N-Heterocyclic Carbene-Mediated Oxidative Electrosynthesis of Esters in a Microflow Cell

Article abstract of DOI:10.1021/acs.orglett.5b01459

An efficient N-heterocyclic carbene (NHC)-mediated oxidative esterification of aldehydes has been achieved in an undivided microfluidic electrolysis cell at ambient temperature. Productivities of up to 4.3 g h^-1 in a single pass are demonstrated, with excellent yields and conversions for 19 examples presented. Notably, the oxidative acylation reactions were shown to proceed with a 1:1 stoichiometry of aldehyde and alcohol (for primary alcohols), with remarkably short residence times in the electrolysis cell (<13 s), and without added electrolyte. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01459

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene-Mediated Oxidative Electrosynthesis of
Esters in a Microflow Cell
Robert A. Green,† Derek Pletcher,† Stuart G. Leach,‡ and Richard C. D. Brown*,†
†Department of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, U.K.
‡GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: An efficient N-heterocyclic carbene (NHC)-mediated oxidative
esterification of aldehydes has been achieved in an undivided microfluidic
electrolysis cell at ambient temperature. Productivities of up to 4.3 g h−1 in a
single pass are demonstrated, with excellent yields and conversions for 19
examples presented. Notably, the oxidative acylation reactions were shown to
proceed with a 1:1 stoichiometry of aldehyde and alcohol (for primary alcohols),
with remarkably short residence times in the electrolysis cell (<13 s), and
without added electrolyte.
sters are ubiquitous in natural and synthetic organic
molecules and materials, with applications spanning all
catalyzed synthesis of esters from aldehydes in an undivided
batch cell.
E
areas of science, engineering and medicine. Despite the success
of traditional synthetic approaches to esters through carbox-
ylate activation,1 substantial effort has been devoted to
alternative methodologies, particularly those that may increase
atom efficiency, avoid toxic reagents, reduce waste, and occur
under mild conditions.2 N-Heterocyclic carbenes (NHCs) have
been identified as powerful organic catalysts for a range of
reactions, including the oxidative conversion of aldehydes to
esters (Scheme 1).3 The majority of NHC-mediated oxidative
Microfluidic electrolysis cells provide a simple-to-use plat-
form for electrosynthesis, and with appropriate channel design,
they can lead to improved mass transfer at the electrode surface
and increased productivity compared with batch reactors.7 We
have described an undivided microfluidic cell wherein high
conversions can be achieved in a single pass at rates of product
formation commensurate with preparative application.8,9 Here
we report an NHC-promoted oxidative esterification of
aldehydes in an undivided electrochemical flow cell that
delivers high rates of product formation and excellent yields
in many cases.
Scheme 1. NHC-Mediated Oxidative Esterification of
Aldehydes
The oxidative esterification of methyl 4-formylbenzoate (4)
with MeOH was selected as a trial reaction (Figure 1). The
optimized conditions consisted of in-flow mixing of two
esterification reactions require the addition of external
stoichiometric chemical oxidant or utilize a substrate containing
an internal redox system (e.g., halide or alkene),4 to transform
Breslow intermediate 1 to activated acyl species 2. Intermediate
2 then reacts with an alcohol, typically in stoichiometric excess,
to afford an ester. Anodic oxidation was first applied to the
conversion of 1 to 2 by Diederich and co-workers, who
reported a thiazolium/flavin dual-catalyst electrochemical
conversion of aldehydes to methyl esters in batch.5 More
recently, Finney et al.6 disclosed a direct electrochemical NHC-
Figure 1. Schematic of the flow arrangement used for the oxidative
esterification of aldehydes.
Received: May 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01459
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
solution streams to generate reactive intermediates: reservoir 1
contained aldehyde 4 (1 equiv), MeOH (1 equiv), thiazolium
salt 3 (1 equiv), and DMSO (5 equiv) in THF, and reservoir 2
contained 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5
equiv) in THF. Each solution flowed at 0.5 mL min−1 into a
mixing T-piece, whereupon a change in color of the exiting
solution to red indicated the formation of Breslow intermediate
5/conjugate base 5cb. Passage through the undivided
electrolysis cell with a current of 850 mA resulted in oxidation
of 5cb to acylthiazolium 6,10 which reacted with MeOH to give
methyl ester 7a in excellent yield (99%) at a high rate of
productivity (2.9 g h−1).
Table 1. NHC-Mediated Electrochemical Oxidative
Esterification of Aldehydes
a b
,
The optimized conditions were then applied to a range of
aldehydes and alcohols (Table 1). In many cases, isolated yields
in excess of 90% were realized, with productivities of up to 4.3 g
h−1 and current efficiencies in the range of 80−100%. Examples
include electron-rich and electron-poor aromatic aldehydes as
well as heteroaromatic substrates reacting in equimolar ratios
with primary alcohols such as MeOH, BnOH, n-BuOH, and
but-2-yn-1-ol. Oxidative esterification of an enolizable aliphatic
aldehyde was demonstrated through the formation of benzyl
dodecanoate (7l). Secondary alcohols (i-PrOH, i-BuOH)
returned higher yields of the corresponding esters 7r (82%)
and 7s (62%) when used in excess (5 equiv). The electron-
deficient secondary alcohol hexafluoroisopropanol afforded the
corresponding benzoate 7q in reduced yield, and the result was
little influenced by the alcohol stoichiometry. For this example,
the current efficiency was also low, indicative of other
competing electrochemistry.
The optimization of the conditions to achieve high
conversions and productivities in a single pass of the
electrochemical microflow reactor was informed by a
combination of approaches. For oxidative esterification of
aldehyde 4 with MeOH, design of experiment identified that no
benefit was gained from using MeOH in stoichiometric excess,
while 5 equiv of DMSO improved the solubility of thiazolium
salt 3 and the resulting yields.11 The use of bistriflimide
(Tf2N−) as the counterion in 3 was important in achieving
−
reproducibility compared with others such as BF4 . We believe
that this is due to the increased hydrophobicity of bistriflimide
salt 3 and its reduced tendency to absorb moisture during
manipulation and storage.
The significance of the loading of DBU on the success of the
reaction is illustrated in a collection of cyclic voltammograms
(CVs) with progressively increased loadings of DBU (Figure
2). The electrochemical oxidation of Breslow intermediates has
been reported to involve two reversible single-electron transfers
(5cb → 9 → 10; Figure 3),6a,12 which are observed as two well-
formed peaks in the CVs when an excess of DBU is present
(pink and green lines). These peaks are not visible when
substoichiometric loadings of DBU are present (red and black
lines). The CV data are also consistent with the results of the
synthetic experiments, where the yields improved up to 1.5
equiv of DBU. A control experiment where thiazolium salt 3
was absent (with Et4NBF4 added as an electrolyte) showed only
recovered starting materials. For electrolyses in undivided cells,
it is also important to consider the reaction at the counter
electrode. In the present case, hydrogen gas is produced by
cathodic reduction of protic species in the medium (e.g.,
a
b
Reactions were performed on 2.5 mmol scale. The flow rate of 1.0
mL min−1 is the total flow rate through the electrochemical cell from
mixing of two flow streams of 0.5 mL min−1 to form Breslow
c
intermediates in situ. Yields of purified isolated materials.
d
Productivities are based upon isolated yields from 10 mL of solution
e
f
(10 min). 5.0 equiv of alcohol was added. The yield was 44% with 1
equiv of (CF3)2CHOH. The yield was 45% with 1 equiv of i-BuOH.
g
We recently reported on the application of a simple plug-flow
model for use in the microflow electrosynthesis cell,13 which
allows estimation of the conversion at a given flow rate and
calculation of the current required to achieve this when the
mass transfer properties of the reactor are known.14 Application
of this model showed that significantly improved productivities
were achieved at higher flow rates when coupled with an
increased current sufficient to drive the oxidation (Table 2). In
the present case, the isolated yields were also found to
substantially increase under conditions of higher current and
1
MeOH/[DBUH]+ → MeO−/DBU + /2H2), which compen-
sates for protons generated in the anodic electrochemistry that
would otherwise reduce the concentration of 5cb as the reaction
progressed.
B
DOI: 10.1021/acs.orglett.5b01459
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Organic Letters
Letter
solution was investigated by resubmitting a crude product
solution to the flow electrolysis with the addition of a second
equivalent of alcohol and aldehyde. In the case of benzyl ester
7m, a combined, unoptimized yield of 78% was obtained.
An additional benefit of conducting electrosynthesis in flow
is the ability to simply extend the run time in order to produce
additional material, avoiding the requirement for a larger
reactor. Therefore, to highlight the preparative value and
scalability of the oxidative esterification in the microfluidic cell,
the electrolysis was performed for an extended period of 5 h,
yielding 21.9 g of 7m (96%) and a productivity rate of 4.4 g h−1
with no significant degradation or fouling of the electrodes.
In conclusion, we have described an NHC-promoted
oxidative esterification of aldehydes in an undivided electro-
chemical flow cell. In many cases, excellent yields and high
productivity rates (up to 4.3 g h−1) were achieved with high
current efficiencies and selectivities using a single equivalent of
alcohol. The very short residence times required for oxidation
in the electrochemical cell highlight its excellent mass transfer
characteristics, and the advantages of performing the reaction in
flow were further demonstrated through the synthesis of >20 g
of ester 7m.
Figure 2. Cyclic voltammograms for the oxidation of Breslow
intermediate 5 (R1 = p-fluorophenyl) with different loadings of
DBU. Conditions: thiazolium salt 3 (0.1 M), p-fluorobenzaldehyde
(0.2 M), DBU (varied), tetrabutylammonium tetrafluoroborate (0.2
M), scan rate 100 mV s−1, rt.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and procedures, design of experiment,
1
compound characterization data, and copies of H and 13C
NMR spectra for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01459.
Figure 3. Formation and anodic oxidation of Breslow intermediate 5.
Table 2. Influence of Concentration, Flow Rate, and Current
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rcb1@soton.ac.uk.
Author Contributions
a
upon the Productivity and Yield of Ester 7a
c
conc.
b
flow rate
current
(mA)
yield of 7a
d
entry
(M)
(mL min−1
)
[productivity]
The manuscript was written through contributions of all
authors.
Notes
1
2
3
0.1
0.5
0.5
0.1
0.1
1.0
16
80
80% [0.05 g h−1
89% [0.26 g h−1
99% [2.9 g h−1
]
]
]
850
The authors declare no competing financial interest.
a
b
Reactions were performed on 0.5−2.5 mmol scale. Concentration of
c
d
4 in THF/DMSO. Yields of purified isolated materials. Productiv-
ACKNOWLEDGMENTS
■
ities are based upon isolated yields from 10 mL of solution (10 min).
The authors acknowledge the EPSRC for financial support
(EP/L003325/1 and EP/K039466/1), GlaxoSmithKline for a
CASE Award (R.A.G.), and the European Regional Develop-
ment Fund (ERDF) for cofinancing the AI-Chem Project
through the INTERREG IV A France (Channel)−England
Cross-Border Cooperation Programme. The authors thank Dr.
Nick Gathergood (Dublin City University) for helpful
discussions relating to counterions.
flow rate. The observed increase in yield may be a consequence
of a shorter residence time between T-piece mixing and
oxidation of the reactive intermediate 5cb in the flow cell.
The total volume of the electrochemical flow cell is ∼210 μL,
leading to a residence time for the reaction mixture of <13 s
(not allowing for H2 gas evolution in the cell). These very short
residence times at higher flow rates coupled with the high
productivity rates of ester formation highlight the excellent
mass transport characteristics of the cell. We have previously
noted that hydrogen evolution, even at substantial rates, can
also improve the conversion efficiency in the microfluidic
electrolysis cell, which we attribute to increased turbulence and
mass transfer at the electrode.13 Even under conditions of high
flow rate, where reactive intermediates are only briefly exposed
to the electrodes, some modest turnover of NHC 8 was
possible: reducing the loading of thiazolium salt 3 to 50 and 20
mol % afforded isolated yields of 76% and 40%, respectively, for
7i. Furthermore, the potential to recycle the NHC/DBU
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Letter
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D
DOI: 10.1021/acs.orglett.5b01459
Org. Lett. XXXX, XXX, XXX−XXX