The synergistic effect of self-assembly and visible-light induced the oxidative C-H acylation of N-heterocyclic aromatic compounds with aldehydes

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Constructing carbon-carbon bonds through oxidative cross-coupling between two hydrocarbon compounds is regarded as a foundational issue in green chemistry. High atom-economy and mild conditions are long term pursued goals in this field. Herein, we develop

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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DOI: 10.1039/C8CC02342E
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Synergistic Effect of Self-assembling and Visible-light Induced the
Oxidative C-H Acylation of N-heterocyclic Aromatic Compounds
with Aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a,b
DOI: 10.1039/x0xx00000x
Lingling Zhang, Guoting Zhang, Yongli Li, Shengchun Wang and Aiwen Lei *
www.rsc.org/
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
Constructing carbon-carbon bonds through oxidative cross- based photocatalysts, the organic dyes have also been used as
coupling between two hydrocarbon compounds respected a the photocatalysts and presented a great potential in
5
c, 6
foundational issue in green chemistry. High atom-economy and photocatalysis.
mild conditions are long term pursuing goals in this field. Herein, availability of the photocatalysts, limited the further
we developed visible-light mediated direct cross-coupling application in the large-scale industrial process chemistry. The
However, the high cost, toxicity or limited
a
between N-heterocycles and aldehydes without the requirement photochemical reaction without any external photo-catalyst is
of photocatalyst. Several N-herterocycles afforded the acylation a significant research filed in photocatalysis. The in-situ formed
products with aromatic or aliphatic aldehydes in good yields. The intermediate would absorb the photon instead of the
reaction can be conducted under room temperature and easily photocatalyst. Recently, the electron donor–acceptor (EDA)
scaled up.
complexes was proven to absorb visible-light and demonstrate
7
the photochemical activity. Besides EDA complex, some
The heterocyclic aryl moieties bearing acyl groups were widely
1
existed in pharmacological compounds. Recently, the
visible-light induced coupling reactions based on the
interaction between substrates and copper catalyst were
8
9
10
oxidative cross-coupling reactions have been proved as a
powerful and straightforward strategy for the bond-formation,
2
since the pre-functionalization step can be obviated. The C-H
developed by Fu, Ackermann, Hwanga and other groups.
Herein, we developed a visible light induced cross-coupling of
aldehydes and electron-deficient N-heterocyclic arenes under
catalyst-free conditions. A various aromatic, and aliphatic
aldehydes could couple with N-heterarenes to form the
desired products. A complex might be formed through the
acylation with aldehyde as the acyl source provides an atom
3
economical route for synthesizing carbonyl compounds. The
Minisci reaction offers a powerful approach for the acylation
of heteroarenes, which involves the interaction of a generated
acyl radicals with the electron-deficient heterocyclic
t
interaction of N-herterocycles, TFA and BuOOH, which was
proposed as a key intermediate in the reaction.
4
aromatics. However, harsh reaction conditions for the radical
t
initiation were generally required, such as high reaction
temperature and the use of transition-metal salts or the extra
additives. Thus, the development of a more atom-economical
reactions methodology for the C-H acylation of heterocyclic
aromatics is highly desirable.
HOO Bu
R
Het
visible-light
N
R
Het
+
R'-CHO
N
O
R'
Scheme 1. Photoredox-induced Minisci coupling under catalyst-free
conditions
Over these years, the visible-light photoredox catalysis has
been increasingly developed to provide a powerful approach
5
for bond-forming reaction. Because most organic molecules
We began our study with the cross-coupling of isoquinoline
can not absorb the visible light, the use of the external
photocatalyst , such as ruthenium and iridium complexes are
(
1a) and 4-methylbenzaldehyde (2a) as the model reaction. To
our delight, the formation of isoquinolin-1-yl(p-
5
often required in photocatalysis. Besides transition-metal
g
tolyl)methanone was observed in 89% yield by using TBHP as
the oxidant under the irradiation of blue LEDs in the presence
of TFA as the additive. The control experiment demonstrated
that oxidant and light are crucial for this transformation (Table
1, entry 3 and entry 4). The dramatically decreased yield was
observed in the absence of TFA (entry 2, Table 1). Aqueous
TBHP provided inferior yields compared with that with TBHP in
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decane (entry 5, Table 1). Decreasing the amount of TBHP or different substituents participated in the oxidative cross-
TFA led to lower yield of 3a (Table 1, entry 6 and entry 8). coupling reactions with 1a to afford diverse benzoylated
Increasing the amounts of TBHP or TFA did not increase the isoquinolines 3a–3m in good efficiencies (Scheme 2). The
reaction yields (entry 7 and entry 9, Table 1).
reaction efficiency was found to be not sensitive to aromatic
aldehydes with electron-donating groups at ortho, meta, and
a
Table 1. Optimization of reaction conditions .
para positions (3a, 3i, and 3k). The products from aldehydes
with electron-withdrawing groups at the para position of aryl
group were obtained in better yields than their ortho-
substituted isomers
(3h and 3j). Polymethly-substituted
benzaldehyde was tolerated with the condition (3l). Similarly,
the reaction is applicable to the aliphatic aldehydes such as
heptanal, octanal and dodecanal, which can furnish the
corresponding acylated products in good yields (Scheme 2, 3h
3j, and 3k).
,
b
Entry
Oxidant
Acid
Yield (%)
89
3i,
1
2
TBHP
TBHP
TBHP
-
TFA
-
trace
d
c
3
TFA
TFA
TFA
TFA
TFA
TFA
TFA
n.r.
c
4
5
6
n.r.
aq.TBHP
TBHP
TBHP
TBHP
TBHP
trace
trace
56
e
f
7
g
8
76
h
9
83
Reaction conditions: isoquinoline (0.50 mmol), 4-methylbenzaldehyde (2.5
mmol), TBHP in decane (2.0 eq. ), TFA (1.5 eq.) in ethyl acetate (1.0 mL) at
b
rt under 3W blue LEDs for 24 h. Determined by GC using biphenyl as an
c
d
e
f
internal standard. n.r.= no reaction. without light. 1 eq. TBHP in decane.
3
g
h
eq. TBHP in decane. 1 eq. TFA. 2 eq. TFA.
Scheme 3. The scope of N-heterocycle components. The reaction was carried
out with 1 (0.5 mmol), 2a (2.5 mmol), TBHP (2.0 eq.) and TFA (1.5 eq.) in EA (1
mL) at room temperature using 3 W blue LEDs for 24 h. Yields of isolated
products are given.
Then the substrate scope of heterocycles was further
examined by using 4-methylbenzaldehyde as the acyl source
(Scheme 3). A variety of N-containing heterocyclic aromatics
can react with aldehyde. Reactions of electron-rich
isoquinolines provided the desired acylation products in good
yield (4a, Scheme 3). When quinoline was employed into the
reaction system, a mixture of mono and disubstituted products
would be obtained (4b-1 and 4b-2, Scheme 3). In contrast, the
quinolones derivatives with either electron-rich or electron-
poor groups at the 2-, 6-, or 7- positions provided desired
products in very good yields (4d-4e, Scheme 3). Besides
isoquinolines and quinolones, other heterocycles, like
quinoxaline, was also proved to be appliacable into this
oxidative C-H acylation reaction in good efficiency (4f, Scheme
3
). In further demonstration of the utility and applicability of
a
Scheme 2. The scope of aldehyde components. The reaction was carried out
with 1a (0.5 mmol), aldehydes 2 (2.5 mmol), TBHP (2.0 eq.) and TFA (1.5 eq.) in
EA (1 mL) at room temperature using 3 W blue LEDs for 24 h. Yields of isolated
products are given.
this method, a gram-scale synthesis of 3 was performed. As
shown in Scheme 4, the gram-scale reaction proceeded well to
form the corresponding acylated product (3a) in 80% yield,
demonstrating the capacity to apply of the protocol.
With the optimized reaction conditions in hand, the reaction
scope was investigated in the respect with aldehyde
components (Scheme 2). Various aromatic aldehydes with
2
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(
for details, see Figure S2, ESI†). Therefore, the above EPR
results evidence a radical process.
The interactions between heteroarene and BuOOH were
t
1
1
confirmed by H NMR spectroscopy. The H NMR spectrum of
the CDCl solution of isoquinoline was shown in Fig. S4, a1.
3
t
When one equivalent of BuOOH was added into the solution,
the NMR peak of isoquinoline was not shifted (Fig. S4, a3). In
contrast, the isoquinoline protons shifted when trifluoroacetic
acid was added to the solution of isoquinoline (Fig. S4, a2),
Scheme 4. Gram-scale synthesis of 3a
.
To understand the mechanism of this acylation reaction, the
since the corresponding trifluoroacetate would be formed.
reaction of isoquinoline with 4-methylbenzaldehyde under the However, when a mixture of isoquinoline, BuOOH and TFA in
t
optimized reaction conditions was carried out in the presence CDCl
3
was determined by NMR, there is a broad peak
appearing at 12.5 ppm (Fig. S4, a4). These results might
δ
=
of TEMPO and BHT (Scheme 5). In these conditions, the
corresponding acylated product failed to be observed.
suggest that the reaction possibly proceeded via the formation
of a complex of heteroarene, TFA and BuOOH.
t
Base on the above experimental mechanistic data and the
mechanistic insights of the previous cases, a plausible pathway
1
1
for this cross-dehydrogenative coupling process is proposed.
The reaction possibly proceeds via the formation of a complex
t
of heteroarene and BuOOH. The complex (A) thus formed in
the presence of visible light (Blue LED) promotes hemolytic
t
cleavage of BuOOH to produce tert-butoxy radical and
hydroxyl radiacal. The tert-butoxy radical or hydroxyl radiacal
then undergoes a critical HAT with ether to give the acyl
radical. The resulting acyl radical is nucleophilic enough to
undergo addition on the protonated heteroarene to afford the
corresponding amine radical. Consequent single electron
transfer from the intermediate afford product (Scheme 7).
Scheme 5. Radical-inhibiting reactions.
Subsequently, two equivalents of 1,1-diphenylethylene were
added as a radical scavenger. It was found that the reaction
was totally inhibited and the corresponding coupled product
12 was obtained in 5% yields. This result indicated that an acyl
radical was formed under the conditions. In contrast, the
corresponding coupled product 12 failed to be obtained in the
absence of isoquinoline. Thus, we believed that the interaction
t
between heteroarene and BuOOH might play a key role for
the formation of acyl radical.
Scheme 6. Mechanistic studies.
Scheme 7 Proposed mechanism
Additionally, the radical mechanism of this transformation was
also investigated using EPR spectroscopy. As shown in Fig. S1,
when radical spin trapping agent DMPO (5,5-dimethyl-1-
pyrroline N-oxide) was added under standard reaction
condition, a strong radical signal was observed (for details, see
black line in Figure S1, ESI†). By compared with the simulated
EPR spectrum (for details, see red line in Figure S1, ESI†), the
radical signal belongs to the mixture of oxy radical (g=2.0065,
A =13.2, A = 8.26, A = 1.82), acyl radical (g=2.0065,
Conclusions
In conclusion, we have developed an efficient, mild and
scalable method for the acylation of a variety of N-heterocycles
with diverse aldehydes. This reaction tolerates a wide range of
functional groups and proceeds efficiently for the acylation of
N-heterocycles.
This work was supported by the National Natural Science
Foundation of China (21390400, 21520102003, 21272180,
N
H1
H2
A =13.95, A = 15.83) and oxidized DMPO (g=2.0065, A =14.2).
N
N
H
2
1302148), the Hubei Province Natural Science Foundation of
While no EPR signal was observed in the absence of blue light
China (2013CFA081), the Research Fund for the Doctoral
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