Effective Utilization of Flow Chemistry: Use of Unstable Intermediates, Inhibition of Side Reactions, and Scale-Up for Boronic Acid Synthesis

Article abstract of DOI:10.1021/acs.oprd.8b00118

Flow chemistry processes for boronic acid syntheses utilizing lithiation-borylation have been developed. The side reactions in the lithiation step that occur in batch were suppressed, and unstable lithium intermediates were handled safely. Flow technology was applied to several kinds of boronic acid syntheses, and scale-up was successfully conducted to allow kilogram-scale production. Some of the key benefits of flow flash chemistry were utilized, both to avoid side reactions and to enable dianion chemistry that is difficult to perform successfully in batch reactions. The examples showed further perspectives on the utility of flow technologies for process development.

Full text of DOI:10.1021/acs.oprd.8b00118

Subscriber access provided by University of Massachusetts Amherst Libraries
Communication
Effective Utilization of Flow Chemistry: Use of Unstable Intermediates,
Inhibition of Side Reactions and Scale-up for Boronic Acid Synthesis
Hirotsugu Usutani, and David G. Cork
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 30 May 2018
Downloaded from http://pubs.acs.org on May 30, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
Organic Process Research & Development
1
2
3
4
5
6
Effective Utilization of Flow Chemistry: Use of Unstable Intermediates,
Inhibition of Side Reactions and Scale-up for Boronic Acid Synthesis
7
8
9
Hirotsugu Usutani1* and David G. Cork2
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
1
Takeda Pharmaceutical Company Ltd., Pharmaceutical Sciences, Process Chemistry, Jusoꢀhonmachi 2ꢀ17ꢀ85,
Yodogawaꢀku, Osaka, 532ꢀ8686, Japan
2
Formerly of Takeda Pharmaceutical Company Ltd., Pharmaceutical Sciences, Process Chemistry, Jusoꢀhonmachi
2ꢀ17ꢀ85, Yodogawaꢀku, Osaka, 532ꢀ8686, Japan
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 21
1
2
3
4
Table of Contents Graphic:
5
6
7
8
9
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
2
ACS Paragon Plus Environment

Page 3 of 21
Organic Process Research & Development
1
2
3
4
Abstract
5
6
7
8
9
Flow chemistry processes for boronic acid syntheses utilizing lithiation-borylation
have been developed. The side reactions in the lithiation step that occur in batch
were suppressed and unstable lithium intermediates were handled safely. Flow
technology was applied to several kinds of boronic acid syntheses and scale-up was
successfully conducted to allow kg scale production. Some of the key benefits of flow
flash chemistry were utilized, for both avoiding side reactions and enabling dianion
chemistry that is difficult to successfully perform in batch reactions. The examples
showed further perspectives on the utility of flow technologies for process
development.
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
Keywords: flow chemistry, flash chemistry, side reactions, scaleꢀup, organolithium chemistry,
unstable intermediates, dianions, aryl boronic acids
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 21
1
2
3
4
INTRODUCTION
5
6
7
8
9
Since its fullꢀscale research and development was started worldwide in the 1990s, Flow
Chemistry (FC) has received much attention and it is becoming one of the most useful and
indispensable technologies for a variety of chemical syntheses, ranging from pharmaceuticals and
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
,
２
agrochemicals to plastics and chemicals.１ FC has several unique features, which most
importantly give advantages that can be used to get improved performance and reduced costs, as
well as offering the potential for added safety and speed when compared to conventional batch
processes. While FC technologies have received significant research interest, both from academia
,
４
and industry,３ due to a lack of general and robust flow reactors for conducting laboratory
process development to scale up production, the potential of this technology has not yet been
fully utilized for manufacturing.
Our desire to explore and expand on the FC methodology for process chemistry stems from
the fact that it shows good utility for successfully handling unstable intermediates, and we have
recently reported an application of FC to a boronic acid synthesis focusing on precise control of
,
７
residence time and temperature,５ especially through the use of "flash chemistry".６ In that
report, by controlling residence time and temperature precisely, FC was shown to allow an
unstable lithium intermediate to be utilized while avoiding the side reaction pathway of
protonation, even though organolithiums are well known to be protonated in THF solvent
,
９
(Scheme 1, side reaction for 4).８
Bromine lithium exchange reactions are widely utilized for generating organolithiums, and
nꢀBuLi is especially used as a reagent. But, the lithium intermediates thus generated (2) often
undergo competing side reactions, such as butylation due to reaction between the organolithium
intermediate and butyl bromide (Scheme 1, side reaction for 5).１０
4
ACS Paragon Plus Environment

Page 5 of 21
Organic Process Research & Development
1
2
3
4
5
6
Scheme 1. Sequence of a BromineꢀLithium Exchange Followed by the Desired Reaction and
7
8
Side Reactions
9
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
In this paper, we demonstrate the use of FC to suppress the typical side reactions
(protonation & butylation), and show an application of FC to control highly unstable lithium
intermediates, including dianionic forms, for boronic acid syntheses. Furthermore, scaleꢀup
production to kgꢀscale will be disclosed.
RESULTS AND DISCUSSION
(1) Feasibility Study & Proof-of-Concept
,１２
As is well known, FC has already been applied to boronic acid synthesis,１１ but the scope of
its application is still limited. The key parameters for robust scaleꢀup are the mixing efficiency,
temperature, and residence time control, even though there are numerous other parameters to be
considered for process development by flow. Based on our previously reported insights,5 it was
planned to utilize FC for the manufacture of (4ꢀ(cyclohexyloxy)phenyl)boronic acid (3a). When
3a was synthesized in batch, a side reaction was found to be unavoidable if a halogenꢀlithium
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 21
1
2
3
4
exchange reaction was utilized, with butylation１３ being a major issue even when the reaction
5
6
was carried out at ꢀ25 °C (Scheme 2).
7
8
9
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
Scheme 2. Unavoidable Side Reaction (Batch Results)
In order to partially suppress the side reaction in batch, a cryogenic condition was required, thus
a flow reaction was investigated to develop a milder condition and further decrease the side
products. Firstly, as a feasibility study, the halogenꢀlithium exchange reaction and its quench by
MeOH was investigated in a flow setꢀup (Figure 1, Table 1).
Figure 1. Setꢀup for a flow feasibility study of halogenꢀlithum exchange
The initial experiments for the feasibility study were conducted with the conditions of; nꢀBuLi
1.07 eq., reaction temperature 0 °C, and residence times of 0.24ꢀ31.42 sec. When less than 1 sec
was allowed for lithiation, not all the raw materials were converted, showing the minimum time
required to consume all the raw materials. However, as the residence time was increased, more
raw material was consumed until 1a was totally converted to the lithiated species when using
6
ACS Paragon Plus Environment

Page 7 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
more than 3.93 sec residence time for lithiation. Surprisingly, the protonated compound (4a),
representing the desired product pathway, was obtained in highest yield in entry 3, and the yield
decreased as the residence time for lithiation was prolonged. Furthermore, the side reaction
(butylation, 5a) increased as the residence time increased.
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
The result showed that about 1.07 eq. of nꢀBuLi was sufficient for the bromineꢀlithium
exchange reaction and ca.4 sec was suitable to avoid the side reaction affording 5a. Too long a
residence time increased the side reaction, allowing the reaction of the aryllithium intermediate
with nꢀBuBr.
Table 1. Feasibility study of the lithiation
lithiation residence time
HPLC area%
entry
τ (s)
0.24
1a
4a 5a
45.9 51.9 0.0
1.2 95.7 0.3
0.0 96.0 1.1
0.0 92.7 3.5
0.0 90.2 6.0
1
2
3
4
5
0.98
3.93
15.71
31.42
Therefore, the condition for entry 3 was used as the optimized condition for the halogenꢀlithium
exchange reaction at 0 °C, and then further investigation for the borylation was carried out
(Figure 2).
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 21
1
2
3
4
5
6
Figure 2. Setꢀup of the lithiationꢀborylation flow system for (4ꢀ(cyclohexyloxy)phenyl)boronic
acid (3a) synthesis
7
8
9
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
As shown in Figure 2, flow synthesis for boronic acid 3a was achieved in good yield through
minimizing the major side reactions. Crystallization in batch was conducted after flow reaction,
and the boronic acid was isolated as white crystals in 75% yield.
(2) Application of Flow for Diversity Oriented Syntheses of Boronic Acids
The flow chemistry process for 3a was successfully developed at lab scale, and the procedure
was applied to other boronic acid syntheses. The concept for a flow process to boronic acids
starting from arylbromides as raw materials is shown in Figure 3１４, and a summary of the results
obtained after an optimization study on the residence time is shown in Table 2.
8
ACS Paragon Plus Environment

Page 9 of 21
Organic Process Research & Development
1
2
3
4
5
6
Figure 3. Flow chemistry process for boronic acid synthesis
7
8
9
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
For phenyl ether type compounds, the desired boronic acids were obtained in good yield using
a few seconds of residence time for the lithiation (entries 1ꢀ3).
When the bromineꢀlithium exchange reaction was conducted for aryl bromides that included
heteroaromatic rings, surprisingly, the optimized residence time was 0.25 sec, even though more
than two equiv. of nꢀBuLi was required for detaching the bromine atom (entry 4). It is thought
that more than two equiv. of nꢀBuLi were essential for this reaction because one equivalent of
nꢀBuLi was consumed to remove the proton on the Bocꢀprotected nitrogen. Therefore, the
dianion intermediate for the boronic acid synthesis was being effectively utilized. Furthermore,
from the viewpoint of our attempts to generate and control dianions, bromobenzyl alcohol was
also successfully lithiated by utilizing more than two equivalents of nꢀBuLi (entry 5). Although it
was really important to control the residence time to less than 1 sec in entry 4, interestingly, ca.
13 sec was required for converting raw material (1e) to generate the lithiated species (2e).
Moreover, selective halogenꢀlithium exchange reactions were attempted for aryl bromides
including one more halide (entries 6 & 7). When both aryl bromide and benzyl chloride were
coꢀexisting, the bromine atom was converted selectively and the corresponding desired product
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 21
1
2
3
4
5
6
was obtained (3f). Also, a mono selective bromineꢀlithium exchange reaction was achieved for
1,3ꢀdibromobenzene in an excellent yield after borylation (1g).
7
8
9
These applications show that FC can contribute to diversity oriented synthesis for boronic acids
via various unique/unstable/uncontrollable intermediates, furthermore, it is thought that this
technique will be extremely useful in library synthesis.
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
Table 2. Application of a flow chemistry process to diversity oriented synthesis of boronic
acids
10
ACS Paragon Plus Environment

Page 11 of 21
Organic Process Research & Development
1
2
3
4
(3) Scale-up Productions
5
6
7
8
Scaleꢀup production for boronic acids 3a and 3b was conducted. In order to improve
productivity, the concentration of raw materials and the flow rates were increased from the lab
conditions, and due to concern about the reduced capacity for thermal exchange, the reaction
temperature was lowered to ꢀ15 °C. As a result, 0.76 kg of 3a was manufactured in good yield
with an operation time of 2 hours and 25 min for the flow mode (Figure 4). The obtained product
showed good quality and didn't include side products 4a and 5a. Also, 1.55 kg of 3b was
manufactured in an excellent yield and its quality was sufficient to carry out the subsequent
reaction.
9
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
Figure 4. Scale up production for 3
EXPERIMENTAL SECTION
HPLC Method. The HPLC method used for IPC analysis as well as for analyzing the purity of
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 21
1
2
3
4
5
6
7
8
9
boronic acid 3 employed a YMCꢀPack ODSꢀA 150×4.6 mm (Sꢀ5um, 12nm) column maintained
at 25 °C. Acetonitrile (MeCN) was used as Mobile Phase A and a 0.01 M aqueous solution of
KH2PO4 as Mobile Phase B. The total flow rate was set to 1.0 mL/ min, the injection volume was
5.0 ꢁL and detection was carried out at 220 nm. The total method analysis time was 60 min. A
gradient was used starting at 50 % of Mobile Phase A, moving to 80 % over 15 min, eluting at
80 % A for 15 min and then moving back to 50 % over 15 min. The final composition was
maintained for 15 min at 50 % to reꢀequilibrate the column.
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
Compounds 1a, 1b, 1c, 1d, 1e, 1f, 1g, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 4a, 4b, 4d, and 5a eluted at a
relative retention time (RRT) of 32.5 min (1a), 29.2 min (1b), 31.2 min (1c), 8.3 min (1d),
3.6min (1e), 15.0 min (1f), 22.9 min (1g), 6.2 min (3a), 4.7 min (3b), 6.4 min (3c), 2.3 min (3d),
1.7 min (3e), 2.9 min (3f), 3.3 min (3g), 26.4 min (4a), 20.7 min (4b), 4.4 min (4d), and 42.6 min
(5a).
General Lab Scale Experimental Procedure (Flow synthesis of 3a, 3b, 3c, 3e, 3f and 3g,
Table 2). All chemicals were purchased from Wako Pure Chemical Industries and used without
further purification. All solvents used were reagent grade unless otherwise specified. Three
microsyringe pumps (ISIS Ltd., Osaka Japan, Fusion 100) were used to pump the solutions of the
three reagents. Feedstock A consisted of compound 1 (aryl halide) dissolved in THF as a 0.3 M
solution. Feedstock B was commercially available 1.6 M nꢀBuLi in hexane used directly from the
supplied bottle, while feedstock C was a solution of triisopropyl borate (B(OiPr)3) freshly
prepared in anhydrous THF (1.8 M (entry 1), 1.0 M (entry 2), 0.55M (entry 3), 1.5 M (entry 5),
1.0 M (entry 6), 1.74 M (entry 7)). All feedstocks were maintained under an atmosphere of
nitrogen and made up using anhydrous THF. The reactors were fabricated from stainless steel
12
ACS Paragon Plus Environment

Page 13 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(SS) tubing with an internal diameter (ID) of 1 mm and an appropriate length defined by the
desired residence time (τ) and flow rates. The residence time for the lithiation step was adjusted
by utilizing a suitable tube length determined by the total flow rate of Feedstocks A and B.
ShimadzuꢀGLC tee pieces (ID 0.50 mm, part number: 6010ꢀ72357) were used as a mixer for
Feedstocks A and B, and a ShimadzuꢀGLC tee piece (ID 1.0 mm, customꢀmade item) was used as
a mixer for Feedstock C and the resulting solution after lithiation. Investigation of the residence
time for the borylation showed that 1 sec was sufficient for the reaction to go to completion and
longer times were not found to be detrimental.
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
To make sure reactants were sufficiently cooled before mixing, preꢀcooling loops (L = 50 cm,
ID = 1.0 mm) were used, and the reactors for both the lithiation and borylation steps were
submerged into a cooling bath set at 0 °C before initiating the three pumps. Once a steady flow
was attained without blockage (typically after 15 s of continuous operation), the product stream
was diverted to a sampling bottle and analyzed by HPLC.
Scale-up Production
(1)Flow Chemistry Process for Manufacturing
Three diaphragm pumps (TACMINA, TPL1M) were used to pump the solutions of the three
reagents. Feedstock A consisted of compound 1 dissolved in anhydrous THF as a 0.75 M solution
and was pumped at 40.0 mL/ min. Feedstock B was commercially available 1.6 M nꢀBuLi in
hexane used directly from the supplied bottle and pumped at 20.0 mL/ min, while feedstock C
was a 0.55 M solution of B(OiPr)3 freshly prepared in anhydrous THF, pumped at 60.0 mL/ min.
All feedstocks were maintained under an atmosphere of nitrogen. The reactors were fabricated
from SS tubing with an ID of 2.17 mm of an appropriate length defined by the desired residence
time (τ) and flow rates. The residence time for the lithiation step was set to 5 s, which firstly
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 21
1
2
3
4
5
6
7
8
9
resulted in a 318 cm long tube (ID 1.00 mm) and secondly a 67.5cm long tube (ID 1.00 mm)
being used with the above flow rates. ShimadzuꢀGLC tee pieces (ID 1.0 mm, customꢀmade item)
were used as mixers. The preꢀcooling loops (L = 1 m, ID = 2.17 mm) and reactors for both the
lithiation and borylation steps were submerged into a cooling bath set at 0 °C before initiating the
three pumps. The temperature in the plug flow reactors was monitored and maintained at
approximately 0 °C. After a steady flow was attained, as indicated by thermal mass flow meters,
the product stream was collected and the process was run for a total of (a) 2 hrs 25 min to afford
compound 3a in 89.9 % HPLC purity, and (b) 4 hrs 50 min to afford compound 3b in 93.8 %
HPLC purity.
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
(2) Work up Procedure for Isolating 3a
The collected product stream from the FC process was quenched with 1 M HCl aq. (9.04 kg) and
toluene (13.0 kg) to allow for efficient liquidꢀliquid extraction, as compound 3a was found to stay
in the organic phase. The organic layer was then further washed with water (10 kg), and then
concentrated. The resulting residue was dissolved in toluene (1.51 kg), precipitated by nꢀheptane
(4.78 kg), and agitated in an ice bath. The resulting slurry was filtered and washed with
iceꢀcooled nꢀheptane (1.19kg) to afford compound 3a as a white crystalline powder in 79 % yield
(0.76 kg) and 97.4 % purity.
(3) Work up Procedure for Isolating 3b
The collected product stream from the FC process was quenched with 2 M HCl aq. (10.65 kg)
and ethyl acetate (9.23 kg) to allow for efficient liquidꢀliquid extraction, as compound 3b was
found to stay in the organic phase. The organic layer was then further washed with water (10 kg),
and then concentrated. The resulting residue was dissolved in ethyl acetate (1.80 kg), precipitated
14
ACS Paragon Plus Environment

Page 15 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
by nꢀheptane (20.40 kg), and agitated in an ice bath. The resulting slurry was filtered and washed
with iceꢀcooled nꢀheptane (5.0 kg) to afford compound 3b as a white crystalline powder in 84 %
yield (1.55 kg) and 97.0 % purity.
9
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
CONCLUSION
An FC process for boronic acid synthesis utilizing lithiation-borylation was
developed and the usefulness of FC for avoiding side reactions of organolithium
intermediates, for example, (1) protonation by THF solvent, (2) butylation by
n-BuBr
generated from bromine-lithium exchange between aryl bromide and -BuLi, were
n
disclosed. Also, FC was shown to be an effective method for diversity oriented boronic
acid synthesis, with examples of the application of flow flash chemistry. Unstable
intermediates, including dianions, were highly controlled for useful application, and
scale-up production to kg-scale was conducted.
We believe that our results show examples that represent good milestones in the
use of FC processes for the manufacture of pharmaceuticals, agrochemicals, plastics,
and chemicals.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hirotsugu.usutani@takeda.com
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 21
1
2
3
4
ACKNOWLEDGMENTS
5
6
7
8
The authors wish to express their sincere thanks to the Process Chemistry Heads: Hideo
Hashimoto and Quentin McCubbin, as well as the Process Chemistry Osaka Directors: Kenji
Kuroda, Toshihiko Fujitani, Hideya Mizufune, Makoto Yamashita, for all of their valuable
discussions and support throughout the course of this study. The authors also deeply appreciate
the Process Chemistry Osaka Associate Directors: Tadashi Urai, Yoichiro Ishimaru, Koji Mukai,
Makoto Noguchi, Yasushi Shida for their meaningful suggestions, valuable discussions, and
constant encouragement during the period of this work. Furthermore, we wish to recognize the
valuable contribution of Motohiro Urakawa, Misayo Sera, and Takashi Nihei for their supply of
compounds and the supplementary information as well as the cooperation obtained from all the
FC team members. The authors also gratefully acknowledge Toshihiro Fujinaka, Kazunori
Sakamoto, Naoya Oshima, Tomoo Hayamizu of FUJIFILM Wako Pure Chemical Corporation for
their contribution to the scaleꢀup synthesis.
9
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
REFERENCES
１
(a) Fletcher, P. D. I.; Haswell, S. J.; PomboꢀVillar, E.; Warrington, B. H.; Watts, P.; Wong, S.
Y. F.; Zhang, X. Micro reactors: principles and applications in organic synthesis, Tetrahedron,
2002, 58, 4735. (b) KiwiꢀMinsker, L.; Renken, A. Microstructured reactors for catalytic reactions,
Catal. Today 2005, 110, 2. (c) Watts, P.; Haswell, S. J. The application of micro reactors for
organic synthesis, Chem. Soc. Rev. 2005, 34, 235. (d) Geyer, K.; Codee, J. D. C.; Seeberger, P. H.
Microreactors as Tools for Synthetic Chemists—The Chemists' Round‐Bottomed Flask of the
21st Century?, Chem.ꢀEur. J. 2006, 12, 8434. (e) Whitesides, G. The origins and the future of
microfluidics, Nature 2006, 442, 368. (f) deMello, A. J. Control and detection of chemical
16
ACS Paragon Plus Environment

Page 17 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
reactions in microfluidic systems, Nature 2006, 442, 394. (g) Song, H.; Chen, D. L.; Ismagilov, R.
F. Reactions in Droplets in Microfluidic Channels, Angew. Chem., Int. Ed. 2006, 45, 7336. (h)
Kobayashi, J.; Mori, Y.; Kobayashi, S. Multiphase Organic Synthesis in Microchannel Reactors,
Chem. Asian J. 2006, 1, 22. (i) 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. (j) AhmedꢀOmer, B.; Brandtand, J. C.; Wirth, T. Advanced organic
synthesis using microreactor technology, Org. Biomol. Chem. 2007, 5, 733. (k) Watts, P.; Wiles,
C. Recent advances in synthetic micro reaction technology, Chem. Commun. 2007, 443. (l)
Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Adventures in Inner Space: Microflow Systems
for Practical Organic Synthesis, Synlett 2008, 151. (m) Jas, G.; Kirschning, A. Continuous Flow
Techniques in Organic Synthesis, Chem.ꢀEur. J. 2003, 9, 5708. (n) Baxendale, I. R.; Ley, S. V. In
New Avenues to Efficient Chemical Synthesis: Emerging Technologies; Seeberger, P. H., Ed.;
Springer: Berlin, 2007; pp 151ꢀ185. (o) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.;
Smith, C. D. In Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; WileyꢀVCH:
Weinheim, 2008; Chapter 4.2, pp 84ꢀ122.
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
２
(a) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Chemistry in Microstructured Reactors,
Angew. Chem., Int. Ed. 2004, 43, 406. (b) Doku, G. N.; Verboom, W.; Reinhoudt, D. N.; van den
Berg, A. Onꢀmicrochip multiphase chemistry—a review of microreactor design principles and
reagent contacting modes, Tetrahedron 2005, 61, 2733. (c) Yoshida, J. Flash chemistry using
electrochemical method and microsystems, Chem. Commun. 2005, 4509. (d) Broom, T.; Hughes,
M.; Szczepankiewicz, B. G.; Ace, K.; Hagger, B.; Lacking, G.; Chima, R.; Marchbank, G.;
Alford, G.; Evans, P.; Cunningham, C.; Roberts, J. C.; Perni, R. B.; Berry, M.; Rutter, A.;
Watson, S. A. The Synthesis of Bromomethyltrifluoroborates through Continuous Flow
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 21
1
2
3
4
5
6
7
8
9
Chemistry, Org. Process Res. Dev. 2014, 18, 1354. (e) Ouchi, T.; Battilocchio, C.; Hawkins, J.
M.; Ley, S. V. Process Intensification for the Continuous Flow Hydrogenation of Ethyl
Nicotinate, Org. Process Res. Dev. 2014, 18, 1560. (f) Kawaguchi, T.; Miyata, H.; Ataka, K.;
Mae, K.; Yoshida, J. Room‐Temperature Swern Oxidations by Using a Microscale Flow System,
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
Angew. Chem. Int. Ed. 2005, 44, 2413. (g) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous‐
Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients,
Angew. Chem., Int. Ed. 2015, 54, 6688. (h) Teoh, S. K.; Rathi, C.; Sharratt, P. Practical
Assessment Methodology for Converting Fine Chemicals Processes from Batch to Continuous,
Org. Process Res. Dev. 2016, 20, 414. (i) Desai, A. A. Overcoming the Limitations of Lithiation
Chemistry for Organoboron Compounds with Continuous Processing, Angew. Chem., Int. Ed.
2012, 51, 9223. (j) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding Whether To Go with
the Flow: Evaluating the Merits of Flow Reactors for Synthesis, Angew. Chem., Int. Ed. 2011, 50,
7502.
３
(a) Roberge, D. M.; Ducry, L.; Bieler, N.; Cretton, P.; Zimmermann, B. Microreactor
Technology: A Revolution for the Fine Chemical and Pharmaceutical Industries?, Chem. Eng.
Technol. 2005, 28, 318. (b) Roberge, D. M.; Zimmermann, B.; Rainone, F.; Gottsponer, M.;
Eyholzer, M.; Kockmann, N. Microreactor Technology and Continuous Processes in the Fine
Chemical and Pharmaceutical Industry: Is the Revolution Underway?, Org. Process Res. Dev.,
2008, 12, 905.
４
(a) Kobayashi, J.; Mori, Y.; Okamoto, K.; Akiyama, R.; Ueno, M.; Kitamori, T.; Kobayashi, S.
A Microfluidic Device for Conducting GasꢀLiquidꢀSolid Hydrogenation Reactions, Science 2004,
304, 1305. (b) Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the
Synthesis of Pharmaceutical Products, Org. Process Res. Dev. 2016, 20, 2. (c) Ley, S. V.;
18
ACS Paragon Plus Environment

Page 19 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M. Organic Synthesis: March of the Machines,
Angew. Chem. Int. Ed. 2015, 54, 3449. (d) Tsubogo, T.; Oyamada, H.; Kobayashi, S. Multistep
continuousꢀflow synthesis of (R)ꢀ and (S)ꢀrolipram using heterogeneous catalysts, Nature. 2015,
520, 329.
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
５
Usutani, H.; Nihei, H.; Papageorgiou, C. D. ; Cork, D.G. Development and Scaleꢀup of a Flow
Chemistry Lithiation−Borylation Route to a Key Boronic Acid Starting Material, Org. Process
Res. Dev. 2017, 21, 669.
６
Flash Chemistry: Fast Organic Synthesis in Microsystems; Yoshida, J., Ed.; Wiley: New York,
2009.
７
(a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H; Nokami, T. Yoshida, J. Generation
and Reactions of oꢀBromophenyllithium without Benzyne Formation Using a Microreactor, J.
Am. Chem. Soc. 2007, 129, 3046. (b) Nagaki, A.; Kim, H.; Yoshida, J. Aryllithium Compounds
Bearing Alkoxycarbonyl Groups: Generation and Reactions Using a Microflow System, Angew.
Chem., Int. Ed. 2008, 47, 7833. (c) Nagaki, A.; Kim, H.; Yoshida, J. Nitro‐Substituted Aryl
Lithium Compounds in Microreactor Synthesis: Switch between Kinetic and Thermodynamic
Control, Angew. Chem., Int. Ed. 2009, 48, 8063. (d) Nagaki, A.; Kim, H.; Usutani, H.; Matsuo,
C.; Yoshida, J. Generation and reaction of cyanoꢀsubstituted aryllithium compounds using
microreactors, Org. Biomol. Chem. 2010, 8, 1212. (e) Kim, H.; Nagaki, A.; Yoshida, J. A
flowꢀmicroreactor approach to protectingꢀgroupꢀfree synthesis using organolithium compounds,
Nat. Commun. 2011, 2: 264. (f) Kim, H.; Min, K.ꢀI.; Inoue, K.; Im, D. J.; Kim, D.ꢀP.; Yoshida, J.
Submillisecond organic synthesis: Outpacing Fries rearrangement through microfluidic rapid
mixing, Science. 2016, 352, 691.
８
“Organolithiums: Selectivity for Synthesis”; Pergamon, (2002). Edited by Clayden, J.
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 21
1
2
3
4
９
(a) Gilman, H.; Gaj, B. J. Preparation and Stability of Some Organolithium Compounds in
5
6
7
8
9
Tetrahydrofuran, J. Org. Chem., 1957, 22, 1165. (b) Honeycutt, S. Kinetics of the cleavage of
tetrahydrofuran by nꢀbutyllithium in hydrocarbon solvent, J. Organomet. Chem. 1971, 29, 1. (c)
Stanetty, P.; Koller, H.; Mihovilovic, M. Directed ortho lithiation of phenylcarbamic acid
1,1ꢀdimethylethyl ester (NꢀBOCꢀaniline). Revision and improvements, J. Org. Chem., 1992, 57,
6833. (d) Bates, R. E.; Kroposki, L.M.; Potter, D. E. Cycloreversions of anions from
tetrahydrofurans. Convenient synthesis of lithium enolates of aldehydes, J. Org, Chem. 1972, 37,
560.
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
１０
Nagaki, A.; Moriwaki, Y.; Haraki, S.; Kenmoku, A.; Takabayashi, N.; Hayashi, A.; Yoshida, J.
Cross‐Coupling of Aryllithiums with Aryl and Vinyl Halides in Flow Microreactors, Chem.
Asian J. 2012, 7, 1061.
１１
Nagaki, A.; Moriwaki, Y.; Yoshida, J. Flow synthesis of arylboronic esters bearing
electrophilic functional groups and space integration with Suzuki–Miyaura coupling without
intentionally added base, Chem. Commun. 2012, 48, 11211.
１２
(a) Hafner, A.; Meisenbach, M.; Sedelmeier, J. Flow Chemistry on Multigram Scale:
Continuous Synthesis of Boronic Acids within 1 s, Org. Lett. 2016, 18, 3630. (b) Hafner, A.;
Mancino, V.; Meisenbach, M.; Schenkel, B.; Sedelmeier. J. Dichloromethyllithium: Synthesis
and Application in Continuous Flow Mode, Org. Lett. 2017, 19, 786. (c) Hafner, A.; Filipponi, P.;
Piccioni, L.; Meisenbach, M.; Schenkel, B.; Venturoni, F.; Sedelmeier, J. A Simple Scaleꢀup
Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities,
Org. Process Res. Dev. 2016, 20, 1833.
１３
Butylation of unfavorable side reactions in halogen lithium exchanges is discussed in: Nagaki,
A.; Kenmoku, A.; Moriwaki, Y.; Hayashi, A.; Yoshida, J. Cross‐Coupling in a Flow
20
ACS Paragon Plus Environment

Page 21 of 21
Organic Process Research & Development
1
2
3
4
5
6
7
Microreactor: Space Integration of Lithiation and Murahashi Coupling, Angew. Chem. Int. Ed.
2010, 49, 7543.
8
9
１４
The reaction mixtures were quenched by HCl solution directly. The importance of rapid
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
quench reactions was highlighted recently in: Wirth, T. Novel Organic Synthesis through
Ultrafast Chemistry, Angew. Chem., Int. Ed. 2017, 56, 682.
21
ACS Paragon Plus Environment