UV-Light-Induced N-Acylation of Amines with α-Diketones

Article abstract of DOI:10.1021/acs.orglett.1c01599

Herein, we develop a mild method for N-acylation of primary and secondary amines with α-diketones induced by ultraviolet (UV) light. Forty-six examples with various functional groups are explored at room temperature with irradiation by three 26 W UV lamps (350-380 nm). The yield reaches 97%. The gram scale experiment product yield is 76%. Moreover, this system can be applied to the synthesis of several amino acid derivatives. Mechanistic studies show that benzoin is generated in situ from benzil under UV irradiation.

Full text of DOI:10.1021/acs.orglett.1c01599

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Letter
UV-Light-Induced N‑Acylation of Amines with α‑Diketones
Zhihui Xu,§ Tianbao Yang,§ Niu Tang, Yifeng Ou, Shuang-Feng Yin, Nobuaki Kambe, and Renhua Qiu*
Cite This: Org. Lett. 2021, 23, 5329−5333
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ABSTRACT: Herein, we develop a mild method for N-acylation
of primary and secondary amines with α-diketones induced by
ultraviolet (UV) light. Forty-six examples with various functional
groups are explored at room temperature with irradiation by three
26 W UV lamps (350−380 nm). The yield reaches 97%. The gram
scale experiment product yield is 76%. Moreover, this system can
be applied to the synthesis of several amino acid derivatives. Mechanistic studies show that benzoin is generated in situ from benzil
under UV irradiation.
Scheme 1. N-Acylation of Amines for the Synthesis of Amides
mides are some of the most important compounds in
1
Aorganic synthesis. The green and efficient synthesis of
amides has gradually attracted the attention of scientists
worldwide.2 Amides are a ubiquitous scaffold that widely exists
in drugs,3 agrochemicals,4 and organic functional materials.5
Many biologically active amides have been developed to cure
diseases, such as paracetamol,6 safinamide,7 procainamide,8 and
moclobemide9 (Figure 1). In addition, amides can serve as
synthetic intermediates for different transformations, such as for
acquiring amines and heterocycles.10
et al.17 reported an amination reaction of carboxylic acids and
amines catalyzed by eosin Y under a white light-emitting diode
(LED) lamp. Song et al.18 reported that thioacids can react with
amines to prepare amides using Mes-Acr-MeBF4 with blue light.
Although much progress has been made in this field, some
limitations remain, such as heavy metal pollution, the use of
excess amounts of starting materials, adding equivalents of
oxidants and additives, and the requirement for external
photocatalysts. Therefore, the development of environmentally
friendly and efficient direct amination is still highly desirable.
Figure 1. Representative drugs.
Traditional methods for amination mainly fall into four
categories: activation of carboxylic acids and amines,11
activation of carboxylic acids alone,12 activation of amines
alone,13 and activation of the acyl group.14 Thermal
condensation of carboxylic acids with amines is displayed in
route 1 (Scheme 1a), and stoichiometric or excess highly active
reagents such as EDC, DCC, and HATU are added in route 2
(Scheme 1a). A series of methods for metal-catalyzed synthesis
of amides have been well developed, as shown in Scheme 1b.15
In recent years, photocatalysis has emerged as a powerful tool for
the construction of C−C bonds and C−Z bonds due to its
cleanliness, sustainability, and simple operation.16 A few
examples of N-acylation of amines with photocatalysts have
been reported, as shown in step i of Scheme 1c. For example, Ke
Received: May 11, 2021
Published: June 28, 2021
https://doi.org/10.1021/acs.orglett.1c01599
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5329−5333
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Inspired by previous works and in the course of our exploration,
we found a mild protocol for direct amination of α-
diketones19−21 and amines irradiated by UV light without the
need for external additives and photocatalysts under ambient
conditions (Scheme 1c, ii).
With the optimized reaction conditions in hand, we first
investigated the substrate scope with respect to secondary
amines (Scheme 2). For cyclic secondary amines, the reaction
a
Scheme 2. Substrate Scope with Various Amines
Initially, we started our investigation by using benzil (1a) and
pyrrolidine (2a) to optimize the reaction conditions, and the
results are depicted in Table 1. Surprisingly, the yield of 3a
a
Table 1. Optimization of the Reaction Conditions
a
entry
1a:2a
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
1:1
1:1.5
1:2
1:3
1:4
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
H2O
acetone
n-hexane
toluene
DMF
EtOAc
1,4-dioxane
THF
2-MeTHF
CH3CN
CH3OH
isopropyl ether
THF
35
35
35
35
35
24
24
24
24
24
24
24
24
24
24
24
24
10
10
10
10
8
43
69
82
81
82
NR
ND
trace
trace
trace
41
54
74
71
37
26
58
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
b
NR
c
THF
THF
THF
THF
THF
THF
88
d
94
e
86
75
a
Reaction conditions: 1a (0.2 mmol, 42.0 mg), 2 (0.4 mmol), three
f
10
10
NR
ND
26 W UV lamps (350−380 nm), THF (2.0 mL), air, room
g
temperature. Isolated yields.
a
Unless otherwise noted, all reactions were carried out with 1a (0.2
mmol, 42.0 mg), 2a (0.4 mmol, 28.4 mg), and a general solvent (2.0
mL) at room temperature under air conditions under one 26 W UV
proceeded smoothly with the desired products obtained in good
yields (3a−3d, 90−94%). In particular, 2 equiv of azetidine gave
3b in a relatively low yield under the standard condition due to
the large tension of the four-membered ring. Product 3b was
obtained in a higher yield when the amount of azetidine was
increased (4 equiv, 92%). For acyclic secondary amines,
diethylamine and dibutylamine afforded the corresponding
amides in moderate yields (3e, 87%, and 3f, 70%). N-Methyl-1-
phenylmethanamine and dibenzylamine with a certain steric
hindrance still generated the target products (3g, 64%, and 3h,
50%).
Next, we explored various primary amines. Isopropylamine,
tert-butylamine, and isobutylamine were added to this reaction
mixture, and they displayed almost quantitative yields (97%,
95%, and 97% for 4a−4c, respectively). Extending the carbon
chain of the amine also gave an excellent yield (4e, 92%). 4-
Phenylbutylamine achieved the same yield as isooctylamine (4f,
92%). Primary amines with three-membered, four-membered,
or five-membered rings enabled one to obtain the target
products (4g−4i, 52−90% yields). Regardless of whether the
benzylamines had electron-rich groups or electron-deficient
groups, good to excellent yields were obtained regardless of the
b
c
lamp (350−380 nm). No light. With two 26 W UV lamps (350−
d
e
380 nm). With three 26 W UV lamps (350−380 nm). With N2.
f
g
With a green lamp (8 W) and a white lamp (20 W). With a blue
lamp (12 W).
(43%) was obtained in a solvent of 2-methyltetrahydrofuran
irradiated by one UV lamp for 35 h (entry 1). Next, we
continued to screen the ratio of the starting materials. Two
equivalents of pyrrolidine gave a ≤82% yield, which was better
than that obtained for 1.5 equiv of 2a (69%) (entries 2−5). We
found that different solvents exhibited various yields (0−74%,
entries 6−17). This reaction did not take place in water (entry
6). It was noted that increasing the number of lamps and the
reaction time can be beneficial for this reaction (entries 19−22).
Finally, the best reaction conditions were determined: 1a
reacted with 2.0 equiv of 2a in THF irradiated by three UV
lamps for 10 h (94%, entry 20). This reaction did not occur
without light, which infers that light is indispensable for realizing
the product (entry 18). The yield of 3a was 86% when the
reaction was conducted under a N2 atmosphere (entry 21),
indicating that an air atmosphere is unnecessary.
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pubs.acs.org/OrgLett
Letter
ortho, meta, and para position groups (4j−4r, 78−97% yields).
The amine containing a ternary ring with a large tension could
also form the desired product in this system (75% yield for 4s).
Reactions of furfurylamine and pyridin-2-ylmethanamine with
heterocycles proceeded smoothly (4t, 52%, and 4u, 70%).
(Tetrahydrofuran-2-yl)methanamine and (tetrahydro-2H-
pyran-4-yl)methanamine with heteroatoms afforded the corre-
sponding products in moderate yields (4v, 85%, and 4w, 89%).
In addition, amines containing olefin, ether, active hydroxyl, and
Boc groups enabled one to smoothly obtain target products,
indicating that there was good functional group compatibility in
this system (4z−4ae, 62−96% yields).
luene (BHT) or 2,2,6,6-tetramethylpiperidinooxy (TEMPO)
was added to the reaction system under standard conditions, and
the results showed that TEMPO can inhibit the reaction, with
only a trace amount of the desired product obtained (Scheme
4a,b). The addition of BHT did not quench the reaction, which
Scheme 4. Control Experiments
In addition, several disubstituted α-diketones exhibited
different activities when they reacted with pyrrolidine (Scheme
3). The results showed that electron-withdrawing -Br (5a) and
Scheme 3. Substrate Scope with α-Diketones and Amino
a
Derivatives
a
Reaction conditions: 1b−1e (0.2 mmol), 2a (2.0 equiv), three UV
lamps (350−380 nm), THF (2.0 mL), air, room temperature. Isolated
yields.
may be due to 2 equiv of amines inhibiting the phenol in this
system. Therefore, it is inferred that the corresponding
mechanism may involve a radical path. The model reaction
was carried out for 6 h, and the byproduct benzoin was detected
by GC-MS (Scheme 4c). Next, we directly used benzoin (1a′) as
the starting material instead of 1a to react with 4-chlorobenzyl-
amine under standard conditions (4l, 88% yield). At the same
time, the reaction did not proceed without light (Scheme 4d).
This result indicated that benzoin may be the key intermediate
in this reaction. We added asymmetric diketones [1-(4-
bromophenyl)-2-phenylethane-1,2-dione (1f)] to this reaction
mixture and obtained two products (3a, 54%, and 5a, 36%).
Moreover, benzaldehyde did not react with pyrrolidine under
standard conditions (Scheme 4f).
To prove that the reaction was related to UV light, we
performed light turn-on and turn-off experiments by controlling
the lamps and reaction time (Figure S2). According to the graph,
the yield of 3a can increase under UV-light irradiation for 1 h
with no distinct difference observed for dark irradiation for 1 h.
Therefore, UV light is essential for this synthesis.
According to the previous control experiments, we propose a
possible mechanism in Scheme 5. 4-Chorobenzylamine (2l)
attacks diketone (1a) in the first step to form intermediate A.
Next, A passes through the Norrish type II route to generate
intermediate B under UV irradiation.22 However, 4b has no α-
C−H on tert-butylamine. It is possible that hydrogen atom
abstraction of THF with oxy occurs during the reaction. Then,
intermediate B soon becomes an enol form compound (C) and
electron-donating -CH3 (5b) in the para position of α-diketones
led to high yields (80% and 93%, respectively). The -OCH3
group in the meta position of α-diketones generated a 52% yield
for amide 5c. The di-2-pyridylglyoxal-containing heteroatom
(5d) afforded the product in 43% yield. Unfortunately, the N,N-
dimethyl group in the para position of α-diketones [5e (Scheme
S2)] did not react in this system. Moreover, we could not find
the desired product when using 1-(4-methoxyphenyl)propane-
1,2-dione and 2,3-butanedione [5f and 5g, respectively (Scheme
S2)]. 1,2-Di(furan-2-yl)ethane-1,2-dione [5h (Scheme S2)]
was unsuccessful and found to be a mixture due to its high
activity for this reaction. The wavelength of light, the activity of
substrates, and the presence of α-H nitrogen atoms may affect
unsuccessful reactions. In addition, aniline could not be applied
to this reaction. Inspired by the N-Boc-ethylenediamine (4ae)
reacting with benzil, we assumed that amino acid derivatives
may also be involved in the system. As expected, reactions with
L-proline tert-butyl ester (6a), methyl-1-aminocyclopropanecar-
boxylate (6b), tert-butyl glycinate (6c), and L-asparagine tert-
butyl ester (6d) proceeded well under the reaction conditions,
giving the proposed amides in moderate to good yields (59−
96%). To demonstrate the practical value of this system, we
carried out a scale-up reaction for benzil and pyrrolidine. Benzil
could be successfully transformed in 76% yield after irradiation
for 5 days (Scheme S1).
To reveal the reaction mechanism, we performed a series of
control experiments. First, 2.0 equiv of butylated hydroxyto-
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pubs.acs.org/OrgLett
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China; orcid.org/0000-0002-8423-9988;
Email: renhuaqiu1@hnu.edu.cn
Scheme 5. Possible Mechanism
Authors
Zhihui Xu − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China
Tianbao Yang − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China
Niu Tang − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China
Yifeng Ou − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China
Shuang-Feng Yin − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China
Nobuaki Kambe − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
China; The Institute of Scientific and Industrial Research,
Osaka University, Ibaraki, Osaka 567-0047, Japan
phenylmethanimine (D). Intermediate C can transfer to
benzoin (F, isolated), and intermediate D can react with H2O
in the system to form E (detected by GC-MS). Then, amine will
attack the carbonyl group of intermediates F and B: water will
interact with hydrogen bonds via proton-coupled electron
transfer (PCET) to form H and radical cations (I) under UV
irradiation.23 Next, these cations become two free radicals (J and
K). The nitrogen radical (K) combines with the carbon radical
(J) to afford intermediate L. Then, L removes anion M to form
the desired amide. The quantum yield is 24.69, which may
involve a radical chain reaction (for detailed data, see the
Supporting Information).24
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01599
Author Contributions
§Z.X. and T.Y. contributed equally to this work.
Notes
In summary, we describe a mild method for the amination of
α-diketones irradiated by UV light without the need for external
additives and photocatalysts. This reaction showed good
functional group tolerance toward various primary and
secondary amides with high yields. The yield reached 97%. In
addition, this protocol was applied to the synthesis of several
amino acid derivatives. Mechanistic studies showed that benzoin
was generated in situ from benzil under UV irradiation. In
addition, this method provides an alternative way to synthesize
amides by using a photoinduced procedure.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21676076, 21725602, 21878071, and 21971060), the
Natural Science Foundation of Changsha (kq2004008), Hu-
Xiang High Talent of Hunan Province (2018RS3042), and the
Recruitment Program for Foreign Experts of China
(WQ20164300353) for financial support.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01599.
■
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AUTHOR INFORMATION
Corresponding Author
■
Renhua Qiu − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R.
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