Cross-Dehygrogenative C?O Coupling of Oximes with Acetonitrile, Ketones and Esters

Article abstract of DOI:10.1002/adsc.201900370

A transition metal-free approach for the generation of radical intermediates via EDA complexes had been developed. This approach enables a cross-dehydrogenative C?O coupling of oximes with acetonitrile, ketones and esters with high yields and regioselectivities. Perfluorobutyl iodide was used as the unique electron acceptor to trigger a new radical formation. The radical pathway was confirmed by UV-Vis spectroscopy, radical inhibiting, trapping and kinetics experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.201900370

Title: Cross-Dehygrogenative C-O Coupling of Oximes with
Acetonitrile, Ketones and Esters
Authors: zhenyu chen, Hua-ju Liang, Ri-xing Chen, Lei Chen, Xiang-
zheng Tang, Ming Yan, and Xue-jing Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900370
Link to VoR: http://dx.doi.org/10.1002/adsc.201900370

10.1002/adsc.201900370
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cross-Dehygrogenative C-O Coupling of Oximes with Acetonitrile,
Ketones and Esters
Zhen-Yu Chen, a Hua-Ju Liang, a Ri-xing Chen,b Lei Chen,a Xiang-Zheng Tang, a Ming Yan*, a Xue-
Jing Zhang* a
a
The Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, China. E-mail: zhangxj33@mail.sysu.edu.cn; yanming@mail.sysu.edu.cn
b
School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: A transition metal-free approach for the generation of series of visible-light promoted radical coupling reactions via
radical intermediates via EDA complexes had been developed.
This approach enables a cross-dehydrogenative C-O coupling of
oximes with acetonitrile, ketones and esters with high yields and
regioselectivities. Perfluorobutyl iodide was used as the unique
electron acceptor to trigger a new radical formation. The radical
pathway was confirmed by UV-Vis spectroscopy, radical
inhibiting, trapping and kinetics experiments.
the formation of EDA complexes. In these cases, the two
radicals generated from EDA complexes are usually coupled
to provide the products. If new radical species are generated
from the original radical intermediates, the new
transformations can be developed.[12] Herein, we report a
transition metal-free approach for the generation of radical
intermediates via EDA complexes. The approach enables a
cross-dehydrogenative C-O coupling of oximes with
acetonitrile, ketones and esters with high yields and
regioselectivities.
Keywords: C-O coupling; cross-dehydrogenative coupling;
oxime ether; electron donor-acceptor complex; C(sp3 )−H
functionalization
Initially, the C-O cross-dehydrogenative coupling reaction of
13
oxime 1a and C4F9I[ was studied. No coupling product was
observed in DMSO with the irradiation of white LED. When
acetonitrile was used as the solvent, the reaction gave the product
2a in a good yield. Further experiment revealed that 2a could be
obtained in a similar yield without the irradiation of white LED
(Scheme 2).
]
Direct transformations of C−H bonds to C−X (X = C, O, N,
S) bonds with high atom/step-economy are powerful and
robust strategies for the synthesis of valuable compounds
such as pharmaceuticals, natural products and materials.[1]
However, the activation of less reactive C(sp3)−H bonds
remains challenging because of high bond-dissociation
energy (BDE).[2] Usually, transition metal catalyzed
activation of C(sp3) − H bonds assisted by the directing
groups of the substrates is one of the most straightforward
method.[3] Cross-dehydrogenative-coupling (CDC) reactions
which avoid the prefunctionalization and defunctionalization
of substrates are also attractive for the direct C−H bond
functionalization.[4] However, most of the reactions require
the use of transition metal catalysts. As a complementary
method, transition-metal free CDC reactions via homolytic
cleavage of C(sp3)−H bonds had been well developed in
recent decades.[5] Even so, the use of strong oxidants, strong
bases, highly toxic organotins and explosive peroxides still
hampers their applications.
Scheme 1. EDA complexes enable radical coupling reactions.
Melchiorre group found that electron-rich enamines can
act as strong reductants upon light excitation. The subsequent
single electron transfer (SET) to electron-deficient organic
halides generates the radical intermediates.[6] It was proposed
that electron donor-acceptor (EDA) complexes are formed
between enamines and organic halides (Scheme 1a). Lately,
Miyake,[7] Yu,[8] Chen,[9] Aggarwal[10] etc.[11] developed a
Scheme 2. Initial results.
1
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10.1002/adsc.201900370
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.[a]
Entry
Base
n (equiv.)
1.5
Yield (%)[a]
1
2
Cs2CO3
CsF
82
50
1.5
3
K3PO4
K2CO3
Na2CO3
CsOAc
NaOH
NaOt-Bu
Et3N
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
2.0
-
40
4
15
5
n.d.
n.d.
trace
trace
n.d.
n.d.
n.d.
75
6
7
8
9
10
11
12
13
14
15[c]
16[d]
DMAP
DBU
Cs2CO3
Cs2CO3
-
82
n.d.
n.d.
80
Cs2CO3
Cs2CO3
1.5
1.5
Scheme 3. Reactions of acetonitrile with oximes.[a]
[a]
Reaction conditions: oximes (0.2 mmol), C4F9I (0.3 mmol),
[a]
Reaction conditions: 1a (0.2 mmol), C4F9I (0.3 mmol), base
Cs2CO3 (0.3 mmol) and CH3CN (1.0 mL) at RT under air.
(0.3 mmol) and CH3CN (1.0 mL) at RT under air.
[b] Isolated yield.
[c] The reaction was conducted in the absence of C4F9I.
[d] The reaction was conducted under argon.
under our C-O coupling conditions. However, when NH2 was
replaced by OH (1m), the reaction was inhibited completely and
most of 1m was recovered. The acidic OH group may be
incompatible with the reaction. The reaction is not limited to aryl
methyl ketone oximes. Other aryl alkyl ketone oximes 1n-1p
afforded the products 2n-2p in good to excellent yields too. The
dialkyl ketone oximes (1q-1s) were also successfully applied. The
products 2q-2s were obtained in moderate to good yields. The
benzaldehyde oxime (1t) was applicable, however, with lower
yield. To further demonstrate the utility of this reaction, a gram-
scale reaction of 1a was examined. The product 2a was obtained
in a good yield (1.14 g, 82%).
The reactions of oxime 1a with esters and ketones were also
explored and the results are summarized in Scheme 4. The
reactions of ethyl acetate and methyl acetate with oxime 1a gave
4a and 4b in good yields. Other alkyl acetates (4c, 4d) were also
applicable, however, the higher reaction temperature (50 C) was
required. The reaction of 2-methoxyethyl acetate gave 4e in a 74%
yield at room temperature. In these reactions, the methyl group
adjacent to carbonyl group was the sole reaction site. When this
site was substituted by an alkyl group or ether group, the reaction
still gave the expected products 4f and 4g, however with lower
yields at higher reaction temperature. The lactone 3h was also
applicable and the C-O coupled product 4h was obtained with a
38% yield. Furthermore, ketones 3i-3h were examined. Acetone
(3i), 2,4-dimethylpentan-3-one (3j), and 2,6-dimethylcyclohexan-
1-one (3k) gave the C-O coupled products in good yields. When
asymmetric methyl alkyl ketones (3l-3n) were used, the C-O
bonds were preferentially formed on the sec- (4l,
The effect of different base was investigated and the results are
summarized in Table 1. CsF, K3PO4 and K2CO3 were also
applicable, but lower yields were obtained in comparison with
that using Cs2CO3 as the base (Table 1, entries 1-4). Other bases
such as Na2CO3, CsOAc, KOH, NaOt-Bu and organic bases (Et3N,
DMAP and DBU) were inefficient (Table 1, entries 5-11). The
loading of Cs2CO3 was also examined. The yield of 2a was
slightly decreased while using 1.2 equivalents of Cs2CO3 (Table 1,
entry 12). Increasing the loading of Cs2CO3 to 2.0 equivalents did
not improve the yield (Table 1, entry 13). The reaction was also
carried out in the absence of Cs2CO3 or C4F9I, however, no
product 2a was obtained (Table 1, entries 14-15).[14] The reaction
under the protection of argon gave the similar result. The
experiment indicated that the oxygen is not the oxidant for this
reaction (Table 1, entry 16).
A variety of oximes 1a-1t were examined in the reaction with
acetonitrile and the results are summarized in Scheme 3. The
reaction of benzophenone oxime gave nitrile compound 2b in
good yield. The substitutions on the benzene ring with electron-
donating groups (1c, 1d), electron-withdrawing groups (1e, 1f)
and halides (1g, 1h) were tolerated very well. The corresponding
products were obtained in good yields (77-83%). Pyridinyl,
thienyl and naphthyl ketone oximes (1i-1k) were also applicable
and moderate to good yields were obtained. Oxime (1l) with a
reactive group of NH2 on the aromatic ring was also tolerated
2
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10.1002/adsc.201900370
Advanced Synthesis & Catalysis
Scheme 5. Control experiments.
Scheme 4. Reactions of oxime 1a with esters and ketones. [a]
substrate 1a was recovered. The reaction was not interfered by
TEMPO. However, after a careful analysis of the HRMS data of
the reaction mixture, we observed the coupling product between
TEMPO and C4F9 radical (see SI 3.3 for the details). To further
understand the reaction mechanism, the trapping of the radical
intermediate with 1,1-diphenylethylene was attempted (Scheme
5b). To our delight, compounds 5, 6, 7 were detected by HRMS.
The radical trapping products were also obtained in the presence
of BHT (see SI for details). All the data demonstrated the
formation of the oxime radical, C4F9 radical and acetonitrile
radical in the reaction. The kinetic isotope effect (KH/KD) was
determined to be 5.67 (Scheme 5c) which showed that acetonitrile
radical was proposed to be generated via a hydrogen abstraction
by C4F9 radical. Previous studies showed that the generation of
acetonitrile radical is difficult without metal catalyst and peroxide
at room temperature, probably due to high bond dissociation
energy of the C−H bond (96.0 kcal/mol).1e
A plausible mechanism is depicted in Scheme 6. The initiation
of radicals was started from the deprotonation of oxime 1a which
gives oxime anion A (pKa = 20.1 in DMSO, 1H NMR data in SI).
Then an EDA complex is formed between oxime A and C4F9I.
After an intermolecular electron transfer from oxime A to C4F9I,
oxime radical B and perfluobutyl radical C are formed.
Perfluobutyl radical C then abstracts a hydrogen from CH3CN to
[a] Reaction conditions: 1a (0.2 mmol), C4F9I (0.3 mmol), Cs2CO3
(0.3 mmol) and solvent (1.0 mL) at RT under air. [b] The reaction
was heated at 50 C. [c] DMSO (1.0 mL) was used as co-solvent,
and the corresponding ester or ketone (10 equiv.) was added.
4m) and tert- (4n) carbons adjacent to carbonyl groups. The
reaction pattern accords with a radical pathway. A gram-scale
reaction of 1a with acetone was also examined, and 4i was
obtained in 68% yield. To enhance the practicability of the
reaction, we can also employ DMSO as co-solvent to decrease the
using amount of expensive ester or ketone (see the yields in the
parentheses).
To gain the insight into the reaction mechanism, we
firstlyperformed UV-vis spectroscopic measurements on various
combinations of 1a, C4F9I and Cs2CO3 in CH3CN (Figure 1). We
observed a red shift of absorption when oxime 1a, C4F9I and
Cs2CO3 were combined in acetonitrile. The color change of this
mixture was also observed. The red shift and color change are
proposed to result from the formation of an electron donor-
acceptor (EDA) complex between the oxime anion and C4F9I.
The control experiments with free radical scavengers such as
TEMPO, DPPH (1,1-diphenyl-2-picrylhydrazyl) and BHT
(butylated hydroxytoluene) were carried out (Scheme 5a). The
reactions with DPPH and BHT were totally inhibited and 90% of
3.00
2.00
1.00
-0.10
350.00
400.00
500.00
600.00
700.00
nm.
Figure 1. (a) UV-vis absorption spectra and (b) the color change
of different combinations of 1a, C4F9I and Cs2CO3 in CH3CN.
Scheme 6. Proposed reaction mechanism.
3
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10.1002/adsc.201900370
Advanced Synthesis & Catalysis
give acetonitrile radical D, which could be trapped by oximeanion
A to form the anion radical E.[15] Subsequently, anion radical E is
oxidized by C4F9I to give the product 2a and regenerate the
perfluobutyl radical C.
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A. Singh, A. Lei, Chem. Rev. 2017, 117, 9016-9085; c) A.
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C.-J. Li, Acc. Chem. Res. 2009, 42, 335-344.
In summary, we have developed new cross-dehydrogenative C-
O coupling of oximes with acetonitrile, ketones and esters. The
reaction occurred under mild conditions without transition metal
catalyst. Perfluorobutyl iodide was used as the unique oxidant.
The formation of the EDA complex between oxime anion and
perfluorobutyl iodide was proposed to enable the single electron
transfer process. The resulting perfluorobutyl radical abstracts the
hydrogen from acetonitrile, esters and ketones. The subsequent
radical coupling with oxime radical provides the final products.
The further applications of this strategy to other radical reactions
are currently under investigation.
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Experimental Section
To the mixture of 1-phenylethan-1-one oxime 1a (27.1 mg, 0.2
mmol) and Cs2CO3 (97.8 mg, 0.3 mmol) in anhydrous acetonitrile
(1.0 mL), nonafluoro-1-iodobutane (52 μL, 0.3 mmol) was added.
The resulting reaction mixture was stirred at room temperature for
6 hours. The reaction mixture was concentrated in vacuo, and the
residue was purified by flash column chromatography on silica
gel (petroleum/EtOAc) to give the compound 2a as a yellow
liquid (28.6 mg, 82%); 1H NMR (400 MHz, CDCl3): δ 7.69–7.64
(m, 2H), 7.42–7.36 (m, 2H), 4.82 (s, 2H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 158.33, 135.24, 129.96, 128.54, 126.38,
116.37, 58.94, 13.03; HRMS (ESI) calculated for C10H11N2O
(M+H)+: 175.0871, found: 175.0867.
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Acknowledgements
We acknowledge the National Natural Science Foundation of
China (no. 21472248, 21772240) and the Guangzhou Science
Technology and Innovation Commission (201707010210) for the
financial support.
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4
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10.1002/adsc.201900370
Advanced Synthesis & Catalysis
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[15] The radical cross-coupling of the two radicals
B and D
may also happened but with little chance because the two
open-shell radicals need to persistent for a period of time
in the solvent before they meet each other.
5
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10.1002/adsc.201900370
Advanced Synthesis & Catalysis
COMMUNICATION
Cross-Dehygrogenative C-O Coupling of Oximes
with Acetonitrile, Ketones and Esters
Adv. Synth. Catal. Year, Volume, Page – Page
Zhen-Yu Chen, Hua-Ju Liang, Ri-xing Chen, Lei
Chen, Xiang-Zheng Tang, Ming Yan,* Xue-Jing
Zhang*
6
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