Synthesis of Biaryls Having a Piperidylmethyl Group Based on Space Integration of Lithiation, Borylation, and Suzuki–Miyaura Coupling

Article abstract of DOI:10.1002/ejoc.201901729

In a flow microreactor, aryllithiums bearing a piperidylmethyl group were generated using nBuLi by precise residence time control and effective temperature control, and then selectively borylated with boronic esters such as 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BpinOiPr) and trimethyl borate B(OMe)₃ by fast mixing. Moreover, the direct integration with Suzuki–Miyaura cross coupling were successfully achieved to obtain nitrogen-containing biaryl compounds. The present method could be applied for the straightforward synthesis of the key intermediate of a bioactive component bearing a piperidylmethyl-biphenyl framework.

Full text of DOI:10.1002/ejoc.201901729

A Journal of
Accepted Article
Title: Synthesis of Biaryls Having a Piperidylmethyl Group Based on
Space Integration of Lithiation, Borylation and Suzuki-Miyaura
Coupling
Authors: Yusuke Takahashi, Yosuke Ashikari, Masahiro Takumi,
Yutaka Shimizu, Yiyuan Jiang, Ryosuke Higuma, Susumu
Ishikawa, Hodaka Sakaue, Ibuki Shite, Kei Maekawa, Yoko
Aizawa, Hiroki Yamashita, Yuya Yonekura, Marco Colella,
Renzo Luisi, Toshihiro Takegawa, Chiemi Fujita, and Aiichiro
Nagaki
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901729
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901729
Supported by

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Biaryls Having a Piperidylmethyl Group Based on
Space Integration of Lithiation, Borylation and Suzuki-Miyaura
Coupling
Dr. Yusuke Takahashi,[a] Dr. Yosuke Ashikari,[a] Masahiro Takumi,[a] Yutaka Shimizu,[a] Yiyuan Jiang,[a]
Ryosuke Higuma,[a] Susumu Ishikawa,[a] Hodaka Sakaue,[a] Ibuki Shite,[a] Dr. Kei Maekawa,[a] Yoko
Aizawa,[a] Hiroki Yamashita,[a] Yuya Yonekura,[a] Marco Colella,[b] Prof. Dr. Renzo Luisi,[b] Toshihiro
Takegawa,[a] Chiemi Fujita,[a] Prof. Dr. Aiichiro Nagaki*[a]
Dedicated to the late Professor Jun-ichi Yoshida
Abstract: In
a
flow microreactor, aryllithiums bearing
a
One route involves two steps: the crosscoupling of aryl halides
and arylboronic esters bearing a formyl group, followed by
reductive amination (Figure 2a).[3] The amination allows
introduction of various amino groups, but a toxic agent such as
NaBH3CN is required, raising concern for the safety. The other
route, Suzuki-Miyaura coupling of an arylboronic esters having
an aminomethyl group, allows biaryl synthesis in one step
without the use of toxic reducing agents (Figure 2b). In general,
however, arylboronic esters should be necessary to be prepared
by the reaction of a Grignard or organolithium reagent with a
trialkyl borate under cryogenic conditions such as -78 °C.
piperidylmethyl group were generated using n-BuLi by precise
residence time control and effective temperature control, and then
selectively borylated with boronic esters such as 2-isopropoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BpinOiPr) and trimethyl
borate B(OMe)3 by fast mixing. Moreover, the direct integration with
Suzuki-Miyaura cross coupling were successfully achieved to obtain
nitrogen-containing biaryl compounds. The present method could be
applied for the straight forward synthesis of the key intermediate of a
bioactive component bearing a piperidylmethyl-biphenyl framework.
(a)
Introduction
OHC
B(OR)2
OHC
Ar
ArX
N
Coupling
Biaryl compounds bearing aminomethyl groups, such as
piperidyl methyl, have attracted much attention because they are
potential bioactive reagents (Figure 1).[1]
Reducing
agent
Ar
N
ArX
(b; this work)
B(OR)2
N
Coupling
Figure 2 Reaction pathways for the synthesis of nitrogen-containing biaryl
N
compounds. Ar: aryl group.
O
N
N
We have already reported that aryllithiums bearing
functional groups such as cyano, nitro, alkoxycarbonyl and
ketone carbonyl group can be rapidly generated and
subsequently reacted with boron compounds[4] in flow
microreactor systems[5-7] by virtue of an extremely short
residence time (flash chemistry[8]).[9] Furthermore, we have
integrated arylboronic ester synthesis and Suzuki-Miyaura
N
N
N
H
N
COOH
dihydroorotate dehydrogenase (DHODH)
inhibitor
amyloid  production inhibitor
NH
O
O
O
N
H
N
coupling.[10]
Therefore,
arylboronic
esters
having
N
N
piperidylmethyl groups could be synthesized effectively at
higher temperature such as 0 oC in a flow microreactor.
Moreover, its integration with Suzuki-Miyaura coupling
successfully produced nitrogen-containing biaryls involving
a key compound of histone deacetylase (HDAC) inhibitory
activity. Herein, we report these results in detail.
O
M3 muscarinic acetylcholine receptor
antagonist
BET bromodomain inhibitor
Figure 1 The nitrogen-containing biaryl compounds.
Biaryls[2] can be synthesized via the two routes shown in figure 2.
[a]
[b]
Department of Synthetic and Biological Chemistry, Graduate School
of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo-
ku, Kyoto 615-8510, Japan.
Results and Discussion
E-mail: anagaki@sbchem.kyoto-u.ac.jp
First, the lithiation of 1-(3-bromobenzyl)piperidine (1) by n-
butyllithium, followed by reaction with methanol was studied in a
conventional batch reactor (Figure 3). The yield of desired
product (3) was moderate even at -60 °C and decreased with
increasing reaction temperature.
URL: http://www.sbchem.kyoto-u.ac.jp/orgsyn-lab/
Department of Pharmacy-Drug Sciences, University of Bari, “A.
Moro”, Via E. Orabona 4, Bari 70125, Italy.
URL: https://www.renzoluisi-lab.com/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
n-BuLi
(1.05 eq)
MeOH
(1.5 eq)
Next, we examined the reactions in a flow microreactor
system consisting of two T-shaped micromixers (M1 and M2)
and two microtube reactors (R1 and R2) (Figure 4). Figure 5
shows the stability and reactivity of lithiated 1-(3-
bromobenzyl)piperidine (2) generated using n-BuLi (Figure 5(a))
and s-BuLi (Figure 5(b)) at various reaction temperatures and
residence times in R1. The values beneath the dots are the 1-
benzylpiperidine (3) yields obtained by trapping 2 with methanol.
As shown in Figure 5 (a), lithiation of 1 proceeded very efficiently
Br
Li
H
N
N
N
THF
THF
T oC, 2 min
T oC, 1 min
1
2
3
59% (T = 0 oC)
76% (T = -60 oC)
Figure 3 Br-Li exchange reaction of 1-(3-bromobenzyl)piperidine (1) with n-
BuLi followed by reaction with methanol using a conventional batch reactor.
o
within the range of T > 0 C and tR1 > 3.1 s. Whereas, at low
temperature and short residence time, the yield of 3 was low
because the conversion of 1 did not progress sufficiently (See
the Supporting Information for details). A similar reaction profile
was obtained for s-BuLi, although the yield decreased slightly
with increasing temperature and residence time.[10] However, n-
BuLi is the preferable lithiating reagent as it is easier to handle.
Borylation, instead of the protonation, also proceeded efficiently
Figure 4 The flow microreactor system used for the lithiation of 1-(3-
bromobenzyl)piperidine (1) by n-BuLi or s-BuLi followed by reaction with
methanol.
o
under optimized conditions (T = 0 C, tR1 = 6.3 s), resulting in
formation of the corresponding arylboronic pinacol ester bearing
piperidylamino group in a good yield, which can be used in a
Suzuki-Miyaura cross-coupling reaction (See the Supporting
Information for details) (Figure 6).
O
O
B
O
O
-BuLi
n
Br
B
(1.05 eq)
(3.0 eq)
O
N
N
tR1 = 6.3 s
tR2 = 4.5 s
1
4
T = 0 o
C
74% (GC yield)
flow microreactor
Generation of lithiated 1-(3-bromobenzyl) piperidine (2)
Figure
6
followed by reaction with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (BpinOiPr) in a flow microreactor.
Next, we tried to develop a more practical method using
easily available boronic ester B(OMe)3 instead of BpinOiPr
and investigated its direct use in a one-flow Suzuki-Miyaura
cross-coupling reaction.[11-12] We have previously reported
that the borylation using trialkyl borate and Suzuki-Miyaura
cross-coupling can be spatially integrated in
a flow
microreactor system. However, in general, when the aryl
boronic ester is synthesized from aryl metal species and
trialkyl borate, it is well known that the reaction efficiency is
lower because borinic acid and triaryl boron are formed
through competitive consecutive reactions.[13] On the other
hand, fast micromixing in
a flow microreactor very
effectively improves the selectivity of the competitive
consecutive reactions.[14]
To investigate the effect of the fast micromixing on the yield of
arylboronic ester, the reaction of lithium intermediates with
B(OMe)3 was carried out using micromixer M2 with an inner
diameter of 1000, 500 or 250 m (Figure 7). The resulting
boronic ester was hydrolysed in a batch reactor, converted to a
more stable arylboronic acid pinacol ester, which was
determined by GC. As shown in figure 8, the narrowest
micromixer gave the greatest yield of 4. The results indicate that
fast mixing in a flow microreactor very effectively supresses
multi-addition and gives high yields of arylboronic esters.
Figure 5 Effects of temperature and residence time in R1 on the yield of the
protonated product (3) from the lithiation of 1-(3-bromobenzyl)piperidine (1)
with (a) n-BuLi and (b) s-BuLi followed by trapping with methanol. The
numbers at the circles are the yields.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
Conclusions
We have developed a method, using a flow microreactor,
of generating aryllithium species bearing piperidylmethyl
groups by precisely controlling temperature and residence
time, followed by the synthesis of arylboronic esters by
reaction with boronic esters. Furthermore, space integration
of borylation with Suzuki-Miyaura cross-coupling reactions
was achieved using an integrated flow microreactor system,
resulting in the key intermediate of a bioactive component
bearing a piperidylmethyl-biphenyl framework.
Figure 7 The flow microreactor system used for the synthesis of arylboronic
ester bearing piperidylmethyl group (4). “Bpin” means pinacolboranyl group.
Experimental Section
General procedure for lithiation of 1-(3-bromobenzyl)piperidine (1)
followed by the reaction with methanol using a flow microreactor
system:
A flow microreactor system consisting of two T-shaped
micromixers (M1 and M2), two microtube reactors (R1 and R2), and
three tube pre-cooling units (P1, P2 and P3 (inner diameter  = 1000 m,
length L = 100 cm)) was used. A solution of 1-(3-bromobenzyl)piperidine
(1, 0.10 M in THF) (flow rate: 6.0 mL/min) and a solution of n-BuLi or s-
BuLi (0.42 M in hexane) (flow rate: 1.5 mL/min) were introduced to M1 by
syringe pumps, and the mixture was passed through R1 ( = 1000 m,
L1 cm). The resulting solution was mixed with methanol (0.30 M in THF)
(flow rate: 3.0 mL/min) in M2. The mixture was passed through R2 ( =
1000 m, L = 100 cm). After a steady state was reached, the product
solution was collected for 30 s while being quenched with sat. aq. NH4Cl
and was analyzed by GC. The conversion of starting material 1 and yield
of product were determined by GC analysis.
Figure 8 The effect of the inner diameter of the micromixer M2 on borylation.
Finally, we demonstrated the space integration of the
borylation and Suzuki-Miyaura cross-coupling to synthesize
a nitrogen-containing biaryl compound using an integrated
flow microreactor system consisting of five micromixers and
five microtube reactors (Figure 9). Nitrogen-containing
biaryl compound (5), previously reported to be a synthetic
intermediate of a compound with histone deacetylase
(HDAC) inhibitory activity, was synthesized by Suzuki-
Miyaura cross-coupling of phenylboronic acid having formyl
Acknowledgments
This work was partially supported by the Grant-in-Aid for
Scientific Research on Innovative Areas 2707 Middle molecular
strategy from MEXT (no. 15H05849), Scientific Research (B) (no.
26288049), Scientific Research (S) (no. 26220804), Scientific
Research (S) (no. 25220913), Scientific Research (C) (no.
17865428), AMED (no. 18ak0101090h), the Japan Science and
Technology Agency’s (JST) A-step program (no. 18067420),
CREST, and the Ogasawara Foundation for the Promotion of
Science & Engineering
groups and aryl iodide (6) (74% yield) followed by reductive
amination with piperidine (85% yield, 2 steps: 63% yield).
[15]
The optimum conditions for the coupling reaction were
as previously described.[11] The generated aryllithium
intermediate was treated with B(OMe)3 at M2 and R2. To
suppress pressure loss, the inner diameter of M2 was set at
500
hydrolyzed at M3 and R3 and then cross-coupled with aryl
iodide ( ) at M5 and R5 using highly reactive Pd catalyst
prepared in M4 and R4.[16] The biaryl compound bearing a
piperidylmethyl group ( ) was quantitatively obtained.
m. The resulting arylboronic acid trimethyl ester was
6
5
Keywords: Borylation • Flow microreactor • Lithiation •
Piperidylmethyl group • Suzuki-Miyaura coupling
[1]
a) B. Budzik, Y. Wang, D. Shi, F. Wang, H. Xie, Z. Wan, C. Zhu, J. J.
Foley, P. Nuthulaganti, L. A. Kallal, H. M. Sarau, D. W. Morrow, M. L.
Moore, R. A. Rivero, M. Palovich, M. Salmon, K. E. Belmonte, D. I.
Laine and J. Jin, Bioorg. Med. Chem. Lett., 2009, 19, 1686; b) R. H.
Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem., 2014, 57,
5845; c) R. Gosmini, V. L. Nguyen, J. Toum, C. Simon, J-M. G. Brusq,
G. Krysa, O. Mirguet, A. M. Riou-Eymard, E. V. Boursier, L. Trottet, P.
Bamborough, H. Clark, C-w. Chung, L. Cutler, E. H. Demont, R. Kaur,
A. J. Lewis, M. B. Schilling, P. E. Soden, S. Taylor, A. L. Walker, M. D.
Walker, R. K. Prinjha and E. Nicodème, J. Med. Chem., 2014, 57,
8111; d) M. Gay, C. Evrard, F. Descamps, P. Carato, N. Renault, M.
Coevoet, S. Eddarkaoui, C. Baud, P-E. Larchanché, L. Buée, J. E.
Figure 9 The integrated flow microreactor system used for the synthesis
of an HDAC inhibitor precursor ( ) by Suzuki-Miyaura cross-coupling.
M1 M2 M3 M4, and M5 are T-shaped micromixers, R1 R2 R3 R4
and R5 are microtube reactors.
5
,
,
,
,
,
,
,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
Bakali, V. Vingtdeux, N. Sergeant and P. Melnyk, Eur. J. Med. Chem.,
2018, 159, 104.
and D. P. Kim, Angew. Chem. Int. Ed. 2013, 52, 6735; Angew. Chem.
2013, 125, 6867; e) C. Brancour, T. Fukuyama, Y. Mukai, T. Skrydstrup
and I. Ryu, Org. Lett. 2013, 15, 2794; f) J. D. Nguyen, B. Reiß, C. Dai
and C. R. J. Stephenson, Chem. Commun. 2013, 49, 4352; g) C.
Battilocchio, J. M. Hawkins and S. V. Ley, Org. Lett. 2013, 15, 2278; h)
A. S. Kleinke and T. F. Jamison, Org. Lett. 2013, 15, 710; i) K. Asano,
Y. Uesugi and J. Yoshida, Org. Lett. 2013, 15, 2398; j) L. Guetzoyan, N.
Nikbin, I. R. Baxendale and S. V. Ley, Chem. Sci. 2013, 4, 764; k) S.
Fuse, Y. Mifune and T. Takahashi, Angew. Chem. Int. Ed. 2014, 53,
851; Angew. Chem. 2014, 126, 870; l) Z. He and T. F. Jamison, Angew.
Chem. Int. Ed. 2014, 53, 3353; Angew. Chem. 2014, 126, 3421; m) A.
Nagaki, Y. Takahashi and J. Yoshida, Chem. Eur. J. 2014, 20, 7931; n)
T. Fukuyama, T. Totoki and I. Ryu, Green Chem. 2014, 16, 2042; o) M.
Chen, S. Ichikawa and S. L. Buchwald, Angew. Chem. Int. Ed. 2015,
54, 263; Angew. Chem. 2015, 127, 265; p) S. Fuse, Y. Mifune, H.
Nakamura and H. Tanaka, Nat. Commun. 2016, 7, 13491; q) A. Nagaki,
Y. Takahashi and J. Yoshida, Angew. Chem. Int. Ed. 2016, 55, 5327;
Angew. Chem. 2016, 128, 5413; r) H. Seo, M. H. Katcher and T. F.
Jamison, Nat. Chem. 2017, 9, 453; s) G. Parisi, M. Colella, S. Monticelli,
G. Romanazzi, W. Holzer, T. Langer, L. Degennaro, V. Pace and R.
Luisi, J. Am. Chem. Soc. 2017, 139, 13648; t) K. Komuro, A. Nagaki, H.
Shimoda, M. Uwamori, J. Yoshida and M. Nakada, Synlett, 2018, 29,
1989; u) H. Kim, Y. Yonekura and J. Yoshida, Angew. Chem. Int. Ed.
2018, 57, 4063; v) K. Tanaka, H. Yoshizawa and M. Atobe, Synlett,
2019, 30, 1194; w) A. Nagaki, H. Yamashita, K. Hirose, Y. Tsuchihashi
and J. Yoshida, Angew. Chem. Int. Ed. 2019, 58, 4027. .
[2]
Some selected recent review: a) G. Dyker, Angew. Chem. Int. Ed. 1999,
38, 1698; b) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev. 2007,
107, 174; c) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev. 2011, 111,
1780; d) J. Magano and J. R. Dunetz, Chem. Rev. 2011, 111, 2177; e)
S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011,
40, 5068; f) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev. 2011,
111, 1417; g) L. Ackermann, Chem. Rev. 2011, 111, 1315; h) F-S. Han,
Chem. Soc. Rev., 2013, 42, 5270.
[3]
Some selected recent examples: a) Y. Kim, H. Park, J. Lee, J. Tae, H. J.
Kim, S-J. Min, H. Rhim and H. Choo, Eur. J. Med. Chem., 2016, 123,
180; b) M. Gay, P. Carato, M. Coevoet, N. Renault, P-E. Larchanché, A.
Barczyk, S. Yous, L. Buée, N. Sergeant and P. Melnyk, Bioorg. Med.
Chem., 2018, 26, 2151; c) L. Tang, C. Huang, J. Zhong, J. He, J. Guo,
M. Liu, J-P. Xu, H-T. Wang and Z-Z. Zhou, Eur. J. Med. Chem., 2019,
168, 221.
[4]
[5]
For review, see: T. Ishiyama, N. Miyaura, J. Organomet. Chem., 2000,
611, 392.
Books on flow microreactor synthesis: a) W.Ehrfeld, V. Hessel and H.
Löwe, Microreactors, Wiley-VCH, Weinheim, 2000; b) V.Hessel, S.
Hardt and H. Löwe, Chemical Micro Process Engineering, Wiely-VCH,
Weinheim, 2004; c) J. Yoshida, Flash Chemistry. Fast Organic
Synthesis in Microsystems, Wiley-Blackwell, Oxford, 2008; d) Micro
Precess Engineering; (Eds.: V. Hessel, A. Renken, J. C. Schouten and
J. Yoshida), Wiley-Blackwell, Oxford, 2009; e) Microreactors in Organic
Chemistry and Catalysis, 2nd ed. (Ed.: T. Wirth), Wiley, Hoboken,
2013; f) Microreactors in Preparative Chemistry (Ed.: W.
Reschetilowski), Wiley-VCH, Weinheim, 2013; g) F. Darvas, V. Hessel
and G. Dorman, Flow Chemistry, DeGruyter: Berlin, 2014; h) J. Yoshida,
Basics of Flow Microreactor Synthesis Springer, Tokyo, 2015; i) Organ-
ometallic Flow Chemistry (Ed.: T. Noël), Springer, Basel, 2016.
Reviews on flow microreactor synthesis: a) P. Watts and S. J. Haswell,
Chem. Soc. Rev., 2005, 34, 235; b) J. Yoshida, A. Nagaki, T. Iwasaki
and S. Suga, Chem. Eng. Technol., 2005, 3, 259; c) K. Geyer, J. D. C.
Codee and P. H. Seeberger, Chem. Eur. J., 2006, 12, 8434; d) G.
Whitesides, Nature, 2006, 442, 368; e) A. J. deMello, Nature, 2006, 442,
394; f) J. Kobayashi, Y. Mori and S. Kobayashi, Chem. Asian J., 2006,
1, 22; g) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan and
D. T. McQuade, Chem. Rev. 2007, 107, 2300; h) B. Ahmed-Omer, J. C.
Brandt and T. Wirth, Org. Biomol. Chem. 2007, 5, 733; i) P. Watts and
C. Wiles, Chem. Commun. 2007, 443; j) T. Fukuyama, M. T. Rahman,
M. Sato and I. Ryu, Synlett 2008, 151; k) W. Lin, Y. Wang, S. Wang
and H. Tseng, Nano Today, 2009, 4, 470; l) K. Geyer, T. Gustafsson
and P. H. Seeberger, Synlett, 2009, 2382; m) R. L. Hartman and K. F.
Jensen, Lab Chip 2009, 9, 2495; n) S. Marrea and K. F. Jensen, Chem.
Soc. Rev., 2010, 39, 1183; o) D. Webb and T. F. Jamison, Chem. Sci.,
2010, 1, 675; p) J. P. McMullen and K. F. Jensen, Annu. Rev. Anal.
Chem. 2010, 3, 19; q) J. Yoshida, H. Kim and A. Nagaki,
ChemSusChem 2011, 4, 331; r) C. Wiles and P. Watts, GreenChem.
2012, 14, 38; s) A. Kirschning, L. Kupracz and J. Hartwig, Chem. Lett.
2012, 41, 562; t) D. T. McQuade and P. H. Seeberger, J. Org. Chem.
2013, 78, 6384; u) K. S. Elvira, X. C. I. Solvas, R. C. R. Wootton and A.
J. deMello, Nat. Chem. 2013, 5, 905; v) J. C. Pastre, D. L. Browne and
S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849; w) I. R. Baxendale, J.
Chem. Technol. Biotechnol. 2013, 88, 519; x) H. P. L. Gem-oets, Y. Su,
M. Shang, V. Hessel, R. Luque and T. Noël, Chem. Soc. Rev. 2016, 45,
83; y) D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel and T.
Noël, Chem. Rev. 2016, 116, 10276; z) M. B. Plutschack, B. Pieber, K.
Gilmore and P. H. Seeberger, Chem. Rev. 2017, 117, 11796.
[8]
a) J. Yoshida, Flash Chemistry. Fast Organic Synthesis in
Microsystems; Wiley-Blackwell, Chichester, United Kingdom, 2008; b) J.
Yoshida, Chem. Commun. 2005, 4509; c) J. Yoshida, A. Nagaki and T.
Yamada, Chem. Eur. J. 2008, 14, 7450; d) J. Yoshida, Chem. Record
2010, 10, 332; e) J. Yoshida, Y. Takahashi and A. Nagaki, Chem.
Commun. 2013, 49, 9896; f) T. Fujita, N. Konno, Y. Watabe, T.
Ichitsuka, A. Nagaki, J. Yoshida and J. Ichikawa, J. Fluorine Chem.
2018, 207, 72; g) Y. Endo, M. Furusawa, T. Shimazaki, Y. Takahashi, Y.
Nakahara and A. Nagaki, Org. Proc. Res. Dev. 2019, 23, 635.
[6]
[9]
a) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami and J.
Yoshida, J. Am. Chem. Soc., 2007, 129, 3047; b) A. Nagaki, E.
Takizawa and J. Yoshida, J. Am. Chem. Soc., 2009, 131, 1654; c) A.
Nagaki, H. Kim, H. Usutani, C. Matsuo, J. Yoshida, Org. Biomol. Chem.,
2010, 8, 1212; d) Y. Tomida, A. Nagaki and J. Yoshida, J. Am. Chem.
Soc., 2011, 133, 3744; e) A. Nagaki, C. Matsuo, S. Kim, K. Saito, A.
Miyazaki and J. Yoshida, Angew. Chem., Int. Ed., 2012, 51, 3245; f) A.
Nagaki, Y. Tsuchihashi, S. Haraki and J. Yoshida, Org. Biomol. Chem.,
2015. 13. 7140; g) H. Kim, K.-I. Min, K. Inoue, D. J. Im, D.-P. Kim and J.
Yoshida, Science, 2016, 352, 691; h) A. Nagaki, Tetrahedron Lett. 2019,
60, 150923; i) A. Nagaki, H. Yamashita, K. Hirose, Y. Tsuchihashi, M.
Takumi and J. Yoshida, Chem. Eur. J. 2019, 25, 13719.
[10] a) G. Barker, P. O’Brien and K. R. Campos, Org. Lett. 2010, 12, 4176;
b) R. Mansueto, V. Mallardo, F. M. Perna, A. Salomone and V. Capriati,
Chem. Commun. 2013, 49, 10160.
[11] A. Nagaki, Y. Moriwaki and J. Yoshida, Chem. Commun. 2012, 48,
11211.
[12] a) A. Nagaki, K. Hirose, Y. Moriwaki, K. Mitamura, K. Matsukawa, N.
Ishizuka and J. Yoshida, Catal. Sci. Technol. 2016, 6, 4690; b) A.
Nagaki, K. Hirose, O. Tonomura, T. Taga, S. Taniguchi, S. Hasebe, N.
Ishizuka and J. Yoshida, Org. Process Res. Dev. 2016, 20, 687; c) O.
Tonomura, S. Taniguchi, K. Nishi, A. Nagaki, K. Hirose, J. Yoshida, N.
Ishizuka and S. Hasebe, Catalysts, 2019, 9, 308; d) A. Nagaki, K.
Hirose, K. Mitamura, K. Matsukawa, N. Ishizuka, T. Yamamoto, M.
Takumi, Y. Takahashi and J. Yoshida, Catalysts, 2019, 9, 300.
[13] V. Hessel, C. Hofmann, H. Löwe, A. Meudt, S. Scherer, F. Schönfeld
and B. Werner, Org. Proc. Res. Dev. 2004, 8, 511.
[7]
Some selected recent examples: a) D. Cantillo, M. Baghbanzadeh and
C. O. Kappe, Angew. Chem. Int. Ed. 2012, 51, 10190; Angew. Chem.
2012, 124, 10337; b) W. Shu and S. L. Buchwald, Angew. Chem. Int.
Ed. 2012, 51, 5355; Angew. Chem. 2012, 124, 5451; c) F. Lévesque
and P. H. Seeberger, Angew. Chem. Int. Ed. 2012, 51, 1706; Angew.
Chem. 2012, 124, 1738; d) K. C. Basavaraju, S. Sharma, R. A. Maurya
[14] a) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae and J. Yoshida, J. Am.
Chem. Soc. 2005, 127, 11666; b) A. Nagaki, N. Takabayashi, Y.
Tomida and J. Yoshida, Org. Lett. 2008, 10, 3937; c) J. Yoshida, A.
Nagaki, T. Iwasaki and S. Suga, Chem. Eng. Technol. 2005, 28, 259; d)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
A. Nagaki, D. Ichinari and J. Yoshida, Chem. Commun. 2013, 49, 3242;
e) A. Nagaki, K. Imai, S. Ishiuchi and J. Yoshida, Angew. Chem. Int. Ed.
2015, 54, 1914; f) A. Nagaki, S. Ishiuchi, K. Imai, K. Sasatsuki, Y.
Nakahara and J. Yoshida, React. Chem. Eng. 2017, 2, 862; g) A.
Nagaki, H. Yamashita, Y. Takahashi, S. Ishiuchi, K. Imai and J.
Yoshida, Chem. Lett. 2018, 47, 71; h) A. Nagaki, K. Sasatsuki, S.
Ishiuchi, N. Miuchi, M. Takumi and J. Yoshida, Chem. Eur. J. 2019, 25,
4946; i) A. Nagaki, Y. Jiang, H. Yamashita, N. Takabayashi and J.
Yoshida, Chem. Eng. Tech. 2019, 42, 2113.
[15] S. K. Anandan, X-Y. Xiao, D. V. Patel and J. S. Ward, Inhibitors of
histone deacetylase, US2005197336, 2005-09-08.
[16] A. Nagaki, N. Takabayashi, Y. Moriwaki and J. Yoshida, Chem. Eur.
J. 2012, 18, 11871.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901729
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A flow microreactor allow for the
generation of aryllithiums bearing a
piperidylmethyl group and then
selectively borylation with boronic
Flow Microreactor
Yusuke Takahashi, Yosuke Ashikari,
Masahiro Takumi, Yutaka Shimizu,
Yiyuan Jiang, Ryosuke Higuma,
Susumu Ishikawa, Hodaka Sakaue,
Ibuki Shite, Kei Maekawa, Yoko
Aizawa, Hiroki Yamashita, Yuya
Yonekura, Marco Colella, Renzo Luisi,
Toshihiro Takegawa, Chiemi Fujita,
Aiichiro Nagaki*
esters.
Moreover,
lithiation,
borylation and Suzuki-Miyaura cross
coupling could be integrated to
obtain nitrogen-containing biaryl
compounds such as
intermediate of a compound with
histone deacetylase (HDAC)
inhibitory activity.
a synthetic
Page No. – Page No.
Synthesis of Biaryls Having
Piperidylmethyl Group Based on
Space Integration of Lithiation,
a
Borylation
Coupling
and
Suzuki-Miyaura
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.