Design of a mesoscale continuous-flow route toward lithiated methoxyallene

Article abstract of DOI:10.1002/cssc.201800760

The unique nucleophilic properties of lithiated methoxyallene allow for C C bond formation with a wide variety of electro-philes, thus introducing an allenic group for further functionali-zation. This approach has yielded a tremendously broad range of (hetero)cyclic scaffolds, including precursors to active pharmaceutical ingredients. To date, however, its valorization at scale is hampered by the batch synthesis procedure, which suf- fers from serious safety issues. Hence, the attractive heat-and mass-transfer properties of flow technology were exploited to establish a mesoscale continuous-flow route toward lithiated methoxyallene. An excellent conversion of 94 % was obtained, corresponding to a methoxyallene throughput of 8.2 g h¹. The process is characterized by short reaction times, mild reaction conditions and a stoichiometric use of reagents.

Full text of DOI:10.1002/cssc.201800760

Accepted Article
Title: Design of a mesoscale continuous flow route towards lithiated
methoxyallene
Authors: Sofie Seghers, Thomas S.A. Heugebaert, Matthias Moens,
Jolien Sonck, Joris Thybaut, and Chris Victor Stevens
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.201800760
Link to VoR: http://dx.doi.org/10.1002/cssc.201800760
A Journal of
www.chemsuschem.org

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
Design of a mesoscale continuous flow route toward lithiated
methoxyallene
Sofie Seghers, Thomas S. A. Heugebaert, Matthias Moens, Jolien Sonck, Joris W. Thybaut, and
Christian V. Stevens*
Abstract: The unique nucleophilic properties of lithiated
methoxyallene allow for C-C bond formation with a wide variety of
electrophiles, thus introducing an allenic group for further
functionalization. This approach has yielded a tremendously broad
range of (hetero)cyclic scaffolds, including API precursors. To date,
however, its valorization at scale is hampered by the batch synthesis
protocol which suffers from serious safety issues. Hence, the
attractive heat and mass transfer properties of flow technology were
exploited to establish a mesoscale continuous flow route toward
lithiated methoxyallene. An excellent conversion of 94% was
obtained, corresponding to a methoxyallene throughput of 8.2 g/h.
The process is characterized by short reaction times, mild reaction
conditions and a stoichiometric use of reagents.
pyrimidines,[12] thiophenes,[16] azepines[17] and diverse large
mono- to even pentacyclic structures.[6d],[6f],[18]
Without exception, these abundant applications of lithiated
methoxyallene 4 all rely on the originally reported batch synthesis
protocol (Scheme 1). Methoxyallene 3 is generated from methyl
propargyl ether 2, obtained from propargylic alcohol 1, in a high
yielding base-catalyzed isomerization after which it is distilled.
Lithiation affords a nucleophilic 1-position which then readily
reacts with electrophiles, introducing an allenic group for further
functionalization. Unfortunately, these academic efforts cannot be
valorized, as the synthesis and distillation of methoxyallene
suffers from serious safety issues. Even when its use provided
the most efficient API (Active Pharmaceutical Ingredient)
synthesis route, it was abandoned due to the lack of scalability.[5]
Low molecular weight ethers and acetylenes (2) are known for
their alarming thermal instability, resulting in a highly energetic
and potentially explosive decomposition. While the small scale
performance – certainly up to 10 g – can be safely operated, the
exothermicity of the isomerization limits the implementation scale
to 200 g. An extremely violent reaction resulting in complete
destruction of the internals of a calorimeter was reported by
Anderson et al. Dilution in THF as a heat sink was imperative and
further risk reduction was pursued by an addition-rate controlled
reaction. The authors state to operate this procedure up to 2 L
scale (330 g).[5] The further lithiation steps face similar challenges
and are essentially performed under cryogenic conditions in view
of the reactive nature of alkyl lithium reagents and the instability
of lithiated methoxyallene.
In essence, all associated safety hazards involve a lack of
control over the reaction environment. Therefore, the translation
of this synthesis route into continuous flow production was
envisioned, including the synthesis of methyl propargyl ether 2.
Owing to the large surface-to-volume ratio, an efficient heat
transfer is observed in micro- and even mesoreactors. The
outstanding control of stoichiometry and reaction parameters and
the small hold-up of the critical intermediates improve process
safety. Straightforward scalability opportunities offer a safe and
less time- and money consuming route toward industrial
production.
Introduction
Allenes, with their curious arrangement of cumulated double
bonds, display unique reactivity. They have been exploited in
many promising transformations, e.g. to build diverse
(hetero)cyclic compounds.[1] The reactivity of an allene moiety can
strongly be influenced by functional groups. In this respect,
alkoxyallenes are claimed to display chameleon type reactivity.
Whilst the double bond bearing this substituent preferentially
reacts with electrophiles, reaction with nucleophiles at the two
terminal carbons (C1 and C3 position) may also occur. Extremely
useful, however, is the smooth metalation at the carbon bearing
the alkoxygroup. Lithiation induces umpolung and generates a
fairly strong nucleophile at the C1-position. (Lithiated)
methoxyallene, has been used extensively in all kinds of
transformations, serving as a versatile C3-building block.[2] Among
others, the pioneering work of Arens et al.[3] and the efforts of the
Reissig group are acknowledged for demonstrating its wide
potential. A tremendously broad spectrum of (heterocyclic)
scaffolds was accessed via lithiated methoxyallene,[2],[4] such as
alkylated
derivatives,[3b]
α,β
and
and
unsaturated
tetrahydropyran-4-ones,[5]
α’-ketols,[3a]
dihydropyranones
2,5-dihydrofuranes
3-oxotetrahydrofuranes,[3c],[6]
pyrrolines,
β-ketoenamides,[10],[11],[12]
the
1,2-oxazines,[7]
and
corresponding
lactones,[8]
pyrrolidinones,[9]
imidazoles,[13]
pyrroles
oxazoles,[10]
Results and Discussion
furanylideenamines,[14] 2,3-dihydropyridines and pyridines,[11],[15]
Preparation of methyl propargyl ether
[*]
ir. S. Seghers, dr. ir. T. S. A. Heugebaert, dr. ir. M. Moens, ir. J.
Sonck, prof. dr. ir. J. W. Thybaut, prof. dr. ir. C. V. Stevens
Department of Green Chemistry and Technology
Faculty of Bioscience Engineering, Ghent University
Coupure Links 653, 9000 Ghent (Belgium)
The methylation of propargylic alcohol 1 was initiated in batch,
varying the methylation reagent and base (Tables 1 and S1). The
Williamson ether synthesis using methyl iodide, catalyzed by
E-mail: Chris.Stevens@Ugent.be
potassium tert-butoxide, showed promise.
A commercially
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
O
Ph
Ph
Li
OH
OMe
5
KOtBu
0.1 equiv.
n-BuLi
0.8-1.2 equiv.
1 equiv.
OMe
•
OMe
•
OMe
•
neat < 200 g
or THF < 330 g
52-55°C (), 3 h
dry THF or Et2O
-78 to 0 °C, 5 min
dry Et2O
2
3
4
6
-30 °C, 30 min
67%
Scheme 1. Batch synthesis pathway toward lithiated methoxyallene 4 and nucleophilic addition to benzophenone 5
available dry solution of KOtBu in THF yielded methoxyallene 3
efficiently in a single reaction step (Table 1, entry 2). Turbid
reaction mixtures, however, were obtained due to the formation of
KI salt crystals which would cause clogging of the flow reactor.
Attempts were made to prevent precipitation of the salt using
exothermic behaviour. As such, the incontrollable heat of reaction
and the toxicity of the methylating agent were an additional driving
force to transfer the aqueous procedure into continuous flow
(Scheme 2). Using a residence time of 30 min, 96% conversion
was obtained, which corresponds to a throughput of 12.8 g/h. A
liquid liquid separator was used to isolate the ether phase in
continuous mode. Fouling of the membrane was avoided by
feeding water downstream of the reactor. The end product 2 was
obtained in 77% isolated yield via distillation.
additives
(tris(dimethylamino)phosphine),
such
as
18-crown-6
ether,
HMPT
HMPA
(hexamethylphosphoramide) and DMF. Aside from persistent
turbidity, methylation was hampered and the allene formation was
no longer observed in the presence of these additives.
Table 1. Selected experiments of the batch optimization of the methylation of
propargylic alcohol 1[a]
The evaluation of a variety of common bases failed to offer an
efficient methylation step free of precipitate. Both LiOtBu and
NaOtBu delivered methyl propargyl ether 2, but inhibited further
reaction (Table 1, entries 3 and 4). Even after additional dosage
of KOtBu, the isomerization to 3 did not occur. Again, the
methylation was partially suppressed by the addition of 18-crown-
6, 12-crown-4, EDTA (ethylenediaminetetraacetic acid), TMEDA
(tetramethylethylenediamine), HMPT or HMPA and allene 3 was
still not observed. In a reaction with Et3N, the nucleophilic
behaviour of the base lead to the formation of the quaternary
ammonium salts. Reaction with n-BuLi lead to an unidentified
complex reaction mixture and, although the use of LiH or LiHMDS
lead to good conversion to the ether 2 (Table 1, entries 5 and 6),
turbid reaction mixtures were again observed. The alternative
methylation reagents dimethylcarbonate and methyl triflate were
rejected respectively because of reactivity and turbidity issues
(Table S1).
None of the water-free methylation routes could provide a
good way to telescope the methylation of the alcohol with the
synthesis of lithiated methoxyallene due to turbidity and/or
reactivity limitations. In batch, methyl propargyl ether 2 is
efficiently synthesized using dimethyl sulfate and sodium
hydroxide in water (Table 1, entry 1).[19] In our hands, performing
this aqueous batch procedure at a 1 L scale showed highly
1H-NMR (%)
Methylation
Base[c]
Solvent
t (h)
reagent[b]
1
2
3
1
2
3
4
5
6
Me2SO4
MeI
MeI
MeI
MeI
NaOH
KOtBu
LiOtBu
NaOtBu
LiH
H2O
THF
THF
THF
THF
THF
2
2
1
1
3
1
5
2
5
1
5
95
2
95
99
95
82
0
96
0
0
0
MeI
LiHMDS
18
0
[a] Full data of all optimization experiments can be found in the Supporting
Information [b] 1 equiv. [c] 1.2 equiv.
Isomerization to methoxyallene
The continuous flow isomerization was next addressed, using a
catalytic amount of potassium tert-butoxide (Scheme 3). In batch,
98% conversion of 2 toward methoxyallene 3 was observed after
45 min at reflux temperature in dry THF, using 0.1 equiv. KOtBu.
Preliminary optimization experiments were performed in a tubular
reactor using syringe pumps and a standard T-connector (Table
S2). A strictly dry environment was found to be crucial, as in the
presence of moisture KOH debris caused clogging of the reactor.
As such, the KOtBu solution was provided through a sample loop
(SL). Several precautions were taken to overcome clogging. In
H2O
2:1 H2O: aq. KOH
aqueous waste
Me2SO4
1 equiv.
96%
L
M
M
OMe
L
55°C
2
12.8 g/h
RT = 30 min
= 2.4 mm
OH
NaOH
IV = 25 mL
1
1 equiv.
1.2 equiv.
(H2O)
Scheme 2. Continuous flow synthesis of methyl propargyl ether 2 from propargyl alcohol 1 using a 5 port mixer and a tubular reactor
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
OMe
Sonication
55 °C
2
1 equiv.
(dry THF)
98%
•
OMe
M
0 °C
3
RT1 = 19.5 min RT2 = 0.5 min
8.2 g/h
= 2.4 mm
= 2.4 mm
dry THF
IV1 = 39 mL
IV2 = 1 mL
SL
IVSL = 25 mL
KOtBu
0.1 equiv.
(dry THF)
Scheme 3. Overview of the optimized continuous flow isomerization of 2 to methoxyallene 3, using a 5 port mixer and a tubular reactor
Table 2. Key experiments in the optimization of the continuous flow isomerization of methyl propargyl ether 2 to methoxyallene 3[a]
Pump
type
IV
(mL)
10
40
40
Φ
(mm)
2
2.4
2.4
2.4
2.4
RT
(min)
15
20
20
T
(°C)
50
45
45
45
55
RTcool
(min)
0
0
0
Conv.[c]
(%)
Entry[b]
1[d]
2[d]
3
4
5
peristaltic
peristaltic
HPRP
HPRP
HPRP
61-98
44-98
77-97
92-96
96-98
40
40
20
20
2.5
2.5
[a] Full data of all optimization experiments can be found in the Supporting
Information [b] [2] = 1.25 M, [KOtBu] = 0.50 M [c] Conversion to 3 via integration
on 1H-NMR [d] Clogging
addition to further dilution and a temperature rise, a higher flow
rate was applied to increase convective and abrasive forces and
Lithiation of methoxyallene and trapping of an
electrophile
mitigate constriction. Sonication was introduced to prevent
aggregation and bridging of the solids. Constrictions in the flow
channel were avoided by the use of a 5 port mixer with a sufficient
internal volume and an increased diameter of the tubular
reactor.[20]
The syringe pumps were replaced by less back pressure
sensitive dual piston syringe and peristaltic pumps (Table S3).
These pumps are more compatible with suspensions and can be
used in a fully continuous mode for injection of larger volumes.
Clogging was delayed, but in spite of these efforts still persistent.
Upon closer inspection, the non-crystalline but strongly viscous
nature of the slurry in a clogged reactor coil suggested beneficial
effects of higher pressure pumps. Finally, a switch to high-
performance reciprocating pumps (HPRP) appeared crucial to
handle the reaction mixture fully continuously.
In this set-up, a good conversion toward methoxyallene 3 was
observed in a residence time of 15 min at 50 °C. However, the
conversion fluctuated strongly (Table S3). Formation of a
gaseous phase was prominent and with regard to the boiling point
of methoxyallene 3 (51 °C), the temperature was lowered to 45 °C
and the residence time was raised to 20 min (Table 2, entry 3).
The gaseous phase and concomitant conversion fluctuations
were still observed and a cooling coil was added at the end of the
reactor set-up. Superior stability and reproducibility was readily
obtained (Table 2 entries 4-5; Table S4).
The established isomerization process is displayed in
Scheme 3. The use of a fresh KOtBu solution is essential to
ensure absence of KOH in order to obtain high conversion and to
avoid reactor clogging. An excellent and steady conversion of
98% toward methoxyallene 3 was observed on 1H-NMR. This
corresponds to a throughput of 8.2 g/h.
Next, the lithiation of methoxyallene 3 was performed inline with
the isomerization, thus avoiding hazardous distillation of the
allene (Scheme 4). A 2.5 M n-butyllithium solution in hexanes was
fed to the reactor using a parallel set-up of two Chemyx® syringe
pumps. Many common pump types are incompatible with alkyl
lithium solutions. In spite of the limited injection volume, in general
syringe pumps or sample loops are preferred for safety and
chemical resistance reasons.[21] At the outlet of the reactor, the
mixture was quenched at room temperature using D2O. The
distribution of methyl propargyl ether 2, methoxyallene 3 and
deuterated methoxyallene 7 was determined via integration of the
1H-NMR spectra (Table S5). In spite of some very promising
results, an unsatisfactory instability of the conversion was
observed. This could possibly be attributed to a high deuterium-
proton exchange capacity of D2O, hampering a reproducible
quench of the reaction mixture under air. In some of the samples,
a large residue of methyl propargyl ether 2 was observed as well,
although the initial isomerization conversion of 98% was
confirmed. In view of selected samples indicating 97% conversion
toward deuterated methoxyallene 7, it was assumed that the
efficiency of the lithiation was not a limiting factor and required
only a minimum amount of time. This is typically the case for
lithiations and there was no indication that the coupled reaction
steps could benefit from an increased residence time.[22] In an
attempt to perform an inline quench, 1 equivalent D2O was fed to
the reactor at room temperature and a third tubular reactor was
added to the set-up (Table 3). A violent reaction was observed,
giving rise to the formation of gas plugs, pressure build-up, flow
irregularities and even back flow of the reagent stream.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
n-BuLi
(hexanes)
1.1-1.2 equiv.
OMe
Sonication
55 °C
•
OMe
2
3
1 equiv.
(dry THF)
0 °C-rt
M
0 °C
RT1 = 19.5-24.5 min RT2 = 0.5 min
= 2.4 mm
IV1 = 39-49 mL
= 2.4 mm
IV2 = 1 mL
RT3 = 1.7-4.2 min
= 2.4 mm
dry THF
SL
IV3 = 5-10 mL
IVSL = 25 mL
KOtBu
0.1 equiv.
(dry THF)
Li
•
OMe
4
D2O
D
•
OMe
7
34-97%
Scheme 4. Continuous flow isomerization, lithiation and quenching of methyl propargyl ether 2 to deuterated methoxyallene 7
Hence, process optimization was continued using a less reactive
Therefore, we suspected traces of water in the starting materials,
causing the formation of KOH. As these plugs only appeared after
the 5 port mixer, the water traces originate from the methyl
propargyl ether 2 solution. Storage of this solution over molecular
sieves improved, but could not overcome clogging of the lithiation
reactor. Further efforts were made by lowering the equivalents of
n-butyllithium and dilution. Clogging was initially avoided by
diluting to a 0.2 M solution of methyl propargyl ether 2. However,
electrophile in flow (Scheme 5 and Table S6). A solution of
benzophenone 5 (1 equiv.) was fed to the reactor using a syringe
pump and a T-connector. When a T-connector and a tubular
reactor were used for the lithiation, the formation of the end
product 6 suffered from variable conversion (Table 3). The
observed side reactions involved the reversed reaction to methyl
propargyl ether 2, deprotonation of the terminal alkyne and
subsequent nucleophilic addition to benzophenone. Clogging only
occurred when more than 1.2 equiv. of n-butyllithium was used.
For fast reactions such as lithiations, mixing efficiency is a critical
parameter to ensure a high, stable and selective conversion.
To enhance the lithiation mixing efficiency, a glass static
micromixer with a volume of 1.6 mL was used. An excellent and
stable conversion, in the 95 to 97% range, and only minimal
amounts of side product were observed (Table 3, entry 3).
However, frequent clogging of the glass chip was faced. Most
likely, the clogging was caused by small amounts of KOH debris
formed in the first isomerization reactor. A solubility and pH check
of this slurry revealed high water solubility and an alkaline pH.
a
decline in conversion was observed. Although these
experiments were unsuccessful, they did show that a slight
excess of 1.05 equivalents of n-butyllithium was sufficient to
obtain an excellent lithiation, given proper mixing.
Whereas the micromixer provided excellent mixing efficiency,
the attainable concentration (0.2 M) is considered too low for a
commercial process. Our process thus required a larger diameter
mixing unit to accommodate higher concentrations while
preserving mixing efficiency. A regular T-connector and helical
static mixing elements, inserted in a tubular reactor, were used
(Table 3). These static mixers were successfully used in literature
for pilot scale lithiations.[21],[23] Performing the lithiation at room
Table 3. Key experiments in the optimization of the continuous flow isomerization and lithiation to lithiated methoxyallene 4 and subsequent electrophilic quench[a]
lithiation
mixing unit
Entry[b]
E[c]
IVlit (mL)
Equiv. n-BuLi
Tlit (°C)
IVquench (mL)
RTquench (min)
EP[d] (%)
1
2
3[e]
4[g]
5
D2O
5
5
5
5
T
T
5
5
2.6
2.6
1.5
1.5
1.2
1.2
1.05
1.05
1.05
1.05
rt
rt
rt
rt
rt
0
10
37
37
37
37
37
3.3
39-91
51-98
95-97
79-94
31-82
91-97
10.2
10.5
11.7
10.5
10.5
MM[f]
MM
T+SM[h]
T+SM
6
5
[a] Full data of all optimization experiments can be found in the Supporting Information [b] [2] = 1.25 M, [KOtBu] = 0.50 M, [5] = 3 M [c] Electrophile [d] Distribution
via integration on 1H-NMR [e] Clogging at the lithiation mixing unit [f] Glass static micromixer [g] Under diluted conditions: [2] = 0.2 M, [KOtBu] = 0.08 M, [5] =
0.48 M [h] Helical static mixing elements
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
n-BuLi
1.05 equiv.
(hexanes)
OMe
Sonication
55 °C
•
OMe
2
3
0 °C
1 equiv.
(dry THF)
98%
M
0 °C
x
x
x
x
x
x
x
RT1 = 19.5 min RT2 = 0.5 min
 = 2.4 mm  = 2.4 mm
IV1 = 39 mL IV2 = 1 mL


dry THF
SL
RT3 = 0.5 min
 
 = 2.4 mm
IV3 = 1.5 mL
IVSL = 25 mL
KOtBu
Li
0.1 equiv.
(dry THF)
•
OMe
4
O
Ph
Ph
94%
OH
OMe
RT4 = 10.5 min
= 2.4 mm
IV4 = 37 mL
•
6
5
1 equiv.
(dry THF)
28.5 g/h
Scheme 5. Telescoped 3-step continuous flow process toward lithiated methoxyallene 4 and nucleophilic addition to benzophenone 5
temperature, however, lead to strong flow irregularities and a
prominent presence of gaseous phases, resulting from insufficient
heat and reaction control. Again, a strong variation in conversion
was observed. Although continuous flow deprotonation and
lithium halogen exchange using alkyl lithium reagents are
abundantly reported in literature, most results are obtained in a
small-scale reactor set-up and a short time-on-stream.[22] Even in
a microstructured device, additional cooling is required and as
such, the lithiation was next performed in an ice bath. Finally, a
mesoscale continuous flow process for the synthesis of lithiated
methoxyallene 4 and nucleophilic addition to 5 was established
with an excellent average conversion of 94%, with only minor
fluctuations (Scheme 5). This corresponded to a throughput 28.5
g/h. Two industrial research groups demonstrated the challenges
for continuous flow lithiation scale-up.[23],[21] Similar to our
observations, the main issues involved guaranteeing isothermal
conditions, even in microstructured reactors, the feedstock quality
and exclusion of moisture and operational problems, e.g.
pressure built-up in pumps, valves or precoolers and flow
pulsations due to the formation of gaseous phases. A critical
bottleneck appeared the clogging of micromixers due to deposits
of salts, by-products or side products and fouling by polymeric
deposits with longer time-on-stream.[21],[23]
Our final process is characterized by short reaction times, mild
reaction conditions and an excellent stoichiometric use of
reagents. It offers valorization opportunities to the abundant
small-scale batch research. By way of example, in need of a large
scale synthesis of an API precursor to support drug development,
researchers at AstraZeneca identified the lithiated methoxyallene
route as the most promising.[5] Using methoxyallene, the number
of steps was reduced and an efficient synthesis was
demonstrated on a small scale. However, the lack of a safe
operation mode forced them to abandon this approach. With the
development of a continuous flow process, we have responded to
their postulation that such powerful chemistry is in need of a
scaled synthesis.
Conclusions
Lithiated methoxyallene is an extremely versatile building block in
the organic synthesis of (hetero)cyclic scaffolds. Although safety
issues limit the batch mode production scale, chemists have relied
on this compound for 50 years. Dealing with exothermicity and
other challenges, a telescoped mesoscale continuous flow route
toward this building block is provided. A single step continuous
flow process for the methylation of propargylic alcohol was
established first. In a residence time of 30 min, 96% of conversion
was reached in water, corresponding to a throughput of 12.8 g/h.
After inline removal of water and intermediate distillation, a 3-step
continuous flow process was presented, starting with the
isomerization and lithiation of methyl propargyl ether to lithiated
methoxyallene and its subsequent nucleophilic addition to
benzophenone as a model electrophile. The prevention of
blockages and preserving the lithiation mixing efficiency and
temperature control appeared to be the critical bottlenecks. A
break-through was reached when high-performance reciprocating
pumps were used and helical static mixing elements were
inserted in a tubular reactor to enhance the lithiation mixing
efficiency. An excellent conversion of 94% toward the addition
product was obtained, using only 1.05 equivalents of n-
butyllithium and 1 equivalent of the electrophile. In a total
residence time of 31 min, a throughput of 28.5 g/h was reached.
Experimental Section
For the fully telescoped continuous flow isomerization and lithiation of
methyl propargyl ether 2 to lithiated methoxyallene 4 and subsequent
nucleophilic addition to benzophenone 5, the experiment was performed
as follows. A solution A of 1.25 M methyl propargyl ether 2 in dry THF was
prepared. Under argon atmosphere, 10.56 mL methyl propargyl ether 2 (1
equiv., 8.76 g, 125 mmol) was transferred to a flame-dried 100 mL flask
and dry THF was added to reach a 100 mL solution. In a flame-dried 50
mL flask, 15 mL of a commercially available 1 M potassium tert.-butoxide
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
solution in THF (13.53 g, 15 mmol) was diluted with 15 mL dry THF under
argon atmosphere to obtain solution B of 0.5 M potassium tert. butoxide in
THF. Solution D of 3 M benzophenone 5 was prepared in a 25 mL
volumetric flask. Under argon atmosphere, 13.67 g benzophenone (75
mmol) was dissolved in dry THF.
Acknowledgements
Financial support for this research from the Fund for Scientific
Research Flanders (FWO Vlaanderen) and VITO (Vlaamse
Instelling voor Technologisch Onderzoek) is gratefully
acknowledged.
Solution A and dry THF, stored under argon atmosphere, were fed to the
reactor using two ReaXus® high-performance reciprocating pumps. The
inlet tubing of the pumps was inserted in the flasks through the sealing
septa. Downstream of pump B, the reactor set up was equipped with a 25
mL sample loop, with an inner diameter of 2.4 mm, to avoid contact of the
potassium tert.-butoxide solution with the pump flow line. The outlet of
pump A and of the sample loop were mixed in a 5 port manifold. The
isomerization reaction was performed in a 40 mL PTFE tubular reactor with
an inner diameter of 2.4 mm. The 5 port mixing unit and 39 mL of the
reactor coil were heated in a water bath at 55 °C. The heated water bath
was equipped with a Hielscher® ultrasonic processor. The residual 1 mL
tubing of the reactor was passed through an ice bath to condense the
Keywords: Allenes • C3 building block • Green chemistry •
Microreactors • Telescoping
[1]
N. Krause, A. S. K. Hashmi, Modern Allene Chemistry, Vol. 1 and 2,
Wiley-VCH, Weinheim, 2008.
[2]
[3]
R. Zimmer, H.-U. Reissig, Chem. Soc. Rev. 2014, 43, 2888-2903.
a) S. Hoff, L. Brandsma, J. F. Arens, Recl. Trav. Chim. Pays-Bas
1968, 87, 1179-1184; b) S. Hoff, L. Brandsma, J. F. Arens, Recl.
Trav. Chim. Pays-Bas 1968, 87, 916-924; c) S. Hoff, L. Brandsma,
J. F. Arens, Recl. Trav. Chim. Pays-Bas 1969, 88, 609-619.
a) M. Brasholz, H.-U. Reissig, R. Zimmer, Acc. Chem. Res. 2009,
42, 45-56; b) T. Lechel, H. U. Reissig, Pure Appl. Chem. 2010, 82,
1835-1844; c) H. U. Reissig, W. Schade, G. M. O. Amombo, R. Pulz,
A. Hausherr, Pure Appl. Chem. 2002, 74, 175-180; d) H.-U. Reissig,
R. Zimmer, Synthesis 2017, 49, 3291-3302.
[4]
gaseous phase. Subsequently,
a commercially available 2.5 M
n-butyllithium solution in hexanes (C) was dosed to the outlet of the first
isomerization reactor via a T-connector using Chemyx® syringe pumps.
During rinsing and equilibration of the isomerization reaction, the inlet
channel of the n-butyllithium solution was closed via a shut-off valve.
Lithiation was performed in a 1.5 mL PTFE tubular reactor with an inner
diameter of 2.4 mm at room temperature. The first 0.5 mL of this reactor
were equipped with four Nordson® static mixing elements with a diameter
of 2.36 mm to enhance the mixing properties. Using a T-connector, the
[5]
[6]
K. R. Anderson, S. L. G. Atkinson, T. Fujiwara, M. E. Giles, T.
Matsumoto, E. Merifield, J. T. Singleton, T. Saito, T. Sotoguchi, J.
A. Tornos, E. L. Way, Org. Process Res. Dev. 2010, 14, 58-71.
a) M. Brasholz, B. Dugovič, H.-U. Reissig, Synthesis 2010, 2010,
3855-3864; b) M. Brasholz, H.-U. Reissig, Eur. J. Org. Chem. 2009,
2009, 3595-3604; c) D. Gange, P. Magnus, J. Am. Chem. Soc.
1978, 100, 7746-7747; d) D. Gange, P. Magnus, L. Bass, E. V.
Arnold, J. Clardy, J. Am. Chem. Soc. 1980, 102, 2134-2135; e) S.
Hormuth, H. U. Reissig, J. Org. Chem. 1994, 59, 67-73; f) S.
Hormuth, W. Schade, H.-U. Reissig, Liebigs Ann. Recl. 1996, 1996,
2001-2006.
outlet of the lithiation reactor was mixed with solution
D of 3 M
benzophenone 5 in dry THF. Solution D was fed to the reactor set-up using
a Chemyx® syringe pump. The nucleophilic addition was subsequently
performed in a 37 mL PTFE tubular reactor with an inner diameter of 2.4
mm at room temperature. Similar to the n-butyllithium solution flow line,
the inlet channel of the benzophenone solution could be closed via a shut-
off valve during initial rinsing and equilibration of the isomerization and
lithiation reactor.
[7]
a) A. Al-Harrasi, H. U. Reissig, Angew. Chem. Int. Ed. 2005, 44,
6227-6231; b) M. Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-
Harrasi, L. Fišera, I. Hlobilová, G. Zahn, H.-U. Reissig, Eur. J. Org.
Chem. 2005, 2005, 1003-1019; c) M. Jasinski, D. Lentz, H. U.
Reissig, Beilstein J. Org. Chem. 2012, 8, 662-674; d) F. Pfrengle, H.
U. Reissig, Chem.-Eur. J. 2010, 16, 11915-11925; e) W. Schade,
H.-U. Reissig, Synlett 1999, 1999, 632-634.
[8]
[9]
E. Yoneda, T. Kaneko, S.-W. Zhang, K. Onitsuka, S. Takahashi,
Org. Lett. 2000, 2, 441-443.
Before process start-up, the entire reaction set-up was thoroughly rinsed
with dry THF, stored in two flame dried 250 mL flasks under argon
atmosphere. The used glass syringes were rinsed with dry THF as well.
Next, the 25 mL sample loop was manually loaded with the 0.5 M
potassium tert.-butoxide solution in THF, using a glass 25 mL syringe. The
flow rates of solution A and dry THF – the actual flow rate of solution B –
were set to respectively 1.60 mL/min and 0.40 mL/min, corresponding to
0.1 equiv. of potassium tert.-butoxide. The residence time in the heated
part of the tubular reactor to carry out the isomerization was 19.5 min,
followed by a 0.5 min during cooling phase. After equilibration of the
isomerization (2 residence times), the conversion of into methoxyallene 3
was verified via 1H-NMR and the shut-off valve in the n-butyllithium flow
line was opened. The flow rate of the n-butyllithium solution in hexanes
was set to 0.84 mL/min, corresponding to 1.05 equiv. of the lithiation
reagent. This resulted in a residence time of 0.5 min in the lithiation reactor.
After equilibration of the lithiation (5 min), the shut-off valve of the inlet flow
channel of the benzophenone 5 solution was opened and the flow rate was
set to 0.67 mL/min. This corresponded to the addition of 1 equiv. of
benzophenone 5 and a residence time of 10.5 min in the third tubular
reactor. During 30 min of monitoring time, multiple samples were collected
at the outlet and analyzed via integration of the crude reaction mixtures on
1H-NMR. The obtained 2-methoxy-1,1-diphenyl-2,3-butadien-1-ol 6 is a
known compound. Spectral data were in agreement with literature.[24] More
experimental details, spectral data, procedures and the results of all
optimization experiments can be found in the Supporting information.
a) M. O. Amombo, A. Hausherr, H. U. Reissig, Synlett 1999, 1871-
1874; b) V. Breuil-Desvergnes, P. Compain, J.-M. Vatèle, J. Goré,
Tetrahedron Lett. 1999, 40, 8789-8792; c) V. Breuil-Desvergnes, J.
Goré, Tetrahedron 2001, 57, 1951-1960; d) V. Breuil-Desvergnes,
J. Goré, Tetrahedron 2001, 57, 1939-1950; e) O. Flögel, M. G.
Okala Amombo, H.-U. Reissig, G. Zahn, I. Brüdgam, H. Hartl,
Chem.-Eur. J. 2003, 9, 1405-1415; f) O. Flogel, H. U. Reissig,
Synlett 2004, 895-897; g) S. Kaden, H. U. Reissig, Org. Lett. 2006,
8, 4763-4766; h) N. A. Nedolya, L. Brandsma, O. A. Tarasova, H. D.
Verkruijsse, B. A. Trofimov, Tetrahedron Lett. 1998, 39, 2409-2410.
a) T. Lechel, M. Gerhard, D. Trawny, B. Brusilowskij, L. Schefzig, R.
Zimmer, J. P. Rabe, D. Lentz, C. A. Schalley, H. U. Reissig, Chem.-
Eur. J. 2011, 17, 7480-7491; b) T. Lechel, D. Lentz, H.-U. Reissig,
Chem.-Eur. J. 2009, 15, 5432-5435.
a) J. Dash, T. Lechel, H.-U. Reissig, Org. Lett. 2007, 9, 5541-5544;
b) O. Flogel, J. Dash, I. Brudgam, H. Hartl, H. U. Reissig, Chem.-
Eur. J. 2004, 10, 4283-4290; c) T. Lechel, J. Dash, C. Eidamshaus,
I. Brudgam, D. Lentz, H. U. Reissig, Org. Biomol. Chem. 2010, 8,
3007-3014.
T. Lechel, S. Möhl, H.-U. Reissig, Synlett 2009, 2009, 1059-1062.
a) M. Gwiazda, H.-U. Reissig, Synthesis 2008, 2008, 990-994; b) M.
Gwiazda, H. U. Reissig, Synlett 2006, 1683-1686.
N. A. Nedolya, B. L., S. N. I., A. A. I., Chem. Heterocycl. Compd.
2001, 37.
a) N. A. Nedolya, N. I. Schlyakhtina, L. V. Klyba, I. A. Ushakov, S.
V. Fedorov, L. Brandsma, Tetrahedron Lett. 2002, 43, 9679-9681;
b) N. A. Nedolya, O. A. Tarasova, A. I. Albanov, B. A. Trofimov,
Russ. J. Organ. Chem. 2015, 51, 281-283.
L. Brandsma, V. Y. Vvedensky, N. A. Nedolya, O. g. A. Tarasova,
B. A. Trofimov, Tetrahedron Lett. 1998, 39, 2433-2436.
N. A. Nedolya, O. A. Tarasova, O. G. Volostnykh, A. I. Albanov, L.
V. Klyba, B. A. Trofimov, Synthesis-Stuttgart 2011, 2192-2204.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
[18]
a) A. R. Hergueta, H. W. Moore, J. Org. Chem. 2002, 67, 1388-
1391; b) M. Pérez, P. Canoa, G. Gómez, M. Teijeira, Y. Fall,
Synthesis 2005, 2005, 411-414.
A. Mames, S. Stecko, P. Mikołajczyk, M. Soluch, B. Furman, M.
Chmielewski, J. Org. Chem. 2010, 75, 7580-7587.
R. L. Hartman, J. R. Naber, N. Zaborenko, S. L. Buchwald, K. F.
Jensen, Org. Process Res. Dev. 2010, 14, 1347-1357.
M. E. Kopach, K. P. Cole, P. M. Pollock, M. D. Johnson, T. M.
Braden, L. P. Webster, J. McClary Groh, A. D. McFarland, J. P.
Schafer, J. J. Adler, M. Rosemeyer, Org. Process Res. Dev. 2016,
20, 1581-1592.
[22]
[23]
[24]
a) H. Kim, A. Nagaki, J. Yoshida, Nat. Commun. 2011, 2, 6; b) J. I.
Yoshida, Chem. Rec. 2010, 10, 332-341.
S. Laue, V. Haverkamp, L. Mleczko, Org. Process Res. Dev. 2016,
20, 480-486.
[19]
[20]
[21]
R. Zimmer, H. U. Reissig, Liebigs Ann. Chem. 1991, 553-562.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201800760
ChemSusChem
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Sofie Seghers, Thomas S. A.
Heugebaert, Matthias Moens, Jolien
Sonck, Joris W. Thybaut, Christian V.
Stevens*
Page No. – Page No.
Design of a mesoscale continuous
flow route toward lithiated
methoxyallene
Pumping a chameleon: Lithiated methoxyallene is an extremely versatile building
block in the organic synthesis of (hetero)cyclic scaffolds. However, its large scale
synthesis pathway suffers from serious safety issues and the abundant small scale
batch research cannot be valorized. Hence, the attractive heat and mass transfer
properties of flow technology were exploited to establish a mesoscale continuous
flow route toward lithiated methoxyallene.
This article is protected by copyright. All rights reserved.