Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex

Article abstract of DOI:10.1002/cssc.201903459

Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH₃?DMS) was used to reduce various esters and amides under continuous-flow conditions. Taking advantage of the solvent-free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E-factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram-scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.

Full text of DOI:10.1002/cssc.201903459

Accepted Article
Title: Continuous Flow Amide and Ester Reductions Using Neat
Borane Dimethylsulfide Complex
Authors: Sándor B. Ötvös and C. Oliver Kappe
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201903459
Link to VoR: http://dx.doi.org/10.1002/cssc.201903459
A Journal of
www.chemsuschem.org

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
Continuous Flow Amide and Ester Reductions Using Neat Borane
Dimethylsulfide Complex
Sándor B. Ötvös*[a] and C. Oliver Kappe*[a,b]
[a]
Dr. S. B. Ötvös, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, A-8010 Graz, Austria
E-mail: sandor.oetvoes@uni-graz.at
[b]
Prof. Dr. C. O. Kappe
Center for Continuous Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering (RCPE)
Inffeldgasse 13, A-8010 Graz, Austria
E-mail: oliver.kappe@uni-graz.at
Supporting information for this article is given via a link at the end of the document.
Abstract: Reductions of amides and esters are of critical importance
in synthetic chemistry and there are numerous protocols for executing
these transformations employing traditional batch conditions. Notably,
flow chemistry-based strategies, especially for amide reductions, are
much less explored. Inspired by this finding, we present herein a
simple process in which neat borane dimethylsulfide complex
(BH3·DMS) is used to reduce various esters and amides under
continuous flow conditions. Taking advantage of the solvent-free
nature of the commercially available borane reagent, high substrate
concentrations were realized allowing for outstanding productivity and
a significant reduction in E-factors. In addition, with the carefully
optimized short residence times, the corresponding alcohols and
amines were obtained in high selectivity and high yields. The synthetic
utility of the inexpensive and easy to set-up flow protocol was further
corroborated by the multigram-scale syntheses of pharmaceutically
relevant products. Owing to its beneficial features, including low
solvent and reducing agent consumption, high selectivity, simplicity
and inherent scalability, the present process demonstrates less
environmental concerns compared to most typical batch reductions
using metal hydrides as reducing agents.
Alternatively, catalytic hydrogenations may reduce environmental
concerns, but they typically require harsh reaction conditions
(particularly in case of amides) and/or costly dedicated
catalysts.[6] From an environmental point of view, heterogeneous
catalytic approaches are especially appealing. However, the
demanding conditions along with selectivity issues often involved,
strongly limit their synthetic applicability in reductions of
carboxylic acid derivatives.[3b,6a]
Borane complexes have proven exceedingly useful for
carbonyl reductions.[3b,7] They offer similar reactivity to that of
diborane (B2H6), however, have less storage and handling
concerns than the pyrophoric gas itself. Amongst the available
complexes, BH3·THF and BH3·DMS are the most popular
reagents.[7] While BH3·THF is more reactive than BH3·DMS, it is
commercially available only as 1 M THF solution. In contrast, the
more stable BH3·DMS is available as a neat reagent. Borane
complexes are prone to intensive thermal decomposition and in
contact with atmospheric moisture, water or acids, pyrophoric
B2H6 and H2 gases are evolved.[7b,8] Due these hazards, both
BH3·THF and BH3·DMS are generally employed in commercially
available 1–2 M solutions.[7] A notable drawback of the application
of borane reagents is that they are often required in a significant
excess.[7] This is particularly due to the complex nature of the
reduction itself. In case of amides for example, numerous hydride
equivalents may be consumed via hydrogen evolution and/or
multiple rounds of borane complexation. These effects and the
amount of the consumed reagent are largely dependent on the
electronic and steric properties of the substrate applied.[9]
Today, sustainability is becoming a key endeavor in the fine
chemical industry.[10] In spite of this fact, the transfer from well-
established reactions and reagents to novel chemistries which
tend to be more sustainable at the lab-scale is not always
straightforward. Even though, the application of metal hydrides
and borane reagents has limitations with respect to sustainability
and process safety, these substances are routinely employed on
manufacturing scales due their efficiency and simplicity.[11]
Not only novel chemistries, but also advanced reaction
technologies may reduce the environmental impact of chemical
processes. Flow chemistry and continuous processing have
received an upsurge of interest in the context of green and
sustainable syntheses.[12] Useful properties, such as enhanced
heat and mass transfer, precise reaction parameter control,
inherent scalability and improved safety,[13] make continuous flow
Introduction
As a consequence of the ubiquity of alcohols and amines,
carbonyl reductions are amongst the most crucial transformations
in synthetic organic chemistry. In comparison to aldehydes and
ketones, reduction of carboxylic acid derivatives are much more
challenging, owing to the low electrophilicity of the carbonyl
carbon and the intrinsic stability of the involved functional group.[1]
Due to their relevance in organic synthetic practice,[2] reductions
involving amides and esters are particularly important among the
various carboxylic acid derivatives.
The most general way for the reduction of amides and esters
is the application of hydride reagents, such as LiAlH4 or NaBH4,
the latter typically at higher temperatures.[3] Although, these
reagents are effective and well-established, major drawbacks are
the formation of stoichiometric amounts of metallic waste, the
need for laborious work-up procedures and the hazards involved
when handling these highly reactive substances.[4] In case of
amides, catalytic reductive hydrosilylations may represent a
useful alternative, even if these reactions are generally much
slower than aluminum or boron hydride-mediated reductions.[5]
1
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
techniques especially appealing for the reduction of various
functional groups.[14] For reduction of aldehydes and ketones,
heterogeneous catalytic hydrogenations have been extensively
studied under flow conditions.[14c,14d] Because of solubility issues
involving most hydride reagents, continuous flow hydridic
reductions often involve solid sources in packed beds, such as
supported borohydride species or solid NaBH4.[15] Alternatively,
liquid reductants, such as LiBHEt3, (CH3)4NBH4 or
diisobutylaluminum hydride (DIBALH), may be employed.[16] In a
few instances, borane complexes have also been applied in
continuous flow carbonyl reductions.[17] In these cases, borane
reagents were used as 1‒2 M solutions, involving low substrate
concentrations and therefore inherently low productivities. As
compared with aldehydes and ketones, continuous reductions of
carboxylic acid derivatives are less explored.[14] This can partially
be explained by the fact that LiAlH4 reductions are virtually
incompatible with flow conditions, and that heterogeneous
catalytic amide and ester hydrogenations are quite limited due to
the harsh conditions required.[3b,6a] Flow reductions of esters to
the corresponding aldehydes were achieved using DIBALH as
reducing agent,[18] but reductions of amides under flow conditions
are extremely scarce in the literature.[17b,19]
We recently communicated a multistep flow process for the
synthesis of the chiral key intermediate of a well-known
antidepressant, and applied neat BH3·DMS as reducing agent in
the final step of the synthesis.[20] On the basis of this preliminary
result, we hypothesized that the direct application of neat
BH3·DMS in flow mode may act as a general and robust strategy
for the reduction of various esters and amides to the
corresponding alcohols and amines. By taking advantage of the
solvent-free borane complex in a continuous manner, we
anticipated higher productivities than in earlier flow carbonyl
reductions, and less environmental concerns compared to the
most typical metal hydride-mediated reductions in batch. Our
findings are presented herein.
According to earlier literature findings, reduction of esters with
borane reagents require more stringent conditions than that of
amides.[3b] Methyl benzoate was therefore selected as a simple
model substrate to investigate the effects of reaction conditions
on the continuous flow reduction (Table 1). As a greener
alternative to traditional solvents,[21] 2Me-THF was selected as
reaction medium and also as carrier solvent.
Table 1. Effects of various reaction parameters on the neat BH3·DMS-
mediated ester reduction under continuous flow conditions (see Figure 1).
O
·DMS (neat, 10 M)
BH3
O
OH
in 2-MeTHF
Flow rate
Substr. /
BH3·DMS
ratio
(µL min‒1
)
csubstr.
(M)
T
(°C)
tr
Conv.
[a]
#
(min)
(%)[b]
P1
P2
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
50
90
90
90
90
90
90
90
250
250
310
330
570
620
450
430
150
150
90
1 : 3.0
1 : 3.0
1 : 1.5
1 : 1.1
1 : 2.0
1 : 1.5
1 : 1.7
1 : 2.0
30
30
30
30
15
15
20
20
42
100
97
70
85
230
180
150
170
96
92
97
100
100
9
4
90
90
330
230
270
370
1 : 2.0
1 : 2.0
20
20
(99)[c]
8
100
(99)[c]
10
(neat)
[a] No side product formation, chemoselectivity was 100% in all reactions.
[b] Determined by 1H-NMR analysis of the crude product. [c] Yield of
isolated product.
Results and Discussion
On exploring the temperature dependence of the reaction, it
was confirmed that heating is necessary for complete conversion
(Table 1, entries 1 and 2). A temperature of 90 °C was selected
as an optimum value, keeping in mind that thermal decomposition
of the reducing agent may lead to intense gas formation and a
decrease in reducing efficacy.[7b] The flow rate of the substrate
and reducing agent stream was fine-tuned to achieve the lowest
possible borane excess at a reasonably short residence time,
while maintaining quantitative reduction of the ester moiety
(entries 3‒8). A residence time of 20 min in combination with a
substrate / BH3·DMS ratio of 1:2.0 was found optimal, and these
conditions were subsequently employed to investigate the
reaction at higher concentrations in an attempt to maximize
synthetic productivity. We were pleased to find that the reaction
was smooth and stable using a substrate concentration of 4 M
and even employing neat methyl benzoate (8 M concentration). In
both cases, the product stream was collected for 10 min resulting
1.41 g of pure benzyl alcohol at 4 M, and 1.97 g in case of the
neat substrate after extractive work-up (entries 9 and 10). These
gave isolated yields of 99% (conversion and chemoselectivity was
100% in both cases), and corresponded to productivities of 8.46
and 11.82 g h‒1 of pure product, respectively. The E-factor was
calculated for both optimized reactions (entries 9 and 10), and
A simple set-up was established for the flow reactions using
commercially available components as detailed in the
Experimental Section and shown in Figure 1. The substrate and
neat BH3·DMS as reducing agent were pumped as separate
streams, and the combined mixture was reacted while passing
through a 12-mL PFA coil (1.58 mm I.D.) which was heated in an
oil bath. A back pressure regulator (BPR) was also installed in
order to eliminate solvent boil-over and minimize gas formation
during the reactions.
SUBSTRATE
12 mL
2-MeTHF P1
10 bar
REDUCTION
PRODUCT
BPR
P2
2-MeTHF
oil bath
·DMS (neat,10 M)
BH3
Figure 1. Continuous flow reactor set-up for the BH3·DMS-mediated reductions.
2
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
O
O
16[d]
17[e]
1
1
67
94
99[j]
98[j]
O2N
also for a hypothetic reaction employing methyl benzoate in a
concentration of 1 M and the 2 equivalents of BH3·DMS as 1 M 2-
MeTHF solution instead of the neat reagent. For the reaction
involving 4 M substrate concentration, a remarkable E-factor of
2.7 was obtained, and in case of using neat methyl benzoate, it
was decreased further to 1.7. In contrast, in the hypothetic
reaction under more dilute conditions (assuming quantitative
conversion and complete selectivity towards the corresponding
alcohol) a much higher E-factor of 22.8 could be calculated, which
clearly indicates the importance of solvent-free or highly
concentrated conditions in sustainable process development.
After getting familiar with the conditions of the flow ester
reduction, we next investigated the scope and generality of the
methodology (Table 2). All reactions were carried out by using a
residence time of 20 min at 90 °C. 2-MeTHF was used as solvent
in all cases, where possible at 4 M concentration. In case of lower
substrate solubility, the concentration was reduced accordingly
and individual flow rates were adjusted to give the desired
residence time and reducing agent excess.
O2N
OH
OH
O
O
18[f]
0.6
0.6
100
100
89[k]
19[g]
100
OH
O
O
OH
100
20[c]
2
100
O
(97)[i]
O
OH
OH
21[d]
22[b]
1
4
100
100
100
100
O
O
O
O
OH
O
OH
23[c]
2
100
100
O
OH
100
24[c]
25[b]
2
4
100
100
O
(99)[i]
OH
O
O
100
O
OH
100
26[b]
4
100
O
O
(95)[i]
Table 2. Substrate scope of the neat BH3·DMS-mediated ester reduction
under continuous flow conditions (see Figure 1 for the flow set-up).[a]
O
27[b]
28[b]
4
4
100
100
100
100
OH
O
csubstr.
(M)
Br
Conv.
(%)[h]
Sel.
Br
OH
#
O
Substrate
Product
(%)[h]
[a] Reaction conditions: substrate in 2-MeTHF, T= 90 °C, tr= 20 min.
[b] P1 at 330 µL min‒1, P2 at 270 µL min‒1, substrate / BH3·DMS ratio 1:2.0.
[c] P1 at 430 µL min‒1, P2 at 170 µL min‒1, substrate / BH3·DMS ratio 1:2.0.
[d] P1 at 500 µL min‒1, P2 at 100 µL min‒1, substrate / BH3·DMS ratio 1:2.0.
[e] P1 at 430 µL min‒1, P2 at 170 µL min‒1, substrate / BH3·DMS ratio 1:4.0.
[f] P1 at 510 µL min‒1, P2 at 90 µL min‒1, substrate / BH3·DMS ratio 1:2.9.
[g] P1 at 490 µL min‒1, P2 at 110 µL min‒1, substrate / BH3·DMS ratio 1:3.7.
[h] Determined by 1H-NMR analysis of the crude product. [i] Yield of isolated
product. [j] Minor product: 3-aminobenzyl alcohol. [k] Minor product: methyl
4-(1-hydroxyethyl)benzoate.
O
O
OH
100
1[b]
2[b]
3[b]
4[c]
4
4
4
2
100
100
100
100
(99)[i]
O
O
OH
OH
OH
100
98
O
O
O
O
93
Not only methyl benzoate, but ethyl, benzyl and even phenyl
benzoate furnished high conversion (93‒100%) and complete
chemoselectivity (Table 2, entries 1‒4). In case of phenyl
benzoate, the slight decrease in conversion may be explained by
extensive conjugation involving both aromatic rings. Methyl and
ethyl benzoates exhibiting diverse substitution patterns were also
submitted to the optimized reaction conditions (entries 5‒20). We
were delighted to find excellent reactivities in cases of various
electron donating and electron withdrawing substituents,
irrespective to their position on the aromatic ring. Even ortho- and
multi-substituted compounds were smoothly transformed to the
corresponding alcohols and gave conversions of ≥99% and
complete chemoselectivities (entries 6, 7, 12 and 15). Notably,
substrates that contained halogen-substituted benzene rings
were reduced with these functional groups remaining intact
(entries 11‒15). Although, methyl 3-nitrobenzoate showed
somewhat lower reactivity, a satisfactory conversion of 94% was
achieved by doubling the reducing agent excess (entries 16 and
17). The nitro group was not reduced under these conditions, only
traces of 3-aminobenzyl alcohol was detected as side product. In
the reaction of methyl 4-acetylbenzoate, both the acetyl and the
ester moieties were reduced and the corresponding diol was
obtained selectively when using a substrate / BH3·DMS ratio of
1:3.7 (entries 18 and 19). Phthalide, an aromatic γ-lactone, was
converted quantitatively and selectively to the corresponding diol
(entry 21). Benzylic esters (either branched or non-branched) and
ethyl hydrocinnamate underwent flow reduction with perfect
O
OH
100
5[b]
4
4
100
100
O
(99)[i]
O
OH
6[b]
100
100
O
O
OH
O
O
7[b]
4
100
OH
8[b]
4
4
4
4
100
99
100
100
100
100
O
tBu
tBu
O
OH
9[b]
O
MeO
MeO
F3C
O
OH
10[b]
11[b]
98
O
F3C
O
OH
100
O
(98)[i]
F
F
O
OH
12[b]
13[b]
14[b]
15[b]
4
4
4
4
100
95
100
100
100
100
O
Cl
Cl
O
Br
Br
OH
O
O
OH
O
96
I
I
O
Br
Br
OH
O
99
Cl
Cl
3
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
results (entries 22‒24). Of the aliphatic esters investigated, not
Table 3. Reduction of various amides with neat BH3·DMS under continuous
flow conditions (see Figure 1 for the flow set-up).[a]
only
linear
ones
but
bulkier
adamantane-
and
cyclohexanecarboxylates were well tolerated providing the
corresponding alcohols in quantitative and selective reactions
(entries 25‒28). In representative examples, the alcohol products
were isolated to give yields of 95‒99% (Table 2, shown in
parentheses).
Conv.
(%)[g]
Sel.
#
Substrate
Product
csubstr. (M)[f]
(%)[g]
H
N
H
N
1
100
1[b]
2[c]
3[c]
100
100
100
(98)[h]
O
(2-MeTHF)
H
N
H
N
The flow conditions used for esters were next applied for neat
BH3·DMS-mediated reductions of amides (Table 3). Due to
significantly lower solubility, the highest concentration employed
for amide substrates was 1 M, and in some of the cases, 2-
MeTHF was replaced by THF in order to have clean solutions.
Excellent results were obtained in reductions of acetanilide
and its substituted derivatives (Table 3, entries 1‒12). Functional
groups such as methyl, methoxy, trifluoromethyl, amino and
halogens were well tolerated on the aromatic rings, and reactions
went smoothly with conversions of ≥96% and with 100%
chemoselectivity in all instances (isolated yields were 96‒98% in
representative examples). When reacting methyl 2-
acetamidobenzoate, a reducing agent amount of 4 equivalents
was sufficient to quantitatively and selectively reduce both ester
and amide moieties and to give the corresponding amino alcohol
in an isolated yield of 95% (entry 13). From a series of aromatic
amides, formanilide, benzanilide and N-benzylbenzamide were
also tested, besides acetanilides (entries 14‒16). Formanilide
gave quantitative conversion and complete chemoselectivity
(entry 14). Whereas, in case of benzanilide, conversion was
somewhat lower due to extensive conjugation of the amide bond
similarly to phenyl benzoate in ester reductions (entry 15). In case
of of N-benzylbenzamide, conversion was 98%, but, apart from
dibenzylamine, benzylamine side product was also formed to an
extent of 15% as a result of undesired C‒N bond cleavage (entry
16). Tertiary amides, such as N-methyl-N-phenylacetamide, N,N-
diphenylacetamide and N-acetylindoline were quantitatively
reduced to corresponding amines (entries 17‒19). Aliphatic
amides performed comparably well to aromatic ones with
conversions of 98% and 84% in cases of 1-
acetamidoadamantane and laurolactam, respectively (entries 20
and 21). Despite the applied back pressure, in most amide
reductions (entries 1‒16), some visible gas formation
(presumably H2) occurred in the reaction coil which did not
influence the system stability. In a few instances, some
precipitation also occurred in the heated reactor zone (e.g. entries
14, 17‒19) which could be handled by the BPR applied (see
Experimental Section).
0.6
(THF)
96
O
H
H
N
N
0.6
(THF)
98
O
EtO
EtO
H
H
N
MeO
MeO
N
1
4[b]
5[b]
6[c]
7[c]
8[b]
9[b]
100
100
100
100
100
100
100
100
100
O
(2-MeTHF)
OMe
OMe
H
H
N
N
1
O
(THF)
F3C
F3C
H
H
N
N
0.6
(THF)
O
I
I
H
H
N
N
0.6
(THF)
100
(96)[h]
O
Br
F
Br
F
H
H
N
N
1
100
O
(2-MeTHF)
H
N
H
N
1
100
(96)[h]
O
(2-MeTHF)
Cl
Cl
H
H
N
N
0.6
(THF)
10[c]
11[d]
12[d]
100
100
100
100
100
100
O
Br
Cl
Br
Cl
H
H
N
H2N
N
H2N
Cl
0.3
(2-MeTHF)
O
Cl
H
N
H
N
0.3
(THF)
O
O
O
HO
H
N
H
N
1
100
13[e]
100
(2-MeTHF)
(95)[h]
O
H
N
H
N
1
14[b]
15[c]
100
100
100
O
O
(2-MeTHF)
H
N
H
N
0.6
(THF)
88
(81)[h]
H
N
1
16[b]
17[b]
98
85[i]
100
H
N
(2-MeTHF)
O
N
N
1
100
O
O
(2-MeTHF)
0.6
(2-MeTHF)
18[c]
19[c]
100
100
100
100
N
N
N
N
Finally, to demonstrate the practical utility of this novel method,
the multigram-scale synthesis of pharmaceutically relevant
products was attempted by applying neat BH3·DMS-mediated
flow reductions. Cinacalcet is a first-in-class drug acting as
calcimimetic. It is sold under brand names Sensipar® and
Mimpara®, and is used for the treatment of hyperparathyroidism
and parathyroid carcinoma.[22] There are numerous procedures
reported for its synthesis, such as approaches involving reductive
amination where alcohol 2 acts as an important intermediate.[23]
In order to synthesize 2 in a simple and scalable manner, the flow
reduction of the corresponding ester was attempted (Figure 2A).
Ester 1, employed as a 4 M solution in 2-MeTHF, was
quantitatively and selectively reduced to alcohol 2 under standard
flow conditions. The product stream was collected for 20 min to
obtain 5.23 g of pure 2 (97% yield) after work-up, which ensured
0.6
(THF)
O
O
HN
HN
0.6
(2-MeTHF)
20[c]
21[c]
98
84
100
100
H
N
H
N
O
0.6
(THF)
[a] Reaction conditions: T= 90 °C, tr= 20 min. [b] P1 at 500 µL min‒1, P2 at
100 µL min‒1, substrate / BH3·DMS ratio 1:2.0. [c] P1 at 530 µL min‒1, P2
at 70 µL min‒1, substrate / BH3·DMS ratio 1:2.2. [d] P1 at 560 µL min‒1, P2
at 40 µL min‒1, substrate / BH3·DMS ratio 1:2.4. [e] P1 at 430 µL min‒1, P2
at 170 µL min‒1, substrate / BH3·DMS ratio 1:4.0. [f] Solvent used is shown
in parentheses. [g] Determined by 1H-NMR analysis of the crude product.
[h] Yield of isolated product. [i] Minor product: benzylamine.
4
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
A
= 20 min
·DMS (neat, 10 M)
90 °C, tr
BH3
substrate / BH3
CF3
4 M
CF3
CF3
·DMS ratio 1:2.0
2
ref. [214
(in 2-MeTHF)
H
O
N
OH
cinacalcet
5.23 g in 20 min (97% yield)
1
O
15.69 g h-1
of pure product
B
= 20 min
·DMS (neat, 10 M)
3
O
90 °C, tr
BH3
substrate / BH3
N
H
COOH
·DMS ratio 1:2.0
NH2
N
DCC, DMAP
+
H
Cl
tecalcet
4
Cl
Cl
1 M (in 2-MeTHF)
OMe
OMe
OMe
2.80 g in 20 min (92% yield)
8.40 g h-1
of pure product
Figure 2. Continuous flow synthesis of pharmaceutically relevant products. (Substrate feed: 330 µL min‒1 for A and 500 µL min‒1 for B. Reducing agent feed: 270
µL min‒1 for A and 100 µL min‒1 for B. See also Figure 1.)
a productivity of 15.69 g h‒1. Notably, the process involved a low
amount of waste formation as indicated by an E-factor of only 1.1.
Alcohol 2 can readily be transformed to the actual drug according
to literature procedures,[23] such as a one-pot oxidation–reductive
amination cascade reported recently by Cossy and co-workers.[24]
The compound named R-568 or tecalcet was originally
investigated for its biological effects similar to those of
cinacalcet.[25] More recently, it has been shown potential in related
areas, for example as a vasculotrope agent.[26] We attempted its
synthesis by means of N,N′-dicyclohexylcarbodiimide (DCC)-
mediated amidation and subsequent amide reduction under
standard flow conditions employing amide 3 in a 1 M 2-MeTHF
solution (Figure 2B). Gratifyingly, amide 3 was quantitatively and
selectively reduced to the corresponding amine, and after work-
up, 2.80 g of pure tecalcet was obtained, which corresponded
to 92% isolated yield. The productivity of the process was 8.40
g h‒1 of pure product and the E-factor was 2.9.
that of a key intermediate of the block-buster drug cinacalcet. The
application of the neat borane complex together with the highly
concentrated substrate solutions and short residence times
enabled a significant chemical intensification and ensured
productivities on the multigram per hour scale. Importantly, due to
low amounts of solvent utilized, remarkably low E-factors were
reached and the risks associated with the handling of the
potentially dangerous borane reagent were reduced by the
inherently safer flow process. As a result of its simplicity, low
solvent and reducing agent consumption, high selectivity and
scalability, the present protocol has improved sustainability
compared to standard batch procedures. We therefore believe
that our flow method may find applications in sustainable
industrial production.
Experimental Section
General Information
Conclusion
All solvents and chemicals were obtained from commercial vendors
(Sigma-Aldrich, TCI, Alfa Aesar, or VWR) and were used as received,
without further purification. Chromatographic purification was carried out
by using a Biotage Isolera automated flash chromatography system with
cartridges packed with KP-SIL, 60 Å (32–63 μm particle size). Analytical
thin-layer chromatography (TLC) were performed on Merck silica gel 60
GF254 plates. Compounds were visualized by means of UV or KMnO4. 1H-
and 13C-NMR spectra were recorded on a Bruker Avance III 300 MHz
instrument at ambient temperature, in CDCl3 as solvent, at 300 MHz and
75 MHz, respectively. Chemical shifts (δ) are reported in ppm using TMS
as internal standard. Coupling constants are given in Hz units. LC-MS
analyses were performed on a Shimadzu HPLC system (DGU20A
degasser, SIL-20A autosampler, CTO20A column oven, LC-20AD pumps)
using a Macherey-Nagel Nucleodur C18 HTec column (150 mm × 4.6 mm,
particle size 5 μm) at 37 °C with mobile phases A (H2O/acetonitrile 9:1 v/v
+ 0.1% TFA) and B (acetonitrile + 0.1% TFA) at a flow rate of 0.6 mL·min–
1). The detection of compounds was accomplished by a diode array
detector (SPDM20A) prior electrospray ionization (ESI) using a Shimadzu
LCMS-QP2020 instrument. The ESI-MS was operating in positive mode
with a scan range of 50–450 m/z. GC-MS spectra were recorded using a
Shimadzu GCMS-QP2010 SE mass spectrometer (EI, 70 V). An Rtx-5MS
column (30 mꢀ×ꢀ0.25 mmꢀ×ꢀ0.25 μm) was used, with helium as carrier gas
(40 cm sec−1 linear velocity). The injector temperature was set to 280 °C.
After 1 min at 50 °C, the temperature was increased by 25 °C min−1 to
A continuous flow protocol utilizing neat BH3·DMS was developed
for amide and ester reductions. The process did not require any
costly special flow equipment, but only a simple heated coil
reactor from commercially available components. The effects of
the reaction temperature and the individual flow rates were
carefully optimized to minimize reducing agent excess while
maintaining a reasonably short residence time. Ester reductions
were completed in 2-MeTHF as solvent, at concentrations
typically as high as 4 M. In the case of methyl benzoate, the flow
reduction was successful even without any solvent present, i.e.
by pumping the neat substrate and reducing agent streams. Due
to lower solubility, amide reductions were carried out at
concentrations as high as 1 M, using 2-MeTHF or THF as solvent.
The scope and generality of the flow protocol was demonstrated
by reductions of a diverse set of aromatic and aliphatic amide and
ester model substrates (47 examples). In most examples,
excellent conversions and selective reductions were observed,
and the corresponding amine or alcohol products were isolated in
pure form typically without chromatographic purification. The
preparative utility of the flow process was verified by the
multigram-scale synthesis of the calcimimetic tecalcet and also by
5
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
300 °C and kept at 300 °C for 3 min. Optical rotation was measured in
CHCl3 (HPLC-grade) at 20 °C against the sodium D-line (λ= 589 nm) on a
Perkin Elmer Polarimeter 341 using a 10-cm pathlength cell. The E-factor
was calculated by dividing the mass of waste generated by the mass of
product formed not including the reaction work-up. The mass of the waste
did not include water.
F. Roschangar, A. Steven, F. J. Weiberth, Green Chem. 2018, 20, 5082-
5103.
[5]
[6]
[7]
a) A. Y. Khalimon, K. A. Gudun, D. Hayrapetyan, Catalysts 2019, 9; b) A.
Chardon, E. Morisset, J. Rouden, J. Blanchet, Synthesis 2018, 50, 984-
997.
a) J. Pritchard, G. A. Filonenko, R. van Putten, E. J. M. Hensen, E. A.
Pidko, Chem. Soc. Rev. 2015, 44, 3808-3833; b) S. Werkmeister, K.
Junge, M. Beller, Org. Process Res. Dev. 2014, 18, 289-302.
a) E. R. Burkhardt, K. Matos, Chem. Rev. 2006, 106, 2617-2650; b) W.
J. Atkins, E. R. Burkhardt, K. Matos, Org. Process Res. Dev. 2006, 10,
1292-1295; c) S. De Angelis, P. Celestini, G. Rebuzzini, L. Degennaro,
R. Luisi, Synthesis 2017, 49, 1969-1971.
General Procedure for Flow Reactions
A solution of the appropriate ester or amide substrate was prepared in dry
2-MeTHF or in dry THF (under Ar atmosphere). Commercially available
solvent-free BH3·DMS (10 M) was used as reducing agent. Starting
materials were pumped as separate feeds by using a UNIQSIS Binary
Pump Module equipped with two high-pressure HPLC pumps (P1:
substrate solution and P2: reducing agent), two injection valves with
sample loops (PFA tubing, 1/16” OD, 0.8 mm ID) and a pressure sensor
to monitor system pressure. Dry 2-MeTHF was used as carrier solvent.
The liquid streams were combined in a Y-mixer at room temperature and
the resulting solution was directed through a 12-mL reaction coil (PFA
tubing, 1/8” OD, 1.58 mm ID) which was heated in an oil bath. The flow
system was pressurized by applying an adjustable BPR assembly from
Vapourtec (part no.: 50-1315) at 10 bar. (See Figure 1 and also the ESI
for a photograph of the flow set-up.) After reaching steady state, the
product stream was collected for 5 or 10 min in smaller scale model
reactions, and for 20 min in the synthesis of 2 and 4. In order to safely
decompose the unreacted reducing agent, the stream exiting the reactor
was collected into a flask containing a well-stirred 1:1 mixture of 3 M HCl
and 2-MeTHF. After the collection period, the mixture was treated with a
NaOH solution (2 M) until pH 10. The resultant mixture was extracted three
times with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated under reduced pressure. In most of
the reactions, pure products were achieved after extractive work-up and
evaporation. In cases where conversion and/or chemoselectivity was
<98%, chromatographic purification was carried out using mixtures of ethyl
acetate/40-60 petroleum ether as eluent. The reaction products were
characterized by means of NMR and MS techniques. For the synthesis of
4, amide 3 was prepared from the corresponding amine and carboxylic
acid in the presence of DCC and DMAP according to literature
procedure.[27]
[8]
[9]
A. M. Monteiro, R. C. Flanagan, Org. Process Res. Dev. 2017, 21, 241-
246.
a) A. F. d. C. Alcântara, H. d. S. Barroso, D. Piló-Veloso, Quím. Nova
2002, 25, 300-311; b) M. DiMare, J. Org. Chem. 1996, 61, 8378-8385; c)
H. C. Brown, S. Narasimhan, Y. O. N. G. M. Choi, Synthesis 1981, 1981,
441-442; d) C. F. Lane, Chem. Rev. 1976, 76, 773-799; f) H. C. Brown,
P. Heim, J. Org. Chem. 1973, 38, 912-916.
[10] H. C. Erythropel, J. B. Zimmerman, T. M. de Winter, L. Petitjean, F.
Melnikov, C. H. Lam, A. W. Lounsbury, K. E. Mellor, N. Z. Janković, Q.
Tu, L. N. Pincus, M. M. Falinski, W. Shi, P. Coish, D. L. Plata, P. T.
Anastas, Green Chem. 2018, 20, 1929-1961.
[11] J. Magano, J. R. Dunetz, Org. Process Res. Dev. 2012, 16, 1156-1184.
[12] a) L. Rogers, K. F. Jensen, Green Chem. 2019, 21, 3481-3498; b) J. A.
M. Lummiss, P. D. Morse, R. L. Beingessner, T. F. Jamison, Chem. Rec.
2017, 17, 667-680; c) D. Dallinger, C. O. Kappe, Curr. Opin. Green
Sustain. Chem. 2017, 7, 6-12; d) C. Wiles, P. Watts, Green Chem. 2014,
16, 55-62.
[13] a) R. Gérardy, N. Emmanuel, T. Toupy, V.-E. Kassin, N. N. Tshibalonza,
M. Schmitz, J.-C. M. Monbaliu, Eur. J. Org. Chem. 2018, 2018, 2301-
2351; b) M. B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem.
Rev. 2017, 117, 11796-11893; c) N. Kockmann, P. Thenée, C. Fleischer-
Trebes, G. Laudadio, T. Noël, React. Chem. Eng. 2017, 2, 258-280; d)
M. Movsisyan, E. I. P. Delbeke, J. K. E. T. Berton, C. Battilocchio, S. V.
Ley, C. V. Stevens, Chem. Soc. Rev. 2016, 45, 4892-4928; e) R. Porta,
M. Benaglia, A. Puglisi, Org. Process Res. Dev. 2016, 20, 2-25; f) I. M.
Mándity, S. B. Ötvös, F. Fülöp, ChemistryOpen 2015, 4, 212-223; g) B.
Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54,
6688–6728; h) V. Hessel, D. Kralisch, N. Kockmann, T. Noël, Q. Wang,
ChemSusChem 2013, 6, 746-789.
CAUTION: BH3·DMS decomposes thermally or in the presence of
atmospheric moisture, water and acids resulting flammable gases (B2H6
and H2) and boric acid. Extreme care must therefore be taken when
handling. Dry conditions must be ensured during experimentation and all
equipment must be set up in a well‐ventilated fume hood. A thorough
safety assessment should be made before conducting any experiments.
[14] a) D. L. Riley, N. C. Neyt, Synthesis 2018, 50, 2707-2720; b) C. J. Mallia,
I. R. Baxendale, Org. Process Res. Dev. 2016, 20, 327-360; c) P. J.
Cossar, L. Hizartzidis, M. I. Simone, A. McCluskey, C. P. Gordon, Org.
Biomol. Chem. 2015, 13, 7119-7130; d) M. Irfan, T. N. Glasnov, C. O.
Kappe, ChemSusChem 2011, 4, 300-316.
[15] a) V. Isoni, K. Mendoza, E. Lim, S. K. Teoh, Org. Process Res. Dev. 2017,
21, 992-1002; b) K. Gilmore, S. Vukelić, D. T. McQuade, B. Koksch, P.
H. Seeberger, Org. Process Res. Dev. 2014, 18, 1771-1776; c) J. L.
NogueiraꢀFernandes, M. C. de Souza, E. C. Souza Brenelli, J. A. Brenelli,
Synthesis 2009, 2009, 4058-4062; d) A. Kirschning, H. Monenschein, R.
Wittenberg, Angew. Chem. Int. Ed. 2001, 40, 650-679.
Acknowledgements
SBÖ acknowledges the Austrian Science Fund (FWF) for
financial support through project M 2413-B21.
[16] a) E. Ballerini, R. Maggi, F. Pizzo, O. Piermatti, D. Gelman, L. Vaccaro,
Org. Process Res. Dev. 2016, 20, 474-479; b) X. Fan, V. Sans, P.
Yaseneva, D. D. Plaza, J. Williams, A. Lapkin, Org. Process Res. Dev.
2012, 16, 1039-1042.
Keywords: amides • borane • continuous flow • esters •
[17] a) A. Karadeolian, D. Patel, P. Bodhuri, G. Weeratunga, B. Gorin, Org.
Process Res. Dev. 2018, 22, 1022-1028; b) S. De Angelis, C. Carlucci,
M. de Candia, G. Rebuzzini, P. Celestini, M. Riscazzi, R. Luisi, L.
Degennaro, Catal. Today 2018, 308, 81-85; c) S. De Angelis, M. De
Renzo, C. Carlucci, L. Degennaro, R. Luisi, Org. Biomol. Chem. 2016,
14, 4304-4311; d) B. Ahmed-Omer, A. J. Sanderson, Org. Biomol. Chem.
2011, 9, 3854-3862.
reduction
[1]
[2]
[3]
P. G. Andersson, I. J. Munslow, Modern reduction methods, John Wiley
& Sons, Weinheim, 2008.
K. C. Nicolaou, J. S. Chen, Classics in total synthesis III: further targets,
strategies, methods, Vol. 3, John Wiley & Sons, Weinheim, 2011.
a) A. Volkov, F. Tinnis, T. Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc.
Rev. 2016, 45, 6685-6697; b) A. M. Smith, R. Whyman, Chem. Rev. 2014,
114, 5477-5510.
[18] a) T. Fukuyama, H. Chiba, H. Kuroda, T. Takigawa, A. Kayano, K.
Tagami, Org. Process Res. Dev. 2016, 20, 503-509; b) M. Yoshida, H.
Otaka, T. Doi, Eur. J. Org. Chem. 2014, 2014, 6010-6016; c) J. de M.
Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortiz, Eur. J. Org. Chem. 2012,
2012, 260-263; d) D. Webb, T. F. Jamison, Org. Lett. 2012, 14, 568-571;
e) C. F. Carter, H. Lange, D. Sakai, I. R. Baxendale, S. V. Ley, Chem.
[4]
M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S. G. Koenig, J. D.
Hayler, M. R. Hickey, S. Hughes, M. E. Kopach, G. Moine, P. Richardson,
6
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
Eur. J. 2011, 17, 3398-3405; f) L. Ducry, D. M. Roberge, Org. Process
Res. Dev. 2008, 12, 163-167.
[19] J. Coetzee, H. G. Manyar, C. Hardacre, D. J. Cole-Hamilton,
ChemCatChem 2013, 5, 2843-2847.
[20] S. B. Ötvös, M. A. Pericàs, C. O. Kappe, Chem. Sci. 2019, 10, 11141-
11146.
[21] D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-
Shehada, P. J. Dunn, Green Chem. 2016, 18, 288-296.
[22] N. Verheyen, S. Pilz, K. Eller, K. Kienreich, A. Fahrleitner-Pammer, B.
Pieske, E. Ritz, A. Tomaschitz, Expert Opin. Pharmacother. 2013, 14,
793-806.
[23] M. Barniol-Xicota, R. Leiva, C. Escolano, S. Vázquez, Synthesis 2016,
48, 783-803.
[24] C. Guérin, V. Bellosta, G. Guillamot, J. Cossy, Eur. J. Org. Chem. 2012,
2012, 2990-3000.
[25] M. Wada, Y. Furuya, J. Sakiyama, N. Kobayashi, S. Miyata, H. Ishii, N.
Nagano, J. Clin. Invest. 1997, 100, 2977-2983.
[26] M. Bonomini, A. Giardinelli, C. Morabito, S. Di Silvestre, M. Di Cesare, N.
Di Pietro, V. Sirolli, G. Formoso, L. Amoroso, M. A. Mariggio, A. Pandolfi,
Plos One 2012, 7, e30682.
[27] A. Chelouan, R. Recio, L. G. Borrego, E. Álvarez, N. Khiar, I. Fernández,
Org. Lett. 2016, 18, 3258-3261.
7
This article is protected by copyright. All rights reserved.

10.1002/cssc.201903459
ChemSusChem
FULL PAPER
Entry for the Table of Contents
A simple yet efficient process is presented in which neat borane·dimethylsulfide complex is used to reduce various esters and amides
under continuous flow conditions. The application of the neat reducing agent in combination with highly concentrated substrate
solutions at short residence times enabled highly productive reductions with less environmental concerns compared to classical metal
hydride-mediated reductions in batch.
Institute and/or researcher Twitter usernames: @sandor_otvos; @KappeLab
8
This article is protected by copyright. All rights reserved.