Visible light mediated photocatalytic oxidative coupling reaction of N-phenyl tetrahydroisoquinoline with β-keto acids

Article abstract of DOI:10.1016/j.tetlet.2017.03.026

A visible light mediated photocatalytic oxidative coupling reaction of N-phenyl tetrahydroisoquinoline with β-keto acids has been developed. This approach provides a mild and operationally simple access to the synthesis of C1-acylmethylated tetrahydroisoquinolines.

Full text of DOI:10.1016/j.tetlet.2017.03.026

Accepted Manuscript
Visible light mediated photocatalytic oxidative coupling reaction of N-phenyl
tetrahydroisoquinoline with β-keto acids
Su Jin Kwon, Min Gyun Gil, Dae Young Kim
PII:
S0040-4039(17)30318-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.026
TETL 48727
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 January 2017
1 March 2017
8 March 2017
Please cite this article as: Kwon, S.J., Gil, M.G., Kim, D.Y., Visible light mediated photocatalytic oxidative coupling
reaction of N-phenyl tetrahydroisoquinoline with β-keto acids, Tetrahedron Letters (2017), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2017.03.026
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Visible light mediated photocatalytic oxidative
coupling reaction of N-phenyl tetrahydroisoquinoline
with β-keto acids
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Su Jin Kwon, Min Gyun Gil, and Dae Young Kim*

1
Tetrahedron Letters
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Visible light mediated photocatalytic oxidative coupling reaction of N-phenyl
tetrahydroisoquinoline with β-keto acids
Su Jin Kwon, Min Gyun Gil, and Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 31538, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A visible light mediated photocatalytic oxidative coupling reaction of N-phenyl
tetrahydroisoquinoline with β-keto acids has been developed. This approach provides a mild and
operationally simple access to the synthesis of C1-acylmethylated tetrahydroisoquinolines.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative coupling reaction,
Photocatalysis,
Radical reaction,
Tetrahydroisoquinolines
The direct transformation of C−H into C−C bonds has
recently received significant attention in the fields of organic and
1
medicinal chemistry. In particular, the direct oxidative cross-
dehydrogenative coupling (CDC) of two C–H bonds can be an
atom-economic and environmentally benign approach in organic
2
synthesis. Since the pioneering work on CDC demonstrated by
Murahashi and Li groups on oxidative iminium formation from
3
tetrahydroisoquinoline (THIQ) derivatives, various nucleophiles
have been utilized to combine the iminium intermediates to
4
construct new C−C bonds under Mannich-type protocols.
The application of visible light mediated photoredox catalysis
has emerged as a novel and efficient tool for chemical
transformations due to its natural abundance, mild and relatively
Scheme 1. Strategies for the visible light mediated
photocatalytic phenacylmethylation of THIQs.
5
clean reaction conditions, and high reactivity. In this context, the
visible-light photocatalytic C−H functionalization of α-carbon
atom of an amino group became a valuable extension of
1
1
expansion. In this letter, we wish to describe visible light
mediated photocatalytic C1-acylmethylation of THIQs.
6
conventional oxidation reactions. Several groups reported the
visible light photocatalytic CDC of the THIQs with aliphatic
ketones and α-trifluofomethyl β-fluorinated gem-diol in the
To determine suitable reaction conditions for the visible light
mediated photocatalytic oxidative coupling reaction of THIQs,
we examined the visible light mediated photocatalytic reaction of
7
presence of photocatalysts. Recently, the Xia group has reported
visible light mediated phenacylmethylation to form C1-
phenacylmethylated THIQ derivatives from the reaction of enol
N-phenyl
tetrahydroisoquinoline
(1)
with
3-oxo-3-
8
silanes with N-phenyl tetrahydroisoquinolines (Scheme 1a). The
phenylpropanoic acid (2a) in the presence of 3 mol %
photocatalyst under visible light irradiation with blue LEDs (5
W, max = 455 nm) in MeOH at room temperature. By screening
photocatalysts (Table 1, entries 1-6), we found that
decarboxylative additions of β-keto acids as of ketones or ketone
enolate equivalents have received much attention. However, the
9
decarboxylative alkylation of β-keto acids to THIQs remains
elusive. We envisioned the decarboxylative Mannich-type
reaction of the β-keto acids to the C1-acylmethylated THIQs by
visible light mediated photocatalytic CDC (Scheme 1b).
Ru(bpy)
3
Cl
2
2
·6H O was the best photocatalyst for oxidative
coupling reaction, affording the corresponding product 3a in 83%
yield (Table 1, entry 3). Among the solvents evaluated (Table 1,
entries 3 and 7-14), the best result was achieved when the
reaction was conducted in MeOH (Table 1, entry 3). Reducing
the photocatalyst loading to 1 mol % had little influence on the
yield (Table 1, entry 15). The control experiment showed that the
reaction could not proceed in the absence of a photocatalyst and
As part of a research program related to redox reaction, we
recently reported the internal redox reaction via C–H bond
1
0
activation and photoredoxcatalytic functionalization/ring

2
Tetrahedron
a,
Table 1. Optimization of photocatalytic oxidative coupling
a
reaction
Table 2. Variation of substrates 2
b
entry
2, R
Ph
time (h)
yield (%)
3a, 82
3b, 82
3c, 66
3d, 78
3e, 65
3f, 75
3g, 73
3h, 86
3i, 80
b
1
2
3
4
5
6
7
8
9
7
7
entry
photocatalyst
Ru(bpy) (PF
Ru(phen) Cl ·H
Ru(bpy) Cl ·6H
fac-Ir(ppy)
solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
time (h)
yield (%)
6 4
4-Br,C H
1
2
3
4
5
6
7
8
9
3
6
)
2
7
7
60
56
83
25
15
23
41
58
4-Cl,C
6
H
4
7
3
2
2
O
4-F,C
6
H
4
7
3
2
2
O
7
4-NO
4-Me,C
4-OMe,C
2
,C
6
H
4
7
3
7
6
H
4
7
7
H
15
15
15
24
24
fluorecein
eosin Y
6
4
7
1-naphthyl
2-furyl
Ru(bpy)
3
Cl
Cl
2
·6H
2
O
O
10
10
1
0
1
2-thienyl
3j, 75
3k, 65
Ru(bpy)
3
2
·6H
2
i-PrOH
1
3 2
CH CH
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
3
3
3
3
3
3
3
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
2
O
O
O
O
O
O
O
O
O
CH
3
CN
15
15
15
15
15
15
7
30
12
15
38
27
29
82
35
0
1
1
1
1
1
0
1
2
3
4
2
DMF
DMSO
acetone
a
Reaction conditions: N-phenyl tetrahydroisoquinoline (1, 0.3 mmol), 3-oxo-
alkanoic acid 2 (0.6 mmol), photocatalyst (0.003 mmol), solvent (2.0 mL) at
2
b
room temperature under visible-light irradiation. Isolated yield
2
2
CH
2
Cl
2
2
THF
c
1
5
6
7
2
MeOH
MeOH
MeOH
MeOH
MeOH
d
e
1
1
2
7
2
7
1
8
-
7
0
1
9
Ru(bpy)
3
Cl
2
·6H
2
O
7
34
a
Reaction conditions: N-phenyl tetrahydroisoquinoline (1, 0.3 mmol), 3-oxo-
-phenylpropanoic acid (2a, 0.6 mmol), photocatalyst (0.009 mmol), solvent
3
b
2.0 mL) at room temperature under visible light irradiation. Isolated yield.
c
(
d e
mol % photocatalyst loading. 0.1 mol % photocatalyst loading. The
Scheme 2. Gram scale photocatalytic oxidative coupling
reaction of N-phenyl tetrahydroisoquinoline (1) with 3-oxo-3-
phenylpropanoic acid (2a).
1
reaction was performed in the dark.
visible light (Table 1, entries 17-18). Under nitrogen after
degassing, the reaction gave reduced yield. It is indicate that
oxygen may play a role in the mechanism but is not explicitly
required (Table 1, entry 19). Therefore, the optimized conditions
The present method is operationally simple and efficient and,
thus, may be valuable for practical chemical synthesis. As shown
in Scheme 2, when N-phenyl tetrahydroisoquinoline (1) was
treated with 3-oxo-3-phenylpropanoic acid (2a) the optimal
reaction conditions, the reaction proceeded smoothly to afford
the desired 1-phenyl-2-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-
entailed the use of 1 mol % of Ru(bpy)
photocatalyst in MeOH at room temperature for 7 h (Table 1,
3
Cl
2
2
·6H O as a
entry 15).
1
-yl)ethanone (3a) at the gram scale with 81% yield (Scheme 2).
With the optimal reaction conditions in hand, we investigated
the scope of this visible light mediated photocatalytic oxidative
coupling reaction of N-phenyl tetrahydroisoquinoline (1) with 3-
In conclusion, we have developed a novel and
environmentally benign process for the visible light mediated
photoredox catalyzed oxidative coupling reaction of N-phenyl
tetrahydroisoquinoline (1) with 3-oxoalkanoic acid acid 2 in the
oxoalkanoic acid
2 in the presence of 1 mol % of
Ru(bpy) Cl ·6H O under light irradiation with blue LEDs in
3
2
2
presence of 1 mol % of Ru(bpy)
a
3
Cl
aimed at developing related asymmetric version of
2
2
·6H O. Current studies are
1
2
MeOH at room temperature. As shown in Table 2, various 3-
oxoalkanoic acid 2 with electron-withdrawing or electron-
donating aryl groups furnished the corresponding migration
products with moderate to good yields (65-82%, Table 2, entries
photocatalytic oxidative coupling reaction for the efficient
buildup of molecular complexity.
1
-7). The naphthyl- and heteroaryl-substituted β-keto acids
provided the desired products with high yields (75-86%, Table 2.
entries 8-10). In addition, alkyl-substituted β-keto acid-like 3-
oxopentanoic acid (1k) participated in this reaction to afford the
corresponding products 3k in 65% yield (Table 2. entry 11).
Acknowledgments
This research was supported by Soonchunhyang University
Research Fund and Basic Science Research Program through the

3
National
2
Research
014R1A2A01006224 and 2016R1D1A1B03933723).
Foundation
of
Korea
(NRF-
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1
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12. General procedure for the visible-light mediated photocatalytic
oxidative coupling reaction of N-phenyl tetrahydroisoquinoline
with β-keto acids: An oven-dried flask was equipped with a
magnetic stir bar, N-phenyl tetrahydroisoquinoline (1a, 63 mg, 0.3
8
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2
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3 2 2
mmol), Ru(bpy) Cl ·6H O (2.3 mg, 0.003 mmol), 3-oxoalkanoic
acid (2, 0.6 mmol) and MeOH (2 mL) under air atmosphere. The
reaction mixture was allowed to stir for 7-24 h under irradiation of
blue LEDs (5 W). After the reaction was finished, the mixture was
added ammonium chloride and extracted with ethyl acetate. The
2 4
organic layers were dried over Na SO , concentrated in vacuum and
purified by chromatography on silica gel (ethyl acetate:n-hexane =
1:20) to afford the C1-acylmethylated THIQs 3.
3
4
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K.; Kim, D. Y. Bull. Korean Chem. Soc. 2011, 32, 1773. (c) Kim,

4
Tetrahedron
Graphical Abstract
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Visible light mediated photocatalytic oxidative
coupling reaction of N-phenyl tetrahydroisoquinoline
with β-keto acids
Leave this area blank for abstract info.
Su Jin Kwon, Min Gyun Gil, and Dae Young Kim*
Fonts or abstract dimensions should not be changed or altered.

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Highlight
1
2
3
. We have developed the photocatalyzed alkylati
on of tetrahydroquinoline derivatives.
. Moderate to high yields (3a-3k, 65-86%) obser
ved.
. This reaction proceeded under mild conditions (
1
mol % photocatalyst with blue LEDs at room
temperature)