Suzuki-Miyaura cross-coupling reaction of monohalopyridines and L-aspartic acid derivative

Article abstract of DOI:10.1016/j.tetlet.2018.11.038

Suzuki-Miyaura cross-coupling reaction of halogenated pyridines and a borated L-aspartic acid derivative was conducted. The reactivity of chloro-, bromo-, and iodo-pyridines with substituents at the C2, C3, and C4 positions was investigated. Electron dens

Full text of DOI:10.1016/j.tetlet.2018.11.038

Accepted Manuscript
Suzuki-Miyaura cross-coupling reaction of monohalopyridines and L-aspartic
acid derivative
Ayame Mikagi, Dai Tokairin, Toyonobu Usuki
PII:
S0040-4039(18)31366-2
https://doi.org/10.1016/j.tetlet.2018.11.038
TETL 50423
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 October 2018
5 November 2018
13 November 2018
Please cite this article as: Mikagi, A., Tokairin, D., Usuki, T., Suzuki-Miyaura cross-coupling reaction of
monohalopyridines and L-aspartic acid derivative, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.11.038
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Suzuki-Miyaura cross-coupling reaction of
monohalopyridines and L-aspartic acid
derivative
Leave this area blank for abstract info.
Ayame Mikagi, Dai Tokairin, Toyonobu Usuki
4
NHCbz
NHCbz
3
1) K3PO4 aq
+
X
B
CO2tBu
CO2tBu
2
2) 5 mol% Pd(PPh3)4
THF, 50 °C, 2 h
N
N
X = Cl, Br, I
yield: up to quant
DFT calculation
(B3LYP/6-31G*)
experiment: Br>I>>Cl; 3>2, 4
DFT: I>>Br, Cl; 4>2, 3
reactivity

1
Tetrahedron Letters
Suzuki-Miyaura cross-coupling reaction of monohalopyridines and L-aspartic acid
derivative
Ayame Mikagi, Dai Tokairin, and Toyonobu Usuki 
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Suzuki-Miyaura cross-coupling reaction of halogenated pyridines and a borated L-aspartic acid
derivative was conducted. The reactivity of chloro-, bromo-, and iodo-pyridines with
substituents at the C2, C3, and C4 positions was investigated. Electron density of halogenated
pyridines was also estimated by density functional theory (DFT) calculations. The order of
experimental yield of halogen substituents was Br>I>>Cl and C3>C2, C4 whereas the DFT
results indicated the reactivity order as I>>Br, Cl and C4>C2, C3. Optimized experimental
conditions (3-bromopyridine) afforded the coupling product quantitatively.
Available online
Keywords:
Suzuki-Miyaura cross-coupling
monohalopyridine
2009 Elsevier Ltd. All rights reserved.
boronated amino acid
Introduction
In 2014, we reported Negishi cross-coupling reaction between
monohalopyridines and a protected L-aspartic acid.6 The results
Suzuki-Miyaura cross-coupling is a powerful C-C bond-
forming reaction.1,2 Despite its usefulness, few reports exist that
describe Suzuki-Miyaura cross-coupling reaction between
pyridine rings and borated amino acids. Expanding the scope of
the cross-coupling reaction could lead to a practical method for
preparation of naturally occurring pyridinium amino acids, such
as the chronic obstructive pulmonary disease (COPD) biomarkers
desmosine (1) and isodesmosine (2),3-5 as illustrated in Figure 1.
showed that reactivity of the halogen substituents on the pyridine
was in the order of I>Br>>Cl but was not related to the position.6
However, a theoretical explanation of these results has not been
reported nor have other cross-coupling reactions between
pyridine rings and amino acid derivative been investigated. The
present report describes Suzuki-Miyaura cross-coupling reaction
of monohalopyridines and a protected amino acid along with the
optimization of reaction conditions. The effect of halogen
substituents (Cl, Br, I) at different positions (C2, C3, C4) on the
pyridine ring on the reaction was investigated experimentally and
calculationally.
CO2H
CO2H
R1
N
NH2
CO2H
Results and discussion
H2N
H2N
R2
For study of the Suzuki-Miyaura cross-coupling reaction, tert-
butyl-20-(S)-benzyloxycarbonylamino-but-19-enolate (3)7 was
chosen as the amino acid substrate. Segment 3 was synthesized
from commercially available N-carbobenzoxy-L-methionine (S1)
in three steps in overall 19% yield (see Supporting Information).
Optical rotation of synthetic 3 ([]D20 -15.6) was good agreement
NH2
CO2H
desmosine (1): R1 =
R2 = H
20
with reported one ([]D -16.5).7 The olefin segment 3 was
prepared for hydroboration before the coupling reaction.
isodesmosine (2): R1 = H
Reaction conditions of Suzuki-Miyaura cross-coupling
between 2.3 equivalents of borated segment (4) and 3-
bromopyridine (5) were investigated (Table 1). Reactions were
conducted after hydroboration of olefin 3, which was prepared
with 4.6 equivalents of 9-borabicyclo[3.3.1]nonane (9-BBN)
NH2
CO2H
R2 =
Figure 1. Structures of desmosine and isodesmosine.
solution
in
tetrahydrofuran
(THF).8
First,
[1,1’-
———
 Corresponding author. Tel.: +81-3-3238-3446; fax: +81-3-3238-3361; e-mail: t-usuki@sophia.ac.jp

2
Tetrahedron
reactions with 2- and 3-iodopyridines afforded the desired
bis(diphenylphosphino)ferrocene]dichloropalladium
(II)
products (6a, 6b) in moderate yields (57% and 80%,
respectively) (entries 7 and 8, Table 2). 4-Iodopyridine gave the
corresponding product 6c in a low 27% yield (entry 9, Table 2).
Thus, order of reactivity was Br>I>>Cl and C3>C2, C4.
[Pd(dppf)Cl2] or tetrakis(triphenylphosphine)palladium (0)
[Pd(PPh3)4] was used as the catalyst in N,N-dimethylformamide
(DMF) (entries 1 and 2, Table 1).9 Reactions proceeded for 20 h
to afford the coupling product (6b) in 15% and 16% yield,
respectively. These unsatisfying yields might be due to
isomerization of the olefin, caused by DMF. When the solvent
was changed to THF, the yield of 6b improved dramatically to
quantitative (entry 3, Table 1). However, when [1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene](3-
Table 2. Suzuki-Miyaura cross-coupling reaction of 4 and
monohalopyridines 6a-c.
NHCbz
9-BBN
chloropyridyl)palladium (II) dichloride (Pd-PEPPSI-IPr)10 and a
combination of tris(dibenzylideneacetone)dipalladium (0)
[Pd2(dba)3] and tri(2-furyl)phosphine [P(2-furyl)3] were used in
THF, yields were 0% and 51%, respectively (entries 4 and 5,
Table 1). The coupling product 6b could be obtained almost
quantitatively, even if reaction time was shortened to 4 h or 2 h
(entries 6 and 7, Table 1). The yield of entry 6 was the same
using either K3PO4 or K2CO3 as the base (data not shown).
CO2tBu
THF, 50 °C
2.5 h
3
X
NHCbz
CO2tBu
N
B
X = Cl, Br, I
1) K3PO4 aq
2) Pd(PPh3)4
(5 mol%)
4
THF, 50 °C, 2 h
Table 1. Investigation of Suzuki-Miyaura cross-coupling
reaction with 4.
NHCbz
CO2tBu
6a: 2-position
6b: 3-position
6c: 4-position
NHCbz
9-BBN
N
CO2tBu
solvent, 50 °C
2.5 h
3
Entry
Position
X
Cl
Cl
Cl
Br
Br
Br
I
Yield (%)
Br
1
2
3
4
5a
6
7
8
9
2
3
4
2
3
4
2
3
4
0
NHCbz
CO2tBu
0
N
B
5
18
98
Quant
40
57
80
27
1) K3PO4 aq
2) Pd cat., solvent
50 °C, time
4
NHCbz
CO2tBu
I
I
N
6b
a Entry is the same as entry 7 in Table 1
Entry
Solvent
DMF
DMF
THF
Pd cat. (mol %)
Pd(dppf)Cl2
Time (h) Yield (%)
Oxidative addition is often the rate-determining step of a
Suzuki-Miyaura cross-coupling reaction,2 and is affected by C-X
bond energy, the HOMO of the palladium species, and the
LUMO of the halopyridines.11 Studies on the LUMO of
halopyridines was expected to explain the reactivity of the
reaction. Therefore, DFT calculations (B3LYP/6-31G*) were
conducted to compute electron density distributions (Figure 2).
While iodopyridines were significantly different from other
halopyridines, 4-chloropyridine and 4-bromopyridine were only
slightly different. These results suggest that the iodopyridines
were more reactive because oxidative addition to the bond
between pyridine and iodide proceeded easily. Theoretical
considerations indicated that reactivity of halogen substituents on
the pyridine ring was in the order I>>Br, Cl, and reactivity of the
substituent positions was in the order C4>C2, C3. However, the
experimental results suggested that 4-bromopyridine and the
iodopyridines were so reactive that interfering side reactions
inhibited the coupling reactions. In contrast, reaction of 4-
chloropyridine proceeded because of the high reactivity of C4-
substituted pyridines. Negishi cross-coupling reaction between
monohalopyridines and amino acid derivatives demonstrated that
experimental reactivity was in the order I>Br>>Cl.6 The
calculation results were consistent with those of the reported
Negishi cross-coupling reaction.
1
2
3
4
20
20
20
20
15
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
16
Quant
0
THF
Pd-PEPPSI-IPr
(5)
5
THF
Pd2(dba)3 (2.5), 20
P(2-furyl)3(10)
51
6
7
THF
THF
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
4
2
99
Quant
Using the optimized conditions (entry 7, Table 1), reactivity of
different halogenated pyridines with chloro, bromo, and iodo
substituents at the C2, C3, and C4 positions of the pyridine ring
was investigated (Table 2). Cross-coupling reaction with 2- and
3-chloropyridine did not provide the desired products (6a, 6b),
and starting materials were not recovered (entries 1 and 2, Table
2). In contrast, the coupling product (6c) was obtained from 4-
chloropyridine in 18% yield (entry 3, Table 2). Reactions of 2-
and 3-bromopyridines gave the corresponding products (6a, 6b)
in nearly quantitative yields (entries 4 and 5, Table 2). Reaction
with 4-bromopyridine resulted in a lower yield (40%) than those
for 2- and 3-bromopyridines (entry 6, Table 2). In addition,

3
Conclusion
Optimization of Suzuki-Miyaura cross-coupling reactions
between a borated aspartic acid derivative and a pyridine
containing a halogen (Cl, Br, I) at different positions (C2, C3,
C4) on the pyridine ring was investigated. 3-Bromopyridine
produced a quantitative yield of the coupling product, which was
the best yield. Localizations of the LUMO of the
monohalopyridines were also determined using DFT
calculations. The experimental yield was in the order Br>I>>Cl,
C3>C2, C4 whereas the calculated reactivity was in the order of
I>>Br, Cl, and C4>C2, C3. These results will be applied to
additional reactions to obtain more amino acid derivatives
including a pyridine ring.
(a) 2-Halopyridines (left: 2-chloropyridine; center: 2-bromopyridine;
right: 2-iodopyridine)
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number
JP17K01953. We thank Mr. Keisuke Yokoyama (Sophia
University) and Prof. Tamao Saito (Sophia University) for
technical assistance with the biological experiments, and Ms.
Yurika Takaku (Sophia University) and Prof. Shinkoh Nanbu
(Sophia University) for advice about the computational
chemistry. A fellowship from Yoshida Scholarship Foundation
(to A.M.) is gratefully acknowledged.
(b) 3-Halopyridines (left: 3-chloropyridine; center: 3-bromopyridine;
right: 3-iodopyridine)
References and notes
1. Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36,
3437-3440.
2. Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 2001, 40, 4544-4568.
3. (a) Partridge, S. M.; Elsden, D. F.; Thomas, J. Nature 1963, 197,
1297-1298. (b) Thomas, J.; Elsden, D. F.; Partridge, S. M. Nature
1963, 200, 651-652.
4. (a) Ma, S.; Lieberman, S.; Turino, G. M.; Lin, Y. Y. Proc. Natl.
Acad. Sci. USA 2003, 100, 12941-12943. (b) Ma, S.; Turino, G.
M.; Hayashi, T.; Yanuma, H.; Usuki, T.; Lin, Y. Y. Anal.
Biochem. 2013, 440, 158-165.
5. (a) Usuki, T.; Yamada, H.; Hayashi, T.; Yanuma, H.; Koseki, Y.;
Suzuki, N.; Masuyama, Y.; Lin, Y. Y. Chem. Commun. 2012, 48,
3233-3235. (b) Yanuma, H.; Usuki, T. Tetrahedron Lett. 2012, 53,
5920-5922. (c) Usuki, T.; Sugimura, T.; Komatsu, A.; Koseki, Y.
Org. Lett. 2014, 16, 1672-1675. (d) Sugimura, T.; Komatsu, A.;
Koseki, Y.; Usuki, T. Tetrahedron Lett. 2014, 55, 6343-6346. (e)
Suzuki, R.; Yanuma, H.; Hayashi, T.; Yamada, H.; Usuki, T.
Tetrahedron 2015, 71, 1851-1862. (f) Koseki, Y.; Sugimura, T.;
Ogawa, K.; Suzuki, R.; Yamada, H.; Suzuki, N.; Masuyama, Y.;
Lin, Y. Y.; Usuki, T. Eur. J. Org. Chem. 2015, 2015, 4024-4032.
6. Usuki, T.; Yanuma, H.; Hayashi, T.; Yamada, H.; Suzuki, N.;
Masuyama, Y. J. Heterocycl. Chem. 2014, 51, 269-273.
7. Tashiro, T.; Fushiya, S.; Nozoe, S. Chem. Pharm. Bull. 1988, 36,
893-901.
(c) 4-Halopyridines (left: 4-chloropyridine; center: 4-bromopyridine;
right: 4-iodopyridine)
Figure 2. LUMO maps of monohalopyridines. Compounds (from
left to right) are chloropyridines (yellow), bromopyridines (red),
and iodopyridines (blue). Blue areas indicate localization of
LUMO, resulting in easier oxidative addition.
The antimicrobacterial activities of the coupling product (6b)
and free amino acid (7) against Escherichia coli b/r and Bacillus
subtilis were assessed using the disc diffusion method. Amino
acid 7 was prepared from 6b in two steps (Scheme 1). Both
products were dissolved in 1% aq. dimethyl sulfoxide (DMSO)
and each disc was loaded with 0.1 mg of the compound. A 1%
DMSO solution and 0.1 mg/disc concentration of ampicillin were
used as controls. The minimal inhibitory concentration (MIC)
assay of the products (6b, 7) was conducted. However, the
compounds did not have significant activity against either
bacteria (>0.4 mg/mL).
8. Guo, L.; Hshiao, C-C.; Yue, H.; Liu, X.; Rueping, M. ACS Catal.
2016, 6, 4438-4442.
9. (a) Laulhé, S.; Blackbrun, J. M.; Roizen, J. L. Org. Lett. 2016, 18,
4440-4443. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M.
J. Am. Chem. Soc. 2002, 124, 14983-14992.
NHCbz
CO2tBu
1) Pd/C (5 mol%), H2
HCl aq, rt, 2 h, 77%
10. Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org.
Chem. 2010, 23, 4343-4354.
2) TFA/H2O (95:5)
rt, 2.5 h, 38%
11. Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk,
K. N. J. Am. Chem. Soc. 2009, 131, 6632-6639.
N
6b
Supplementary Material
NH2
CO2H
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/...
N
7
Scheme 1. Preparation of 7.
Click here to remove instruction text...

4
Tetrahedron
Highlights




Suzuki-Miyaura coupling of halopyridines and
boronated amino acid was conducted.
Protected boronated L-aspartic acid was
prepared from protected L-methionine.
The reaction proceeded quantitatively when
using 3-bromopyridine.
Electron density of monohalopyridines was
estimated by DFT calculations.