Letter
1038/s41586-019-1539-y
Hindered dialkyl ether synthesis with
electrogenerated carbocations
Jinbao Xiang1,2,9, Ming Shang1,9, Yu Kawamata1, Helena Lundberg1,3, Solomon H. Reisberg1, Miao Chen1, Pavel Mykhailiuk1,4,5,
Gregory Beutner6, Michael R. Collins7, Alyn Davies8, Matthew Del Bel7, Gary M. Gallego7, Jillian E. Spangler7, Jeremy Starr8,
Shouliang Yang7, Donna G. Blackmond1 & Phil S. Baran1*
Hindered ethers are of high value for various applications; however,
they remain an underexplored area of chemical space because
they are difficult to synthesize via conventional reactions1,2.
Such motifs are highly coveted in medicinal chemistry, because
extensive substitution about the ether bond prevents unwanted
metabolic processes that can lead to rapid degradation in vivo.
Here we report a simple route towards the synthesis of hindered
ethers, in which electrochemical oxidation is used to liberate
high-energy carbocations from simple carboxylic acids. These
reactive carbocation intermediates, which are generated with low
electrochemical potentials, capture an alcohol donor under non-
acidic conditions; this enables the formation of a range of ethers
(more than 80 have been prepared here) that would otherwise be
difficult to access. The carbocations can also be intercepted by
simple nucleophiles, leading to the formation of hindered alcohols
and even alkyl fluorides. This method was evaluated for its ability to
circumvent the synthetic bottlenecks encountered in the preparation
of 12 chemical scaffolds, leading to higher yields of the required
products, in addition to substantial reductions in the number of
steps and the amount of labour required to prepare them. The use
of molecular probes and the results of kinetic studies support the
proposed mechanism and the role of additives under the conditions
examined. The reaction manifold that we report here demonstrates
the power of electrochemistry to access highly reactive intermediates
under mild conditions and, in turn, the substantial improvements
in efficiency that can be achieved with these otherwise-inaccessible
intermediates.
The Williamson ether synthesis3,4 is a long-established method by
which to synthesize primary alkyl ethers via SN2 substitution (Fig. 1a).
However, in contexts involving secondary or tertiary alkyl halides the
reaction often derails, leading to elimination byproducts or to no
reaction at all. Hindered ether 1, which is a key intermediate in the
synthesis of an aurora kinase modulator, exemplifies this commonly
faced challenge. Despite the documented utility of hindered ethers1,2,
very little progress has been made in facilitating access to them. The
alternative workhorse method, the Mitsunobu reaction, also fails in
such settings owing to the steric demands of the SN2 process and the
pKa requirements of the nucleophile5. To the best of our knowledge,
the most frequently used method for the synthesis of hindered dialkyl
ether bonds still uses carbocation chemistry accessed from olefins
(hydroalkoxylation) under strongly acidic conditions6. Although this
transformation has been known for nearly a century, its use is sub-
stantially limited in scope owing to sluggish reactivity and a lack of
chemoselectivity7. For example, in order to prepare hindered ether 1,
a multi-step route via 4-hydroxyproline 2 (R = CO2Me) was used. The
synthesis required over 6 days of reaction time and gave the required
product in less than 4% overall yield; the key C–O bond-forming reac-
tion—the treatment of methylenecyclobutane with BF3·Et2O in the
1
Department of Chemistry, Scripps Research, La Jolla, CA, USA. 2The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin
University, Jilin, People’s Republic of China. 3Department of Chemistry, KTH Royal Institute of Technology, Stockholm, Sweden. 4Enamine Ltd, Kiev, Ukraine. 5Chemistry Department, Taras
Shevchenko National University of Kyiv, Kiev, Ukraine. 6Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA. 7Department of Chemistry, La Jolla Laboratories,
Pfizer Inc, San Diego, CA, USA. 8Pfizer Medicinal Sciences, Groton, CT, USA. 9These authors contributed equally: Jinbao Xiang, Ming Shang. *e-mail: pbaran@scripps.edu
https://doi.org/10.
presence of the requisite secondary alcohol—provides the ether in only
11% yield8.
Distinct from sterically sensitive SN2 and strongly acidic carboca-
tion pathways, there is a third class of ether synthesis that has been
known for many years but has remained largely underexplored. This
class (Fig. 1a, yellow inset) stems from the oldest synthetic organic
electrochemical reaction, the Kolbe dimerization, which was discov-
ered9 in 1847. In the so-called interrupted Kolbe variant, known as
the Hofer–Moest reaction10, electrolytic oxidation of a carboxylic acid
under mildly alkaline conditions generates a carbocation that can be
captured by incipient nucleophiles10–18. A distinct advantage of this
reaction is the non-acidic generation of high-energy carbocations
directly from carboxylic acids.
We were therefore surprised to find a dearth of applications of the
Hofer–Moest reaction in synthetic contexts (Fig. 1b). Indeed, much
more complex catalytic systems that take advantage of photolytic con-
ditions have been developed to make alkyl–aryl ethers19. There are
probably two reasons for the limited exploration of electrolytic decar-
boxylative ether synthesis: first, the barrier to entry into electrosynthesis
has traditionally been high for a practicing synthetic organic chem-
ist20. Second, all Hofer–Moest systems known so far have required
solvent-quantities of the alcoholic nucleophile, which is untenable for
complex ethereal substrates. The alcoholic solvent—in addition to func-
tioning as a reagent—permits current to pass and also acts as an electron
sink to balance the electrochemical process, liberating hydrogen gas.
Herein, we report how the generation of carbocations from unac-
tivated, aliphatic carboxylic acids—and their subsequent capture by
heteroatom nucleophiles—can be leveraged to provide a wide array of
hindered C–X bonds.
Several key literature precedents can be highlighted that aided this
development. It is known that carbon-based electrodes favour the
desired carbocation generation, whereas platinum electrodes favour
unproductive radical (Kolbe-type) dimerization21. It is also known that
inert, non-oxidizable anions (for example, ClO4−) enhance cation-like
reactivity in the Hofer–Moest reaction22. Mildly alkaline conditions
are known to be beneficial for the desired carbocation formation22,23.
Finally, simple undivided cells are generally used in this process, which
suggests that cathodic reduction would not interfere substantially with
the reaction.
It became immediately apparent that limiting the amount of alco-
hol posed several considerable challenges: the decomposition of the
carbocation due to the low nucleophilicity of alcohols; the competitive
trapping of the carbocation by water; the consumption of alcohols by
anodic oxidation; and the necessity of an external electron-acceptor in
order to balance electrons. Figure 1c summarizes the results of around
1,000 experiments (see Supplementary Information for an extensive
sampling) that were undertaken in order to solve these problems.
Not surprisingly, initial exploratory experiments using the proposed
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 RESEARCH Letter

a Pathways to hindered dialkyl ethers b Previous decarboxylative etherifications

Me
Photochemistry
X
R1 [Ir] cat. R1
X = LG or OH R2 R2
+ [Cu] cat.
SN2; problematic on hindered tertiary systems R3 CO2A* HO R3 O
FG hQ FG
Me Alkyl NHPI esters Phenols Alkyl aryl ethers
O BF3-cat. addition HO
NCbz (11% yield) NCbz
Hydroalkoxylation; <4% overall yield (>6 d) Electrochemistry
1, kinase R A
OH 2 R1
modulator intermediate R1 CO2H O
Me + Alkyl–OH Alkyl
CO2H R2 R2
R3 Anodic oxidation R3
This work

Direct decarboxylative etherification Typical acid scope Alcohol scope (solvent)

A R2 HO2C OH
X R 1 R1 MeOH
R1 + R3 R–OH R1 O R6 CO2H
R1 CO2H R2
2 R2 R5 Me OH
R Anodic CO2H
R3 R2 R3 R4 OH
oxidation X = N, O, Si
Alkyl acid Carbocation Hindered ethers Me Me
HO
Alkyl–CO2H (Me, nPr, etc.)
• Ubiquitous • Reactive • Difficult to access
• Inexpensive • Non-acidic generation • Medicinally important

c Reaction optimization
Byproducts (from 3)
Me Base Me Me Me
Me Me Me Ph Me Me
Electrolyte (0.1 M) Ph + Me
+ Ph H
Ph CO2H HO Ph Additive, solvent, RT Ph O Ph Ph OH
Me Me
3 4 Me 5
+C/–C, 10 mA, 3 h 6 7 8
(0.2 mmol) (0.6 mmol)
From radical Elimination Hydration
Entry Conditionsa Yield (%)b 5 6 7 8 9 10
1 Et3N, nBu4NClO4, DMF or acetone <1 – – <1 <1 –
2 K2CO3, nBu4NClO4, DMF <1 15 <1 40 <1 – Byproducts (from 4)
3 2,4,6-collidine, nBu4NPF 6, DMF 6 3 28 14 <1 – Me Me O
via Me
4 2,4,6-collidine, nBu4NPF 6, CH2Cl2 40 4 - 14 6 – Ph
5 2,4,6-collidine, nBu4NPF 6, 3 Å MS, CH2Cl2 43 5 2 <1 3 – O Ph Ph O +

6c AgPF6, 2,4,6-collidine, nBu4NPF6, 3 Å MS, CH2Cl2 79 (77)d – – – 7 – Me Me Ph

9 10
7 As in entry 6, 1 equiv. alcohol 34 <1 <1 <1 6 <1 Anodic oxidation Ionization
8 AgPF6, nBu4NPF6, 3 Å MS, CH2Cl2 – <1 <1 – 22 54

Fig. 1 | Background and reaction development. a, The synthesis of
hindered ethers is a long-standing challenge in organic synthesis.
A; constant-current electrolysis; cat., catalyst; Cbz, carboxybenzyl;
LG, leaving group. b, Historical context and previous strategies for
decarboxylative etherification. FG, functional group; NHPI,
N-hydroxyphthalimide. c, Development and optimization of hindered
ether synthesis depicted through electromechanistic analysis. aCompound
3 (0.2 mmol), 3.0 equiv. of alcohol 4 (except where designated). bYield
based on gas chromatography. All entries were performed in triplicate.
c
Conditions: acid 3 (0.2 mmol), alcohol 4 (0.6 mmol), AgPF6 (0.3 mmol),
2,4,6-collidine (0.6 mmol), nBu4NPF6 (0.1 M), 3 Å molecular sieves
(150 mg), dichloromethane (CH2Cl2; 3 ml), current (I) = 10 mA, 3 h.
d
Isolated yield. DMF, N,N-dimethylformamide; RT, room temperature;
+C/−C represents the graphite electrodes.

conversion of 3 and 4 to 5 as an example—based on the literature prece-
dent available11,22—led to only trace amounts of product (entry 1). The
conversion of the carboxylate was improved by choosing potassium
carbonate or 2,4,6-collidine as a non-oxidizable base (entries 2, 3),
although 6 and 7 were identified as major byproducts due to the pres-
ence of radical intermediate22 and elimination pathways, respectively.
These problems were effectively suppressed by changing the solvent
to dichloromethane (entry 4), which resulted in a large increase of the
desired ether product. In dichloromethane, hydration of the carboca-
tion (leading to 8) persisted (entry 4), which was suppressed by the
addition of 3 Å molecular sieves (entry 5). It was also found that dichlo-
romethane was apparently reduced at the cathode (Supplementary
Fig. 2), acting as an electron sink. Past approaches using water or simple
alcohols as the solvent did not need to address this issue, as the solvent
can serve as both the reagent and an electron sink (via proton reduc-
tion). Accordingly, the addition of a better sacrificial oxidant (silver
hexafluorophosphate, AgPF6) considerably improved the yield of 5,
leading to our optimized conditions (entry 6). The addition of AgPF6
also completely suppressed the formation of 6 and 7, although this
effect was found to vary by substrate and—in some cases—silver addi-
tives are not necessary at all. Negative controls confirmed the necessity
of a slight stoichiometric excess of the alcoholic partner (entry 7). In
the absence of base, no desired product was observed, with the major
products being the ketone 9 and the ester 10 (entry 8).
The patent literature is replete with examples of hindered ethers in
various pharmaceutical and materials applications. Although carbo-
cation-based routes from olefins predominate in the literature, elec-
trochemical access to such valuable entities has notable advantages in
terms of the time required, the step count and the overall yield. Figure 2
shows an abbreviated depiction of six such applications as well as the
more than 80 ethers prepared (see Supplementary Information for a full
listing of substrates as well as a comparison to previous routes). Primary
carboxylic acids and certain secondary systems are not compatible with
electrochemical etherification, because the resultant carbocations are
not sufficiently stable. However, this limitation is inconsequential from
a synthetic perspective, as those ethers can be easily prepared through
standard SN2-type approaches3–5. Acids bearing various functional
groups are tolerated, such as Boc-protected amines (17), aryl and alkyl
halides (25, 27, 30), olefins (26), esters (29, 39), enones (39), ethers (35,
36, 62) and even oxidation-prone boronic esters (28). Similarly, the
scope of alcohol coupling partners is vast and includes acid-labile and
oxidation-prone chiral secondary benzylic alcohols (17), deuterated
systems (49), azetidinyl alcohols (50), protected sugars (53) and olefin-
containing alcohols (48, 51, 59), as well as alcohols containing acetals and
esters (44), halides (15), nitriles (45), nitro groups (see Supplementary
Information) and even Lewis-basic heterocycles (42, 43, 45). The ability
to tolerate chiral, ionizable secondary alcohols is worth emphasizing,
because acidic methods for ether synthesis using such alcohols would

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 Letter RESEARCH

O 2,4,6-collidine (3.0 equiv.)

R4 n
Bu4NPF 6 (0.1 M) R1 R4
R1 R5 R2 R5
OH +
R2 HO R6 AgPF 6 (1.5 equiv.) R3 O R6
R3 3 Å MS, CH2Cl2 (3 ml), RT
(0.2 mmol, 1.0 equiv.) (3.0 equiv.) +C/–C, 10 mA, 3 h
Applicationsa
Me CO2Me CO2Me Me Me
O BocN O O Me
NCbz O Br
O Me O
NHCbz NHCbz
Me O Me
Me Me Me Me O
OH
1 11 12 13 14 15
Current route: 2 steps 1 step 1 step 1 step 1 step 1 step
(51%, 15 h) (32%, 3 h) (40%, 3 h) (21%, 3 h) (42%, 3 h) (81%, 3 h)
Previous route: 3 steps 5 steps 7 steps 6 steps 4 steps 2 steps
(<4% overall, >6 d) (31% overall, 2.5 d) (37% overall, >3 d) (24% overall, 2 d) (47% overall, >2 d) (<2% overall, >5 d)
Tertiary acids Secondary alcohols k CD3
Me Me
Me Me D
Me Me Me Me
O O O O CD3
O O Me Me 49: 82%j
Me
Me BocN Me Me
n Me O Me Me Me NCbz
16, 65% 17, 45% b,c n = 2, 18: 54%b,c / 40%c,d
95% e.e. n = 1, 19: 40% b,c
/ 32% c,d CF 3 N Me O
R Ts
46, 60%b 47, 39%e 48, 32%e 50, 70%f
O Cl
O O Cl
R O
Cl Me Me
Me Me Me Me
Me Me Me Me Me
R = H, 22: 61%e
R = nPr, 20: 52%b,c 25, 24%f,g / 43%f,g,h Me
b
R = Me, 23: 58% / 62%b,j / 50%d Me H Me
R = Bn, 21: 41% O
R = PhCH2CH2, 24: 35% b,c
/ 28% c,d
NBoc Me
R R Me Me Me O Me
O Me
H H
CO2Me O O Me
O O Ph e Ph
O 52, 66%
Ph O 51, 54%e
Me Me O
X 53, 52%f O
Me Me Me Me
26, 43%f,g / 31%d R = R = –(CH2) 5–, X = F, 27, 46%f
5, 77% j / 78%f / 54%i R = R = Me, X = BPin, 28, 54%f Tertiary alcoholsk Me

Me Me
Secondary acids BocN Me Me Me Me
Cl Me Me
CO2Me
O Me O Me O Me O
O Me
O Me Cl
54, 42% 55, 65% 56, 52%
Me
Me Me Me
29, 41%f,g 30, 74%, d.r. = 1:1 Me
31, 68%f
Me Me Me O Me
Me
O Me Me Me Me
O O
O 16
O
Me CF 3 Me
Me 57, 46%f 59, 28%b,c
58, 65% j/54%i
32, 80% / 48%f,j i 33, 57%f 34, 7%

α-heteroatom acids Fluorinated ethersk

O Me CF 3 OMe Me
O F F F F NCbz
BocN
O N O O Ph
O O O
O
35, 58% O 37, 82%f
36, 55%j 60, 46%f,g 61, 23%f 62, 88%f,g, d.r. = 1:1
Drugs/natural products CF 2H
O Me
Me Me O
Me H CF 3 OMe Me Me Me CH2F
Me O Ph
Me O AcO H Me O Me O CH2F
H
Me Me
Me Me Me
63, 42%f,g 64, 51%f,g 65, 42%f,g,j
38, 90% j, d.r. = 1:1 39, 35%b,c, d.r. = 1:1
Primary alcoholsk
PEG ethers
Ar H
O Me N N Ph Me Me
Ph O
Me Me O OH
Me Me Ph O S O O O
Cl OMe
O 41, 59%j O Me
H Ar = 2,4-diF 66, 59%f
Me Me Me Cl Me
40, 48%f 42, 68%e –Ph R O
Me Me O O O Me
O Me NC
Ph O Me
Me O
Me Me
O O O Me Et CN BocN
N Me Me
N
Ph O N Cl
Me Me Ph R =
O O Me
N O
Me Me 44, 52%f Me 67, 48%e,j
Me 45, 42%e e 69, 25%b,c
OMe Et 68, 57%
43, 50%f

Fig. 2 | Applications, and partial scope of hindered ether synthesis molecular sieves (100 mg), CH2Cl2 (2 ml), I = 10 mA, 3 h. fAgClO4
via electrochemical decarboxylation. aSee Supplementary Information (0.6 mmol) instead of AgPF6, nBu4NClO4 (0.1 M) instead of nBu4NPF6. g4.0
for literature routes. bAgSbF6 (0.3 mmol) instead of AgPF6. cDBU or 6.0 equiv. alcohol. h1.5 ml CH2Cl2, I = 7.5 mA, 4 h. i nBu4NClO4 (0.1 M)
(1,8-diazabicyclo[5.4.0]undec-7-ene; 0.6 mmol) instead of 2,4,6-collidine. instead of nBu4NPF6, no AgPF6. jReaction performed in triplicate; yield is
d
KSbF6 (0.3 mmol) instead of AgPF6. eAlcohol as limiting reagent, average of three runs. kSee Supplementary Information for more examples.
conditions: alcohol (0.15 mmol), carboxylic acid (0.45 mmol), AgClO4 Boc, tert-butyloxycarbonyl; d.r., diastereomeric ratio; MS, molecular
(0.6 mmol), 2,4,6-collidine (0.675 mmol), nBu4NClO4 (0.2 M), 3 Å sieves; Ts, tosyl.

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 RESEARCH Letter

O 2,4,6-collidine (1.5 equiv.) CO2Me CO2Me

nBu NPF (0.1 M) R1 Nu Commercially
R1 + Nu
4 6
OH R 2 available
Acetone (3 ml), RT
R2 R3 HO2C 70 HO2C 71
R3 +C/–C (10 mA), 3 h
(0.2 mmol, 1.0 equiv) Me OH
F

Applicationsa F H
O
CO2H CO2Me NH2 CO2Me Me Me Me

H H Me
MeO HO MeO HO HO HO
72 73 74 75 76 77
Me Me
Current route: 2 steps 1 step 2 steps 2 steps 3 steps 1 step
(56%, 9 h) (66%, 3 h) (31%, 24 h) (22%, 27 h) (17%, 21 h) (61%, d.r. = 1.1:1, 3 h)
Previous route: 7 steps 9 steps 7 steps 14 steps 7 steps 5 steps
(21% overall, >4 d) (15% overall, >5 d) (12% overall, 3 d) (5% overall, >9 d) (8% overall, 62 h) (yield not reported)
Me
Tertiary and secondary acidsb
OH Me
Me OH Me
18 Me Me Me O
OH Me OH
Me Me OH
OH Me
R H N
OH Me
N Me
MeO2C R R O
Me Me OH
c c c
R = Ph, 78, 52% 80, 95%c 81, 61% yield R = Boc, 82: 32% R = Br, 84: 67% c
86, 53% from 87, 32%c (d.r. = 3:1) 88, 40% c
R = PhO, 79, 66%c (67.1% R = Ts, 83: 69%c R = Bpin, 85: 55%c (1S)-(–)-camphanic acid from dehydroabietic acid from indoprofen
18
O labelled)c
Esterification Fluorination Amidation
F Me F O Me H
F F O F F O Me Me
N

O F N F
O CO2Me O
N
Cl Cl Boc O

89, 31%d 90, 36%d 91, 35%e 92, 58%e 93, 18%e 94, 62%e 95, 14%d

Scale-up

Me Me Me Me A
CO2H OH
Me Me
+ HO Ph O + H2O
Ph CO2H
MeO2C MeO2C
3 (±)-4 71
1.97 g (12 mmol) 4.40 g (36 mmol) (±)-5, 2.08 g (72%)f 1.53 g (7.2 mmol) 0.6 ml 81, 0.86 g (65%)g

Fig. 3 | Applications and partial scope of trapping electrogenerated
carbocations with other nucleophiles along with scalability
demonstration. aSee Supplementary Information for literature routes.
b
See Supplementary Information for more examples. cH2O (0.1 ml) as
nucleophile. dCarboxylic acid or phenylacetonitrile as nucleophile
(0.6 mmol, 3 equiv.), conditions: AgClO4 (0.6 mmol, 3 equiv.),
2,4,6-collidine (0.6 mmol, 3 equiv.), nBu4NClO4 (0.1 M), 3 Å molecular
sieves (150 mg), CH2Cl2 (3 ml). eKF (0.72 mmol, 3.6 equiv.) as nucleophile,
conditions: 18-crown-6 (0.72 mmol, 3.6 eq), AgClO4 (0.6 mmol, 3 equiv.),
2,4,6-collidine (0.6 mmol, 3 equiv.), nBu4NPF6 (0.1 M), 3 Å MS (150 mg),
CH2Cl2 (3 ml). fConditions for scale-up to (±)-5 (each reaction): 3
(2.4 mmol), (±)-4 (7.2 mmol), 2,4,6-collidine (3.6 mmol), nBu4NClO4
(0.1 M), 3 Å molecular sieves (450 mg), CH2Cl2 (9 ml) +C/−C (10 mA),
RT, 15 h. gConditions for scale-up to 81 (each reaction): 71 (1.2 mmol),
H2O (0.1 ml), 2,4,6-collidine (1.8 mmol), nBu4NPF6 (0.02 M), acetone
(9 ml), +C/−C (10 mA), RT, 12 h. Nu, nucleophile; pin, pinacolato.

lead to elimination or racemization (17 is formed in 95% enantiomeric
excess (e.e.)). Electrogenerated cations bearing fluorine atoms can also
be intercepted, opening up a range of organofluorine-containing ether
systems that were previously either difficult to access or unknown
(see Supplementary Information for full listing of fluorinated ethers).
Finally, the synthesis of polyethyleneglycol (PEG) ethers—which histori-
cally has been laborious—can be achieved in a modular fashion using this
process (no PEG ethers analogous to 66–69 are known). To ensure the
robustness of the process, ten randomly selected examples in Fig. 2 were
run in triplicate, with yields varying by no more than 5% between runs.
As mentioned above, the use of simple alcohols such as methanol—
as well as water—is already known in electrochemical decarboxyla-
tive processes10–18 (Fig. 1b). However, the scope of such processes is
quite limited. The conditions developed here were therefore adapted
for these related reactions (Supplementary Information). In order to
render this reaction general, the choice of electrolyte (tetrabutylam-
monium hexafluorophosphate, nBu4NPF6) and base (2,4,6-collidine)
was crucial, whereas silver additives were found to be unnecessary. As
with the synthesis of hindered ethers, the most convincing case for
the use of this reaction stems from its ability to substantially truncate
synthetic pathways. Six such examples (72–77) are illustrated in Fig. 3
(see Supplementary Information).
The addition of water to generate various tertiary and secondary
alcohols is a broadly applicable process, with selected examples depicted
in Fig. 3 (for additional examples, see Supplementary Information).
Again, the chemoselectivity is on par with that observed in the syn-
thesis of hindered ethers: aryl bromides (84), boronic esters (85),
electron-rich aromatics (87), lactams (88), ethers (79) and esters (81)
are tolerated. In preliminary studies, the possibility of adding other
nucleophiles to the putative electrogenerated carbocations was also
studied. Carboxylates that are not capable of decarboxylation under
these conditions could act as nucleophiles, thus providing hindered
esters (89, 90)24. Useful organofluorine building blocks could also be
accessed (91–94) in a process that might be of use in radiolabelling
studies, because the fluorine source used (the inexpensive salt potas-
sium fluoride) is preferred in such situations25. Finally, using benzoni-
trile as a nucleophile led to the expected Ritter-type product (95), albeit
in lower yield26. The robust and practical nature of this process was
also demonstrated by the gram-scale preparation of 5 and 81 through
etherification and hydroxylation processes, respectively. In the case of

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large-scale etherification, the silver salt additive could be left out with
a only minimal effect on yield (78% in the presence of silver salt, com-
pared with 72% when this additive is omitted).
Extensive mechanistic studies were also undertaken in order to under-
stand the role of the additives and the nature of the reactive interme-
diate. In summary, the mechanism is likely to involve the rate-limiting
oxidation of a carboxylate on the anode to generate a carbocation,
followed by nucleophilic attack by an alcohol to afford the ether product
(see Supplementary Information for full details).
It is anticipated that the mild electrogeneration of carbocations
reported herein will find use in numerous settings in which standard
SN2 and carbocation-based approaches are unsuccessful in forming
hindered functionalized carbogenic frameworks.
Online content
Any methods, additional references, Nature Research reporting summaries,
source data, extended data, supplementary information, acknowledgements, peer
review information; details of author contributions and competing interests; and
statements of data and code availability are available at https://doi.org/10.1038/
s41586-019-1539-y.
Received: 21 March 2019; Accepted: 12 July 2019;
Published online xx xx xxxx.
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 RESEARCH Letter
Methods
Here we describe a typical procedure for the decarboxylative etherification. Further
experimental details are provided in the Supplementary Information.
General procedure for decarboxylative etherification. With no precautions to
exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged
with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-
collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular
sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn
vial cap equipped with anode (graphite) and cathode (graphite) were inserted into
the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed
at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and
electrodes were rinsed with Et2O (2 ml), which was combined with the crude
mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The
resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml),
dried over Na2SO4 and concentrated in vacuo. The crude material was purified
by preparative thin-layer chromatography to furnish the desired product. Full
experimental details and characterization of new compounds can be found in
the Supplementary Information.
Data availability
The data that support the findings of this study are available within the paper and
its Supplementary Information. Metrical parameters for the structures of (2R)-77
and (11R)-138 are available free of charge from the Cambridge Crystallographic
Data Centre (https://www.ccdc.cam.ac.uk/) under reference numbers 1918528
and 1903823, respectively.
Acknowledgements Financial support for this work was provided by Pfizer,
Inc., the National Science Foundation (CCI Phase 1 grant 1740656), and the
National Institutes of Health (grant number GM-118176). China Scholarship
Council and Jilin University supported a fellowship to J.X., Zhejiang Yuanhong
Medicine Technology Co. Ltd supported a fellowship to M.S., The Hewitt
Foundation supported a fellowship to Y.K., The Swedish Research Council
supported a fellowship to H.L., Fulbright Fellowship supported a fellowship to
P.M., and S.H.R. acknowledges an NSF Graduate Research Fellowship Program
(no. 2017237151) and a Donald and Delia Baxter Fellowship. We thank
D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; J. Chen
for measuring the high-resolution mass spectroscopy data, and A. Rheingold,
C. E. Moore and M. A. Galella for X-ray crystallographic analysis.
Author contributions J.X., M.S. and P.S.B. conceived the project. J.X., M.S., Y.K.,
H.L., D.G.B. and P.S.B. designed the experiments and analysed the data. J.X. and
M.S. developed the electrochemical decarboxylative methods and performed
their applications. H.L. and Y.K. carried out the mechanistic study. J.X., M.S.,
S.H.R., M.C., P.M., G.B., M.R.C., A.D., M.D.B., G.M.G., J.E.S., J.S. and S.Y. conducted
experiments to demonstrate the substrate scope. P.S.B. wrote the manuscript.
J.X., M.S., Y.K., S.H.R., P.M., H.L. and D.G.B. assisted in writing and editing the
manuscript.
Competing interests The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/
10.1038/s41586-019-1539-y.
Correspondence and requests for materials should be addressed to P.S.B.
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reprints.