Scalable Continuous Synthesis of Grignard Reagents from in Situ-Activated Magnesium Metal

Article abstract of DOI:10.1021/acs.oprd.9b00493

The continuous synthesis of Grignard reagents has been investigated under continuous processing conditions using Mg turnings at variable liquid throughputs and concentrations. A novel process window easily accessible through continuous processing was employed, namely, using a large molar access of Mg turnings within the reactor and achieving Mg activation by mechanical means. A laboratory and a 10-fold-increased pilot-scale reactor setup were built and evaluated, including integrated inline analytics via ATR-IR measurements. The main goal of this work was to explore the full potential of classic Grignard reagent formation through the use of scalable flow chemistry and to allow for fast and safe process optimization. It was found that on both the laboratory and pilot scales, full conversion of the employed halides could be achieved with a single passage through the reactor. Furthermore, Grignard reagent yields of 89-100% were reached on the laboratory scale.

Full text of DOI:10.1021/acs.oprd.9b00493

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Communication
Scalable continuous synthesis of Grignard
reagents from in situ activated magnesium metal
Gabriele Menges-Flanagan, Eva Deitmann, Lars Gössl, Christian Hofmann, and Patrick Löb
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 10 Jan 2020
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Scalable continuous synthesis of Grignard reagents
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from in situ activated magnesium metal
Gabriele Menges-Flanagan,†,* Eva Deitmann,†, ‡ Lars Gössl,†,‘ Christian Hofmann,† Patrick
Löb.†
† Fraunhofer IMM, Carl-Zeiss-Strasse 18-20, 55129 Mainz, Germany.
‡ Hochschule Emden Leer, Constantiaplatz 4, 26723 Emden, Germany.
‚ Hochschule Darmstadt, Stephanstrasse 7, 64295 Darmstadt, Germany.
Table of Contents Graphic and Synopsis
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ABSTRACT
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The continuous synthesis of Grignard reagents has been investigated under continuous processing
conditions using Mg turnings at variable liquid throughputs and concentrations. A novel process
window easily accessible through continuous processing was employed, namely using a large
molar access of Mg turnings within the reactor and achieving Mg activation by mechanical means.
A laboratory as well as a tenfold increased pilot-scale reactor set-up was built and evaluated
including integrated inline analytics via ATR-IR measurements. The main goal of this work was
to explore the full potential of classic Grignard reagent formation through the use of scalable flow
chemistry and to allow for fast and safe process optimization. It was found that on the laboratory
as well as the pilot scale full conversion of the employed halides could be achieved with a single
passage through the reactor. Furthermore, yields of 89-100 % of Grignard reagent were reached
on the laboratory scale.
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KEYWORDS Grignard reagent formation, solid processing, flow chemistry, organomagnesium
compound, continuous processing, scale-up.
INTRODUCTION
Organomagnesium reagents, also known as Grignard reagents, constitute one of the most
important intermediates in C-C bond formation reactions.1,2 Their formation and reaction with
e.g. carbonyl compounds was discovered by Victor Grignard in 1900, earning him the Nobel prize
for chemistry in 1912.3 In an industrial setting they are prepared in batch mode by charging the
reaction vessel with solid magnesium in the form of powder or turnings and a small amount of
appropriate solvent, and slowly adding the organic halide while maintaining tight control over the
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reaction temperature. Key challenges are controlling the Grignard reagent formation initiation and
not overcharging the vessel with halide and risking a runaway reaction.4
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Given the above, the classic reagent formation via elemental magnesium is obviously plagued by
a number of drawbacks: depending on the halide used, variable-length incubation periods are
observed and activating agents for the Mg such as previously prepared Grignard reagent, iodine,
bromine, or an additional active halide may be needed to aid the start up. Furthermore, once started,
the Grignard reagent formation is an exothermic reaction, side product formation diminishes yields
e.g. through Wurtz coupling of starting material and product, in batch it is dosing controlled to
dissipate the heat generated, and often requires long reaction times to drive the reaction to
completion.
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Therefore, in the past decade a growing number of efforts have been undertaken to gain access to
Grignard reagents with the most important one being the approach through means of halogen-
metal exchange. Here, through the use of an auxiliary agent such as ethyl magnesium bromide or
iso-propyl magnesium chloride (often in conjunction with LiCl) a large number of
organomagnesium compounds with excellent tolerance to sensitive functional groups can be
obtained.5-8 This approach has also been taken up for continuous processing9 and has even been
scaled-up recently.10
In addition to that, with the field of flow chemistry gaining more and more interest not only
academically but also industrially, a growing number of publications have used Grignard reagents
in flow applications to synthesize a large number of molecules, mainly for the production of active
pharmaceutical ingredients (APIs).11-19 Notable examples here are the use of (3-
methoxyphenyl)magnesium bromide in the synthesis of Tramadol used to treat pain12,
allylmagnesium chloride (Allyl MgCl) in the synthesis of the antipsychotic Clopixol14, and
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phenylmagnesium bromide (PhMgBr) in the synthesis of Tamoxifen used for treating breast
cancer.16 For such seemingly simple Grignard reagents, carrying no potentially sensitive functional
groups, an easily accessible continuous approach to them directly from metallic magnesium would
be desirable. This could then easily be included in the above described continuous flow synthesis,
freshly preparing the reactive intermediate Grignard reagents and omitting the need for storage of
such reagents over time diminishing their quality, and thereby potentially improving the product
quality through purer intermediates.
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The direct Grignard reagent formation from Mg in the form of turnings as described here is an
ideal candidate for continuous processing since it can benefit tremendously from improved heat
management and fast reaction control, allowing temperature jumps as needed for optimal thermal
management. Furthermore, through flow chemistry a continuous provision of a large excess of Mg
throughout the reaction can be achieved, Mg activation can be integrated, and Mg can be
continuously replenished throughout the course of the reaction. The general considerations made
for the case of Grignard reagent formations are also applicable to other solid/liquid processes.
Therefore, the developed set-up dedicated to continuous solid/liquid processing is applicable to a
variety of other processes. The proof-of-concept for the set-up however has been performed via a
Grignard reagent formation.
A number of patents have been concerned with the preparation of Grignard reagents from metallic
Mg20-22, and recently two papers have been published detailing the laboratory scale synthesis of
PhMgBr as well as other Grignard reagents continuously without Mg replenishing.23,24
Furthermore, Eli Lilly has performed Barbier as well as Grignard reactions in a series of continuous
stirred tank reactors mapping the operational space for continuous Grignard reagent formation and
consumption combining a modeling approach with experimental runs at scale.25-27
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In this paper, the Fraunhofer IMM approach to Grignard reagent formation on the laboratory scale
as well as the pilot scale is shown. The developed set-ups use Mg turnings activated in situ
throughout the reaction. The set-ups allow access to a novel process window, namely a large excess
of Mg (5-25 molar excess) to suppress unwanted side reactions and to allow the reaction to proceed
within only a few minutes residence time while yielding 100% conversion within a single passage
through the reactor. Analysis of the reaction progress was performed using inline IR monitoring
and verified via titration. A tenfold scale-up is described and particular care given to the thermal
management of the reaction.
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RESULTS AND DISCUSSION
A laboratory scale reactor was designed and manufactured by 3D laser melting. This technology
was used for the reactor fabrication to enable cost efficient manufacturing of the hardware and
plays a crucial role in establishing sufficiently effective heat exchange structures for the scale-up.
Heating/cooling therewith can be achieved efficiently according to the reaction’s needs and
progression. Figure 1 shows the flow chart of the Grignard reagent formation with the reactor at
its midst, Figure 2 details the reactor constructed and patented28 detailing fluid inlet and outlet,
temperature measuring points along the reactor, as well as showing integrated viewing windows
for visual inspection of reaction progress. Four temperature measuring points are included with T1
being situated at the entrance of the fluid into the reactor, and T4 placed at the top of the reaction
zone. The reactor is manufactured from two identical halves, allowing two different temperature
zones to be used within the reactor since it was found that the lower half of the reactor exhibited
significantly more heat release than the upper part.
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Figure 1: Flow chart detailing the components for Grignard reagent formation.
Inner diameter ca. 20mm
Grignard
Heat/Cool out
reagent out
T4
T3
Heat/Cool
out
Heat/Cool in
T2
T1
Halide in
Heat/Cool in
Figure 2: Laboratory-scale Grignard reagent formation reactor.
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As an instantaneous inline analysis tool, an ATR-IR spectrometer was incorporated. Additionally,
titration either with menthol and 1,10-phenanthroline29 or via iodine/LiCl30 was used. In the case
of benzylmagnesium chloride, samples were quenched with methanol and analysed via GC. The
operating conditions were chosen as follows: The magnesium turnings had an average size of 0.5-3
mm. Activation of the Mg was performed mechanically through a jogging motor, which provides
abrasion on the surface of the magnesium by mutual rubbing of the turnings. In most cases, no
other activation such as auxiliary chemicals or pretreatment with Grignard reagent was necessary.
Water-free THF was used but other appropriate solvents can also be employed. Temperature can
be rapidly varied via a thermostatic bath, and very sensitive Grignard reagents can be formed by
employing a chiller. Alkyl or aryl halides can be used in concentrations from about 0.5-3.0 molar
with the upper limit given by the solubility of the formed Grignard reagent. Residence times in the
reactor ranged from 5.0-30.0 minutes (residence time distribution measurements show a behavior
close to a PFR with Bodenstein Numbers up to about 90 at flow rates between 1-4 ml/min under
Mg activation) given by the flow rate used and dependent on the Grignard reagent’s reaction time
needed to reach full conversion of the used halide within one passage through the reactor. In terms
of safety considerations, it was estimated from available reaction enthalpies that a heat being
released within the reactor of up to only a few tens of Watts can be expected, so the integrated heat
exchanger is able to handle the temperature rise within the reactor and remove the heat efficiently.
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For each investigated Grignard reagent, multiple runs were performed varying temperature of the
thermostat bath employed for heating/cooling the reactor as well as flow rate in order to achieve
complete halide conversion within one reactor passage with the goal of achieving maximum flow
rate at minimal energy expenditure in terms of excessive heating/cooling necessary. Initial
Grignard reagent formation reactions were investigated with the reactor as given above. Later on
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an Mg replenishing unit was established to render the reaction truly continuous in both, liquid and
solid, feed. Figure 3 shows an example of typical temperature profiles obtained along the reactor,
here shown for processing of a 1M ethyl bromide solution in THF.
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Flow rate
Time [min]
T4
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Thermostat bath
Figure 3: Temperature progression along the reactor: Flow rate: 2 ml/min (Filling: 4 ml/min),
1M EtBr in THF, Thermostat bath setting: 18°C.
For this Grignard reagent care had to be taken to not exceed the boiling point of the starting
material ethyl bromide (38°C) during processing. More halide starting materials of common
Grignard reagents on the market were explored and their synthesis optimized in flow aiming at
maximum flow rate for full halide conversion within a single passage through the reactor while
using minimal energy input namely thermostat bath settings with minimal heating/cooling
possible. Table 1 summarizes the Grignard reagent synthesis investigated detailing halide
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concentrations employed, maximum flow rate possible for full conversion, temperature setting of
the thermostat bath, and yields of Grignard reagents achieved (determined by manual titration).
For comparison, concentration ranges for commercially available reference materials are also
given.
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Table 1: Reaction conditions and yields for investigated standard Grignard reagents.
It is noteworthy that with the exception of the 2-thienylmagnesium bromide all results achieved
lay within the range of the reference materials but are narrower than the commercial products.
Additionally it should be mentioned that the given flow rates correspond to residence times of the
halide over the Mg bed of about 7.5-30 minutes. As mentioned above, the Mg turnings are
mechanically activated through vibration within the reactor. In order to verify that this in situ
activation really had a significant influence on the Grignard reagent formation, the optimized
reaction conditions for a number of the reagents were tested without Mg activation. Table 2
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summarizes the differences in time of start of reaction after halide is being introduced into the
reactor.
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Table 2: Comparison of Grignard reagent formation with and without Mg mechanical activation.
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It was found that without Mg activation the Grignard reagent formation does still start without the
need for auxiliary chemicals for initiation; however, the time is much higher and no more full
conversion of halides is achieved on the previously optimized reaction conditions.
It had been found that the reactor was performing so well that Mg was consumed very fast and that
a Mg replenishing unit was needed to be able to run reactions over an extended period of time and
to render the set-up truly continuous. A manual portion-wise Mg refilling unit was constructed and
attached to the reactor as depicted in Figure 4.
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Figure 4: Laboratory-scale Grignard reagent formation reactor including the Mg refilling unit.
The replenishing unit and two temperatures zones were then used in the synthesis of
benzylmagnesium chloride. Figure 5 shows the temperature profiles within the reactor over time.
It has to be noted that 2-Me THF instead of THF was used to suppress side product formation.
Furthermore, the Mg turnings were pre-activated through ultrasound to decrease the incubation
period observed in the reactor when only using the mechanical activation through vibration as
implemented in the reactor.
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Figure 5: Temperature progression along the reactor: Flow rate: 3ml/min (Filling: 8ml/min), 1M
BenzylCl in 2-Me THF, Thermostat bath setting: 50°C (top), 35°C (bottom).
It was found that full conversion of halide and steady-state operation with full chloride conversion
could be reached after only about 30 minutes of run time. Yield of Grignard reagent as determined
by GC analysis was found to be 97% with the main by-product being benzyl alcohol (2%) and
very little Wurtz coupling product and no remaining starting material benzyl chloride being
observed. In addition, the reaction could be conducted for about 3 hours with Mg being replenished
six times (each time about 5-10% of total Mg amount in the reactor is added from the top, refilling
is initiated, when a gap in the top viewing window can be observed) so about half of the initial Mg
amount was consumed and refilled within one single experiment without loss in product quality.
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In terms of scalability of the process to industrially relevant throughputs, a pilot reactor allowing
a tenfold increased flow through has been built and tested and is depicted in Figure 6.
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Figure 6: Pilot-scale Grignard reagent formation reactor with implemented automated Mg
refilling.
It includes an automated Mg replenishing unit however only has one accessible temperature zone
within the reactor. It has been successfully tested with 1M phenylmagnesium bromide and efforts
are under way to build a pilot plant at Fraunhofer IMM that will ultimately allow flow rates of up
to 15 l/h halide throughput.
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EXPERIMENTAL SECTION
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FLOW PROCEDURE FOR GRIGNARD SYNTHESIS
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The reactor was charged with about 20 g of Mg turnings, inerted with Argon and four
thermocouples were placed along the Magnesium bed for temperature monitoring. Activation of
the magnesium turnings was started using a jogging motor placed at the bottom of the reactor (3V,
150 mA). Then the reactor was filled with a solution of starting material halide in dry THF at an
elevated flow rate using a Postnova syringe pump resulting in a temperature increase as a hint for
initiation of the exothermic reaction (filling with educt was carried out without additional
heating/cooling for most Grignards). As soon as the reactor was completely filled with educt
solution, temperature control was started using a thermostat bath and the flow rate was reduced to
keep temperatures below the solvent’s (here THF) boiling point. The course of the reaction was
observed by means of an ATR-IR fiber probe placed in the reactor outlet. Samples of the outlet
solution were titrated to determine the Grignard concentration. Specific reaction conditions for
investigated Grignard reagents are shown in Table 1.
MATERIALS AND METHODS
All solvents and reagents were purchased from commercial suppliers and were used without
further purification. Namely the chemicals used and their suppliers were: allyl chloride (Sigma-
Aldrich, 99%), 2M allylmagnesium chloride in THF (Sigma-Aldrich), benzyl chloride (Thermo
Fischer Kandel, 99%, stabilized), bromobenzene (Merck KGaA, 99%), bromoethane (Sigma-
Aldrich, 98%), 2-bromothiophene (Fluorochem Ltd., 98%), chlorobenzene (Sigma-Aldrich,
>99.5%), chloropropane (Sigma-Aldrich, >99%), 1M ethylmagnesium bromide in THF (Sigma-
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Aldrich), iodine (Fluka Chemie AG, >99.5%), 2M isopropylmagnesium chloride (Sigma-Aldrich),
lithium chloride (Sigma-Aldrich, >98%, waterfree), Mg turnings (Merck KGaA, >99%), menthol
(Sigma-Aldrich, 99%), methanol (T H Geyer, 99.95%), 1,10-phenanthroline (Sigma-Aldrich,
>99%), 1M phenylmagnesium chloride in THF (Sigma-Aldrich), THF (T H Geyer, 99.9%,
waterfree), 1M 2-thienylmagnesium bromide (Sigma-Aldrich), toluene (Carl Roth, 99.5%).
Pumps used were Postnova syringe pumps (PN 1610 Syringe Dosing System). For tempering of
the reactors, thermostatic baths from Lauda (C6CS), Julabo (F31-C), and Peter Huber
Kältemaschinenbau (CC-405, CC-3) were used. The temperatures were measured using miniature
thermocouples (type K from RS Components), recorded by a data logger (either Siemens PCS7
Lab or Type Expert Key 200L, from Delphin Technology) and for evaluation transferred to a
notebook. Inline ATR-IR monitoring was performed using a Bruker Matrix-MF spectrometer and
a self-constructed flow through cell. Titration of the Grignard reagent was done following the
method of Lin and Paquette for the titration with 1,10-phenanthroline29 and following the method
of Krasovskiy and Knochel when using the titration with iodine.30 Analysis for the
benzylmagnesium chloride was done via quenching Grignard reagent samples in methanol and
analyzing via calibrated GC measurements. Here, a Varian GC 3900 system with Varian 8400 GC-
autosampler was used.
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CONCLUSIONS
In conclusion, a continuously operating laboratory set-up for Grignard reagent formation was
established including inline process monitoring and a process control unit, allowing for the
optimization of process parameters for scalable continuous Grignard reagent formation. Reaction
conditions for full halide conversion in one single reactor passage were found aiming for maximum
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throughput with minimal energy input. The reactor allows processing in a novel process window
of large Mg access also allowing for in situ Mg activation. An Mg replenishing unit as add-on to
the reactor was built and tested allowing for truly continuous halide processing without loss of
product quality. Furthermore, the scale-up to pilot-scale throughput (scale-up factor of 10)
including a continuous mechanical Mg replenishing unit and sensors for Mg level filling was
established and investigated. Efforts to increase its throughput to halide solution flow rates of up
to 15 l/h are underway.
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ACKNOWLEDGMENT
The authors would like to acknowledge the Fraunhofer IMM for internal funding.
AUTHOR INFORMATION
Corresponding Author
*Corresponding author. Tel: +49 6131 990425; Fax: +49 6131 990205; E-mail address:
gabriele.menges-flanagan@imm.fraunhofer.de
REFERENCES
[1] Silverman, G. S.; Rakita, P. E. Handbook of Grignard Reagents; CRC Press: Boca Raton,
USA; 1996.
[2] Richey Jr., H. G. Grignard Reagents: New Developments; Wiley: New York, USA; 1999.
[3] Grignard, V.; Sur quelques nouvelles combinaisons organométalliques du magnèsium et leur
application à des synthèses d'alcools et d'hydrocarbures. In CR Hebd. Séances Acad. Sci., Ser. C.
130, 1900, pp 1322–1324. (Nobelpreis für Chemie 1912).
[4] Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed., Wiley, New York, 2005.
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2
3
4
5
6
7
8
9
[5] Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.;
Vu, V. A. Highly Functionalized Organomagnesium Reagents Prepared through Halogen-Metal
Exchange, Angew. Chemie Int. Ed. 2003, 42, 4302-4320.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[6] Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Preparation and Reactions of Heteroaryl
Organomagnesium Compounds, Chem. Lett. 2006, 35 (1), 2-7.
[7] Petersen, T. P.; Becker, M. R.; Knochel, P. Continuous flow magnesiation of functionalized
heterocycles and acrylates with TMPMgCl⋅LiCl, Angew. Chemie Int. Ed. 2014, 53, 7933-7937.
[8] Li-Yuan Bao, R.; Zhao, R.; Shi, L. Progress and developments in the turbo Grignard reagent i-
PrMgCl·LiCl: a ten-year journey, Chem. Comm. 2015, 51, 6884-6900.
[9] Brodman, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Continuous Preparation of
Arylmagnesium Reagents in Flow with Inline IR Monitoring, Org. Process Res. Dev. 2012, 16,
1102-1113.
[10] Wakami, H.; Yoshida, J. Grignard Exchange Reaction Using a Microflow System:ꢀ From
Bench to Pilot Plant, Org. Process Res. Dev. 2005, 9, 787-791.
[11] Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener
Approaches to Organic Synthesis Using Microreactor Technology, Chem. Rev. 2007, 107, 2300-
2318.
[12] Riva, E.; Gagliardi, S.; Martinelli, M.; Passarella, D.; Vigo, D.; Rencursio, A. Reaction of
Grignard reagents with carbonyl compounds under continuous flow conditions, Tetrahedron 2010,
66, 3242-3247.
[13] Cervera-Padrell, A. E.; Nielsen, J. P.; Pedersen, M. J.; Müller Christensen, K.; Mortensen, A.
R.; Skovby, T.; Dam-Johansen, K.; Kiil, S.; Gernaey, K. V. Monitoring and Control of a
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Page 18 of 20
1
2
3
4
5
6
7
8
9
Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient
Intermediate Using Inline NIR spectroscopy, Org. Process Res. Dev. 2012, 16, 901-914.
[14] Pedersen, M. J.; Holm, T. L.; Rahbek, J. P.; Skovby, T.; Mealy, M. J.; Dam-Johansen, K.;
Kiil, S. Full-Scale Continuous Mini-Reactor Setup for Heterogeneous Grignard Alkylation of a
Pharmaceutical Intermediate, Org. Process Res. Dev. 2013, 17, 1142-1148.
[15] Mateos, C.; Rincón, J. A.; Villanueva, J. Efficient and scalable synthesis of ketones via
nucleophilic Grignard addition to nitriles using continuous flow chemistry, Tetrahedron Letters
2013, 54, 2226-2230.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[16] Murray,P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Continuous
Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and
the Telescoped Flow Synthesis of (E/Z)-Tamoxifen, Org. Process Res. Dev. 2013, 17, 1192-1208.
[17] Wu, J.; Yang, X.; He, Z.; Mao, X.; Hatton, T. A.; Jamison, T. F. Continuous Flow Synthesis
of Ketones from Carbon Dioxide and Organolithium or Grignard Reagents, Angew. Chemie Int.
Ed. 2014, 53, 8416-8420.
[18] Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis
of Pharmaceutical Products, Org. Process Res. Dev. 2016, 20, 2-25.
[19] Baumann, M.; Baxendale, I. R. The synthesis of active pharmaceutical ingredients (APIs)
using continuous flow chemistry, Beilstein J. Org. Chem, 2016, 11, 1194-1219.
[20] Enke, S.; Röttel, G. Verfahren zur Herstellung von Grignard Addukten. DE 103 04 006 B3,
19 August 2004.
[21] Szeja, W.; Helman, J.; Kiraga, K.; Derfla S. Process for the preparation of Grignard reagents.
WO2010/117285, 14 October 2010.
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6
7
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[22] Thathager, M.; Poechlauer, P.; Reintjens, R. W.; Ghislain, E.; Goldbach, M. Preparation of
Grignard Reagents using a Fluidized Bed. WO2014/207206, 31 December 2014.
[23] Goldbach, M.; Danieli, E.; Perlo, J.; Kaptein, B.; Litvinov, V. M.; Blümich, B.; Casanova, F.;
Duchateau, A. L. L. Preparation of Grignard reagents from magnesium metal under continuous
flow conditions and on-line monitoring by NMR spectroscopy, Tetrahedron Lett. 2016, 57, 122-
125.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[24] Huck, L.; de la Hoz, A.; Díaz-Ortiz, A.; Alcázar, J. Grignard Reagents on a Tab: Direct
Magnesium Insertion under Flow Conditions, Org. Lett. 2017, 19, 3747-3740.
[25] Kopach, M. E.; Roberts, D. J.; Johnson, M. D.; Mc Glary Groh, J.; Adler, J. J.; Schafer, J. P.;
Kobierski, M. E.; Trankle, W. G. The continuous flow Barbier reaction: an improved
environmental alternative to the Grignard reaction?, Green Chem. 2012, 14, 1524-1536.
[26] Changi, S. M.; Wong, S.-W. Kinetics Model for Designing Grignard Reactions in Batch or
Flow Operations, Org. Process Res. Dev. 2016, 20, 525-539.
[27] Wong, S.-W.; Changi, S. M.; Shields, R.; Bell, W.; McGarvey, B.; Johnson, M. D.; Sun, W.-
M.; Braden, T. M.; Kopach, M. E.; Spencer, R. D.; Flanagan, G.; Murray, M. Operation Strategy
Development for Grignard Reaction in a Continuous Stirred Tank Reactor, Org. Process Res. Dev.
2016, 20, 540-550.
[28] Hofmann, C.; Menges-Flanagan, G. Kontinuierliches Verfahren zur Herstellung von
Grignard-Addukten und Vorrichtung zu dessen Durchführung. DE 10 2016 206 211 A1, 13. April
2016.
[29] Lin, H.-S.; Paquette, L. A. A Convenient Method for Determining the Concentration of
Grignard Reagents, Synth. Commun. 1994, 24(17), 2503-2506.
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[30] Krasovskiy, A.; Knochel, P. Convenient Titration Method for Organometallic Zinc,
5
6
Magnesium, and Lanthanide Reagents, Synthesis 2006, 5, 890-891.
7
8
9
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