C-H allylation of N-aryl-tetrahydroisoquinolines by merging photoredox catalysis with iodide catalysis

Article abstract of DOI:10.1007/s11426-015-5548-x

A dual catalytic system, combing visible light photoredox catalysis and iodide catalysis, has been developed for the functionalization of inert C-H bonds. By doing so, radical allylation reactions of N-aryl-tetrahydroisoquinolines (THIQs) were realized un

Full text of DOI:10.1007/s11426-015-5548-x

SCIENCE CHINA
Chemistry
•
·
ARTICLES •
SPECIAL TOPIC · Organic Photochemistry
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doi: 10.1007/s11426-015-5548-x
C–H allylation of N-aryl-tetrahydroisoquinolines by merging
photoredox catalysis with iodide catalysis
†
†
*
*
Zhujia Feng , Tingting Zeng , Jun Xuan, Yunhang Liu, Liangqiu Lu & Wenjing Xiao
CCNU-uOttawa Joint Research Center, College of Chemistry, Central China Normal University, Wuhan 430079, China
Received October 26, 2015; accepted November 16, 2015
A dual catalytic system, combing visible light photoredox catalysis and iodide catalysis, has been developed for the function-
alization of inert C–H bonds. By doing so, radical allylation reactions of N-aryl-tetrahydroisoquinolines (THIQs) were realized
under extremely mild conditions, affording a wide variety of allyl-substituted THIQs in up to 78% yields.
visible light photocatalysis, iodide catalysis, allylation, tetrahydroisoquinolines
Citation:
Feng ZJ, Zeng TT, Xuan J, Liu YH, Lu LQ, Xiao WJ. C–H allylation of N-aryl-tetrahydroisoquinolines by merging photoredox catalysis with iodide
catalysis. Sci China Chem, doi: 10.1007/s11426-015-5548-x
1
Introduction
inolines (N-aryl-THIQs) through the combination of palla-
dium catalysis and photoredox catalysis (Pd/PC, Scheme
1
(a)) [5c]. Critical to this success is the generation of the
The construction of C–C bonds in an efficient and sustaina-
ble way has attracted continuous attention from both indus-
trial and academic community [1]. Among them, palladium-
catalyzed allylation reactions (Tsuji-Trost reaction) play an
important role in the C–C bond formation processes [2].
Despite advances, less progress has been made towards
radical allylations with -allylic palladium intermediates
under reductive conditions [3]. Usually, only intramolecular
radical addition reactions have been successfully developed
in the presence of stoichiometric metal reducing reagents.
In recent years, photoredox catalysis has been identified
as a green and mild method for C–C bond formations [4].
Particularly, direct functionalization of inert C–H bonds by
merging photoredox catalysis with other catalysis modes
has been largely explored [5]. As part of our ongoing efforts
on heterocycle synthesis [6], we recently accomplished a
redox-neutral -C–H allylation of N-aryl-tetrahydroisoqu-
key allylic radical from a -allyl palladium complex under
visible light-mediated reduction conditions. Thereafter, the
allylic radical species reacts with the -amino radical,
which is formed in a visible light-mediated event, to con-
struct the C–C bond via a radical-radical cross coupling
process. In the course of investigating the mechanism of this
reaction, we found that the allylic bromide could be em-
ployed as an allylic source and this allylation reaction was
able to proceed in the absence of the palladium catalyst,
albeit with very low efficiency (allylic bromide: 9% GC
yield, Scheme 1(a)). Thus, we speculated that allylic halide
would serve as a suitable counterpart of -allyl palladium
complex. If so, it may enable the development of palladium
catalyst-free, visible light-driven photocatalytic C–H allyla-
tion of N-aryl-THIQs.
Inspired by Stephenson’s work [7] on the reduction
cleavage of carbon-iodide under photoredox catalytic con-
ditions, we presumed that allylic iodide would be more ac-
tive than allylic bromide as an allylic source. With this hy-
pothesis in mind, we initially examined the reaction of
†
*
Contributed equally to this work
Corresponding authors (email: luliangqiu@mail.ccnu.edu. cn;
wxiao@mail.ccnu.edu.cn)
©
Science China Press and Springer-Verlag Berlin Heidelberg 2016
chem.scichina.com link.springer.com

2
Feng et al. Sci China Chem Februray (2016) Vol.59 No.2
a)
Table 1 Optimization of reaction conditions
I source x (equiv.) Ratio of 1a:5a
Base
Yield (%)
52
b)
Entry
1
2
3
4
5
6
7
8
9
KI
LiI
NaI
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.2
0.2
0.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
–
–
–
–
–
24
35
t
Bu
4
NI
40
KI
55
KI
KI
KI
KI
KI
KI
KI
KI
KI
–
Cs
2
CO
3
40
t
BuONa
13
t
BuOK
n.d.
50
KOAc
1
1
1
1
1
0
1
2
3
4
Na
NaCO
NaCO
2
CO
3
58
2
CCl
3
60
CF
CF
CF
3
65
Scheme 1 Dual catalysis for C–H allylation of THIQs.
2
KCO
2
3
52
c)
NaCO
2
3
64 (53)
N-phenyltetrahydroisoquinoline 1a and allylic iodide 4b in
15
16
17
NaCO CF3
0
0
0
2
d)
e)
the presence of Ir(ppy)
2
(dtbbpy)PF
6
under the irradiation of
KI
KI
NaCO CF3
2
7
W blue LEDs. Unfortunately, no desired product was
NaCO
(dtbbpy)PF
a, iodide salt (x equiv.), base (0.4 mmol) in MeCN (2 mL), 7 W blue LED
2 3
CF
formed after 12 h, while the substrate 1a was all consumed.
Then, as depicted in Scheme 1(b), we envisioned that the
iodide salt could be applied as the nucleophilic catalyst [8,9]
to react with allylic ester to produce catalytic amount of
allylic iodide in situ, so that allylic iodide would proceed
with the desired reaction immediately, instead of oxidizing
THIQs or decomposing under visible light photocatalysis
conditions. Notably, the iodide anion could be regenerated
during the oxidation step of Ir(II) catalyst by allylic iodide
a) Reaction conditions: 1a (0.2 mmol), Ir(ppy)
2
6
(2 mol%),
5
irradiation at r.t., 12h; b) GC yield with tetradecane as the internal
standard; c) isolated yield; d) without photocatalyst; e) in the dark.
2 3
Sodium trifluoroacetate (NaCO CF ) was identified as the
optimal choice, producing product 3a in 65% yield. We
were pleased to find that the loading of KI can be reduced to
0
Under these conditions, the final allylation product 3a was
detected in 64% GC yield and 53% isolated yield (entry 14)
.2 equiv., with no erosive effect on the reaction efficiency.
(see Scheme 2 for the detailed mechanism).
[
11]. Control experiments showed that iodide salt, photo-
catalyst and visible light were all essential for this radical
allylation reaction (entries 15–17).
2
Results and discussion
With the optimal reaction conditions identified, we then
examined the generality of this dual catalysis system. As
shown in Figure 1, this catalysis system appeared to be
quite compatible with various THIQs. For example, varia-
tions of the aromatic substituents on the nitrogen atom were
tolerant. Substrates with electron-donating (1b, 1c) or elec-
tron-withdrawing groups (1d–1f) were converted to the
corresponding allylation products (3b–3f) in 40%–66%
yields. A variety of substituents on the benzene ring of
THIQs can be successfully incorporated, delivering the al-
lylation products in satisfactory yields (3g–3i: 34%–78%
yields). We were delighted to find that N-2-naphthyltetra-
hydroisoquinoline can be also applied to this I/PC dual ca-
talysis system and furnished the desired product 3j in 48%
yield. Notably, this was an unsuccessful example of our
previous Pd/PC catalysis system. Moreover, this I/PC dual
catalytic system can be significantly extended to other sub-
stituted allylic reagents, i.e. 5k and 5l, affording the corre-
sponding product 3k in 20% yield and 3l in 50% yield.
Initially, we examined the dual I/PC catalytic system of
Ir(ppy) (dtbbpy)PF (ppy: 2-phenylpyridine; dtbbpy: 4,4-di-
tert-butyl-2,2′-bipyridine) and potassium iodide (KI) for the
photocatalytic radical allylation of THIQ 1a with a wide
range of allylic esters. To our delight, the combination of KI
2
6
(
0.5 equiv.) and allyl 4-methylbenzenesulfonate 5a (1.2
equiv.) under the irradiation of 7 W blue LEDs afforded the
desired allylation product in 52% GC yield (entry 1, Table
1
). Encouraged by this result, we screened a representative
set of iodide salts. We found that all the iodide salts were
suitable for the reaction, though the desired product were
given in moderate yields (24%–40%, entries 2–4). Employ-
ing different photoredox catalysts, light sources or reaction
media, unfortunately, failed to improve the reaction effi-
ciency [10]. Increasing the amount of the allylic ester 5a
gave a slightly better yield (55%, entry 5). To further en-
hance the yield, a wide range of bases were added to neu-
tralize the byproduct p-toluenesulfonic acid (entries 6–13).

Feng et al. Sci China Chem Februray (2016) Vol.58 No.2
3
-amino alkyl radical int-II. Concurrently, the nucleophilic
catalytic cycle is initiated by the iodide-substitution process
of allylic esters. The allylic iodide int-III is subsequently
reduced by Ir(II) to form allylic radical int-IV, and the io-
dide anion and ground-state Ir(III) are regenerated. Finally,
the radical cross-coupling of int-II and int-IV provides the
C–C bond formation and the desired α-amino allylation
product is afforded.
3
Conclusions
In conclusion, we have developed a dual catalytic system
for the inert C–H functionalization by merging visible light
photocatalysis and iodide catalysis. Compared with our pri-
or dual catalytic system using palladium and photoredox
catalysts, inexpensive and economical potassium iodide was
utilized as the nucleophilic catalyst. Under these conditions,
3
a direct allylation of sp C–H of THIQs was realized under
extremely mild conditions.
Acknowledgments This work was supported by the National Natural
Science Foundation of China (21232003, 21202053, 21572074), the Foun-
dation for the Author of National Excellent Doctoral Dissertation of China
(
(
201422) and Outstanding Youth Funding in Hubei Province
2015CFA033) for the support of this research.
Figure 1 Generality of I/PC dual catalysis in the allylation of THIQs.
Reaction conditions: 1 (0.5 mmol), Ir(ppy) (dtbbpy)PF (2 mol%), 5 (0.75
mmol), KI (20 mol%), NaCO CF (1.0 mmol) in MeCN (5 mL), 7 W blue
2
6
2
3
Conflict of interest The authors declare that they have no conflict of
LEDs at r.t., 12h; the yields are isolated yields.
interest.
Supporting information The supporting information is available online
at http://chem.scichina.com and http://link.springer.com/journal/11426.
The supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
Though great efforts have been made, this dual catalysis
system failed to be applied to other tertiary amines.
A plausible mechanism was proposed to better under-
stand the radical allylation process. As depicted in Scheme
1
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1
1
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Scheme 2 Proposed reaction mechanism (color online).

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10 For detailed condition optimization, including the evaluation of pho-
tocatalysts, solvents, light sources and bases, see Supporting Inform-
ation
11 General Procedure: In a 10 mL dry flask equipped with magnetic bar
was charged with 1 (0.5 mmol, 1.0 equiv.) and Ir(bpy) (dtbbpy)PF (2
2
6
mol%), 5 (0.75 mmol, 1.5 equiv.), KI (20 mol%), NaCO
2
CF
3
(1.0
mmol, 2.0 equiv.) and MeCN (5 mL). The mixture was degassed via
freeze-pump-thaw method (3 times) and then stirred under the
irradiation of 7 W blue LEDs at room temperature for 12 h. The
resultant mixture was filtered under vacuum to remove the solid. The
filtrate was purified by flash chromatography on silica gel (petroleum
ether/DCM=10:1) to afford the desired product 3. Analytical data of
1
12–116
1-allyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3a): light yellow oil;
H NMR (600 MHz, CDCl )  (ppm) 7.18 (m, 6H), 6.89 (d, J=8.2
3
1
6
a) Zou YQ, Lu LQ, Fu L, Chang NJ, Rong J, Chen JR, Xiao WJ.
Angew Chem Int Ed, 2011, 50: 7171–7175; b) Xuan J, Cheng Y, An
J, Lu LQ, Zhang XX, Xiao WJ. Chem Commun, 2011, 47: 8337–
Hz, 2H), 6.73 (t, J=7.1 Hz, 1H), 5.89–5.82 (m, 1H), 5.06 (t, J=13.1
Hz, 2H), 4.74 (t, J=6.7 Hz, 1H), 3.72–3.52 (m, 2H), 3.08–2.96 (m,
1H), 2.88 (dt, J=15.7, 5.2 Hz, 1H), 2.78–2.65 (m, 1H), 2.49 (dt,
8
339; c) Zou YQ, Chen JR, Liu XP, Lu LQ, Davis RL, Jørgensen
1
3
KA, Xiao WJ. Angew Chem Int Ed, 2012, 51: 784–788; d) Xuan J,
Feng ZJ, Duan SW, Xiao WJ. RSC Adv, 2012, 2: 4065–4068; e)
Xuan J, Xia XD, Zeng TT, Feng ZJ, Chen JR, Lu LQ, Xiao WJ.
Angew Chem Int Ed, 2014, 53: 5653–5656, and Refs. [3c,3g,3k]
3
J=14.1, 7.2 Hz, 1H); C NMR (100 MHz, CDCl )  (ppm) 149.4,
138.1, 135.6, 134.9, 129.2, 128.5, 127.3, 126.5, 125.7, 117.2, 117.0,
+
113.8, 59.3, 41.9, 40.9, 27.4; HRMS: m/z (ESI) calculated [M+H]
250.1590, measured 250.1594.