From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C?H Metalations

Article abstract of DOI:10.1002/chem.201903267

Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling optimal conditions to be found with 95 % yield by significantly suppressing the formation of byproducts, followed by the second C?H metalation step in 95 % yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO₂, isolating 2.3 g for 10 min of operation time.

Full text of DOI:10.1002/chem.201903267

A Journal of
Accepted Article
Title: From p-Xylene to Ibuprofen in Flow: 3-Step Synthesis via Unified
Sequence of Chemoselective C–H Metalations
Authors: Hyune-Jea Lee, Heejin Kim, and Dong-Pyo Kim
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From p-Xylene to Ibuprofen in Flow: 3-Step Synthesis via Unified
Sequence of Chemoselective C–H Metalations
Hyune-Jea Lee,[a] Heejin Kim,*[b] and Dong-Pyo Kim*[a]
Abstract: Ibuprofen was prepared from an inactive and inexpensive
p-xylene by 3-step flow functionalizations through chemoselective
metalations of benzyl positions in sequence using an in-situ generated
LICKOR-type superbase. The flow approach in the microreactor
facilitated to comprehensively explore over 100 conditions in the first-
step reaction by varying concentrations, temperatures, solvents, and
equivalents of reagents, enabling to find the optimal condition with
95% yield by significantly suppressing the formation of byproducts,
followed by the second C–H metalation step in 95% yield. Moreover,
gram-scale synthesis of ibuprofen in the final step was achieved by
biphasic flow reaction of solution-phase intermediate with CO2,
isolating 2.3 g for 10 min of operation time.
batch reactors,[7] but using flow devices.[8] In all cases of flow
synthesis reported by three research groups, isobutylbenzene
was used in common as a starting material for Friedel-Crafts
acylation at high temperature. We envisage alternative flow
synthesis of ibuprofen from a low-cost substrate at favorable
conditions, inspired by previous studies on sequential generations
of benzylic anions for the synthesis in a flask.[9] Especially, we
could improve the previous method[9b] on the basis of the flow
synthetic manner. It would be highly desirable for value-added
API production from commodity chemicals.
Flow chemistry based on microfluidics has been recognized as
the promising technology in modern synthetic chemistry.[1] The
application area of flow chemistry has been well expanded to wide
range of research field including synthesis of pharmaceutical and
agrochemical compounds. Recently, flow synthesis of active
pharmaceutical ingredients (APIs) has also been caught great
attentions in pharmaceutical industries as well as academic
laboratories from the viewpoint of better safety and sustainability
than the conventional synthesis in a batch reactor.[2] Among
various advantages of the flow synthesis, the rapid and precise
control over reaction conditions is one of the most distinct and
unique features. The small dimension and high surface-to-volume
ratio of reactors are very efficient for the heat management.[3] Also,
the reaction time and stoichiometry of reagents can be accurately
adjusted by meticulously changing the flow rate of each solutions.
In particular, flash chemistry often requires the control of reaction
time in extremely short scale down to milliseconds order or less.[4]
Therefore, the flow microreactors would be ideal platforms to
handle highly unstable intermediates that are rapidly generated
and decomposed.[5]
Scheme 1. Flow approach for the three-step synthesis of ibuprofen from p-
xylene through sequential and chemoselective C–H functionalizations.
We herein report an efficient three-step flow synthesis of
ibuprofen from p-xylene using sequential and chemoselective C‒
H metalations in a precisely controlled manner (Scheme 1). Three
metalation steps of the benzyl position as an unified sequence
were carried out by in-situ generated LICKOR-type superbase[10]
under the optimal flow conditions which were comprehensively
explored over 100 conditions to suppress competitive side
reactions. As a starting material, we used a simple and inactive
starting compound, p-xylene, to achieve an atom-economic flow
process. Moreover, in the final step, synthesis of ibuprofen in the
high productivity was attained by efficient flow reaction of biphasic
segments between highly reactive intermediate in the solution
and CO2 gas,[11] which was fully utilized the merit of microreactor
with high surface-to-volume ratio.
Ibuprofen is an analgesic, antipyretic and nonsteroidal anti-
inflammatory drug (NSAID) used to relive the pain and fever,
which is listed by World Health Organization (WHO) as an
essential medicine. In the medication statistics of United States,
there was more than 21 million prescriptions in 2016.[6] Since the
general synthetic process was developed by Boot Pure Drug
Company in early 1960s, many research groups have reported
various synthetic methodologies not only using conventional
[a]
H. –J. Lee, Prof. Dr. D. –P. Kim
Centre for Intelligent Microprocess of Pharmaceutical Synthesis
Department of Chemical Engineering
POSTECH (Pohang University of Science and Technology),
Pohang, 790-784 (South Korea)
In order to establish the suitable synthetic route for a flow
process, we firstly looked over the selective benzylic C‒H
metalation of p-xylene using a superbase, in-situ generated from
butyllithium (BuLi) and potassium tert-butoxide (t-BuOK).
E-mail: dpkim@postech.ac.kr
Prof. Dr. H. Kim
Department of Chemistry, College of Science, Korea University
Seoul, 02841 (South Korea)
E-mail: heejinkim@korea.ac.kr
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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compared to those in 2-MeTHF (Figure S1-a and b);[13] 3) the
reaction at low temperature was inevitable to inhibit the side
reactions; 4) the moderate concentration of reagents was crucial
for efficient reaction, because the viscosity may affect to the
mixing efficiency (Figure S1-c).[14] In addition, it is noteworthy that
the flow methodology facilitates to conduct the labor-consuming
parameter study, whereas conventional batch reactor takes much
longer to complete the experiments.
We then conducted the flow reactions under the optimized
concentration of solutions and the equivalent of reagents. A
mixture of p-xylene with t-BuOK (1.2 equiv) was mixed with t-BuLi
(1.2 equiv) in M1 and reacted in R1. The resulting solution was
sequentially mixed with methyl triflate in M2 and reacted in R2.
The reaction was carried out under various residence times in R1
(t; from 0.25 s to 24.8 s) and temperature (T; from –70 °C to 25 °C).
The residence time in R1 was precisely controlled by changing
the length of tube reactor. At high temperatures such as 25 °C,
the yields were moderate probably because of unselective side
reactions. At low temperature less than –40 °C, the low yields
were probably due to the low reactivity and reduced mixing
efficiency. The best result was obtained when the residence time
in R1 was 3.14 s at –20 °C (Figure 1-b) to give the desired product
in 95% yield. In this reaction condition, the formation of
dimethylated byproduct (1,4-diethylbenzene) was suppressed to
1% (entry 101, Table S3).
In a similar vein, the second reaction step in flow was optimized
using isopropyl iodide as an electrophile (Table 1). Because
isopropyl iodide is relatively less reactive than MeOTf, benzyl-
metalation was carried out under relatively long residence time
(63 s) in R1 at –20 °C.
Figure 1. Benzyl-metalation of p-xylene and reaction with MeOTf in flow. a) the
reaction scheme in a flow reactor (micromixers: M1 and M2, tube reactors: R1
and R2). b) Correlation map of the effects of temperature (T) and residence time
(t) on the yield [%] of p-ethyl toluene 1 (A solution of p-xylene (0.3 M with 1.2
equiv of t-BuOK in 2-MeTHF and a solution of t-BuLi (1.2 M in penatne:hexane
2:1 v/v) were used for reaction).
Table 1. Metalation of p-ethyl toluene and the subsequent reaction with
isopropyl iodide using a flow reactor.
In addition, it was found that the one-pot synthetic method as
reported[9b] showed lack of reproducibility even when we followed
the protocol (Table S1, See the Supporting Information for details).
We explored different types of lithium reagents (n-BuLi or t-BuLi)
for the selective and rapid generation of benzyl-metalated xylene.
The metalation time was kept to 10 min at –78 ºC in a flask. The
use of n-BuLi led to form methylated product 1 in 68% yield (entry
1, Table S1), whereas the use of t-BuLi was inefficient with
decreased conversion probably due to the competitive side
reaction with THF solvent (entry 2, Table S1).[12] Notably, it
demands to establish the well-controlled synthetic protocol for
suppressing the unwanted side reactions by thorough study on
various reaction parameters.
We next examined a continuous-flow generation of benzyl-
metalated xylene and its methylation in a capillary microreactor
consisting of two micromixers M1 and M2 (inner diameter ø of M1:
250 μm, ø of M2: 500 μm) and two tube reactors R1 and R2 (ø: 1
mm) as illustrated in Figure 1-a. We explored 111 reactions by
varying the concentration of each reagent, types of the solvent,
and equivalents of the base (See the Supporting Information for
details). From the obtained experimental results (Table S3), we
could conclude that; 1) the use of n-BuLi lowered the conversion
(Figure S1-a); 2) the use of THF accelerated the reaction but
caused more side reaction between superbase and THF,
Entry
t [s]
4.5
T [ºC]
50
Conv. of 1 [%][a]
Yield of 2 [%][a]
1
2
3
4
5
6
78
81
85
89
90
98
77
79
4.5
25
4.5
–20
50
82
17.9
17.9
17.9
88
25
89
–20
95 (93)[b]
[a] Determined by GCMS using 1,3,5-trimethoxybenzene as an internal
standard. [b] Yield of isolated product.
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Table 2. Metalation of 1-ethyl-4-isobutylbenzene and the subsequent reaction
with methyl iodide using a flow reactor.
Figure 2. Gram-scale synthesis of ibuprofen through the biphasic reaction of
compound 2 with carbon dioxide in flow.
At –40 °C and –20 °C, the yields of product 3 were 20% and
13%, respectively (entry 1 and 2, Table 2), due to the low
conversion. When the equivalent of the base was increased from
1.5 equiv to 3.0 equiv, only slight increase of the yield was
observed (entries 3 and 4, Table 2). However, the use of higher
concentration of reagents significantly increased the yield of
product to 67% (entries 5–8, Table 2). These results imply that
the lower concentration of reagents enhanced side reaction of
superbase with solvent, resulting in low yields.
Entry
Concentration
Equiv of
t-BuLi/t-BuOK
T
[ ºC]
Yield
[%][a]
of 2 [M]
Along with the optimal conditions (0.5 M of 2 with 52 s residence
time in R1) to generate anionic intermediate of 2 at –40 ºC,
synthesis of ibuprofen was conducted by biphasic reaction with
CO2 (Figure 2). The flow microreactor was constructed from three
micromixers (ø of M1: 250 m, ø of M2 and M3: 500 m) and
three tube reactors (ø: 1 mm, length L of R1: 10 m, L of R2 and
R3: 1 m). For the efficient biphasic reaction, the resulting solution
after the metalation was slightly diluted using identical solvent (2-
MeTHF) in 3.9 s of residence time in R2, because high
concentration of intermediate limits the dissolution of CO2 gas as
well as the practical issue of possible clogging in flow. Three
equivalents of CO2 gas introduced through a mass flow controller
formed the biphasic segment flow to produce the ibuprofen. For a
gram-scale synthesis, the flow reaction was continuously
operated for 10 min to produce 2.3 g of ibuprofen (57% isolated
yield by recrystallization).
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.4
0.4
0.5
0.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
–20
–40
–20
–40
–20
–40
–20
–40
13
20
24
31
57
59
65
67
[a] Determined by GCMS using 1,3,5-trimethoxybenzene as an internal
standard.
We optimized the reaction by changing the residence time and
temperature in second micromixer and tube reactor (M2 and R2).
Although the yield of 1-ethyl-4-isobutylbenzene 2 was moderate
in 4.5 s of reaction time at 50 °C (entry 1, Table 1), it was improved
with decreasing the temperature to –20 °C (entries 2 and 3, Table
1) due to the better stability of the generated intermediate under
low temperature.[15] At increased residence time in R2 and
decreased temperature, the yields were gradually increased
(entries 4–6, Table 1). Finally, the reaction for 17.9 s of residence
time in R2 at –20 °C rendered the desired product in high isolated
yield (93%) without any detectable byproduct (entry 6, Table 1).
For the optimization of final step to produce the ibuprofen, the
reaction condition for the direct metalation of compound 2 was
optimized using methyl iodide (Table 2). Through the trapping with
methyl iodide, the yield of generated metalized intermediate can
be indirectly confirmed, as often reported in many literatures.[16] It
is much more difficult to metalize the benzyl position of compound
2 compared to that of p-xylene or compound 1, because of the
steric hindrance as well as electronic nature of benzylic position.
The residence time for the metalation using 1.5 equivalents of t-
BuLi/t-BuOK was fixed to 52 s.
In conclusion, we have developed a 3-step flow-assisted
synthesis of ibuprofen from p-xylene via in-situ generation of
LICKOR-type superbase by optimizing the reaction parameters.
The chemoselective C–H metalation of benzyl proton was
sequentially optimized in very high yields 95% at both 1st and 2nd
step by minimizing the competitive side reactions. Eventually, the
gram-scale productivity of ibuprofen (2.3 g in 10 min) was
successfully achieved by biphasic reaction between metalized
intermediate solution and CO2 in the microreactor. We believe
that the chemoselective metalation by superbase in a flow manner
could be further utilized to synthesize various bioactive molecules
including drugs and APIs.
Experimental Section
Synthesis of p-ethyl toluene (1): A microfluidic system consisting of two T-
shaped micromixers (M1 and M2), two tube reactors (R1 and R2) and
three tube pre-temperature-retaining units (for P1 and P3, 1 mm of inner
diameter (ø) and 50 cm of length (L); for P2, 1 mm of inner diameter and
1 m of length) were used. A solution of p-xylene and potassium tert-
butoxide (0.3 M in 2-MeTHF) and a solution of t-BuLi (1.44 M in hexane or
pentane/hexane) were individually introduced to M1 (ø: 250 μm) by syringe
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pumps. The resulting solution was passed through R1 (ø: 1 mm, L: 50 cm)
and was mixed with a solution of methyl trifluoromethanesulfonate
(MeOTf; 3.0 equiv in ether) in M2 (ø: 500 μm). The resulting solution was
passed through R2 (ø: 1 mm, L: 1 m). The flow rate for solution of p-xylene,
t-BuLi and MeOTf was kept at 6.0: 1.5: 3.0 mL/min, respectively. After a
steady state was reached, the product solution was collected for 30 s while
being quenched with saturated aqueous NH4Cl solution (5 mL). Then, the
crude product was extracted with ether (3 x 20mL) and was washed with
brine (15 mL). The organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
column chromatography (hexane) to give desired product 1 in 94% yield.
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A microfluidic system
consisting of two T-shaped micromixers (M1 and M2), two tube reactors
(R1 and R2) and three tube pre-temperature-retaining units (for P1 and P3,
ø: 1 mm, L: 50 cm; for P2, ø: 1 mm, L: 1 m) were used. A solution of p-
ethyl toluene (1) and potassium tert-butoxide (0.20 M and 0.24 M in 2-Me
THF, respectively) and a solution of t-BuLi (1.2 M in pentane:hexane=2:1
v/v) were individually introduced to M1 (ø: 250 μm) by syringe pumps. The
resulting solution was passed through R1 (ø: 1 mm, L: 10 m) and was
mixed with a solution of 2-iodopropane (0.6 M in 2-MeTHF) in M2 (ø: 500
μm). The resulting solution was passed through R2 (ø: 1 mm, L: 1 m and
ø: 1 mm, L: 4 m). The flow rate for p-ethyl toluene (1), t-BuLi and 2-
iodopropane was kept at 6.0:1.5:3.0 mL/min, respectively. After a steady
state was reached, the product solution was collected for 30 s while being
quenched with saturated aqueous NH4Cl solution (5 mL). Then, the crude
product was extracted with ether (3 x 20mL) and was washed with brine
(15 mL). The organic phase was dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (hexane) to give desired product 2 in 93% yield.
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Synthesis of ibuprofen: A microfluidic system consisting of two T-shaped
micromixers (M1 and M2), two tube reactors (R1 and R2) and three tube
pre-temperature-retaining units (for P1 and P3, ø: 1 mm, L: 50 cm; for P2,
ø: 1 mm and L: 1 m) were used. A solution of 1-ethyl-4-isobutylbenzene
(2) and potassium tert-butoxide (0.5 M and 1.5 M in 2-MeTHF) and a
solution of t-BuLi (1.2 M in pentane:hexane=2:1 v/v) were individually
introduced to M1 (ø: 250 μm) by syringe pumps. The resulting solution was
passed through R1 (ø: 1 mm, L: 10 m) and was mixed with 2-MeTHF in
M2 (ø: 500 μm). The resulting solution was passed through R2 (ø: 1 mm,
L: 1 m). The resulting solution of which concentration was decreased was
mixed in M3 with CO2 (ø: 500 μm) and passed through R3 (ø: 1 mm, L: 1
m). The flow rate for 1-ethyl-4-isobutylbenzene (2), t-BuLi and 2-MeTHF
was kept at 4.0:5.0:3.0 mL/min, respectively. The flow rate of CO2 was
controlled by mass flow controller (MFC) and kept at 144.4 mL/min (3.0
equiv). After a steady state was reached, the product solution was
collected for 30 s while being quenched with H2O (5 mL). Then aqueous
phase was washed with ether (3 x 20 mL). After acidification with 1 M
hydrochloric acid to pH 2, and then extracted with ether (3 x 20 mL). The
organic layer was washed with a 1% aqueous solution of NaHCO3 (2 x 10
mL) and dried. After the concentration, the crude product was
recrystallized from hexane to give ibuprofen in 57% isolated yield.
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Acknowledgements
We gratefully acknoledge the support from the National Research
Foundation (NRF) of Korea grant funded by the Korean
government (NRF-2017R1A3B1023598).
[6]
[7]
The Top 300 Drugs of 2016 in the United States for details see website:
https://clincalc.com/DrugStats/Top300Drugs.aspx
Keywords: ibuprofen • flow chemistry • superbase • reaction
optimization • C-H metalation
For selected patent references towards ibuprofen, see: a) D. A. Ryan,
U.S. Patent US 4,929,773, May 29, 1990; b) D. D. Lindley, T. A. Curtis,
T. R. Ryan, E. M. de la Garza, C. B. Hilton, T. M. Kenesson, U.S. Patent
This article is protected by copyright. All rights reserved.

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COMMUNICATION
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From p-Xylene to Ibuprofen in Flow:
3-Step Synthesis via Unified
Sequence of Chemoselective C–H
Metalations
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