Visible-light induced Cross-Dehydrogenative-Coupling (CDC) reactions of N-aryl tetrahydroisoquinolines under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2021.153102

A visible-light induced cross-dehydrogenative-coupling (CDC) reaction of N-aryl tetrahydroisoquinolines was developed under mild aerobic conditions. This protocol proceeded smoothly with a large range of nucleophiles (nitroalkane, dimethyl phosphite, dimethyl malonate, N-methyl indole, TMSCN) under metal-free conditions and an oxygen atmosphere, forming a new C–C bond. Visible-light played a significant acceleration effect in this reaction.

Full text of DOI:10.1016/j.tetlet.2021.153102

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible-light induced Cross-Dehydrogenative-Coupling (CDC) reactions
of N-aryl tetrahydroisoquinolines under aerobic conditions
a
b,
Chao Lin a, , Peiwu Li , Lin Wang
⇑
⇑
a Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, China
b Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A visible-light induced cross-dehydrogenative-coupling (CDC) reaction of N-aryl tetrahydroisoquinolines
was developed under mild aerobic conditions. This protocol proceeded smoothly with a large range of
nucleophiles (nitroalkane, dimethyl phosphite, dimethyl malonate, N-methyl indole, TMSCN) under
metal-free conditions and an oxygen atmosphere, forming a new CAC bond. Visible-light played a signif-
icant acceleration effect in this reaction.
Received 22 February 2021
Revised 11 April 2021
Accepted 16 April 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Cross-dehydrogenative-coupling
N-aryl tetrahydroisoquinolines
Oxygen
The development of methods for exploring CAC bond formation
plays a central role in organic synthesis. Transition-metal catalyzed
CAC bond coupling reactions and transition-metal catalyzed CAH
activation with subsequent CAC bond formation have seen enor-
mous progress in recent years [1]. However, these reactions typi-
cally require a pre-functionalized precursor. In the last decade,
cross dehydrogenative coupling (CDC), which directly forms new
CAC bonds by utilizing two different CAH bonds under oxidative
conditions [2], have attracted considerable interest.
Among the reported CDC reactions, the oxidative coupling reac-
tions of N-aryl tetrahydroisoquinolines with a number of nucle-
ophiles have received considerable attention and significant
advances have been made in this field. The pioneering work of
Murahashi and Li demonstrated the utility of transition metal cat-
alysts (Ru and Cu) for CDC reactions [3,4]. Recently, other transi-
tion metal catalysts, such as Fe [5], V [6], Rh [7], Au [8], Pt [9],
Ru [10], Zr [11], and Mo [12] or photocatalysts, such as Ir(ppy)2-
(dtbbpy) [13], Ru(bpy)3 [14b], Co(II)-dmgh [15a], TiO2 [15b], and
eosin Y [16] have also been applied to these CDC reactions. In addi-
tion, transition-metal free methods using a stoichiometric amount
of an oxidant, such as PhI(OAc)2 [17], DDQ [18], N-ethoxy-2-
methyl-pyridinium tetrafluoroborate [19], or the tropylium ion
[19], have also been reported. Moreover, oxygen has been used
in combination with catalytic amounts of a co-oxidant, such as
DDQ, iodine, or sulfuryl chloride (Scheme 1, A-1) [20] or in the
presence of acetic acid under metal-free conditions (Scheme 1, A-
2) [21]. Recently, our group reported an efficient visible-light
induced isoindole formation/Diels-Alder reaction, providing access
to bridged-ring heterocycles [22]. To the best of our knowledge,
there are no reports that only utilize visible-light to prompt CDC
reactions. As an extension of our continued interest in the develop-
ment of reactions induced by visible-light, herein, we describe the
visible-light induced metal-free oxidative reactions of N-aryl
tetrahydroisoquinolines with various nucleophiles in the presence
of oxygen under ambient conditions (Scheme 1, B).
Our initial studies focused on the cross-coupling reaction of N-
phenyl tetrahydroisoquinoline (1a) and nitromethane (2a) under
irradiation with a 400–450 nm wavelength 6 W blue LED in the
presence of oxygen at room temperature. To our delight, the
desired cross-coupling product 3aa was obtained in 41% yield after
72 h when MeOH was used as a solvent (Entry 1, Table 1). To
enhance the reaction efficiency, different solvents were evaluated
under otherwise identical conditions. When the reaction was con-
ducted in DMF, the best yield of 69% yield was achieved (Entry 6,
Table 1). The reaction under a nitrogen atmosphere did not pro-
ceed (Entry 7, Table 1). When the reaction was conducted under
an air atmosphere, the yield decreased to 53% (Entry 8, Table 1).
Compared with the reaction irradiated by the blue LED, the reac-
tion under dark conditions or in sunlight afforded the desired pro-
duct in only 5% and 22% yield, respectively (Entries 9, 10, Table 1).
These findings indicate that the 400–450 nm wavelength of the
blue LEDs and oxygen play critical roles in this oxidative cross-cou-
pling reaction. Decreasing the amount of nitromethane to 1.5
equivalents resulted in a lower yield (Entry 12, Table 1). When
⇑
Corresponding authors.
E-mail addresses: linchao46@163.com (C. Lin), rushanwanglin@126.com
(L. Wang).
https://doi.org/10.1016/j.tetlet.2021.153102
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: C. Lin, P. Li and L. Wang, Visible-light induced Cross-Dehydrogenative-Coupling (CDC) reactions of N-aryl tetrahydroisoquinolines
under aerobic conditions, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153102

C. Lin, P. Li and L. Wang
Tetrahedron Letters xxx (xxxx) xxx
effect of different substituents on the tetrahydroisoquinoline. Sub-
strates with electron-donating groups (Entries 10, 13) gave the cor-
responding products in good yields (76–80%). In contrast,
substrates with electron-withdrawing groups (Entries 11–12)
afforded the desired products in lower yields (54–63%).
The reaction scope using the different nucleophiles is shown in
Scheme 2. The reaction with nitroethane provided the desired pro-
duct 4a in 57% yield as a diastereomeric mixture. Dimethyl phos-
phite could also be employed in the oxidative CDC reaction,
affording the corresponding product 4b in 71% yield. In addition,
the reaction with dimethyl malonate gave the desired product 4c
in 57% yield. N-Methyl indole was also a suitable nucleophile for
this reaction, providing product 4d in 54% yield. Furthermore, the
oxidative CDC reaction proceeded smoothly with using TMSCN as
a nucleophile to give product 4e in 75% yield.
A plausible mechanism for the formation of product 3aa based
on previous literature is shown in Scheme 3 [21,22]. Initially, visi-
ble-light irradiation of O2 in the presence of N-phenyl tetrahy-
droisoquinoline 1a generates radical cation Int-1 and
a
superoxide radical anion (OÅ2À). Hydrogen atom abstraction of Int-
1 by OÅ2À provides iminium ion Int-2. Finally, the desired product
3aa was formed via nucleophilic substitution between Int-2 and
the nucleophile. A control experiment was performed in the pres-
ence of the radical inhibitor 2,6-di-tert-butyl-4-methylphenol. The
conversion rate was lower than without 2,6-di-tert-butyl-4-
methylphenol and product 3aa was obtained in only 23% yield.
In conclusion, a visible-light induced oxidative CDC reaction of
N-aryl tetrahydroisoquinolines with various nucleophiles under
aerobic conditions has been developed. This protocol is compatible
with a wide range of nucleophiles, including N-methyl indole. Sig-
nificantly, the reaction only proceeds in the presence of visible-
light and oxygen, and no metal catalyst or external oxidant is
required. Further studies are ongoing to expand the synthetic util-
ity of this transformation.
Scheme 1. O2 as an oxidant in CDC reactions.
the amount of the nucleophile was increased to 1.0 mL, the best
yield of 80% was achieved (Entry 13, Table 1).
With the optimal reaction conditions in hand, we turned our
attention to exploring the generality of the reaction. As shown in
Table 2, a wide array of N-aryl tetrahydroisoquinolines 1 with dif-
ferent substituents on the phenyl ring proceeded smoothly in the
oxidative CDC reaction. Electron-donating groups (Entries 2–5,
Table 2) gave good yields (73–81% yields), while electron-with-
drawing groups (Entries 6–8, Table 2) provided the desired prod-
ucts in lower yields (36–65%). When 1-naphthyl group was
employed in the reaction, the corresponding product 3ia was
obtained in 47% yield (Entry 9, Table 2). Next, we evaluated the
Table 1
Optimization of the reaction conditions.a
b
Entry
Nitromethane
(equiv.)
Solvent
Time (h)
Yield 3aa (%)
1
2
3
4
5
6
10
10
10
10
10
10
10
10
10
10
5
MeOH
CH2Cl2
THF
72
48
24
48
24
48
48
48
48
48
48
48
48
41
34
21
43
19
69
trace
53
5
22
68
49
80
DCE
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
7c
8d
9e
10f
11
12
13g
1.5
a
b
c
d
e
f
Reagents and conditions: 1a (0.3 mmol), solvent (3.0 mL), 6 W blue LED, room temperature.
Isolated yields.
Under a N2 atmosphere.
Under an air atmosphere.
Under dark conditions.
In sunlight.
g
Using MeNO2 (1.0 mL).
2

C. Lin, P. Li and L. Wang
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Substrate scope of N-aryl tetrahydroisoquinolines.a
Entry
1
R1
R2
3
Yield 3 (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
H
H
H
H
H
H
H
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
80
81
68
79
73
36
65
61
47
80
63
54
76
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-BrC6H4
1-Naphthyl
Ph
9
H
10
11
12
13
1j
1k
1l
6-MeO
6-Br
7-NO2
6,7-(MeO)2
3ja
3ka
3la
Ph
Ph
Ph
1m
3ma
a
Reagents and conditions: 1 (0.3 mmol), 2a (1.0 mL), DMF (3.0 mL), 6 W blue LED, room temperature, 48 h.
Isolated yields.
b
Acknowledgment
The study was supported by the Science and Technology Inno-
vation Development Planning Project of Yantai (2020MSGY057).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153102.
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