Rapid electrochemical deprotection of the isonicotinyloxycarbonyl group from carbonates and thiocarbonates in a microfluidic reactor

Article abstract of DOI:10.1021/op500155f

Electroreductive deprotection of the isonicotinyloxycarbonyl (iNoc) group from hydroxy, thiol, and amino groups was carried out in an electrochemical microreactor. The small distance of the platinum electrodes in the microreactor enables a rapid electrochemical redox reaction without added electrolytes. As a result, the electrochemical deprotection of O- and S-iNoc aromatic substrates was achieved in short reaction times (<2 min), while N-iNoc and nonaromatic substrates did not react under the same reaction conditions. This method enables a rapid and site-selective deprotection of O- or S-iNoc groups without removal of N-iNoc moieties.

Full text of DOI:10.1021/op500155f

Article
pubs.acs.org/OPRD
Rapid Electrochemical Deprotection of the Isonicotinyloxycarbonyl
Group from Carbonates and Thiocarbonates in a Microfluidic Reactor
Kenta Arai and Thomas Wirth*
School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, U.K.
S
* Supporting Information
ABSTRACT: Electroreductive deprotection of the isonicotinyloxycarbonyl (iNoc) group from hydroxy, thiol, and amino groups
was carried out in an electrochemical microreactor. The small distance of the platinum electrodes in the microreactor enables a
rapid electrochemical redox reaction without added electrolytes. As a result, the electrochemical deprotection of O- and S-iNoc
aromatic substrates was achieved in short reaction times (<2 min), while N-iNoc and nonaromatic substrates did not react under
the same reaction conditions. This method enables a rapid and site-selective deprotection of O- or S-iNoc groups without
removal of N-iNoc moieties.
of such reactors have been reported.6 The flow technology
developed for these reactions indicates that rapid and efficient
electrolysis can be performed by using electrochemical
microreactors.
INTRODUCTION
The reductive removal of a protecting group from a functional
moiety is traditionally carried out under reaction conditions
using at least stoichiometric amounts of reagents and/or metal
■
catalysis, which are undesirable from the viewpoint of green
chemistry. On the other hand, clean and effective electro-
chemical deprotections without additional reagents have also
been developed in several laboratories.1
Veber and co-workers developed the isonicotinyloxycarbonyl
(iNoc) group (Figure 1), which has a high polarity and is useful
RESULTS AND DISCUSSION
■
In this paper, we report the cathodic reduction of iNoc-
protected hydroxyl groups (i.e., carbonates), thiol groups (i.e.,
thiocarbonates), and amino groups (i.e., carbamates) using
platinum electrodes. We initially prepared O-iNoc phenols, 3a,
3b, and 3c (Scheme 1).7 These compounds were successfully
synthesized in high yields (92−98%) by the reaction of the
corresponding phenols 1 with isonicotinyl p-nitrophenyl
carbonate 2 in the presence of a base in DMF. The reagent
2 for iNoc protection was prepared following the literature
protocol.2
Figure 1. Isonicotinyloxycarbonyl group.
To achieve the electrochemical removal of the iNoc group,
the electrolysis of iNoc-protected substrates 3 was performed
by continuous flow of a water/DMF (1:5) solution containing
93 mM iNoc-protected substrate 3 and 50 mM tetrabutyl-
ammonium iodide (TBAI) as an electrolyte. The electro-
chemical microreactor has a flow channel of 23 μL volume (3
mm × 30 mm × 254 μm) with the electrolysis being performed
at a constant current (16.7 mA cm−2), at room temperature,
and at a flow rate of 15 μL min−1 (residence time = 92 s)
(Scheme 2). The reaction conditions were optimized in
for the protection of the ε-amino group of lysine residues
during peptide synthesis, and the iNoc group can be selectively
deprotected using Zn(II) reagents.2 They also showed that the
iNoc group could be electroreductively removed using a
mercury cathode. However, the reaction time was long (40−90
min) in the chemical and electrolytic deprotection of simple L-
lysine. In addition, the electrochemical technique has not been
applied to peptide molecules.
We have developed an electrochemical microreactor, which
enables rapid and effective electrochemical reactions, and
applied it to some practical procedures of organic syntheses.3
Very recently, we demonstrated rapid difluoro- and trifluoro-
methylation of alkenes using the Kolbe electrolysis of difluoro-
and trifluoroacetic acid in this electrochemical microreactor.4
The electrochemical microreactor has a FEP (fluorinated
ethylene propylene) flow channel sandwiched between
platinum electrodes, as shown in Figure 2, where the thickness
of the FEP foil defines the very short diffusion distances leading
to high space−time yields. Different microreactor systems have
already been well-established for synthetic studies and have
been successfully used for electrochemical reactions.5 In verity,
some synthetic protocols and other examples for practical use
1
preliminary experiments. The analysis (TLC and H NMR)
of the crude products collected at the outlet of the
electrochemical microreactor showed that the compounds 3
had completely disappeared and the deprotected phenols 1
with some byproducts had been formed. The byproducts were
not identified but may include oxidized phenols. After
extraction and purification by column chromatography, the
deprotected phenols 1 were isolated in 40−60% yield (Scheme
Special Issue: Continuous Processes 14
Received: May 15, 2014
Published: June 27, 2014
© 2014 American Chemical Society
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Figure 2. (A) Electrochemical microreactor device (opened). (B) Flow setup for the electrochemical deprotection of the iNoc group.
Phenols are common moieties, for example, as side chains of
tyrosine (Tyr) residues in peptides and protein. The
deprotection of a natural protecting group such as a phosphate
ester from Tyr is important as such a process can trigger
biologic activities of proteins.8 In addition, an aqueous solution
of a short peptide including protected Tyr residues can be
converted to an aqueous gel, which is useful as a biomaterial, by
deprotection of Tyr and formation of hydrogen bond network
between the hydroxyl groups.9 The electrochemical depro-
tection of iNoc groups from phenols could be applied to
electrochemically trigger such biochemical phenomena. In
order to show the possibility for such applications, the
electrolysis of a dipeptide including an iNoc-protected Tyr
(Fmoc-Phe-Tyr(OiNoc)-OMe 4) was performed. Compound
4 was prepared by protection of the Tyr-unprotected dipeptide.
The reaction conditions for electrolysis were slightly modified
so that 4 was converted completely (Figure 3). As a result, the
Scheme 1. Synthesis of iNoc-Protected Phenols 3
Scheme 2. Electrochemical Cleavage of the iNoc Protecting
Group
Figure 3. Peptide and carbamate substrates.
2). The applicability of this technique for process chemistry
could be regarded as being weak due to the low yields and
productivity (11.5 mg/h for 1a) under the conditions
employed here. However, we only demonstrated the
electrolysis with a typical reactor having a small channel
volume to prove the usability for laboratory scale, and the
productivity can be easily and largely improved by increasing
the number of the reactor channels. This is one of the
advantages of a microfluidic reactor.
In order to demonstrate the synthetic utility of the
electrochemical microreactor for this type of reaction, the
electrolysis of 3a under batch conditions was carried out. A
similar solution of 3a in water/DMF (1:5) containing 50 mM
TBAI was electrolyzed in an undivided cell fitted with two
platinum foils as electrodes at a constant current (16.7 mA
cm−2). The progress of the reaction was monitored by TLC.
The results clearly show that the starting material gradually
decreased and completely disappeared after 6.5 h, while the
concentration of 1a increased. Finally, 1a was obtained in 53%
yield after purification by column chromatography. This result
therefore clearly shows that the electrochemical microreactor is
superior than batch electrolysis with regards to yield and
reaction time.
iNoc-deprotected dipetide Fmoc-Phe-Tyr-OMe was isolated in
12% yield. Although the yield decreased from simple phenols,
we successfully demonstrated the electrochemical iNoc
deprotection from a peptide molecule for the first time.
To investigate whether the electroreduction established for
carbonates can be applied to carbamate substrates, N-iNoc-
benzylamine 5 and α-N-iNoc-phenylalanine methyl ester 6
were electrolyzed. Initially, the reaction conditions for
carbonates were employed. According to the analysis of the
crude reaction mixture, these reactions did not progress at all
and only starting material was observed. The current was
increased to 140 mA cm−2, and although the starting materials
disappeared, only byproducts probably resulting from anodic
oxidation of the aromatic moieties were observed. Carbamates
are more stable under the electrolysis conditions than
carbonates, which would allow a site-selective deprotection of
iNoc groups in a molecule with multiple protection groups.
While we did not achieve the electrochemical deprotection of
carbamates, Veber et al. previously demonstrated that the iNoc
moiety can be electrochemically removed from the ε-amine of
lysine.2 However, it should be noted that they employed a
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mercury cathode while we used platinum. The redox activities
are clearly influenced by the electrode material.10
shown in this paper would enable a chemoselective
deprotection of iNoc protection groups.
We then investigated the electrochemical reduction of iNoc-
protected thiols, which is, for example, a functional group in L-
cysteine. iNoc-protected benzenethiol 7 as a simple model
substrate was prepared by the reaction of benzenethiol with 2
in DMF in good yield (93%). The electrochemical cleavage
conditions for carbonates were applied (16.7 mA cm−2),
leading to diphenyl disulfide 8 and (S)-phenyl benzenesulfono-
thioate 9 as reaction products. As shown in Scheme 3, it seems
EXPERIMENTAL SECTION
■
General. Melting points were obtained in open capillary
1
tubes and are uncorrected. H NMR and 13C NMR spectra
were recorded on an AV-400 Bruker spectrometer in the
indicated solvents at 400 MHz. Mass spectrometric data were
obtained on a Varian 1200 quadrupole mass spectrometer and
Micromass Quadro II spectrometer. ESI: Thermofisher LTQ
Orbitrap XL. All reactions were monitored by thin-layer
chromatography (TLC), which was performed on precoated
sheets of silica gel 60 (Merck). The electrochemical micro-
reactor, with a Pt foil (0.1 mm) as anode and cathode and
fluorinated ethylene polymer (FEP) channel, as shown in
Figure 1 and already described,4 was used. The galvanostatic
reactions were performed with a GWINSTEC GPR-30H100.
Isonicotinyl p-nitrophenyl carbonate 2,2 4-hydroxybenzoic acid
methyl ester 1c,7 and N-acetyl-L-cysteine methyl ester12 were
prepared by following the previously reported procedures.
Dipeptide Fmoc-Phe-Tyr-OMe was kindly provided by Dr.
Robert Mart and Prof. Dr. Rudolf Allemann. All other
chemicals were used as purchased without further purification.
General Procedure for Preparation of iNoc-Protected
Compounds. To prepare 3a and 3b, phenol 1a (1.20 mmol,
0.113 g) or 4-methoxyphenol 1b (0.95 mmol, 0.235 g) as the
starting material was dissolved in 2 mL of DMF and stirred for
3.5−16 h at 50 °C in the presence of iNoc reagent 2 (1.2
equiv) and K2CO3 (1.0 equiv). To prepare 3c, 4, 5, 6, 7, and
10, on the other hand, 4-hydroxybenzoic acid methyl ester 1c
(0.6 mmol, 91 mg), Fmoc-Phe-Tyr-OMe (0.30 mmol, 0.169 g),
benzylamine (0.20 mmol, 22 μL), L-phenylalanine methyl ester
hydrochloride (1.85 mmol, 0.400 g), benzenethiol (0.8 mmol,
82 μL), or N-acetyl-L-cysteine (0.60 mmol, 0.106 g) as the
starting material was dissolved in 0.5−3.0 mL of DMF and
stirred for 18 h at room temperature in the presence of the
iNoc reagent 2 (1.2 equiv), diisopropylethylamine (1.0 equiv),
and catalytic amounts of DMAP. After the reaction, 10 mL of
EtOAc and 10 mL of water were added to the reaction solution
and extracted with EtOAc (3 × 10 mL). The yellow organic
layer was washed with 1 M aqueous NaHCO3 (2 × 15 mL) and
brine (20 mL) and dried with over anhydrous MgSO4. After
filtration, the solvent was removed by evaporation under
reduced pressure to obtain a yellow oil of crude mixture. The
crude product was then purified by column chromatography
(silica gel). The collected fractions containing the iNoc-
protected compound were combined and evaporated under
reduced pressure.
Scheme 3. Electrochemical Cleavage of Thiocarbonates
that 8 was electrochemically generated by sequential oxidation
of deprotected 7 and was further oxidized to sulfonothioate 9.
It should be noted that deprotected 7 (benzenethiol) was not
observed in the crude reaction mixture even when the solution
exiting the microreactor was directly inserted into an aqueous
solution of 0.3 M HCl to stop any spontaneous oxidation of
thiols. This suggests that the disulfide and sulfonothioate
formation occurs directly in the electrochemical microreactor.
As electro-oxidation of thiols is a challenging task from both the
viewpoint of clean peptide synthesis and the structural biology
associated with protein folding,11 this protocol might be useful
to induce disulfide formation in other systems.
Therefore, the electrolysis of iNoc-protected L-cysteine
derivative 10 was investigated to reveal whether the desired
disulfide 11 can be obtained. N-Acetyl-L-cysteine methyl ester12
was protected with an iNoc group, and 10 was electrolyzed. To
achieve the full conversion of 10 during the electrolysis, the
reaction conditions were optimized. As with the results of 7,
1
TLC and H NMR analysis showed formation of disulfide
cystine 11 and possibly also the corresponding sulfonothioate
in the crude reaction mixture. However, these products are only
formed in minor amounts. In light of the results that the
electrolysis of 10 did not effectively progress while 7 was easily
electrolyzed to the desired products, it seems that the benzene
ring enhances the electroreductive deprotection of iNoc from
the substrates.
Phenylpyridin-4-ylmethyl Carbonate 3a. The reaction
was performed in 2.5 mL of DMF for 3.5 h. The colorless solid
of 3a was obtained by purification of the crude product by
using column chromatography (Et2O/EtOAc 3:2). Isolated
yield: 0.263 g (96%).
4-Methoxyphenylpyridin-4-ylmethyl Carbonate 3b.
The reaction was performed in 2.5 mL of DMF for 3.5 h.
The colorless solid of 3b was obtained by purification of the
crude product by using column chromatography (Et2O/EtOAc
9:1). Isolated yield: 0.227 g (92%).
Methyl 4-((Pyridin-4-ylmethoxy)carbonyloxy)-
benzoate 3c. The reaction was performed in 1.0 mL of
DMF. The colorless solid of 3c was obtained by purification of
the crude product by using column chromatography (Et2O/
EtOAc 3:2). Isolated yield: 0.169 g (98%).
CONCLUSIONS
■
In conclusion, we successfully accomplished the rapid electro-
chemical deprotection of an iNoc group from phenols and
benzenethiol by using the electrochemical microreactor. It was
also revealed that the N-iNoc group (carbamate) is enormously
stable for the electrolysis in the conditions employed here,
while the O-iNoc (carbonates) and S-iNoc (thiocarbonates)
were easily cleaved, meaning that the reduction potentials of O-
iNoc and S-iNoc compounds are more positive than that of N-
iNoc compound under the reaction conditions employed.
These results further indicate that the electrochemical method
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Fmoc-Phe-Tyr(O-iNoc)-OMe 4. The reaction was per-
formed in 1.5 mL of DMF. The colorless solid of 4 was
obtained by purification of the crude product by using column
chromatography (Et2O/EtOAc 1:4). Isolated yield: 0.125 g
(59%).
Pyridin-4-ylmethyl Benzylcarbamate 5. The reaction
was performed in 0.5 mL of DMF. The colorless solid of 5 was
obtained by purification of the crude product by using column
chromatography (Et2O/EtOAc 3:5). Isolated yield: 52 mg
(94%).
(S)-Methyl 3-Phenyl-2-((pyridin-4-ylmethoxy)-
carbonylamino)propanoate 6. The reaction was performed
in 3.0 mL of DMF. The yellow oil of 6 was obtained by
purification of the crude product by using column chromatog-
raphy (EtOAc/MeOH 7:1). Isolated yield: 0.46 g (79%).
(S)-Phenyl O-Pyridin-4-ylmethyl carbonothioate 7.
The reaction was performed in 1.5 mL of DMF. The colorless
solid of 7 was obtained by purification of the crude product by
using column chromatography (Et2O/EtOAc 3:2). Isolated
yield: 0.188 g (93%).
Electrolysis of 4: 2.0 mL of a solution containing 4 (0.19
mmol, 0.13 g) and TBAI (0.1 mmol, 37 mg) was electrolyzed
with constant current (19.4 mA cm−2) at a continuous flow (12
μL min−1, residence time = 115 s). Following purification of the
crude product using column chromatography (Et2O/hexane
5:1), the product (Fmoc-Phe-Tyr-OMe) was obtained as a
colorless solid. Isolated yield: 13 mg (12%).
Electrolysis of 7: 3 mL of a solution containing 7 (0.28
mmol, 71 mg) and TBAI (0.15 mmol, 55 mg) was electrolyzed
with constant current (16.7 mA cm−2) at continuous flow (15
μL min−1, residence time = 92 s). Following purification of the
crude product using column chromatography (Et2O/hexane
1:1), 8 and 9 were obtained as colorless solids. Isolated yield for
8: 19 mg (30%). Isolated yield for 9: 13 mg (18%).
Electrochemical Deprotection of 3a under Batch
Conditions. A mixture of 3a (0.95 mmol, 0.218 g) and
TBAI (0.51 mmol, 0.188 g) dissolved in DMF/H2O (5:1 v/v,
10.2 mL) was stirred and electrolyzed under aerobic conditions
at room temperature in an undivided cell (7.4 cm tall and 2.5
cm in diameter) fitted with two platinum foils (1.2 × 0.7 cm2)
as the anode and cathode. A constant current density (16.7 mA
cm−2) was applied. After TLC analysis (silica gel, Et2O/hexane
5:1) indicated that the starting material disappeared, the
electrolysis was stopped and 35 mL of water was added to the
black color of resulting solution. The solution was extracted
with EtOAc (3 × 30 mL). The combined extracts was washed
with water (3 × 30 mL) and brine (40 mL), dried over MgSO4,
and concentrated in vacuum. The residual black material was
purified by column chromatography (silica gel) equilibrated
with a mixture of Et2O/hexane (5:1 v/v) as eluent. The
fractions containing deprotected phenol were combined and
evaporated to give the colorless solid 1a in a yield of 47 mg
(53%).
(R)-Methyl 2-Acetamido-3-((pyridin-4-ylmethoxy)-
carbonylthio)propanoate 10. The reaction was performed
in 1.0 mL of DMF. The colorless solid of 10 was obtained by
purification of the crude product by using column chromatog-
raphy (EtOAc/MeOH 5:1). Isolated yield: 0.178 g (95%).
General Procedure for Electrochemical Deprotection
in Flow. Compound 3a, 3b, 3c, 4, 7, or 10 was dissolved in
DMF/H2O (5:1 v/v) containing 50 mM tetrabutylammonium
iodide so that the final concentration was 93 mM. The mixture
(2−4 mL) was introduced into the electrochemical micro-
reactor equipped with a FEP channel (0.3 cm × 3.0 cm × 254
μm) through a syringe pump (flow rate = 12−15 μL min−1,
residence time = 92−115 s) with an applied current of 30−35
mA (current density = 16.7−19.4 mA cm−2) and collected in a
glass vial at the outlet. The solution was diluted with 10 mL of
water and extracted with EtOAc (3 × 10 mL). The combined
extracts were washed with water (3 × 20 mL) and brine (40
mL), dried over MgSO4, and concentrated in vacuum. The
residual black material was purified by column chromatography
(silica gel). The fractions containing deprotected substrate were
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*Telephone and Fax: +44 29 2087 6968. E-mail: wirth@cf.ac.
■
1
combined and evaporated. The products were identified by H
NMR and/or MS.
Electrolysis of 3a: 4 mL of a solution containing 3a (0.37
mmol, 93 mg) and TBAI (0.2 mmol, 74 mg) was electrolyzed
with constant current (16.7 mA cm−2) at continuous flow (15
μL min−1, residence time = 92 s). Following purification of the
crude product using column chromatography (Et2O/hexane
5:1), 1a was obtained as a white solid. Isolated yield: 51 mg
(61%).
Electrolysis of 3b: 4 mL of a solution containing 3b (0.37
mmol, 96 mg) and TBAI (0.2 mmol, 74 mg) was electrolyzed
with constant current (16.7 mA cm−2) at continuous flow (15
μL min−1, residence time = 92 s). Following purification of the
crude product using column chromatography (Et2O/hexane
5:1), 1b was obtained as a colorless solid. Isolated yield: 20 mg
(43%).
uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by a generous grant from the Japan
Society for the Promotion of Science (JSPS) to K.A. Support
from the School of Chemistry, Cardiff University, is also
gratefully acknowledged. We thank Dr. Robert Mart (Cardiff
University) for the synthesis of Fmoc-Phe-Tyr-OMe, Prof. Dr.
Hironobu Hojo (Osaka University, Japan) for valuable
suggestions, and the EPSRC National Mass Spectrometry
Facility, Swansea, for mass spectrometric data.
Electrolysis of 3c: 3.5 mL of a solution containing 3c (0.33
mmol, 95 mg) and TBAI (0.17 mmol, 65 mg) was electrolyzed
with constant current (16.7 mA cm−2) at continuous flow (15
μL min−1, residence time = 92 s). Following purification of the
crude product using column chromatography (Et2O/hexane
5:1), 1c was obtained as a colorless solid. Isolated yield: 25 mg
(50%).
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