Ring-closing metathesis as a key step in the synthesis of 2-pyridones and pyridine triflates

Article abstract of DOI:10.1055/s-2008-1067180

The ring-closing metathesis transformation has been employed to construct a library of functionalized 2-pyridones and pyridine triflates. Using this mild approach, a range of substituent patterns can be built into the aromatic core, including groups which

Full text of DOI:10.1055/s-2008-1067180

PRACTICAL SYNTHETIC PROCEDURES
2665
Ring-Closing Metathesis as a Key Step in the Synthesis of 2-Pyridones and
Pyridine Triflates
S
ynthesis of 2-P
i
yridon
m
es and Pyridine
T
rif
o
lates thy J. Donohoe,*a Lisa P. Fishlock,a Panayiotis A. Procopioub
a
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK
E-mail: timothy.donohoe@chem.ox.ac.uk
GlaxoSmithKline Research & Development Limited, Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
b
PSP
Received 19 May 2008
No129
Abstract: The ring-closing metathesis transformation has been employed to construct a library of functionalized 2-pyridones and pyridine
triflates. Using this mild approach, a range of substituent patterns can be built into the aromatic core, including groups which can be de-
manding to incorporate using alternative protocols.
Key words: ring-closing metathesis, elimination, 2-pyridone, pyridine, triflation
O
R3
R2
Br
Cl
BnO
H
OBn
R1
OBn
R1
N
HN
R3
Et3N
O
N
R1
Zn, THF
NH4Cl (aq)
r.t., 47–100%
R2
CH2Cl2, r.t.
58–100%
R2
1
2
3
10 examples
Hoveyda–Grubbs II
(5–10 mol%)
CH2Cl2–PhMe
40–95 °C
59–98%
Cl
OTf
N
O
O
R3
R3
R3
OBn
N
N
NTf2
DBU
NH
THF
r.t. to 50 °C
63–95%
R1
R1
R1
KHMDS
THF, –78 °C
62–94%
R2
R2
R2
6
5
4
Scheme 1 Preparation of 2-pyridones and pyridines
Ruthenium-catalyzed ring-closing metathesis (RCM) has benzyl alcohol was carried out using DBU to provide the
recently emerged as a powerful tool for the synthesis of desired 2-pyridone 5 in excellent yield. Using this flexible
aromatic heterocycles and carbocycles.1 The relatively procedure, it was possible to incorporate an array of sub-
mild conditions of the RCM transformation allow the in- stituents at R1 (including methyl ester, 2-pyridinyl, 2-
corporation of a wide range of functional groups, which quinolinyl, 2-quinoxalinyl), R2 (methyl, phenyl), and R3
presents a flexible method for de novo syntheses of aro- (methyl, trifluoromethyl). In addition, 2-pyridones 5
matic motifs.
could be manipulated further by bromination at C-3 or
C-5. Futhermore, their efficient conversion into pyridine
triflates 6 was achieved using the protocol developed by
Comins et al.;2 such intermediates can be functionalized
using a variety of coupling procedures.3
This approach has recently been employed to construct a
library of functionalized 2-pyridones (Scheme 1).1g The
heterocyclic core of 5 was constructed by RCM of acryl-
amide 3, which was equipped with a leaving group (OBn)
on nitrogen. Following cyclization, the elimination of The synthesis of substituted 2-pyridones and pyridines is
of importance due to the abundance of these motifs in nat-
ural products, pharmaceutical drugs, agrochemicals, and
coordination chemistry.4 Therefore, we have utilized this
procedure to produce significant quantities of 2-pyridone
11 (Scheme 2). RCM precursor 9 was synthesized from
SYNTHESIS 2008, No. 16, pp 2665–2667
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1067180; Art ID: Z11508SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

2666
T. J. Donohoe et al.
PRACTICAL SYNTHETIC PROCEDURES
ether 7 was prepared according to literature procedures.6 Petroleum
ether (PE) used refers to the fraction boiling in the range 40–60 °C.
oxime ether 7 in two steps and 64% yield. The key cy-
clization was carried out with 1 mol% Hoveyda–Grubbs
second-generation catalyst at 40 °C, which provided the
dihydropyridone 10 in 95% yield after 18 hours. The de-
sired 2-pyridone 11 was obtained upon treatment of 10
with DBU in THF at room temperature. Thus, the overall
yield of aromatic 11 from oxime ether 7 was 58%.
Methyl 2-(Benzyloxyamino)pent-4-enoate (8)6b
A 100 mL round bottom flask containing oxime ether 7 (1.50 g, 7.77
mmol) was charged with THF (6.5 mL) and sat. aq NH4Cl (33.5
mL). Zn dust (1.12 g, 17.1 mmol) was added and the suspension was
stirred at r.t. Allyl bromide (1.21 mL, 14.0 mmol) was then added
dropwise over 5 min, whereupon an exotherm was observed. The
suspension was stirred for a further 30 min at r.t. before transferring
to a separating funnel and extracting with EtOAc (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure. The remaining colorless oil was purified by
flash column chromatography (12 cm × 4 cm, 9:1 PE–EtOAc) to
give 8 as a colorless oil (1.30 g, 71%).
OBn
BnO
H
Br
HN
N
OMe
OMe
Zn, THF
NH4Cl (aq)
r.t., 71%
O
O
7
8
IR (film): 3264, 3032, 2953, 1743, 1642, 1496, 1436, 1365, 1202,
993, 913, 743 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.32–2.37 (2 H, m), 3.70 (1 H, t,
J = 7.0 Hz), 3.75 (3 H, s), 4.72 (2 H, s), 5.06–5.13 (2 H, m), 5.73 (1
H, ddt, J = 17.0, 10.5, 7.0 Hz), 5.96 (1 H, br s), 7.27–7.36 (5 H, m).
acryloyl chloride
Et3N, CH2Cl2, r.t.
90%
O
O
Hoveyda–Grubbs II
(1 mol%)
OBn
N
13C NMR (100 MHz, CDCl3): d = 33.9, 52.0, 63.3, 76.2, 118.2,
127.8, 128.3, 128.5, 133.0, 137.6, 173.6.
OBn
N
OMe
OMe
CH2Cl2
40 °C, 95%
Methyl 2-[N-(Benzyloxy)acrylamido]pent-4-enoate (9)
A 50 mL round-bottomed flask containing amine 8 (1.30 g, 5.53
mmol) was purged with argon before charging with CH2Cl2 (20
mL). Et3N (1.54 mL, 11.1 mmol) was added to the stirred solution
at r.t. before cooling to 0 °C. Acryloyl chloride (674 mL, 8.30 mmol)
was added dropwise over 5 min at 0 °C, during which time the so-
lution turned yellow. The solution was then warmed to r.t. and
stirred for a further 10 min. The dark orange mixture was then trans-
ferred to a separating funnel and washed with 1.0 M aq HCl (20 mL)
and the aqueous layer was extracted with CH2Cl2 (10 mL). The
combined organic layers were washed with sat. aq NaHCO3 (10
mL), dried (Na2SO4), and concentrated under reduced pressure. The
remaining orange oil was purified by flash column chromatography
(12 cm × 4 cm, 8:1 PE–EtOAc) to give 9 as a very pale yellow oil
(1.44 g, 90%).
O
O
10
9
DBU
THF, r.t.
96%
O
NH
OMe
O
11
Scheme 2 Preparation of methyl 6-oxo-1,6-dihydropyridine-2-car-
boxylate (11)
IR (film): 2952, 1746, 1665, 1620, 1410, 1229, 986, 920, 787, 744,
699 cm–1.
In conclusion, we have developed an efficient and flexible
route to a variety of functionalized 2-pyridones and py-
ridines. Using this approach, a range of substitution pat-
terns can be built into the aromatic core and groups (e.g.,
CF3), which can be demanding to incorporate with other
procedures.
1H NMR (400 MHz, CDCl3): d = 2.75–2.89 (2 H, m), 3.77 (3 H, s),
4.93 (1 H, d, J = 10.5 Hz), 5.02 (1 H, d, J = 10.5 Hz), 5.04–5.07 (1
H, m), 5.11 (1 H, dd, J = 10.5, 1.0 Hz), 5.18 (1 H, dd, J = 17.0, 1.0
Hz), 5.78 (1 H, dd, J = 10.5, 2.0 Hz), 5.82 (1 H, ddt, J = 17.0, 10.5,
7.0 Hz), 6.45 (1 H, dd, J = 17.0, 2.0 Hz), 6.73 (1 H, dd, J = 17.0,
10.5 Hz), 7.38–7.41 (5 H, m).
13C NMR (100 MHz, CDCl3): d = 32.6, 52.5, 60.7, 79.0, 118.4,
126.0, 128.7, 129.0, 129.0, 130.2, 133.6, 134.3, 168.3, 170.3.
MS (ESI): m/z (%) = 312 (100, MNa+), 290 (30, MH+), 236 (10),
218 (10).
HRMS (ESI): m/z calcd for C16H19NO4Na (MNa+): 312.1206;
found: 312.1207 (–0.18 ppm).
THF was purified by filtration through two columns of activated
alumina (grade DD-2) as supplied by Alcoa, employing the method
of Grubbs et al.5 CH2Cl2 was purified by filtration through two col-
umns of basic activated alumina (Brockman I, standard grade, ~150
mesh, 58 Å) as supplied by Aldrich. Et3N was purified by distilla-
tion over CaH2, and stored over CaH2. TLC was performed on
Merck Kieselgel 60 F254 0.25 mm precoated aluminum backed silica
plates. Flash column chromatography was carried out using Merck
Methyl 1-(Benzyloxy)-6-oxo-1,2,3,6-tetrahydropyridine-2-car-
boxylate (10)
1
Kieselgel 60 (40–63 mm). H NMR spectra were recorded on a
A 250 mL round-bottomed flask fitted with a condenser and con-
taining acrylamide 9 (1.44 g, 4.98 mmol) was purged with argon be-
fore charging with CH2Cl2 (200 mL). Hoveyda–Grubbs second-
generation catalyst (31 mg, 0.05 mmol) was added and the green so-
lution was heated at reflux for 18 h, during which time the solution
became golden brown in color. The solvent was removed under re-
duced pressure and the remaining brown oil was purified by flash
column chromatography (12 cm × 4 cm, 2:1 PE–EtOAc) to give 10
Bruker Avance AV 400 (400 MHz) spectrometer. 13C NMR spectra
were recorded on the same spectrometer at 100 MHz. IR spectra
were recorded on a Bruker Tensor 27 Ft-IR spectrometer. Mass
spectra (ESI) were recorded on a Fisons Platform II. Accurate mass
(HRMS) data were recorded under conditions of ESI on a Micro-
mass LCT (resolution = 5000 FWHM) or a Bruker MicroToF spec-
trometer (resolution = 10000 FWHM). Melting points were
obtained using a Leica VMTG heated-stage microscope. Oxime
Synthesis 2008, No. 16, 2665–2667 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of 2-Pyridones and Pyridine Triflates
2667
as a very light brown oil (1.24 g, 95%), which partially solidified
upon standing.
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IR (film): 2954, 1750, 1692, 1389, 1210, 1080, 998, 809, 757, 699
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.62–2.66 (2 H, m), 3.73 (3 H, s),
3.94–3.98 (1 H, m), 4.96 (1 H, d, J = 11.0 Hz), 5.04 (1 H, d, J = 11.0
Hz), 5.94 (1 H, ddd, J = 10.0, 2.0, 1.0 Hz), 6.34–6.46 (1 H, m),
7.35–7.46 (5 H, m).
13C NMR (100 MHz, CDCl3): d = 29.4, 52.8, 62.3, 77.4, 125.3,
128.5, 128.8, 129.8, 135.6, 137.1, 165.1, 170.8.
MS (ESI): m/z (%) = 284 (100, MNa+), 262 (100, MH+).
HRMS (ESI): m/z calcd for C14H15NO4Na (MNa+): 284.0893;
found: 284.0894 (–0.14 ppm).
Methyl 6-Oxo-1,6-dihydropyridine-2-carboxylate (11)
A 50 mL round-bottomed flask containing dihydropyridone 10
(1.24 g, 4.75 mmol) was purged with argon before charging with
THF (30 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (4.97 mL, 33.3
mmol) was added dropwise and stirring was continued at r.t. for
1.75 h, during which time the solution became yellow in color. The
mixture transferred directly to the column, then purified by flash
column chromatography (12 cm × 4 cm, EtOAc → 10:1 EtOAc–
MeOH) to give 11 as a colorless solid (699 mg, 96%); mp 100–
103 °C.
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Terauchi, Y.; Kubota, T.; Kumagai, H.; Itoh, S.; Satoh, H.;
Yano, W.; Ogata, H.; Tokuyama, K.; Takamoto, I.;
Mineyama, T.; Ishikawa, M.; Moroi, M.; Sugi, K.;
Yamauchi, T.; Ueki, K.; Tobe, K.; Noda, T.; Nagai, R.;
Kadowaki, T. J. Biol. Chem. 2006, 281, 8748.
IR (film): 3305, 1725, 1661, 1613, 1543, 1440, 1352, 1308, 1194,
1132, 1062, 1005, 891 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.94 (3 H, s), 6.83 (1 H, dd,
J = 9.5, 1.0 Hz), 6.97 (1 H, dd, J = 7.0, 1.0 Hz), 7.45 (1 H, dd,
J = 9.5, 7.0 Hz), 11.28 (1 H, br s).
13C NMR (100 MHz, CDCl3): d = 51.3, 109.6, 126.9, 133.9, 139.7,
161.4, 163.1.
MS (ESI): m/z = 176 (100%, MNa+).
HRMS (ESI): m/z calcd for C7H7NO3Na (MNa+): 176.0318; found:
176.0318 (–0.73 ppm).
Acknowledgment
We would like to thank GlaxoSmithKline for funding this project.
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Synthesis 2008, No. 16, 2665–2667 © Thieme Stuttgart · New York