Rhodium-Catalyzed C6-Selective C-H Borylation of 2-Pyridones

Article abstract of DOI:10.1021/acs.orglett.6b01762

A pyridine-directed, rhodium-catalyzed C6-selective C-H borylation of 2-pyridones with bis(pinacolato)diboron (pinB-Bpin) has been developed. The reaction proceeds smoothly under relatively mild conditions, and the corresponding C6-borylated 2-pyridones are obtained with perfect site selectivity. Subsequent palladium-catalyzed Suzuki-Miyaura cross-coupling is followed by the removal of the pyridine directing group to form the C6-arylated NH-pyridone in an acceptable overall yield.

Full text of DOI:10.1021/acs.orglett.6b01762

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed C6-Selective C−H Borylation of 2‑Pyridones
Wataru Miura, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
*
S Supporting Information
ABSTRACT: A pyridine-directed, rhodium-catalyzed C6-
selective C−H borylation of 2-pyridones with bis(pinacolato)-
diboron (pinB−Bpin) has been developed. The reaction
proceeds smoothly under relatively mild conditions, and the
corresponding C6-borylated 2-pyridones are obtained with
perfect site selectivity. Subsequent palladium-catalyzed Suzu-
ki−Miyaura cross-coupling is followed by the removal of the pyridine directing group to form the C6-arylated NH-pyridone in an
acceptable overall yield.
wing to the ubiquity in pharmaceutical targets and
biologically active natural and unnatural products, the
phenylpyridine, were investigated, but no desired arylated
product was detected as far as we tested (Scheme 1).
1
9
O
development of protocols for the functionalization of a 2-
pyridone ring has received significant attention in organic
synthetic chemistry. While the traditional strategies rely on the
halogenated 2-pyridone as the starting material, recent advances
Scheme 1. Unsuccessful Attempts of Catalytic C6-Selective
C−H Arylation of N-(2-Pyridyl)-2-pyridone (1a)
2
in metal-promoted C−H functionalization allow for the direct
bond-forming reaction without preactivation steps such as
halogenation. However, there are four possible reactive C−H
bonds on the pyridone ring, and thus the control of the site
selectivity is the major challenging issue. To date, the site-
selective C−H alkylation and arylation reactions at the
3
4
relatively electron-rich C5- and C3-positions have been
developed with the aid of transition metal catalysts as well as
the unique nature of radical intermediates. On the other hand,
the selective access to the more electron-deficient C6 position
is still underdeveloped. Nakao and Hiyama reported an elegant
nickel/aluminum cooperative catalysis for the otherwise
difficult C6-selective C−H alkylation and alkenylation of the
Thus, we turned our attention into the corresponding C−H
borylation: given the rich chemistry based on the organoboron
compounds, it can provide a useful synthetic platform for
versatile C6-functionalized 2-pyridones. To our delight, the
reaction of 1a (0.25 mmol) with bis(pinacolato)diboron
(
pinB−Bpin, 0.38 mmol) proceeded in the presence of 2 mol
%
[Ir(OMe)(cod)] , the representative catalyst for the aromatic
5
,6
2
2
-pyridone. Our group also developed the copper-mediated
10
C−H borylation, in refluxing octane, and the C6-borylated 2-
C6-selective C−H heteroarylation with 1,3-azoles by the
pyridone 2a was formed albeit with an 18% NMR yield (Table
introduction of the pyridine-based directing group on the
1
, entry 1). The structure of 2a involving the intramolecular
11
7
nitrogen atom of the 2-pyridone. Since then, some research
1
13
11
N−B coordination was determined by H, C, B NMR,
groups reported the rhodium-catalyzed C−H alkylation and
12
HRMS, and X-ray analysis. To improve the reaction
efficiency, we added several nitrogen-based ligands, which are
well-known to accelerate the iridium-catalyzed C−H boryla-
alkynylation at the C6 position by using the same pyridine-
8
directed strategy. Despite the above-mentioned certain
10,13
progress, there still remains a demand for more diverse direct
functionalization at the C6 position. In this letter, we report a
rhodium-catalyzed C6-selective C−H borylation of 2-pyri-
dones. The resulting C−B moiety can be a useful synthetic
handle for further manipulations. As such an example, the
Suzuki−Miyaura cross-coupling of the borylated pyridone is
also described herein.
tion.
However, they gave negative or negligible impact on
the yield of 2a (entries 2−5). After a brief screening of solvents,
toluene was found to be better, but the yield was still moderate
(entries 6 and 7). Thus, we then tested the alternative
14
[Rh(OMe)(cod)] catalyst. Pleasingly, the full conversion of
2
1a was observed, and the NMR yield of 2a increased to 60%
(entry 8). The rhodium catalyst promoted the reaction even at
lower temperature (entries 9 and 10), and finally the best result
was obtained in THF at room temperature (74% isolated yield;
During our continuous studies on the site-selective C−H
4a−c,7
functionalization of 2-pyridones,
we initially attempted the
catalytic direct arylation of N-(2-pyridyl)-2-pyridone (1a) at the
C6 position. Various transition metal catalysts, particularly
effective for the direct arylation of a structurally similar 2-
Received: June 17, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01762
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization Studies for Catalytic C6-Selective C−
Scheme 2. Catalytic C6-Selective C−H Borylation of Various
a
a
H Borylation of N-(2-Pyridyl)-2-pyridone (1a)
2-Pyridones 1
b
entry
catalyst/ligand
conditions
yield (%)
1
2
3
4
5
6
7
8
9
[Ir(OMe)(cod)] /none
octane, reflux, 4 h
octane, reflux, 4 h
octane, reflux, 4 h
octane, reflux, 4 h
octane, reflux, 4 h
THF, reflux, 4 h
toluene, reflux, 4 h
toluene, reflux, 4 h
toluene, 80 °C, 24 h
toluene, rt, 24 h
THF, rt, 24 h
18
0
2
[Ir(OMe)(cod)] /dtbpy
2
[Ir(OMe)(cod)] /phen
0
2
[Ir(OMe)(cod)] /L1
14
12
15
23
60
40
68
2
[Ir(OMe)(cod)] /L2
2
[Ir(OMe)(cod)] /none
2
[Ir(OMe)(cod)] /none
2
[Rh(OMe)(cod)] /none
2
[Rh(OMe)(cod)] /none
2
1
1
1
1
0
1
2
3
[Rh(OMe)(cod)] /none
2
c
[Rh(OMe)(cod)] /none
(74, 83 )
2
[Rh(OMe)(cod)] /dtbpy
THF, rt, 24 h
0
2
[Rh(OMe)(cod)] /PPh
THF, rt, 24 h
19
2
3
a
Reaction conditions: 1a (0.25 mmol), pinB−Bpin (0.38 mmol),
catalyst (0.0050 mmol), ligand (0.010 mmol), solvent (1.5 mL), N .
2
b
1
c
H NMR yield. Isolated yields are given in parentheses. 2.5 mmol
scale.
a
Reaction stoichiometry: 1 (0.25 mmol), pinB−Bpin (0.38 mmol),
[
Rh(OMe)(cod)] (0.0050 mmol), solvent (1.5 mL). Isolated yields
2
are given. Conditions employed are in parentheses (A−D). Conditions
entry 11). The rhodium-catalyzed C−H borylation could also
be easily performed on a 10-fold larger scale, and 2a was
isolated in 83% yield. As shown in the case of [Ir(OMe)-
A: THF, rt, 24 h. Conditions B: THF, reflux, 4 h. Conditions C: o-
b
xylene, 150 °C, 2 h. Conditions D: THF, 150 °C, μw, 2 h. With
c
[
Ir(OMe)(cod)] instead of [Rh(OMe)(cod)] . With 0.010 mmol of
2
2
(
cod)] , the addition of dative ligands such as dtbpy and PPh3
2
[
Rh(OMe)(cod)]2.
was detrimental (entries 12 and 13). Additionally, simpler 1a-
Me and 1a-Ph gave no borylated products under the rhodium
catalysis, thus indicating the necessity of the coordination
15
ability of the pyridyl group in 1a.
limitation is the inaccessibility to C5-substituted pyridones,
probably due to steric factors (2j). Overall, the reactivity was
highly dependent on the electronic nature of the substituent,
and fine-tuning of the reaction temperature (conditions A−D)
was essential for a satisfactory yield in each case. However,
most borylated products were formed with synthetically useful
yields, and the site selectivity was perfectly controlled.
We next investigated the scope and limitation of the 2-
pyridone. Representative C6-borylated products are shown in
Scheme 2. The rhodium catalysis was compatible with electron-
donating methyl and benzyloxy groups as well as an electron-
withdrawing trifluoromethyl group at the C4 position, and the
corresponding 2b−2d were obtained in good yields. In the
cases of the C3-substituted pyridones, electron-poor substrates
showed better reactivity (2e−2g), although the [Ir(OMe)-
The obtained C6-borylated 2-pyridone 2a could be readily
converted to the corresponding difluoroborane 2a-BF upon
2
(
cod)] catalyst was found to be uniquely effective for the 3-
treatment with KHF in THF/H O (Scheme 3). Notably, even
2
2
2
16
chloropyridone derivative (2g). The electron-rich 3-methyl-
pyridone was reluctant under any tested conditions (2h);
however, modification of the directing group to a more strongly
coordinating 4-methylpyridyl moiety dramatically improved the
reaction efficiency (2h′). This directing group was also
promising for the simple pyridone (2a′). The benzene-fused
isoquinolinone could also be employed for this transformation
to form the desired 2i in an acceptable yield. A current
in the presence of excess fluoride anion, the intramolecular N−
11
B interaction was retained, which was assigned by B NMR as
12
well as X-ray analysis. Moreover, the Pd(OAc) /P[3,5-
2
(CF ) C H ] -catalyzed Suzuki−Miyaura cross-coupling with
3
2
6
3 3
17
iodobenzene was also possible, and the C6-arylated 2-pyridone
18
3a was obtained in 72% isolated yield. The exclusive C6-
arylation was unambiguously confirmed by the crystallographic
12
analysis. Subsequent MeOTf-driven reductive removal of the
B
DOI: 10.1021/acs.orglett.6b01762
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
III
Scheme 3. Derivatization of C6-Borylated 2-Pyridone 2a
formation of 2a and Rh (Bpin)(1a)(H) through reductive
III
elimination, and (iv) regeneration of Rh (Bpin) (1a) by the
metathesis of Rh (Bpin)(1a)(H) with pinB−Bpin (Scheme 4).
2
III
Scheme 4. Plausible Mechanism
pyridine directing group afforded the 6-phenyl-NH-2-pyridone
19
(3a-H) in an acceptable overall yield.
The following control experiments with the deuterium-
labeling pyridone 1b-d6 indicate that the irreversible and
selective C−H cleavage occurs at the C6 position (eq 1) and
The observed negative or negligible effect of the external
ligands (Table 1, entries 2−5, 12, and 13) also suggests that 1a
is the ligand to the rhodium as well as the substrate to be
20a
borylated.
However, an alternative Rh(I)/Rh(III) mecha-
nism cannot be completely excluded, and further efforts are
essential for clarification of the exact mechanism.
In conclusion, we have developed a pyridine-directed,
rhodium-catalyzed C−H borylation of 2-pyridones at the C6
position. To the best of our knowledge, this is the first
successful example of C6-selective direct introduction of the
heteroatom substituent. The formed borylated pyridone can be
a useful synthetic handle for versatile C6-functionalized 2-
pyridones; its capacity is demonstrated by the Suzuki−Miyaura
cross-coupling while still preliminary. Additional transforma-
tions of the borylated products and more detailed mechanistic
studies are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01762.
CIF file of 2a (CIF)
CIF file of 2a-BF (CIF)
2
CIF file of 3a (CIF)
H, C{ H}, B, and F NMR spectra for products and
1
13
1
11
19
this step can be involved in the rate-limiting step (k /k = 3.0,
ORTEP drawings (PDF)
H
D
eq 2). Additionally, two stoichiometric reactions in a ratio of
Rh/pinB−Bpin = 1/1 or 1/2 suggest a tris(boryl)rhodium
AUTHOR INFORMATION
Corresponding Authors
■
*
III
complex [Rh (Bpin) ] to be an active species (eq 3). The
3
20
above findings and literature information can support the
E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
Notes
Rh(III)/Rh(V) redox mechanism involving (i) initial gener-
III
III
ation of Rh (Bpin) (1a) via Rh (Bpin) -promoted C−H
2
3
rhodation of 1a, (ii) the directed oxidative addition of C−H of
a to Rh (Bpin) (1a) forming Rh (Bpin) (1a) (H), (iii)
III
V
1
The authors declare no competing financial interest.
2
2
2
C
DOI: 10.1021/acs.orglett.6b01762
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Reviews: (c) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J.
M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (d) Hartwig, J. F. Chem.
Soc. Rev. 2011, 40, 1992.
ACKNOWLEDGMENTS
■
1
1
This work was supported by JSPS KAKENHI Grant Nos.
5K13696 (Grant-in-Aid for Exploratory Research) and
5H05485 (Grant-in-Aid for Young Scientists (A)) to K.H.
11) For the observation of the N−B interaction by 11B NMR, see:
(
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E. V. J. Am. Chem. Soc. 2006, 128, 1222. (b) Murakami, R.; Tsunoda,
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K.; Iwai, T.; Sawamura, M. Chem. - Eur. J. 2014, 20, 13127.
(
12) Crystallographic data for the structures have been deposited
with the Cambridge Crystallographic Data Center (CCDC 1483627,
483628, and 1483629). See the Supporting Information for details.
13) (a) Larsen, M. A.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136,
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DOI: 10.1021/acs.orglett.6b01762
Org. Lett. XXXX, XXX, XXX−XXX