N-Heterocyclic Carbene-Mediated Microfluidic Oxidative Electrosynthesis of Amides from Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b00339

A flow process for N-Heterocyclic Carbene (NHC)-mediated anodic oxidative amidation of aldehydes is described, employing an undivided microfluidic electrolysis cell to oxidize Breslow intermediates. After electrochemical oxidation, the reaction of the intermediate N-acylated thiazolium cation with primary amines is completed by passage through a heating cell to achieve high conversion in a single pass. The flow mixing regimen circumvented the issue of competing imine formation between the aldehyde and amine substrates, which otherwise prevented formation of the desired product. High yields (71-99%), productivities (up to 2.6 g h^-1), and current efficiencies (65-91%) were realized for 19 amides.

Full text of DOI:10.1021/acs.orglett.6b00339

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene-Mediated Microfluidic Oxidative
Electrosynthesis of Amides from Aldehydes
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, Herts SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: A flow process for N-Heterocyclic Carbene (NHC)-
mediated anodic oxidative amidation of aldehydes is described, employing
an undivided microfluidic electrolysis cell to oxidize Breslow intermedi-
ates. After electrochemical oxidation, the reaction of the intermediate N-
acylated thiazolium cation with primary amines is completed by passage
through a heating cell to achieve high conversion in a single pass. The flow
mixing regimen circumvented the issue of competing imine formation
between the aldehyde and amine substrates, which otherwise prevented
formation of the desired product. High yields (71−99%), productivities (up to 2.6 g h−1), and current efficiencies (65−91%)
were realized for 19 amides.
Scheme 1. Approaches to the Synthesis of Amides from
Aldehydes Mediated by NHCs
he amide functional group is of fundamental importance
Tas a structural and functional motif present in a vast array
of natural and synthetic substances, from small molecule drugs
to biopolymers and materials.1 Consequently, the synthesis of
amides is widely practiced and highly relevant across many
areas. Traditional approaches to amide formation by means of
carboxylate activation are often highly efficient in terms of
conversions and yields,2 but can exhibit low atom economy or
the requirement for corrosive and toxic reagents and
intermediates.3,4
A number of alternative methodologies have been proposed,
including oxidative conversions of alcohols or aldehydes to
amides.5 N-Heterocyclic carbenes (NHCs) have been identified
as organic catalysts for a range of reactions including the
oxidative conversion of aldehydes to amides (Scheme 1).6
Reported NHC-mediated acylations from aldehydes require the
addition of an external stoichiometric chemical oxidant7 or
utilize substrates that contain an internal redox system (e.g., α-
halo or α,β-unsaturated aldehydes),8 to transform Breslow
intermediate 1 or 5 to the activated acyl donor 2 or 6
respectively. Direct amidation of aldehydes mediated by NHC
salts can be inhibited by a competing reaction between the
aldehyde and amine, and formation of water as a byproduct,
which may intercept any activated acyl intermediates formed.
Solutions to this problem have included the addition of
nucleophilic catalysts such as HOBt and imidazole,8c,d or by
performing the reaction with the amine as a separate step
following the formation of an activated ester intermediate.9
Electrochemical oxidation of Breslow intermediates 1 (or
1cb) presents an appealing alternative to the use of a
stoichiometric oxidizing equivalent, in the form of either an
added reagent or a pre-existing functionality within either
substrate. This electrosynthesis approach has been applied to
the formation of esters and thioesters in batch, and recently by
us, using a microfluidic electrolysis cell (Figure 1).10 Herein we
describe a flow process for NHC-mediated synthesis of amides
from aldehydes using an electrochemical microflow cell in
sequence with a heating chip, where high conversions and
yields can be achieved in a single pass.
3,4,5-Trimethoxybenzaldehyde (8) and benzyl amine were
selected as test substrates for initial investigation of anodic
oxidative amidation using the thiazolium bistriflimide 7 as an
NHC precursor (Scheme 2), employing a microfluidic
electrolysis cell previously described by us.11 Direct application
Received: February 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00339
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Organic Letters
Letter
Table 1. Optimization of Electrochemical Formation of
a
Amide 11a
Figure 1. NHC-mediated oxidative synthesis of esters from aldehydes
and alcohols using a microfluidic electrolysis cell.10d
Scheme 2. Electrosynthesis of Amide 11a from Aldehyde 8
Mediated by Thiazolium Bistriflimide 7
e
flow rate
(mL/min)
current
c
temp
yield of 11a
b
d
entry
1
solvent
THF/
DMSO
(mA)
(°C)
(%)
0.12
10−12
rt
40
2
3
4
5
6
7
DMF
0.12
1.2
1.2
1.2
1.2
1.2
10−12
105
rt
rt
80
39
99
80
99
59
DMF
DMF
DMF
DMF
DMF
f
105
rt
105
50
105
60
105
100
a
Reactions performed on 0.5 mmol scale with a final concentration of
8 of 0.025 M at a combined flow rate of 0.12 or 1.2 mL min−1 before
entering the electrolysis cell (electrolysis cell residence time <10 s at
b
1.2 mL min−1). Flow rate represents the total combined flow rate
c
from mixing three streams before entering the electrolysis cell. Total
of the conditions for NHC-mediated electrochemical ester-
ification (Figure 1), whereby the alcohol nucleophile was
simply replaced with BnNH2, failed to deliver any of the desired
amide 11a.10a In the esterification process, the solution exiting
the mixing T-piece displayed a red coloration, which we
consider to be indicative of the formation of the Breslow
intermediate 9/9cb. Notably, in the failed amidation attempt,
the characteristic red color was absent, presumably as a
consequence of competing imine formation.
cell current once the cell is flooded with the reaction mixture.
d
Temperature of heating chip (residence time <50 s at 1.2 mL min−1).
e
f
Isolated yield of purified amide 11a. The total reaction mixture was
stirred in the collection vessel for 2 h before workup.
of 1.2 mL min−1 the flow run was completed in less time,
accounting for the observed decrease in yield/conversion at the
time of workup. Complete conversion was achieved when the
reaction mixture was held in the collection flask for 2 h before
workup (entry 4). However, a more efficient solution was
realized by flowing the reaction mixture through a heating chip
after exiting the electrolysis cell resulting in quantitative yield at
60 °C (entry 6). Lower, or higher, temperatures at the same
flow rate gave incomplete conversion or led to some
degradation (entries 5 and 7 respectively).
The results detailed above highlight the remarkably efficient
anodic oxidation of thiazolium-derived Breslow intermediates,
at residence times of no more than 10 s in the electrolysis cell at
1.2 mL min−1 (this neglects the increased flow rate caused by
evolution of hydrogen gas at the cathode). An additional
benefit of the process stems from the ability to heat the
postelectrolysis flow stream and thereby accelerate and
complete the addition of the amine to the acylthiazolium,
which is comparatively slower than the corresponding reaction
with simple alcohols.10a,12
A significant benefit of performing reactions in flow is the
ability to easily control reactant and reagent mixing, which
herein enabled formation of the NHC and Breslow
intermediate in flow prior to mixing with the amine and before
the reaction mixture entered the electrolysis cell (see Table 1).
Indeed, this in-flow mixing regimen led to encouraging isolated
yields of amide 11a of 30−40% in a THF/DMSO solvent
mixture with a total flow rate of 0.12 mL min−1 at rt (entry 1,
Table 1). DMF has been suggested as a superior solvent to
THF for acyl transfer,8b in addition to being regarded as a
favorable electrochemical solvent due to its high dielectric
constant, and significantly for the current application, it is
effective in solubilizing the thiazolium salt 7. Further improve-
ment followed from a solvent switch to DMF at the same flow
rate, resulting in an 80% yield of amide 11a (entry 2, Table 1).
With the objective of increasing the rate of production of
amide 11a, the flow rate through the cell was increased to 1.2
mL min−1, with a commensurate adjustment of the cell current
(entry 3, Table 1). However, an unexpected drop in the
product yield was observed. Further investigation revealed that
the reaction of benzylamine with the acyl thiazolium
intermediate 10 was incomplete when the reaction mixture
exited the flow cell. As a consequence of the increased flow rate
The optimized conditions were applied to a range of
aldehydes and primary amines with productivity rates between
0.3 and 0.6 g h−1 (Table 2). Electron-rich aromatic and
heteroaromatic aldehydes underwent amidation in good to
excellent isolated yields (94−99%, entries 1, 5, and 7).
Furthermore, primary amines containing electron-rich electro-
B
DOI: 10.1021/acs.orglett.6b00339
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Letter
chemically oxidizable functionalities such as indole, furan, and
phenol groups afforded amides in 71−86% yields (entries 15,
18, and 19). An unbranched aliphatic aldehyde afforded the
corresponding N-benzylamide 11i in 71% yield (entry 9). The
conditions of the undivided cell also tolerated the aryl bromide
functionality (71−97% yields, entries 10−19). Current
efficiencies for the two-electron anodic process were in the
range 65−91%, indicating good selectivity with respect to
secondary oxidations.13 Unfortunately, attempts to use bulkier
secondary amines only led to a trace amount of products being
isolated, underscoring the lower reactivity of amines with
acylthiazoliums.
Table 2. Examples of NHC-Mediated Electrochemical
Amidation of Aldehydes in Flow
a
With the objective of delivering larger quantities of material,
efforts to improve the rate of productivity examined increasing
initial substrate concentration to 0.5 M along with the cell
current required to effect the required chemical conversion
(Table 3). At the higher concentration of aldehyde 8 (0.5 M)
Table 3. Increasing the Productivity Rate for the
a
Electrosynthesis of Amide 11a
c
current
(mA)
temp
productivity
d
b
entry
(°C)
yield of 11a (%)
(g h−1
)
1
2
3
4
510
575
510
510
60
60
71
54
71
94
1.9
1.5
1.9
2.5
80
110
a
Reactions performed on 2.5 mmol scale with a final concentration of
8 of 0.125 M at a combined flow rate of 1.2 mL min−1 before entering
b
the electrolysis cell. Yield is that of purified isolated material.
c
Productivity is based upon isolated yields from 16.67 min run time.
d
Temperature of heating chip.
and with the heater chip at 60 °C, the yield of amide 11a was
found to decrease to 71% (entry 1). This can be understood by
the significantly increased flow through the heater chip due to
the increased cathodic hydrogen gas production at the higher
current, and consequent decreased residence time. Further
increase of the cell current led to a further reduction in yield of
amide 11a (entry 2). Gratifyingly, excellent yield (94%) and a
high rate of production (2.5 g h−1) could be achieved when the
heater chip temperature was increased to 110 °C (entry 4),
producing 706 mg of amide in 16.7 min.
Finally, to demonstrate the robustness of the process, an
extended run over 8.3 h produced 21.5 g (97%) of isolated
amide 11a at a productivity rate of 2.58 g h−1.
In conclusion, an in-flow process for NHC-mediated anodic
oxidative amidation of aldehydes has been described, employing
an undivided microfluidic electrolysis cell in series with a heater
chip to achieve high conversion in a single pass. High yields
(71−99%), productivities (up to 2.6 g h−1), and current
efficiencies (65−91%) were achieved on scales up to 20 g.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00339.
■
a
Reactions performed on 0.5 mmol scale with a final concentration of
S
R1CHO/R2NH2 of 0.025 M at a combined flow rate of 1.2 mL min−1
b
before entering the electrolysis cell. Temperature of heating chip.
c
d
Yield is that of purified isolated material. Productivity is based upon
16.67 min run time.
C
DOI: 10.1021/acs.orglett.6b00339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For a description of the cell used in this work: (a) Kuleshova, J.;
Hill-Cousins, J. T.; Birkin, P. R.; Brown, R. C. D.; Pletcher, D.;
Underwood, T. J. Electrochim. Acta 2012, 69, 197. (b) Green, R. A.;
Brown, R. C. D.; Pletcher, D. J. Flow Chem. 2015, 5, 31.
(12) Samanta, R. C.; De Sarkar, S.; Frohlich, R.; Grimme, S.; Studer,
A. Chem. Sci. 2013, 4, 2177.
Experimental details and procedures, compound charac-
terization data, current efficiencies, and copies of 1H and
13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(13) See Supporting Information for further details.
*E-mail: rcb1@soton.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from EPSRC (EP/
L003325/1 and EP/K039466/1), GlaxoSmithKline for a CASE
award (R.A.G.), and the European Regional Development
Fund (ERDF) for cofinancing the AI-Chem project through
the INTERREG IV A France (Channel)−England cross-border
cooperation Programme.
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DOI: 10.1021/acs.orglett.6b00339
Org. Lett. XXXX, XXX, XXX−XXX