Metal-, Photocatalyst-, and Light-Free Minisci C-H Acetylation of N-Heteroarenes with Vinyl Ethers

Article abstract of DOI:10.1021/acs.orglett.1c01310

Herein, we report a mild, operationally simple method for Minisci C-H acetylation of N-heteroarenes using vinyl ethers as robust, inexpensive acetyl sources. The reactions do not require a conventional photocatalysis, electrocatalysis, metal catalysis, light activation, or high temperature. This method is thus significantly more sustainable than previously reported methods in terms of cost, reagent toxicity, and waste generation. This protocol can be expected to obtain medically relevant molecules from abundant feedstock materials.

Full text of DOI:10.1021/acs.orglett.1c01310

pubs.acs.org/OrgLett
Letter
Metal‑, Photocatalyst‑, and Light-Free Minisci C−H Acetylation of
N‑Heteroarenes with Vinyl Ethers
Jianyang Dong, Jianhua Liu, Hongjian Song, Yuxiu Liu, and Qingmin Wang*
Cite This: Org. Lett. 2021, 23, 4374−4378
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ABSTRACT: Herein, we report a mild, operationally simple
method for Minisci C−H acetylation of N-heteroarenes using vinyl
ethers as robust, inexpensive acetyl sources. The reactions do not
require a conventional photocatalysis, electrocatalysis, metal
catalysis, light activation, or high temperature. This method is
thus significantly more sustainable than previously reported
methods in terms of cost, reagent toxicity, and waste generation.
This protocol can be expected to obtain medically relevant molecules from abundant feedstock materials.
N-Heterocycles,1 especially N-heteroarenes,2 are widely
present in drug molecules. Therefore, it is of great significance
to develop methods for the functionalization of N-hetero-
arenes;3 this is particularly true for C−H acylation, owing to
the many pharmaceutical drugs and natural products
containing acylated N-heteroarenes (Scheme 1A).4 Although
Minisci acetylation reactions are typically carried out with
acetaldehyde using Fe(II)/t-BuOOH, Fe(II)/(NH4)2S2O8, or
phenyliodine bis(trifluoroacetate)/TMSN3 oxidation systems
(Scheme 1B).7 In addition, Ag(I)/(NH4)2S2O8,8 Fe(II)/
(NH4)2S2O8,9 photoredox catalysis,10 and electrocatalysis
have been employed to induce Minisci acylation reactions
with α-keto acids.11 Recently, Reddy et al. reported iron-
catalyzed acetylation of electron-deficient N-heteroarenes
using triethyl orthoformate as the acetyl source and tert-butyl
hydroperoxide as an oxidant.12 In parallel, Kudalea and Wang
acetylated N-heteroarenes by using PEG-400 as a coupling
partner in combination with potassium persulfate (K2S2O8) at
high temperature (Scheme 1B).13 However, most of the
previous methods require transition-metal catalysts, expensive
photocatalysts, excess radical precursors, or high temperatures.
Therefore, these methods are generally not suitable for
complex natural products and drug molecules. Moreover, the
harsh conditions make the reaction incompatible with certain
functional groups, and various radical-addition byproducts are
formed. Therefore, we want to develop a practical Minisci
acetylation reaction without a metal, a photocatalyst, or high
temperature.
Scheme 1. Minisci Acetylation of N-Heteroarenes
We speculated that reaction of vinyl ethers with acid could
result in the generation of acetaldehyde, which can be used as
the acetyl-radical precursor. Recently, we discovered that
Minisci C−H alkylation of N-heteroarenes with alkyl oxalates
can be accomplished without a metal, a photocatalyst, or light
2−
in dimethyl sulfoxide (DMSO) containing persulfate (S2O8
)
electron-rich aromatic compounds can readily be acylated via
the Friedel−Crafts reaction, very few reactions are used for
acylation of N-heteroarenes. Minisci reaction provides a good
method for acylation of N-heteroarenes.5 Following this
seminal work, a variety of protocols for acylation of N-
heteroarenes with aldehydes,6b α-keto acids,6c benzylamines,6d
and aryl methanes6e have been reported.6 However, Minisci
C−H acetylation of N-heteroarenes is challenging.6
Received: April 16, 2021
Published: May 24, 2021
https://doi.org/10.1021/acs.orglett.1c01310
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4374−4378
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as an oxidant.14 The DMSO allows for uncatalyzed
With optimized conditions established, we examined the
scope of the acetylation (Table 2). Quinolines bearing various
2−
−•
decomposition of S2O8 to a sulfate radical anion (SO4
)
at low temperatures (50 °C), presumably because the
decomposition rate is solvent dependent.15 As part of our
a
Table 2. Scope of the Acylation Reaction
ongoing work on Minisci reactions,16 we envisioned that
−•
SO4
generated from S2O82−/DMSO could undergo a
hydrogen atom transfer reaction with acetaldehyde (generated
from readily available vinyl ethers) to produce an acetyl radical.
Indeed, we now report the first protocol for acetylation of N-
heteroarenes using vinyl ethers as acetyl radical precursors
(Scheme 1C).
We began by investigating the acetylation reaction with
lepidine (1, 1 equiv), n-butyl vinyl ether (2a, 3 equiv),
Na2S2O8 (3 equiv), and trifluoroacetic acid (TFA, 2 equiv) in
1,2-dichloroethane at 60 °C for 24 h (Table 1). Unfortunately,
a
Table 1. Optimization of Acetylation
b
entry
oxidant
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
TBHP
t-BPA
O2
Na2S2O8
Na2S2O8
−
DCE
<5
NR
NR
84 (80% )
58
66
43
<5
<5
58−73
49
NR
21
CH3CN
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
d
e
f
Na2S2O8
a
General conditions: 1 (0.2 mmol), 2 (0.6 mmol), oxidant (0.6
mmol), TFA (0.4 mmol), and DMSO (6 mL) under Ar atmosphere.
a
DCE, 1,2-dichloroethane; TBHP, tert-butyl hydroperoxide; t-BPA,
Reactions were performed on a 0.2 mmol scale. Isolated yields are
b
tert-butylperacetate. NR = no reaction. Determined by 1H NMR
given.
c
spectroscopy using dibromomethane as an internal standard. Isolated
d
e
yield. Vinyl ethers 2b, 2c, and 2d were used instead of 2a. Reaction
f
substituents (methyl, phenyl, fluorine, chlorine) gave the
acetylation products at C2 or C4 in good yields (3−7, 54−
85%), depending on the position of the substituent. We were
pleased to find that a compound with a fluorine atom, which is
often linked to the drug-like activity, was suitable for this
reaction (giving 5). Quinoline substrate gave the C2
acetylation product 8a in 76% yield and trace of C2 and C4
difunctionalization product 8b. Notably, isoquinolines bearing
various substituents (methoxy, methyl, bromine, ester) under-
went acetylation at C1, giving 9−15 in 58−89% yields.
Phenanthridine was also suitable for this reaction, giving 16 in
62% yield, and acetylation of 4-phenylpyridine gave mono-
acetylated product 17 in 41% yield. This reaction was also
suitable for N-heteroarenes containing two nitrogen atoms:
quinazolines (18−20, 73−80%). Notably, 4-hydroxyquinazo-
line also participated in the reaction, giving 21 in 65% yield.
Although radical-type SNAr reactions have been reported,17 we
observed no products of substitution reactions involving the
C−Cl bonds of the chloro-substituted compounds we tested
(i.e., those that gave 4, 5, and 7). Finally, we tested this
acylation protocol with other vinyl ethers. Fortunately, ethyl
propenyl ether and 1-butenyl ethyl ether afforded the
performed at 20 °C. No TFA.
we could only obtain a very low yield of desired product 3,
owing to the poor solubility of K2S2O8 (entry 1). Then we
tested other solvents (entries 2−4) and were delighted to find
that 3 could be obtained in excellent yield when DMSO was
used as the solvent (entry 4). When we used other persulfates,
the yields of 3 were decreased (entries 5 and 6), which also
resulted with use of the peroxide oxidants tert-butyl hydro-
peroxide and tert-butylperacetate (entries 7 and 8). The use of
oxygen as the oxidant was strongly deleterious (entry 9). When
other vinyl ethers were employed under the conditions shown
in entry 4, the yields were only 58−73% (entry 10). When we
performed the reaction at 20 °C, the yield of 3 was decreased
to 49% (entry 11). Control experiments showed that Na2S2O8
and TFA were necessary for the reaction (entries 12 and 13).
Notably, the reaction proceeded only in DMSO; none of the
2−
typical Minisci solvents worked. As discussed above, S2O8
decomposes more readily in DMSO,14,15 and DMSO has the
added benefit of being more environmentally benign than the
commonly used solvent CH3CN.
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corresponding acylated heteroarenes (22 and 23) in 58% and
61% yields. Incomplete conversion of N-heteroarenes
accounted for the moderate yields of some of the products
(e.g., 6, 17, 21, 22, 23). Notably, a gram-scale (8 mmol)
reaction of 1 and 2a afforded 3 in an isolated yield of 67%.
Then we studied the mechanism (Scheme 2). To determine
Scheme 3. Proposed Mechanism for Acetylation of N-
Heteroarenes
1
the acetyl source, we used H NMR spectroscopy. After the
Scheme 2. Mechanistic Studies
2−
single electron transfer reaction with S2O8 or via abstraction
−•
of a hydrogen radical by SO4
.
In summary, a method for metal-, photocatalyst-, and light-
free acetylation of N-heteroarenes using vinyl ethers as robust,
inexpensive acetyl sources is reported. The application of this
protocol to obtain medically relevant molecules is being
studied in our group.18
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01310.
Experimental procedures, characterizations and copies of
1H and 13C NMR spectra of products (PDF)
1
reaction, acetaldehyde was detected by H NMR (Scheme
AUTHOR INFORMATION
Corresponding Author
2A). When n-butyl vinyl ether (2a) was allowed to react with
TFA, acetaldehyde was detected by gas chromatography−mass
■
1
spectrometry and H NMR (Scheme 2B). These experiments
Qingmin Wang − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China; Collaborative Innovation Center
of Chemical Science and Engineering (Tianjin), Tianjin
300071, People’s Republic of China; orcid.org/0000-
0002-6062-3766; Email: wangqm@nankai.edu.cn
demonstrated that reaction of 2a and TFA generated
acetaldehyde in situ and that acetaldehyde was converted to
an acetyl radical in the presence of Na2S2O8. This was
confirmed by the fact that reaction of 1 and acetaldehyde
afforded desired product 3 in 63% yield (Scheme 2C). Then
we optimized the acetylation reaction with acetaldehyde
substrate; however, we only obtained a 68% yield in the best
situation. Next, we carried out experiments with radical
inhibitors (Scheme 2D). When the radical scavenger
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added to
the reaction, the yield of 3 decreased markedly (to 16%).
When radical scavenger 1,1-diphenylethylene was added to the
reaction, the reaction was completely inhibited, and radical
trapping product 4,4-diphenylbut-3-en-2-one (24) was de-
tected by high-resolution mass spectrometry.
Authors
Jianyang Dong − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Jianhua Liu − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Hongjian Song − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China; orcid.org/0000-0001-7105-
1196
Yuxiu Liu − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Based on these experimental results, the mechanism is
−•
2−
outlined in Scheme 3. The generation of SO4 from S2O8
typically proceeds via metal mediation or photolysis.5
However, in our system, S2O8 decomposes under mild
2−
conditions without catalysis, which we attribute to the solvent-
dependence of the decomposition rate (as mentioned above,
2−
S2O8 reportedly decomposes much more readily in DMSO
than in other solvents15). At the same time, in the presence of
TFA, n-butyl vinyl ether (2a) reacts to generate acetaldehyde
−•
in situ. Then SO4 selectively abstracts the hydrogen atom
from acetaldehyde to afford acetyl radical A. Nucleophilic
radical A adds to the protonated N-heteroarene to afford
radical cation B. Finally, product 3 can then form either via a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01310
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Letter
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21732002, 22077071) for generous financial support
for our programs. Dedicated to the 100th anniversary of
Chemistry at Nankai University.
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