N-Heterocyclic Carbene Catalyzed Photooxidation: Intramolecular Cross Dehydrogenative Coupling of Tetrahydroisoquinoline-Tethered Aldehydes

Article abstract of DOI:10.1002/adsc.202000164

An N-heterocyclic carbene catalyzed photooxidation reaction via intramolecular cross dehydrogenative coupling of tetrahydroisoquinoline-tethered aldehydes was developed, giving the corresponding oxidative cyclization products in moderate to good yields. T

Full text of DOI:10.1002/adsc.202000164

Title: N-Heterocyclic Carbene Catalyzed Photooxidation:
Intramolecular Cross Dehydrogenative Coupling of
Tetrahydroisoquinoline-Tethered Aldehydes
Authors: Zhong-Hua Gao, Zi-Hao Xia, Lei Dai, and Song Ye
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10.1002/adsc.202000164
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
N-Heterocyclic Carbene Catalyzed Photooxidation:
Intramolecular Cross Dehydrogenative Coupling of
Tetrahydroisoquinoline-Tethered Aldehydes
Zhong-Hua Gao,a Zi-Hao Xia,a,b Lei Dai,a,b and Song Yea,b*
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Email: songye@iccas.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An N-heterocyclic carbene catalyzed
photooxidation reaction via intramolecular cross
dehydrogenative coupling of tetrahydroisoquinoline-
tethered aldehydes was developed, giving the
corresponding oxidative cyclization products in
moderate to good yields. This reaction features mild
conditions with oxygen as the terminal oxidant in the
absence of photocatalyst.
of acyl fluorides via photo-NHC catalysis
(Scheme 1e).[12]
Keywords: N-heterocyclic carbene; photocatalysis;
organocatalysis; oxidation; dehydrogenative coupling
In the past decades, N-heterocyclic carbenes
(NHCs)
have
emerged
as
powerful
organocatalysts, especially for the construction of
heterocycles.[1] The cooperative catalysis of NHC
with other catalysts, such as transition-metals,[2]
Brønsted acids,[3] Lewis acids[4] and other
organocatalysts,[5] provides new possibility
beyond single catalysis.[6] Photoredox catalysis,
which
activates
substrates
by
excited
photosensitizers, exhibits great potential for inert-
bond activation.[7] In recent years, several
photo/NHC cooperative catalysis has been
developed. In 2012, Rovis and co-workers
disclosed a pioneering photo/NHC dual catalysis
for α-acylation of tertiary amines (Scheme 1a).[8]
Lately, Sun group reported one example of
photo/NHC cocatalyzed γ-dichloromethylenation
of enal (Scheme 1b).[9] Recently, we reported the
photo/NHC cocatalyzed γ-and
preoxidized enals (Scheme 1c),[10] and an
NHC/photo-cocatalyzed oxidative Smiles
rearrangement of O-aryl salicylaldehydes in the
presence of 9-mesityl-10-methylacridin-10-ium
perchlorate as the photocatalyst (Scheme 1d).[11]
Very recently, the Hopkinson group reported an
interesting photoenolization/Diels–Alder reaction
-alkylation of -
Scheme 1. NHC/photo dual catalysis and NHC
catalyzed
intramolecular
cross
oxidative
dehydrogenative coupling reactions.
Tetrahydroisoquinoline (THIQ) motif is widely
present in natural and non-natural compounds
possessing versatile bioactivities,[13] which attracts
chemists to develop synthetic methodologies for its
1
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10.1002/adsc.202000164
Advanced Synthesis & Catalysis
construction and transformations.[14] The cross
dehydrogenative-coupling (CDC) has become an
efficient tool for C-C or C-X bond formation via
activation of C(sp3)-H bond.[15] Nowadays, CDC
reactions for the transformation of THIQs with
different oxidative agents, such as DDQ, nitro-
(hetero)arenes and carbocations, and/or in
combination with transition-metal catalysts have been
well established.[16] Among them, visible-light-
induced CDC reactions of THIQs have received
considerable attention for their mild and
[e] PreNHC B was used instead of A.
[f] Air was directly used instead of O2.
[g] H2O2 (30% aq., 4.5 equiv) was used instead of O2.
At the very beginning, our design of the coupling
reaction was based on the combination of
photocatalyst (transition metal complexes) with NHC
catalyst. Thus, we initiated our investigation by
employing
tetrahydroisoquinoline-derived
benzaldehyde 1a as the substrate, molecular oxygen
as the oxidant and Ir(ppy)3 as the photocatalyst (Table
1). As a result, the desired CDC product could be
environmentally benign redox conditions.[17] Recently, afforded in 14% yield when the reaction was carried
our group disclosed an NHC catalyzed intramolecular
α-oxygenation of amines using hypervalent iodine
(III) agent as the terminal oxidant (Scheme 1f).[18] To
further improve the practicality and atom economy of
this methodology, herein, we report an NHC
catalyzed photooxidation reaction utilizing oxygen as
the oxidant (Scheme 1g). Notably, this photo-
promoted oxidative CDC reaction proceeds well
without external photocatalyst.
out under 18 W blue LED irradiation at room
temperature with 1.2 equiv of DABCO as the base
and acetonitrile as the solvent (Table 1, entry 1).
To further improve the efficiency, a catalytic
amount of tetrabutylammonium iodide (TBAI),
which often served as (co)catalyst in oxidation
reactions,[19] was added to the reaction system. To our
delight, the yield improved dramatically (66%, entry
2), while further increasing the loading of TBAI did
not give a significant improvement (68%, entry 3).
Solvent screening revealed that DMF, DMSO,
toluene or dioxane gave no better results than
acetonitrile (entries 4-7). The reaction could not
proceed in the absence of preNHC (entry 8). To our
surprise, the corresponding coupling product could be
isolated in 75% yield in the absence of irridium
photocatalyst (entry 9). However, the reaction could
not proceed well without blue LED irradiation, giving
2a in only 7% yield (entry 10), which confirmed the
involvement of photoactivation without photocatalyst.
Then, further screening of halide salts revealed that
KI or NaI gave similar results (entries 11 and 12),
while only trace amount of 2a was afforded using
Table 1. Reaction optimization.[a]
Yield
Entry PC (mol%) Halide (mol%) Solvent
(%)[b]
1
2
3
4
5
6
Ir(ppy)3 (2)
Ir(ppy)3 (2)
Ir(ppy)3 (2)
Ir(ppy)3 (2)
Ir(ppy)3 (2)
Ir(ppy)3 (2)
/
CH3CN
CH3CN
CH3CN
DMF
DMSO
toluene
1,4-
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
14
66
68
56
29
tetrabutylammonium
bromide
(TBAB)
or
nBu4NI (10)
nBu4NI (20)
nBu4NI (10)
nBu4NI (10)
nBu4NI (10)
tetrabutylammonium chloride (TBAC) instead
(entries 13 and 14), which demonstrated the
significance of iodide. Thus, NaI was selected as the
iodide source for further optimization test for its very
low cost. However, when triazolium iodide B was
used as the NHC precursor without the addtion of
NaI, only trace amount of 2a was detected for the
reaction (entry 15). It should be noted that decreased
yield was resulted when air or H2O2 (aq.) was used as
the oxidant instead of molecular oxygen (entries 16
& 17).
trace
7
Ir(ppy)3 (2)
nBu4NI (10)
trace
8[c]
9
Ir(ppy)3 (2)
nBu4NI (10)
nBu4NI (10)
nBu4NI (10)
KI (10)
NaI (10)
nBu4NBr (10) CH3CN
trace
75
7
76
77
trace
trace
trace
32
/
/
/
/
/
/
/
/
/
10[d]
11
12
13
With the optimized reaction conditions in hand,
the substrate scope was then explored. Substrates
with various substituents on tetrahydroisoquinoline-
derived benzaldehyde were evaluated (Scheme 2). It
was found that benzaldehydes with electron-donating
(5’-OMe and 5’-Me) or electron-withdrawing groups
(5’-Cl and 5’-Br) at C-5’ position gave the
corresponding CDC products in moderate to good
yields (2b-2e). It is worth noting that substrates with
5’-vinyl, 5’-p-methoxybenzyloxy and 5’-benzyloxy,
which were sensitive to strong oxidative conditions,
could be well tolerated in this reaction system (2f-2h).
Substrates with electron-withdrawing groups (4’-Cl,
4’-Br and 4’-CF3) at the C-4’ position could also
afford the desired coupling products in moderate to
14
nBu4NCl (10) CH3CN
15[e]
16[f]
17[g]
/
CH3CN
CH3CN
CH3CN
NaI (10)
NaI (10)
27
[a]
General conditions: 1a (0.2 mmol), preNHC A
(0.04 mmol, 20 mol%), DABCO (1.2 equiv),
halide salt (0.02 mmol, 10 mol%), PC (0.004 mmol,
2 mol%), solvent (2 mL), irradiated under 18 × 1W
blue LEDs at room temperature for 48 h under O2
atmosphere (balloon).
[b]
Isolated yields.
[c] No preNHC was added.
[d] Without irradiation.
2
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10.1002/adsc.202000164
Advanced Synthesis & Catalysis
good yields (2i-2k). 4’,5’-Dimethoxy substituted and
3’-methoxy substituted aldehydes worked as well (2l
and 2m). Notably, the corresponding carboxylic acid
from the aldehyde was detected as the side product
for those reactions in low yields.
Substrates with different substituents on the
THIQ skeleton were then evaluated (Scheme 3). The
THIQ with 6-OMe gave the corresponding product in
moderate yield (2n). Aldehydes bearing 7-Br or 7-Ph
were effective in generating the targeted products
with moderate efficiency (2o and 2p). In addition,
cyano and methoxycarbonyl groups on the aromatic
ring were also tolerable to give the desired coupling
product in good yields (2q and 2r).
Scheme 3. Substrate scope: Substituents on the aryl
ring of THIQ skeleton.
The model reaction could be scaled up even with a
decreased preNHC loading (10 mol%) and product 2a
was obtained without apparent loss of yield (72%,
Scheme 4).
Scheme 4. Gram-scale reaction.
To obtain further insight into the mechanism of
this photo-promoted NHC-catalyzed CDC reaction, a
series of control experiments were conducted (Table
2). In the absence of NHC catalyst, only 17% of the
desired product could be detected by NMR analysis
of the crude reaction mixture along with 25% of
amide byproduct 4a (Table 2, entry 1). The reaction
did not occur without visible light irradiation even at
higher temperature (40 oC) (entry 2). Radical
quenching experiment revealed that the reaction was
inhibited when 1.5 equiv of TEMPO was added
(entry 3), which indicates the possible involvement of
a radical intermediate. The reaction of THIQ-tethered
benzoic acid 3a instead of aldehyde 1a gave the
corresponding product 2a in 32% NMR yield in the
absence of NHC catalyst (entry 4). The significant
loss of the yield indicated that the acid could
participate in the reaction but possible not an active
intermediate for the reaction of aldehyde. In addition,
the CDC reaction of 3a could not proceed in the
absence of either visible light or molecular oxygen
(entries 5 and 6). These experiments suggest the
intermediate generated from aldehyde and NHC is
possibly involved in the photoredox process.
Scheme 2. Substrate scope: Variation of the
substituents in benzaldehyde.
3
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10.1002/adsc.202000164
Advanced Synthesis & Catalysis
Table 2. Control experiments.[a]
pair III of amino radical cation and superoxide
radical anion. The 1,2-H shift of amino radical cation
followed by proton abstraction by superoxide radical
affords α-amino radical IV,[17a, 20] which is further
oxidized to iminium VI[21] via α-iodoamine V under
iodide catalysis.[22] The oxidation of Breslow
intermediate by oxygen generates a radical cation VII,
followed by deprotonation gives zwitterionic radical
species VIII. The intermediate VIII is further
oxidized by the in situ generated hydroperoxide
radical to afford acyl azolium intermediate IX,[11]
which is hydrolysed to regenerate NHC catalyst and
provide the iminium/carboxylate intermediate X after
deprotonation under basic condition. Intramolecular
nucleophilic addition to the iminium affords the final
product.
Yield (%)[b]
2a
17
trace
trace
Variation from standard
conditions
Entry
4a
25
/
/
/
/
1
2
3
4
5
No preNHC
No irradiation, 40 oC
TEMPO (1.5 equiv)
3a instead of 1a, no preNHC 32
3a instead of 1a, no
irradiation
0
6
3a instead of 1a, no O2
0
/
In summary, we have developed a photo-
[a]
Standard conditions: 1a (0.2 mmol), preNHC A (0.04
promoted
intramolecular cross dehydrogenative coupling of
tetrahydroisoquinoline-tethered aldehydes. The
N-heterocyclic
carbene
catalyzed
mmol, 20 mol%), DABCO (1.2 equiv) and NaI (0.02 mmol,
10 mol%) in CH3CN (2 mL), and irradiated under 18 × 1W
blue LEDs at room temperature for 48 h under O2
atmosphere (balloon).
corresponding oxidative cyclization products were
obtained in moderate to good yields. This reaction
features mild conditions using molecular oxygen as
the terminal oxidant without photocatalyst. Based on
the control experiments, an excited Breslow
intermediate is proposed for the photooxidation
process. Detailed mechanism investigation and
further application of this NHC-catalyzed
photooxidation are underway in our laboratory.
[b]
NMR yield with 1,3,5-trimethoxybenzene as internal
standard.
The fluorescence spectra of aldehyde and the
reaction mixture with aldehyde and NHC under
irradiation at 446 nm were then investigated (Figure
1). It was found that both of them showed
fluorescence but with a slight redshift for the reaction
mixture (red line), probably due to the formation of
an intermediate from aldehyde and NHC catalyst.
1a
4000
1a+preNHC A+DABCO+NaI
3500
3000
2500
2000
1500
1000
500
0
-500
450
500
550
600
650
700
Wavelength (nm)
Figure 1. Fluorescence spectra of 1a and the
reaction mixture, recorded in CH3CN in 1 cm path
quartz cuvettes (excited at 446 nm). [1a] = 0.05 M,
[preNHC A] = 0.01 M, [DABCO] = 0.06 M, [NaI] =
0.005 M.
Based on the control experiments and fluorescence
spectra, we speculate that the activation of aldehyde
by NHC promotes the whole photooxidation process.
A plausible mechanism is presented as follows
(Figure 2). The addition of carbene (I), generated in
situ under basic conditions, to aldehyde provides the
corresponding Breslow intermediate (II). The excited
Breslow intermediate (II*) under photoexcitation is
oxidized by O2 via a SET process to give a radical
Figure 2. Plausible mechanism.
Experimental Section
To a 25 mL Schlenk tube equipped with a rubber septum
and
a
magnetic stir bar was charged with
tetrahydroisoquinoline derivative 1a (47.4 mg, 0.2 mmol),
preNHC A (14.5 mg, 0.04 mmol), DABCO (26.9 mg, 0.24
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000164
Advanced Synthesis & Catalysis
mmol), and NaI (3.0 mg, 0.02 mmol). The tube was
evacuated and backfilled with O2 (balloon) and was added
CH3CN (2.0 mL) with a syringe. The mixture was then
irradiated by 18 W blue LEDs. After 12-48 h, the reaction
mixture was concentrated under reduced pressure and the
crude product was purified by flash chromatography on
silica gel (200−300 mesh) to afford the desired product 2a.
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos 21702208, 21672216), and Beijing National
Laboratory for Molecular Sciences (BNLMS-CXXM-202003),
and the Chinese Academy of Sciences is greatly acknowledged.
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