Hz, 1 H, 4′-H), 7.22–7.19 (m, 2 H, 6-H and/or
7-H and/or 8-H), 7.19–7.17 (m, 2 H, 5-H and 6-H or 7-H or 8-H), 6.68
(dt, J = 8.6, 1.0 Hz, 1 H, 3′-H), 6.60 (ddd, J = 7.1, 5.0, 0.9 Hz, 1 H, 5′-H),
4.71 (s, 2 H, 1-H), 3.85 (t, J = 6.0 Hz, 2 H, 3-H), 2.98 (t, J = 5.9 Hz, 2 H, 4-
H).
13C NMR (126 MHz, CDCl3):  = 158.9 (C-2′), 148.1 (C-6′), 137.6 (C-4′),
135.6 (C-4a), 134.5 (C-8a), 128.5 (C-5), 126.7 (C-8), 126.5 (C-6 or C-7),
126.3 (C-6 or C-7), 112.6 (C-5′), 106.8 (C-3′), 47.3 (C-1), 42.7 (C-3),
29.2 (C-4).
Rf = 0.14 (MeOH/DCM + AcOH, 5:95 + 1).
IR (ATR): 3333, 2922, 2586, 1709, 1632, 1547, 1488, 1434, 1372, 1229,
1009, 828, 750 cm–1
.
1H NMR (500 MHz, DMSO-d6):  (contains residual AcOH) = 12.22 (s, 2
H, 1-COOH and 2′′-COOH), 8.46 (t, J = 5.4 Hz, 1 H, CONH), 7.64 (s, 1 H,
5′-H or 7′-H), 7.64–7.61 (m, 1 H, 5′-H or 7′-H), 7.40 (s, 1 H, 6-H), 7.28
(d, J = 7.9 Hz, 1 H, 8′-H), 7.10 (dd, J = 9.2, 2.7 Hz, 1 H, 4-H), 6.69 (d, J =
8.7 Hz, 1 H, 3-H), 4.23 (s, 2 H, 1′-H), 3.45 (q, J = 6.7 Hz, 2 H, 1′′-H), 3.36
(t, J = 5.8 Hz, 3 H, 3′-H), 2.95 (t, J = 5.8 Hz, 2 H, 4′-H), 2.53 [d, J = 1.6 Hz,
2 H, 2′′-H (collapses with DMSO)].
13C NMR (126 MHz, DMSO-d6):  (contains residual AcOH) = 172.9 (C-
3′′), 171.8 (1-COOH), 166.2 (CONH), 156.2 (C-2), 141.8 (C-5), 138.1 (C-
8a′), 134.3 (C-4a′), 132.3 (C-6′), 127.4 (C-5′), 126.5 (C-8′), 124.5 (C-7′),
HRMS (EI): m/z [M]•+ calcd for C14H14N2•+: 210.1151; found: 210.1150.
The analytical data are in accordance with those published in the lit-
erature.30
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L

L
C. Glas et al.
Paper
Synthesis
122.8 (C-4), 117.6 (C-6), 116.4 (C-3), 52.3 (C-1′), 48.2 (C-3′), 35.6 (C-
1′′), 33.8 (C-2′′), 28.6 (C-4′′); [C-1′ not clearly visible].
HRMS (ESI): m/z [M – H]– calcd for C20H19N2O6–: 383.1249; found:
(7) (a) Hodson, H. F.; Batchelor, J. F.; Selway, J. W. T.; Vinter, J. G.;
Iyer, R. US4801593, 1989. (b) Almena, J.; Foubelo, F.; Yus, M. Tet-
rahedron 1996, 52, 8545. (c) Ma, Y.-N.; Yang, X.-J.; Pan, L.; Hou,
Z.; Geng, H.-L.; Song, X.-P.; Zhou, L.; Miao, F. Chem. Pharm. Bull.
2013, 61, 204.
383.1249.
(8) Mottinelli, M.; Leese, M. P.; Potter, B. V. L. Beilstein J. Org. Chem.
2017, 13, 1871.
Funding Information
(9) (a) Schütz, R.; Meixner, M.; Antes, I.; Bracher, F. Org. Biomol.
Chem. 2020, 18, 3047. (b) Schütz, R.; Schmidt, S.; Bracher, F. Tet-
rahedron 2020, 76, 131150. (c) Schütz, R.; Müller, M.; Gerndt, S.;
Bartel, K.; Bracher, F. Arch. Pharm. 2020, 353, e2000106.
(d) Schütz, R.; Müller, M.; Geisslinger, F.; Vollmar, A.; Bartel, K.;
Bracher, F. Eur. J. Med. Chem. 2020, 207, 112810. (e) Melzer, B.
C.; Bracher, F. Beilstein J. Org. Chem. 2017, 13, 1564. (f) Melzer, B.
C.; Felber, J. G.; Bracher, F. Beilstein J. Org. Chem. 2018, 14, 130.
(g) Melzer, B.; Bracher, F. Org. Biomol. Chem. 2015, 13, 7664.
(10) Glas, C.; Dietschreit, J. C. B.; Wössner, N.; Urban, L.; Ghazy, E.;
Sippl, W.; Jung, M.; Ochsenfeld, C.; Bracher, F. Eur. J. Med. Chem.
2020, 206, 112676.
This work was funded by the Deutsche Forschungsgemeinschaft
(DFG) (German Research Foundation) (Project-ID: 325871075–SFB
1309).Deutsch
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Acknowledgment
We thank Doreen Reuter and Karl Sauvageot-Witzku for technical
support.
Supporting Information
(11) Kamlah, A.; Bracher, F. Lett. Org. Chem. 2019, 16, 931.
(12) (a) Vögerl, K.; Ong, D. N.; Bracher, F. Synthesis 2018, 50, 1323.
(b) Bracher, F. SynOpen 2018, 2, 96. (c) Vögerl, K.; Ong, N.;
Senger, J.; Herp, D.; Schmidtkunz, K.; Marek, M.; Müller, M.;
Bartel, K.; Shaik, T. B.; Porter, N. J.; Robaa, D.; Christianson, D.
W.; Romier, C.; Sippl, W.; Jung, M.; Bracher, F. J. Med. Chem.
2019, 62, 1138.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706002.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–L