Scalable and sustainable electrochemical allylic C-H oxidation

Article abstract of DOI:10.1038/nature17431

New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as € classics €. Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.

Full text of DOI:10.1038/nature17431

LEttER
doi:10.1038/nature17431
Scalable and sustainable electrochemical allylic
C–H oxidation
1
1
2
2
3
3
1
Evaꢀ J. hꢁrꢀ *, Braꢀdꢁꢀ R. Rꢁseꢀ *, Yꢁꢀg Cꢂeꢀ , Jiaze taꢀg , Ke Cꢂeꢀ , Marꢃiꢀ D. Easꢃgaꢃe & Pꢂil S. Baraꢀ
New methods and strategies for the direct functionalization of
From the outset of this work, we avoided the use of expensive elec-
C–H bonds are beginning to reshape the field of retrosynthetic trodes such as precious metals (for example, platinum or gold), focusing
analysis, affecting the synthesis of natural products, medicines our efforts exclusively on carbon. Initial optimization was undertaken
1
and materials . The oxidation of allylic systems has played a using graphite rods, but despite clean conversion of starting material to
prominent role in this context as possibly the most widely applied desired product, mass recovery was typically low. We considered that
C–H functionalization, owing to the utility of enones and allylic this might have partially been due to absorption of the substrate onto
alcohols as versatile intermediates, and their prevalence in natural the graphite. Switching to reticulated vitreous carbon (100 pores per
2
and unnatural materials . Allylic oxidations have featured in inch, acquired from K. R. Reynolds Co. for about US$3 per electrode)
hundreds of syntheses, including some natural product syntheses electrodes proved to be far more productive.
3
14
regarded as “classics” . Despite many attempts to improve the
In our laboratory, the original conditions applied to valencene (4)
efficiency and practicality of this transformation, the majority led to only 6% isolated yield of nootkatone (5), the principal fragrance
of conditions still use highly toxic reagents (based around toxic component of grapefruit aroma (Fig. 2). Our hypothesis was that air
elements such as chromium or selenium) or expensive catalysts was the oxygen-atom source in this transformation, which was qual-
2
(
such as palladium or rhodium) . These requirements are itatively confirmed by bubbling O2 gas in the reaction, resulting in
16–18
problematic in industrial settings; currently, no scalable and an improved isolated yield of 18%. However, NHPI/O
2
systems
sustainable solution to allylic oxidation exists. This oxidation have been explicitly avoided by the pharmaceutical industry, along
strategy is therefore rarely used for large-scale synthetic with other oxygen-mediated reactions, owing to the challenges relating
applications, limiting the adoption of this retrosynthetic strategy to flammability, and other issues arising from reliably and safety in
1
9,20
by industrial scientists. Here we describe an electrochemical C–H performing oxygen-mediated reactions on a large scale
; as
oxidation strategy that exhibits broad substrate scope, operational such, applications of aerobic oxidations in the pharmaceutical and
2
1–23
simplicity and high chemoselectivity. It uses inexpensive and fine-chemical industries remain sparse
. Thus, a number of co-
readily available materials, and represents a scalable allylic C–H oxidants were evaluated, using NHPI as a mediator, and tert-butyl
t
oxidation (demonstrated on 100 grams), enabling the adoption hydroperoxide ( BuOOH) led to substantial increases in reaction
of this C–H oxidation strategy in large-scale industrial settings conversion and reproducibility, delivering 5 in 51% yield. Using
t
without substantial environmental impact.
BuOOH without the NHPI mediator led to only 18% isolated yield
Electrochemical oxidation presents an attractive alternative to tra- under otherwise identical conditions.
ditional chemical reagents for large-scale applications, in a large part
With a suitable co-oxidant selected, attention turned to the opti-
owing to the generation of less toxic waste than that produced by cur- mization of base, solvent and electrolyte. We evaluated a variety of
4,5
rent chemical processes . In addition, electrochemical conditions are organic and inorganic bases, with pyridine proving to be ideal. The
6–10
compatible with a wide range of functional groups , tend to have use of acetone as solvent led to a slightly increased yield (56% 5
higher overall energy efficiency as compared to thermal processes and, isolated) and was chosen as a general solvent for this reaction owing to
owing to their limited use, offer new intellectual property space for its ability to solubilize a wide range of organic substrates. Acetonitrile,
4
small-molecule synthesis . The first electrochemical allylic oxidation dichloromethane, pyridine or mixtures of these four solvents could
11,12
was reported in 1968
4 4
(Fig. 1c). Direct oxidation of α-pinene (1) also be used. The electrolyte LiBF could be used in place of LiClO
led to the fragmentation of the cyclobutane ring with incorporation of with little decrease in yield, but tetraalkylammonium salts were not
methanol or acetic acid (depending on the solvent) to give products 2 competent electrolytes.
in 22%–24% yield. A major advance in this field came in 1985, when
Although most of the other mediators studied were inferior to the
the indirect oxidation of 1 using N-hydroxyphthalimide (NHPI) as an original NHPI, we reasoned that the addition of electron-withdrawing
13–15
electrochemical mediator was reported
(Fig. 1c). Unfortunately, groups to the phthalamide scaffold would improve the reactivity of
24
verbenone (3) was isolated in only 13%–23% yield. Although these the catalyst . Thus, tetrachloro-N-hydroxyphthalimide (Cl4NHPI)
reactions are not useful in a preparative sense, they were a proof of was chosen, owing to its ease of preparation from tetrachlorophthalic
concept that served as a foundation for our work.
anhydride, an industrial non-toxic flame retardant (which is easily
In our own laboratory, systematic and extensive experimentation obtained for about US$30 per kilogram from suppliers of chemicals for
led to the identification of three modifications of the original laboratories). The expectation of increased reactivity was supported by
13–15
precedent
, which transformed this process into a synthetically use- cyclic voltammetry data. In the case of NHPI, a reversible redox couple
ful electrochemical allylic C–H oxidation (Fig. 2). As described below, is observed at 0.78V versus Ag/AgCl in the presence of excess pyri-
these modifications include the addition of a simple co-oxidant, the dine, whereas Cl4NHPI shows a redox couple at 0.87V versus Ag/AgCl
identification of a new electrochemical mediator, and the design of a under identical conditions. This slightly increased oxidation potential
reliable and inexpensive set-up.
is consistent with the generation of a higher-energy and more-reactive
1Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. 2Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457,
China. 3Chemical Development, Bristol–Myers Squibb, New Brunswick, New Jersey 08903, USA.
*
These authors contributed equally to this work.
0
0 M o n t h 2 0 1 6 | V o L 0 0 0 | n A t U R E | 1
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2016 Macmillan Publishers Limited. All rights reserved

reSeArCH Letter
a
a
b
10 mA mmol–1
Me
Me
Me
Me
Me
Me
H
H
O
•
•
•
Fundamental organic transformation
Featured in >100 natural product syntheses
About 80% use Cr, Se, Pd or Rh reagents
Mediator, base
R
R
Co-oxidant
Solvent/electrolyte
O
Valencene 4
$1.3 per gram
Nootkatone 5
~$21 per gram
~
b
[Cr] HO
OH
O
NHAr
Me
AcO
O
Me
OH
O
O
O
O
Me
O
N
Me
H
Me
H
Me
Me
Me
Me
Me
Me
N
OH
N
OH HO
N
N OH
H
Me
H
RO
Cr]
O
OH
[Se]
Me
O
H
O
O
O
O
[
OH
OBz OAc
OH
Phorbol
NHPI (56%)
NHS (21%)
(6%)
TEMPO (26%)
O
OH
Platencin
Paclitaxel
Cl
O
O
N
N
N
O
Cl
OR
c
Me
Me
N
N
N
N OH
Me
via
N+
Me O–
ROH-Et4NOTs
Cl
OH
OH
Me
R = Ac; 24%
R = Me; 22%
(
Me
O
Me
Me
Cl
Cl4NHPI (77%)
NMBHA (n.d.) DABCO (0%) HOBt (17%) NMO (n.d.)
Anodic [O]
2
Ref. 12)
Figure 2 | Optimization of a sustainable allylic C–H oxidation. a, Co-
Me
Me
H
Me
oxidants (NHPI, pyridine, CH3CN): air (6%), bubbling O2 (18%), Bz2O2
H
Me
NHPI, pyridine
t
t
via
(0%), Bu2O2 (0%), H2O2, (27%), BuOOH (51%), PhC(CH3)2OOH (43%).
α-Pinene
MeCN-NaClO4
t
1
Me
Me
Verbenone
Me
Me
Bases (NHPI, BuOOH, CH3CN): pyridine (51%), 2,6-lutidine (10%),
–1
1
2
3% (0.9 F/mol
)
O
2,4,6,-collidine (13%), Et3N (0%), DBU (0%), Li2CO3 (trace). Solvents
3% (1.5 F/mol–1)
t
(NHPI, BuOOH, pyridine): CH3CN (51%), pyridine (40%), acetone
(
Ref. 14)
3
(
56%), CH2Cl2 (21%), MeOH (trace), DMF (5%), DMSO (14%), HFIP
t
Figure 1 | Widely applied allylic oxidation. a, Sustainable allylic C–H
oxidation is an unsolved problem. b, Case studies from classic total
syntheses. c, Electrochemical oxidation represents a potential solution.
(0%), EtOAc (trace), THF (trace). Electrolyte (NHPI, BuOOH, pyridine,
acetone): LiClO4 (56%), LiBF4 (41%), Et4NClO4 (0%). b, Mediators
t
( BuOOH, pyridine, acetone). Optimized electrochemical parameters:
t
Cl4NHPI (0.2 equiv.), pyridine (2 equiv.), BuOOH (1.5 equiv.), LiClO4
(
0.6 equiv.), acetone (0.16 M in substrate), reticulated vitreous carbon
4
phthalimido-N-oxyl radical, and the use of Cl NHPI as a mediator led electrodes, 10 mA per mmol of substrate. n.d., not detected.
to a cleaner reaction profile and an isolated yield of 77%.
The final optimized conditions for oxidation of 4 to 5 is as fol- blocks in synthesis. As such, we evaluated the efficiency with which
t
lows: 20mol% Cl4NHPI, pyridine (2.0 equiv.), BuOOH (1.5 equiv.), the electrochemical allylic oxidation could be applied to these sub-
and LiClO as the supporting electrolyte (0.1M) in acetone (6ml per stances. Verbenone (3), previously prepared in 13%–23% yield , was
4
14
mmol of substrate) under constant-current conditions in an undivided prepared in 67% yield. Both isomers of the food additive theaspirane
cell. No precautions to exclude oxygen or water were undertaken, could be oxidized to the natural products cis- and trans-theaspirone
and technical-grade solvents and reagents and a simple set-up of two 19 and 20 in 63% and 49% yield, respectively. Carvone-derived enone
reticulated vitrous carbon electrodes separated by a glass slide were 21 was prepared in 47% yield, whereas carvone (22) was prepared in
used (see Supplementary Information for a photographic guide of the 42% yield. Myrtenol acetate and nopol acetate were converted to the
experimental set-up).
corresponding oxo-myrtenol and oxo-nopol compounds 23 and 24 in
Our initial explorations into the tolerance focused on several 64% and 43% yield, respectively. Furthermore, aza-nopol analogues
cycloalkene-derived substrates relevant to drug discovery (Fig. 3); 25 and 26 were prepared in 42% and 53% yield, respectively, further
tert-butyl cyclohexenone 6 could be prepared as a single regioisomer highlighting the tolerance for nitrogen-containing functionalities under
in 52% yield, whereas phenyl cyclohexenone 7 was prepared in 55% these reaction conditions. In all cases, isolated yields are comparable to
yield. Cyclopentenone 8 could be prepared from trimethylsilyl (TMS)- those in the literature using other methods, and low product yields were
protected cyclopentenol in 52% yield. Unprotected tertiary alcohols obtained when using previously reported NHPI/O
2
conditions after
1
6–18
9
–12 could be prepared from the corresponding aryl-substituted prolonged heating
. To put these results in context, an extensive
cyclohexenols in reasonable yields. The Lewis-basic pyridine-containing comparative survey of literature conditions and yields is included in
enone 12 was prepared in 60% yield. No alcohol elimination and aro- Supplementary Information.
matization was observed, and no allylic transposition occurred; this
Sesquiterpenoid and diterpenoid natural products, many of which
complimentary reactivity to most chromium-based oxidants and the are components of essential oils, have provided inspiration for many
use of unprotected alcohols is particularly notable. Furthermore, the strategies and methods in synthesis, primarily owing to their complex
25
unsubstituted cyclohexenone products 13 and 14 were prepared in 56% and dense structures and their promising biological activities . Allylic
and 51% yield, respectively, comparing favourably to previously reported oxidation of valencene gave nootkatone (5) in 77% yield (see above).
V
(
see Supplementary Information) Cr -mediated oxidation for the Sclareolide-derived terpene 27 was synthesized in 75% yield using the
synthesis of 13. Substitution at the alpha position of the enone was electrochemical method. Eudesmane natural products carissone (28, as
tolerated as well, with 15 being isolated in 58% yield. In addition to the its TMS ether) and cyperone (29) were prepared in 54% and 51% yields,
cyclic substrates described above, several acyclic alkenes of various chain respectively. The related aubergenone skeleton was successfully oxidized
lengths were successfully oxidized under the reaction conditions. Enones to give enone 30 in 67% yield. Isolongifolenone (31) was prepared from
1
6 and 17 were prepared in 46% and 51% yields, respectively. Propargylic the feedstock chemical isolongifolene in 91% yield. Natural products
alcohol 18 was formed in 52% yield from its corresponding alkyne.
in the guaiane family were oxidized to afford the natural products
Owing to their prevalence in the drug discovery, flavour and pancherione acetate (32) and rotundone (33) in 41% and 44% yield,
fragrance industries, our subsequent efforts focused on a variety of respectively, and the complex [3.2.1]-bicyclic system in cedrene was
representative terpene classes. The oxidation products of monoter- oxidized to give cedren-10-one (34) in 53% yield. Under electrochem-
penes are among the most widely used and correspondingly valuable ical conditions, abietic acid derivative 35 could be prepared in 66%
substances not only as fragrances and flavours, but also as building isolated yield along with 12% recovered starting material. Although
2
| n A t U R E | V o L 0 0 0 | 0 0 M o n t h 2 0 1 6
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2016 Macmillan Publishers Limited. All rights reserved

Letter reSeArCH
Cycloalkene and acyclic
O
R
X
1
0 mA mmol–1
Me
Me
OTMS HO Me
HO Me
R
R
Bu
t
Cl4NHPI, BuOOH,
pyridine, acetone
Me
n
n
OMe
•
40 examples
15 natural products
Sustainable
Scalable
Inexpensive carbon electrodes
Inexpensive reagents
Open flask
•
O
O
6
O
O
9 (R = H); 68%
10 (R = C(Me2)OH); 42%
O
•
; 52%
7; 55%
8; 52%
11 (X = CH); 72%
12 (X = N); 60%
(+about 5% s.m.)
•
(
+about 4% s.m.) (+about 8% s.m.)
•
‡
‡
[
[
Rh]; 94%
Pd]; 85%
[Rh]; 77%
[Pd]; 75%
[Mn]; 70%
•
‡
‡
•
‡
‡
[Mn]; 76%
HO
R
TMSO Me
O
N
Monoterpene-derived
Me
Me OH
O
AcX
Me
Me
Me
Me
n
Me
O
Me
O
O
Me
O
O
13 (R = Me); 56% 15; 58%
Me
Me
Me
‡
Me
Me
[CrV]; 44%
O
Me
Me
O
Me
O
O
21; 47%
14 (R = Ph); 51%
3
; 67%*
19 (α-Me); 63%
22; 42%
(Carvone)
23 (X = O, n = 1); 64%
26; 53%
OH
Me
(
Verbenone) (cis-Theaspirone)
[
[
24 (X = O, n = 2); 43% (+about 12% s.m.)
Cr]; 49%‡
20 (β-Me); 49%
‡
[Cr]; 21% 25 (X = NH, n = 2); 42%
Mn]; 63%‡
(trans-Theaspirone)
‡
Me
n Me
[Rh]; 44%
O
1
6 (n = 0); 46%
Sesquiterpene-derived
1
7 (n = 4); 51%
Me Me
Me
Me
Me
Me
O
OH
Me
Me
H
Me
Me
Me
AcO
O
O
Me
Me
27; 75%
OTMS
O
Me
Me
Me
29; 51%
Me
O
5
; 77%
Nootkatone)
28; 54%
(Carissone silyl ether)
‡
18; 52%
(
4 equiv. Na2CrO4; 60%
(+about 15% s.m.)
‡
1
5 equiv. CrO3•pyr; 80%
NHPI, cat. [Co]; 68%
(Cyperone)
‡
Me
Me
O
Diterpene-derived
O
O
iPr
Me
Me
Me
O
O
Me
Me
Me
O
H
Me
9
Me
O
8
OTES
O
Me
Me
OAc
H
Me
Me
Me
Me
31; 91%
(Isolongifolenone)
0.5 equiv. Cr(CO)6; 82%
Me
Me
7
O
Me
32; 41%*
Me
33; 44%
3
0; 67%
34; 53%
MeO2C Me
(
Epi-aubergenone
(Pancherione acetate) (+about 6% s.m.) (Cedrene-10-one)
35; 66% (+12% s.m.)
‡
silyl ether)
(Rotundone)
Steroid-derived
O
O
O
Me
Me
Me
OR
O
Me
H
Me
H
Me
H
RO
RO
H
H
O
H
H
O
H
H
AcO
HO
O
O
3
6; 81%
‡
OR
1
.8 equiv. [Cr]; 93%
3
7; 72% (+about 4% s.m.)
t
‡
[
[
[
Mn], BuOOH; 91%
t
‡
†
[
Co], NHPI, BuOOH; 81%
39 (R = Bz); 60%
40 (R = H); 38%
t
‡
Cu], BuOOH; 89%
Rh], BuOOH; 87%
t
‡
†
[
Rh], BuOOH; 84%
t
‡
‡
1
.8 equiv. [Cr]; 51%
t
‡
0
.62 mol% [Ru], BuOOH; 69%
Me
Triterpene-derived
Me Me
Me Me
Me CO2Me
Me
H
O
Me
H
H
H
O
O
O
O
Me
H
Me Me
CO2Me
Me Me
CO2Me
Me Me
Me
H
H
H
H
H
Me
H
H
Me
H
H
Me
AcO
O
HO
O
HO
†
3
8; 74%
t
Me Me
Me Me
Me Me
‡
[
Co], NHPI, BuOOH; 76%
1; 43%†
42; 46%†
43; 41%†
4
t
‡
[
Mn], BuOOH; 72%
(
Methyl glycyrrhetinate)
*
†
Figure 3 | Scope of the electrochemical allylic oxidation. Yields refer
to isolated yields of products after chromatography on SiO2. Standard
conditions: terpenoid substrate (0.5 mmol), Cl4NHPI (0.1 mmol),
acetone (3 ml). MeCN (3 ml) replaced acetone as solvent. Terpenoid
substrate (0.25 mmol), Cl4NHPI (0.1 mmol), pyridine (1.0 mmol),
‡
LiClO4 (0.3 mmol), CH2Cl2 (1.5 ml) and acetone (1.5 ml) were used. See
Supplementary Information for references. s.m., starting material.
t
pyridine (1.0 mmol), BuOOH (0.75 mmol), LiClO4 (0.3 mmol),
0
0 M o n t h 2 0 1 6 | V o L 0 0 0 | n A t U R E | 3
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reSeArCH Letter
a
Me
b
c
1
,000 mA
Conditions
6-V lantern battery
37% + 15% r.s.m.
22
Deoxy-36
36
4
5
Me
44%
(
>50% improvement
in PGS)
(
27 grams)
(
198 mmol)
O
56%
Me
60
50
Me
Me
H
3
7%
4
3
0
0
3
2%
H
H
O
Me
Me
; 46%
100 grams)
734 mmol)
O
RO
20
10
3
36 (R = Ac); 62% 37 (R = H); 48%
(100 grams)
(303 mmol)
0
(
(
(100 grams)
(347 mmol)
[
Cr]
[Ru]
e-Chem
Figure 4 | Practicality of the electrochemical method. a, Electrochemical
allylic oxidation on a 100-g scale. b, Calculated Process Greenness Score
toxicity associated with chromium and ruthenium use and disposal are
not included in the PGS. c, Use of 6-V lantern battery as a readily available
(
PGS) for CrO3-mediated, RuCl3-catalysed, electrochemical oxidation
power source for allylic oxidation. r.s.m., recovered starting material.
of deoxy-36 to 36 shows improvement from 32.1% to 55.8%. Cost and
7
,8
the starting material contained the ∆ bond, isomerization to the manufacturing processes. The scoring parameters are closely aligned
8
,9
7,8
28
∆
olefin occurred, and no ∆ -enone was observed. This anomalous with the 12 principles of green chemistry , among which limiting
result may be due to hydrogen-atom abstraction at the C9 position waste generation and maximizing process efficiency are two main
followed by trapping of the allylic radical at the C7 position.
metrics of environmentally friendly processes. A greener reaction has
The oxidation of steroid and triterpene substrates has been shown a higher PGS. Oxidation reactions, especially aliphatic C–H oxidations,
to improve properties such as solubility and pharmacokinetics, and are generally associated with lower-than-average PGSs due to typically
the development of tools to modify their ‘oxidation barcodes’ are low process yields and the common use of toxic metal mediators in sto-
2
6
of immediate importance . Electrochemical oxidation of acetate- ichiometric quantities. Unsurprisingly, the CrO
3
-mediated oxidation of
-catalysed
1% yield. Unprotected DHEA could also be oxidized to give enone oxidation had an improved, albeit still modest, PGS of 37.1%. We were
7 in 72% yield. Diosgenin acetate underwent smooth oxidation to pleased to find that the electrochemical allylic oxidation showed a
protected dehydroepiandrosterone (DHEA) gave enone product 36 in deoxy-36 scored lowest in terms of PGS (32.1%). The RuCl
3
8
3
give 38 in 74% yield. Encouraged by the tolerance for free alcohols and markedly improved PGS of 55.8% (an improvement of >50%). This
sensitive acetals, glycosylated derivatives of DHEA were evaluated. The difference is substantial and shows the step-change in applicability of
tetrabenzoyl protected glycoside 39 was prepared in 60% yield and this new technology. For comparison, the PGS for a typical amide bond
the unprotected glycoside 40 could be prepared in 38% yield, demon- formation (EDC, HOBt) ranges from 55% to 70%, whereas the PGS
strating chemoselectivity that would not be possible using classical of the widely used palladium-catalysed cross-coupling of aryl halides
oxidants such as chromium. Free-hydroxyl-containing methyl olean- with boronic acids falls between 45% and 60%. As a further testament
olate derivative 41 was prepared in 43% isolated yield, whereas oxida- to its robustness, the electrochemical oxidation was carried out using
2
9,30
tion of the ketone-containing substrate gave the desired enone 42 in a 6-V lantern battery
(Fig. 4c), with valencene being converted to
4
6% yield. Methyl glycyrrhetinate (43), an important starting material nootkatone in 37% yield with 15% recovered starting material.
for a variety of oxidized, medicinally relevant triterpenes, was also pre-
pared in 41% yield.
Although this reaction is useful for the oxidation of numerous
natural and unnatural carbon skeletons, it is not without its limita-
In nearly all substrates evaluated, isolated yields compare favoura- tions. For example, although cyclic substrates are all reactive, not all
bly to literature precedent using traditional reagent-based oxidants. In acyclic alkenes give very high conversion to enone products, nor do
some cases, such as the known conversion of 4 to 5 using 15 equiva- electron-deficient alkenes. In some cases, allylic alcohol products were
3
lents of CrO •pyridine in 80% yield, not only is the isolated yield com- isolated alongside enone products, although with prolonged reaction
parable, but our conditions obviate the need for the excessive use of times these products are converted to the desired enones. Yields for
toxic reagents and minimize the use of solvent and aqueous media for some substrate classes were modest (for example, 32 and 33), in part
extraction and isolation.
owing to incomplete conversion, substrate decomposition, or adsorp-
We demonstrate the feasibility of adopting this technology in a tion to the electrode surface. However, in nearly all cases isolated yields
process setting, using the described conditions. These reactions were are comparable to alternative procedures present in the literature.
conducted using inexpensive graphite plate electrodes in a beaker
Mechanistic aspects of the initiation step of this new transformation
16–18
open to air (Fig. 4a, inset photograph), and LiBF4 was used as the sup- may have parallels to other NHPI-catalysed oxidations
(Fig. 5).
porting electrolyte. Using this set-up, 22 was prepared on a 27-g scale Thus, deprotonation of Cl4NHPI by pyridine, followed by anodic
(
198mmol) from limonene in 44% yield, and 3 was prepared in 55%
yield on a 27-g scale. Further scale-up to 100g (734mmol) gave 46%
yield of 3. Carrying out the identical transformation with traditional
chromium reagents (for example, toxic chromium hexacarbonyl) would
require at least 81 g of chromium reagent followed by extensive efforts
to remove chromium-based contaminants. Sterol 37 and its acetate 36
were produced in 48% yield (100g, 347mmol) and 62% yield (100g,
t
OO Bu
O
tBuOOH
+
–
–tBuOH
–
H
R
R
–e
4
4
R2N O• R2N OH 45
R
R
–e–
Anode)
R2N O–
46
47
C5H5NH+
Cl
(
3
03mmol), respectively. Highlights of this successful external field test
O
Cl
R2N OH =
Cl
include operational simplicity, safe procedure, simple workup and ease
of product isolation.
5 5
C H N
N
OH
–
1
+
(
e , H2
2
To verify the improved environmental footprint of the electrochemi-
cal allylic oxidation, we compared the Process Greenness Scores (PGSs)
for the electrochemical preparation of 36 to two known literature
Cathode)
O
Cl
Figure 5 | Proposed mechanism for electrochemical allylic oxidation.
20,27
methods
(Fig. 4b). The PGS is a method often used by industrial The boxed structure is the catalyst, which is abbreviated in the catalytic
companies to evaluate the potential environmental impact of chemical cycle as R2N–OH.
4
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2016 Macmillan Publishers Limited. All rights reserved

Letter reSeArCH
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Acknowledgements This work was supported by an NSF predoctoral fellowship
(B.R.R.), National Institute of General Medical Sciences grant GM-097444,
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Author Contributions E.J.H., B.R.R. and P.S.B. conceived this work; E.J.H., B.R.R.,
K.C., M.D.E. and P.S.B. designed the experiments; E.J.H. and B.R.R. conducted
the experiments and analysed the data; Y.C. and J.T. performed the large-scale
experiments; E.J.H., B.R.R., K.C., M.D.E. and P.S.B. wrote the manuscript.
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Author Information Metrical parameters for the structure of 24 are available
free of charge from the Cambridge Crystallographic Data Centre under
reference number CCDC-1058554. Reprints and permissions information
is available at www.nature.com/reprints. The authors declare no competing
financial interests. Readers are welcome to comment on the online version of
the paper. Correspondence and requests for materials should be addressed to
P.S.B. (pbaran@scripps.edu).
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