Thiourea-catalyzed oxidative coupling reaction of N-phenyl tetrahydroisoquinoline with β-keto acids

Full text of DOI:10.1002/bkcs.11354

Communication
DOI: 10.1002/bkcs.11354
BULLETIN OF THE
H. J. Jeong et al.
KOREAN CHEMICAL SOCIETY
Thiourea-catalyzed Oxidative Coupling Reaction of N-Phenyl
Tetrahydroisoquinoline with β-Keto Acids
*
Hyun Jung Jeong, Yong Hwan Kim, and Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan 31538, Korea. *E-mail: dyoung@sch.ac.kr
Received October 9, 2017, Accepted November 13, 2017
Keywords: Oxidative coupling reaction, Tetrahydroquinolines, Organocatalysis, Decarboxylative
alkylation
The direct transformation of C─H into C─C bonds has
recently received considerable attention from synthetic
organic chemists.1 Among these reactions, the direct oxida-
tive cross-dehydrogenative coupling (CDC) of two C─H
bonds can be an atom- and step-economic strategy in syn-
thetic organic chemistry.2 Since the pioneering work on CDC
demonstrated by the Murahashi and Li groups on formation
of oxidative iminium ions from tetrahydroisoquinoline
(THIQ) derivatives,3 various nucleophiles have been utilized
to combine the iminium ions to construct new C─C bonds
under Mannich-type protocols.4 Recently, several groups
have reported phenacylmethylation to form C1-phenacyl-
methylated THIQ derivatives from the reaction of enol silanes
or acetophenones using transition metals as catalysts, visible-
light mediated photocatalysis, mechanochemical process, or
organic oxidants.5 Very recently, Zhang and coworkers
reported the efficient thiourea-catalytic CDC of C(sp3)-H with
phosphites and nitroalkanes by using peroxide as a terminal
oxidant.6 The decarboxylative additions of β-keto acids as
ketones or ketone enolate equivalents have received much
attention.7 We envisioned the decarboxylative Mannich-type
reaction of the β-keto acids to the C1-acylmethylated THIQs
by organocatalytic CDC under mild conditions.
hydroperoxide (TBHP) with 20 mol% of organocatalysts
(Figure 1). By screening catalysts (Table 1, entries 1–5),
we found that thiourea catalyst IV was a suitable catalyst
for oxidative coupling reaction, affording the corresponding
product 3a in an 84% yield (Table 1, entry 4). Among the
solvents evaluated (Table 1, entries 4 and 7–13), the best
result was achieved when the reaction was conducted in
acetonitrile (Table 1, entry 4). The control experiment
showed that the reaction could not proceed in the absence
of thiourea catalyst IV (Table 1, entry 14). A trace
amount of product 3a was detected in the presence of the
radical inhibitor (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl
Table 1. Optimization of the reaction conditions.a
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
l
II
llI
lV
V
VI
lV
lV
lV
lV
lV
lV
lV
—
lV
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CHCl3
EtOAc
THF
EtOH
DMF
PhMe
CH3CN
CH3CN
20
20
20
20
48
48
20
20
24
20
20
24
24
20
24
74
29
58
84
23
25
48
40
33
20
21
34
45
Trace
Trace
As part of a research program related to redox reaction,
we recently reported the internal redox reaction via C─H
bond activation.5f,8 Herein, we report the C1-
phenacylmethylation of THIQs with β-keto acids using
thiourea organocatalyst. To determine the optimal reaction
conditions for the thiourea-catalyzed oxidative coupling
reaction of THIQs, we examined the organocatalytic reac-
tion of N-phenyl tetrahydroisoquinoline (1) with 3-oxo-3-
phenylpropanoic acid (2a) in the presence of tert-butyl
9
10
11
12
13
14c
15d
a
Reaction conditions: N-phenyl tetrahydroisoquinoline (1, 0.3 mmol),
3-oxo-3-phenylpropanoic acid (2a, 0.45 mmol), TBHP (0.6 mmol),
catalyst (0.06 mmol), solvent (2.0 mL) at room temperature.
Isolated yield.
Reaction was carried out without a catalyst.
Reaction was carried out in the presence of 2.0 equiv of TEMPO.
b
c
d
Figure 1. Structures of organocatalysts.
Bull. Korean Chem. Soc. 2017
© 2017 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
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ISSN (Print) 0253-2964 | (Online) 1229-5949
BULLETIN OF THE
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Table 2. Substrate scope.a
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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Entry
2, R
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Ph
20
20
24
24
24
15
12
10
20
48
36
36
36
48
3a, 84
3b, 82
3c, 78
3d, 81
3e, 77
3f, 75
3g, 88
3h, 76
3i, 73
3j, 73
3k, 82
3l, 79
3m, 74
3n, 61
4-F,C6H4
4-Cl,C6H4
4-Br,C6H4
3-Br,C6H4
4-NO2,C6H4
4-OMe,C6H4
4-Me,C6H4
3-Me,C6H4
2-Me,C6H4
1-Naphthyl
2-Furyl
9
10
11
12
13
14
a
2-Thienyl
CH3CH2
Reaction conditions: N-phenyl tetrahydroisoquinoline (1, 0.3 mmol),
3-oxoalkanoic acid 2 (0.45 mmol), TBHP (0.6 mmol), catalyst (IV,
0.06 mmol), acetonitrile (2.0 mL) at room temperature.
Isolated yield.
b
(TEMPO) (Table 1, entry 15). The inhibitory effect of
TEMPO indicated that this reaction proceeded via radical
intermediate(s).
After determining the optimal reaction conditions, we
investigated the scope of this thiourea-catalyzed oxidative
coupling reaction of N-phenyl tetrahydroisoquinoline (1)
with 3-oxoalkanoic acid 2 in the presence of 20 mol% of
thiourea catalyst IV in acetonitrile at room temperature. As
shown in Table 2, various 3-oxoalkanoic acids 2 with
electron-donating or electron-withdrawing substituents in
aryl groups afforded the corresponding coupling products
with moderate to high yields (73–88%, Table 2, entries
1–10). The naphthyl- and heteroaryl-substituted β-keto
acids provided the desired products with high yields
(74–82%, Table 2, entries 11–13). In addition, alkyl-
substituted β-keto acid, 3-oxopentanoic acid, also afforded
the corresponding product 3n, but with relatively lower
yield (61%, Table 2, entry 14).
In conclusion, we presented a novel and environmentally
benign process for the thiourea-catalyzed oxidative cou-
pling reaction of N-phenyl tetrahydroisoquinoline (1) with
3-oxoalkanoic acid acids 2 in the presence of thiourea
catalyst IV.
Acknowledgment. This research was supported by Soon-
chunhyang University Research Fund.
Bull. Korean Chem. Soc. 2017
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