Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer–Moest Reaction under Flow Conditions

Article abstract of DOI:10.1002/chem.201904479

The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. The first electrochemical functionalisation of cubane by oxidative decarboxylative ether formation (Hofer–Moest reaction) was demonstrated. The mild conditions are compatible with the presence of other oxidisable functional groups, and the use of flow electrochemical conditions allows straightforward upscaling.

Full text of DOI:10.1002/chem.201904479

A Journal of
Accepted Article
Title: Cubane electrochemistry: direct conversion of cubane carboxylic
acids to alkoxy cubanes using the Hofer-Moest reaction under
flow conditions
Authors: Diego E. Collin, Ana A. Folgueiras-Amador, Derek Pletcher,
Mark E Light, Bruno Linclau, and Richard Charles Downie
Brown
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201904479
Link to VoR: http://dx.doi.org/10.1002/chem.201904479
Supported by

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
Cubane electrochemistry: direct conversion of cubane carboxylic
acids to alkoxy cubanes using the Hofer–Moest reaction under
flow conditions
Diego E. Collin, Ana A. Folgueiras-Amador, Derek Pletcher, Mark E. Light, Bruno Linclau, and Richard
C. D. Brown*[a]
Abstract: The highly strained cubane system is of great interest as
a scaffold and rigid linker in both pharmaceutical and materials
chemistry. We demonstrate the first electrochemical functionalisation
of cubane by oxidative decarboxylative ether formation (Hofer–
Moest reaction). The mild conditions are compatible with the
presence of other oxidisable functional groups, and the use of flow
electrochemical conditions allows straightforward upscaling.
above. Additionally, the possibility of forming cubyl cations is
inferred from solvolyses of corresponding iodide or triflate.[24]
This precedent, together with our ongoing interest in the area of
electrosynthetic transformations,[25] led us to explore the
application of electrochemistry as a direct approach to generate
these reactive intermediates[26] from cubanecarboxylic acids. In
Kolbe electrolysis, anodic oxidation of carboxylic acid salts
initially forms alkyl radicals, which may undergo coupling to give
symmetrical or unsymmetrical products. The initially formed
radicals may be further oxidised to give carbocations which can
react with a nucleophile to give alcohols, ethers, esters, etc.[27]
This non-Kolbe carbocation pathway, known as the Hofer-Moest
reaction, has very recently been optimised by Baran, Blackmond
and co-workers for the synthesis of hindered ethers via
carbocation formation under batch electrolysis conditions.
Despite reporting an impressive array of ether products (>80),
cubane carboxylic acid was reported to be a challenging
substrate, which did not afford the Hofer-Moest product under
their conditions.[28] Herein we report direct anodic
functionalisation from the commercially available carboxylic acid
1 under flow conditions as a convenient method for cubane to
give a variety of ethers. Furthermore, the scalability of the
process is demonstrated.
First synthesised in the 1960’s,[1] and originally proposed as 3D
benzene bioisostere in the 1990’s,[2] it is only in the past decade
that cubanes have gained real traction in medicinal
chemistry.[3],[4] Substituting a phenyl ring by a cubyl unit can lead
to improved physical and biological properties.[5] In addition, 1,4-
disubstituted cubanes have applications as non-aromatic rigid
spacers in organic materials and polymers.[6]
The only practical large-scale synthesis of cubane to date
leads to 1,4-cubanedicarboxylic acid,[1],[7] and while cubane
functionalisation has been extensively investigated,[8] in practice
it has relied heavily on interconversions of the carboxylic acid
functional group or indirect decarboxylative functionalisations
(Scheme 1). To the best of our knowledge, the only direct
decarboxylative cubane C–C bond formation is a single example
of Pb(OAc)4-mediated Kochi coupling reported by Moriarty
(Scheme 1).[9] More generally, Redox-Active Esters (RAE), such
as the N-phthalimido ester 3, have proven to be useful
intermediates in Fe-catalysed cubyl–aryl coupling to give 4.[10],[11]
Baran also showed RAE’s as intermediates for Giese radical
reactions (not shown),[12] and they have been employed for
decarboxylative cubyl-heteroatom bond formation (e.g.
decarboxylative borylation, 3→5).[13],[14] Other examples of
Direct functionalisation:
CO2H
Moriarty 1989
(66%)
Pb(OAc)4
benzene
MeO2C
1
2
MeO2C
Redox-Active
Esters (RAE):
O
R
SET
[Fe], [Ni] or hν
O
N
decarboxylative
reported.[15],[16]
radical-based
methods
have
been
O
O
MeO2C
3
4 R = Ar (0-58%) Baran 2016, Senge 2017
5 R = Bpin (45-46%) Aggarwal, Baran 2017
MeO2C
The synthesis of alkoxy cubanes 7 has been reported from
the iodide 6, which is again accessed from cubane carboxylic
acids,[17]-[19] or their pyridyl esters.[20],[21] Eaton reported that
photolysis of a dilute (0.03 M) solution of 1,4-diiodocubane in
methanol afforded 1-iodo-4-methoxycubane in 10% yield.[22]
Subsequently, Irngartinger[23] and later Williams[21a] improved the
efficiency with photolysis yields up to 58%, providing access to
methoxycubanes as anisole isosteres.
PhI(OAc)2, I2,
Ether formation:
CO2H
benzene, reflux, 8 h
Priefer 2010 (70%)
I
a) SOCl2
b)
6
R'
R'
1
CF3CH2I, hν
CH2Cl2
hν, MeOH, 17-22 h
R' = CO2Me, R = Me
N
NaO
Eaton 1991 (92%)
S
Irngartinger 1999 (31%)
Williams 2019 (58%)
this work
The viability of processes proceeding via the intermediacy of
cubyl radicals is amply supported by the examples described
base, ROH, rt
Ammonite electrolysis flow cell
OR
7-22
7 (R' = CO2Me,
R = Me)
Pt or C/PVDF anode
stainless steel (SS) cathode
R'
[a]
D. E. Collin, Dr. A. A. Folgueiras-Amador, Prof. Dr. D. Pletcher, Dr.
M. E. Light, Prof. Dr. B. Linclau, Prof. Dr. R. C. D. Brown
School of Chemistry, University of Southampton
Scheme 1. Decarboxylative cubane functionalisation.
Highfield, Southampton, SO17 1BJ (UK)
E-mail: Bruno.linclau@soton.ac.uk, r.c.brown@soton.ac.uk
Supporting information for this article is given via a link at the end of
the document.
Our electrochemical investigations of cubanecarboxylic
This article is protected by copyright. All rights reserved.

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
acids were facilitated through the application of flow electrolysis
cells.[29] Interest in laboratory electrosynthesis in continuous flow
has grown significantly over the last decade[30] and presents
some advantages compared to batch electrolysis. In flow cells,
the electrode surface to reactor volume ratio is much higher than
in batch, facilitating higher productivity and more efficient mass
transfer. Moreover, the interelectrode gap is usually small
(typically between 0.1–1 mm), allowing a low loading or even
elimination of supporting electrolyte.[31]
omission of AcOH achieved a further improvement to 52% (entry
8). Significantly, anodic oxidation using the C/PVDF anode, 200
mA (2.5 F) and 0.5 mL min–1 allowed for the formation of 7 with
increased productivity and substantially improved current
efficiency (42% compared to 14% at Pt).
Table 1. Selected electrolysis optimisation conditions.
–2 e–, –CO2
CO2H
OMe
+
R
MeO2C
MeO2C
MeO2C
8 R = OAc
For initial exploration of the reactivity of the cubane moiety
towards electrolysis, and whether radical or carbocation
reactivity would be observed, cubane carboxylic acid 1 was
subjected to typical Kolbe-type electrolysis conditions in an
undivided flow reactor.[32] Partial deprotonation using KOH as
base and excess current (6.2 F) was applied in MeOH, using Pt
as anode material.[25a] Without supporting electrolyte, preliminary
experiments established that 0.5 equivalents of base was
required to reach the desired cell current and methyl 4-methoxy-
1-cubanecarboxylate (7) was obtained in 14% as the major
product (Table 1, entry 1). In addition, starting material 1 (50%)
and a small amount of the hydrogenolysis product 10 (<5%)
were observed. This promising initial result showed that the
cubane ring itself is clearly compatible with anodic oxidation, and
that processes proceeding through cubane carbocation
formation are viable.
base (0.5 equiv.), MeOH
1
7
additive / supp. electrolyte
Ammonite 8, SS cathode
anode (see Table 1)
9 R = Me
10 R = H
observed
byproducts
major
product
condi-
tions
flow rate
current
(charge)
RSM
[%][a]
yield
[%][b]
entry
anode
[mL min–1
]
200 mA
(6.2 F)
1
Pt
Pt
Pt
Pt
Pt
KOH
0.2
0.2
0.4
0.2
0.2
0.2
0.5
0.5
0.25
0.5
0.5
0.5
0.5
50
none
none
none
82
14
40
36[d]
44
8
2[c]
KOH,
AcOH
200 mA
(6.2 F)
KOH,
AcOH
400 mA
(6.2 F)
3
4[c]
Et3N,
AcOH
200 mA
(6.2 F)
200 mA
(6.2 F)
5
Et3N
Optimisation efforts continued using Pt and carbon-based
anodes (see SI for details). For the Pt anode, it was observed
that the presence of supporting electrolytes such as Et4NBF4
and perchlorate salts (from NaClO4, LiClO4) supressed
decarboxylation of cubane, with only traces of 7 observed.
Interestingly, while basic conditions are required to form the
carboxylate, addition of acetic acid resulted in a significantly
improved yield of 40% (entry 2). As anticipated, the
corresponding acetoxycubane 8 and the cross-Kolbe product 9
were observed as minor byproducts in the crude reaction
mixtures. However, the addition of an excess of acetic acid was
not found to significantly increase the formation of 8 and 9.
6[c]
7[c]
8
none
none
none
none
32
12
44
52
24
4
C/
PVDF
Et3N,
AcOH
200 mA
(6.2 F)
C/
PVDF
Et3N,
AcOH
200 mA
(2.5 F)
C/
PVDF
200 mA
(2.5 F)
Et3N
C/
PVDF
200 mA
(5.0 F)
9
Et3N
10[e]
11[e]
12
13[f]
C/
PVDF
Et3N,
NaClO4
200 mA
(2.5 F)
Doubling the flow rate and maintaining the amount of charge
(0.4 mL min–1, 400 mA (6.2 F)) led to the isolation of product 7 in
36% yield in a gramme-scale reaction, along with the formation
of the reported byproducts (entry 3). However, attempts to use
other alcohols as nucleophiles were hampered by poor solubility
of the inorganic base, limiting further development of these
conditions. While heterogeneous solutions can be used in a
batch electrochemical setup,[28] such approach is not desirable in
a flow system. Hence, the use of an organic base was explored,
with Et3N affording the best results leading to 7 in 44% yield
(entry 4).[33] Omitting acetic acid led to reduced conversion and
only 8% of the desired product (entry 5).
Carbocation formation is reported to be favoured using
carbon anodes under basic conditions with added perchlorate
salts as supporting electrolyte.[27] In the current work,
exchanging the Pt anode for a carbon material (C/PVDF, carbon
polyvinylidene fluoride composite) under the previously
optimised conditions, resulted in a reduced yield of 7 (12%, entry
6) alongside decomposition products (1H NMR analysis).
However, decreasing the applied charge to 2.5 F gave an
elevated yield (44%) of the methyl ether 7 (entry 7), and
C/
PVDF
Et3N,
Et4NBF4
200 mA
(2.5 F)
20
12
34
C/
PVDF
200 mA
(2.5 F)
DBU
Et3N
none
22
C/
PVDF
200 mA
(2.5 F)
36
[a]
General conditions: 0.25 mmol of 1, MeOH (5 mL), c = 0.1 M.
[b]
Determined using calibrated GC; Yield of 7 determined using calibrated
[e]
GC. [c] AcOH (1.0 eq.). [d] Isolated yield: 1.03 g of 1 gave 350 mg of 7.
5
[f]
mM of supporting electrolyte.
Starting Material.
Et3N (0.75 equiv.). RSM: Remaining
Decreasing the flow rate, while maintaining the same cell current
(double amount of charge, 5.0 F), also gave a decreased yield of
24% (entry 9), highlighting the potential for overoxidation of the
methoxylated product 7. This was confirmed by resubmitting the
reaction mixture containing 7 to the electrolysis conditions,
resulting in a decreased yield of 30% (from 50% with one pass
through the reactor). Different bases and supporting electrolytes
This article is protected by copyright. All rights reserved.

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
were explored (entries 10–13 and SI), but the yield was not
improved further, and the presence of NaClO4 or Et4NBF4
retarded decarboxylation.
identified as a bioisostere of the highly electron rich and
relatively toxic p-anisidine 26 (Scheme 3), and its synthesis was
undertaken. Saponification of ester 7 gave 4-methoxycubane
carboxylic acid 24 in 94% yield, which was followed by Yamada–
Curtius[37] rearrangement to give the corresponding Boc-amine
23 in 69% yield. Cleavage of the carbamate protecting group
delivered 4-methoxy-1-cubanamine as its hydrochloride salt 25.
With optimised conditions in hand, we explored different
alcohols as nucleophiles (Figure 1). A range of alkoxylated
products from alcohols with different steric hindrance were
successfully synthesised (7, 11–13). This included deuterated
ethers, illustrated by the synthesis of methyl 4-methoxy(d3)-1-
cubanecarboxylate (11) in 40% yield. The corresponding crystal
structure was obtained (see SI, Section 10.4). Selectively
deuterated substrates are of interest for medicinal chemistry
studies, where the use of deuteration has shown, in some cases,
to improve the pharmacokinetic properties.[34] Furthermore,
fluorinated cubane ethers (14 and 15) were obtained in
moderate to good yields from TFE (2,2,2-trifluoroethanol) and
HFIP (1,1,1,3,3,3-hexafluoroisopropanol), respectively. The
application of fluorinated alcohols was not viable using the
C/PVDF anode, which swells in fluorinated solvents (see SI,
Section 3.5.3), but was possible using a Pt anode. Other
sources of carbon that could be used with fluorinated solvents,
such as glassy carbon,[35] showed inferior results for this
particular reaction.
CO2H
–2 e–, –CO2
OR
MeO2C
1
R'
or
Et3N (0.5 equiv.), ROH or ROD
Ammonite 8, 200 mA, SS cathode
anode: Pt (0.2 mL min–1, 6.2 F)
or C/PVDF (0.5 mL min–1, 2.5 F)
CO2H
R'
OMe
OCD3
O
MeO2C
48%a, 47%b
MeO2C
11
40%a, 32%b
MeO2C
7
12
41%a
[x-ray]
CF3
CF3
O
O
O
CF3
The substrate scope was further explored using different
functional groups on the cubane moiety, with attention to
potential chemoselectivity issues including oxidation of C—H
bonds adjacent to nitrogen in amides.[36] Pleasingly, oxidation of
the carboxylate occurred in preference, leading to compounds
16–19 in good yields (48–60%). Piperidine (e.g. 16) and
morpholine rings (e.g. 19) remained unchanged, offering
interesting potential scaffolds for application in drug discovery.
Benzyl ethers, which are susceptible to anodic oxidation, were
also tolerated albeit with the desired decarboxylative coupling
product 20 obtained in a reduced 20% yield. Gratifyingly, the
presence of a free alcohol in the molecule did not disturb the
electrochemical transformation and compound 21 was obtained
in 46% yield as the main product. However, while a t-butyl ester
is compatible with the reaction conditions (22, 41%), a Boc-
protected amine with or without the use of base did not lead to
the desired electrolysis product 23, and starting material was
recovered.
MeO2C
MeO2C
MeO2C
14
15
13
9%a
24%b (36%)c
27%b (53%)c
[x-ray]
OMe
OMe
OMe
OMe
O
O
O
N
O
16
17
18
19
N
N
N
57%a
59%a
60%a
48%a
O
OMe
OMe
OMe
OMe
O
O
BocHN
20
21
22
44%a
23
n.r.a
O
OH
20%a
46%a
Figure 1. Reaction scope. a Isolated yield with C/PVDF 1, Et3N (0.5 equiv.)
b
and corresponding alcohol; Isolated yield with Pt anode, 1 equiv. AcOH
added. 19F NMR yield with α,α,α-trifluorotoluene as internal standard. Vi:
c
internal volume of the Ammonite 8 reactor.
To demonstrate the ease of laboratory scale-up using the
flow electrolysis approach described herein, 12.5 mmol of
starting material was successfully oxidised using the same
reactor, giving 1 gramme of pure methoxy-cubane 7 in only 4 h
(Scheme 2). While, on small scale, the formation of methyl 1-
cubanecarboxylate 10 as hydrogenolysis byproduct is
insignificant, on gramme-scale ~150 mg of 10 was isolated.
–2 e–, –CO2
CO2H
R
CO2Me
7 (+ 10)
CO2Me
Et3N (0.5 equiv.), MeOH
Ammonite 8, 0.5 mL min–1
C/PVDF (+) / SS (–)
1
(12.5 mmol)
7 R = OMe + 10 R = H
45% (1.08 g) 8% (152 mg)
200 mA (4.2 h, 2.5 F)
It is worth noting that applying similar conditions in a batch-
type cell (similar geometry to commercial batch reactors),
compound 7 was obtained in 50% yield. However, 3 h of
electrolysis time was required instead of 10 minutes in flow for
the same scale (0.5 mmol), and a considerably increased
amount of charge (4.0 F) was applied in order to achieve full
conversion (see SI, Section 5).
Scheme 2. Gramme-scale decarboxylative functionalisation of cubane.
As
a
further illustrative example, following Williams’
synthesis of a number of pravadoline analogues featuring
anisole bioisosteres,[21a] the cubane derivative of the synthetic
drug anisindione (30) was investigated. Anisindione (30), known
under the brand name Miradon®, is used as anticoagulant. 4-
Methoxy 1-cubanecarboxylic acid (24) was reduced to 4-
methoxy-1-cubanemethanol in 82% yield, and subsequent
The demonstration of a one-step Hofer-Moest process in
flow making 7 accessible on gramme-scale, opens up possible
applications of 7 as primary building block for the synthesis of
methoxylated phenyl bioisosteres. Cubanisidine 25 was
This article is protected by copyright. All rights reserved.

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
oxidation to the corresponding aldehyde 27 was achieved using
electrochemical reaction involving cubanes will be of great
interest in medicinal and materials chemistry, with great promise
for further developments. Further applications are under
investigation in our laboratories.
Dess-Martin periodinane (DMP). Finally,
a
condensation
reaction[38] of 4-methoxy-1-cubanecarbaldehyde (27) and
phthalide 28 using NaOMe in EtOAc gave the desired
cubanisindione 29 in 33% yield.
anode
–1 e–
–CO2
OMe
OMe
OMe
–1 e–
DPPA
Et3N
OMe
CO2Me
CO2Me
CO2Me
HCl
Cl–
t-BuOH
reflux
MeOH
(91%)
H3N
CO2R
NHBoc
23
(69%)
CO2Me
H2N
–
CO2
25 (456 mg)
26
R = Me 7
NaOH
(94%)
p-anisidine
bioisostere
p-anisidine
(relatively toxic)
–H+
R = H 24
H2 + 2 RO–
cathode
OR
2 ROH
ROH
OMe
i. BH3•SMe2 ii. DMP
THF (82%) CH2Cl2 (69%)
OMe
+2 e–
O
O
NaOMe
EtOAc
OMe
O
O
O
30
O
O
29 (33%)
Anisindione (Miradon®) derivative
“Cubanisindione”
H
27
28
Scheme 3. Methyl 4-methoxy-1-cubanecarboxylate (7) as a precursor of
anisole bioisosteres.
In the electrolysis at a Pt anode (but not a C/PVDF anode),
the addition of acetic acid was essential in order to achieve a
satisfactory yield of the methoxylated cubane 7. Cyclic
voltammetry confirmed the electroactive species to be the
carboxylate anion (Figure 2); in the absence of Et3N, no
oxidation peak is observed (green curve) at potentials prior to
solvent decomposition, but after the addition of the base a clear
peak (red curve) is seen. This peak is unchanged by the addition
of acetic acid (blue line, see SI for further details, Section 6).
The poor yield of 7 at Pt in the absence of acetic acid is
surprising: we postulate that the presence of acetic acid modifies
the properties of the surface, possibly by adsorbed methyl
radicals.[39] In addition, the observation of the cross Kolbe-
product 9 and the hydrogenolysis product, 10, indicate that the
cubyl radical is an intermediate in the formation of the
carbocation.
Figure 2. Proposed mechanism and cyclic voltammograms of the acidic
Hofer–Moest reaction conditions.
Acknowledgements
The authors acknowledge financial support from the ERDF
(LabFact: InterReg V project 121) and EPSRC (Photo-Electro
Programme Grant EP/P013341/1 and EP/K039466/1).
Keywords: cubane • electrosynthesis • flow electrochemistry •
oxidative decarboxylation • bioisostere
[1]
[2]
[3]
P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157-3158.
P. E. Eaton, Angew. Chem. Int. Ed. 1992, 31, 1421-1436.
T. A. Reekie, C. M. Williams, L. M. Rendina, M. Kassiou, J. Med. Chem.
2019 62, 1078-1095.
In conclusion, to the best of our knowledge, we report the
first electrochemical cubane ring system functionalisation,
through a Hofer-Moest oxidative decarboxylative ether formation.
Successful investigation of the substrate scope involving
potentially electrochemical oxidisable functionalities clearly
indicates the mildness of the reaction conditions. The use of flow
electrolysis facilitates laboratory scale-up, as shown by a
gramme-scale synthesis in a matter of hours in the same reactor
and under the same conditions, nicely demonstrating the
advantage of this approach. A further straightforward 3-step
process provided a cubanisidine biosiostere building block, and
another example of a methoxycubane analogue of a drug is
[4]
[5]
P. K. Mykhailiuk, Org. Biomol. Chem. 2019, 17, 2839-2849.
B. A. Chalmers, H. Xing, S. Houston, C. Clark, S. Ghassabian, A. Kuo,
B. Cao, A. Reitsma, C. E. P. Murray, J. E. Stok, G. M. Boyle, C. J.
Pierce, S. W. Littler, D. A. Winkler, P. V. Bernhardt, C. Pasay, J. J. De
Voss, J. McCarthy, P. G. Parsons, G. H. Walter, M. T. Smith, H. M.
Cooper, S. K. Nilsson, J. Tsanaktsidis, G. P. Savage, C. M. Williams,
Angew. Chem. Int. Ed. 2016, 55, 3380-3385.
[6]
[7]
G. M. Locke, S. S. R. Bernhard, M. O. Senge, Chem. Eur. J. 2019, 25,
4590-4647.
(a) M. J. Falkiner, S. W. Littler, K. J. McRae, G. P. Savage, J.
Tsanaktsidis, Org. Process Res. Dev. 2013, 17, 1503-1509; (b) N. B.
Chapman, J. Key, K. J. Toyne, J. Org. Chem. 1970, 35, 3860-3867.
K. F. Biegasiewicz, J. R. Griffiths, G. P. Savage, J. Tsanaktsidis, R.
Priefer, Chem. Rev. 2015, 115, 6719-6745.
[8]
[9]
described. Organic electrosynthesis is considered as
a
sustainable methodology, since electrical current replaces
potentially hazardous/toxic and costly chemical reagents, and
any ensuing waste stream.[40] This is clearly shown here, with
facile access to the methoxycubane core from the commercially
available 1 by only using methanol as solvent and triethylamine
(0.5 equiv.) as reagent. No supporting electrolytes were required,
facilitating purification. Hence, this first demonstration of an
R. M. Moriarty, J. S. Khosrowshahi, R. S. Miller, J. Flippen-Andersen, R.
Gilardi, J. Am. Chem. Soc. 1989, 111, 8943-8944.
[10] F. Toriyama, J. Cornella, L. Wimmer, T. G. Chen, D. D. Dixon, G.
Creech, P. S. Baran, J. Am. Chem. Soc. 2016, 138, 11132-11135.
[11] S. S. R. Bernhard, G. M. Locke, S. Plunkett, A. Meindl, K. J. Flanagan,
M. O. Senge, Chem. Eur. J. 2018, 24, 1026-1030.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
[12] T. Qin, L. R. Malins, J. T. Edwards, R. R. Merchant, A. J. Novak, J. Z.
Zhong, R. B. Mills, M. Yan, C. Yuan, M. D. Eastgate, P. S. Baran,
Angew. Chem. Int. Ed. 2017, 56, 260-265.
[28] J. Xiang, M. Shang, Y. Kawamata, H. Lundberg, S. Reisberg, M. Chen,
P. Mykhailiuk, G. Beutner, M. Collins, A. Davies, M. Del Bel, G. Gallego,
J. Spangler, J. T. Starr, S. Yang, D. Blackmond, P. Baran, Nature 2019,
573, 398-402.
[13] A. Fawcett, J. Pradeilles, Y. Wang, T. Mutsuga, E. L. Myers, V. K.
Aggarwal, Science 2017, 357, 283.
[14] C. Li, J. Wang, L. M. Barton, S. Yu, M. Tian, D. S. Peters, M. Kumar, A.
Yu, W, K. A. Johnson, A. K. Chatterjee, M. Yan, P. S. Baran, Science
2017, 356, eaam7355.
[29] M. Küpper, V. Hessel, H. Löwe, W. Stark, J. Kinkel, M. Michel, H.
Schmidt-Traub, Electrochim. Acta 2003, 48, 2889-2896.
[30] Reviews: (a) D. Pletcher, R. A. Green, R. C. D. Brown, Chem. Rev.
2018, 118, 4573-4591; (b) M. Atobe, H. Tateno, Y. Matsumura, Chem.
Rev. 2018, 118, 4541-4572; (c) A. A. Folgueiras-Amador, T. Wirth, in
Science of Synthesis, Thieme, Stuttgart, 2018, pp. 147-189; (d) J. -i.
Yoshida, Chem. Commun. 2005, 4509-4516.
[15] E. Della, J. Tsanaktsidis, Aust. J. Chem. 1986, 39, 2061-2066.
[16] R. Gianatassio, S. Kawamura, C. L. Eprile, K. Foo, J. Ge, A. C. Burns,
M. R. Collins, P. S. Baran, Angew. Chem. Int. Ed. 2014, 53, 9851-9855.
[17] R. S. Abeywickrema, E. W. Della, J. Org. Chem. 1980, 45, 4226-4229.
[18] J. R. Griffiths, J. Tsanaktsidis, G. P. Savage, R. Priefer, Thermochim.
Acta 2010, 499, 15-20.
[31] (a) M. Elsherbini, B. Winterson, H. Alharbi, A. A. Folgueiras-Amador, C.
Génot, T. Wirth, Angew. Chem. Int. Ed. 2019, 58, 9811-9815; (b) C.
Gütz, A. Stenglein, S. R. Waldvogel, Org. Process Res. Dev. 2017, 21,
771-778.
[19] R. M. Moriarty, J. S. Khosrowshahi, T. M. Dalecki, J. Chem. Soc.,
Chem. Commun. 1987, 675-676.
[20] J. Tsanaktsidis, P. E. Eaton, Tetrahedron Lett. 1989, 30, 6967-6968.
[21] (a) H. Xing, S. D. Houston, X. Chen, S. Ghassabian, T. Fahrenhorst-
Jones, A. Kuo, C. P. Murray, K. A. Conn, K. N. Jaeschke, D. Y. Jin, C.
Pasay, P. V. Bernhardt, J. M. Burns, J. Tsanaktsidis, G. P. Savage, G.
M. Boyle, J. J. De Voss, J. McCarthy, G. H. Walter, T. H. J. Burne, M. T.
Smith, J. K. Tie, C. M. Williams, Chem. Eur. J. 2019, 25, 2729-2734; (b)
S. D. Houston, H. Xing, P. V. Bernhardt, T. J. Vanden Berg, J.
Tsanaktsidis, G. P. Savage, C. M. Williams, Chem. Eur. J. 2019, 25,
2735-2739.
[32] R. A. Green, R. C. D. Brown, D. Pletcher, B. Harji, Electrochem.
Commun. 2016, 73, 63-66.
[33] For the use of Et3N in anodic oxidation of carboxylic acids to generate
carbocationic intermediates: (a) E. J. Corey, N. L. Bauld, R. T. La
Londe, J. Casanova Jr., E. T. Kaiser, J. Am. Chem. Soc. 1960, 82,
2645-2656; (b) P. Renaud, D. Seebach, Synthesis 1986, 5, 424-426.
[34] T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 2019,
62, 5276−5297.
[35] L. Schulz, M. Enders, B. Elsler, D. Schollmeyer, K. M. Dyballa, R.
Franke, S. R. Waldvogel, Angew. Chem. Int. Ed. 2017, 56, 4877-4881.
[36] M. A. Kabeshov, B. Musio, P. R. D. Murray, D. L. Browne, S. V. Ley,
Org. Lett. 2014, 16, 4618-4621.
[22] D. S. Reddy, G. P. Sollott, P. E. Eaton, J. Org. Chem. 1989, 54, 722-
723.
[23] H. Irngartinger, S. Strack, F. Gredel, A. Dreuw, E. W. Della, Eur. J. Org.
Chem. 1999, 1253-1257.
[37] T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. 1972, 94, 6203-
6205.
[24] (a) P. E. Eaton, C. X. Yang, Y. Xiong, J. Am. Chem. Soc. 1990, 112,
3225-3226; (b) R. M. Moriarty, S. M. Tuladhar, R. Penmasta, A. K.
Awasthi, J. Am. Chem. Soc. 1990, 112, 3228-3230.
[38] K. Inoue, K. Urushibara, M. Kanai, K. Yura, S. Fujii, M. Ishigami-Yuasa,
Y. Hashimoto, S. Mori, E. Kawachi, M. Matsumura, Eur. J. Med. Chem.
2015, 102, 310-319.
[25] Review: (a) R. A. Green, R. C. D. Brown, D. Pletcher, J. Flow Chem.
2016, 6, 191-197; Selected examples: (b) R. A. Green, K. E. Jolley, A.
A. M. Al-Hadedi, D. Pletcher, D. C. Harrowven, O. De Frutos, C.
Mateos, D. J. Klauber, J. A. Rincón, R. C. D. Brown, Org. Lett. 2017, 19,
2050-2053; (c) R. A. Green, D. Pletcher, S. G. Leach, R. C. D. Brown,
Org. Lett. 2016, 18, 1198-1201; (d) R. A. Green, D. Pletcher, S. G.
Leach, R. C. D. Brown, Org. Lett. 2015, 17, 3290-3293; (e) J. T. Hill-
Cousins, J. Kuleshova, R. A. Green, P. R. Birkin, D. Pletcher, T. J.
Underwood, S. G. Leach, R. C. D. Brown, ChemSusChem 2012, 5,
326-331.
[39] B. E. Conway, T. C. Liu, J. Electroanal. Chem. 1988, 242, 317-322.
[40] (a) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R.
Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594-5619; (b) K. D.
Moeller, Chem. Rev. 2018, 118, 4817-4833; (c) M. Yan, Y. Kawamata,
P. S. Baran, Chem. Rev. 2017, 117, 13230-13319; (d) O. Hammerich,
B. Speiser, Organic electrochemistry: revised and expanded, CRC
Press, 2015; (e) T. Fuchigami, S. Inagi, Fundamentals and Applications
of Organic Electrochemistry, Vol. 5, Wiley Online Library, 2015.
[26] J. -i. Yoshida, A. Shimizu, R. Hayashi, Chem. Rev. 2018, 118, 4702-
4730.
[27] H. J. Schäfer, in Electrochemistry IV, Springer, 1990, pp. 91-151.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904479
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Diego E. Collin, Ana A. Folgueiras-
Amador, Derek Pletcher, Mark E. Light,
Bruno Linclau, and Richard C. D.
Brown*
Page No. – Page No.
Cubane electrochemistry: direct
conversion of cubane carboxylic
acids to alkoxy cubanes using the
Hofer–Moest reaction under flow
conditions
Oxidative anodic decarboxylation of cubane carboxylic acids leading to cubyl
ethers is described. This first direct electrochemical functionalisation at the cubane
system is chemoselective, and scalable, with yields of up to 60%.
This article is protected by copyright. All rights reserved.