DMSO-Enabled Selective Radical O?H Activation of 1,3(4)-Diols

Article abstract of DOI:10.1002/anie.202007187

Control of selectivity is one of the central topics in organic chemistry. Although unprecedented alkoxyl-radical-induced transformations have drawn a lot of attention, compared to selective C?H activation, selective radical O?H activation remains less explored. Herein, we report a novel selective radical O?H activation strategy of diols by combining spatial effects with proton-coupled electron transfer (PCET). It was found that DMSO is an essential reagent that enables the regioselective transformation of diols. Mechanistic studies indicated the existence of the alkoxyl radical and the selective interaction between DMSO and hydroxyl groups. Moreover, the distal C?C cleavage was realized by this selective alkoxyl-radical-initiation protocol.

Full text of DOI:10.1002/anie.202007187

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Accepted Article
Title: DMSO Enabled Selective Radical O-H Activation of 1,3(4)-Diols
Authors: Ning Jiao, Yuchao Zhu, Ziyao Zhang, Rui Jin, Jianzhong Liu,
Guoquan Liu, and Bing Han
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DMSO Enabled Selective Radical O-H Activation of 1,3(4)-Diols
Yuchao Zhu, [a] Ziyao Zhang, [a] Rui Jin, [a] Jianzhong Liu, [a] Guoquan Liu, [a] Bing Han, [b] and Ning
Jiao*[a]
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Abstract: Selectivity control is one of the central topics in organic
chemistry. Although the alkoxyl radical induced unprecedented
transformations have drawn more attentions, compared to the
booming selective C-H activation, the selective radical O-H activation
remains less explored. Herein, we report a novel selective radical O-
H activation strategy of diols by combining spatial effect with proton
coupled electron transfer (PCET). We found the common molecule
DMSO is an essential reagent that enables the regioselective
transformation of diols. Mechanistic studies indicated the existence of
the alkoxyl radical and the selective interaction between DMSO and
hydroxyls. Moreover, the distal C-C cleavage is realized by this
selective alkoxyl radical initiation protocol.
The selective transformation of hydroxyl (OH) groups in di- and
polyols is a frequently encountered problem in organic synthesis,
in contexts ranging from simple alcohol transformations to the
preparation of highly functionalized natural products.[1] Despite
the importance of this issue, strategies for the selective O-H
activation are rare compared to the fast-growing studies on
selective C-H activation.[2] The classic methods for selective
activation of one hydroxyl in diols involve ionic transformations by
steric regulation or based on special hydrocarbon structure.[3]
Unlike traditional ionic alcohol transformations involving
nucleophilic substitution/addition,[4] oxidation[5] and elimination[6]
of hydroxyls, the alkoxyl radical induced transformations have
drawn more attention with the discovery of unprecedented
strategies for the generation of alkoxy radicals from alcohol
without the need for pre-activation.[7] The O-H radical processes
greatly enlarged the reaction types of alcohols either with alkoxyl
10]
radical induced β scission[8] or hydrogen abstraction.[9,
Scheme 1. Selective hydroxyl activation of diols.
However, to the best of our knowledge, the general methods for
the alkoxyl radical induced distal C-C cleavage remains
To address this problem, we paid our attention to the strategy
unexplored (Scheme 1a). Moreover, the realized O-H radical
of proton coupled electron transfer (PCET), which was reported
transformations are limited to the activation of mono-ols, so far,
that a Brønsted base and an oxidant can synergistically remove a
there is a lack of selective radical O-H activation due to the almost
proton and an electron from the substrate to afford a free radical
identical bond-dissociation energy between two hydroxyls in diols
(Scheme 1c).[12] Recently, Knowles and coworkers significantly
achieved the O-H bond homolysis through PCET.[13] Inspired by
these reports, we hypothesized that if we could find a proper
Brønsted or Lewis base that can selectively form a hydrogen bond
with one hydroxyl in diols, we would have a chance to selectively
activate one O-H bond and realize the selective alkoxyl radical
transformation of diols (Scheme 1d).
(~105 kcal mol-1)[11] (Scheme 1b).
[a]
Y. Zhu, Z. Zhang, R. Jin, J. Liu, G. Liu, Prof. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Rd. 38, Beijing 100191 (China)
Prof. N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
E-mail: jiaoning@pku.edu.cn
Taking this strategy in hand and based on our previous
works,[14] we herein report an unprecedented Ag-catalyzed
selective radical O-H activation of diols (Scheme 1e). We found
the common molecule DMSO is an essential reagent to enable
the high selective O-H activation under mild conditions by
selectively forming hydrogen bonds with one hydroxyl in diols.
Moreover, the alkoxyl radical induced distal C-C cleavage is
realized, which is a formidable challenge in organic chemistry.[15,
Homepage: http://sklnbd.bjmu.edu.cn/nj
Prof. B. Han
[b]
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000 (China)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under.
1
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10.1002/anie.202007187
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16]
This new strategy that combines the spatial effect with PCET
would strategically enlarge the transformation of alcohols and can
also promote the development of selective X-H radical activation
reactions.
Table 2. Substrate scope of distal (hetero)aryl migration reaction.[a]
Table 1. Optimization of reaction conditions.[a]
[a] Reaction conditions: see entry 9, Table 1. Isolated yields. [b] 0.5 mL CH3CN
was added. [c] Yield based on recovered alcohol. [d] 0.1 mL DMSO was used.
By increasing the loading of K2S2O8 to 4.0 equiv, new
migration-oxygenation products by a further alkyl substituents
oxidation process were detected (Scheme 3). Under these
conditions, various benzaldehyde derivatives were obtained in
moderate yields (2p-t). It was noteworthy that we obtained 2r and
2s with excellent regioselectivity. The ketone product 2u can also
be isolated in 51% yield. Besides, the diols 1v-x afforded the
same oxygenation product 2v in 47% to 65% yields via the
oxidative oxygen element incorporation reaction.
[a] Reaction conditions: 1a (0.2 mmol), catalyst (x mol%), oxidant (1.5 equiv),
additive (3.0 equiv), solvent (2 mL) under Ar at 50 oC for 24h. NMR yields with
1,1,2,2-Tetrachloroethane as standard. [b] 2.0 equiv DMSO was used. [c] The
number in the parenthesis is isolated yield.
For proof-of-concept, we chose 1,1-diphenylpropane-1,3-diol
(1a) as model substrate. Interestingly, when 1a was treated with
AgNO3 catalyst in the presence of K2S2O8 oxidant in different
solvents, a novel phenyl migration product 2a via alkoxyl radical
induced distal C-C cleavage was obtained with the formation of β
scission product 3a, indicating the unselective activation of two
hydroxyls (Table 1, entries 1-3). Of various silver salts, AgClO4
showed the best catalytic efficiency (Entry 4). To improve the
regio-selectivity by PCET, we turned to screening a series of lewis
bases and found adding DMSO as a reagent can significantly
improve the regioselectivity (Entries 5-9). Other lewis bases like
pyridine derivatives and sulphones with larger steric hindrance
are less effective compared to DMSO (Entries 9-14), indicating
the spatial effect can significantly impact the interaction between
hydroxyls and selected reagents.
Table 3. Substrate Scope of Migration-Oxygenation Reaction.[a]
With the optimum conditions in hand, we explored the scope
of this reaction. For the symmetrical diaryl-substituted diols, the
aryl bearing Cl, F, Me groups were tolerated (2b-e). Especially,
the selective generation of secondary alkoxyl radical and tertiary
alkoxyl radical was efficient to afford 2f and 2g in good yields. The
unsymmetrical diaryl-substituted diols were also tested. 1h
worked well to afford 2h and 2h’ in totally 64% yield in a ratio of
1:7. The migration ability of 4-chlorophenyl was stronger than
phenyl to afford 2i and 2i’ in 1:1.7 ratio. Furthermore, in F and CN
substituted diols, phenyl migration products 2j and 2k were the
main products. In general, the migration of electron-rich aryl
groups is easier than electron-deficient groups to react with the
electron deficient O-centered radicals.
[a] Reaction conditions: see entry 9, Table 1. Isolated yields. [b] Yield of
chlorophenyl migration product. [c] Yield of Heteroaryl migration product. [d] 0.5
mL CH3CN was added. [e] Yield of phenyl migration product.
We further applied this reaction to cyclic diols. Although the
strained diol 1l was favored to undergo β scission pathway
(Scheme 1d) and afforded 2l in 60% yield, to our delight, 10-
membered cyclic ketone 2m was high selectively obtained by the
present protocol. Heteroaryl substituted diols were also
investigated and we found the penzothiazolyl is a good migration
group, affording 2n and 2o in 55% and 66% yields with excellent
regioselectivity.
We further explored the generality of this distal (hetero) aryl
migration reaction using aryl alkyl disubstituted diol 1y as the
substrate. Unfortunately, no 2y was detected (eq 1). We also
investigated 1,4-diol 4 under standard conditions and found the
1,5-aryl migration is compatible (eq 2). On the contrary, the 1,3-
aryl migration is incompatible because of the strained and
unstable four-membered ring transition state (eq 3). Also, we
2
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10.1002/anie.202007187
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tested the reaction activity by expanding the scale of several
substrates to 2 mmol. As shown in eqs 4-5, 1a, 1f and 1p could
transform to the corresponding migration products in moderate to
good yields.
influence in our case. We further investigated the selectivity of this
reaction in the presence of dimethyl sulfone, as it could be
produced by the oxidation of DMSO in this oxidative environment.
However, the control experiments show the yields of 2a and 3a
were similar when dimethyl sulfone was used or not, both
regioselectivities were poor (eqs 8, 9). These results further
support DMSO as the key additive for the high regioselectivity of
this protocol.
Furthermore, we turned to study the interaction between
DMSO and the hydroxyls of diols (Figure 2).We had hypothesized
that DMSO can selectively form the hydrogen bonding with the
hydroxyl. To prove this, we studied the reaction between 3,3-
diphenylpropan-1-ol 12 and a radical acceptor 8, which afforded
phenyl migration product 13 in 18% yield via silver catalyzed O-H
homolysis process.[15g, 20] Interestingly, the yield of 13 increased
with the addition of DMSO, and then decreased when DMSO was
added too much. In contrast, when 14 was used, the reaction
efficiency was not significantly affected by DMSO. These results
indicate that the diaryl substituted tertiary hydroxyl group may not
interact with DMSO, probably due to the steric hindrance.
In previous reports, the aryl radical cation could be involved in
an intramolecular electron transfer leading to the alkoxyl
radical,[13a] therefore we tested our catalyst system using alkanols
as substrates. As shown in eqs 6-7, alkanols 7 and 10 can react
to afford 9 and 11 either by alkoxyl radical induced 1,5-HAT or β-
scission process under our conditions. These results support our
assumption that the alkoxyl radicals are generated through PCET.
Next, we carried out EPR experiments with DMPO as radical
scavenger (Figure 1, A). To our delight, we detected the clear RO-
DMPO signal at 60 minutes under standard conditions (Figure 1,
A1).[17] However, in the absence of AgClO4, the RO-DMPO signal
became very weak and the signal of the oxidation product of
DMPO, 5,5-dimethyl-2-oxopyrroline-1-oxyl (DMPOX)[18] was
detected (Figure 1, A2). Besides, no signal was detected when
the reaction conducted without K2S2O8. These results suggest
K2S2O8 is necessary to initiate the alkoxyl radical and silver
catalyst greatly increased reaction rate.
Figure 2. The yields of 13 and 3a with different amount of DMSO.
A
B
100
(1)
(2)
(3)
2a
80
60
2a
3a
Yield
(%)
40
20
3a
0
3450
3470
3490
3510
3530
3550
1
2
3
4
5
H/G
DMSO (x equiv)
Figure 1. Mechanism studies. (A) Detected EPR signals at 60 minutes. (1)
Standard conditions. (2) Without AgClO4. (3) Without K2S2O8. (B) DMSO is
essential to the regioselectivity.
It is noteworthy that DMSO is essential to the regioselectivity.
With the increase of DMSO loading, the regioselectivity improved.
(Figure 1, B). DMSO may act as a ligand for the silver catalyst,[19]
but the IR experiments (Figures S8-9, SI) indicate it has little
Figure 3. 1H-NMR studies. (A) 1H-NMR analysis of 15 with different amount of
DMSO. (1) without DMSO (2) with 1.0 equiv DMSO (3) with 3.0 equiv DMSO (4)
3
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with 5.0 equiv DMSO (B) 1H-NMR analysis of 1a with different amount of DMSO.
(1) without DMSO. (2) with 3.0 equiv DMSO (3) with 5.0 equiv DMSO (4) with 1
mL DMSO.
Scheme 2. Proposed mechanism.
In conclusion, we have disclosed a novel and efficient
selective radical O-H activation strategy. The alkoxyl radicals
were selectively generated from corresponding diols without pre-
activation. Mechanistic studies indicate that the common
molecule DMSO can selectively form hydrogen bonds with the
less-hindered hydroxyls, which facilitates the site-selective
alkoxyl radical initiation of alcohols via the combination of spatial
effect and PCET process. Meanwhile, we addressed a long-
standing problem to realize the distal (hetero)aryl migration from
C to O via alkoxyl radical induced distal C-C cleavage. We hope
this chemistry could inspire the development of selective X-H
activation and controlled radical chemistry.
Figure 4. The crystal structure and the hydrogen bonds of 15 and 1a.
Acknowledgements
We next conducted 1H-NMR analysis. The results showed the
hydrogen signal of the tertiary hydroxyl in 15 is not affected by
DMSO (Figure 3, A), probably because the difficulty to break the
internal hydrogen bonds between the tertiary hydroxyl and
methoxy groups (See the crystal structure of 15 in Figure 4, A).
Financial support from the National Natural Science Foundation
of China (Nos. 21632001, 21772002, 81821004), and the Drug
Innovation Major Project (2018ZX09711-001), Peking University
(No. PKU2020PKYZX004), and the Open Research Fund of
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes are greatly appreciated. We thank Dr. Shihui Shi in this
group for reproducing the results of 2b and 2s.
1
However, the H-NMR analysis of 1a showed that the shifts of
both hydroxyl hydrogen signals moved toward the low field with
the increase of DMSO loading (Figure 3, B). According to the
crystal structure of 1a (Figure 4, B), we speculate that the less
hindered hydrogen bonds between the primary hydroxyl and O
atom in the tertiary hydroxyls were destroyed by the addition of
DMSO, which caused the hydroxyls signals shift (Figure 3, B).
These results indicated that the hydrogen bonds exist between
DMSO and the primary hydroxyl.[21] Although it was not
completely clear, we believed that the larger steric hindrance
prevented the direct interaction between DMSO and the tertiary
hydroxyl group.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Selectivity • Alkoxyl radical • DMSO • C-C cleavage
• Silver
On the basis of the above experiments and precedent
reports,[13, 14, 15g-j] we proposed a plausible mechanism (Scheme
2). The addition of DMSO initially breaks the less hindered
hydrogen bonds between the primary hydroxyl and O atoms in the
tertiary hydroxyls, and yields stronger new hydrogen bonds.
Subsequently, through the PCET effect, the activated Ag(II)
catalyst selectively coordinates with the DMSO assisted hydroxyl
to afford intermediate II which undergoes homolytic cleavage to
afford alkoxyl radical III and Ag(I). Then, the intramolecular
electrophilic radical addition of species III occurs giving a spiro
intermediate IV, which undergoes the relay of oxidation, dealkyl
aromatization via C-C cleavage, and deprotonation processes to
afford 2a (Scheme 2). Although the formation of aryl radical cation
could interact with alcohols to afford the same inetrmediate IV
after deprotonation, we didn’t detect the nucleophilic addition
products by adding benzylamine, TMSCN, or imidazole into our
reaction system (Eqs S1-3, SI).[22] These results, combined with
the EPR experiments, indicate that the formation of radical cation
followed by deprotonation is not the main process in our
transformations.
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10.1002/anie.202007187
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Selective Radical Transformation
Y. Zhu, Z. Zhang, R. Jin, J. Liu, G. Liu, B.
Han, N. Jiao*
__________ Page – Page
DMSO Enabled Selective Radical O-H
Activation of 1,3(4)-Diols
● New application of common chemical DMSO: selective alkoxyl radical initiation
● Ag-catalyzed alkoxyl radical process for distal (hetero)aryl migration from C to O atom
This work discloses a new radical strategy for selective activation of one hydroxyl in
diols, and thereby achieves the novel alkoxyl radical induced distal (hetero)aryl
migration reactions through C-C cleavage.
6
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