Redox-neutral C–H cyanation of tetrahydroisoquinolines under photoredox catalysis

Article abstract of DOI:10.1016/j.tetlet.2018.07.030

Redox-neutral cyanation of C–H bond adjacent to a nitrogen atom was achieved by using the combination of a photoredox catalyst and p-toluenesulfonyl cyanide. The reaction of tetrahydroisoquinolines proceeded smoothly, affording the corresponding cyanated products selectively in good to high yield. Although the reaction rate became slower in the case of the substrates having electron-withdrawing groups, high yields were achieved by elongating the reaction time. Although the yields were only moderate, the reaction conditions were also applicable to N,N-dialkylanilines.

Full text of DOI:10.1016/j.tetlet.2018.07.030

Accepted Manuscript
Redox-neutral C − H cyanation of tetrahydroisoquinolines under photoredox
catalysis
Takafumi Ide, Kazunori Shimizu, Hiromichi Egami, Yoshitaka Hamashima
PII:
S0040-4039(18)30890-6
https://doi.org/10.1016/j.tetlet.2018.07.030
TETL 50139
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 May 2018
4 July 2018
10 July 2018
Please cite this article as: Ide, T., Shimizu, K., Egami, H., Hamashima, Y., Redox-neutral C − H cyanation of
tetrahydroisoquinolines under photoredox catalysis, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.07.030
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Redox-neutral C−H cyanation of
tetrahydroisoquinolines under photoredox
catalysis
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Takafumi Ide, Kazunori Shimizu, Hiromichi Egami, and Yoshitaka Hamashima*

1
Tetrahedron Letters
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Redox-neutral C−H cyanation of tetrahydroisoquinolines under photoredox catalysis
Takafumi Ide, Kazunori Shimizu, Hiromichi Egami, and Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Redox-neutral cyanation of C−H bond adjacent to a nitrogen atom was achieved by using the
combination of a photoredox catalyst and p-toluenesulfonyl cyanide. The reaction of
tetrahydroisoquinolines porceeded smoothly, affording the corresponding cyanated products
selectively in good to high yield. Although the reaction rate became slower in the case of the
substrates having electron-withdrawing groups, high yields were achieved by elongating the
reaction time. Although the yields were only moderate, the reaction conditions were also
applicable to N,N-dialkylanilines.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:cyanation, C−H functionalization, redox-
neutral, photoredox catalysis, tetrahydroisoquinoline
The cyano group, which can be found in various
pharmaceutical compounds, is an important and useful functional
group in organic synthesis, since it can be easily transformed to
other functional groups.1 Thus, the introduction of a cyano group
as a C1 unit into an organic framework has been well studied.
Among various cyanide compounds, α-amino nitrile derivatives
are representative as a substructure of bioactive molecules and
synthetic intermediates of α-amino carbonyl compounds and 1,2-
diamines.2 The addition of a cyanide anion to an imine, so-called
Strecker reaction, is the most reliable method for the preparation
of the α-amino nitrile derivatives.3
various bioactive compounds.12 In 2011, Inoue and coworkers
reported an elegant work on the C−H cyanation using a photo-
excited benzophenone and p-toluenesulfonyl cyanide (TsCN), in
which the reaction would proceed via hydrogen atom transfer
from
a substrate to the oxygen radical derived from
benzophenone, followed by the attack of the resulting carbon
radical to TsCN.13
We recently disclosed a redox neutral C−C bond-forming
reaction between THIQs and activated alkyl bromides under
photoredox catalysis and the photo-mediated C−H fluorination
and trifluoromethylation.14 As part of our research project on
photochemical C−H functionalization, we planned to investigate
redox-neutral C−H cyanation of amine compounds. To design
redox neutral system for C−H cyanation, we employed TsCN as
an electrophilic cyanide source.15 TsCN is usually utilized as a
radical trapping cyanide source, and it reacts with a carbon
radical to generate the corresponding cyanide compound together
with a sulfonyl radical. Considering the electronic property of
TsCN, we assumed that TsCN itself could accept one electron
from a photoredox catalyst (vide infra).16 In this report, we
demonstrate the redox neutral C−H cyanation of THIQ
derivatives and two N,N-dialkylaniline derivatives.
C−H functionalization is a current topic to materialize
environmentally benign synthesis by reduction of wastes and
reaction steps in organic synthesis.4,5 To date, oxidative C−H
cyanation of amine compounds via iminium cation intermediates
has been actively investigated. A pioneering work of C−H
cyanation of N,N-dialkylanilines using a ruthenium catalyst was
reported by Murahashi and coworkers.6 Followingly, a variety of
oxidative C−H cyanation reactions of amines were developed
with transition metal catalysts including copper and iron salts.7 In
addition, simple combinations of oxidants and cyanide sources
were also applicable to oxidative C−H cyanation.8 On the other
hand, recent progress of photoredox catalysis enables direct
functionalization of C−H bonds.9 In this context, direct C−H
cyanation of amines has been achieved under photoredox
catalysis with a terminal oxidant and a cyanide ion equivalent.10
In order to optimize the reaction conditions, N-phenyl-1,2,3,4-
tetrahydroisoquinoline (1a) was selected as a test substrate (Table
1). Based on our previous work,14a the initial reaction was carried
out with Ir(ppy)3 in MeCN (entry 1). As expected, product 2a
was obtained in 70% yield. To improve the reaction efficiency,
various solvents were screened (entries 2-7). Other non-protic
polar solvents generally afforded high yields of 2a, and an almost
quantitative yield (99%) was achieved when using DMA as the
solvent (entry 4). In contrast to the preceding reports, less polar
solvents, such as THF and CH2Cl2, were also applicable to this
reaction (entries 6 and 7). Other Ir and Ru photoredox catalysts
Among various C−H functionalizations under photoredox
catalysis, a redox-neutral approach has attracted much attention,11
and there are many reports including C−C bond formation
reactions via radical-radical coupling.11b However, redox neutral
−H cyanation of amines
C
is surprisingly rare even for a
benchmark test substrates such as tetrahydroisoquinoline (THIQ)
derivatives, which are one of the fundamental framework of

2
Tetrahedron
were examined, revealing that the desired product 2a could be
applied to this reaction, providing the cyanation product in 71%
yield (entry 8). Unfortunately, N-methyl- and N-Boc-THIQs did
not provide the desired cyanation products under our reaction
conditions, probably because of higher anodic peak potentials of
these THIQs in comparison with those of N-Ar-THIQs.
obtained, but Ir(ppy)3 is superior to other catalysts (entries 8 and
9). The use of K2HPO4 as base decreased the reaction efficiency
(entry 10), probably because of decomposition or isomerization
of TsCN.17 Control experiments suggest that a photoredox
catalyst and light irradiation are essential for this reaction (entries
11 and 12).
Table 2. Substrate scope of THIQs[a]
Table 1. Optimization of the reaction conditions[a]
Entry
1
Product
Yield (%)[b]
89
2b
2c
2d
2e
Entry
Solvent
MeCN
DMSO
DMF
P. C.
Time (h)
Yield (%)[b]
1
Ir(ppy)3
2
2
2
2
2
2
2
2
2
4
2
2
70
2
Ir(ppy)3
73
2
3
4
89
97
87
3
Ir(ppy)3
91
4
DMA
MeOH
THF
Ir(ppy)3
99 (94)[c]
5
Ir(ppy)3
57
79
86
90
67
43
0
6
Ir(ppy)3
7
CH2Cl2
DMA
DMA
DMA
DMA
DMA
Ir(ppy)3
8
[Ir(ppy)2dtbpy]PF6
[Ru (bpy)3](PF6)2
Ir(ppy)3
9
5
2f
82
78
10[d]
11
-
6[c]
2g
12[e]
Ir(ppy)3
0
[a]
The reactions were carried out with photoredox catalyst
(P.C.) (1 mol %) and TsCN (1 equiv) on a 0.1 mmol scale, unless
otherwise mentioned.
7[c]
2h
2i
83
71
[b] Determined by 1H NMR analysis of the crude mixture using
1,1,2,2-tetrachloroethane as an internal standard.
8[c]
[c] Isolated yield.
[a]
[d] Run with K2HPO4 (1 equiv).
[e] Run under the dark.
The reactions were carried out with Ir(ppy)3 (1 mol %),
TsCN (1 equiv) in DMA (1 mL) at room temperature for 2 h,
unless otherwise mentioned.
[b] Isolated yield.
[c] Run with TsCN (2 equiv) for 10 h.
Encouraged by the above results, the reaction of N,N-
dialkylaniline derivatives was next examined (Scheme 1).
Although the desired cyanation occurred, the reaction was slow
and the products 4a and 4b were obtained in 33% and 20%
isolated yields, respectively. The low yield may be associated
with the insufficient oxidation potential of 3a and 3b.
Additionally, it seems that the addition of the in-situ generated
sulfonyl radical to the benzene ring of the aniline substrates
occurred competitively. However, the exact structure of the by-
products has not been determined yet.
Having established the optimized conditions, the generality of
substituted THIQ derivatives were examined (Table 2). The
substitution on the N-aryl ring did not affect the reaction
efficiency. Thus THIQs with ortho-, meta- and para-tolyl groups
were converted to the corresponding products in high yields
(entries 1-3). Although electron-rich substrates were applicable to
this cyanation reaction without difficulty (entries 4 and 5),
electron-withdrawing groups somewhat retarded the reaction.
Indeed, the yields of 2g and 2h were 55% and 43% NMR yields,
when the reaction of 1g and 1h were operated under the standard
conditions. To our delight, however, prolonged reaction time and
an excess amount of TsCN (2.0 equiv) resulted in higher yields,
and 78% of 2g and 88% of 2h were isolated, respectively (entries
6 and 7). In addition, 7-chloro-substituted THIQ 1i could be

3
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Scheme 2. Plausible mechanism of the present cyanation
In summary, we have developed the redox-neutral C−H
cyanation of tetrahydroisoquinolines under photoredox
catalysis.20 The present reaction proceeded smoothly and only 1
equivalent of TsCN was enough to achieve good to high yields,
especially in the reactions of electron-rich substrates. The related
studies are underway in our laboratory.
Acknowledgments
This work supported by Basis for Supporting Innovative Drug
Discovering and Life Science Research (BINDS) from AMED.
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at https://doi.org/10/1016/j.tetlet.

4
Tetrahedron
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5
Highlights
ꢀ
Redox-neutral C−H cyanation was achieved
under simple photoredox catalyst conditions.
Only 1 equivalent of TsCN was required.
Good to high yields were generally observed
in the reactions of tetrahydroisoquinoline
derivatives.
ꢀ
ꢀ