Visible-Light-Induced α-Amino C-H Bond Arylation Enabled by Electron Donor-Acceptor Complexes

Article abstract of DOI:10.1021/acs.orglett.1c00984

Enabled by electron donor-acceptor complexes, a novel visible-light-induced α-amino C-H bond arylation protocol, without a photoredox catalyst, has been disclosed. The protocol does not require any transition metal, oxidant, or exclusion of oxygen or moisture. A direct irradiation of the mixture of tertiary amines and benzonitriles with visible light in N,N-diethylethanamide in the presence of Cs2CO3 afforded α-arylated amines in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.1c00984

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Letter
Visible-Light-Induced α‑Amino C−H Bond Arylation Enabled by
Electron Donor−Acceptor Complexes
Chang Xu, Fang-Qi Shen, Gaofeng Feng,* and Jian Jin*
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ABSTRACT: Enabled by electron donor−acceptor complexes, a novel visible-light-induced α-amino C−H bond arylation protocol,
without a photoredox catalyst, has been disclosed. The protocol does not require any transition metal, oxidant, or exclusion of
oxygen or moisture. A direct irradiation of the mixture of tertiary amines and benzonitriles with visible light in N,N-
diethylethanamide in the presence of Cs2CO3 afforded α-arylated amines in good to excellent yields.
Benzylic amines are ubiquitous and privileged structural
isible light is the most green and abundant natural energy
Vsource. The utilization of visible light has been attracting motifs found among natural products, biologically active
synthetic molecules, and medical agents, among which, many
are simple derivatives.8 Therefore, the assembly and elabo-
ration of such structures through α-amino arylation have been
attracting the attention of synthetic chemists. Numerous
seminal methods have been established. Among them, an
elegant methodology is exemplified by a decarboxylative
photoredox catalysis employing α-amino acids as feedstocks.9
However, the specific site selectivity comes at the price of
having to remove the carboxylic group. Without question, the
direct α-amino C−H bond arylation of amines is considered as
the most efficient and straightforward approach.10−13 In this
context, mechanistically diverse protocols were disclosed
through the formation of an α-amino cation,10 an α-amino
anion,11 an α-amino radical,12 and an α-amino C−Ru/Pd/Rh
complex13 as key intermediates (Figure 1a−d). While great
advancements have been achieved, transition-metal catalysts or
stoichiometric oxidants are necessary in these strategies.
Recently, inspired by MacMillan’s pioneer work3b on
Ir(ppy)3-catalyzed photoredox α-amino C−H bond arylation
from readily available tertiary amines and cyanoaromatics
(Figure 1e), Ye and co-workers14 achieved the same
transformation through a convergent paired electrolysis in
the efforts of scientists to develop efficient light-harvesting
technologies to promote chemical processes.1 One of the
breakthroughs is the visible-light-mediated photoredox catal-
ysis.2 Highlighting the unique catalytic mode and wonderful
compatibility with other catalysis, it has been demonstrated as
a powerful strategy since the pioneering work by MacMillian,3
Yoon,4 and Stephenson,2f enabling a number of previously
inaccessible transformations with the assistance of a photo-
catalyst. While useful and powerful, photoredox catalysis has
somewhat suffered from (i) the high cost of photocatalysts, (ii)
difficulty in recovering and reusing photocatalyst from
homogeneous reaction media,5 and (iii) the need to exclude
oxygen from the reaction system in many cases. The
development of mechanistically novel and operationally simple
protocols using the fewest reagents for challenging trans-
formations is an ideal goal for synthetic chemists. Recently,
photocatalyst-free electron donor−acceptor (EDA) complex
photochemistry has emerged as a fresh and intriguing
alternative.6,7 In this new reaction mode, the ground-state in
situ aggregation of an electron-donating substrate with an
electron-accepting substrate forms an EDA complex, which
enables the absorption of visible-light energy to trigger an
intramolecular single-electron-transfer event, ultimately pro-
ducing reactive radical intermediates without the assistance of
any photocatalyst. Although this new reaction mode is
mechanistically novel and eco-friendly, it was not until very
recently that the synthetic application of EDA complexes
attracted the growing attention of chemists. Representative
achievements are quite limited in the contemporary literature.
Received: March 28, 2021
https://doi.org/10.1021/acs.orglett.1c00984
© XXXX American Chemical Society
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A

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a
Table 1. Optimization of the Reaction Conditions
b
entry
1:2
solvent, base (eq)
3, 3a yields (%)
1
2
3
4
5
6
7
8
1:1.5
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
2:1
3:1
3:1
3:1
3:1
DMA, NaOAc (2.9)
DMA, NaOAc (1.5)
DMA, K3PO4 (1.5)
DMA, KOAc (1.5)
(21), (44)
(37), (26)
64, 16
56, 16
66, 22
51, 24
81 (78), 18 (12)
65, 28
DMA, K2CO3 (1.5)
DMA, CsOAc (1.5)
DMA, Cs2CO3 (1.5)
DMA, Na3PO4.12H2O
DMA, Cs2CO3 (2.0)
DMA, Cs2CO3 (2.2)
DMA, Cs2CO3 (3.0)
DMSO, Cs2CO3 (2.0)
DMF, Cs2CO3 (2.0)
NMP, Cs2CO3 (2.0)
CH3CN, Cs2CO3 (2.0)
CH2Cl2, Cs2CO3 (2.0)
THF, Cs2CO3 (2.0)
DMA-H2O, Cs2CO3(2.0)
DMA, Cs2CO3 (1.5)
DMA, Cs2CO3 (1.5)
DMA, Cs2CO3 (1.5)
9
86, 22
10
11
12
13
14
15
16
17
18
87 (83), 28 (24)
89 (83), 28 (18)
36, 19
78, 32
77, 35
trace, trace
0, 0
0, 0
0, 0
40, 17
3:1
3:1
3:1
3:1
Figure 1. Strategies for α-amino C−H bond arylation.
the presence of a catalytic amount of 2,2,6,6-tetramethylpiper-
idinooxy, 2 equiv of n-BuNClO4, and 2 equiv of 2,6-lutidine
under a N2 atmosphere (Figure 1f). Very soon, the same
transformation was achieved by Jensen and co-workers
employing microfluidic electrochemistry.15 From the viewpoint
of atom economy and environmental impact, both transition-
metal and oxidant free, and operationally simple protocols are
highly appealing. Herein, we report a visible-light-induced,
transition-metal-free, oxidant-free, and operationally simple α-
amino C−H bond arylation process through the formation of
EDA complexes.
3:1
c
19
20
21
1.5:1
1.5:1
1.5:1
d
trace, trace
7, 3
e
a
Yields were determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as the internal standard after workup, and the
yields in brackets are isolated yields. Mole ratio of N-phenyl-
pyrrolidine (1) to 1,4-dicyanobenzene (2). 75% of light power (30
W) was used. 50% of light power (20 W) was used. Light
wavelength is 440 nm.
b
c
d
e
We began our investigation on the α-amino C−H arylation
process by directly subjecting the N,N-diethylethanamide
(DMA) solution of N-phenylpyrrolidine (1) and 1,4-
dicyanobenzene (2) to visible-light irradiation (two Kessil 40
W 427 nm light-emitting diode lamps) for 12 h with sodium
acetate (NaOAc) as the base. To our delight, the desired
arylation product 3 was isolated in a 21% yield, along with
cyanation byproduct 3a in a 44% yield (Table 1, entry 1).
When 1,4-dicyanobenzene was used as the limiting substrate,
the product 3 was isolated in an improved yield of 37% as the
major product (entry 2). We assumed that the reaction
proceeded through a single-electron oxidation of N-phenyl-
pyrrolidine (1), followed by the deprotonation of the resulting
radical cation by a base to form the key α-amino radical. Thus,
the base should play a crucial role for the transformation.
Accordingly, a brief survey of commonly used bases, such as
K3PO4, KOAc, K2CO3, CsOAc, Cs2CO3, and Na3PO4·12H2O,
was performed (entries 3−8), indicating that Cs2CO3 was the
most efficient and provided the desired arylation product 3 and
the cyanation byproduct 3a in 78% and 12% isolated yields,
respectively. Increasing the amount of Cs2CO3 and N-
phenylpyrrolidine resulted in slightly improved yields (entries
9−11). An examination of other common solvents, such as
dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), N-
methylpyrrolidone (NMP), MeCN, CH2Cl2, tetrahydrofuran
(THF), and DMA−H2O (4:1), showed that DMA was the
superior solvent (entries 12−18). Notably, it was found by
control experiments that both the light power and wavelength
were of great importance. The yield of 3 was dramatically
reduced to 40% when the light power was reduced to 75% (30
W) (entry 7 vs entry 19), and nearly no reaction took place
with 50% (20 W) of the light power (entry 20). Moreover, it
was revealed that the light wavelength was also crucial, as only
a 7% yield of the product 3 was observed with irradiation of a
longer light wavelength (440 nm). It is worth mentioning that
the protocol is operationally simple, as all reactions proceed
without nitrogen purging and moisture exclusion.
With the optimal conditions in hand, the substrate scope
was then evaluated. Later on, it was found that higher yields
could be achieved by extending the reaction time from 15 to
40 h; thus, the following reactions were performed for 40 h. As
shown in Scheme 1, a diverse range of substituted N-
arylpyrrolidines were arylated with 1,4-dicyanobenzene,
providing the desired arylated products 4−8 in moderate to
good yields (50−73%). Variations of the substitutions include
Me, Br, and Cl groups at the meta or para position of the
phenyl ring. On the one hand, gratifyingly, the β-naphthyl
analogue was also compatible in the protocol, affording the
desired product 9 in a 55% yield. On the other hand, six-
membered piperidine and morpholine as well as seven-
membered azepane derivatives were also suitable substrates,
providing the corresponding products 10−12 in the yields
ranging from 30% to 73%. The acyclic tertiary amines N,N-
dimethylaniline and N,N-diethylaniline also proceeded
smoothly to afford 13 and 14 in 43% and 60% yields. The
higher yield of 14 as compared to 13 might suggest the
involvement of an easily formed (or a much more stable)
B
https://doi.org/10.1021/acs.orglett.1c00984
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Scheme 1. Substrate Scope Investigation
Scheme 2. Substrate Scope Investigation
intermediate in the reaction. Moreover, 1,2-dicyanobenzene
and 1,3-dicyanobenzene readily underwent the same reaction
with N-arylpyrrolidines to afford the products 15−17 in 48−
51% yields. To our delight, methyl 4-cyanobenzoate was also
an amenable substrate to form 18, albeit with a low yield of
11%. We reasoned that, in some cases, the relatively low yields
should be attributed to the formation of α-cyanation
byproducts, which formed through the addition of CN− to
an iminium ion intermediate. For example, α-cyanation
byproducts 10a and 14a were detected in 21% and 11%
yields, respectively.
protocol, affording the desired product 33 in an 82% yield,
along with an inseparable α-cyanation byproduct 33a in a 14%
yield. Two other inseparable α-cyanation byproducts 27a and
28a were also detected in 21% and 16% yields, and their
structures were confirmed by a gas chromatography-mass
spectrometry (GC-MS) analysis. Moreover, N-allyl-1,2,3,4-
tetrahydroquinoline was also arylated smoothly on the ring site
with 1,4-dicyanobenzene to afford product 34 in 64% yield,
leaving both the double bond and allylic position intact. It was
interesting to observe that N-phenyl-1,2,3,4-tetrahydroisoqui-
noline produced the product 35 (74%) in favor of arylation at
the benzylic position on the ring. Moreover, N-arylmethyl and
N-phenyl indolines were also amenable to this α-arylation
strategy, albeit with a little bit lower yields than those of the
corresponding tetrahydroquinoline counterparts. A variation of
the substitutions, including p-/m-methylbenzyl, p-/m-methox-
ybenzyl, and p-bromo/p-chlorobenzyl, was tolerated with
excellent regioselectivity on the ring, affording the arylated
indolines 36−42 in 44−81% yields. Delightedly, the reaction
of N-phenylindoline could proceed smoothly, and the desired
arylated product 43 was isolated in an excellent yield (90%).
Finally, with the employment of 4 mmol of 1,4-
dicyanobenzene as the limiting substrate, a gram-scale
synthesis of the product 19 was performed, and a comparable
yield was achieved (1.008 g, 78% vs 77%), indicating the
wonderful potential for the practical utility of the protocol
(Scheme 3).
Tetrahydroquinolines, tetrahydroisoquinolines, and indo-
lines are privileged heteroaromatics commonly found in
pharmaceuticals and biologically active compounds. The
derivatization of these heteroaromatics further highlights the
synthetic utility of this operationally simple and green protocol.
The arylation of tetrahydroquinoline derivatives was first
performed (Scheme 2). A variety of N-arylmethylated
tetrahydroquinolines, including benzyl, p-/m-methylbenzyl,
p-/m-methoxybenzyl, and p-bromo-/p-chlorobenzyl, were
suitable substrates, and good to excellent yields (77−97%) of
the products 19−25 were achieved under the optimal
conditions. Similarly, N-arylated tetrahydroquinolines possess-
ing phenyl, p-/m-alkylphenyl, and p-/m-fluorophenyl sub-
stituents furnished the products 26−30 in 75−90% yields,
although the arylation of N-(3-chlorophenyl)-1,2,3,4-tetrahy-
droquinoline with 1,4-dicyanobenzene afforded product 31 in
a moderate yield (48%). The results demonstrated that both
electron-donating (Me, OMe) and electron-withdrawing (Br,
Cl, F) substitutions on the N-arylmethyl and N-aryl groups
were tolerated. It was found that N-methyl-1,2,3,4-tetrahy-
droquinoline demonstrated good reactivity in the arylation
reaction to give the product 32 in 71% yield. Notably, for N-
benzyl-substituted tetrahydroquinolines, there is a specific
preference for the arylation at the ring position as opposed to
the acyclic benzylic site, and no regioisomers were detected.
The regioselectivity was consistent with the findings made by
MacMillan group’s.3b Delightedly, N-(benzofuran-6-yl)-
1,2,3,4-tetrahydroquinoline was amenable via the arylation
To get insight into the reaction mechanism, UV−vis
absorption spectra of N-phenylpyrrolidine (1), 1,4-dicyano-
benzene (2), the mixture of 1 and 2, and the combination of 1,
Scheme 3. A Gram-Scale Synthesis of the Product 19
C
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2, and Cs2CO3 were recorded in DMA (see the Supporting
Information). A bathochromic shift of the mixture of 1 and 2
was observed, indicating the formation of an EDA complex.
The results are consistent with the obvious color change from
colorless to yellowish when 1 and 2 were mixed. Meanwhile,
only a trace amount of 3 was detected when a radical scavenger
(2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO)) was
added to the reaction mixture of 1 and 2, indicating the
probable formation of radical intermediates. On the basis of
the above observations and literature reports, a plausible
mechanistic explanation was proposed in Figure 2. The
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00984.
■
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Experimental procedures, compound characterization,
and NMR spetra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Gaofeng Feng − Zhejiang Key Laboratory of Alternative
Technologies for Fine Chemicals Process, Shaoxing University,
Shaoxing 312000, China; orcid.org/0000-0001-8521-
8305; Email: chfeng@usx.edu.cn
Jian Jin − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, Shanghai
200032, China; orcid.org/0000-0001-9685-3355;
Email: jjin@sioc.ac.cn
Authors
Chang Xu − Zhejiang Key Laboratory of Alternative
Technologies for Fine Chemicals Process, Shaoxing University,
Shaoxing 312000, China
Fang-Qi Shen − Zhejiang Key Laboratory of Alternative
Technologies for Fine Chemicals Process, Shaoxing University,
Shaoxing 312000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00984
Figure 2. Proposed mechanistic pathway.
Notes
The authors declare no competing financial interest.
mixture of tertiary amine 1 (electron-donor) and benzonitrile
2 (electron-acceptor) in DMA forms the EDA complex 44.
Upon irradiation with visible light, a direct single-electron
transfer event from electron-rich amine 1 to electron-deficient
benzonitrile 2 took place, generating the arene radical anion 2a
and amino radical cation 1a simultaneously. 1a then under-
went deprotonation (the C−H bond adjacent to nitrogen
atom) by a base to afford the key α-amino radical 1b. The
coupling of α-amino radical 1b with arene anion radical 2a
generates the key intermediate 45, which undergoes the
ACKNOWLEDGMENTS
■
We are grateful for the financial support by National Natural
Science Foundation of China (Grant Nos. 21676166 and
21302130) and Natural Science Foundation of Shanghai
(19ZR1468700).
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