Copper(i)-catalyzed radical carboamination reaction of 8-aminoquinoline-oriented buteneamides with chloroform: synthesis of-β-lactams

Article abstract of DOI:10.1039/d1ra05233k

A novel Cu(CH₃CN)₄PF₆-catalyzed carboamination reaction of 8-aminoquinoline-oriented buteneamides with chloroform to afford 4-(2,2,2-trichloroethyl)-β-lactams is described. The reaction proceeded at 110 °C in air with di-t

Full text of DOI:10.1039/d1ra05233k

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Copper(I)-catalyzed radical carboamination
reaction of 8-aminoquinoline-oriented
Cite this: RSC Adv., 2021, 11, 28081
buteneamides with chloroform: synthesis of-b-
lactams†
a
a
Zixu Gan,a Ke Zhang,a Peng Shi,b Yingsheng Zhao
and Runsheng Zeng
*
*
Received 7th July 2021
Accepted 11th August 2021
A novel Cu(CH3CN)4PF6-catalyzed carboamination reaction of 8-aminoquinoline-oriented buteneamides
with chloroform to afford 4-(2,2,2-trichloroethyl)-b-lactams is described. The reaction proceeded at
110 ꢀC in air with di-t-butyl peroxide. Preliminary studies indicated that the reaction undergoes a free
radical mechanism via a Cu(I)/Cu(II)/Cu(III) catalytic cycle.
DOI: 10.1039/d1ra05233k
rsc.li/rsc-advances
intramolecular amination of aliphatic or amino acid derivatives
with different guiding groups (Scheme 1a). The C–H function-
Introduction
alization strategy is more efficient and convenient than classic
intramolecular condensation and nucleophilic reactions.
However, the difficulty of these methods was that it rst need to
obtain functionalized acids as the reaction substrates through
monoarylation.
Nitrogen-containing heterocycles are notable compounds
known for their bioactivity in nature.1 In particular, function-
alized b-lactams are the core skeleton of many natural products
and antibiotics drug molecules with specic effects, such as
penicillins,2 carbapenems,3 cephalosporins4 and monocyclic b-
lactams5 (Fig. 1).
These b-lactams are known for their clinical use as antibi-
otics, which have high medicinal synthetic value due to their
low toxicity, good bactericidal activity and wide indications.6
Therefore, during the past 2 decades, great efforts have been
focused on the core skeleton construction of b-lactams in
synthetic chemistry, such as the Staudinger ketene-imine [2 + 2]
cycloaddition,7 Beckmann rearrangement,8 Kinugasa alkyne–
nitrone cycloaddition,9 and Schmidt reactions,10 Until now, the
C(sp3)–H bond activation,11 C–C,12 C–N,13 C–P,14 and C–S15 bond
strategy have provided a straightforward pathway to synthesize
b-lactams.
The research groups of Shi rstly used transition metal
palladium-catalyzed intramolecular amination of aliphatic or
amino acid derivatives with different guiding groups to generate
a-amino-b-lactam.16 Aerwards, Wu group has also demon-
strated that the propionamide-linked bidentate aminoquino-
line (AQ or Q) directing group can facilitate the C(sp3)–H
activation under Pd catalysis.17 The research groups of Ge,18
Kanai19 and Chantani20 used transition metal like nickel, cobalt
and copper catalyst to generate a-amino-b-lactam by
Later, on the basis of the reaction of nucleophiles and 8-
aminoquinoline-oriented buteneamide compounds in the
Engle's research group,21 our group rst used buteneamide
compounds as substrates to oxidize toluene with DTBP to
generate benzyl radicals, then benzyl radicals attacked inactive
double bonds, and coordinated with copper to generate b-lac-
tams successfully.22 The reaction mode is efficient and can
enrich the preparation method of b-lactam. Subsequently,
Chen23 group used cis-3-hexenamide compounds with 8-amino-
5-iodoquinoline as the substrates, 4-benzyl Hantzsch esters as
the alkyl radical precursor, and rarely used biaryl diphosphine
oxide as a chiral ligand to synthesize a series of chiral b-lactam
compounds (Scheme 1b). In order to verify the applicability of
this method, we tried other free radicals. Doyle24 and Sheng25
used chloroform as a solvent and a source of free radicals to
achieve the functionalization of unsaturated double bond. It
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry
Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu
215123, China. E-mail: yszhao@suda.edu.cn; zengrunsheng@suda.edu.cn
bInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg1, 52074
Aachen, Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra05233k
Fig. 1 Natural products and antibiotics drug molecules.
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Table 1 Optimization of reaction conditionsa
Entry Catalyst (%)
Oxidant Temperature Base
Yieldb
1
2
3
4
5
6
7
CuBr
DTBP
DTBP
DTBP
DTBP
DTBP
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
110 ꢀ
120 ꢀ
100 ꢀ
C
C
C
C
C
C
C
C
C
C
50%
45%
76%
62%
61%
88%
0%
92%
41%
83%
tr
Cu(OAc)2
Cu(OTf)2
CuBr2
Cu(acac)2
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 TBHP
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 DTBP
Cu(CH3CN)4PF6 DTBP
c8
c9
c10
c11
c12
c13
90 ꢀ
C
110 ꢀ
110 ꢀ
C
C
Na2CO3 44%
K2HPO4 53%
a
Scheme 1 One step intramolecular amination reaction.
Reaction condition: 1a (0.2 mmol), DTBP (1 mmol), Cu(CH3CN)4PF6,
(0.02 mmol), chloroform (2 ml), at 110 ꢀC in air atmosphere, 6 h.
b
Yields are given for isolated products. c DTBP (1.2 mmol).
can be seen that chloroform is a good source of poly-
chloromethyl radicals,26 Therefore, we used chloroform as the
free radical source and found that the chloroform was decom-
posed into trichloromethyl radicals triggered by DTBP, and then
equiv. gave a higher yield of 2a at 92% yield (Table 1, entry 8).
However, as the reaction temperature rises to 120 C, the yield
reacted
with
8-aminoquinoline-oriented
buteneamide
ꢀ
compounds to achieve the 2,2,2-trichloroehtyl-b-lactams
(Scheme 1c).
of product 2a was reduced to 41% (Table 1, entry 9). The reac-
tion could hardly go on when temperature was below 90 ꢀC
(Table 1, entry 11). To further improve the efficiency of the free
radical reaction, we added several base to reaction system, but
this measure has no effect (Table 1, entry 12-13).
Results and discussion
When the model reaction of the directing group-protected
butenoic acid derivative (1a) with chloroform was performed
in the presence of oxidants such as tert-butyl hydroperoxide
(TBHP), no desired products were obtained (Table 1, entries 7).
Aer the addition of 10 mol% di-t-butyl peroxide (DTBP), the
reaction proceeded smoothly to afford the desired product,
2,2,2-trichloroehtyl-b-lactam (2a).
From the experiment results we can see that trichloromethyl
free radical in the presence of copper(I) and DTBP carry out the
cascade radical addition/intramolecular amination to perform
2,2,2-trichloroehtyl-b-lactam in a single step. When the croto-
namide compound 1a with 8-aminoquinoline guiding group
was reacted with copper acetate (10 mol%) and DTBP (5 equiv.)
in chloroform at 110 ꢀC for 6 h, the cyclized product 2a was
obtained in 45% yield, and some of the starting material was
recovered (Table 1, entry 2). Encouraged by this result, several
Cu catalysts such as most commonly used CuBr, CuBr2,
Cu(OTf)2, Cu(acac)2 and Cu(CH3CN)4PF6 were tested and the
results showed that both Cu(I) and Cu(II) salt could get product
2a. Interestingly, Cu(CH3CN)4PF6 gave the best yield of 2a at
88% (Table 1, entry 6).
With the optimized reaction conditions established, we
examined the substrate scope of N-(quinolin-8-yl)but-3-enamide
derivatives under optimized conditions: DTBP as an oxidant,
Cu(CH3CN)4PF6 as a catalyst at 110 ꢀC, for 6 hours in air. As can
be seen from the Table 2, the most a-substituted N-(quinolin-8-
yl)but-3-enamide derivatives were well tolerated. Mono-
substituted N-(quinolin-8-yl)but-3-enamide derivatives were all
compatible and had less effect on the C–H activation reaction.
Various functional groups, like methyl, ethyl, methylcyclopropyl
and benzyl etc., gave the corresponding products (2b–2m) in
moderate to good yields. Unfortunately, when there were two
methyl groups at a position, the b-lactam product yield was only
43% (2n). When the g-substituted N-(quinolin-8-yl)but-3-
enamide derivatives were used as the substrates, the products
were obtained in low yields (2o–2q), and a large amount of raw
materials were not reacted completely. It may abate the activity
of the reaction substrates due to steric hindrance.
To further demonstrate the synthetic utility of the reaction,
the gram–scale reaction was further performed. We found that
the corresponding b-lactam product 2a was acquired in 78%
yield under the optimized reaction conditions (Scheme 2).
In order to understand the carboamination reaction mecha-
nism better, we did the following control experiments (Scheme 3).
The control experiment also clearly showed that Cu(CH3-
CN)4PF6 and di-tert-butyl peroxide were indispensable for this
reaction. Additionally, increasing the amount of DTBP to 6
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Table 2 Scope studies of 2,2,2-trichloroehtyl-b-lactamsa
Scheme 3 Control experiments.
research group captured the tribromomethyl radical by using
2,6-di-tert-butyl-4-methylphenol (BHT) successfully,27 we try to
captured the trichloromethyl radical by using the same method.
It's exciting to obtain the BHT trapped trichloromethyl radical
compound 4 (Scheme 3A). And then, when copper salt and
DTBP were not added to the reaction system, the reaction did
not proceed, which showed that copper salt and DTBP are very
important in the reaction (Scheme 3B).
On the basis of the mechanistic studies and experimental
results, a plausible mechanism is proposed in Scheme 4.
Initially, the copper(I) catalyst reacted with di-tert-butyl
peroxide, leading to the copper(II) catalyst, tert-butoxy radical
and tert-butoxy anion. Thereaer, tert-butoxy radical reacted
with chloroform to generate trichloromethyl radicals and tert-
butoxy anion pulled out the hydrogen on the nitrogen of the
reaction substrate (1a), the copper(II) catalyst was coordinated
with nitrogen anion to form intermediate I. Finally, the
a
Reaction condition: 1a (0.2 mmol), DTBP (1.2 mmol), Cu(CH3CN)4PF6,
(0.02 mmol), chloroform (2 ml), at 110 ꢀC in air atmosphere, 6 h. Yield of
isolated products are given. ‘dr’ decided by NMR is >20 : 1 if not stated
otherwise.
Scheme 2 Gram-scale reaction.
First, we carried out the radical inhibition and capture experi-
ment. When 2 equiv. of 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) was added in the reaction system under standard
conditions, the target product was not produced. It showed that
the reaction may be a way of free radical reaction.
When using 1,1-stilbene to capture free radicals, we didn't
detect the presence of trichloromethyl radical capture product,
but obtained chlorine radical capture product 3. This may be
due to the decomposition of trichloromethyl radicals into
chlorine radicals and dichloromethyl carbene. Since Ghosh
Scheme 4 Proposed reaction mechanism.
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intermediate I captured the trichloromethyl radical to form the
intermediate II,28 which was reduced and eliminated to obtain
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Conclusions
In conclusion, a novel method for carbon–nitrogen bond
formation was developed through the carboamination reaction
of 8-aminoquinoline-oriented buteneamides with chloroform
catalyzed by 10% Cu(CH3CN)4PF6. The reaction proceeded at
110 ꢀC in air with di-t-butyl peroxide to afford 4-(2,2,2-tri-
chloroethyl)-b-lactams from medium to good yields. Further we
will nd new free radicals and expand the applicability of the
free radical reaction to form b-lactams.
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There are no conicts to declare.
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We gratefully acknowledge nancial support from the
Prospective Study Program of Jiangsu (BY2015039-08), the
National Natural Science Foundation of China (No. 21572149),
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