Electrochemical Deprotection of para-Methoxybenzyl Ethers in a Flow Electrolysis Cell

Article abstract of DOI:10.1021/acs.orglett.7b00641

Electrochemical deprotection of p-methoxybenzyl (PMB) ethers was performed in an undivided electrochemical flow reactor in MeOH solution, leading to the unmasked alcohol and p-methoxybenzaldehyde dimethyl acetal as a byproduct. The electrochemical method removes the need for chemical oxidants, and added electrolyte (BF₄NEt₄) can be recovered and reused. The method was applied to 17 substrates with high conversions in a single pass, yields up to 92%, and up to 7.5 g h^-1 productivity. The PMB protecting group was also selectively removed in the presence of some other common alcohol protecting groups.

Full text of DOI:10.1021/acs.orglett.7b00641

Letter
pubs.acs.org/OrgLett
Electrochemical Deprotection of para-Methoxybenzyl Ethers in a
Flow Electrolysis Cell
Robert A. Green,† Katherine E. Jolley,† Azzam A. M. Al-Hadedi,† Derek Pletcher,† David C. Harrowven,†
Oscar De Frutos,‡ Carlos Mateos,‡ David J. Klauber,§ Juan A. Rincon,‡ and Richard C. D. Brown*,†
́
†Department of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, U.K.
‡Centro de Investigacion
́
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
§Early Chemical Development, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: Electrochemical deprotection of p-methoxybenzyl
(PMB) ethers was performed in an undivided electrochemical flow
reactor in MeOH solution, leading to the unmasked alcohol and p-
methoxybenzaldehyde dimethyl acetal as a byproduct. The electro-
chemical method removes the need for chemical oxidants, and added
electrolyte (BF4NEt4) can be recovered and reused. The method was
applied to 17 substrates with high conversions in a single pass, yields up
to 92%, and up to 7.5 g h−1 productivity. The PMB protecting group
was also selectively removed in the presence of some other common
alcohol protecting groups.
he use of protecting groups is common during multistep
syntheses of target molecules of even moderate complex-
Scheme 1. Examples of Deprotections of PMB Ethers
T
ity,1 adding reaction steps and reducing atom economy.2 Yet,
without protecting groups the scope of application of many
synthetic methods would be greatly compromised. Although
efforts to avoid protecting groups or to combine their
introduction and/or removal with other chemical trans-
formations have had some success,3 for now the use of
protecting groups seems inevitable. Therefore, the development
of more sustainable deprotection methods is a worthy line of
investigation, particularly where the ultimate objective will
involve scale up.
The p-methoxybenzyl (PMB), or p-methoxyphenylmethyl
(MPM), group is a well-known protecting group used to mask
the reactivity of alcohols in multistep synthesis.1,4 PMB
protection of carboxylic acids and nitrogen-containing com-
pounds can also be useful.5 Typical conditions for cleavage of
PMB ethers employ stoichiometric excesses of DDQ or CAN
(Scheme 1),6 but various other deprotection methods have
been reported.1a,7,8 PMB ethers are frequently employed in
situations where a benzyl-type protecting group is desirable, but
other functionality present in the substrate are incompatible
with removal by hydrogenolysis or dissolving metal conditions.
On the other hand, PMB and benzyl ethers can be used
together in orthogonal protecting group strategies.9
Benzylic oxidation is very well-known in the electrochemical
literature, with the oxidation of p-tert-butyltoluene to p-tert-
butylbenzaldehyde performed on an industrial scale.10 Electro-
synthesis offers an opportunity for substantial reduction in the
waste associated with PMB deprotection, by removing the need
for chemical oxidants completely or allowing catalytic loadings
of a mediator. In 1974 Weinreb reported direct electrochemical
deprotection of PMB ethers using a divided batch cell (Scheme
1), while in 1978 Streckhan reported the use of tris(p-
bromophenyl)amine as an electrochemical mediator to cleave
PMB and benzyl protected alcohols, also in a divided batch
cell.11 Microfluidic electrolysis cells offer some advantages over
batch reactors, such as favorable electrode area to reactor
volume, improved control over heat transfer, and ease of scale-
up by extending the period of operation.12 Furthermore,
narrow interelectrode gaps allow reduced amounts of electro-
lyte to be used.13 Recently, we described extended path
microflow electrolysis reactors for laboratory synthesis on 100
mg to 100 g scales, which are designed to achieve high
Received: March 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conversion in one pass.14 Here we report their application in
reagent-free anodic cleavage of PMB ethers.
a
Table 2. Electrochemical Cleavage of PMB Ethers
The electrochemical deprotection of PMB ether 1 was
selected for initial optimization using an undivided cell
containing an extended spiral flow channel (length: 1000
mm, width: 2 mm, interelectrode gap: 0.5 mm) formed by a
perfluoroelastomer spacer separating a carbon/PVDF anode
and a stainless steel cathode.14a MeOH and H2O were
considered to be suitable solvents, functioning as nucleophilic
traps for the benzylic cations produced at the anode, while also
providing useful cathode counter electrode reactions, where
formation of methoxide or hydroxide and H2 counteracts
buildup of H+ in the flow channel. Formation of gas bubbles
may also increase turbulence and improve reactor perform-
ance.15
A general electrochemical deprotection protocol was
established for the PMB ether 1, using a 0.10 M MeOH
solution, containing Et4NBF4 (0.05 M) as an added electrolyte,
at a flow rate of 0.25 mL min−1. It is important to recognize
that sufficient current is needed to drive the desired chemical
change,15 and electrolysis conditions were optimized to achieve
full conversion, which requires at least 80 mA under conditions
of mass transfer control. In practice, a scan of currents of 80−
135 mA (Table 1, entries 1−4) revealed conversions in the
a
Table 1. Optimization of Electrochemical Deprotection
b
entry current (mA) cell voltage (V) current efficiency (%) yield (%)
1
2
3
4
5
6
7
8
9
80
100
120
135
160
135
135
135
135
3.4
3.3
3.4
3.5
3.7
3.6
5.5
3.4
3.0
79
68
58
55
41
45
49
30
8
79
84
87
92
82
75
82
51
13
c
d
e
f
a
a
Reactions performed in the Ammonite 8 electrochemical flow
reactor, fitted with a C/PVDF anode and stainless steel cathode. All
reactions conducted on 0.50 mmol scale (20 min run time with 5 mL
Reactions performed on a 0.5 mmol scale (5.0 mL) in the Ammonite
b
8 electrochemical flow reactor. Yield determined using calibrated GC.
c
Reaction solvent was MeOH/H2O (10:1); byproduct was 4-
b
c
d
d
e
total volume). Isolated yield. GC yield. Reaction performed at 80
methoxybenzaldehyde. Reduced electrolyte (0.005 M). Electrolyte
was NaBF4 (0.05 M). Pt electrode.
e
f
f
mA. Yield based on recovered 12. Reaction performed at 70 mA.
g
18% yield of diol product was also obtained.
range 94−100%, with the highest yield of 2 obtained at 135 mA
(entry 4). Increasing the current further (entry 5) led to a
reduction in yield due to over-oxidation. The results in MeOH
alone were superior in comparison to MeOH/H2O (10:1)
mixtures (entry 6). Reducing the amount of electrolyte
(Et4NBF4) to 0.005 M (entry 7) gave a modest decrease in
yield of 2, and an expected increase in cell voltage due to the
more poorly conducting medium. Changing the electrolyte to
NaBF4 or anode material to Pt (sheet, 0.1 mm thickness,
99.9%) both resulted in substantial reductions in yield. It is
noteworthy that the Et4NBF4 is conveniently recovered from
the crude reaction mixture by trituration with EtOAc and can
be recrystallized and reused over many electrosyntheses.
The conditions established for anodic deprotection of PMB
ether 1 proved to be effective for a range of substrates
containing unsaturation and sulfonyl functionality (Table 2,
entries 3 and 4), a protected sugar derivative (entry 6), and
examples of saturated and unsaturated nitrogen heterocycles
(entries 7−10). Selective cleavage of the PMB ether was
generally achieved, including examples where oxidizable
nitrogen functional groups were present (entries 8−11). For
PMB deprotection of Boc-protected amines 10 and 12 a
reduced current of 80 mA was used to avoid oxidation α to the
nitrogen functionality (entries 9 and 11).16 Piperazine and
tosyl-protected piperidine substrates, 9 and 11 (entries 8 and
10), were deprotected without overoxidation under the higher
current conditions.
Anodic cleavage of the PMB group was also achieved in the
presence of other common alcohol protecting groups, including
OTHP, OAc, OTBDPS, OTBS, and OBn. Notably, PMB
ethers of diols protected with TBS or THP groups at the
primary alcohol positions proved to be more sensitive to the
B
DOI: 10.1021/acs.orglett.7b00641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
deprotection conditions, and the TBS ethers 15 and 18
afforded fully deprotected diols as the major products at 135
mA (entries 12, 14, 17, and 18). Selective removal of the PMB
ether group was achieved by reducing the cell current to 70 mA
(entries 14 and 17). It is possible that increased local acidity in
the proximity of the anode, a consequence of oxidation of the
PMB group, may catalyze cleavage of the more acid sensitive
silyl ether functionality.
Current efficiencies for electrochemical deprotection in flow
were ∼50% for most of the examples studied, which is expected
under conditions of excess current. This is due to oxidation of
the solvent and formation of minor unidentified byproducts.
Significant over-oxidation was only observed for the N-Boc
derivatives 10 and 12, but the methoxylated byproducts were
minimized at lower current. It is emphasized, however, that the
conditions have been optimized to favor high conversion rather
than high current efficiency, and the cost of electricity is not
important on a laboratory scale, and considerably less than that
of common oxidizing agents.
Ammonite 15 reactor, with a 2 m long channel and reactor
volume of 5.0 mL, allows for a higher flow rate while preserving
high conversions.14b At a substrate concentration of 0.30 M and
flow rate to 4.0 mL min−1, 63 g of the alcohol 2 was obtained
over 8.3 h without additional optimization.
Sustainability metrics provide a useful guide to assess the
impact of a reaction or process, and their application is
becoming more widespread.17 With this in mind we performed
a comparative analysis of the electrochemical PMB depro-
tection with that of other reported deprotections (Table 4).17a
Atom economy (AE) scores are inherently compromised for
deprotection reactions and are largely dependent on the size of
the molecule compared to the protecting group. Consequently,
for the low molecular weight molecules being compared, mostly
scores that raise concern are observed (entries 1, 2, 4 and 5).
Reaction mass efficiency (RME), which also considers reagents
and stoichiometry, can provide a good assessment of the
sustainability credentials. Here the electrochemical deprotec-
tion scores favorably (entries 1 and 2), as only a small amount
of electrolyte is required to facilitate the reaction. RME can be
improved by electrolyte recovery. For the other deprotection
methods RME values are lower due to the requirement for
excess reagents or additives (entries 3−5), and use of metals
with potential future supply issues is also of concern (entries 3
and 5).17a Finally, solvent selection is highly influential on the
impact of a reaction, as it is often the largest single component
added,17a and replacement of chlorinated solvent or MeCN
with MeOH is advantageous.
A benefit of electrosynthesis in flow is the ability to quickly
scale up the reaction by (a) increasing the flow rate, (b)
increasing the concentration, or (c) increasing the volume of
the reaction solution. To demonstrate the ease of laboratory
scale-up the deprotection of 1, generating 2, was investigated at
higher concentration and flow rate, over a longer duration
(Table 3). Increasing the concentration to 0.475 M in the
Table 3. Scale up of Electrochemical Deprotection in Flow
There are many metrics available to assess sustainability
credentials, and the ones used here focus on the reactions and
do not include work-up and purification steps because these
have not been optimized. However, reagentless processes such
as this electrochemical methodology can help to reduce the
process mass intensity (PMI) through further process develop-
ment by simplifying work-ups as excess reagent or byproduct
does not need to be removed.18
In summary, an electrochemical deprotection of PMB ethers
in a microflow cell has been described, and demonstrated for a
range of substrates. Furthermore, the ease of scale up in a
laboratory context has been highlighted, with the Ammonite 8
reactor producing 17.2 g of alcohol 2 in 20 h and the
Ammonite 15 yielding 63.0 g (consuming 153.8 g of starting
a
concn
flow rate
current
(A)
yield
(%)
productivity
entry
1 (M)
(mL min−1
)
(g h−1
)
b
d
1
0.475
0.30
0.25
4.00
0.65
6.00
89
77
0.86
c
e
2
7.6
a
b
Isolated yield. Ammonite 8 electrochemical flow reactor (A).
c
d
e
Ammonite 15 electrochemical flow reactor (B). 6.3 mmol h−1. 55.5
mmol h−1.
Ammonite 8, along with an adequate increase in current, led to
the isolation of 17.2 g (89%) of product 2 over 20 h. The larger
a
Table 4. Comparison of Selected Sustainability Metrics for PMB Ether Deprotection Reactions16
a
b
Key: green = desired/no problems; orange = problematic; red = undesired/very problematic/hazardous. RME value taking into consideration
recovery of Et4NBF4 by precipitation from the crude reaction mixture.
C
DOI: 10.1021/acs.orglett.7b00641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00641.
Experimental details and procedures, compound charac-
terization data, description of flow electrolysis cells, cyclic
1
voltammetry, expanded metrics tables, and copies of H
and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
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Corresponding Author
*E-mail: rcb1@soton.ac.uk.
ORCID
Heineman, W. R.; Hilt, G.; Hoormann, D.; Jorissen, J.; Kroner, L.;
̈
̈
Richard C. D. Brown: 0000-0003-0156-7087
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The authors declare the following competing financial
interest(s): The Ammonite electrochemical flow cells used in
this work were co-developed by Brown and Pletcher with
Cambridge Reactor Design.
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ACKNOWLEDGMENTS
■
The authors acknowledge financial support from EPSRC (EP/
L003325/1 and EP/K039466/1). This work was also
supported by Eli Lilly and Company through the Lilly Research
Award Program (LRAP).
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DOI: 10.1021/acs.orglett.7b00641
Org. Lett. XXXX, XXX, XXX−XXX