Direct sp3 C-H acroleination of N-aryl-tetrahydroisoquinolines by merging photoredox catalysis with nucleophilic catalysis

Article abstract of DOI:10.1039/c3ob42453g

Sequence catalysis merging photoredox catalysis (PC) and nucleophilic catalysis (NC) has been realized for the direct sp³ C-H acroleination of N-aryl-tetrahydroisoquinoline (THIQ). The reaction was performed under very mild conditions and afforded products in 50-91% yields. A catalytic asymmetric variant was proved to be successful with moderate enantioselectivities (up to 83 : 17 er).

Full text of DOI:10.1039/c3ob42453g

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Direct sp3 C–H acroleination of N-aryl-
tetrahydroisoquinolines by merging photoredox
catalysis with nucleophilic catalysis†
Cite this: Org. Biomol. Chem., 2014,
12, 2037
Received 9th December 2013,
Accepted 28th January 2014
Zhu-Jia Feng,a Jun Xuan,a Xu-Dong Xia,a Wei Ding,a Wei Guo,a Jia-Rong Chen,a
You-Quan Zou,a Liang-Qiu Lu*a and Wen-Jing Xiao*a,b
DOI: 10.1039/c3ob42453g
www.rsc.org/obc
Sequence catalysis merging photoredox catalysis (PC) and nucleo- Encouraged by our success of both NC (eqn (1))9 and PC
philic catalysis (NC) has been realized for the direct sp3 C–H acro- (eqn (2)),10 we recently questioned whether it might be poss-
leination of N-aryl-tetrahydroisoquinoline (THIQ). The reaction ible to merge these two powerful catalytic models, with the
was performed under very mild conditions and afforded products goal of direct functionalization of inactive C–H bonds.
in 50–91% yields. A catalytic asymmetric variant was proved to be Inspired by elegant work from the Wang group on the tertiary
successful with moderate enantioselectivities (up to 83 : 17 er).
amine/copper co-catalysed oxidative olefination reaction
of THIQ,11 we chose the same transformation to test our pro-
posal. The challenge is the compatibility of a nucleophilic cata-
lyst under PC conditions since traditional nucleophilic
catalysts (i.e. DABCO and PPh3) might be oxidized in the pres-
ence of oxidative radicals (vide infra).
The development of efficient and sustainable processes to con-
struct new C–C bonds has attracted considerable attention
from the chemical community.1 From the viewpoint of green
catalysis, visible light photoredox catalysis (PC) is an ideal
complement to the conventional thermal procedures.2,3 Par-
ticularly, sequence catalysis by merging PC with other catalytic
models has become extremely powerful in direct functionaliza-
tions of inert C–H bonds.4,5 Pioneered by the Stephenson
group,6 N-aryl-tetrahydroisoquinoline (THIQ) has been widely
employed as the testing platform5 to verify the feasibility of
sequence catalysis (Scheme 1).7 Notably, Rueping and co-
workers have developed direct Mannich reactions of THIQs
with methyl ketones by integrating PC with enamine cata-
lysis.5g Since then, sequence catalysis combining PC and
N-heterocyclic carbene (NHC) catalysis,5d H-bonding catalysis5a
and transition metal catalysis5e,f have been successfully develo-
ped by the groups of Rovis, Rueping, Stephenson and Jacob-
sen, respectively, to install the carbonyl, alkynyl or methyl
ester moiety into C–H bonds adjacent to a N-atom. Despite
these impressive advances, sequence catalysis involving visible
light photoredox catalysis has not achieved its full potential.
Over the past few decades, nucleophilic catalysis (NC) has
grown at a dramatic pace in C–C formation reactions.8
The acroleination of sp3 C–H bonds of THIQs was evaluated
using N-phenyl tetrahydroisoquinoline 1a and acrolein 2a as
the substrates in the presence of different nucleophilic cata-
lysts, photocatalysts, and oxidants (Table 1). It was found that
oxidized isoquinoline, 2-phenyl-3,4-dihydroisoquinolin-1(2H)-
one, was isolated as the major product when Ru(bpy)3Cl2·6H2O
(I) was employed as the photoredox catalyst and oxygen was
used as the oxidant (Table 1, entry 1). To our delight, the pro-
posed acroleination reaction did proceed when BrCCl3 was
introduced as the oxidant (Table 1, entry 2: 49% yield). To
address the compatibility of nucleophilic catalysts with photo-
redox catalysts and oxidants, we examined the stoichiometric
reaction of nucleophilic catalysts, DABCO and PPh3, with
aKey Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei
430079, China. E-mail: wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041;
Tel: +86 27 67862041
bCollaborative Innovation Center of Chemical Science and Engineering, Tianjin,
China
†Electronic supplementary information (ESI) available: Substrates preparation,
experimental procedures and compound characterisation data. See DOI:
10.1039/c3ob42453g
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Table 2 Substrate scopea
Scheme 1 Representative examples of functionalization of C–H bonds
of THIQ via PC-based sequence catalysis.
Table 1 Optimization of reaction conditionsa
Photoredox Nucleophilic
Yieldb
(%)
a Reaction conditions: 1 (0.5 mmol), Ir(ppy)2(dtbbpy)PF6 (II) (2 mol%),
BrCCl3 (3.0 equiv.) in solvent (2 mL), blue LED irradiation at r.t., 3 h,
then no light, 2 (5.0 equiv.), DABCO (1.0 equiv.), K2CO3 (1.0 equiv.).
Entry catalyst
catalyst
Oxidant Solvent
1
I
I
I
I
DABCO
DABCO
DABCO
DBU
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
THF
n.d.
49
75
Trace
71
79
11
73
69
46
2c
3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
4
5
6
7
8
9
10
11
12
13
acid acceptor (K2CO3) and 2a were added to the reaction
mixture after removing blue LED irradiation.5a,f To our delight,
by this manipulation an increased yield of product 2a was
achieved (75% yield, Table 1, entry 3). In addition, the effect
of different photosensitizers and nucleophilic catalysts
was explored, and the results showed that the combination of
Ir(ppy)2(dtbbpy)PF6 (II) and DABCO was the best (Table 1,
entries 4–8). To further improve the reaction efficiency,
different reaction media were screened. As presented in
Table 1, the reaction was applicable with a variety of different
I
PPh3
II
IIId
IVe
II
II
II
II
II
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMSO
DCM
79
79
DMSO–DCM = 83
1 : 1
a Reaction conditions: 1a (0.5 mmol), photoredox catalyst (2 mol%),
BrCCl3 (3.0 equiv.) in solvent (2 mL), blue LED irradiation at r.t., 3 h,
then no light, 2a (5.0 equiv.), nucleophilic catalyst (1.0 equiv.), K2CO3 solvents such as MeCN, THF, DCM, and DMSO (entries 9–13).
(1.0 equiv.). b Yield of isolated product. c Reaction conditions: 1a
The use of a mixed solvent (DMSO–DCM = 1 : 1) gave the best
(0.5 mmol), photoredox catalyst (2 mol%), 2a (5.0 equiv.), nucleophilic
result (83% yield, Table 1, entry 13).12
catalyst (1.0 equiv.), K2CO3 (1.0 equiv.) and oxygen (1 atm) or BrCCl3
(3.0 equiv.) in DMF (2 mL) under blue LED irradiation at r.t. d Esion Y
Under the optimal reaction conditions, the scope of N-sub-
stituted THIQs for this acroleination reaction was next exam-
ined. The electronic nature of the aromatic substituents on the
nitrogen atom shows no pronounced effect on the overall reac-
(III). e Ru(bpy)3PF6 (IV).
BrCCl3 under PC conditions. The results indicated that tion outcomes. As highlighted in Table 2, substrates bearing
DABCO decomposed completely in the presence of BrCCl3 an electron-donating (p-OMe) or electron-withdrawing group
under irradiation of blue light, but remains unchanged (p-F) on the phenyl rings participate in this transformation
without blue light. In addition, PPh3 disappears quickly with efficiently (3b: 78% yield, 3e: 89% yield). Moreover, this acro-
or without the blue light irradiation. Thus, one-pot operation leination reaction tolerated the o-OMe group well (3d: 83%
was applied to the designed reaction: 1a was mixed with yield), which did not show a steric hindrance for the addition
BrCCl3 and Ru(bpy)3Cl2·6H2O (I) to generate the iminium step. Though an undetermined by-product was isolated from
intermediates in situ under PC conditions, and then DABCO, the resultant mixture in the case of m-OMe substituted
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substrate 1c, the desired product was still obtained in a good
isolated yield (3c: 65% yield). Incorporation of chloro and
methyl substituents at the para-position of the N-phenyl group
is possible without loss in reaction efficiency (3f: 91% yield;
3g: 82% yield). Perhaps more importantly, significant struc-
tural variation on the tetrahydroquinoline scaffold can also be
realized. A variety of substituents can be successfully incorpor-
ated on the THIQ at different positions (3h: 79% yield, 3i: 50%
yield, 3j: 91% yield, 3k: 61% yield and 3l: 85% yield). Notably,
when acrylonitrile was used instead of acrolein, the reaction
could also proceed well and the desired product was obtained
in 65% yield (eqn (3)).
Notes and references
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ð3Þ
A catalytic asymmetric acroleination has been carried out
by using a chiral nucleophilic catalyst. With the use of 20 mol%
β-isocupreidine (β-ICD) as the nucleophilic catalyst, the reac-
tion afforded the enantioenriched (S)-3a and (S)-3b (eqn (4),
3a: 82% yield, 83 : 17 er; 3b: 64% yield, 78 : 22 er), respectively.
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ð4Þ
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Conclusions
In summary, we have developed the first example of sequence
catalysis by merging visible light photoredox catalysis and
nucleophilic catalysis. This process is able to directly assemble
acrolein to the sp3 C–H at the α-position of tertiary amines in
moderate to excellent yields (52–93%). The primary trial on
catalytic asymmetric acroleination of THIQ was realized with
moderate enantioselectivity.
Acknowledgements
We are grateful to the National Science Foundation of China
(no. 21272087, 21202053 and 21232003) and the National
Basic Research Program of China (2011CB808603) for support
of this research.
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12 For the control experiments, see ESI† for details.
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