Visible-light-enhanced ring opening of cycloalkanols enabled by br?nsted base-tethered acyloxy radical induced hydrogen atom transfer-electron transfer

Article abstract of DOI:10.1021/acs.orglett.8b00161

A metal-free ring opening/halogenation of cycloalkanols, which combines both PPO/TBAX oxidant system and blue LEDs irradiation, is presented. This method produces diverse γ, α, and even more remotely halogenated ketones in moderate to excellent yields under mild conditions. Interestingly, experimental and computational studies demonstrate the novel ring size-dependent concerted/stepwise (four-/five- to eight-membered rings) hydrogen atom transfer-electron transfer induced by Br?nsted base-tethered acyloxy radical, which indicates distinct advantages brought by the cyclic structure of diacyl peroxides.

Full text of DOI:10.1021/acs.orglett.8b00161

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Enhanced Ring Opening of Cycloalkanols Enabled by
Brønsted Base-Tethered Acyloxy Radical Induced Hydrogen Atom
Transfer-Electron Transfer
Rong Zhao,†,‡,∥ Yuan Yao,‡,∥ Dan Zhu,†,‡ Denghu Chang,†,‡ Yang Liu,‡ and Lei Shi*,†,‡,§
†Shenzhen Graduate School, Harbin Institute of Technology, Shenzhen 518055, P. R. China
‡MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical
Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China
§State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A metal-free ring opening/halogenation of
cycloalkanols, which combines both PPO/TBAX oxidant
system and blue LEDs irradiation, is presented. This method
produces diverse γ, δ, and even more remotely halogenated
ketones in moderate to excellent yields under mild conditions.
Interestingly, experimental and computational studies demon-
strate the novel ring size-dependent concerted/stepwise
(four-/five- to eight-membered rings) hydrogen atom trans-
fer-electron transfer induced by Brønsted base-tethered acyloxy radical, which indicates distinct advantages brought by the cyclic
structure of diacyl peroxides.
Scheme 1. Different Reaction Intermediates Generated from
Cyclic Diacyl Peroxides
rganic peroxides are worthy of study owing to their
Owidespread applications in industry and organic synthesis,
bleaching, and disinfection and as polymerization promoters.1
Acyclic peroxides, such as tert-butyl hydroperoxide (TBHP) and
3-chloroperoxybenzoic acid (m-CPBA),2 have been extensively
applied and studied; however, the research on cyclic peroxides
remains largely unexplored in comparison with their similarly
atom-connected counterparts.3 Despite that, the reported results
about cyclic diacyl peroxides have preliminarily revealed its
outstanding advantages, such as greater thermal stability,4 mild
reaction conditions,5 and selectively generating oxidation
products, such as phenols,6 which are more reactive than the
starting commercial arenes. This convinced us there are more
attractive properties about cyclic diacyl peroxides, beyond simple
oxidation, which are worthy of exploration.
Phthaloyl peroxides (PPO) and malonoyl peroxides (MPO) as
two kinds of burgeoning cyclic diacyl peroxides exhibit the divine
dichotomy mechanisms in the reported literatures. In 2013,
Houk and Siegel6 described a reverse-rebound mechanism of
oxidation of aromatic carbon−hydrogen bonds in the presence of
PPO through diradical intermediate (Scheme 1a). In contrast,
Tomkinson7 raised an zwitterion mechanism of the similar
reaction oxidized by MPO supported by isotopic labeling in 2015
(Scheme 1b). Besides, PPO also achieves oxidation of sulfides/
thioketones by zwitterion mechanism in our previous work.5a
Herein, we report the ring opening of the cyclic alcohols realized
by unique radical/anion intermediate generated by the
interaction of parent phthaloyl peroxides and halogen anions
(Scheme 1c). The radical/anion intermediate effeciently
enhances the ability to promote hydrogen atom transfer
(HAT)8a than a tranditional benzoyloxy radical8b (Scheme
1d), and accomplishes homolytic cleavage of pronouncedly
stable oxygen−hydrogen bond (O−H BDFEs ≈ 105 kcal/mol)9
Received: January 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00161
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Letter
with the assistance of tethered hydrogen bonds (Scheme 1e),
which is supported by quantum-mechanical calculations.
Scheme 3. Scope of Radical Ring Opening of Different-
Membered Cyclic Alcohols
Radical ring opening of strained cycloalkanols has been
realized by different methods (Scheme S-1), and its correspond-
ing products such as halogenated ketones (Figure S-1) are key
intermediates of many bioactive molecules. In 2015, Zhu et al.10
reported transition-metal-catalyzed ring opening of cyclo-
alkanols. In their mechanism of silver-catalyzed fluorination
(Scheme 2a),10a the incorporation of cyclobutanol and a silver
Scheme 2. Different Mechanisms of Radical Ring Openings of
Strained Cycloalkanols
a
b
2 equiv of PPO-2 was used as an oxidant. Gram scale: 1a (1 g, 6.75
mmol).
bromination by basic byproduct carboxylate F, and generates the
α,β-unsaturated ketone 5 (Scheme S-2). Subsequently, four- to
eight-membered cyclic alcohols were used to test the influences
of ring strain. Gratifyingly, all ring sizes evaluated in this study
underwent β-scission readily. With the increase of the ring’s
members, yields of halogenated linear ketones declined from
excellent to low yields in general, and reaction times gradually
lengthened to several hours in bromination and iodination
reactions, which coincide with reduced reactivities of less
strained cyclic alcohols. On account of the unsuccessful
combination of PPO and TBACl, the Cl source was changed
to alkali salt CsCl, and a low yield was obtained from the same
blue LEDs irradiation conditions (Scheme S-2). Efforts to reduce
these constraints are ongoing.
Subsequently, we turned our attention to study the
substitution pattern on cyclic alcohols (Scheme 4). Most
surprising was all of the reactions achieved within 3 h under
standard conditions, which are in general the shortest reaction
times in reported literatures as far as we know. Different steric
substituted γ-halogenated ketones were obtained with good-
salt exchanges F with SelectFluor by proton transfer (PT), and
then alkoxy radical is generated by subsequent electron transfer
(ET). Knowles et al.11 employed the intermolecular cooperation
of a Brønsted base and an oxidant to generate alkoxy radical
through proton-coupled electron transfer (PCET) in 2016
(Scheme 2b). In comparison, our multisite radical/anion
intermediate in this work comprises an oxidizing acyloxy radical
outfitted with a tethered carboxylate base (Scheme 2c). The
oxidative carboxylic radical can, in conjuction with the Brønsted
base, engender the HAT by simultaneous hydrogen-bond
interaction rather than a PCET process (Table S-2). In all of
the above-mentioned reactions, there are the generations of
alkoxy radicals, and more stable C-centered radicals are
subsequently obtained by ring-strain-promoted rearrangements.
However, in this ring size-dependent concerted/stepwise
mechanism, no alkoxy radical is found in the quantum-
mechanical calculations of concerted hydrogen atom-electron
transfer mechanism about the cyclobutanols, supported by
intrinsic reaction coordinate (IRC) calculations (Figure S-4),
while a stepwise mechanism is proposed for five- to eight-
membered cycloalkanols.
Scheme 4. Substrate Scope of Radical Ring Opening of
Different Substituted Cyclic Alcohols
Currently, most ring openings of strained cycloalkanols rely on
metal catalysts (Scheme S-1), and just a few cases can produce
ring openings by oxidants,12a,b photocatalysts,12c or Brønsted
bases.12d Intrigued by the electrophilic halogenation in nature,13
we combined various peroxides and bromide sources and chose
cyclobutanol 1a as the model substrate to optimize the ring
opening/bromination reaction (Table S-1). Despite being
intuitively more favorable on entropic grounds than cyclic
peroxides, acyclic benzoyl peroxide (BPO) led to much lower
yield. After condition screening, PPO was mainly used with
tetrabutylammonium bromide (TBAB) in the ring opening of
cyclic alcohols, and PPO-2 served as an oxidant replacement.
Having established the optimized reaction conditions, we first
attempted to explore the influence of different ring sizes (Scheme
3). Unfortunately, cyclopropanol 4 proceeds elimination after
a
2 equiv of PPO-2 was used as an oxidant.
B
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yields (2f−h). Compared with the moderate yields of cyclo-
butanols with electron-donating groups on phenyl (1n, 1p),
substrates with electron-withdrawing groups usually gave the
corresponding γ-brominated ketones in better yields (2i−m).
Additionally, low yields of aromatic heterocyclic substituted
substrates (1t, 1u) were likely due to their instability to be easily
oxidized to other byproducts. Importantly, we observed that
different substituents on six-membered ring (1x−z) could be
accommodated and furnish excellent yields (77−93%), suggest-
ing that steric influence on the ring is not a prerequisite for
efficient bond scission. Besides aromatic groups, cyclic and chain
aliphatic substituted cycloalkanols also proceed smoothly with
good yields (2v, 2w). Furthermore, the ring-opening/bromina-
tion reaction of cycloalkanols on different sites of the
adamantane skeleton (2aa, 2ab) and late-stage functionalization
of the derivative of the natural product were performed
successfully as well (2ac). Notably, PPO-2 can be an alternative
oxidant to significantly increase yields of most inactive substrates
(2m, 2q, 2r, and 2s).
reaction (Scheme 5b), which suggested that a radical-mediated
mechanism might be involved. To further evaluate the cleavage
of the O−H bond, the kinetic isotope effect was roughly
estimated as 1.4 from parallel experiments of protiated (1a) or
deuterated substrate (1a′) with 1n as a reference substance
(Scheme 5c), due to the indistinguishability of γ-brominated
ketones from direct KIE experiments. The influence of
hydrogen−deuterium exchange between substrates is not
excluded, but may be ignored due to short reaction time. This
approximate result of 1.4 matches previously reported KIE values
(1.41,14a 1.4,14b and 1.4 0.114c) for HAT process of active C−H
bonds realized by oxygen radical, lending support to the
proposed HAT process. Similarly, secondary kinetic isotope
effects have been measured under standard conditions using
protiated and deuterated substrates in the same reaction flask.
The apparent distinctions between cyclobutanol (KIE ≈ 1.31)
and five- and six-membered cycloalkanols (KIE ≈ 1.15, 1.12)
possibly indicated different mechanisms on turnover-limiting
steps between four- and other-membered rings (Scheme 5c).
To validate our hypothesis, we then performed DFT
calculations to uncover the fundamental mechanism. PPO
directly yields diradical molecule (INT1A) through O−O
bond homolysis, followed by single-electron transfer (SET)
with bromide anion to give radical/anion intermediate INT4 and
bromide radical (Figure S-3). Compound 1a undergoes a
concerted HAT and C−C bond cleavage of the ring to directly
provide carbon radical INT6 (Figure 1). The spin density
To gain insights into the possible mechanistic pathways,
several control experiments (Scheme 5) and UV/vis detection
Scheme 5. Control and Competitive Experiments and
Mechanistic Studies
Figure 1. Potential energy profiles for the radical ring opening of cyclic
alcohols.
analysis confirmed that HAT process, not PCET, is involved in
the reaction, in agreement with KIE results mentioned above. In
sharp contrast, 1b−e undergo a HAT to generate stable alkoxy
radicals INT2D, followed by the subsequential C−C bond
cleavage to give carbon radicals INT6. The activation free
energies for this stage gradually increased from 1a to 1e,
consistent with reaction times shown in Scheme 3.
Based on mechanistic observations and DFT calculations, a
proposed mechanism was outlined in Scheme 6. Intermediate B,
in situ produced by PPO and TBAB, led to the homolytic
cleavage of O−Br bond under illumination condition to generate
radical/anion intermediate C and bromide radical. When
cyclobutanol served as a substrate, a kinetic coupling of hydrogen
atom abstraction and electron transfer enabled the homolyzing of
strong O−H bond and C−C bond of the strained ring in concert
to provide carbon radical G and byproduct F directly. In contrast,
five- to eight-membered cyclic alcohols first undergo HAT driven
by active radical/anion intermediate C. The generated alkoxy
(Figure S-2) were performed. First, to investigate substituent
effects on phenyl, the product ratio obtained from the pairwise
comparison experiments among 1a, 1n, and 1l demonstrated that
the relative reactivities increase obviously with the increasing
electron-withdrawing abilities of the para substituents of the
aromatic ring of 1-arylcyclobutan-1-ol (Scheme 5a), which is
consistent with yields shown in Scheme 4. Subsequently, the
additions of known effective radical inhibitors as TEMPO and
BHT under identical conditions significantly suppressed the
C
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Letter
Author Contributions
Scheme 6. Proposed Mechanism of the Radical Ring-Opening
of Cyclic Alcohols
∥R.Z. and Y.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by the “Fundamental
Research Funds for the Central University” (HIT.BRE-
TIV.201502). The authors thank Dr. Xiao Zhang in the School
of Chemistry and Chemical Engineering, Harbin Institute of
Technology, for assistance with the single-crystal X-ray analysis
of byproduct F.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00161.
Experimental procedures, compound characterization
data, mechanistic studies, crystallographic data, and
calculation details for products (PDF)
(11) Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H. S.; Knowles, R.
R. J. Am. Chem. Soc. 2016, 138, 10794−10797.
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CCDC 1580138 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lshi@hit.edu.cn.
ORCID
Yuan Yao: 0000-0003-0033-971X
Lei Shi: 0000-0002-6865-1104
D
DOI: 10.1021/acs.orglett.8b00161
Org. Lett. XXXX, XXX, XXX−XXX