Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals

Article abstract of DOI:10.1021/acs.orglett.9b03652

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale.

Full text of DOI:10.1021/acs.orglett.9b03652

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Manganese-Catalyzed Electrochemical Deconstructive Chlorination
of Cycloalkanols via Alkoxy Radicals
Benjamin D. W. Allen,†,§ Mishra Deepak Hareram,†,§ Alex C. Seastram,† Tom McBride,†
Thomas Wirth,‡ Duncan L. Browne,*,† and Louis C. Morrill*,†
†Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.
‡School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.
S
* Supporting Information
ABSTRACT: A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This
electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various
cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore,
the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a
gram scale.
traditional methods for alkoxy radical generation involve the
lkoxy radicals are highly transient species that exhibit
1
Adiverse reactivity, including hydrogen atom transfer, homolysis of weak oxygen-heteroatom bonds within prefunc-
addition to π systems,2 and β-scission processes (Scheme 1A).3
The generation of alkoxy radicals directly from aliphatic
alcohols is challenging, partly due to the high dissociation
energy of RO−H bonds (∼105 kcal/mol).2b As such,
tionalized radical precursors in combination with radical
initiators and/or thermal or photochemical activation (Scheme
1B).1,2 Alternatively, transition metal salts can be employed in
combination with stoichiometric oxidants (e.g., K2S2O8 or
hypervalent iodine reagents) for the generation of alkoxy
radicals.4 Recent advances have developed photocatalytic
approaches for alkoxy radical generation employing various
radical precursors5 including peroxides,6 N-alkoxyphthali-
mides,7 N-alkoxypyridiniums,8 N-alkoxybenzimidazoles,9 N-
alkoxytriazoliums,10 and unprotected alcohols.11 Despite these
important advances, many existing approaches require the use
of prefunctionalized substrates, (super)stoichiometric reagents
(generating waste/byproducts), and/or precious metal
(photo)catalysts.
Scheme 1. Context and Outline of Electrochemical Strategy
Organic electrochemistry represents one of the cleanest
possible chemical processing technologies,12 which has
recently undergone a renaissance due partly to the increasing
availability of standardized batch and flow electrochemical
reactors.13 By careful tuning of electrochemical parameters,
specific single electron transfer processes can be targeted,
accessing powerful radical intermediates.14 Despite these
characteristics, the development of electrochemical methods
for the generation of alkoxy radicals from alcohols has received
little attention and remains largely limited to the generation of
methoxy radicals,15 which requires expensive boron-doped
diamond or platinum anodes.16 To this end, herein we report
Received: October 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03652
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the manganese-catalyzed electrochemical deconstructive
chlorination of cycloalkanols via alkoxy radical intermediates,17
accessing synthetically useful β- and γ-chlorinated ketones
(Scheme 1C). Furthermore, by employing microreactor
technology and recirculating flow, the electrochemical method
can be performed on gram scale, with continuous inline
purification incorporated.
Mn(OTf)2 could be lowered to 2 equiv and 5 mol %,
respectively, without significant reduction in conversion
(entries 14 and 15). A Faradaic efficiency of 67% was obtained
when 2 F/mol of charge was passed (entry 16), which
indicated that most of the electricity passing through the cell is
utilized productively.
The full scope of the electrochemical process was explored
starting with the deconstructive chlorination of cyclobutanols
to form γ-functionalized ketones (Scheme 2A). From the
outset, it was found that 1-arylcyclobutan-1-ols containing
aromatic systems with electron-releasing groups at the 2- or 4-
positions (e.g., 4-tBu) or extended π systems (e.g., 4-Ph)
undergo decomposition using the optimized reaction con-
ditions (Table 1, entry 11). This instability was attributed to
ionization of the C−OH bond in the presence of Brønsted
and/or Lewis acids, forming stabilized carbocations that are
unproductive for the desired transformation. In such cases, this
issue was addressed by employing syringe pump addition of
the substrate over 2 h and using TBAOAc as the supporting
electrolyte. With a choice of two suitable reaction conditions in
hand, a variety of 1-arylcyclobutan-1-ols were converted to the
corresponding γ-chlorinated ketone products in good to
excellent isolated yields (products 2−20). Within the aryl
unit, various alkyl and aryl substitution was tolerated at the 4-,
3-, and 2-positions in addition to halides and electron-
withdrawing substituents (e.g., 4-CF3). The electrochemical
method exhibits good functional group tolerance as demon-
strated by the presence of aldehyde, carboxylic acid, methyl
ester, primary amide, nitrile, benzylic primary alcohol, and silyl
ether functionalities present within products 14−20. A
selection of 1-alkylcyclobutan-1-ols were also converted into
the corresponding γ-chlorinated ketones in good isolated yields
(products 21−26). Benzo-fused cyclobutanols participated in
deconstructive chlorination, giving benzyl chloride products
27−31, including the formation of 7-, 8-, 9-, and 10-membered
rings. This strategy was also applied to the formation of
disubstituted cycloheptane 32 in 77% isolated yield. Additional
substitution at the 2- and 3-positions of the cyclobutanol was
tolerated, accessing γ-chlorinated ketones 33−35 in high
yields. We also investigated the deconstructive chlorination of
cyclopropanols (Scheme 2B). Gratifyingly, it was found that a
representative selection of 1-arylcyclopropan-1-ols and 1-
alkylcyclopropan-1-ols could be readily converted to the
corresponding β-chlorinated ketones in good yields (36−39).
Additional substitution is tolerated within the cyclopropanol,
giving secondary radical derived product 40 as the major
regioisomer. Furthermore, bicyclo[4.1.0]heptan-1-ol was con-
verted to 3-chlorocycloheptan-1-one 41 in 48% isolated yield.
At the current stage of development, the electrochemical
method does not tolerate larger ring sizes with reduced ring
strain. For example, despite assessing various reaction
conditions, 1-phenylcyclopentan-1-ol underwent decomposi-
tion, whereas 1-phenethylcyclopentan-1-ol was unreactive.21
In order to demonstrate scalability, the batch process was
translated to a flow electrochemical setup.22 By employing the
To commence our studies, 1-phenylcyclobutan-1-ol 1 was
selected as the model substrate (Table 1). After extensive
a
Table 1. Optimization of Electrochemical Process
b
entry
variation from “standard” conditions
none
no electricity
yield (%)
1
2
82
<2
3
no MnCl2.4H2O
<2
4
5
6
7
8
9
10
11
12
13
14
15
16
Ecell = 2.4 V
66
74
80
82
82
75
82
i = 12.5 mA, janode = 9.8 mA/cm2
i = 7.5 mA, janode = 5.9 mA/cm2
TBAPF6 instead of LiClO4
Pt foil cathode instead of graphite
Ni plate cathode instead of graphite
Mn(OAc)2·4H2O instead of MnCl2·4H2O
Mn(OTf)2 instead of MnCl2·4H2O
LiCl instead of MgCl2
97 (78)
64
c
c
NaCl instead of MgCl2
MgCl2 (2 equiv)
Mn(OTf)2 (5 mol %)
<2
76
75
67
c
c
cd
,
Q = 2 F/mol
a
Reactions performed with 0.3 mmol of cyclobutanol 1 using the
b
ElectraSyn 2.0 batch electrochemical reactor. [1] = 0.05 M. Yield
after 3 h as determined by H NMR analysis of the crude reaction
1
mixture with 1,3,5-trimethylbenzene as the internal standard. Isolated
c
d
yield given in parentheses. Mn(OTf)2 as catalyst. 96 min reaction
time.
optimization,18 it was found that an electrochemical system
composed of MnCl2.4H2O (10 mol %) as catalyst,19 MgCl2 (5
equiv) as chloride source, and LiClO4 as supporting electrolyte
in MeCN/AcOH (7:1, [1] = 0.05 M) using galvanostatic
conditions (i = 10 mA, janode = 7.8 mA/cm2, Q = 3.73 F/mol)
and graphite electrodes at 25 °C for 3 h under N2, enabled the
deconstructive chlorination of 1, giving γ-chlorinated ketone 2
in 82% NMR yield (entry 1). No conversion occurs in the
absence of electricity or the manganese catalyst (entries 2 and
3). Employing a constant cell potential (Ecell = 2.4 V) or
variation of the current (i = 12.5 mA or 7.5 mA) lowered the
NMR yield of 2 (entries 4−6). Employing TBAPF6 as
electrolyte (entry 7) or substituting the graphite cathode for
Pt foil or Ni plate (entries 8 and 9) each had a negligible
impact on conversion. However, upon evaluating alternative
Mn(II) salts (entries 10 and 11), it was found that 97%
conversion was obtained using Mn(OTf)2 as catalyst, which
was adopted for further optimization. Employing LiCl or NaCl
as the chloride source was detrimental to conversion,
presumably due to decreased solubility in MeCN/AcOH
(entries 12 and 13).20 Gratifyingly, the quantities of MgCl2 and
commercially available Ammonite8 flow electroreactor,23
a
variety of reaction parameters were evaluated including
electrolyte loading, temperature, solvent ratio, residence time,
charge, and mixing efficiency (Scheme 2C). However, by using
MnCl2·4H2O (10 mol %) as catalyst, the conversion to 2 could
not be increased beyond 20% using single-pass flow electro-
chemistry.18 The yield was increased by applying the optimized
reaction parameters to a recirculating flow electrochemical
B
DOI: 10.1021/acs.orglett.9b03652
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Letter
Scheme 2. Substrate Scope: Batch and Flow Electrochemistry*
*
Reactions performed with 0.3 mmol of cycloalkanol using the ElectraSyn 2.0 batch electrochemical reactor with isolated yields after
a
chromatographic purification quoted unless stated otherwise. Cycloalkanol was added over 2 h via syringe pump, TBAOAc (0.1 M) as electrolyte.
b
c
1
TBAOAc (0.1 M) as electrolyte. Yield as determined by H NMR analysis of the crude reaction mixture with 1,3,5-trimethylbenzene as the
d
internal standard. 6 h.
C
DOI: 10.1021/acs.orglett.9b03652
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Letter
setup, which provided access to 2 in 84% isolated yield
(Scheme 2D).24 Advantageously, due to the decreased distance
between the electrodes in flow, a supporting electrolyte was
not required. Furthermore, by employing a 6-port 2-position
switching valve, the flow could be redirected from recirculation
to continuous inline purification (Scheme 2E). Once the
electrochemical reaction was complete, the valve was switched
from position 1 to position 2 to redirect the flow into the path
of workup solvents. The flow was passed through a mixing unit
before entering a liquid/liquid phase separator containing a
hydrophobic membrane that allowed separation of the organic
layer, which was subsequently dried over MgSO4, filtered, and
concentrated in vacuo to provide 1.2 g of product. This flow
setup, which combines recirculating flow electrochemistry and
continuous inline purification for the first time, might be
suitable for >1 g scale processing by increasing reactor volume
and operation time.
Cyclic voltammetry was employed in order to gain
mechanistic insight into the electrochemical process.18 In
accordance with the literature,19d the combination of
Mn(OTf)2 and MgCl2 produced a new quasi-reversible redox
event at ∼0.8 V vs Fc/Fc+,25 which provided evidence for the
generation of a Mn(III)X2Cl species from [Mn(II)X2Cl]−.
Furthermore, an increase in the oxidation current was observed
upon addition of 1-phenylcyclobutan-1-ol 1, which suggested
that Mn(III)X2Cl is consumed by 1. When methyl ether
cyclobutane 42 was employed as the substrate using the
standard electrochemical reaction conditions, no γ-chlorinated
ketone 2 was observed, with 82% starting material recovered
(Scheme 3A). This indicated that the proposed Mn(III)X2Cl
species does not promote cyclobutane ring opening in the
absence of a hydroxyl functional group. As such, a plausible
reaction mechanism initiates with the formation of
[Mn(II)X2Cl]− from Mn(II)X2 and MgCl2, which is oxidized
at the anode to form Mn(III)X2Cl (Scheme 3B). This
intermediate undergoes ligand exchange with the cycloalkanol
to form a Mn(III) alkoxide, with subsequent homolysis
generating an alkoxy radical, which can undergo reversible β-
scission. Alternatively, the Mn(III) alkoxide may undergo
reversible β-scission, rather than a free alkoxy radical
intermediate. Trapping of the transient primary carbon-
centered radical with the persistent Mn(III)X2Cl species
forms a new C−Cl bond.26 Hydrogen gas is generated via
proton reduction at the cathode.
In conclusion, we have developed a new electrochemical
method for alkoxy radical generation from alcohols and utilized
this for the manganese-catalyzed electrochemical deconstruc-
tive chlorination of cycloalkanols. The method is applicable
across various cyclopropanols and cyclobutanols, accessing a
broad range of synthetically useful β- and γ-chlorinated ketones
(40 examples). Furthermore, the combination of recirculating
flow electrochemistry and continuous inline purification was
employed to access products on gram scale. Ongoing studies
are focused on further applications of earth-abundant
transition metals in synthetic organic electrochemistry, and
these results will be reported in due course.27
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03652.
Optimization data, experimental procedures, character-
ization of new compounds and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 3. Mechanistic Studies
*E-mail: morrilllc@cardiff.ac.uk.
*E-mail: dlbrowne@cardiff.ac.uk.
ORCID
Benjamin D. W. Allen: 0000-0002-8536-8677
Thomas Wirth: 0000-0002-8990-0667
Duncan L. Browne: 0000-0002-8604-229X
Louis C. Morrill: 0000-0002-6453-7531
Author Contributions
§B.D.W.A. and M.D.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Information about the data that underpins the results
presented in this article, including how to access them, can
be found in the Cardiff University data catalogue at http://doi.
org/10.17035/d.2019.0087324419.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the School of Chemistry, Cardiff
University, for generous support and the EPSRC for a standard
research grant (EP/R006504/1) and doctoral training grants
for Ph.D. studentships (A.S., EP/R513003/1; T.M., EP/
N509449/1).
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DOI: 10.1021/acs.orglett.9b03652
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