Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine

Article abstract of DOI:10.1002/chem.201501785

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.

Full text of DOI:10.1002/chem.201501785

DOI: 10.1002/chem.201501785
Communication
&
Flow Chemistry
Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and
Local Anesthetic Lidocaine
Joshua Britton, Justin M. Chalker, and Colin L. Raston*[a]
delivered to the dynamic thin film in the rapidly rotating glass
Abstract: Thin film flow chemistry using a vortex fluidic
tube, dramatically accelerating organic reactions.[15,17] Under
device (VFD) is effective in the scalable acylation of
continuous flow, the reagents proceed up the walls of the
amines under shear, with the yields of the amides dramati-
tube, exiting at the top for straightforward and controlled
cally enhanced relative to traditional batch techniques.
product collection (Figure 1).[11] This strategy was field tested
The optimized monophasic flow conditions are effective
in ꢀ80 seconds at room temperature, enabling access to
structurally diverse amides, functionalized amino acids
and substituted ureas on multigram scales. Amide synthe-
sis under flow was also extended to a total synthesis of
local anesthetic lidocaine, with sequential reactions carried
out in two serially linked VFD units. The synthesis could
also be executed in a single VFD, in which the tandem re-
actions involve reagent delivery at different positions
along the rapidly rotating tube with in situ solvent re-
placement, as a molecular assembly line process. This fur-
ther highlights the versatility of the VFD in organic synthe-
sis, as does the finding of a remarkably efficient debenzy-
lation of p-methoxybenzyl amines.
The efficient formation of amide bonds is essential for the syn-
thesis of pharmaceuticals, biologically active compounds, natu-
ral products, synthetic polymers, peptides, and proteins.[1,2]
Figure 1. Schematic of a VFD with a 17.7 mm internal diameter (20 mm OD)
glass tube and the injection regime. Full workings and schematics of the
VFD have been previously reported.[17]
More than 50% of the top 200 highest-selling pharmaceuticals
contain an amide bond.[3,4] Therefore, methodology that
streamlines amide synthesis is critical in modern chemistry.[5]
Additionally, reaction scale-up in a short timeframe is an im-
portant consideration, especially with hit-to-lead optimizations
in medicinal chemistry.[6–10] With these considerations in mind,
we have developed a single-phase flow chemistry approach
for rapid amide synthesis, with scalability addressed at the
outset of the research. The centerpiece of this strategy involves
the use of a thin film vortex fluidic device (VFD).[11]
for gaining access to an extensive library of amide motifs on
multigram scales over a short time period, with a dramatic in-
crease in yield in comparison to conventional “round-bottom
flask chemistry”. The structurally diverse amide products fea-
turing modified amino acids and pharmaceutically important
motifs were accessed on a large scale (more than 100 g in
some cases) in short processing times. Moreover, the ꢁ250 mm
thin film in the VFD results in controlled heat transfer for the
highly exothermic acylation reactions, which was observed by
real-time IR imaging, with such flow chemistry improving the
safety metrics of amide synthesis.[11] We also demonstrate that
a new assembly line approach to molecular synthesis can be
achieved by using a VFD.
The VFD is a thin film flow-chemistry platform that has
emerged as effective technology in organic synthesis.[11–16] The
VFD can operate under continuous flow, in which reagents are
introduced through jet feeds into the hemisphere of an in-
clined rapidly rotating tube. The reagents experience high
shear forces and intense micromixing, with mechanoenergy
A classical approach to amide synthesis features the cou-
pling of acyl chlorides to amines, with the reaction carried out
in a traditional batch-type reactor.[18] Few examples of such
acylations have been reported in flow, which is likely due to
complications associated with acid chloride hydrolysis, reactor
clogging upon salt formation, and the challenges in incorpo-
rating biphasic solutions[19] into conventional channel flow
[a] J. Britton, Dr. J. M. Chalker, Prof. Dr. C. L. Raston
Centre for NanoScale Science and Technology
School of Chemical and Physical Sciences
Flinders University, Bedford Park, South Australia, 5042 (Australia)
E-mail: Colin.Raston@flinders.edu.au
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501785.
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chemistry systems. Though notable exceptions exist,[20–22]
a more general solution to these problems is warranted. For
acylation reactions, it was unclear whether biphasic Schotten–
Baumann conditions would be possible in a VFD due to the in-
tense micromixing of an acyl chloride with water.[19] Initially, we
established that hydrolysis of the acid chloride was indeed the
major reaction pathway, with butyryl chloride, for example,
being hydrolyzed to butyric acid in 77% yield after 80 seconds
residence time on the VFD when mixed with appropriate vol-
umes of water, CHCl3, and triethylamine (TEA) at a flow rate of
2.0 mLminÀ1 (see the Supporting Information). Accordingly,
non-aqueous monophasic conditions for the acylation of
amines in the VFD were explored.
tating tube was titled at a 458 angle relative to the horizontal
position, for a rotational speed of 6950 rpm. Such conditions
are optimal for a number of organic reactions and corresponds
to the generation of a Faraday wave at these operating param-
eters.[14–16] The optimized conditions were also effective for
other amide syntheses (Table 1). Reagent equivalents are speci-
fied per amide bond and were scaled proportionally for acyla-
tion of substrates that contain multiple amine residues. The
amides are generated in short time scales, in high yield and
with no complex post VFD operations required, with the prod-
uct simply collected, washed with 2m HCl, dried and recrystal-
lized if obtained as a solid. In furthering this flow methodology,
other factors were subsequently explored, namely, the use of
an inert atmosphere of argon blanket over the film to circum-
vent mass transfer of moisture from air into the thin film,
which could hydrolyze the acyl chloride, and the use of pyri-
dine as the base, which is common in acylation reactions.[23,24]
However, the effect on the yield was minimal (see the Support-
ing Information). Some subtle features related to flow rate
were also revealed in this exploratory work. For example, using
lower flow rates (longer residence time of the liquid in the
tube), there was a dramatic increase in evaporation of CHCl3
that lead to unwanted salt precipitation. Such efficient solvent
evaporation is due to the high surface area of the thin film of
the liquid in the VFD.[15] An interesting consequence of this
phenomenon is that higher flow rates (shorter residence time)
lead to higher yields for this system, at least up to
Conditions were first identified that prevented precipitation
of the triethylamine hydrochloride byproduct, noting that any
such salt precipitation will perturb the fluid flow in the tube.
Both the pristine 20 mm diameter borosilicate glass NMR tube
used in the VFD and its nonpolar silane-coated analogue were
ineffective in preventing salt from adhering to the walls of the
tubes.[15] Independently, several solvents were tested for their
ability to dissolve and carry the salt in flow. Of these, CHCl3
was the solvent of choice with no precipitate formed at 1.2 g/
20 mL, which corresponds to the maximum amount of salt
that would be generated. The reaction between benzylamine
and butyryl chloride was then optimized in this solvent
(Figure 2). Although THF, DMF, hexanes, acetonitrile, and diox-
ane were also considered, salt build-up was prevalent in these
solvents.
2.0 mLminÀ1
,
with high conversions still observed at
The synthesis of N-benzylbutrylamide was optimized for
a 2.0 mLminÀ1 flow rate, a 1.25 molar ratio of TEA to amine,
a 1.75 molar ratio of acid chloride to amine, and a 0.075 volu-
metric ratio of TEA to CHCl3 (1.50 mL in 20 mL CHCl3). The ro-
8.0 mLminÀ1 (Figure 2a).
This optimized method was effective for a wide range of
coupling partners, providing structurally diverse amides, func-
tionalized amino acids, unsymmetrical ureas, and pre-drug
motifs (Table 1). For comparison,
the same reactions were carried
out in a round bottom flask
using the same solvent as in
flow, at the same reagent con-
centration for the same reaction
time, with the reagents rapidly
stirred and the acyl chloride
added in a single portion, and
the reaction quenched with 2m
HCl after 80 seconds. Such
batch-type reactions typically
suffer from violent exotherms
that result in reagent degrada-
tion, lower yields, and safety
concerns. The use of thin film
VFD processing overcomes these
issues, with significantly im-
proved yields observed in most
cases. For example, the reaction
between cyclohexylamine and
Figure 2. Reaction Scheme for optimizations. (a) Flow rate of reagents through the VFD (mLminÀ1). (b) Molar ratio
of butyryl chloride to benzylamine. (c) Molar ratio of triethylamine to benzylamine. (d) Volumetric ratio of triethyl-
amine to chloroform. Circled data points correspond to standard conditions used for assessment of substrate
scope in Table 1.
butyryl chloride (Table 1, entry 3)
provides the target amide in
94% yield in 80 seconds (resi-
dence time), with the same reac-
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Table 1. Yields of amides formed in the VFD under flow with the opti-
mized conditions in Figure 2; the corresponding reactions carried out in
a round-bottom flask compare the total reaction time for a reaction at
the same total scale and concentration.
Table 1. (Continued)
Entry
Amide
VFD 80 s [%]
Batch 80 s [%]
37
18
78
19
20
21
67
12
30
63
Entry
1
Amide
VFD 80 s [%]
95
Batch 80 s [%]
35
57
87[a]
2
3
95
94
31
9
22
72
41
4
5
6
7
8
9
>99.9
82
68
36
11
62
6
23
24
79
66
31
69
82
25
>99.9
36
80
49
26
27
68
19
19
56
40
<1
10
11
87
14
79
28
90
44
>99.9
12
13
60
91
2
[a] Reoptimized conditions gave an increase in yield of this amide as de-
scribed in the text.
64
tion in batch mode resulting in 9% yield for the same reaction
time. Likewise, the yield of the reaction of morpholine with cy-
clopropane carbonyl chloride (Table 1, entry 12) is 60% using
the VFD compared to 2% for batch processing. Several other
reactions were also dramatically enhanced by using the VFD
(Table 1). The typically higher yield by using VFD processing
arises from a number of possible factors. This includes local-
ized reactions resulting from plug flow conditions and the con-
tinuous processing capability of the VFD that control exo-
therms by rapid heat dissipation from the thin film to the bor-
osilicate glass tube, thereby preventing runaway reactions and
reagent degradation. In this context, there was no noticeable
increase in heat using thermal IR imaging (see the Supporting
14
15
16
87
83
88
73
65
47
17
57
31
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Information). Then there is the likely enhancement of the rate
of reaction in the VFD due to rapid micromixing and increased
collisional frequency between reagents subject to shear forces
in the thin film in the rapidly rotating tube.[15] Also noteworthy
is that reactions under flow conditions using the VFD do not
suffer from clogging, which is a pervasive problem in conven-
tional microfluidics.[25]
185 mgminÀ1 or 100 g in just over 9 hours. The second substi-
tution step involving diethylamine requires heating and is inef-
fective in CHCl3, whereas it is effective in DMF at 608C at
a slower flow rate of 0.2 mLminÀ1, which corresponds to
a total residence time of the overall two-step reaction of only
12.5 minutes. However, herein isolation of the intermediate
amide is required, and in attempting to overcome this, two
new continuous-flow methods were explored.
The synthesis of functionalized amino acids was also effec-
tive using the VFD (Table 1, entries 25 and 26) with the prod-
ucts obtained in high yields, establishing that the method is ef-
fective for sterically hindered and complex motifs. Moreover,
di- and triacylations are accessible (entries 23, 24, and 28) with-
out reoptimization of the system, further highlighting the utili-
ty of the reaction in the VFD. Interestingly, piperazine bearing
a single p-methoxybenzyl group did not give the targeted
monoacylated product in only 80 seconds residence time.
Rather, acylation of both amines occurred with concomitant
debenzylation, providing the diacylated symmetrical piperazine
in a synthetically useful 55% yield. By simply increasing the
amount of acyl chloride to 3.5 equivalents, the bis(amide)
could be isolated in an excellent 98% yield [Eq. (1)]. Presuma-
bly, the 4-methoxybenzyl group (PMB) is expelled as the corre-
sponding benzyl chloride. Although related debenzylations
have been reported,[26] the reaction described herein is note-
worthy in that both the secondary amine and the more hin-
dered PMB–amine are acylated with such high efficiency in
a single operation.
The first method used two sequential VFD units, in which
the amide product from the first VFD was delivered to
a second VFD for the final substitution reaction (Figure 3b).
This is the first example of the use of series arrays of VFD
units. The second method requires only one VFD unit, in which
each step is carried out at different heights of the VFD tube in
an “assembly-line process” (Figure 3c).
The methodology was optimized by using two separate VFD
units (Figure 3a) that could be directly translated into a contin-
uous-flow process using a series of VFD units (Figure 3b) with-
out the need for purification of the intermediate amide. How-
ever, solvent exchange in the VFD tube was necessary. This
was carried out by heating the bottom of the second VFD
tube to facilitate evaporation of the CHCl3, with simultaneous
addition of an equivolume of DMF. Addition of diethylamine
was 6 cm from the bottom of the 19 cm long tube. A larger
excess (three molar equivalents) of triethylamine was used in
the first VFD to ensure neutralization of the acid throughout
the entire process. In addition, for every 40 mg of intermediate
amide introduced, 160 mg of pure diethylamine was added.
This was found to be necessary to increase the yield to 85%,
which is remarkable for a total residency time of only 534 sec-
onds under flow.
We then targeted the synthesis of lidocaine as a multiple
step synthesis in a single VFD tube (Figure 3c), which required
four individual reagent jet feed outputs. Two jet feeds were
used for the synthesis of the amide, delivering the reagents to
the hemispherical bottom of the tube. Another jet feed locat-
ed 5 cm up the tube delivered DMF with in situ removal of
CHCl3, which is facilitated by heating at specific locations on
the tube (Figure 3c). This was monitored in real time by infra-
red imaging to ensure even and localized heating (see the
Supporting Information). The final jet feed situated 9.5 cm up
the tube delivered pure diethylamine. These operating param-
eters gave lidocaine in 15% yield (Figure 3c) with a residence
time of 780 seconds, producing lidocaine at a rate of 27 mg
per hour. Although the yield here is low, the result neverthe-
less establishes the first example of a multistep synthesis by
using thin-film flow chemistry in a single platform. The removal
of solvent in situ is analogous to in-line evaporation and sol-
vent-switching strategies in channel-based microreactor sys-
tems.[31]
More generally, such CÀN bond cleavage and functional
group conversion is an important transformation in synthe-
sis,[26] but recourse to harsh reaction conditions and reducing
metals is often required.[27] This debenzylation lends further
credence that VFD flow chemistry can lead to unexpected
types of reactivity.[11] Given that reactions in the VFD under
continuous-flow mode generally take only 20 minutes for
gram-scale quantities, we anticipate that new and interesting
reactivity can be identified on a short time scale without signif-
icant labor and expense. VFD processing is high throughput,
with the ability to rapidly scan flow space and field effects,[15]
in defining new possibilities in organic synthesis under shear.
With the synthesis of all the compounds given in Table 1
using generic optimized conditions, the reoptimization of syn-
thetically important amide (entry 21) was undertaken (see the
Supporting Information). This amide is a precursor to the anes-
thetic lidocaine, a World Health Organization essential medi-
cine.[28–30] The synthesis of lidocaine itself involved investigat-
ing tandem reactions in a scalable and continuous process
(Figure 3). Each step was initially optimized independently on
the VFD. For the first step, a flow rate of 2.5 mLminÀ1 gave
In conclusion, we have established the use of the VFD in en-
hancing the rate of formation and yield of a diverse number of
amides relative to batch processing. Importantly, the synthesis
of the amides, including the modified amino acids, addresses
safety concerns for exothermic acylation reactions, and is readi-
ly scalable to 100 g of the product. This is for a single relatively
inexpensive VFD unit housing a 20 mm OD borosilicate glass
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Figure 3. VFD synthesis of lidocaine involving (a) isolation of the amide for subsequent amine substitution; (b) series array of VFD units; (c) an assembly line
approach using four strategically placed jet feeds in a single VFD tube.
tube. Essentially, the device addresses the issue of scalability at
the point of inception, without the need for laborious process
engineering for large-scale reactions. In addition, we have also
accomplished the first total synthesis of lidocaine in flow, for
two VFD units operating in series, and for the same reactions
in a single VFD unit with selected use of solvents and position-
ing of the jet feeds along the tube. Indeed, these findings
define new capabilities of the VFD with both types of opera-
tion of the VFD being without precedent. Furthermore, the ef-
ficient debenzylation reaction in Equation (1) suggests that the
VFD may be useful in provoking interesting and unexpected
reactions that are useful in synthesis. The control of reactivity
herein adds to the growing ability to control reactivity in the
VFD, which also includes the more recently established high
yielding photoredox catalysis.[32] Overall, this technology is des-
tined for medicinal-chemistry applications with the ability to
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Experimental Section
The VFD was set at a tilt angle, q, of 458 relative to the horizontal
position. A commercially available, pristine 20 mm diameter borosi-
licate glass NMR tube (internal diameter 17.7 mm) was inserted.
Two syringes were used in this procedure. The first syringe con-
tained the amine (8.61 mmol, 1.00 equiv) and triethylamine
(10.8 mmol, 1.25 equiv) dissolved in CHCl3. The second syringe con-
tained the acyl chloride (15.1 mmol, 1.75 equiv) and CHCl3. A total
volume of 20 mL CHCl3 was used in each experiment and was dis-
pensed between both feeds so that each syringe was of equivo-
lume. Computer-automated syringe pumps dispensed the liquid at
the desired flow rate into the rotating tube. The liquid exited the
device into NH4Cl (2m, 20 mL) as a quench. The liquid was trans-
ferred to a separating funnel and washed with H2O (20 mL), HCl
(2m, 20 mL), NaOH (2m, 20 mL), and H2O (20 mL), then dried using
MgSO4, filtered and the solvent was removed in vacuo. The crude
product was then purified by recrystallization (CHCl3/hexanes) or
by column chromatography (see the Supporting Information).
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Received: May 7, 2015
Published online on June 19, 2015
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