Nickel-Catalyzed Directed C6-Selective C-H Alkylation of 2-Pyridones with Dienes and Activated Alkenes

Article abstract of DOI:10.1021/acs.joc.7b00682

A pyridine-directed, C6-selective nickel-catalyzed ring-contracting C-H alkylation of 2-pyridones with 1,5-cyclooctadiene (cod) has been developed. The reaction proceeds smoothly under external-ligand-free conditions and is accelerated uniquely by a K₃PO₄ base. Preliminary mechanistic investigations with deuterium-labeled substrates and related reactions with some alkenes are also disclosed.

Full text of DOI:10.1021/acs.joc.7b00682

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Article
Nickel-Catalyzed Directed C6-Selective C–H Alkylation
of 2-Pyridones with Dienes and Activated Alkenes
Wataru Miura, Koji Hirano, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2017
Downloaded from http://pubs.acs.org on April 27, 2017
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Nickel-Catalyzed Directed C6-Selective C–H Alkylation
of 2-Pyridones with Dienes and Activated Alkenes
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Wataru Miura, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka
565-0871, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
A pyridine-directed, C6-selective nickel-catalyzed ring-contracting C–H alkylation of 2-pyridones with
1,5-cyclooctadiene (cod) has been developed.
The reaction proceeds smoothly under
external-ligand-free conditions and is accelerated uniquely by a K3PO4 base. Preliminary mechanistic
investigation with deuterium-labeling substrates and related reactions with some alkenes are also
disclosed.
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Introduction
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A 2-pyridone is one of representative six-membered nitrogen-containing heterocycles, and its nucleus
is widely found in natural products, pharmaceutical targets, and biologically active compounds. Such
well-known compounds include ciclopirox, milrinone, camptothecin, fredericamycin, perampanel, and
cytisine.1 Thus, synthetic chemists have developed many synthetic methodologies for the preparation
and functionalization of 2-pyridone ring. While conventional strategies largely rely on the preactivated
starting substrates such as halogenated 2-pyridones, recent advances in metal-mediated C–H activation2
can provide a potentially more efficient approach to densely functionalized pyridones from the
relatively simple starting molecules. The pyridone has four reactive C–Hs (C3, C4, C5, and C6
positions), and thus control of site selectivity is the most important and challenging issue in the C–H
functionalization of 2-pyridone. Radical-promoted C3-selective functionalization was independently
developed by our group and Maiti (Scheme 1a). In the presence of Ni,3 Mn,4 Fe,5 or Ir6 salt,
C3-alkylated and arylated 2-pyridones were obtained with high site-selectivity. More recently, an
O2-mediated similar reaction with arylhydrazines was also reported.7 Access to the C4 position still
remains underdeveloped, but C–H borylation is possible when the C6 position is blocked by suitable
substituents (Scheme 1b).8 The Pd-mediated C–H alkenylation at the most electron-rich C5 position
was first reported by Ouseto and Itahara in 1984,9 and about 30 years later the catalytic variant was
developed by Li10 (Scheme 1c). The same research group also found the Pd-catalyzed direct arylation
with polyfluoroarenes. Although the C–H functionalization at the electron-deficient C6 position was
relatively difficult, Nakao and Hiyama overcame such innate electronic biases and achieved
C6-selective alkylation and arylation under elegantly designed Ni/Al cooperative catalysis11 (Scheme
1d). Our research group also introduced a pyridine-based directing group strategy and succeeded in
the Cu- and Rh-catalyzed C–H heteroarylation12 and borylation13 at the C6 position. Subsequently,
several groups reported related catalytic C6-selective alkylation, alkynylation, arylation, and thiolation
by using the same directing group strategy.14 During our continuous studies on the pyridine-directed
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C6-selective functionalization, we have serendipitously found an Ni-catalyzed ring-contracting
alkylation with 1,5-cyclooctadiene (cod; Scheme 2). The reaction proceeds smoothly under
external-ligand-free conditions and is accelerated uniquely by a K3PO4 base. Preliminary mechanistic
investigation with deuterium-labeling substrates and related reactions with some alkenes are also
reported herein.
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Scheme 1. Site-Selective C–H Functionalization of 2-Pyridones
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Scheme 2. Ni-Catalyzed C6-Selective C–H Alkylation of 2-Pyridones with Dienes and Alkenes
(This Work)
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Results and Discussion
We initially attempted a Ni(cod)2-catalyzed directed C–H arylation of 2-pyridone 1a with PhB(OH)2
in the presence of Cs2CO3/MeOH and cyclohexene as basic additives and oxidant, respectively (Scheme
3). Unfortunately, the desired phenylated product was not detected at all, but we serendipitously
detected a small amount of C6-alkylated pyridone 2a, which apparently arose from the cod ligand in
Ni(cod)2 catalyst. Additionally, the unique ring contraction of cod unit concomitantly occurred. The
structure of 2a was first assigned by NMR and HRMS, and finally determined by X-ray crystallographic
analysis of the major diastereomer after dibromination with dibromohydantoin.15
Such a
ring-contracting coupling with cod is not trivial.16 Thus, the preliminary but intriguing result in
Scheme 3 prompted us to optimize conditions for the unique catalytic C–H alkylation of 2-pyridone
with cod as a coupling partner (Table 1). Initial additive screening (entries 1–4) revealed that neither
PhB(OH)2 nor MeOH were necessary but Cs2CO3 played a pivotal role in this reaction. Thus, we then
tested various inorganic and organic bases (entries 5–10). Several inorganic bases accelerated the
reaction, with K3PO4 proving to be optimal (entry 5). Finally, with 20 mol % loading of Ni(cod)2, 2a
was obtained in 64% yield (entry 11). Some additional observations are to be noted: addition of
external ligands such as pyridine, lutidine, dppe, and IPr•HCl gave negligible or negative impact on the
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reaction efficiency as far as we tested. The corresponding N-Me- and N-Ph-2-pyridones did not react
with cod at all, thus suggesting the indispensable coordinating ability of pyridine moiety in 1a. No
reaction of N-Me-2-pyridone occurred even under Ni(cod)2/IPr/MAD (MAD = methylaluminum
bis(2,6-di-tert-butyl-4-methylphenoxide)) cooperative catalysis reported by Nakao and Hiyama.11b
The observed reactivity was unique to the pyridone, and structurally similar 2-phenylpyridine gave no
coupling products under conditions identical to entry 11 in Table 1.
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Scheme 3. Initial Finding
Ni(cod)2 (10 mol %)
Cs2CO3 (2.0 equiv)
MeOH (3.0 equiv)
cyclohexene (2.0 equiv)
H
+
(HO)2B Ph
(0.50 mmol)
O
N
Ph
O
N
O
N
1,4-dioxane, 110 ˚C, 4 h
Py
Py
Py
H
not detected
1a (0.25 mmol)
2a 6% (GC yield)
76:24 dr
Br
O
N
O
Br
Br
H
N
Br
O
N
MeCN, 100 ˚C, 2 h
52%
Py
H
2a-Br2
crystal structure of 2a-Br2
Table 1. Optimization Studies for Nickel-Catalyzed Ring-Contracting C–H Alkylation of
2-Pyridone 1a with 1,5-Cyclooctadiene (cod)a
entry
1
additives (mmol)
none
2a, NMR yield (%)b
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PhB(OH)2 (0.50)
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MeOH (0.75)
Cs2CO3 (0.50)
K3PO4 (0.50)
K2CO3 (0.50)
KOAc (0.50)
LiO-t-Bu (0.50)
NaO-t-Bu (0.50)
Et3N (0.50)
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11c
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K3PO4 (0.50)
81 (64)
a Reaction conditions: 1a (0.25 mmol), cod (0.50 mmol), Ni(cod)2 (0.025 mmol), additives, 1,4-dioxane
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(1.5 mL), N2.
NMR yield was calculated with dibenzyl ether as an internal standard. Yield is in
c
parentheses. The product 2a was generally obtained as a 76:24 mixture of diastereomers.
With 20
mol % of Ni(cod)2 (0.050 mmol). Py = 2-pyridyl.
With promising conditions in hand, we investigated the scope of 2-pyridone 1 (Scheme 4).
Electron-withdrawing CF3 group at the C3 and C4 positions was tolerated, and the corresponding
alkylated products 2b and 2c were obtained in 68% and 83% yields, respectively. The ester
functionality was also accommodated under the standard conditions to deliver 2d in a synthetically
useful yield. On the other hand, the pyridone bearing an electron-donating benzyloxy substituent
showed moderate reactivity (2e). As observed in our previous work,12,13 the present catalysis was
sensitive to steric factors: the C5-substituted pyridones did not couple with cod. The introduction of
methyl substituent also suppressed the reaction while we have no explanation for the reason at present.
The halogenated pyridones were reluctant substrates and a small but significant amount of
dehalogenated starting pyridones were detectedbecause of the competitive oxidative addition of
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C-halogen bond to low-valent Ni center; however, the latent halogenation could be possible as shown in
Scheme 3, which can be a synthetic handle for further manipulations. Notably, the 4-methylpyridyl
directing group was found to somewhat improve the reaction efficiency, and the desired alkylated
product 2f was formed in 90% yield even with 10 mol % catalyst loading.17
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Scheme 4. Nickel-Catalyzed Ring-Contracting C–H Alkylation of Various 2-Pyridones 1 with
1,5-Cyclooctadiene (cod)a
a
Reaction conditions: 1 (0.25 mmol), cod (0.50 mmol), K3PO4 (0.50 mmol), 1,4-dioxane (1.5 mL),
N2, 110 ˚C, 4 h. All products 2 were obtained as ca. 80:20 mixture of diastereomers. b 1H NMR
yield. c With 10 mo % of Ni(cod)2 (0.025 mmol).
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The reactivity of some dienes and alkenes were also investigated (Scheme 5). In addition to cod
(1,5-diene), 1,4- and 1,3-dienes also reacted with 1a under identical conditions (Scheme 5a). The
former afforded a mixture of ring-forming (3) and simple addition products (3’ and 3”), but each
product could be easily separated and a combined yield was also good (84%). No double addition
product was detected; chemoselectivity of which is completely different from that of the reported Ni/Al
catalysis.11b On the other hand, the latter formed the simple linear adduct 4 exclusively. However,
conjugated 1,3-diene, 1,6-diene that bears longer methylene tether, and simple aliphatic terminal alkene
did not give any detectable amount of coupling products. Several strained alkenes were also reactive,
and norbornadiene and norbornene furnished the corresponding exo-adducts 5 and 6 in good yields
(Scheme 5b). The structure of 5 was unambiguously confirmed by X-ray analysis.15 Notably, in the
case of norbornene, the addition of K3PO4 was not necessary. Additionally, electronically activated
styrene coupled with 1a to produce the branched adduct 7 selectively, where the positive effect of H2O
(4.0 equiv) was observed (Scheme 5c). In all cases, a small amount of cod-coupled 2a was observed,
but it could be readily separated from the desired product by column chromatography.
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Scheme 5. Nickel-Catalyzed C–H Alkylation of 2-Pyridone 1a with Several Dienes and Alkenes
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a) Reaction with 1,n-dienes
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7
Ni(cod)2 (10 mol %)
K3PO4 (2.0 equiv)
O
N
+
1,4-dioxane, 110 ˚C, 4 h
Py
8
9
1a (0.25 mmol)
(0.50 mmol)
+
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+
O
N
O
N
O
N
Py
Py
Py
3' 14%
3 28%
3" 42%
Ni(cod)2 (10 mol %)
K3PO4 (2.0 equiv)
O
N
+
O
N
1,4-dioxane, 110 ˚C, 4 h
Py
1a (0.25 mmol)
Py
(0.50 mmol)
4 54%
unsuccessful substrates (<2% product)
b) Reaction with strained alkenes
Ni(cod)2 (10 mol %)
K3PO4 (1.0 equiv)
O
N
+
1,4-dioxane, 110 ˚C, 4 h
Py
1a (0.25 mmol)
(0.50 mmol)
O
N
Py
5 67%
crystal structure of 5
Ni(cod)2 (20 mol %)
O
N
+
O
N
1,4-dioxane, 110 ˚C, 4 h
Py
Py
1a (0.25 mmol)
(0.50 mmol)
6 78%
c) Reaction with styrene
Ni(cod)2 (20 mol %)
K3PO4 (2.0 equiv)
H2O (4.0 equiv)
Ph
Ph
O
N
O
N
+
1,4-dioxane, 110 ˚C, 4 h
Py
7 70% (49% w/o H2O)
Py
1a (0.25 mmol)
(0.50 mmol)
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To get mechanistic insight, several control experiments with deuterium-labeled 1a-d1 (90–95% D) and
styrene-d8 (>99% D) were performed (Scheme 6). In the absence or presence of styrene, the deuterium
content of recovered 1a-d1 decreased considerably (eqs 1 and 2). Additionally, in the latter case the
recovered styrene18 as well as alkylated product 7 was partially deuterated (eq 2). Also in the reaction
of 1a with styrene-d8, the deuterium incorporation into alkylated product 7 was observed whereas some
deuteriums were distributed to the recovered 1a and the remaining styrene partially lost the deuterium
(eq 3). Additionally notable is that the addition of K3PO4 showed negligible effect on the H/D
exchange of 1a-d1 (eq 1).19
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Scheme 6. Deuterium-Labeling Experiments
On the basis of our findings and literature information, we propose the reaction mechanism of 1a with
styrene as shown in Scheme 7. The starting Ni(cod)2 initially undergoes the ligand exchange with 1a20
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and styrene to form a tricoordinated Ni σ-complex 8 including the pyridone C–H at the C6 position.
Subsequent concerted proton transfer occurs (8 to 9), in which one C–H is cleaved and two C–Ni bonds
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6
are formed.21
The resulting σ-benzyl Ni intermediate 9 is in equilibrium with more
7
8
9
thermodynamically stable π-benzyl Ni 9’.22 Productive reductive elimination and coordination of
another 1a generates the product-containing complex 10. Final ligand exchange with additional
styrene releases the alkylated pyridone 7 to close the catalytic cycle. The results of deuterium-labeling
experiments in Scheme 6 suggest that the proton transfer process (8 to 9) is facile and reversible, and
reductive elimination (9 to 10) is the irreversible rate-determining step. Although the exact role of
K3PO4 is not clear at this stage, it can work as an additional anionic ligand to Ni23 and accelerate the
rate-limiting reductive elimination.
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Given the reactivity trend of alkenes observed in Scheme 5, suitable binding nature to Ni center is
essential for the successful reaction: highly strained norbornadienes and norbornene and moderately
electronically activated styrene meet such a demand. In the case of 1,n-dienes, their bidentate
coordination ability can be a major driving force.24 However, the reaction pattern is dependent on the
tether length; particularly, cod might be more tightly coordinated to Ni and second olefin moiety
undergoes insertion into the alkyl–Ni bond of intermediate 11 following the proton transfer process
(Scheme 8).
Scheme 7. Plausible Mechanism for Reaction of 1a with Styrene
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Scheme 8. Proposed Pathway in Reaction of 1a with cod
Conclusion
We have developed a pyridine-directed, Ni-catalyzed C6-selective C–H alkylation of 2-pyridones with
dienes and alkenes. The reaction proceeds under external-ligand-free conditions and is uniquely
accelerated by the addition of K3PO4 base. Additionally, a non-trivial ring-contracting coupling with
cod is observed. The Ni catalysis can provide additional access to relatively challenging C–H at the
C6 position of 2-pyridone ring. Moreover, this is a rare example of Ni-catalyzed sp2 C–H
functionalizations by using monodentate directing groups.25
Experimental Section
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Instrumentation and Chemicals 1H, 13C{1H}, and 19F{1H} NMR spectra were recorded at 400,
1
2
3
100, 376 MHz, respectively, for CDCl3 or DMSO-d6 solutions. Note: products 2, 3”, 5, and 6
4
5
1
contained rotamers associated with the C–N axis, and thus H and 13C{1H} NMR analysis of 2a, 5, and
6
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9
6 were performed in DMSO-d6 at higher temperature. HRMS data were obtained by APCI using TOF.
GC analysis was carried out using a silicon OV-17 column (2.6 mm i.d. x 1.5 m) or a CBP-1 capillary
column (0.5 mm i.d. x 25 m). TLC analyses were performed on commercial glass plates bearing a
0.25 mm layer of Merck silica gel 60F254. Silica gel was used for column chromatography. Gel
permeation chromatography (GPC) was performed with a CHCl3 or an ethyl acetate eluent (UV
detector). Unless otherwise noted, materials obtained from commercial suppliers were used as
received. 1,4-Dioxane was dried on a Glass Contour Solvent dispensing system (Nikko Hansen & Co.,
Ltd.) prior to use. The starting pyridones 1 were prepared according to the reported procedure.12 The
diastereomeric ratios of 2a, 2b, 2c, 2d, and 2a-Br2 were assigned by 1H or 19F NMR spectrum. On the
other hand, we could not determine the isomeric ratio of 2f.
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Preparation of 1a-d1. 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-[1,2'-bipyridin]-2-one
(343 mg, 1.2 mmol) prepared by our previous method13 and Cs2CO3 (562 mg, 1.7 mmol) were place in a
50 mL two-necked reaction flask, which was filled with nitrogen by using the standard Schlenk
technique. THF (6.0 mL) and D2O (0.62 mL, 35 mmol) were injected via a syringe, and the mixture
was stirred for 24 h at 40 R. The resulting mixture was allowed to cool to room temperature and then
quenched with water. The mixture was extracted with EtOAc three times. The combined organic
layer was dried over anhydrous Na2SO4. After concentration under reduced pressure, GPC purification
with EtOAc eluent afforded 6-deuterio-2H-[1,2'-bipyridin]-2-one (1a-d1; 115 mg, 0.66 mmol, 90-95%
D) in 58% yield.
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Typical Procedure for Ni-Catalyzed Alkylation of 2-Pyridones. The synthesis of 2a is
representative (Scheme 4). In a glovebox filled with nitrogen, 2H-[1,2’-bipyridine]-2-one (1a; 43 mg,
0.25 mmol), K3PO4 (106 mg, 0.50 mmol), and Ni(cod)2 (14 mg, 0.050 mmol) were placed in a Schlenk
flask. The flask was then sealed with a septum and taken out of the glovebox. 1,5-Cyclooctadiene
(cod; 61 µL, 0.50 mmol) and 1,4-dioxane (1.5 mL) were sequentially injected via a syringe. The
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mixture was stirred for 4 h at 110 C. The resulting mixture was allowed to cool to room temperature
and then quenched with water. The mixture was extracted with EtOAc three times. The combined
organic layer was dried over anhydrous Na2SO4. After concentration under reduced pressure, silica gel
column purification with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) followed by GPC with CHCl3 eluent
afforded a 76:24 diastereomixture of 6-(octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one (2a; 45 mg,
0.16 mmol) in 64% yield.
A 76:24 diastereomixture of 6-((3aR*,6aR*)-octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one
(2a). Purified by column chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an
o
1
eluent followed by GPC (CHCl3); 45 mg (64%), white solid; mp 93.1-95.1 C (from CDCl3); H NMR
(400 MHz, DMSO-d6 at 60 ℃): δ 0.63 (br, 0.24×2H), 0.93-2.46 (m, 11H), 3.15-3.18 (m, 1.52H), 6.27
(dd, J = 1.0, 6.9 Hz, 0.24×1H), 6.29-6.34 (m, 0.24×1H and 0.76×2H), 7.43-7.54 (m, 0.76×3H and
0.24×3H), 8.01 (m, 0.76×1H and 0.24×1H), 8.63 (dd, J = 1.0, 5.0 Hz, 0.76×1H and 0.24×1H).
13C{1H} NMR (100 MHz, DMSO-d6 at 60 ℃): δ 23.7, 24.8, 25.0, 26.3, 26.4, 31.6, 31.7, 32.8, 32.9,
34.0, 34.69, 34.71, 41.3, 42.4, 48.3, 50.4, 101.7, 102.2, 116.9, 117.2, 123.8, 123.9, 124.2, 124.3, 138.3,
138.4, 140.3, 140.5, 148.9, 149.1, 151.7, 151.8, 152.7, 154.1, 162.3, 162.4. HRMS (APCI) m/z
([M+H]+) calcd for C18H21N2O 281.1648, found 281.1653.
An
82:18
diastereomixture
of
6-((3aR*,6aR*)-octahydropentalen-1-yl)-3-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one
(2b).
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Purified by column chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an
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3
1
eluent; 59 mg (68%), oil; H and 13C NMR spectra of 2b are complicated by the presence of
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5
1
diastereomers and rotamers associated with the C-N axis. Thus, all observed signals are described. H
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8
9
NMR (400 MHz, CDCl3): δ 0.54-1.12 (m, 2H), 1.16-1.44 (m, 4H), 1.57-1.71 (m, 3H), 1.98-2.19 (m,
2H), 2.46-2.63 (m, 2H), 6.26-6.30 (m, 1H), 7.34-7.39 (m, 1H), 7.42-7.46 (m, 1H), 7.75-7.79 (m, 1H),
7.90-7.94 (m, 1H), 8.68 (d, J = 3.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 25.6, 27.0, 32.5, 32.8,
33.5, 33.6, 33.7, 34.6, 34.78, 34.81, 34.85, 35.5, 35.6, 39.6, 40.4, 42.0, 42.1, 43.3, 43.5, 49.0, 49.7, 50.9,
51.9, 101.3, 101.9, 122.92 (q, J = 269.8 Hz), 122.95 (q, J = 269.7 Hz), 124.1, 124.4, 124.5, 138.5, 138.7
(q, J = 2.5 Hz), 139.5 (q, J = 4.3 Hz), 149.8, 150.1, 151.0, 151.2, 158.4, 159.8, 160.0. 19F{1H} NMR
(376 MHz, CDCl3): δ -65.63, -65.58. HRMS (APCI) m/z ([M+H]+) calcd for C19H20F3N2O 349.1522 ,
found 349.1529.
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A
72:28
diastereomixture
of
6-((3aR*,6aR*)-octahydropentalen-1-yl)-4-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one (2c). Purified
by column chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent; 72 mg
o
13
(83%), brown solid; mp 93.8-95.8 C (from CDCl3); C NMR spectrum of 2c is complicated by the
presence of diastereomers and rotamers associated with the C-N axis. Thus, all observed signals are
1
described. H NMR (400 MHz, CDCl3): δ 0.54-2.18 (m, 11H), 2.46-2.64 (m, 2H), 6.30 (d, J = 1.8 Hz,
0.28×1H), 6.32 (d, J = 1.7 Hz, 0.72×1H), 6.78 (d, J = 1.7 Hz, 0.72×1H), 6.80 (d, J = 1.8 Hz, 0.28×
1H), 7.31-7.38 (m, 1H), 7.43-7.48 (m, 1H), 7.94 (ddd, J = 1.9, 7.7, 7.7 Hz, 1H), 8.69 (dd, J = 1.9, 4.2
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 25.5, 26.9, 32.4, 32.8, 33.4, 33.50, 33.53, 33.6, 34.6,
34.8, 35.5, 35.6, 39.6, 40.2, 41.8, 42.0, 43.1, 43.4, 48.9, 49.6, 50.9, 51.7, 98.0 (q, J = 12.2 Hz), 98.5 (q, J
= 10.3 Hz), 115.5 (q, J = 3.7 Hz), 115.9 (q, J = 4.3 Hz), 122.4 (q, J = 272.6 Hz), 122.5 (q, J = 272.6
Hz), 123.9, 124.2, 124.4, 138.6, 138.8, 141.66 (q, J = 33.1 Hz), 141.70 (q, J = 33.2 Hz), 149.8, 150.1,
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151.3, 151.4, 155.7, 157.1, 157.3, 163.0. 19F{1H} NMR (376 MHz, CDCl3): δ -66.95, -66.87. HRMS
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2
3
(APCI) m/z ([M+H]+) calcd for C19H20F3N2O 349.1522, found 349.1510.
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8
An
84:16
diastereomixture
of
methyl
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6-((3aR*,6aR*)-octahydropentalen-1-yl)-2-oxo-2H-[1,2'-bipyridine]-4-carboxylate (2d). Purified by
column chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed
by GPC (CHCl3); 46 mg (55%), oil; 13C NMR spectrum of 2d is complicated by the presence of
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diastereomers and rotamers associated with the C-N axis. Thus, all observed signals are described. H
NMR (400 MHz, CDCl3): δ 0.88-1.02 (m, 1H), 1.15-1.82 (m, 8H), 1.96-2.36 (m, 2H), 2.50-2.60 (m,
2H), 3.93 (s, 3H), 6.70 (d, J = 1.4 Hz, 0.16×1H), 6.72 (d, J = 1.5 Hz, 0.84×1H), 7.13 (d, J = 1.5 Hz,
0.84×1H), 7.15 (d, J = 1.4 Hz, 0.16×1H), 7.32-7.38 (m, 1H), 7.41-7.44 (m, 1H), 7.92 (dd, J = 7.8, 7.8
Hz, 1H), 8.68 (d, J = 2.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 25.5, 27.0, 32.4, 32.6, 32.8,
33.5, 33.6, 33.7, 34.7, 34.9, 35.6, 39.7, 39.8, 40.1, 42.0, 43.1, 43.3, 48.8, 49.5, 50.8, 51.7, 52.9, 101.3,
101.8, 120.0, 120.3, 124.0, 124.2, 138.5, 138.7, 140.86, 140.88, 149.8, 150.0, 151.7, 151.9, 154.0,
155.3, 155.5, 163.80, 163.84, 165.5, 165.6. HRMS (APCI) m/z ([M+H]+) calcd for C20H23N2O3
339.1703, found 339.1709.
A
diastereomixture
of
4'-methyl-6-((3aR*,6aR*)-octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one
(2f).
(The
diastereometric ratio cannot be determined.). Purified by column chromatography on silica gel with
CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (CHCl3); 66 mg (90%), oil; 1H and
13C NMR spectra of 2f are complicated by the presence of diastereomers and rotamers associated with
1
the C-N axis. Thus, all observed signals are described. H NMR (400 MHz, CDCl3): δ 0.57-2.20 (m,
12H), 2.44-2.45 (m, 3H), 2.48-2.60 (m, 1H), 6.17-6.20 (m, 1H), 6.47-6.51 (m, 1H), 7.13-7.23 (m, 2H),
7.36 (ddd, J = 7.1, 9.5, 9.5 Hz, 1H), 8.51 (d, J = 4.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 21.2,
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25.7, 27.1, 32.7, 32.9, 33.4, 33.6, 33.8, 33.9, 34.7, 35.0, 35.4, 40.0, 42.0, 42.2, 43.2, 43.4, 48.6, 49.2,
50.8, 51.9, 102.8, 103.3, 118.2, 118.6, 124.8, 125.09, 125.13, 140.2, 149.3, 149.6, 150.0, 150.1, 152.3,
152.4, 153.3, 164.1. HRMS (APCI) m/z ([M+H]+) calcd for C19H23N2O 295.1805, found 295.1817.
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6-(Cyclopentylmethyl)-2H-[1,2'-bipyridin]-2-one (3). Purified by column chromatography on silica
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gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (CHCl3); 18 mg (28%),
o
white solid; mp 105.8-107.8 C (from CDCl3); 1H NMR (400 MHz, CDCl3): δ 1.01 (br, 2H), 1.43-1.53
(m, 4H), 1.59-1.66 (m, 2H), 1.89 (dt, J = 7.3, 7.9 Hz, 1H), 2.23 (d, J = 7.3 Hz, 2H), 6.12 (dd, J = 1.0,
7.0 Hz, 1H), 6.52 (dd, J = 1.0, 9.2 Hz, 1H), 7.33-7.37 (m, 2H), 7.41 (ddd, J = 1.0, 4.9, 7.6 Hz, 1H), 7.90
(ddd, J = 1.9, 7.6, 7.6 Hz, 1H), 8.67 (ddd, J = 1.0, 1.9, 4.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3):
δ 24.9, 32.6, 37.9, 39.3, 105.8, 118.6, 124.1, 124.2, 138.6, 140.2, 149.5, 149.9, 152.0, 164.0. HRMS
(APCI) m/z ([M+H]+) calcd for C16H19N2O 255.1492, found 255.1502.
6-(Hex-5-en-1-yl)-2H-[1,2'-bipyridin]-2-one (3’). Purified by column chromatography on silica gel
with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (CHCl3); 9.0 mg (14%), white
o
1
solid; mp 66.2-68.2 C (from CDCl3); H NMR (400 MHz, CDCl3): δ 1.25 (dt, J = 7.3, 7.6 Hz, 2H),
1.44 (br, 2H), 1.92 (ddd, J = 6.8, 6.8, 7.4 Hz, 2H), 2.22 (t, J = 7.6 Hz, 2H), 4.90-4.95 (m, 2H), 5.69
(dddd, J = 6.8, 6.7, 10.4, 17.0, 1H), 6.11 (d, J = 6.9 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 7.33-7.37 (m,
2H), 7.41 (ddd, J = 1.0, 4.9, 7.6 Hz, 1H), 7.90 (ddd, J = 1.9, 7.6, 7.6 Hz, 1H), 8.67 (ddd, J = 1.0, 1.9, 4.9
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 27.3, 28.3, 32.9, 33.3, 105.1, 114.9, 118.7, 124.1, 124.2,
138.3, 138.6, 140.3, 149.9, 150.0, 151.9, 164.0. HRMS (APCI) m/z ([M+H]+) calcd for C16H19N2O
255.1492, found 255.1480.
6-(Hex-5-en-2-yl)-2H-[1,2'-bipyridin]-2-one (3’’). Purified by column chromatography on silica gel
with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (CHCl3); 27 mg (42%), oil; 1H
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13
and C NMR spectra of 3’’ are complicated by the presence of rotamers associated with the C-N axis.
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3
1
Thus, all observed signals are described. H NMR (400 MHz, CDCl3): δ 1.04 (br, 1H), 1.18 (br, 1.4H),
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5
6
7
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1.43 (br, 1H), 1.60-1.65 (m, 1.6H), 1.86-2.00 (m, 2H), 2.18 (br, 1H), 4.83-4.92 (m, 2H), 5.47-5.59 (m,
1H), 6.14 (dd, J = 1.0, 7.0 Hz, 1H), 6.50 (dd, J = 1.0, 9.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.38-7.42
(m, 2H), 7.89 (ddd, J = 1.9, 7.8 Hz, 1H), 8.67 (dd, J = 1.9, 4.0 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 20.5, 31.3, 35.0, 35.1, 35.6, 36.1, 102.7, 102.9, 115.0, 115.2, 118.3, 123.9, 124.1, 124.4,
137.4, 137.7, 138.5, 138.6, 140.4, 150.0, 151.9, 155.5, 163.9. HRMS (APCI) m/z ([M+H]+) calcd for
C16H19N2O 255.1492, found 255.1482.
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6-(3-Methylpent-4-en-1-yl)-2H-[1,2'-bipyridin]-2-one (4). Purified by column chromatography on
silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (CHCl3); 34 mg
(54%), oil; 1H NMR (400 MHz, CDCl3): δ 0.84 (d, J = 6.8 Hz, 3H), 1.42 (br, 2H), 1.65 (dddq, J = 6.8,
6.8, 6.9, 7.0 Hz, 1H), 2.13-2.28 (m, 2H), 4.79 (ddd, J = 1.0, 1.7, 10.3 Hz, 1H), 4.81-4.83 (m, 1H), 5.38
(ddd, J = 7.6, 10.3, 17.5 Hz, 1H), 6.10 (dd, J = 1.0, 6.9 Hz, 1H), 6.52 (dd, J = 1.0, 9.2 Hz, 1H),
7.32-7.36 (m, 2H), 7.41 (ddd, J = 1.0, 4.9, 7.6 Hz, 1H), 7.90 (ddd, J = 1.9, 7.6, 7.6 Hz, 1H), 8.67 (ddd, J
= 1.0, 1.9, 4.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 20.0, 31.0, 35.0, 37.5, 105.3, 113.7, 118.7,
124.1, 124.3, 138.6, 140.3, 143.3, 150.0, 150.2, 151.9, 164.0. HRMS (APCI) m/z ([M+H]+) calcd for
C16H19N2O 255.1492, found 255.1496.
6-((1R*,2S*,4R*)-Bicyclo[2.2.1]hept-5-en-2-yl)-2H-[1,2'-bipyridin]-2-one (5). White solid. Purified
by column chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent
followed by GPC (CHCl3); 38 mg (57%). mp 151.9-153.9 oC (from CDCl3). X-ray quality crystals were
grown from CH2Cl2/heptane. 1H NMR (400 MHz, DMSO-d6 at 120 ℃): δ 0.78-0.83 (m, 1H), 1.37 (d, J
= 8.7 Hz, 1H), 1.53-1.59 (m, 2H), 2.11 (dd, J = 5.0, 8.7 Hz, 1H), 2.85 (d, J = 2.7 Hz, 1H), 2.93 (d, J =
2.7 Hz, 1H), 5.89 (dd, J = 2.7, 5.5 Hz, 1H), 5.98 (dd, J = 2.7, 5.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 6.33
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The Journal of Organic Chemistry
(d, J = 9.2 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.43-7.47 (m, 2H), 7.96 (ddd, J = 1.8, 7.8, 7.8 Hz, 1H),
8.59 (ddd, J = 1.0, 1.8, 5.0 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6 at 120 ℃): δ 32.6, 40.1, 41.1,
1
2
3
4
5
6
7
8
45.3, 45.7, 101.4, 117.0, 123.2, 124.2, 135.7, 137.0, 137.6, 139.5, 148.5, 151.5, 153.3, 162.2. HRMS
(APCI) m/z ([M+H]+) calcd for C17H17N2O 265.1335, found 265.1337.
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6-((1R*,2R*,4S*)-Bicyclo[2.2.1]heptan-2-yl)-2H-[1,2'-bipyridin]-2-one (6). Purified by column
chromatography on silica gel with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC
1
(CHCl3); 52 mg (78%), oil; H NMR (400 MHz, DMSO-d6 at 120 ℃): δ 0.65-0.69 (m, 1H), 0.88-0.99
(m, 1H), 1.06-1.16 (m, 2H), 1.28-1.45 (m, 2H), 1.47-1.54 (m, 2H), 2.18-2.22 (m, 2H), 2.34 (s, 1H), 6.18
(d, J = 7.3 Hz, 1H), 6.31 (d, J = 9.6 Hz, 1H), 7.39-7.50 (m, 3H), 7.98 (ddd, J = 1.4, 7.8, 7.8 Hz, 1H),
8.62 (d, J = 5.0 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6 at 120 ℃): δ 27.2, 29.0, 35.2, 35.3, 37.3,
40.9, 43.1, 101.2, 116.9, 123.2, 124.2, 137.6, 139.4, 148.6, 151.6, 153.6, 162.2. HRMS (APCI) m/z
([M+H]+) calcd for C17H19N2O 267.1492, found 267.1480.
6-(1-Phenylethyl)-2H-[1,2'-bipyridin]-2-one (7). Purified by column chromatography on silica gel
with CH2Cl2/EtOAc/Et3N (1/1/0.02, v/v/v) as an eluent followed by GPC (EtOAc); 48 mg (70%), oil;
1H NMR (400 MHz, CDCl3): δ 1.45 (d, J = 7.0 Hz, 3H), 3.96 (q, J = 7.0 Hz, 1H), 6.41 (d, J = 6.8 Hz,
1H), 6.45 (d, J = 8.1 Hz, 1H), 6.58-6.62 (m, 3H), 7.07-7.09 (m, 3H), 7.22-7.24 (m, 1H), 7.37 (dd, J =
13
6.3, 7.6 Hz, 1H), 7.47 (dd, J = 7.9, 8.1 Hz, 1H), 8.62 (d, J = 3.2 Hz, 1H). C{1H} NMR (100 MHz,
CDCl3): δ 22.2, 41.7, 104.6, 119.7, 123.6, 125.5, 125.6, 126.8, 126.9, 128.6, 137.4, 139.9, 143.3, 149.1,
152.1, 164.0. HRMS (APCI) m/z ([M+H]+) calcd for C18H17N2O 277.1335, found 277.1353.
Typical Procedure for Dibromination of 2a. 1,3-Dibromo-5,5-dimethylhydantoin (53 mg, 0.18
mmol) was place in a 20 mL two-necked reaction flask, which was filled with nitrogen by using the
standard
Schlenk
technique.
A
76:24
diastereomixture
of
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6-(octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one (2a; 43 mg, 0.15 mmol) in acetonitrile (1.5 mL)
was injected via a syringe, and the mixture was stirred for 4 h at 100 R. The resulting mixture was
allowed to cool to room temperature and then quenched with water. The mixture was extracted with
EtOAc three times. The combined organic layer was dried over anhydrous Na2SO4. After
concentration under reduced pressure, silica gel column purification with hexane/EtOAc/Et3N (2/1/0.02,
v/v/v) afforded a diastereomixture of 3,5-dibromo-6-(octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one
(2a-Br2; 35 mg, 0.080 mmol) in 52% yield. X-ray quality crystals were grown from CH2Cl2/heptane.
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diastereomixture
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3,5-dibromo-6-((3aR*,6aR*)-octahydropentalen-1-yl)-2H-[1,2'-bipyridin]-2-one (2a-Br2). Purified
by column chromatography on silica gel with hexane/EtOAc/Et3N (2/1/0.02, v/v/v) as an eluent; 35 mg
o
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(52%), white solid; mp 165.8-167.8 C (from CH2Cl2/heptane); H and C NMR spectra of 2a-Br2 are
complicated by the presence of diastereomers and rotamers associated with the C-N axis, and all
observed signals are thus described. 1H NMR (400 MHz, CDCl3): δ 0.59-0.63 (m, 0.5H), 0.79-0.89
(m, 1H), 1.03-1.09 (m, 1H), 1.13-1.25 (m, 2H), 1.42-1.50 (m, 3H), 1.54 (br, 0.1H), 1.57-1.59 (m, 0.3H),
1.70 (br, 0.5H), 1.78-1.84 (m, 0.4H), 1.91-2.06 (m, 1.5H), 2.21-2.30 (m, 0.7H), 2.43-2.45 (m, 1H),
2.58-2.62 (m, 0.7H), 3.15-3.19 (m, 0.7H), 7.23-7.25 (m, 0.4H), 7.30-7.34 (m, 0.6H), 7.42-7.47 (m, 1H),
7.89-7.94 (m, 2H), 8.63-8.69 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 24.8, 27.1, 32.1, 32.6, 34.2,
34.8, 35.0, 36.0, 36.1, 42.4, 42.8, 44.2, 47.1, 47.3, 51.0, 51.6, 53.6, 97.9, 98.2, 114.2, 114.5, 123.3,
123.5, 124.3, 124.5, 124.6, 138.7, 138.9, 139.1, 147.2, 147.28, 147.33, 148.1, 149.4, 149.4, 150.2,
152.5, 152.597, 152.640, 159.27, 159.30. HRMS (APCI) m/z ([M+H]+) calcd for C18H19Br2N2O
436.9864, found 436.9848.
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Author Information
Corresponding Authors
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*E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
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Koji Hirano: 0000-0001-9752-1985
Masahiro Miura: 0000-0001-8288-6439
Notes
The authors declare no competing financial interest.
Acknowledgment.
This work was supported by JSPS KAKENHI Grant Nos. 15K13696
(Grant-in-Aid for Exploratory Research), and 15H05485 (Grant-in-Aid for Young Scientists (A)) to
K.H. and 24225002 (Grant-in-Aid for Scientific Research (S)) to M.M.
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Supporting Information: H, C{1H}, and F{1H} NMR spectra for products, ORTEP drawings of
2a-Br2 and 5. This material is available free of charge via the Internet at http://pubs.acs.org.
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Saraev, V. V.; Kraikivskii, P. B.; Matveev, D. A.; Bocharova, V. V.; Petrovskii, S. K.; Zelinskii, S. N.;
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(17) Unfortunately, the positive effect of 4-methylpyridyl group was specific to the unsubstituted
pyridone ring.
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(19) The origin of H atom is considered to be cod: the reaction of 1a-d1 (95% D) with 100 mol % of
Ni(cod)2 formed the less deuterated 1a (48% D) along with deuterated 2a (exact deuterium content
being unclear) while the deuterated cod was not observed. On the other hand, even in 1,4-dioxane-d8,
no deuterium incorporation into any substrates was observed.
(20) We observed the dissociation of cod by NMR analysis upon simple mixing of 1a and Ni(cod)2 in
1,4-dioxane-d8 at room temperature.
(21) For recent computational studies, see: (a) Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.;
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Semba, K.; Sakaki, S.; Nakao, Y. J. Am. Chem. Soc. 2016, 138, 14699.
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with CO2: Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14936.
(24) For similar higher reactivity of 1,n-dienes in the Rh-catalyzed hydroacylation, see: (a) Tanaka, M.;
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(25) (a) Khake, S. M.; Soni, V.; Gonnade, R. G.; Punji, B. Chem.–Eur. J. 2017, 23, 2907. For many
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C. M.; Chatani, N. Chem. Lett. 2015, 44, 410.
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