The Ag-promoted α-C-H arylation of alcohols

Article abstract of DOI:10.1039/c9ra09954a

We herein report the functionalization of α-C-H in alcohols through cross-dehydrogenative coupling reactions. Selectfluor was used as a mild oxidant. In situ-generated HF participated in the reaction and no external strong acid was necessary. A variety of heteroaryl-substituted alcohols were achieved with good yields and with good functional group tolerance.

Full text of DOI:10.1039/c9ra09954a

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The Ag-promoted a-C–H arylation of alcohols†
ac
*
Shoufeng Wang,
ab Shuya Xing,a Yingying Zhang,a Yafei Fan,ab Huaiqing Zhao,
Cite this: RSC Adv., 2019, 9, 41847
ab
Jianfeng Wang,d Shuxiang Zhangab and Wengui Wang
*
We herein report the functionalization of a-C–H in alcohols through cross-dehydrogenative coupling
reactions. Selectfluor was used as a mild oxidant. In situ-generated HF participated in the reaction and
no external strong acid was necessary. A variety of heteroaryl-substituted alcohols were achieved with
good yields and with good functional group tolerance.
Received 22nd November 2019
Accepted 2nd December 2019
DOI: 10.1039/c9ra09954a
rsc.li/rsc-advances
Alcohols are one of the most important types of compounds, structures are present in many bioactive molecules (Fig. 1).
because they exist universally in bioactive molecules and are Great efforts have been expended to the synthesis of arylated
also found in nature in the form of sugars, steroids, etc. alcohols. In 2014, Liu reported the reaction of alcohol mole-
Furthermore, alcohols can be used as versatile building blocks, cules and isocyanide, and various alkyl-substituted phenan-
and be transformed into other functional groups. The synthesis thridines were achieved.9
of alcohols is a classic topic in organic chemistry. Late-stage
Cross-dehydrogenative coupling reactions have been the
functionalization has attracted the interest of chemists focus of many researchers and have been shown to be powerful
because in this way complex molecules could be modied. In and convenient tools in organic synthesis.10 The activation of
particular, functionalization of C–H is a very efficient way to the C–H groups in two molecules allows application of starting
build various structures, as pre-functionalization here is not materials without further functionalization. This simple
needed. Thus, transformation of C–H in alcohols is a direct process with high atomic economy provides an ideal trans-
method to prepare diverse alcohols from simple molecules.
formation for the preparation of various target compounds. The
During the past several decades, activations of the a sp3 C–H Minisci reaction has been widely explored since the 1960s.
groups of alcohols have been achieved through radical-involved Palmer and McIntyre rst reported the hydroxymethylation of
processes. In the early research, functionalizations of a C–H quinolone in the presence of hydroxylamine-O-sulphonic acid
groups in alcohols were always initiated by light or di-tert-butyl (HSA).11 Minisci further developed an Fe-catalyzed process that
peroxide, and the generated radicals could add to alkenes, resulted in good yields.12 PdCl2 (ref. 13) and TiCl3 (ref. 14) were
affording alkylated alcohols.1 This reaction was developed by also shown to be efficient catalysts for the Minisci reaction.
Duan to construct hydroxyl-containing oxindoles through Metal-free reactions initiated by TBHP15 and M2S2O8 (M ¼ Na,
a tandem addition/cyclization reaction.2 Also, amino alcohols K, NH4)16 have also been developed. Very recently, as visible
were prepared through addition of radicals generated from light-promoted processes nd applications in organic
alcohols to unactivated alkenes.3 Reactions catalyzed by metals synthesis, visible light-induced Minisci reactions have been
such as Rh,4 Fe,5 Cu and Co6 have also been applied. In 2009, reported.17 However, a strong oxidant, external acid, and
addition of such radicals to alkynes was reported. Homoallylic complex system are always needed for these reactions. In our
alcohols were prepared using simple alcohol molecules.7 The research, we found that Selectuor could be used as a mild
reactions of alcohols and cinnamic acids were also reported and oxidant for the functionalizations of C–H groups in ethers, and
allylic alcohols were obtained.8 However, arylations of the a C–H the HF generated in situ could be made to participate in the
in alcohols have attracted much interest because such reaction process.18 Herein, we report an Ag/Selectuor-catalyzed
Minisci reaction, in which Selectuor was used as a mild
oxidant and no external acid was necessary (Scheme 1).
aSchool of Chemistry and Chemical Engineering, University of Jinan, 336 West Road of
Nan Xinzhuang, Jinan, 250022, China. E-mail: chm_wangwf@ujn.edu.cn;
chm_wangwg@ujn.edu.cn
bShandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials,
336 West Road of Nan Xinzhuang, Jinan, 250022, China
cKey Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong,
336 West Road of Nan Xinzhuang, Jinan, 250022, China
dDepartment of Respiratory Diseases, The Affiliated Hospital of Hangzhou Normal
University, Hangzhou, Zhejiang, 310015, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra09954a
Fig. 1 Bioactive molecules containing alcoholic hydroxyl groups.
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ꢀ
and 10). Increasing and decreasing the temperature from 80 C
also both led to a worse result (Table 1, entries 11 and 12).
With the optimal conditions in hand, we explored a series of
quinaldines substituted with various groups or atoms.
Hydroxymethylation of substituted substrates went smoothly
with high yields. 6-Substituted quinaldines were shown to be
proper starting materials. Good yields were observed for
a variety of introduced substituents, such as F (3b), Br (3c), I
(3d), Me (3e) and CF3 (3f). Electron-withdrawing atoms and
groups were favourable for high yields. However, molecule with
electron-donating group gave a low yield (3e). This result may be
caused by the lower stability of the in situ-generated interme-
diate containing an electron-withdrawing group. 8-Substituted
quinaldines could also undergo this process. However, the
yields were lower than those of 6-substituted substrates. We
supposed that this was the result of steric effects. The substit-
uents present on the 8-position may have protected the
heterocycles from protonation, an effect harmful for the
hydroxymethylation. Here again, electron-withdrawing substit-
uents were more efficient than electron-donating groups. 7-
Chloroquinaldine reacted under the standard conditions,
giving the product (3l) in 94% yield. Multiuorinated hetero-
cycles were used, and good results were obtained (3m, 3n).
Lepidine was also hydroxymethylated on the 2-position in 85%
yield (3o) (Scheme 2).
Scheme 1 Arylations of a sp3 C–H groups in alcohols.
We chose quinaldine as the model substrate and carried out
the reactions (Table 1). When 0.25 eq. Selectuor was used, only
a trace amount of product was observed (Table 1, entry 1).
Increasing the number of equivalents of Selectuor led to better
results (Table 1, entries 1–4), and a high yield was realized when 4
eq. Selectuor were added (Table 1, entry 4). The yield was
improved to 88% when 1 eq. AgNO3 was used (Table 1, entry 5).
Further increasing of the amount of AgNO3 used showed no
obvious improvement of the yields (Table 1, entry 6). Then we
examined the ratio of the solvent components (Table 1, entries 6–
8). An excellent yield was achieved when the volume ratio of
MeOH to H2O was 9 : 1. The presence of a little water may have
promoted the dissolution of Selectuor and AgNO3. However,
when more water was included, lower yields were observed, which
may have been the result of its inuence on the reactivity of the
intermediate. Increasing and decreasing the reaction time from
4 h both showed a slight decrease of the yield (Table 1, entries 9
Table 1 Screening of the reaction conditionsa
Selectuor
Entry AgNO3 (eq.) (eq.)
Time (h) MeOH : H2Ob Yieldc (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
1
2
1
1
1
0.25
0.5
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2
6
4
4
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
1 : 1
9 : 1
9 : 1
9 : 1
9 : 1
9 : 1
Trace
7
24
76
88
89
88
96
93
93
90
85
9
10
11d
12e
1
1
1
4
4
4
a
Conditions: 0.2 mmol of 1a, AgNO3, Selectuor, and 2 mL of solvent
Scheme 2 Quinaldine substrate scope. Standard conditions: 1 (1
mmol), AgNO3 (1 eq.), Selectfluor (4 eq.), and 10 mL of solvent (MeOH/
H2O ¼ 9 : 1) were added into a tube that was then sealed. The system
was heated at 80 ꢀC for 4 h.
were added in a tube that was then sealed. The system was heated at
b
the indicated temperature. Volume ratio. c Isolated yields. d Reaction
e
temperature was 60 ꢀC. Reaction temperature was 100 ꢀC.
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Scheme 4 Proposed mechanism.
a kinetic isotopic effect was observed using [2H4]methanol (KIE
¼ 2.8), indicating that the hydrogen atom abstraction from
methanol was the rate-limiting step. Based on these data,
a mechanism was derived (Scheme 4). First, the Ag(I) species
was oxidized to Ag(II) by Selectuor, generating a uorine
radical and 5. Then the a-H in the alcohol molecule was
abstracted by the uorine radical, and an alkyl radical (Int I) was
generated. Meanwhile, HF was released and combined with the
heterocycles, giving an intermediate cation (Int II). This cation
was attacked by Int I, resulting in the radical cation Int III. Then
a proton was released and the radical Int IV was oxidized by
Ag(II) to give a cation (Int V). Finally, a proton was abstracted by
external base, leading to the desired product. If the base was
added at the beginning of the reaction, the released HF could be
trapped, and the intermediate Int II was not generated, result-
ing in a disturbance of the process. Our results together with the
derived mechanism indicated that the in situ-generated HF
played a signicant role in this reaction.
In summary, we developed an efficient method for the
arylation of a sp3 C–H groups in alcohols using heterocycles
through CDC catalyzed by Ag. Selectuor was used as a mild
oxidant and no external acid was needed. Instead, in situ-
generated HF played an important role. Various substituents
were tolerated, such as halogens, alkyl groups, CF3, etc. Multi-
substituted quinaldines also underwent this reaction
smoothly. Common alcohols, such as methanol, ethanol and
1-propanol were explored as materials and all the alcohols
could be used without further purication. Mechanism
studies showed that a radical process occurred and the
hydrogen abstraction step was determined to be the rate-
limiting step.
Scheme 3 Alcohol substrate scope. Standard conditions: 1 (1 mmol),
AgNO3 (1 eq.), Selectfluor (4 eq.), and 10 mL of solvent (RCH2OH/H2O
¼ 9 : 1) were added into a tube that was then sealed. The system was
heated at 80 ꢀC for 4 h.
Next, we examined the scope of alcohols. To our delight,
ethanol reacted with substituted quinaldines smoothly. Ary-
lation of the a sp3 C–H in ethanol occurred with good yields.
Various substituents, such as F (4a, 4e), Cl (4b, 4f), Br (4c) and
I (4d), were tolerated and the position of the substituent
showed little inuence on the yield. 1-Propanol was also tested
as a starting material and arylations using this starting
material proceeded with good yields, albeit slightly lower than
those for ethanol (4g, 4h, 4i). This result may be caused by
a steric effect, leading to lower reactivity of the generated
radicals (Scheme 3).
To explore the reaction mechanism, some control experi-
ments were carried out. When base was added together with
starting materials, no product was obtained. When TEMPO was
added, also no product was observed according to liquid
chromatography-mass spectrometry (LC-MS) results. However,
several new species were present besides the original hetero-
cycle and alcohol. A peak at a position corresponding to
a molecular weight of 161.0548 was assigned to salt 5, which
was generated by the reaction of Selectuor and AgNO3. The
peak characterized by a molecular weight of 158.1548 was
attributed to compound 7. We did not, however, observe a peak
corresponding to compound 6, which had been expected to
result from the combination of TEMPO and hydroxymethyl
radical. We supposed that 6 was a hemiacetal, which due to its
instability was hydrolysed rapidly to give 7. Furthermore,
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
Financial support from the Natural Science Foundation
(31972850), the Shandong Provincial Natural Science Founda-
tion
(ZR2016HM44,
ZR2016BQ31,
ZR2016JL009
and
ZR2017ZC0529), the Shandong Key Research Program
(2017GSF218061) and the University of Jinan are gratefully
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