An Electrocatalytic Newman-Kwart-type Rearrangement

Article abstract of DOI:10.1021/acs.orglett.8b03257

An electrochemical approach toward rearrangement of O-aryl thiocarbamates to the corresponding S-aryl thiocarbamates is presented. The protocol requires only catalytic amounts of electric charge and allows for operation at room temperature. The electrolys

Full text of DOI:10.1021/acs.orglett.8b03257

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Electrocatalytic Newman−Kwart-type Rearrangement
Timo Broese, Arend F. Roesel, Adrian Prudlik, and Robert Francke*
Institute of Chemistry, Rostock University, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
S
* Supporting Information
ABSTRACT: An electrochemical approach toward rearrangement of
O-aryl thiocarbamates to the corresponding S-aryl thiocarbamates is
presented. The protocol requires only catalytic amounts of electric
charge and allows for operation at room temperature. The electrolysis
can be carried out with the simplest equipment, i.e., under galvanostatic
conditions in an undivided cell. Furthermore, it is demonstrated that
when the electrolysis is performed in a microflow reactor, almost
quantitative yields can be achieved without using supporting electrolyte.
constitutes one of the most attractive possibilities for the
generation of 4.2 The possibility for conversion of 3 into
related sulfur containing compounds such as sulfones,
sulfoxides, sulfonic acids, and thioethers further broadens the
scope of the NKR.3 Not surprisingly, the field of applications
encompasses numerous examples from medicinal chemistry,
materials, agrochemistry, ligand synthesis (including applica-
tions in homogeneous catalysis), supramolecular chemistry,
etc.1,2,4 Industrial applications, mostly carried out in flow
reactors, have also been reported.5−7
he thermally induced rearrangement of O-aryl thiocarba-
Tmates 2 to the corresponding S-aryl thiocarbamates 3,
commonly known as the Newman−Kwart rearrangement
(NKR), represents the key reaction in the three-step
transformation of phenols 1 to thiophenols 4 (see Figure
1).1 In view of the good availability of various phenols, the
readily achieved conversion of 1 to 2 as well as the facile
cleavage of the rearrangement product 3, the NKR route
The NKR is generally assumed to proceed via intramolecular
nucleophilic ipso substitution at the aromatic ring, passing
through the highly strained spirocyclic intermediate 5 (see
Figure 1).8 The generation of this high-energy intermediate is
favored in the presence of electron-withdrawing groups on the
aromatic ring and typically requires temperatures >200 °C. In
many cases, these harsh conditions lead to competing
decomposition reactions, ultimately resulting in diminished
yields, product charring and complicated separation proce-
dures.1 Since the appearance of the first reports in 1966,9 a
number of studies have therefore dealt with the development
of protocols having milder reaction conditions. Important parts
of this development are the exploration of the microwave-
assisted NKR,10 and of the use of a continuous flow reactor
under supercritical conditions.5,6 Other approaches are based
on the use of catalysts in order to lower reaction temperatures.
In some examples, the addition of catalytic amounts of BF3·
OEt2 helped to lower the reaction temperature and to improve
the yields, whereby the catalytic effect did not turn out to be
general.11 A catalytic system with a broader scope was
introduced in 2009 by Lloyd-Jones et al., who demonstrated
that the use of palladium bis(tri-tert-butylphosphine) allows for
conversion of several para-substituted substrates 2 to the
corresponding NKR products at 100 °C.12
A subsequent report by Nicewicz et al. showed that the
rearrangement can even be achieved at room temperature
Figure 1. Conversion of phenols 1 to thiophenols 4 via Newman−
Kwart rearrangement (NKR).
Received: October 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03257
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Letter
using a photochemical approach: Upon irradiation with blue
LEDs in the presence of a pyrylium-based photoredox catalyst
(see Figure 1), a number of substrates 2 having electron-
donating groups in ortho- and/or para-position were
successfully subjected to NKR.13 Due to the inversion of the
selectivity compared to the thermal rearrangement, the
reaction was proposed to proceed via a cation radical 2•+,
which rearranges in an intramolecular aromatic substitution.
Just recently, Pittelkow et al. have demonstrated that a similar
outcome can be achieved when the photocatalytic system is
replaced by catalytic amounts of cerium ammonium nitrate
and oxygen as terminal oxidant.14 In parallel, we have explored
the NKR under electrochemical conditions in our laboratory
and developed a protocol where the transfer of catalytic
amounts of charge triggers the rearrangement at room
temperature.
and good conductivity) as well as the relatively low pKa, which
facilitates H2 generation as a cathodic half-reaction.18
Due to the redox neutrality of the NKR and the fact that
substoichiometric amounts of charge are sufficient for the
conversion, we can conclude that the reaction is electro-
catalyzed.19 At this point, we define the parameter TONe as
the number of molecules converted per transferred electron
(TONe = 7.6, see entry 5) in order to characterize the
efficiency of the reaction.20 While the deviation from i = 10
mA does not lead to any improvements (entries 6−8),
variation of the substrate concentration leads to a further
optimization of TONe (compare entries 5, 9, and 10). Using
the optimized values for i as well as for [2a] and applying an
increased amount of charge in order to achieve higher
conversion (0.3 F per mole 2a), the product 3a is obtained
in 95% isolated yield (TONe = 3.0, entry 11). More details on
the influence of passed charge, the electrode material, the water
content, and the presence of oxygen are provided in the
Supporting Information.
We initiated our study with a screening of the electrolysis
parameters using 2a as test substrate under batch conditions
(see Table 1). These experiments were carried out at rt in an
Using the optimized reaction conditions, the scope of the
protocol was investigated (Figure 2). Electrolysis of substrates
with alkoxy substituents in ortho- and/or para-position
generally yields the corresponding NKR products 3 in ≥90%
yield and with TONe values ranging from 3.0 to 4.6 (see 3a−
c). A comparison to the yields obtained from the thermal
rearrangement of 2a−c shows significant improvements (for
details, see the Supporting Information). The influence of
different O- and N-alkyl substitutions was also investigated,
whereby no major influence of the alkyl chain lengths on the
yields was found (3d−f).
a
Table 1. Optimization of the Electrolysis Parameters
b
c
entry
solvent
Q mol−1 [F]
i [mA]
3a [%]
TONe
1
2
3
4
5
6
7
8
MeOH
TFE
CH3CN
CH2Cl2
HFIP
1
1
1
1
0.1
0.1
0.1
0.1
0.05
0.05
0.3
10
10
10
10
10
20
30
5
0
17
0
0
0.2
0
0
0
Applying the standard conditions to sesamol-derived
substrate 2g leads to a clean NKR rearrangement, showing
that acetal groups are not affected by the reaction conditions.
Additional aryl substituents such as methyl, fluoro, and bromo
are also tolerated and lead to yields between 70% and 90%
(3h−j). We also found that the aliphatic alkoxy groups can be
replaced by a thioether (3k), acetamido (3l), Boc-protected
amino (3m) or a phenoxy group (3n), leading to slightly
inferior results (68−85% yield). Good results were also
obtained when the aryl substituent in 2 was replaced by a
naphthyl group (3o, 72%). The presence of an allyl-, a vinyl-,
or a dimethylamino substituent in the para position of the
arene ring, however, leads to significantly decreased yields
(35−54% after full conversion of 2p−r). We note that apart
from the desired product, no significant amounts of further low
molecular compounds were detected by GC in these cases. We
therefore assume that oligo- or polymerization reactions
represent the competing pathways lowering the yields of
3p−r. The conversion of methoxy hydroquinone-derived
substrate 2s under the standard conditions turned out to be
similarly problematic, since 3s was formed in only 32% yield
(along with a number of unidentified low-molecular side
products). The structure of 3s was additionally confirmed via
X-ray analysis of a single crystal (see Figure 2, top right).
Interestingly, the p-methyl-substituted substrate 2t is only
slowly converted under the standard conditions (12%
conversion after passing 0.5 F, formation of byproducts).
However, conducting the electrolysis at reflux temperature (bp
of HFIP: 58 °C) under otherwise identical conditions gives 3t
in 70% yield (TONe = 0.8). The same conditions were also
required in order to achieve rearrangement of estradiol
derivative 2u to the corresponding NKR product 3u. In
contrast, no conversion was observed upon electrolysis of the
80
54
39
81
79
22
7.6
5.1
3.7
7.8
15.2
4.2
3.0
HFIP
HFIP
HFIP
d
9
10
11
HFIP
10
10
10
e
HFIP
d
f
HFIP
95
a
Conditions: WE = RVC, CE = Pt wire, 0.1 M NBu4ClO4, HFIP (10
mL), 2a (42.2 mg, 0.2 mmol, 0.02 M), stirring with 700 rpm (see the
Supporting Information for more information), Ar atmosphere.
Yields determined via GC (external calibration). TONe refers to
the number of molecules 2a converted to 3a per transferred electron.
b
c
d
e
f
[2a] = 0.1 M. [2a] = 0.2 M. Isolated yield.
undivided cell using a reticulated vitreous carbon (RVC)
anode (an optimization of the anode material is described in
the Supporting Information), a platinum wire cathode,15 and
0.1 M NBu4ClO4 as supporting electrolyte. A particular
importance can be ascribed to the choice of the solvent
(entries 1−5). While employing MeOH, CH3CN, or CH2Cl2
leads exclusively to negative results, the use of 2,2,2-
trifluoroethanol (TFE) gives 3a in 17% yield after passing a
charge equivalent of 1 F per mole 2a. A more promising
outcome is obtained when 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) is employed under the same conditions, which leads to
80% yield after passing only 0.1 F at i = 10 mA (entry 5). The
benign influence of HFIP may be explained by its ability to
stabilize radical and ionic intermediates,16 which is why this
solvent turned out to be crucial in several previously reported
electrosynthetic transformations.17 Further advantages of HFIP
are excellent electrochemical properties (high anodic stability
B
DOI: 10.1021/acs.orglett.8b03257
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Figure 2. Scope of the electrocatalyzed NKR. Isolated yields, TONe in parentheses. Standard conditions: Undivided cell, rt, WE: RVC, CE: Pt-
wire, i = 10 mA, 10 mL HFIP (0.1 M Bu4NClO4), substrate, 1.0 mmol 2, Ar atmosphere. bElectrolysis carried out under reflux conditions (bp of
HFIP: 58 °C).
p-F- and p-NO2-substituted O-aryl-thiocarbamates (2v and
2w), neither at room temperature, nor under reflux conditions.
Taken together, these results suggest that electron-donating
groups are required to facilitate the electrocatalyzed NKR,
which is in sharp contrast to the thermally induced NKR1,2 and
may be explained by formation of a radical cation intermediate
2•+ and subsequent rearrangement via intramolecular aromatic
substitution (vide infra).
In order to investigate the scalability of the reaction, we
increased the batch size for the conversion of 2a to 3a from 1
to 10 mmol (Scheme 1). The upscaling was achieved by
increasing the electrolyte volume, the size of the electrode and
the current (100 mA), while [2a] was maintained at 0.1 M.
After passing 90 C (15 min), 2.1 g of 3a were isolated (99%
yield).
Next, we explored the possibility for further improvements
under flow conditions. Generally, a decrease of the required
supporting electrolyte load, an improvement of the mass
transport and a more homogeneous potential distribution
across the electrode surfaces can be expected when a microflow
reactor with a parallel plate design is used.21 We have therefore
carried out studies using a sandwich-type microflow reactor
(single pass) consisting of a glassy carbon working electrode
and a platinum counter electrode, which are separated from
each other by a Teflon spacer with a rectangular notch (3.0 ×
0.3 cm) that together with the electrodes defines the reaction
channel (for details, see the Supporting Information). It is
worth noting that the conversion of 2a to 3a proceeds
efficiently without added supporting electrolyte, which can be
explained by the overlap of the diffusion layers in the
microreactor.22 Under these conditions, the electrochemically
formed ionic intermediates provide sufficient ionic conductiv-
ity to close the electric circuit.
Scheme 1. Conversion of 2a to 3a on the Gram Scale
The optimization was carried out without supporting
electrolyte by variation of the feed concentration [2a], the
̇
current density j, the flow rate V, and the interelectrode
distance l. We found that excellent results are obtained when a
charge of 0.16 F per mole substrate is passed. The results along
with the optimized parameters are summarized in Table 2 (all
optimization steps are shown in the Supporting Information).
−1
̇
Quantitative yield in 3a was obtained with V = 1.0 mL min
and j = 19.9 mA cm−2, whereby the product was obtained in
analytical purity (1H NMR and GC) after completed
electrolysis and removal of the solvent (see Table 2, entry
1). We also found that the product forming rate PFR can be
C
DOI: 10.1021/acs.orglett.8b03257
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Organic Letters
Letter
Table 2. Electrocatalytic NKR of 2a to 3a under Flow Conditions: Optimized Product Yield, TONe, and Product Forming Rate
a
(PFR) along with the Corresponding Process Parameters at Q mol−1 = 0.16 F
b
b
−1
entry
[2a] [mM]
]
j [mA cm−2
]
2a [%]
3a [%]
TONe
PFR [g h−1
]
̇
V [mL min
c
1
70
100
150
1.0
1.1
1.2
19.9
31.3
51.1
<1
2
11
>99
98
89
6.3
6.2
5.6
0.89
1.37
2.03
d
2
d
3
a
b
c
d
Conditions: rt, undivided cell, WE = glassy carbon, CE = Pt, Aelectrode = 0.9 cm2, l = 110 μm. Isolated yields. Batch size: 2.0 g 3a Batch size: 1.0
g 3a.
−1
̇
improved when V and j are increased at constant Q mol
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03257.
■
(Table 2, entries 2 and 3), whereby the conversion is
simultaneously decreasing. Noteworthy, in a long-term experi-
ment we did not observe any indication of electrode
passivation after 24 h of electrolysis.
On the basis of our observations and in analogy to the
findings by Nicewicz et al.,13 we suggest the mechanism shown
in Scheme 2. Both the benign influence of the HFIP solvent
S
Experimental procedures, product characterization data
(PDF)
Accession Codes
Scheme 2. Mechanistic Proposal for the Electrocatalytic
CCDC 1872953 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Newman−Kwart-type Rearrangement
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: robert.francke@uni-rostock.de.
ORCID
Robert Francke: 0000-0002-4998-1829
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
and the restriction of the scope to electron-rich substrates are
strong indicators for the involvement of radical cation
intermediates. The sequence is initiated by anodic generation
of 2•+, followed by a rearrangement to 3•+, possibly via a
spirocyclic intermediate similar to species 5. Reduction of 3•+
either by discharge at the cathode or by reaction with another
molecule 2 closes the catalytic cycle. The latter possibility, a
radical chain mechanism, would explain why catalytic amounts
of charge are sufficient for full conversion.
■
RF is grateful for a Liebig Fellowship (Fonds der Chemischen
Industrie). Additional financial support by the German
Research Foundation (DFG, Grant No. FR 3848/1-1) and
the German Federal Ministry of Education and Research
(BMBF, Project No. 031A123) is acknowledged. We thank
Peter Kumm (Institute of Chemistry, Rostock University) for
machining the electrochemical flow cell and Dr. Alexander
Villinger (Institute of Chemistry, Rostock University) for the
X-ray structural analysis.
In conclusion, we have demonstrated that Newman−Kwart-
type rearrangements can be carried out in a galvanostatic
electrolysis by applying catalytic amounts of charge at ambient
temperature without using catalysts. Our procedure is
straightforward, scalable and applicable to a broad range of
activated phenols. Compared to the heat-induced NKR, our
protocol exhibits an inverted selectivity with respect to the
aromatic substitution, preferring electron-rich arene moieties
over electron-deficient ones. Further improvements were
achieved by operation under flow conditions, which allows
for omission of the supporting electrolyte and renders the
product in analytical purity and quantitative yields after
removal of the solvent. Our current efforts are focused on
the expansion of the scope and on establishing the mechanistic
details of the reaction.
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