Supporting-Electrolyte-Free Anodic Oxidation of Oxamic Acids into Isocyanates: An Expedient Way to Access Ureas, Carbamates, and Thiocarbamates

Article abstract of DOI:10.1021/acs.oprd.1c00112

We report a new electrochemical supporting-electrolyte-free method for synthesizing ureas, carbamates, and thiocarbamates via the oxidation of oxamic acids. This simple, practical, and phosgene-free route includes the generation of an isocyanate intermediate in situ via anodic decarboxylation of an oxamic acid in the presence of an organic base, followed by the one-pot addition of suitable nucleophiles to afford the corresponding ureas, carbamates, and thiocarbamates. This procedure is applicable to different amines, alcohols, and thiols. Furthermore, when single-pass continuous electrochemical flow conditions were used and this reaction was run in a carbon graphite C_gr/C_gr flow cell, urea compounds could be obtained in high yields within a residence time of 6 min, unlocking access to substrates that were inaccessible under batch conditions while being easily scalable.

Full text of DOI:10.1021/acs.oprd.1c00112

pubs.acs.org/OPRD
Article
Supporting-Electrolyte-Free Anodic Oxidation of Oxamic Acids into
Isocyanates: An Expedient Way to Access Ureas, Carbamates, and
Thiocarbamates
Alessia Petti, Corentin Fagnan, Carlo G. W. van Melis, Nour Tanbouza, Anthony D. Garcia,
Andrea Mastrodonato, Matthew C. Leech, Iain C. A. Goodall, Adrian P. Dobbs, Thierry Ollevier,
and Kevin Lam*
Cite This: https://doi.org/10.1021/acs.oprd.1c00112
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report a new electrochemical supporting-electrolyte-free method for synthesizing ureas, carbamates, and
thiocarbamates via the oxidation of oxamic acids. This simple, practical, and phosgene-free route includes the generation of an
isocyanate intermediate in situ via anodic decarboxylation of an oxamic acid in the presence of an organic base, followed by the one-
pot addition of suitable nucleophiles to afford the corresponding ureas, carbamates, and thiocarbamates. This procedure is applicable
to different amines, alcohols, and thiols. Furthermore, when single-pass continuous electrochemical flow conditions were used and
this reaction was run in a carbon graphite Cgr/Cgr flow cell, urea compounds could be obtained in high yields within a residence time
of 6 min, unlocking access to substrates that were inaccessible under batch conditions while being easily scalable.
KEYWORDS: isocyanates, electrosynthesis, urea, carbamates, phosgene-free, flow electrosynthesis, anodic decarboxylation, oxamic acids
cleavage conditions.6,11−14 Conventionally, these are synthe-
INTRODUCTION
■
sized via isocyanates, which can be prepared in situ by treating
Carbamates, thiocarbamates, and ureas have found numerous
primary amines with phosgene (Figure 2).15,16 Although
applications across fields ranging from medicinal chemistry to
materials chemistry.1−4 They are mostly used to produce
industrial processes still use stoichiometric amounts of highly
poly(urea-urethanes) or PUreas, which are valuable polymers
in the manufacture of flexible and rigid foams, coatings, and
adhesives.5,6 For instance, a biodegradable polymer, such as
poly(propylene carbonate), is a widely used packing material
and medicinal material.7 Up to 24 million tons of polyurethane
are produced annually, mainly using aromatic isocyanates, such
as toluene diisocyanate (TDI) and diphenylmethane diisocya-
nate (MDI).8 Additionally, numerous medicinal compounds
bear carbamate or urea groups, such as sorafenib (a
multikinase inhibitor for hepatocellular carcinoma and
advanced renal cell carcinoma), ritonavir (an antiretroviral
used to treat HIV/AIDS), and albendazole (a drug used to
treat parasitic worm infestations) (Figure 1).9,10
Carbamates and ureas are also useful protecting groups in
organic synthesis because of their high stability and selective
Figure 2. Overview of the synthesis of carbamates and ureas.
Special Issue: Unleashing the Potential to Electrify
Process Chemistry: From Bench to Plant
Received: March 31, 2021
Figure 1. Examples of active pharmaceutical ingredients containing
carbamates and ureas.
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Organic Process Research & Development
pubs.acs.org/OPRD
Article
toxic phosgene,17 there is a growing impetus for the
development of greener and less harmful approaches to
prepare isocyanates. Alternative methods do exist, including
the Hofmann, Curtius, and Lossen rearrangements, which
avoid the use of phosgene or phosgene derivatives.18−24 They
generate isocyanates under relatively mild conditions but still
require the use of toxic reagents or elaborate precursors. For
instance, the use of an alkaline solution of bromine in the
Hofmann rearrangement and the formation of potentially
explosive azides in the Curtius rearrangement limit their use
for large-scale synthesis.25 As an alternative, the Lossen
rearrangement provides access to isocyanates under relatively
mild conditions but still requires the synthesis of a potentially
unstable hydroxamic acid.26,27 Some recent developments
using dehydrating agents, such as carbonyldiimidazole
(CDI),28 and activating reagents, such as dimethyl carbonate
(DMC),27 have received particular attention (Figure 2).
Additional developments, such as amine carboxylation using
CO2 as the carbon source,29−33 reductive carboxylation of
nitroaromatics,34 and carbamate metathesis,35 have
emerged.36−39 However, these methods still suffer from the
limited availability and stability of the commercial starting
materials, metal catalysts,40 and toxic gas reagents, which could
be disfavored by industries.
Chemical oxidation of oxamic acids into isocyanates using
peroxydisulfate in the presence of a Cu or Ag catalyst was first
disclosed in 1995 by Minisci.41 We have previously reported
that the anodic oxidation of oxamic acid derivatives in
methanol leads cleanly to the formation of the corresponding
methylcarbamates via the formation of isocyanates.42 After-
ward, Landais et al. applied this method to the preparation of a
variety of carbamates.43 Unfortunately, the methodology is
limited to the synthesis of simple carbamates that could very
often be accessed more rapidly by using the commercially
available chloroformates. Indeed, Landais’s methodology is
compatible only with alcohols as nucleophiles and requires
them to be stable toward anodic oxidation and used in a vast
excess as the solvent. A wasteful supporting electrolyte is also
needed (0.1 equiv), and the reaction is run at extremely low
current densities (5 mA·cm−2). In this work, we have
developed an improved electrolytic method for the generation
of isocyanates from oxamic acids that is applicable to the
synthesis of ureas, carbamates, and thiocarbamates (Figure 2).
This anodic decarboxylation of oxamic acids into isocyanates
uses no supporting electrolyte and is compatible with a wide
range of nucleophiles without having to use them in significant
excess.
Table 1. Optimization of the Reaction Conditions for the
Electrosynthesis of Isocyanates and the One-Pot Synthesis
of Urea 2aa
a
b
entry
base
collidine
DMAP
equiv additive (equiv) yield of 2aa (%)
1
2
3
4
5
6
7
8
9
2.5
2.5
2.5
2.5
2.5
1
−
−
−
−
−
−
quantitative
72
39
0
39
60
methylimidazole
Cs2CO3
NEt3
collidine
collidine
collidine
collidine
collidine
collidine
collidine
2
−
92
5
−
93
10
−
95
10
2.5
2.5
2.5
LiClO4 (1)
4 Å MS
−
72
c
11
quantitative
quantitative
d
e
12
a
Reaction conditions: 1a (0.32 mmol), n-propylamine (3 equiv), and
ACN (5 mL) in a 10 mL Electrasyn vial, Cgr/Cgr electrodes, 12.5 mA·
b
cm−2, 3 F·mol−1, alternating polarity (30 s) at rt. Determined by 1H
NMR spectroscopy postworkup using CH2Br2 as an internal standard.
c
d
25 mg of 4 Å molecular sieves was used. 1a (0.64 mmol) and ACN
e
(5 mL) in a 5 mL Electrasyn vial at 25 mA·cm−2. Isolated yield.
MS analyses of the reaction mixture confirmed the formation
of 1-isocyanatohexane.
Much to our delight, the electrolysis of 1a in the presence of
2.5 equiv of collidine led to the quantitative formation of the
desired urea 2aa (Table 1, entry 1). The exact effect of
collidine remains unclear and is under further investigation.
Interestingly, GC−MS analyses of the reaction mixture showed
that collidine was found intact at the end of the reaction. Both
decreasing and increasing the amount of collidine led to a
decrease in the urea yield (Table 1, entries 6−9). Changing the
base to 4-(dimethylamino)pyridine (DMAP), methylimida-
zole, or triethylamine led to a similar drop in yield, while using
an inorganic base as Cs2CO3 gave no trace of the desired urea
2aa (Table 1, entries 2−5). The addition of a supporting
electrolyte, such as LiClO4, was shown to be detrimental
(Table 1, entry 10). Moreover, using molecular sieves to
remove possible traces of moisture was shown to be
unnecessary (Table 1, entry 11). Doubling the concentration
of oxamic acid still led to the quantitative formation of the
desired urea and allowed the electrolysis to be run at a higher
current because of the solution’s increased conductivity,
shortening the electrolysis time per millimole of substrate
(Table 1, entry 12). Finally, attempts to replace acetonitrile
(ACN) with other solvents, such as dimethyl sulfoxide,
dimethylformamide, or dichloromethane, led to poor yields
and complex mixtures of products that were challenging to
separate.
RESULTS AND DISCUSSION
■
Our general strategy relies on the use of a cheap electrode
material (graphite) and easily synthesized oxamic acid
derivatives in combination with collidine to generate a
carboxylate ion in situ. In a typical experiment, the oxamic
acid is first electrolyzed, and then a nucleophile is added to the
solution postelectrolysis and allowed to react with the
anodically formed isocyanate. An acidic workup followed by
a rapid filtration over silica gel allows the isolation of the pure
coupled product. We first investigated the synthesis of ureas
from electrogenerated isocyanates. The electrochemical
conditions for the anodic decarboxylation of oxamic acid 1a
were optimized by screening bases and additives with n-
propylamine as a nucleophile (Table 1). Encouragingly, GC−
Cyclic voltammetry measurements performed on 1a showed
an ill-defined oxidation at ca. 2.25 V vs Fc/Fc+ in ACN (see
the Supporting Information (SI)). The addition of 0.5 equiv of
triethylamine resulted in the formation of the anion of 1a,
B
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
a
Scheme 1. Scope of Urea Compounds
a
Isolated yields are shown. The yield in parentheses was determined by 1H NMR spectroscopy postworkup using CH2Br2 as an internal standard.
which displayed a lower oxidation potential (Epa = 0.75 V vs
Fc/Fc+). However, when more than 1 equiv of base was added,
a secondary feature at a lower potential (Epa = 0.52 V vs Fc/
Fc+) was observed, arising from the anodic oxidation of the
excess triethylamine. At least 2 equiv of base are needed to
generate the desired isocyanate, and triethylamine would be
unsuitable for our reaction since it would be oxidized before
the oxamate anion. The use of collidine as an alternative base
was investigated because of its high tolerance toward anodic
oxidation. As in the previous case, upon titration with 0.5 equiv
alkane chains gave urea compounds in moderate to good yields
(31−86%) with either aliphatic or aromatic amines (2ba−db;
Scheme 1).
Impressively, this method tolerates N-protecting groups, as
the corresponding isocyanates led to urea compounds 2e−fb
in moderate yields (16−57%). Electrolyzing the alkene- and
alkyne-bearing oxamic acids 2-(allylamino)-2-oxoacetic acid
(1h) and 2-oxo-2-(prop-2-yn-1-ylamino)acetic acid (1i) gave
ureas 2h and 2i in modest yields. This procedure is also
compatible with oxamic acids bearing benzylic groups, which
gave ureas 2ja and 2jb in 70% and 78% yield, respectively. In
addition, an oxamic acid with a homobenzylic group yielded
urea 2k in 65% yield with cyclohexylamine. Most of the lower
yields were obtained with substrates that are less conductive or
form highly reactive isocyanates. Unfortunately, this method
does not seem to tolerate aryl amines as nucleophiles, as shown
by the inability to prepare 2l.
Encouraged by the positive results obtained for the synthesis
of ureas, we investigated the possibility of transposing the
methodology to the synthesis of carbamates. Unfortunately,
low yields were obtained. Instead of the desired carbamate, the
unreacted alcohol and amine (generated by the hydrolysis of
the unreacted isocyanate) were found to be the primary
products at the end of the reaction (Table 2). Again, this
observation seems to be in line with collidine’s ability to
moderate the reactivity of isocyanates. For instance, when 1a
was electrolyzed under our optimal conditions and allowed to
react with octan-1-ol (3 equiv) for 18 h at room temperature,
of collidine, an anion with a lower oxidation potential (Epa
=
0.87 V vs Fc/Fc+) was formed, and no additional redox
processes were observed upon further addition of base up to a
total of 2.5 equiv. In both cases, anodic fouling of the electrode
was observed when potentials greater than 1.75 V were applied
(see the SI).
With the optimized conditions in hand, the scope and
limitations of the newly developed anodic synthesis of ureas
were explored (Scheme 1). When 1a was used under the
previously optimized conditions, the corresponding ureas were
obtained in high yields (72%−quant) in the presence of a
primary amine (2aa−ac; Scheme 1). Diisopropylamine, as a
nucleophile, afforded 2ad in a slightly decreased yield of 58%,
presumably due to its higher steric hindrance, leaving
unreacted isocyanate, which degraded over time and during
the workup. However, with pyrrolidine and morpholine as
nucleophiles, ureas 2ae and 2af were obtained in 89% and 72%
yield, respectively. Oxamic acids 1b−d with linear and cyclic
C
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Table 2. Reoptimization of the Reaction Conditions for the
Electrosynthesis of Carbamate 3aa
Table 3. Optimization of Flow Conditions for the
Electrosynthesis of Carbamate 2aa
interelectrode
gap (mm)
Vcell
flow rate
residence
yield of 2aa
a
b
entry
(mL) (μL/min) time (min)
(%)
1
2
3
0.25
0.5
1
1
1
0.3
0.6
1.2
1.2
1.2
1.2
100
100
100
200
200
400
3
6
12
6
6
3
N.R.
48
70
a
b
entry T (°C)
base
collidine
collidine
collidine
collidine
methylimidazole
DMAP
collidine
collidine
collidine
collidine
collidine
collidine
catalyst (mol %) yield of 3aa (%)
1
2
3
4
5
rt
−
7
c
4
5
quantitative
40
60
80
rt
−
12
d
e
53
−
23
e
6
1
44
−
23
a
Reaction conditions: a solution of 1a (0.3 mmol) and collidine (2.5
−
−
traces
traces
63
73
28
equiv) in ACN (0.15 M) was injected into a flow cell equipped with
Cgr/Cgr electrodes and the indicated spacer at the indicated flow rate
at rt, and the collection unit was equipped with a vial containing
6
rt
7
rt
DBTDL (10)
DBTDL (10)
BF3·OEt2 (10)
DBU (10)
FeCl3
b
propylamine (1 mL). Determined by 1H NMR spectroscopy
8
9
10
60
60
60
60
60
c
postworkup using CH2Br2 as an internal standard. 3 equiv of
propylamine was used. [1a] = 0.3 M. Incomplete conversion.
d
e
9
11
0
67
c
d
12
DBTDL (10)
a
the expected carbamate 3aa was formed in only 7% yield
(Table 2, entry 1). Increasing the temperature after addition of
the alcohol led to slightly improved yields (up to 23%; Table 2,
entries 2−4). Changing the base to either methylimidazole or
DMAP led to only traces of the carbamates (Table 2, entries 5
and 6). However, using 10 mol % dibutyltin dilaurate
(DBTDL), a well-known catalyst for addition of alcohols to
Reaction conditions: 1a (0.32 mmol), octan-1-ol (3 equiv), and
ACN (5 mL) in a 10 mL Electrasyn vial, Cgr/Cgr electrodes, 12.5 mA·
b
cm−2, 3 F·mol−1, alternating polarity (30 s) at rt. Determined by 1H
NMR spectroscopy postworkup using CH2Br2 as an internal standard.
c
1a (0.64 mmol) and ACN (5 mL) in a 5 mL Electrasyn vial at 25
d
mA·cm−2. Isolated yield.
Scheme 2. Scope of Carbamates and Thiocarbamates
D
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
c
Scheme 3. Flow Synthesis of Urea Compounds
a
The reaction was run at 100 μL/min with a residence time of 12
b
min. LiClO4 (0.1 M) was used as supporting electrolyte. Yields in
brackets are determined by H NMR spectroscopy postworkup using
CH2Br2 as an internal standard. Isolated yields are shown. Yields in
parentheses were determined by H NMR spectroscopy postworkup
1
c
1
using CH2Br2 as an internal standard.
carbonyl groups, gave 3aa in 63% yield (Table 2, entry 7).
Increasing the reaction temperature to 60 °C after the addition
of octan-1-ol in the presence of DBTDL (10 mol %) further
increased the yield to 73% (Table 2, entry 8). Attempts to
replace DBTDL with BF3·OEt2 or 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) led to lower yields, and no trace of the
desired carbamate was observed when FeCl3 was employed
(Table 2, entries 9−11). Finally, as discussed previously,
increasing the concentration of the oxamic acid in the
electrochemical cell increased the rate of electrolysis by
allowing it to be run at 25 mA·cm−2. Under such conditions,
using DBTDL (10 mol %) at 60 °C, the desired carbamate 3aa
was obtained in 67% yield (Table 2, entry 12).
To explore the scope of this new carbamate synthesis, a
series of oxamic acids were electrolyzed and subsequently
treated with alcohols in the presence of a catalytic amount of
DBTDL at 60 °C (Scheme 2). Thiocarbamate formation was
also briefly explored with the same substrates by using thiols
instead of alcohols under similar conditions. When oxamic acid
1a was electrolyzed and then treated with prop-2-yn-1-ol or
phenol, the corresponding carbamates 3ab and 3ac were
obtained in moderate yields (48% and 50%, respectively). In
comparison, thiocarbamate 4a was formed in 77% yield when
1a was treated with phenylmethanethiol. 2-(Octylamino)-2-
oxoacetic acid (1b), 2-(cyclohexylamino)-2-oxoacetic acid
(1c), and 2-(adamantan-1-yl)amino-2-oxoacetic acid 1d
afforded carbamates 3b−d in moderate to good yields (40−
86%) and thiocarbamates 4b and 4c in moderate yields.
Alkynyl and benzylic oxamic acids were also compatible with
the optimized electrolytic conditions for the synthesis of
carbamates 3i−lb and thiocarbamate 4j. Not only does the
new methodology tolerate alkyl halides, but pleasingly, free
hydroxyl groups are also compatible, as shown by the
successful syntheses of 3m and 3n in 25% and 46% yield,
respectively.
Figure 3. Proposed mechanism for the anodic oxidation of oxamic
acids.
To further streamline this synthetic method and emphasize
its usefulness industrially, we decided to translate it into a
continuous flow setup. The use of flow electrochemistry has
been gaining significant traction over the past few years and is
among the most efficient ways to conduct electrosynthesis on a
large scale.44−48 The small interelectrode gap and the high
electrode surface area to reaction volume ratio significantly
decreases resistance.49,50 In this study, we aimed at having a
flow method that works as efficiently as the batch method
while also resolving issues with substrates that were
inaccessible because of high reactivity or low conductivity.
Initially, we sought to investigate flow conditions for obtaining
urea 2aa from oxamic acid 1a and propylamine (Table 3). A
complete description of the flow systems used can be found in
the SI. A solution of the oxamic acid (0.15 M) was prepared in
acetonitrile with 2.5 equiv of collidine and introduced into a
flow cell equipped with two graphite electrodes at various flow
rates, and the interelectrode gap (i.e., the spacer) and hence
the volume of the flow cell were also varied. The power supply
was set to a maximum of 100 mA, and the output was then
introduced into stirring propylamine (excess) to trap the
isocyanate. It was found that at a significantly small
interelectrode gap (0.25 mm), no conversion was observed
because of the small volume and hence short residence time of
E
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
the oxamic acid in the cell (3 min) (Table 3, entry 1). The
impedance was so low with a 0.25 mm spacer that the
electrolysis of the solvent itself, without any supporting
electrolyte, allowed a current of 100 mA to be reached at a
maximum voltage of 30 V. Using thicker spacers (0.5 and 1
mm) resulted in the formation of the desired urea in 48% and
70% yield, respectively (Table 3, entries 2 and 3). Running the
reaction at a doubled flow rate (200 μL/min) with a 1 mm
spacer resulted in a residence time of 6 min and gave urea 2aa
in quantitative yield (Table 3, entry 4). Increasing the
concentration of the oxamic acid to 0.3 M reduced the
conversion, as did increasing the flow rate to 400 μL/min
(Table 3, entries 5 and 6). This successful translation into flow
conditions allows shorter reaction times (12 min vs 100 min
on a 0.6 mmol scale) with comparable yields.
nucleophile leads to the formation of the desired urea,
carbamate, or thiocarbamate B.
CONCLUSION
■
We have developed an original method for the batch and flow
electrochemical synthesis of carbamates, ureas, and thiocarba-
mates via oxidative decarboxylation of oxamic acids. This
practical approach gives rapid and easy access to highly
functionalized unsymmetrical ureas, carbamates, and thiocar-
bamates. The newly developed procedure affords the desired
products in moderate to excellent yields under mild and
oxidant free conditions without the use of any toxic reagents or
the isolation of highly reactive and toxic isocyanates. Lastly,
this one-pot synthesis shows broad functional group
compatibility and represents an efficient and practical way to
access pharmaceutical targets on both laboratory and industrial
scales.
The reaction of oxamic acid 1a under the optimized reaction
conditions gave urea 2aa in quantitative yield on a 0.3 mmol
scale. When the reaction was run on a 1 g (5.37 mmol) scale,
the desired urea was obtained in 81% yield. The slightly
decreased yield during scale-up can be explained by the fouling
of the electrodes during the longer electrolysis run, resulting in
incomplete conversion of the oxamic acid. This could possibly
be improved by alternating the electrodes’ polarity and
adapting the cell design to accommodate large-scale
electrolyses. During our screening of substrates, the absence
of a supporting electrolyte proved that the conductivity is
highly substrate-dependent. Substrates that resulted in low
conductivity were selected to be run under the optimized flow
conditions. Indeed, 2-oxo-2-(pent-4-en-1-ylamino)acetic acid
(1o) and aryl oxamic acids 1p−r suffered from poor
conductivities in batch, and no isocyanate was formed. When
oxamic acids 1p−r were electrolyzed, no traces of the desired
ureas were obtained under standard batch conditions. The
addition of a supporting electrolyte did not lead to any
improvements; 2p was obtained in only 4% yield, while no
trace of 2q was observed. However, in continuous flow,
solutions of 1o−1r with collidine were sufficiently conductive
to be electrolyzed and led to the clean formation of the
corresponding ureas after reaction with propylamine (Scheme
3). Urea 2o was obtained in 84% yield from 1o, and aryl
oxamic acids 1p−r bearing p-Cl, p-OMe, and m-Br
substituents, respectively, led to the desired urea compounds
2p−2r, albeit in low yields. Ureas 2da, 2fa, and 2fb were also
made under flow conditions in an attempt to improve the
yields compared with batch, and slightly increased yields were
obtained; hence, a substrate-specific optimization would be
required to address these. Even though no significant increase
in yield was obtained in these cases, it is worth noting that
these single-pass flow reactions are not only faster than batch
electrolyses but also much cleaner. Performing a simple acidic
workup at the end of the flow reaction is enough to obtain the
pure urea without further chromatographic purifications (see
the SI).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00112.
Experimental details and procedures, including copies of
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Kevin Lam − School of Science, University of Greenwich,
Chatham, Kent ME4 4TB, U.K.; orcid.org/0000-0003-
1481-9212; Email: k.lam@greenwich.ac.uk
Authors
Alessia Petti − School of Science, University of Greenwich,
Chatham, Kent ME4 4TB, U.K.
Corentin Fagnan − School of Science, University of Greenwich,
Chatham, Kent ME4 4TB, U.K.
Carlo G. W. van Melis − School of Science, University of
Greenwich, Chatham, Kent ME4 4TB, U.K.
Nour Tanbouza − Département de Chimie, Université Laval,
Québec, QC G1V 0A6, Canada; orcid.org/0000-0002-
9729-0918
Anthony D. Garcia − School of Science, University of
Greenwich, Chatham, Kent ME4 4TB, U.K.
Andrea Mastrodonato − School of Science, University of
Greenwich, Chatham, Kent ME4 4TB, U.K.
Matthew C. Leech − School of Science, University of
Greenwich, Chatham, Kent ME4 4TB, U.K.; orcid.org/
0000-0003-3524-2897
Iain C. A. Goodall − School of Science, University of
Greenwich, Chatham, Kent ME4 4TB, U.K.; orcid.org/
0000-0003-2212-2052
Finally, we propose a mechanism for the anodic oxidation of
oxamic acids (Figure 3). First, oxamic acid 1 is deprotonated
by collidine to form the corresponding anion A, which
undergoes electrostatic attraction to the positive anode. At the
same time, the protonated collidine gets reduced at the
cathode, regenerating the free base. At the anode, oxidation of
A generates acyloxy radical I, which subsequently undergoes
anodic decarboxylation (Hofer−Moest-type mechanism) to
form carbamoyl cation III. The latter is then deprotonated to
give isocyanate intermediate V. Finally, addition of a
Adrian P. Dobbs − School of Science, University of Greenwich,
Chatham, Kent ME4 4TB, U.K.; orcid.org/0000-0002-
7241-7118
Thierry Ollevier − Département de Chimie, Université Laval,
Québec, QC G1V 0A6, Canada; orcid.org/0000-0002-
6084-7954
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.1c00112
F
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
(13) Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M.
Deprotection of a primary Boc group under basic conditions.
Tetrahedron Lett. 2004, 45, 905−906.
Author Contributions
The manuscript was written through the contributions of all
authors. All of the authors approved the final version of the
manuscript.
(14) Noshita, M.; Shimizu, Y.; Morimoto, H.; Ohshima, T.
Diethylenetriamine-Mediated Direct Cleavage of Unactivated Carba-
mates and Ureas. Org. Lett. 2016, 18, 6062−6065.
Funding
We are grateful to the Engineering and Physical Sciences
Research Council (Grant EP/S017097/1 to K.L. and M.C.L.),
the University of Greenwich (Vice Chancellor’s Ph.D.
Scholarship to A.P. and C.G.W.v.M.), and the University
Alliance “Applied Biosciences for Health” (Marie Skłodowska-
Curie Grant 801604, Ph.D. scholarships to A.D.G., C.F. and
A.M.) for financial support. N.T. is grateful to the Natural
Sciences and Engineering Research Council of Canada
(NSERC) for a doctoral award (PGSD3-546986-2020) and
the Royal Society of Chemistry for a Researcher Mobility
Grant (M19-0357) to fund her visit to work with K.L.
(15) Babad, H.; Zeiler, A. G. Chemistry of phosgene. Chem. Rev.
1973, 73, 75−91.
(16) Cotarca, L.; Eckert, H. Phosgenations - A Handbook; Wiley-
VCH: Weinheim, Germany, 2004.
(17) Vaish, A. K.; Consul, S.; Agrawal, A.; Chaudhary, S. C.; Gutch,
M.; Jain, N.; Singh, M. M. Accidental phosgene gas exposure: A
review with background study of 10 cases. J. Emerg. Trauma Shock
2013, 6, 271−275.
(18) Shono, T.; Matsumura, Y.; Yamane, S.-i.; Kashimura, S. The
Hofmann Rearrangement Induced by Electroorganic Method. Chem.
Lett. 1982, 11, 565−568.
(19) Huang, X.; Keillor, J. W. Preparation of Methyl Carbamates via
a Modified Hofmann Rearrangement. Tetrahedron Lett. 1997, 38,
313−316.
Notes
The authors declare no competing financial interest.
(20) Matsumura, Y.; Maki, T.; Satoh, Y. Electrochemically Induced
Hofmann Rearrangement. Tetrahedron Lett. 1997, 38, 8879−8882.
(21) Gogoi, P.; Konwar, D. An efficient modification of the
Hofmann rearrangement: synthesis of methyl carbamates. Tetrahedron
Lett. 2007, 48, 531−533.
ACKNOWLEDGMENTS
■
K.L. thanks IKA for material support and Vapourtec and Syrris
for their generous loan of the flow systems and electrochemical
flow cells. N.T. thanks Vanessa Kairouz (Centre in Green
Chemistry and Catalysis, Université de Montréal) for training
in flow chemistry under the NSERC-CREATE Program.
(22) Scriven, E. F. V.; Turnbull, K. Azides: their preparation and
synthetic uses. Chem. Rev. 1988, 88, 297−368.
(23) Ghosh, A. K.; Sarkar, A.; Brindisi, M. The Curtius
rearrangement: mechanistic insight and recent applications in natural
product syntheses. Org. Biomol. Chem. 2018, 16, 2006−2027.
(24) Kornblum, N.; Scott, A. A new method for protecting amines. J.
Org. Chem. 1977, 42, 399−400.
(25) Organic Azides: Syntheses and Applications; John Wiley & Sons:
Chichester, U.K., 2009; pp i−xxviii.
(26) Manne, S. R.; Thalluri, K.; Giri, R. S.; Chandra, J.; Mandal, B.
Ethyl 2-(tert-Butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma):
An Efficient Reagent for the Racemization Free Synthesis of Ureas,
Carbamates and Thiocarbamates via Lossen Rearrangement. Adv.
Synth. Catal. 2017, 359, 168−176.
(27) Kreye, O.; Wald, S.; Meier, M. A. R. Introducing Catalytic
Lossen Rearrangements: Sustainable Access to Carbamates and
Amines. Adv. Synth. Catal. 2013, 355, 81−86.
(28) Dubé, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M.
Carbonyldiimidazole-Mediated Lossen Rearrangement. Org. Lett.
2009, 11, 5622−5625.
(29) Sakakura, T.; Saito, Y.; Okano, M.; Choi, J.-C.; Sako, T.
Selective Conversion of Carbon Dioxide to Dimethyl Carbonate by
Molecular Catalysis. J. Org. Chem. 1998, 63, 7095−7096.
(30) Chaturvedi, D.; Ray, S. Versatile Use of Carbon Dioxide in the
Synthesis of Carbamates. Monatsh. Chem. 2006, 137, 127−145.
(31) Riemer, D.; Hirapara, P.; Das, S. Chemoselective Synthesis of
Carbamates using CO2 as Carbon Source. ChemSusChem 2016, 9,
1916−1920.
REFERENCES
■
(1) Walter, W.; Bode, K.-D. Syntheses of Thiocarbamates. Angew.
Chem., Int. Ed. 1967, 6, 281−384.
(2) Rath, N. C.; Huff, W. E.; Huff, G. R.; Kannan, L. Induction of
Tibial Dyschondroplasia by Carbamate and Thiocarbamate Pesticides.
Avian Dis. 2007, 51, 590−593.
(3) Ghosh, A. K.; Brindisi, M. Organic carbamates in drug design
and medicinal chemistry. J. Med. Chem. 2015, 58, 2895−2940.
(4) Scattolin, T.; Bouayad-Gervais, S.; Schoenebeck, F. Straightfor-
ward access to N-trifluoromethyl amides, carbamates, thiocarbamates
and ureas. Nature 2019, 573, 102−107.
(5) Akindoyo, J. O.; Beg, M. D. H.; Ghazali, S.; Islam, M. R.;
Jeyaratnam, N.; Yuvaraj, A. R. Polyurethane types, synthesis and
applications − a review. RSC Adv. 2016, 6, 114453−114482.
(6) Kozakiewicz, J.; Rokicki, G.; Przybylski, J.; Sylwestrzak, K.;
Parzuchowski, P. G.; Tomczyk, K. M. Studies of the hydrolytic
stability of poly(urethane−urea) elastomers synthesized from
oligocarbonate diols. Polym. Degrad. Stab. 2010, 95, 2413−2420.
(7) Ghosh, A. K.; Brindisi, M. Urea Derivatives in Modern Drug
Discovery and Medicinal Chemistry. J. Med. Chem. 2020, 63, 2751−
2788.
(8) Market volume forecast of polyurethane worldwide from 2016 to
2021. https://www.statista.com/statistics/720341/global-
polyurethane-market-size-forecast/#statisticContainer (accessed
2021-03-14).
(32) Ren, Y.; Rousseaux, S. A. L. Metal-Free Synthesis of
Unsymmetrical Ureas and Carbamates from CO2 and Amines via
Isocyanate Intermediates. J. Org. Chem. 2018, 83, 913−920.
(33) Hussong, C.; Langanke, J.; Leitner, W. Carbon2Polymer: A
CO2-based Route to Polyurethanes via Oxidative Carbonylation of
TDA with Methyl Formate. Chem. Ing. Tech. 2020, 92, 1482−1488.
(34) Cenini, S.; Crotti, C.; Pizzotti, M.; Porta, F. Ruthenium
Carbonyl Catalyzed Reductive Carbonylation of Aromatic Nitro
Compounds. A Selective Route to Carbamates. J. Org. Chem. 1988,
53, 1243−1250.
(35) Kébir, N.; Benoit, M.; Legrand, C.; Burel, F. Non-isocyanate
thermoplastic polyureas (NIPUreas) through a methyl carbamate
metathesis polymerisation. Eur. Polym. J. 2017, 96, 87−96.
(36) Chaturvedi, D. Perspectives on the synthesis of organic
carbamates. Tetrahedron 2012, 68, 15−45.
(9) Llovet, J. M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.;
Blanc, J.-F.; de Oliveira, A. C.; Santoro, A.; Raoul, J.-L.; Forner, A.;
Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T. F.; Galle,
P. R.; Seitz, J.-F. o.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan,
M.; Moscovici, M.; Voliotis, D.; Bruix, J. Sorafenib in Advanced
Hepatocellular Carcinoma. N. Engl. J. Med. 2008, 359, 378−390.
(10) Chen, Z.; Digiacomo, M.; Tu, Y.; Gu, Q.; Wang, S.; Yang, X.;
Chu, J.; Chen, Q.; Han, Y.; Chen, J.; Nesi, G.; Sestito, S.; Macchia,
M.; Rapposelli, S.; Pi, R. Discovery of novel rivastigmine-
hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer’s
disease. Eur. J. Med. Chem. 2017, 125, 784−792.
(11) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis,
5th ed.; John Wiley & Sons: Hoboken, NJ, 2014.
(12) Wicks, D. A.; Wicks, Z. W., Jr. Blocked isocyanates III: Part A.
Mechanisms and chemistry. Prog. Org. Coat. 1999, 36, 148−172.
G
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
pubs.acs.org/OPRD
Article
(37) Fan, H.; Wan, Y.; Pan, P.; Cai, W.; Liu, S.; Liu, C.; Zhang, Y. A
cascade approach to 3D cyclic carbamates via an ionic decarboxylative
functionalisation of olefinic oxamic acids. Chem. Commun. 2020, 56,
86−89.
(38) Pawar, G. G.; Robert, F.; Grau, E.; Cramail, H.; Landais, Y.
Visible-light photocatalysed oxidative decarboxylation of oxamic
acids: a green route to urethanes and ureas. Chem. Commun. 2018,
54, 9337−9340.
(39) Wang, L.; Wang, H.; Wang, Y.; Shen, M.; Li, S. Photocatalyzed
synthesis of unsymmetrical ureas via the oxidative decarboxylation of
oxamic acids with PANI-g-C3N4-TiO2 composite under visible light.
Tetrahedron Lett. 2020, 61, 151962.
(40) Petersen, W. F.; Taylor, R. J. K.; Donald, J. R. Photoredox-
catalyzed procedure for carbamoyl radical generation: 3,4-dihydro-
quinolin-2-one and quinolin-2-one synthesis. Org. Biomol. Chem.
2017, 15, 5831−5845.
(41) Minisci, F.; Fontana, F.; Coppa, F.; Yan, Y. M. Reactivity of
Carbamoyl Radicals. A New, General, Convenient Free-Radical
Synthesis of Isocyanates from Monoamides of Oxalic Acid. J. Org.
Chem. 1995, 60, 5430−5433.
(42) Petti, A.; Leech, M. C.; Garcia, A. D.; Goodall, I. C. A.; Dobbs,
A. P.; Lam, K. Economical, Green, and Safe Route Towards
Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals.
Angew. Chem., Int. Ed. 2019, 58, 16115−16118.
(43) Ogbu, I. M.; Lusseau, J.; Kurtay, G.; Robert, F.; Landais, Y.
Urethanes synthesis from oxamic acids under electrochemical
conditions. Chem. Commun. 2020, 56, 12226−12229.
(44) Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow Electrolysis
Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev.
2018, 118, 4573−4591.
(45) Pletcher, D.; Walsh, F. C. Industrial Electrochemistry, 2nd ed.;
Springer: Dordrecht, The Netherlands, 1993; p 672.
(46) Leech, M. C.; Petti, A.; Garcia, A. D.; Dobbs, A.; Lam, K.
Organic Electrosynthesis: From Academia to Industry. React. Chem.
Eng. 2020, 5, 977−990.
(47) Tanbouza, N.; Ollevier, T.; Lam, K. Bridging Lab and Industry
with Flow Electrochemistry. iScience 2020, 23, 101720.
(48) van Melis, C. G. W.; Penny, M. R.; Garcia, A. D.; Petti, A.;
Dobbs, A. P.; Hilton, S. T.; Lam, K. Supporting-Electrolyte-Free
Electrochemical Methoxymethylation of Alcohols Using a 3D-Printed
Electrosynthesis Continuous Flow Cell System. ChemElectroChem
2019, 6, 4144−4148.
(49) Noël, T.; Cao, Y.; Laudadio, G. The Fundamentals Behind the
Use of Flow Reactors in Electrochemistry. Acc. Chem. Res. 2019, 52,
2858−2869.
(50) Yoshida, J.-i.; Kataoka, K.; Horcajada, R.; Nagaki, A. Modern
Strategies in Electroorganic Synthesis. Chem. Rev. 2008, 108, 2265−
2299.
H
https://doi.org/10.1021/acs.oprd.1c00112
Org. Process Res. Dev. XXXX, XXX, XXX−XXX