Visible-Light-Induced Radical Acylation of Imines with α-Ketoacids Enabled by Electron-Donor-Acceptor Complexes

Article abstract of DOI:10.1021/acs.orglett.9b01169

A visible-light-induced radical acylation of imines with α-ketoacids has been achieved, enabled by an electron-donor-acceptor (EDA) complex. This EDA complex-mediated process eradicates the use of a photocatalyst. Visible light is used as the sole promote

Full text of DOI:10.1021/acs.orglett.9b01169

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced Radical Acylation of Imines with α‑Ketoacids
Enabled by Electron-Donor−Acceptor Complexes
Hong-Hao Zhang and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: A visible-light-induced radical acylation of
imines with α-ketoacids has been achieved, enabled by an
electron-donor−acceptor (EDA) complex. This EDA com-
plex-mediated process eradicates the use of a photocatalyst.
Visible light is used as the sole promoter for this reaction, and
CO2 is the only side product. Substrates with amide, cyanide,
ester, ether, halides, and heterocycles were compatible. This
radical acylation allows access structurally diverse α-amino
ketones (32 examples) in up to 90% isolated yields.
ver the past decade, visible-light-driven photocatalysis
has emerged as a synthetically valuable tool to induce
O
radical reactions. This strategy takes advantage of the redox
potential of the excited photocatalyst under visible-light
irradiation.1 The success of this catalytic mode has largely
relied on the use of an exogenous photocatalyst, which harvests
visible light energy and utilizes it for the transformation of non-
visible-light-absorbing reactants into products through either
an electron-transfer or energy-transfer pathway.2 In contrast,
photoabsorbing electron-donor−acceptor (EDA) com-
plexes3−5 generated by the molecular noncovalent interactions
between electron donors and acceptors can be excited by
visible light to generate radical species for the synthetically
valuable transformations without an exogenous photocatalyst.
These visible-light-induced and photocatalyst-free organic
transformations have received increasing attention due to
their mechanistically novel and economic features.6 Despite
these significant advances, more synthetic applications of EDA
complexes are in need of further investigation.7
Figure 1. Synthesis of α-amino ketones by radical couplings.
α-Amino ketones are an important class of biologically
relevant molecules.8 Efforts have been made by the synthetic
community to develop efficient and general methods for their
synthesis.9 Several ionic methods, such as hydrogenation of α-
ketoketimines,10 cross coupling of aldehydes with imines,11
and amination of enols,12 have been established. Considering
the importance of α-amino ketone derivatives, we envisaged
that the synthesis of α-amino ketones could be achieved
through radical cross couplings of α-aminoalkyl radicals13 and
acyl radicals14 (Figure 1a). It is known that α-aminoalkyl
radicals can be generated from imines through one-electron
reduction under photochemical conditions.15 α-Ketoacids16
can be involved in EDA complexes as electron donors and,
thus, serve as the precursors of acyl radicals under irradiation.
Motivated by these works, as well as our continuing research
interest in EDA complexes,17 we propose that an imine and an
α-ketoacid can engage in an EDA complex. Upon visible-light
irradiation, this complex dissociates into an α-aminoalkyl
radical and an acyl radical, respectively. Cross coupling of these
two radicals gives α-amino ketone (Figure 1b). This EDA
complex-mediated process eradicates the use of a photo-
catalyst. Visible light is used as the sole promoter and CO2 is
the only side product.
This hypothesis was examined using imine 1a and 2-oxo-2-
phenylacetic acid (2a) as the coupling partners. After shining
light on a mixture of 1a (1 equiv) and 2a (1 equiv) in CH2Cl2
with a 90 W blue LEDs for 12 h, the desired acylation product
3a was indeed observed, but in a moderate 48% GC yield
(Table 1, entry 1). Solvents were then screened to improve the
yield of this reaction (entries 2−5), but no solvent was
Received: April 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01169
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Letter
a
We next examined the scope of α-ketoacid components. As
described in Figure 3, this protocol was amenable to α-
Table 1. Reaction Condition Optimization
b
entry
solvent
1a/2a
3a (%)
1
2
3
4
5
6
7
8
CH2Cl2 (1 mL)
PhCF3 (1 mL)
1,4-dioxane (1 mL)
DMF (1 mL)
EtOAc (1 mL)
CH2Cl2 (1 mL)
CH2Cl2 (2 mL)
CH2Cl2 (2 mL)
CH2Cl2 (2 mL)
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:1.5
48
24
12
7
13
23
63
c
80 (73 )
NR
d
9
a
Reaction conditions: a solution of 1a (0.10 mmol) and 2a in the
b
indicated solvent was irradiated by blue LEDs for 12 h. GC yields.
c
d
Isolated yield. In dark. PMP = p-methoxyphenyl. NR = no reaction.
superior to CH2Cl2. The improvement of light transmission of
the reaction mixture led to better yield (63%) when the
reaction solution was diluted (entry 7). The use of 1.5 equiv of
2a resulted in 80% GC yield (73% isolated yield, entry 8). No
reaction could be observed without irradiation (entry 9).
After determining the optimized conditions, we proceeded
to explore the scope and limitations of this visible-light-
induced radical acylation. As shown in Figure 2, aldimines
Figure 3. Scope of α-ketoacids. Reaction conditions: a solution of 1a
or 1b (0.10 mmol) and 2 (0.15 mmol) in CH2Cl2 (2 mL) was
irradiated by blue LEDs for 12 h. The yields were based on the
isolated products.
ketoacids with different substituents of the benzene ring no
matter the electronic property and position, affording the
corresponding products 4a−4j in 52−90% yields. It is worth
noting that 2-oxo-2-mesitylacetic acid worked well to deliver
the product 4j in excellent yield (90%). 2-Naphthyl- and 3-
thiophene-yl-substituted α-ketoacids were also suitable sub-
strates (70% yield for 4k and 60% yield for 4l, respectively). As
further detailed in Figure 3, aliphatic α-ketoacid could also
serve as the efficient coupling partner to give the acylation
products 4m in 53% yield. Remarkably, this protocol was also
applicable to α-ketoamides 2o and 2p to give 2-aminoamide
derivatives 4n (74% yield) and 4o (60% yield).
The utility and practicality of this radical acylation reaction
were elaborated by a gram-scale preparation of α-amino ketone
3b. As shown in Figure 4a, 5 mmol of imine 1b could be
acylated with α-ketoacid 2a under our established conditions,
and a comparative isolated yield of 3b (70%, 1.32 g) was
obtained. The overall efficiency of this reaction could be
Figure 2. Scope of imines. Reaction conditions: a solution of 1 (0.10
mmol) and 2a (0.15 mmol) in CH2Cl2 (2 mL) was irradiated by blue
LEDs for 12 h. The yields were based on the isolated products.
derived from different functionalized benzaldehydes were
acylated with α-ketoacid 2a. In all cases, good reactivity was
observed in the presence of both electron-withdrawing and
electron-donating groups on the aryl ring, giving products 3a−
o in good yields (50−77%). Functional group tolerance was
investigated. Remarkably, substrates with functional groups,
such as ester (3b), cynide (3d), halogen (3e, 3f, 3i, and 3k),
aryl (3g), ether (3h, 3j, and 3l) and heterocyles (3o), could be
tolerated in this reaction. Both meta-substituted aldimine and
ortho-substituted aldimines could go through this trans-
formation smoothly (3i−3l, 54−77% yields).
Figure 4. Gram-scale and one-pot synthesis of 3b.
B
DOI: 10.1021/acs.orglett.9b01169
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further improved with the generation of the imine in situ. A
three-component reaction of aromatic amine 5, aldehyde 6 and
α-ketoacid 2a could also give the product 3b (62%) on a gram
scale (Figure 4b).
mixture of imine 1a and α-ketoacid 2a (Figure 6a). The 1a/2a
stoichiometric ratio in the EDA complex was determined to be
1:1 using Job’s method (Figure 6b).19
To understand this transformation, a number of control
experiments and analytical surveys were performed. Termi-
nation of the desired reaction with TEMPO and observation of
TEMPO-trapped product 7 by high-resolution mass spectrom-
etry implied that this reaction involved radical pathway (Figure
5a). The radical nature of this reaction could be further
Figure 6. (a) Optical absorption spectra of the reaction components.
(b) Job’s plot between 1a and 2a.
On the basis of these experimental phenomena, a
mechanism for this radical acylation reaction is posited. As
shown in Figure 7, imine 1a interacts with α-ketoacid 2a
Figure 7. Proposed mechanism.
reversibly to generate an EDA complex. Upon visible-light
irradiation, this complex is excited and then dissociates into a
pair of radicals. After the release of CO2 from the carboxylic
radical, the resultant acyl radical couples with the α-aminoalkyl
radical to give the final product 3a. The quantum yield of this
reaction was determined to be 0.08 (for details, see the SI),
and this experiment strongly implies that this reaction
proceeds through a cross radical coupling rather than a radical
propagation.
In summary, we have established a visible-light-induced
radical acylation of imines with α-ketoacids via EDA
complexes. This mild decarboxylative acylation can proceed
without any photocatalyst or additive. Visible light is used as
the sole promoter and CO2 is the only side product. Substrates
with amide, cyanide, ester, ether, halides, and heterocycles
were compatible. The radical-based methodology presented
here allows to access structurally diverse α-amino ketones (32
examples) in up to 90% isolated yields.
Figure 5. Control experiments.
confirmed by using α-ketoacids 2q and 2r as the acyl radical
precursors. As described in Figure 5b, when 2q and 2r were
employed to react with 1b, the desired products 4p and 4q
were generated in 52% and 25% isolated yields, respectively,
together with alkylation byproducts 4p′ (16% yield) and 4q′
(72% yield). This observation could be explained by the
generation of acyl radicals and the existence of a simultaneous
decarboxylation process (release of CO2) and decarbonylation
process (release of CO).14,18 When potassium 2-oxo-2-
phenylacetate 11 was used instead of its acid, no reaction
took place. The addition of trifluoroacetic acid (TFA) into this
reaction mixture promoted the formation of the desired
product (Figure 5c). This phenomenon implied that proton
was crucial to this transformation. The desired reaction could
not be observed in the dark, even by heating to 100 °C, which
verified this reaction was a photochemical process rather than a
thermodynamic one (Figure 5d).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01169.
This photochemical reaction was proposed to be enabled by
an EDA complex between an imine and an α-ketoacid, which
could be supported by the observation of a bathochromic shift
and a charge transfer band in the UV−vis spectrum of the
Full experimental and characterization data for all
compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b01169
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Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yushouyun@nju.edu.cn.
ORCID
Shouyun Yu: 0000-0003-4292-4714
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation
of China (21672098 and 21732003) and the National Key
Research and Development Program of China
(2018YFC0310900) is acknowledged.
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