Transition-Metal-Free Oxidative Cross-Coupling of Triorganoindium Reagents with Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.joc.9b00928

Triorganoindium reagents (R₃In) react with tetrahydroisoquinolines (THIQs) in the presence of Ph₃CBF₄ as an oxidant to afford 1-substituted THIQs. The reaction proceeds in good yields at rt using 50 mol % R₃In with a variety of organic groups. ¹H NMR studies show the generation of an iminium ion intermediate, supporting a two-step mechanism based on THIQ oxidation and R₃In nucleophilic addition. This reaction was applied to the synthesis of the alkaloid nuciferine in three steps.

Full text of DOI:10.1021/acs.joc.9b00928

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Note
Transition-Metal-Free Oxidative Cross-Coupling of
Triorganoindium Reagents with Tetrahydroisoquinolines
José M. Gil-Negrete, José Pérez Sestelo, and Luis A. Sarandeses
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00928 • Publication Date (Web): 11 Jul 2019
Downloaded from pubs.acs.org on July 11, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 24
The Journal of Organic Chemistry
1
2
3
4
5
Transition-Metal-Free Oxidative Cross-Coupling of
Triorganoindium Reagents with Tetrahydroisoquinolines
6
7
8
9
José M. Gil-Negrete, José Pérez Sestelo,* and Luis A. Sarandeses*
10
11
12
13
14
15
16
17
18
19
20
21
22
Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química,
Universidade da Coruña, E-15071 A Coruña, Spain.
TOC
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph3CBF4
(110 mol %)
R’
R’
+
R3In
N
N
CH2Cl2/THF (4:1)
rt, 16 h
Cbz
Cbz
R
(50 mol %)
R = aryl, heteroaryl,
alkynyl, alkyl
54–93%
(16 examples)
Abstract. Triorganoindium reagents (R3In) react with tetrahydroisoquinolines (THIQs) in the
presence of Ph3CBF4 as oxidant to afford 1-substituted THIQs. The reaction proceeds in good
1
yields at rt using 50 mol % of R3In with a variety of organic groups. H NMR studies show the
generation of an iminium ion intermediate supporting a two-step mechanism based on THIQ
oxidation and R3In nucleophilic addition. This reaction was applied to the synthesis of the alkaloid
Nuciferine in three steps.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
1
2
3
4
5
6
7
8
9
Tetrahydroisoquinolines (THIQs) are one of the most common nitrogen-containing heterocycles
that can be encountered among bioactive natural products and pharmaceutical drugs.1 For example,
THIQ antitumor antibiotics such as Quinocarcin display broad-range cytotoxicity against several
types of human cancer cells.2 Numerous naturally occurring alkaloids with the THIQ core possess
many relevant biological properties as well, like antiprotozoal Emetine3a or analgesic Reticuline.3b
Pharmaceuticals like antimuscarinic agent Solifenacin4 (VesiCare®), used in the treatment of
spasmodic bladder, also display the THIQ motif in their structures (Figure 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Examples of Biologically Relevant Tetrahydroisoquinolines
MeO
CO2H
H
H
N
N
Me
MeO
N
H
Et
H
H
H
O
MeO
HN
Quinocarcin
Emetine
MeO
HO
N
N
O
Me
OH
O
N
OMe
Reticuline
Solifenacin (VesiCare)
The selective functionalization of tetrahydroisoquinolines at the C-1 position constitutes one
attractive approach for the synthesis of derivatives. Several methods have been developed including
transition-metal catalyzed reactions,5 metal-free oxidative coupling reactions,6 photocatalytic and
electrochemical methods7 and dehydrogenative cross-coupling reactions.8
Oxidative coupling reactions constitute a modern and efficient method for the C–H
functionalization of the C-1 position of THIQ. These reactions are based on the generation of an
iminium ion through C-1 oxidation and further reaction with nucleophiles. As part of a research
project devoted to the development of synthetic applications of indium organometallics in organic
synthesis, we recently became interested in the development of novel transition-metal-free reactions
of triorganoindium reagents.9 Recently, we reported the coupling of benzopyranyl acetals with
triorganoindium reagents in the presence of Lewis acids.10. Herein, we report the transition metal-
free oxidative coupling reactions of R3In with THIQs.
Our investigation started with the reaction of triphenylindium (Ph3In) with N-protected
tetrahydroisoquinolines in the presence of various oxidant reagents. Considering the ability of
2
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
triorganoindium reagents (R3In) to transfer more than one organic group in metal-catalyzed cross-
coupling reactions, our initial experiments were designed using 50 mol % of R3In. As solvent we
chose a CH2Cl2/THF (4:1) mixture, since R3In are usually prepared in THF and the oxidants
commonly require a chlorinated solvent. In our first experiments, the reaction of Ph3In with N-Cbz-
THIQ (1a, Table 1) using DDQ or PIFA as the oxidant only provided trace amounts of the coupling
product 2a (entries 1 and 2). Interestingly, the use of triphenylcarbenium salts as oxidants afforded
the coupling product in better yields.6f,6h Therefore, the reaction of 1a using Ph3CClO4 (110 mol %)
in CH2Cl2/THF (4:1) gave 2a in 56% yield after 16 h at rt (entry 3). Under the same conditions,
using the commercially available Ph3CBF4, 2a was obtained in a slightly better yield (61%, entry
4). Further experiments using higher temperatures and longer reaction times provided similar yields
(entries 5 and 6), and larger amounts of Ph3In or the oxidant did not improve the reaction yields
(entries 7 and 8). Finally, we found that the protecting group at the nitrogen played a critical role in
the reaction. The coupling product 2a was not obtained using Boc or tosyl N-protected 1 (entries 9
and 10). As it has been reported,6d benzyl carbamate (Cbz) showed the most efficient N-protecting
group when Ph3CBF4 is used as oxidant.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Reaction Optimization
oxidant
+
Ph3In
N
N
conditions
PG
PG
Ph
1
2a
entrya
PG
mol % of Ph3In oxidant (mol %)
yield (%)d
1
2
3
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Cbz (1a)
Boc
50
50
50
50
50
50
100
50
50
50
DDQ (110)
PIFA (110)
—
—
56
61
44
52
66
51
—
—
Ph3CClO4 (110)
Ph3CBF4 (110)
Ph3CBF4 (110)
Ph3CBF4 (110)
Ph3CBF4 (110)
Ph3CBF4 (150)
Ph3CBF4 (110)
Ph3CBF4 (110)
4
5b
6c
7
8
9
10
Ts
a
b
c
Reactions performed in CH2Cl2/THF (4:1) at rt for 16 h. 72 h reaction.
Reaction performed in DCE/THF (4:1) at 80 °C for 16 h. d Isolated yields.
With the optimized conditions in hand, we explored the reaction scope using different
triorganoindium reagents (Scheme 1). In general, reactions of 1a (R’ = H) with triarylindium
reagents afforded good yields of the corresponding 1-aryltetrahydroisoquinolines 2a–2c (61–89%).
It is remarkable that the use electron-rich indium reagents such as tri(4-methoxyphenyl)indium gave
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
6
7
8
9
higher yields (89%). These results were already observed in transition-metal-free BF3•OEt2
mediated reactions of R3In with chromene and isochroman acetals, and could be reasoned based in
a higher nucleophilicity of the indium reagents.10 Heteroaryl indium reagents such as tri(2-
thienyl)indium and tri(5-phenyl-2-thienyl)indium also provided the corresponding
tetrahydroisoquinolines 2d and 2e in 80% and 93% yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Furthermore, the reaction of 1a with trialkynylindium reagents produced the functionalized THIQs
2f and 2g in satisfactory yields (72% and 61%). The insertion of alkyne moieties in the C-1 position
of THIQs is particularly attractive due to the possibility of further transformation of the triple bond,
including potentially the construction of tricyclic amines,11 and covers the synthetic limitations of
other organometallics.6e Additionally, the coupling of tribenzylindium with 1a under the established
conditions afforded 2h in an excellent 93% yield. Overall, these results showed the versatility of
R3In in these reactions and their atom-efficiency in which more than one organic group attached to
indium is transferred.
In a further step, we studied the oxidative coupling reaction using functionalized N-protected
THIQs. In these reactions, we found that the incorporation of a methoxy group at C-6 in the THIQ
core did not affect the reactivity of R3In, resulting in the transference of aryl an heteroaryl moieties
in good yields (2i–2k, 54–90%). It should be also noted that the reactions with N-Cbz-THIQs
furnished with electron withdrawing groups (such 5-Cl or 5-Br) did not afford the coupling
products or gave low yields (<15%). On the other hand, the reactions using the 6,7-dimethoxy
substituted THIQ 1c resulted in improved yields, a behavior previously observed in the reactivity of
iminium and oxonium intermediates generated under oxidative conditions.6,8b,12 Here, reaction of
triphenylindium with 1c afforded 2l in a good 80% yield, and using tribenzylindium, 2m was
obtained in an excellent 93% yield. In addition, the more reactive 1c was also successfully coupled
with alkylindium reagents, such as methyl and butyl, affording 2n and 2o in 63% and 83% yields,
respectively. Overall, these results highlight the usefulness and versatility of indium reagents in
transition-metal-free oxidative coupling reactions with tetrahydroisoquinolines.
4
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
1
2
3
Scheme 1. Oxidative Coupling Reaction of Triorganoindium Reagents with N-Cbz-
4
5
Tetrahydroisoquinolinesa
6
7
8
9
Ph3CBF4
(110 mol %)
R’
R’
+
R3In
N
N
CH2Cl2/THF (4:1)
rt, 16 h
Cbz
Cbz
Cbz
(50 mol %)
R
1a–c
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
S
Cbz
Cbz
Cbz
2a
2b
2c
2d
(61%)
(77%)
(89%)
(80%)
Me
OMe
N
N
S
N
N
Cbz
Cbz
Cbz
Cbz
2e
2f
2g
2h
Ph
TMS
Ph
(93%)
(72%)
(61%)
(93%)
MeO
MeO
MeO
N
N
N
Cbz
Cbz
Cbz
S
2i
2j
2k
(80%)
(54%)
(90%)
OMe
N
MeO
MeO
MeO
MeO
N
N
Cbz MeO
Cbz MeO
Cbz
R2
2n, R2 = Me (63%)
2o, R2 = n-Bu (83%)
2l
2m
(80%)
(93%)
a 1a, R’ = H; 1b, R’ = 6-OMe; 1c, R’ = 6,7-(OMe)2
To gain an insight into the reaction mechanism, several control experiments were conducted. A
plausible mechanistic proposal could involve the generation of an intermediate iminium ion
resulting from hydride abstraction by the triphenylcarbenium salt, followed by nucleophilic addition
1
of the R3In. With this idea in mind, we performed H NMR studies that allowed the detection of a
new signal at 9.47 ppm which can be assigned to the C-1 iminium hydrogen of the intermediate
(Figure 2). Alongside the iminium ion, an equimolar quantity of Ph3CH was also appreciated in the
NMR spectrum (7.17–7.25 ppm). The radical pathway was ruled out when we found that the
reaction of tribenzylindium (50 mol %) with 1c in the presence of the radical inhibitor BHT (100
mol %) afforded the coupling product 2m in 85% yield. According to these results, we believe that
in the coupling reaction, THIQ might undergo hydride abstraction by the oxidant, resulting in a N-
acyliminium ion that suffers the nucleophilic addition of the triorganoindium species to deliver the
corresponding coupling product. In this proposal more than one organoindium species could be
involved.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
Figure 2. 1H NMR Spectrum of the Reaction of 1c with Ph3CBF4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR spectra in CD2Cl2: (a) 1c; (b) Ph3CBF4; (c) Iminium ion generated after
10 min reaction of 1c with Ph3CBF4 (1.1 equiv).
Having established the reaction scope and studied the reaction intermediates, we applyied this
methodology to the synthesis of the aporphine alkaloid Nuciferine, a natural product from the plants
Nelumbo nucifera and Nymphaea caerulea with a range of psychoactive properties.13 In this
endeavor, the construction of the tetracyclic core of the molecule was devised by oxidative coupling
of a THIQ with a benzyl indium reagent followed by intramolecular Pd-catalyzed biaryl coupling.
Gratifyingly, the reaction of tri(2-bromobenzyl)indium (50 mol %) with 1c, under the optimized
reaction conditions, afforded 3 in 87% yield (Scheme 2). Subsequent intramolecular Pd-catalyzed
biaryl cross-coupling using Pd(OAc)2 (5 mol %), DavePhos (10 mol %) and K2CO3 in DMF gave 4
in 75% yield after 24 h.14 Final reduction of the carbamate with LiAlH4 at 80 °C provided (±)-
Nuciferine (5) in 52% yield. Alternatively, we also explored the synthesis of Nuciferine from N-
Cbz-8-bromo-6,7-dimethoxytetrahydroisoquinoline (1d). In this approach the oxidative coupling of
tribenzylindium with 1d, gave 6 in 77% yield using 70 mol% of the organoindium reagent. Ensuing
intramolecular biaryl Pd-coupling afforded 4 in 55% yield although with higher catalyst loading (20
mol %). This lower reactivity can be explained by the increase of steric hindrance at the C-1
position of the THIQ and by the presence of the electron-withdrawing bromide in the benzene ring.
Overall, the synthesis of (±)-Nuciferine was achieved following two different synthetic approaches,
demonstrating the usefulness of indium reagents in oxidative coupling reactions with
tetrahydroisoquinolines.
6
ACS Paragon Plus Environment

Page 7 of 24
The Journal of Organic Chemistry
1
2
3
Scheme 2. Synthesis of (±)-Nuciferine (5).
4
Y
Y = H, Br
5
6
7
8
3 In
(50–70 mol %)
MeO
MeO
MeO
MeO
N
N
Ph3CBF4 (110 mol %)
CH2Cl2/THF (4:1)
rt, 16 h
Cbz
Cbz
X
X
9
1c, X = H
1d, X = Br
3, X = H, Y = Br
6, X = Br, Y = H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
77–87 %
Y
Pd(OAc)2 (5–20 mol %)
DavePhos (10–40 mol %)
K2CO3, DMA
55–75 %
130 °C, 24 h
MeO
MeO
MeO
LiAlH4 (300 mol %)
N
N
Me
MeO
Cbz
THF, 80 °C, 16 h
52 %
4
5
(±)-Nuciferine
In summary,
a
new oxidative coupling of triorganoindium reagents with N-Cbz-
tetrahydroisoquinolines using stoichometric ammounts of Ph3CBF4 was developed. The reaction
proceeds with a variety of R3In affording N-Cbz-1-susbtituted THIQs in good yields. Mechanistic
experiments suggest the generation of an intermediate iminium ion that reacted with the indium
reagents. The utility of this methodology was demonstrated with a concise synthesis of the
aporphine alkaloid (±)-Nuciferine. This contribution represents a new example of the synthetic
utility of organoindium reagents in carbon–carbon bond forming reactions under transition metal-
free conditions.
Experimental Section.
General Methods.
All reactions were carried out in flame-dried glassware, under argon using standard gas-tight
syringes, cannulae and septa. THF was dried by distillation from sodium benzophenone ketyl.
Reaction temperatures refer to external bath temperatures. Organolithium or Grignard reagents were
titrated prior to use using N-benzylbenzamide or 1-pyreneacetic acid as indicators.15 Organic
extracts were dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator at
aspirator pressure. Reactions were monitored by TLC using pre-coated silica gel plates (Alugram
Xtra SIL G/UV254, 0.20 mm thick), UV light as the visualizing agent and ethanolic
phosphomolybdic acid as the developing agent. Flash column chromatography was performed with
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
7
8
9
230-400 mesh silica gel. 1H and 13C NMR spectra were recorded in CDCl3 at 300 K using a Bruker
Avance 300 MHz or a Bruker Avance 500 MHz spectrometer, and calibrated to the solvent peak.
DEPT data were used to assign carbon types. Mass spectra were obtained with a MAT 95XP
Magnetic Sector EI spectrometer or with a QSTAR Elite hybrid quadrupole Time-of-Flight (TOF)
ESI mass spectrometer, both operating in positive ionization mode.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of Triorganoindium Reagents.
Triorganoindium compounds were prepared according to previously published methods16 by
treatment of the corresponding organolithium or Grignard reagent (3.0 equiv, ~0.5 M in THF) with
a solution of InCl3 (1.0 equiv, 0.45 M in THF) at –78 °C and warming to rt. Phenylacetylene,
ethynyltrimethylsilane, thiophene, and 2-phenylthiophene were lithiated by treatment with n-BuLi
(1.0 equiv) at –78 °C and warming to rt. Organolithium reagents derived from 2-bromonaphtalene,
b-bromostyrene, and cyclopropylbromide were prepared by metal-halogen exchange reaction with
t-BuLi (2.0 equiv) at –78 °C.
General Procedure for the Preparation of N-Cbz-THIQs (General Procedure A).
N-carboxybenzyl tetrahydroisoquinolines 1a–1c were prepared by addition of benzyl chloroformate
(9.59 mmol) to a solution of tetrahydroisoquinoline (8 mmol) and triethylamine (1.34 mL, 9.59
mmol) in CH2Cl2 (20 mL) at 0 °C. After 3 h of stirring at rt, water (50 mL) was added. The organic
phase was extracted with CH2Cl2 (2 ´ 20 mL) and the combined organic extracts were washed with
brine (50 mL), dried, filtered, and concentrated in vacuo. The crude was purified by flash
chromatography to afford, after concentration and high-vacuum drying, the corresponding coupling
products.
Benzyl 3,4-Dihydroisoquinoline-2(1H)-carboxylate (1a).17
Following the General Procedure A, benzyl chloroformate (1.37 mL, 9.59 mmol) was added to a
solution of tetrahydroisoquinoline (1.06 g, 8 mmol) and Et3N (1.34 mL, 9.59 mmol) in CH2Cl2 (20
mL) at 0 °C. Purification by flash chromatography (EtOAc/hexanes 20:80, 3% Et3N) afforded 1a
(1.00 g, 47%) as a yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.49–7.29 (m, 5H),
7.25–7.07 (m, 4H), 5.20 (s, 2H), 4.67 (s, 2H), 3.82–3.70 (m, 2H), 2.96–2.81 (m, 2H); 13C{1H}
8
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
NMR (CDCl3, 75 MHz, rotamers mixture) d 155.5, 136.8, 134.6, 134.5, 133.5, 133.1, 128.8, 128.7,
128.5, 128.03, 127.97, 126.5, 126.3, 67.2, 45.8, 41.6, 41.4, 29.0, 28.8; HRMS (ESI-TOF) m/z calcd
for C17H18NO2 [M + H]+ 268.1332, found 268.1342.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 6-Methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1b).6g
Following the General Procedure A, benzyl chloroformate (1.37 mL, 9.59 mmol) was added to a
solution of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (1.30 g, 8 mmol) and triethylamine (1.34 mL,
9.59 mmol) in CH2Cl2 (20 mL) at 0 °C. Purification by flash chromatography (EtOAc/hexanes
1
20:80, 3% Et3N) afforded 1b (1.19 g, 50%) as a yellow oil: H NMR (CDCl3, 300 MHz, rotamers
mixture) d 7.45–7.28 (m, 5H), 7.10–6.95 (m, 1H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 6.70–6.65 (m,
1H), 5.19 (s, 2H), 4.60 (s, 2H), 3.79 (s, 3H), 3.76–3.65 (m, 2H), 2.90–2.76 (m, 2H); 13C{1H} NMR
(CDCl3, 75 MHz, rotamers mixture) d 158.3, 155.6, 136.9, 135.9, 128.6, 128.12, 128.06, 127.4,
125.5, 113.5, 112.7, 67.3, 55.4, 45.4, 41.6, 29.3; HRMS (ESI-TOF) m/z calcd for C18H19NO3Na [M
+ Na]+ 320.1257, found 320.1260.
Benzyl 6,7-Dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1c).18
Following the General Procedure A, benzyl chloroformate (1.37 mL, 9.59 mmol) was added to a
solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.55 g, 8 mmol) and Et3N (1.34 mL, 9.59
mmol) in CH2Cl2 (20 mL) at 0 °C. Purification by flash chromatography (EtOAc/hexanes 20:80,
3% Et3N) afforded 1c (1.41 g, 54%) as a yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture)
d 7.44–7.27 (m, 5H), 6.67–6.52 (m, 2H), 5.18 (s, 2H), 4.58 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.77–
3.65 (m, 2H), 2.84–2.70 (m, 2H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 155.5,
147.8, 147.7, 136.9, 128.6, 128.1, 126.5, 126.3, 125.3, 124.8, 111.6, 109.1, 67.3, 56.0, 43.5, 41.8,
41.6, 28.5, 28.4; HRMS (ESI-TOF) m/z calcd for C19H22NO4 [M + H]+ 328.1543, found 328.1551.
General Procedure the Oxidative Coupling Reaction of R3In with N-Cbz-THIQs (General
Procedure B).
To a solution of Ph3CBF4 (136 mg, 0.411 mmol) in CH2Cl2 (10 mL), N-protected THIQ (0.374
mmol) and R3In (3 mL, 0.062 M in THF, 0.186 mmol) were sequentially added at rt and the
resulting mixture was left stirring overnight and then quenched with MeOH (1 mL). The solvent
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
5
6
7
8
9
was concentrated in vacuo and Et2O (20 mL) was added. The organic phase was successively
washed with water (2 ´ 20 mL) and brine (20 mL), dried, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography to afford, after concentration and high-vacuum
drying, the corresponding 1-substituted-THIQs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 1-Phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2a).19
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with triphenylindium
(3 mL, 0.062 M in THF, 0.186 mmol) and Ph3CBF4 (136 mg, 0.411 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2a (78 mg, 61%) as a
1
colorless oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.53–7.01 (m, 14H), 6.65–6.22 (m,
1H), 5.40–5.10 (m, 2H), 4.30–3.98 (m, 1H), 3.43–3.23 (m, 1H), 3.13–2.91 (m, 1H), 2.88–2.69 (m,
1H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 155.5, 142.7, 136.8, 135.4, 135.1, 129.0,
128.6, 128.5, 128.4, 128.2, 127.5, 127.1, 126.3, 67.5, 57.9, 38.4, 28.6; HRMS (ESI-TOF) m/z calcd
for C23H21NO2Na [M + Na]+ 366.1470, found 366.1464.
Benzyl 1-(p-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2b).6f
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with tri-p-tolylindium
(3 mL, 0.062 M in THF, 0.186 mmol) and Ph3CBF4 (136 mg, 0.411 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2b (103 mg, 77%) as a
yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.51–7.29 (m, 5H), 7.28–6.90 (m, 8H),
6.64–6.18 (m, 1H), 5.40–5.08 (m, 2H), 4.28–3.95 (m, 1H), 3.40–3.20 (m, 1H), 3.15–2.68 (m, 2H),
2.33 (s, 3H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 153.3, 139.7, 137.1, 136.7,
135.5, 134.9, 129.3, 128.93, 128.85, 128.5, 128.4, 128.0, 127.4, 126.9, 126.1, 67.3, 57.5, 38.1, 28.6,
21.1; HRMS (ESI-TOF) m/z calcd for C24H24NO2 [M + H]+ 358.1801, found 358.1801.
Benzyl 1-(4-Methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2c).20
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with tri-(4-
methoxyphenyl)indium (3 mL, 0.062 M in THF, 0.186 mmol) and Ph3CBF4 (136 mg, 0.411 mmol)
afforded, after purification by flash chromatography (EtOAc/hexanes 10:90, 3% Et3N), 2c (124 mg,
1
89%) as a yellow oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.46–7.29 (m, 5H), 7.24–
10
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6.96 (m, 6H), 6.89–6.71 (m, 2H), 6.60–6.16 (m, 1H), 5.40–5.07 (m, 2H), 4.31–3.98 (m, 1H), 3.78
(s, 3H), 3.36–3.16 (m, 1H), 3.12–2.91 (m, 1H), 2.87–2.68 (m, 1H). 13C{1H} NMR (CDCl3, 75
MHz, rotamers mixture) d 158.8, 155.3, 136.7, 135.5, 134.9, 129.6, 128.9, 128.5, 128.0, 127.93,
127.91, 126.9, 126.1, 113.5, 67.3, 57.1, 55.2, 37.9, 28.5. HRMS (ESI-TOF) m/z calcd for
C24H24NO3 [M + H]+ 374.1750, found 374.1748.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 1-(Thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2d).6d
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with tri(thiophen-2-
yl)indium (4 mL, 0.047 M in THF, 0.19 mmol) and Ph3CBF4 (136 mg, 0.411 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 10:90, 3% Et3N), 2d (111 mg, 80%) as a
yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.45–7.30 (m, 5H), 7.27–7.12 (m, 5H),
6.95–6.85 (m, 1H), 6.84–6.47 (m, 2H), 5.34–5.15 (m, 2H), 4.36–3.99 (m, 1H), 3.51–3.23 (m, 1H),
3.14–2.70 (m, 2H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 155.3, 146.3, 136.6,
135.2, 134.6, 129.1, 128.6, 128.5, 128.2, 127.4, 126.7, 126.4, 126.2, 125.4, 67.6, 53.8, 38.5, 37.9,
28.5. HRMS (ESI-TOF) m/z calcd for C21H19NO2NaS [M + Na]+ 372.1028, found 372.1033.
Benzyl 1-(5-Phenylthiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2e).
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with tri-(5-
phenylthiophen-2-yl)indium (4 mL, 0.047 M in THF, 0.19 mmol) and Ph3CBF4 (136 mg, 0.411
mmol) afforded, after purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2e
1
(148 mg, 93%) as a yellow oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.57–7.05 (m,
16H), 6.86–6.40 (m, 2H), 5.43–5.10 (m, 2H), 4.37–4.06 (m, 1H), 3.58–3.27 (m, 1H), 3.17–2.79 (m,
2H). 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 146.9, 145.6, 144.2, 136.6, 134.5,
134.2, 128.8, 128.6, 128.1, 127.9, 127.6, 127.45, 127.41, 127.3, 126.2, 125.7, 122.2, 67.4, 53.9,
38.4, 37.9, 29.7, 28.5, 28.4. HRMS (ESI-TOF) m/z calcd for C27H23NO2NaS [M + Na]+ 448.1341,
found 448.1353.
Benzyl 1-(Phenylethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2f).6d
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with
tri(phenylethynyl)indium (4 mL, 0.047 M in THF, 0.19 mmol) and Ph3CBF4 (136 mg, 0.411 mmol)
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
1
2
3
afforded, after purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2f (99 mg,
4
5
1
72%) as a yellow oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.58–7.04 (m, 14H), 6.37–
6
7
8
9
6.05 (m, 1H), 5.45–5.09 (m, 2H), 4.49–4.09 (m, 1H), 3.68–3.37 (m, 1H), 3.15–2.75 (m, 2H);
13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 154.9, 136.8, 129.1, 128.5, 128.3, 128.1,
128.0, 127.9, 127.5, 127.3, 127.2, 126.6, 122.67, 122.64, 88.3, 83.3, 67.5, 47.4, 29.7, 28.4; HRMS
(ESI-TOF) m/z calcd for C25H22NO2 [M + H]+ 368.1656, found 368.1645.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 1-((Trimethylsilyl)ethynyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2g).6d
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with
tris(trimethylsilylethynyl)indium (4 mL, 0.047 M in THF, 0.19 mmol) and Ph3CBF4 (136 mg, 0.411
mmol) afforded, after purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2g (83
1
mg, 61%) as a colorless oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.45–7.27 (m, 6H),
7.24–7.08 (m, 3H), 6.10–5.80 (m, 1H), 5.43–5.05 (m, 2H), 4.40–4.06(m, 1H), 3.61–3.29 (m, 1H),
3.05–2.72 (m, 2H), 0.12 (s, 9H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 155.0, 136.8,
129.2, 128.7, 128.2, 128.1, 128.0, 127.7, 127.4, 126.7, 104.5, 88.0, 67.6, 47.7, 28.5, 0.1; HRMS
(ESI-TOF) m/z calcd for C22H26NO2Si [M + H]+ 364.1727, found 364.1731.
Benzyl 1-Benzyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2h).6d
Following the General Procedure B, the reaction of 1a (100 mg, 0.374 mmol) with tribenzylindium
(3 mL, 0.062 M in THF, 0.186 mmol) and Ph3CBF4 (136 mg, 0.411 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2h (124 mg, 93%) as a
1
colorless oil: H NMR (CDCl3, 500 MHz, rotamers mixture) d 7.47–7.34 (m, 4H), 7.32–7.09 (m,
9H), 7.09–6.91 (m, 1H), 5.52–5.32 (m, 1H), 5.28–5.10 (m, 1H), 5.05–4.76 (m, 1H), 4.32-3.88 (m,
1H), 3.53–3.38 (m, 1H), 3.26–2.83 (m, 3H), 2.82–2.61 (m, 1H); 13C{1H} NMR (CDCl3, 125 MHz,
rotamers mixture) d 155.5, 138.2, 138.0, 137.0, 136.55, 136.52, 134.43, 134.36, 129.8, 129.6,
129.1, 128.54, 128.51, 128.4, 128.3, 128.2, 128.1, 128.03, 127.98, 127.95, 127.8, 127.5, 127.29,
127.25, 126.9, 126.8, 126.54, 126.46, 126.1, 67.2, 67.0, 56.71, 56.66, 43.2, 42.8, 39.4, 38.1, 28.6,
28.5; HRMS (ESI-TOF) m/z calcd for C24H24NO2 [M + H]+ 358.1801, found 358.1806.
12
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
1
2
3
Benzyl 6-Methoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2i).
4
5
6
7
8
9
Following the General Procedure B, the reaction of 1b (100 mg, 0.336 mmol) with triphenylindium
(3 mL, 0.056 M in THF, 0.168 mmol) and Ph3CBF4 (122 mg, 0.370 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 20:80, 3% Et3N), 2i (68 mg, 54%) as a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
colorless oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.55–7.09 (m, 10H), 7.07–6.88 (m,
1H), 6.86–6.70 (m, 2H), 6.58–6.18 (m, 1H), 5.38–5.10 (m, 2H), 4.26–3.97 (m, 1H), 3.82 (s, 3H),
3.38–3.18 (m, 1H), 3.11–2.88 (m, 1H), 2.86–2.66 (m, 1H); 13C{1H} NMR (CDCl3, 75 MHz,
rotamers mixture) d 158.6, 155.5, 142.9, 136.9, 136.4, 129.6, 128.6, 128.43, 128.35, 128.1, 127.7,
127.5, 113.5, 112.6, 67.5, 57.5, 55.4, 38.3, 28.9; HRMS (ESI-TOF) m/z calcd for C24H24NO3 [M +
H]+ 374.1750, found 374.1761.
Benzyl 6-Methoxy-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2j).
Following the General Procedure B, the reaction of 1b (100 mg, 0.336 mmol) with tri-(4-
methoxyphenyl)indium (3 mL, 0.056 M in THF, 0.168 mmol) and Ph3CBF4 (122 mg, 0.370 mmol)
afforded, after purification by flash chromatography (EtOAc/hexanes 20:80, 3% Et3N), 2j (122 mg,
1
90%) as a yellow oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.50–7.28 (m, 5H), 7.23–
7.01 (m, 2H), 6.99–6.88 (m, 1H), 6.86–6.64 (m, 4H), 6.52–6.12 (m, 1H), 5.35–5.09 (m, 2H), 4.23–
3.97 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.34–3.13 (m, 1H), 3.08–2.87 (m, 1H), 2.83–2.63 (m, 1H);
13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 158.8, 158.3, 155.2, 136.8, 136.1, 135.1,
129.5, 128.5, 128.0, 127.7, 113.5, 113.3, 112.5, 67.3, 56.7, 37.7, 28.8; HRMS (ESI-TOF) m/z calcd
for C25H26NO4 [M + H]+ 404.1856, found 404.1856.
Benzyl 6-Methoxy-1-(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2k).
Following the General Procedure B, the reaction of 1b (100 mg, 0.336 mmol) with tri(thiophen-2-
yl)indium (4 mL, 0.042 M in THF, 0.168 mmol) and Ph3CBF4 (122 mg, 0.370 mmol) afforded,
after purification by flash chromatography (EtOAc/hexanes 5:95, 3% Et3N), 2k (102 mg, 80%) as a
yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.51–7.27 (m, 5H), 7.23–7.16(m, 1H),
7.16–6.97(m, 1H), 6.95–6.92 (m, 4H), 6.62–6.34 (m, 1H), 5.33–5.13 (m, 2H), 4.33–3.81 (m, 1H),
3.81 (s, 3H), 3.49–3.16 (m, 1H), 3.08–2.68 (m, 2H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers
mixture) d 158.8, 146.8, 136.8, 135.9, 129.6, 128.6, 128.2, 128.14, 128.09, 126.6, 126.4, 125.4,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
1
2
3
113.5, 112.7, 67.6, 55.4, 53.4, 38.2, 37.8, 28.9; HRMS (ESI-TOF) m/z calcd for C22H22NO3S [M +
4
5
H]+ 380.1314, found 380.1331.
6
7
8
9
Benzyl 6,7-Dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2l). 21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following the General Procedure B, the reaction of 1c (100 mg, 0.305 mmol) with triphenylindium
(3 mL, 0.051 M in THF, 0.153 mmol) and Ph3CBF4 (110 mg, 0.335 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 30:70, 3% Et3N), 2l (98 mg, 80%) as a
1
colorless oil: H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.52–7.06 (m, 10H), 6.67 (s, 1H),
6.60–6.15 (m, 2H), 5.40–5.08 (m, 2H); 4.27–4.00 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.39–3.11 (m,
13
1H), 3.09–2.84 (m, 1H), 2.77–2.57 (m, 1H); C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d
155.4, 148.2, 147.6, 142.6, 136.8, 128.6, 128.3, 128.1, 128.01, 127.97, 127.5, 127.1, 126.9, 111.4,
111.2, 67.4, 57.4, 56.05, 55.98, 37.9, 28.1; HRMS (ESI-TOF) m/z calcd for C25H26NO4 [M + H]+
404.1856, found 404.1872.
Benzyl 1-Benzyl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2m).6d
Following the General Procedure B, the reaction of 1c (100 mg, 0.305 mmol) with tribenzylindium
(3 mL, 0.051 M in THF, 0.153 mmol) and Ph3CBF4 (110 mg, 0.335 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 20:80, 3% Et3N), 2m (118 mg, 93%) as a
yellow oil: 1H NMR (CDCl3, 500 MHz, rotamers mixture) d 7.44–7.29 (m, 4H), 7.28–7.15 (m, 4H),
7.14–6.98 (m, 2H), 6.67–6.52 (m, 1H), 6.28–6.07 (m, 1H), 5.37–5.10 (m, 2H), 5.07–4.82 (m, 1H),
4.28–4.06 (m, 1H), 3.90–3.80 (m, 3H), 3.73–3.55 (m, 3H), 3.50–3.29 (m, 1H), 3.25–3.06 (m, 1H),
3.05–2.52 (m, 3H); 13C{1H} NMR (CDCl3, 125 MHz, rotamers mixture) d 155.5, 147.9, 147.8,
147.1, 147.0, 138.4, 138.3, 137.1, 136.7, 130.1, 129.8, 128.61, 128.55, 128.44, 128.38, 128.32,
128.28, 128.11, 128.06, 127.9, 126.6, 126.5, 126.4, 126.2, 115.0, 111.2, 110.7, 110.4, 67.4, 67.1,
56.5, 56.0, 55.9, 55.8, 43.3, 42.8, 39.4, 38.4, 28.3, 28.2; HRMS (ESI-TOF) m/z calcd for
C26H28NO4 [M + H]+ 418.2012, found 418.2022.
Benzyl 6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2n).22
Following the General Procedure B, the reaction of 1c (100 mg, 0.305 mmol) with trimethylindium
(4.5 mL, 0.034 M in THF, 0.153 mmol) and Ph3CBF4 (110 mg, 0.335 mmol) afforded, after
14
ACS Paragon Plus Environment

Page 15 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
purification by flash chromatography (EtOAc/hexanes 15:85, 3% Et3N), 2n (66 mg, 63%) as a
yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.47–7.28 (m, 5H), 6.68–6.47 (m, 2H),
5.37–5.05 (m, 3H), 4.37–4.03 (m, 1H), 3.85 (s, 6H), 3.42–3.13 (m, 1H), 3.00–2.75 (m, 1H), 2.73–
2.54 (m, 1H), 1.45 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers mixture) d 155.2,
155.0, 147.7, 137.0, 130.6, 130.1, 128.6, 128.1, 126.1, 125.7, 111.5, 109.8, 67.3, 67.1, 56.1, 56.0,
50.2, 37.9, 37.5, 28.6, 28.5, 22.4, 21.9; HRMS (ESI-TOF) m/z calcd for C20H24NO4 [M + H]+
342.1699, found 342.1714.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 1-Butyl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2o).
Following the General Procedure B, the reaction of 1c (100 mg, 0.305 mmol) with tributhylindium
(3 mL, 0.051 M in THF, 0.153 mmol) and Ph3CBF4 (110 mg, 0.335 mmol) afforded, after
purification by flash chromatography (EtOAc/hexanes 15:85, 3% Et3N), 2o (97 mg, 83%) as a
yellow oil: 1H NMR (CDCl3, 300 MHz, rotamers mixture) d 7.50–7.27 (m, 5H), 6.71–6.47 (m, 2H),
5.34–4.97 (m, 3H), 4.34–4.02 (m, 1H), 3.84 (s, 6H), 3.44–3.14 (m, 1H), 3.03–2.76 (m, 1H), 2.73–
2.53 (m, 1H), 1.94–1.59 (m, 2H), 1.55–1.15 (m, 4H), 1.02–0.77 (m, 3H); 13C{1H} NMR (CDCl3, 75
MHz, rotamers mixture) d 155.7, 147.8, 147.5, 137.1, 136.8, 130.4, 130.0, 128.5, 128.3, 128.1,
128.0, 127.8, 126.1, 125.8, 111.7, 111.5, 110.3, 110.0, 67.3, 67.1, 56.1, 56.0, 54.7,. 54.6, 38.2, 37.5,
36.8, 36.6, 28.8, 28.7, 28.3, 27.9, 22.7, 14.2; HRMS (ESI-TOF) m/z calcd for C23H30NO4 [M + H]+
384.2169, found 384.2164.
Benzyl 1-(2-Bromobenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (3).
Following the General Procedure B, the reaction of 1c (200 mg, 0.611 mmol) with tri-(2-
bromobenzyl)indium (4.5 mL, 0.068 M, 0.306 mmol) and Ph3CBF4 (223 mg, 0.672 mmol)
afforded, after purification by flash chromatography (EtOAc/hexanes 20:80, 3% Et3N), 3 (264 mg,
87%) as a yellow oil. In a larger scale, following the General Procedure B, the reaction of 1c (715
mg, 2.18 mmol) with tri-(2-bromobenzyl)indium (13.8 mL, 0.080 M, 1.10 mmol) and Ph3CBF4
(795 mg, 2.41 mmol) in CH2Cl2 (55 mL) afforded, after purification by flash chromatography
1
(EtOAc/hexanes 20:80, 3% Et3N), 3 (902 mg, 83%) as a yellow oil: H NMR (CDCl3, 500 MHz,
rotamers mixture) d 7.55–7.48 (m, 0.40H), 7.44–7.40 (m, 0.66H), 7.37–7.27 (m, 3.70H), 7.20–7.11
(m, 2.70H), 7.09–6.99 (m, 1.70H), 6.64–6.61 (m, 1.40H), 6.60–6.58 (m, 0.30H), 6.40–6.37 (m,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
1
2
3
4
5
6
7
8
9
0.30H), 5.51–5.45 (m, 0.30H), 5.44–5.38 (m, 0.67H), 5.13–5.01 (m, 0.60H), 4.91–4.86 (m, 0.66H),
4.56–4.52 (m, 0.65H), 4.40–4.32 (m, 0.67H), 4.10–4.02 (m, 0.30H), 3.87–3.83 (m, 3H), 3.80–
3.77(m, 2H), 3.70–3.67 (m, 1H), 3.56–3.49 (m, 0.30H), 3.46–3.37 (m, 0.67H), 3.33–3.25 (m, 1H),
3.23–3.16 (m, 0.30H), 3.11–3.03 (m, 0.67H), 2.98–2.89 (m, 0.68H), 2.87–2.79 (m, 0.30H), 2.75–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2.65 (m, 1H); C{1H} NMR (CDCl3, 125 MHz, rotamers mixture) d 155.3, 147.9, 147.8, 147.3,
147.1, 137.8, 136.9, 136.2, 132.7, 132.6, 131.7, 128.9, 128.7, 128.5, 128.28, 128.26, 128.21,
128.16, 128.13, 127.92, 127.89, 127.8, 127.3, 127.2, 126.2, 126.1, 125.5, 125.1, 111.3, 111.0,
109.8, 67.2, 66.9, 55.90, 55.88, 55.8, 54.7, 54.0, 42.7, 42.0, 38.8, 37.5, 28.2, 28.1; HRMS (ESI-
TOF) m/z calcd for C26H27NO4Br [M + H]+ 496.1123, found 496.1132.
Benzyl 8-Bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1d).
Following the General Procedure A, benzyl chloroformate (0.335 mL, 2.35 mmol) was added to a
solution of 8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 23 (0.53 g, 1.96 mmol) and
triethylamine (0,34 mL, 2,35 mmol) in CH2Cl2 (20 mL) at 0 °C. Purification by flash
1
chromatography (EtOAc/hexanes 20:80, 3% Et3N) afforded 1d (0.64 g, 80%) as a yellow oil: H
NMR (CDCl3, 300 MHz, rotamers mixture) d 7.44–7.28 (m, 5H), 6.65 (s, 1H), 5.20 (s, 2H), 4.56 (s,
2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.74–3.64 (m, 2H), 2.80 (s, 2H); C{1H} NMR (CDCl3, 75 MHz,
13
rotamers mixture) d 155.4, 151.7, 145.0, 136.7, 131.7, 128.5, 128.0, 127.9, 117.8, 111.9, 67.2, 60.5,
56.1, 46.7, 41.1, 41.0, 29.1, 28.9; HRMS (ESI-TOF) m/z calcd for C19H21NO4Br [M + H]+
406.0648, found 406.0670.
Benzyl 1-Benzyl-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (6).
Following the General Procedure B, the reaction of 1d (200 mg, 0.492 mmol) with tribenzylindium
(5.5 mL, 0.063 M, 0.344 mmol) and Ph3CBF4 (180 mg, 0.541 mmol) afforded, after purification by
flash chromatography (EtOAc/hexanes 20:80, 3% Et3N), 6 (188 mg, 77%) as a yellow oil: 1H NMR
(CDCl3, 500 MHz, rotamers mixture) d 7.38–7.20 (m, 8H), 7.17–7.05 (m, 2H), 6.71–6.60 (m, 1H),
5.76–5.72 (m, 0.34H), 5.63–5.56 (m, 0.64H), 5.13–5.08 (m, 0.34H), 5.03–4.98 (m, 0.33H), 4.94–
4.86 (m, 0.64H), 4.68–4.60 (m, 0.64H), 4.27–4.20 (m, 0.64H), 3.91–3.83 (m, 6.6H), 3.63–3.52 (m,
1H), 3.45–3.38 (m, 0.35H), 3.33–3.27 (m, 0.64H), 2.99–2.82 (m, 1.6H), 2.78–2.66 (m, 1H), 2.49–
13
2.41 (0.33H); C{1H} NMR (CDCl3, 125 MHz, rotamers mixture) d 155.43, 155.38, 152.3, 152.2,
16
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
145.18, 145.15, 138.4, 138.1, 137.0, 137.6, 131.8, 131.7, 129.6, 129.5, 129.3, 129.1, 128.5, 128.4,
128.2, 128.0, 127.9, 127.7, 127.5, 126.6, 126.5, 118.7, 118.4, 112.1, 111.8, 67.04, 67.01, 60.68,
60.66, 56.5, 56.2, 56.0, 39.5, 39.4, 38.5, 37.2, 28.4, 28.2; HRMS (ESI-TOF) m/z calcd for
C26H26NO4NaBr [M + Na]+ 518.0937, found 518.0944.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 1,2-Dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-carboxylate (4).
To a mixture of Pd(OAc)2 (5 mg, 0.020 mmol), DavePhos (16 mg, 0.040 mmol), and dried K2CO3
(111 mg, 0.806 mmol) in DMA (25 mL), a solution of 3 (200 mg, 0.403 mmol) in DMA (4 mL)
was added via cannula and the reaction was stirred at 130 °C for 24 h. After cooling to rt, Et2O (150
mL) was added and the organic phase was washed with water (5 ´ 20 mL), brine (100 mL), dried,
filtered, and concentrated in vacuo, to afford, after purification by flash chromatography
(EtOAc/hexanes 10:90, 3% Et3N), 4 (125 mg, 75%) as a yellow oil.
Alternatively, following the same procedure, the reaction of 6 (160 mg, 0.323 mmol) with
Pd(OAc)2 (14.5 mg, 0.065 mmol), DavePhos (51.2 mg, 0.130 mmol), and dried K2CO3 (89 mg,
0.646 mmol) afforded, after purification by flash chromatography, 4 (73 mg, 55%) as a yellow oil:
1H NMR (CDCl3, 300 MHz, rotamers mixture) d 8.44 (d, J = 7.8 Hz, 1H), 7.47–7.18 (m, 8H), 6.68
(s, 1H), 5.35–5.25 (m, 1H), 5.22–5.11 (m, 1H), 4.85–4.74 (m, 1H), 4.57–4.43 (m, 1H), 3.90 (s, 3H),
3.67 (s, 3H), 3.10–2.80 (m, 4H), 2.73–2.61 (m, 1H); 13C{1H} NMR (CDCl3, 75 MHz, rotamers
mixture) d 155.3, 152.2, 145.8, 136.9, 136.8, 131.8, 129.7, 128.62, 128.59, 128.4, 128.1, 127.9,
127.8, 127.7, 127.2, 126.2, 111.6, 67.2, 60.2, 56.1, 51.8, 39.1, 30.5; HRMS (ESI-TOF) m/z calcd
for C26H26NO4 [M + H]+ 416.1861, found 416.1863.
1,2-Dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline [(±)-Nuciferine] (5).24
To a suspension of LiAlH4 (28 mg, 0.735 mmol) in THF (15 mL), a solution of 4 (102 mg, 0.245
mmol) in THF (5 mL) was added at 0 °C. The mixture was heated to 80 °C and left stirring
overnight. The reaction was quenched by addition of EtOAc (15 mL), and chilled water (15 mL),
and then it was filtered through celite. The solution was basified to pH 10 by addition of 2.0 M
NaOH and the aqueous phase was extracted with EtOAc (2 ´ 20 mL). The combined organic
extracts were dried, filtered, and concentrated to afford, after purification by flash chromatography
(MeOH/CH2Cl2 2:98, 3% Et3N), 5 (35 mg, 48%) as a yellow solid: mp 160–161 °C (lit.24 mp 168–
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
1
2
3
4
5
6
7
8
9
1
169 °C); H NMR (CDCl3, 300 MHz) d 8.29 (d, J = 7.9 Hz, 1H), 7.29–7.10 (m, 3H), 6.56 (s, 1H),
3.81 (s, 3H), 3.59 (s, 3H), 3.17–2.90 (m, 4H), 2.67–2.52 (m, 2H), 2.47 (s, 3H), 2.44–2.37 (m, 1H);
13C{1H} NMR (CDCl3, 75 MHz) d 152.1 (C), 145.3(C), 136.6 (C), 132.3 (C), 128.8 (C), 128.4
(CH), 128.1 (C), 128.0 (CH), 127.4 (CH), 127.1 (CH), 127.0 (C), 111.4 (CH), 62.5 (CH), 60.3
(CH3), 56.0 (CH3), 53.4 (CH2), 44.1 (CH3), 35.2 (CH2), 29.3 (CH2); HRMS (ESI-TOF) m/z calcd
for C19H22NO2 [M + H]+ 296.1650, found 296.1660.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgments
We are grateful to the Spanish Ministerio de Economía y Competitividad (CTQ2015-68369-P),
Xunta de Galicia (GRC2014/042) and EDRF funds for financial support.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1H and 13C{1H} NMR spectra.
Author Information
Corresponding Authors
*E-mail: sestelo@udc.es (J.P.S.)
*E-mail: luis.sarandeses@udc.es (L.A.S.)
ORCID
José M. Gil-Negrete: 0000-0003-3782-070X
José Pérez Sestelo: 0000-0001-7036-6217
Luis A. Sarandeses: 0000-0003-1114-7107
Notes
The authors declare no competing financial interest.
References and Notes
1
(a) Herbert, R. B. In The Chemistry and Biology of Isoquinoline Alkaloids; Phillipson, J. D.,
Roberts M. F., Zenk M. H., Eds.; Springer-Verlag: Berlin-Heidelberg, 1985; pp 213–228. (b)
Scott, J. D.; Williams, R. M. Chemistry and Biology of the Tetrahydroisoquinoline Antitumor
18
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
Antibiotics. Chem. Rev. 2002, 102, 1669–1730. (c) Sridharan, V.; Suryavanshi, P. A.;
Menéndez, J. C. Advances in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011, 111,
7157–7259. (d) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Asymmetric
Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem. Rev. 2016, 116, 12369–12465.
Hiratsuka, T.; Koketsu, K.; Minami, A.; Kaneko, S.; Yamazaki, C.; Watanabe, K.; Oguri, H.;
Oikawa, H. Core Assembly Mechanism of Quinocarcin/SF-1739: Bimodular Complex
Nonribosomal Peptide Synthetases for Sequential Mannich-Type Reactions. Chem. Biol.
2013, 20, 1523–1535.
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
(a) Phillipson, J. D.; Wright, C. W. Antiprotozoal Agents From Plant Sources. Planta Med.
1991, 57, S53–S59. (b) Custódio, D. L.; da Veiga Junior, V. F. Lauraceae Alkaloids. RSC
Adv. 2014, 4, 21864–21890.
4
5
Mealy, N.; Castañer, J. YM-905: Treatment of Urinary Incontinence, Muscarinic M3
Antagonist. Drugs Future 1999, 24, 871–874.
(a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. Aerobic Ruthenium-Catalyzed
Oxidative Cyanation of Tertiary Amines with Sodium Cyanide. J. Am. Chem. Soc. 2003, 125,
15312–15313. (b) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnürch, M. Facile,
Solvent and Ligand Free Iron Catalyzed Direct Functionalization of N-Protected
Tetrahydroisoquinolines and Isochroman. Chem. Commun. 2010, 46, 8836–8838. (c) Xie, J.;
Li, H.; Zhou, J.; Cheng, Y.; Zhu, C. A Highly Efficient Gold-Catalyzed Oxidative C–C
Coupling From C–H Bonds Using Air as Oxidant. Angew. Chem., Int. Ed. 2012, 51, 1252–
1255. (d) Boess, E.; Schmitz, C.; Klussmann, M. A Comparative Mechanistic Study of Cu-
Catalyzed Oxidative Coupling Reactions with N-Phenyltetrahydroisoquinoline. J. Am. Chem.
Soc. 2012, 134, 5317–5325. (e) Wang, T.; Schrempp, M.; Berndhäuser, A.; Schiemann, O.;
Menche, D. Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with
Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical Intermediate. Org. Lett. 2015,
17, 3982–3985. (f) Ho, H. E.; Ishikawa, Y.; Asao, N.; Yamamoto, Y.; Jin, T. Highly Efficient
Heterogeneous Aerobic Cross-Dehydrogenative Coupling via C-H Functionalization of
Tertiary Amines Using a Nanoporous Gold Skeleton Catalyst. Chem. Commun. 2015, 51,
12764–12767. (g) Huang, T.; Liu, X.; Lang, J.; Xu, J.; Lin, L.; Feng, X. Asymmetric Aerobic
Oxidative Cross-Coupling of Tetrahydroisoquinolines with Alkynes. ACS Catal. 2017, 7,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
1
2
3
4
5654–5660.
For a review, see: (a) Campos, K. R. Direct sp3 C–H Bond Activation Adjacent to Nitrogen in
Heterocycles. Chem. Soc. Rev. 2007, 36, 1069–1084. Selected references: (b) Muramatsu, W.;
Nakano, K.; Li, C.-J. Simple and Direct sp3 C–H Bond Arylation of Tetrahydroisoquinolines
and Isochromans via 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Oxidation Under Mild
Conditions. Org. Lett. 2013, 15, 3650–3653. (c) Muramatsu, W.; Nakano, K.; Li, C.-J. Direct
sp3 C-H Bond Arylation, Alkylation, and Amidation of Tetrahydroisoquinolines Mediated by
Hypervalent Iodine(III) Under Mild Conditions. Org. Biomol. Chem. 2014, 12, 2189–2192.
(d) Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.; Lou, H. Practical Metal-Free
C(sp3)–H Functionalization: Construction of Structurally Diverse a-Substituted N-Benzyl and
N-Allyl Carbamates. Angew. Chem., Int. Ed. 2014, 53, 3904–3908. (e) Liu, X.; Sun, S.;
Meng, Z.; Lou, H.; Liu, L. Organocatalytic Asymmetric C–H Vinylation and Arylation of N-
Acyl Tetrahydroisoquinolines. Org. Lett. 2015, 17, 2396–2399. (f) Yan, C.; Liu, Y.; Wang, Q.
Direct C–H Allylation of N-Acyl/Sulfonyl Tetrahydroisoquinolines and Analogues. Org. Lett.
2015, 17, 5714–5717. (g) Oss, G.; de Vos, S. D.; Luc, K. N. H.; Harper, J. B.; Nguyen, T. V.
Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines. J. Org. Chem.
2018, 83, 1000–1010. (h) Chen, L.; Sun, C.; Feng, G.; Cao, M.; Zhao, S.-L.; Yan, J.; Wan, R.-
Z.; Liu, L. Direct Oxidative C-H Alkynylation of N-Carbamoyl Tetrahydroisoquinolines and
Dihydroisoquinolines. Org. Biomol. Chem. 2018, 16, 2792–2799.
5
6
7
8
6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
(a) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Dual Catalysis:
Combining Photoredox and Lewis Base Catalysis for Direct Mannich Reactions. Chem.
Commun. 2011, 47, 2360–2362. (b) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C.
R. J. Functionally Diverse Nucleophilic Trapping of Iminium Intermediates Generated
Utilizing Visible Light. Org. Lett. 2012, 14, 94–97. (c) Xuan, J.; Zeng, T.-T.; Feng, Z.-J.;
Deng, Q.-H.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J.; Alper, H. Redox-Neutral Α-Allylation of
Amines by Combining Palladium Catalysis and Visible-Light Photoredox Catalysis. Angew.
Chem., Int. Ed. 2015, 54, 1625–1628. (d) Fu, N.; Li, L.; Yang, Q.; Luo, S. Catalytic
Asymmetric Electrochemical Oxidative Coupling of Tertiary Amines with Simple Ketones.
Org. Lett. 2017, 19, 2122–2125. (e) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung,
C.-H. Visible-Light-Promoted Asymmetric Cross-Dehydrogenative Coupling of Tertiary
20
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Amines to Ketones by Synergistic Multiple Catalysis. Angew. Chem., Int. Ed. 2017, 56,
3694–3698. (f) Zhou, W.-J.; Cao, G.-M.; Shen, G.; Zhu, X.-Y.; Gui, Y.-Y.; Ye, J.-H.; Sun, L.;
Liao, L.-L.; Li, J.; Yu, D.-G. Visible-Light-Driven Palladium-Catalyzed Radical Alkylation of
C−H Bonds with Unactivated Alkyl Bromides. Angew. Chem., Int. Ed. 2017, 56, 15683–
15687. (g) Ren, L.; Cong, H. Visible-Light-Driven Decarboxylative Alkylation of C–H Bond
Catalyzed by Dye-Sensitized Semiconductor. Org. Lett. 2018, 20, 3225–3228.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
For reviews see: (a) Li, C.-J. Cross-Dehydrogenative Coupling (CDC): Exploring C−C Bond
Formations Beyond Functional Group Transformations. Acc. Chem. Res. 2009, 42, 335–344.
(b) Girard, S. A.; Knauber, T.; Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3–H
Bonds: a Versatile Strategy for C–C Bond Formations. Angew. Chem., Int. Ed. 2014, 53, 74–
100. (c) Gini, A.; Brandhofer, T.; García Mancheño, O. Recent Progress in Mild Csp3-H
Bond Dehydrogenative or (Mono-) Oxidative Functionalization. Org. Biomol. Chem. 2017,
15, 1294–1312. (d) Cheng, M.-X.; Yang, S.-D. Recent Advances in the Enantioselective
Oxidative a-C–H Functionalization of Amines. Synlett 2017, 28, 159–174. (e) Varun, B. V.;
Dhineshkumar, J.; Bettadapur, K. R.; Siddaraju, Y.; Alagiri, K.; Prabhu, K. R. Recent
Advancements in Dehydrogenative Cross Coupling Reactions for C–C Bond Formation.
Tetrahedron Lett. 2017, 58, 803–824. Selected references: (f) Huo, C.; Wang, C.; Wu, M.;
Jia, X.; Wang, X.; Yuan, Y.; Xie, H. Catalytic Amounts of Triarylaminium Salt Initiated
Aerobic Oxidative Coupling of N-Aryl Tetrahydroisoquinolines. Org. Biomol. Chem. 2014,
12, 3123–3128. (g) Ma, Y.; Zhang, G.; Zhang, J.; Yang, D.; Wang, R. Organocatalyzed
Asymmetric Oxidative Coupling of a-Csp3-H of Tertiary Amines to a,b-Unsaturated g-
Butyrolactam: Synthesis of MBH-Type Products. Org. Lett. 2014, 16, 5358–5361. (h) Wu,
C.-J.; Zhong, J.-J.; Meng, Q.-Y.; Lei, T.; Gao, X.-W.; Tung, C.-H.; Wu, L.-Z. Cobalt-
Catalyzed Cross-Dehydrogenative Coupling Reaction in Water by Visible Light. Org. Lett.
2015, 17, 884–887. (i) Fang, L.; Li, Z.; Jiang, Z.; Tan, Z.; Xie, Y. A Metal-Free Oxidative
Cross-Dehydrogenative Coupling of N-Aryl Tetrahydroisoquinolines and 2-Methylazaarenes
Using a Recyclable Oxoammonium Salt as Oxidant in Aqueous Media. Eur. J. Org. Chem.
2016, 2016, 3559–3567.
9
(a) Pérez, I.; Pérez Sestelo, J.; Sarandeses, L. A. Atom-Efficient Metal-Catalyzed Cross-
Coupling Reaction of Indium Organometallics with Organic Electrophiles. J. Am. Chem. Soc.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
7
8
9
2001, 123, 4155–4160. Recent references: (b) Martínez, M. M.; Peña-López, M.; Pérez
Sestelo, J.; Sarandeses, L. A. Synthesis of Functionalized Thiophenes and Oligothiophenes by
Selective and Iterative Cross-Coupling Reactions Using Indium Organometallics. Org.
Biomol. Chem. 2012, 10, 3892–3898. (c) Mosquera, Á.; Fernández, M. I.; Canle López, M.;
Pérez Sestelo, J.; Sarandeses, L. A. Nonsymmetrical 3,4-Dithienylmaleimides by Cross-
Coupling Reactions with Indium Organometallics: Synthesis and Photochemical Studies.
Chem. Eur. J. 2014, 20, 14524–14530. (d) Pérez-Caaveiro, C.; Pérez Sestelo, J.; Martínez, M.
M.; Sarandeses, L. A. Triorganoindium Reagents in Selective Palladium-Catalyzed Cross-
Coupling with Iodoimidazoles: Synthesis of Neurodazine. J. Org. Chem. 2014, 79, 9586–
9593. (e) Mato, M.; Pérez-Caaveiro, C.; Sarandeses, L. A.; Pérez Sestelo, J. Ferrocenylindium
Reagents in Palladium-Catalyzed Cross-Coupling Reactions: Asymmetric Synthesis of Planar
Chiral 2-Aryl Oxazolyl and Sulfinyl Ferrocenes.Adv. Synth. Catal. 2017, 359, 1388–1393. (f)
Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Synthesis of Bench-Stable Solid
Triorganoindium Reagents and Reactivity in Palladium-Catalyzed Cross-Coupling Reactions.
Chem. Commun. 2018, 54, 1453–1456.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10 Gil-Negrete, J. M.; Pérez Sestelo, J.; Sarandeses, L. A. Transition-Metal-Free Cross-Coupling
of Indium Organometallics with Chromene and Isochroman Acetals Mediated by BF3·OEt2.
Org. Lett. 2016, 18, 4316–4319.
11 (a) Sato, Y.; Nishimata, T.; Mori, M. Asymmetric Synthesis of Isoindoline and Isoquinoline
Derivatives Using Nickel(0)-Catalyzed [2 + 2 + 2] Cocyclization. J. Org. Chem. 1994, 59,
6133–6135. (b) Li, Z.; Li, C.-J. CuBr-Catalyzed Efficient Alkynylation of sp3 C−H Bonds
Adjacent to a Nitrogen Atom. J. Am. Chem. Soc. 2004, 126, 11810–11811.
12 Tsang, A. S. K.; Jensen, P.; Hook, J. M.; Hashmi, A. S. K.; Todd, M. H. An Oxidative
Carbon–Carbon Bond-Forming Reaction Proceeds via an Isolable Iminium Ion. Pure Appl.
Chem. 2011, 83, 655–665.
13 (a) Cuny, G. D. Intramolecular ortho-Arylation of Phenols Utilized in the Synthesis of the
Aporphine Alkaloids (±)-Lirinidine and (±)-Nuciferine. Tetrahedron Lett. 2003, 44, 8149–
8152. (b) Munusamy, V.; Yap, B. K.; Buckle, M. J. C.; Doughty, S. W.; Chung, L. Y.
Structure-Based Identification of Aporphines with Selective 5-HT2A Receptor-Binding
Activity. Chem. Biol. Drug Des. 2013, 81, 250–256. (c) Poklis, J. L.; Mulder, H. A.; Halquist,
22
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
M. S.; Wolf, C. E.; Poklis, A.; Peace, M. R. The Blue Lotus Flower (Nymphea Caerulea)
Resin Used in a New Type of Electronic Cigarette, the Re-Buildable Dripping Atomizer. J.
Psychoact. Drugs 2017, 49, 175–181.
9
14 Lafrance, M.; Blaquiere, N.; Fagnou, K. Aporphine Alkaloid Synthesis and Diversification
via Direct Arylation. Eur. J. Org. Chem. 2007, 2007, 811–825.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15 (a) Kiljunen, H.; Hase, T. A. Titration of Organolithiums and Grignards with 1-Pyreneacetic
Acid. J J. Org. Chem. 1991, 56, 6950–6952. (b) Burchat, A. F.; Chong, J. M.; Nielsen, N.
Titration of Alkyllithiums with a Simple Reagent to a Blue Endpoint. J. Organomet. Chem.
1997, 542, 281–283.
16 Pena, M. A.; Pérez Sestelo, J.; Sarandeses, L. A. Palladium-Catalyzed Aryl−Aryl Cross-
Coupling Reaction Using ortho-Substituted Arylindium Reagents J. Org. Chem. 2007, 72,
1271–1275.
17 Shinohara, T.; Toda, J.; Sano, T. An Improved Synthesis of 1,2,3,4-Tetrahydroisoquinolines
via Intramolecular Cyclization of N-Acyl-N-(aryl)methyl-2-(phenylsulfinyl)ethylamine by
Pummerer Reaction. Chem. Pharm. Bull. 1997, 45, 813–819.
18 Kim, H. J.; Yoon, U. C.; Jung, Y.-S.; Park, N. S.; Cederstrom, E. M.; Mariano, P. S.
Oxidative Pictet−Spengler Cyclizations. J. Org. Chem. 1998, 63, 860–863.
19 Ludwig, M.; Hoesl, C. E.; Höfner, G.; Wanner, K. T. Affinity of 1-Aryl-1,2,3,4-
tetrahydroisoquinoline Derivatives to the Ion Channel Binding Site of the NMDA Receptor
Complex. Eur. J. Med. Chem. 2006, 41, 1003–1010.
20 Schweitzer-Chaput, B.; Klussmann, M. Brønsted Acid Catalyzed C-H Functionalization of N-
Protected Tetrahydroisoquinolines via Intermediate Peroxides. Eur. J. Org. Chem. 2013,
2013, 666–671.
21 Dunetz, J. R.; Ciccolini, R. P.; Fröling, M.; Paap, S. M.; Allen, A. J.; Holmes, A. B.; Tester, J.
W.; Danheiser, R. L. Pictet–Spengler Reactions in Multiphasic Supercritical Carbon
Dioxide/CO2-Expanded Liquid Media. In Situ Generation of Carbamates as a Strategy for
Reactions of Amines in Supercritical Carbon Dioxide. Chem. Commun. 2005, 4465–4467.
22 Pinet, S.; Chavant, P. Y.; Averbuch-Pouchot, M.-T.; Vallée, Y. Total Synthesis of
Bernumicine and Bernumidine, Two Alkaloids From Berberis nummularia. J. Chem. Res. (S)
2001, 2001, 65–67.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
8
23 Ronson, T. O.; Kitsiou, C.; Unsworth, W. P.; Taylor, R. J. K. Synthetic Approaches to
Pallimamine and Analogues Using Direct Imine Acylation. Tetrahedron 2016, 72, 6099–
6106.
9
24 Rossini, A. F. C.; Muraca, A. C. A.; Casagrande, G. A.; Raminelli, C. Total Syntheses of
Aporphine Alkaloids via Benzyne Chemistry: an Approach to the Formation of Aporphine
Cores. J. Org. Chem. 2015, 80, 10033–10040.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
ACS Paragon Plus Environment