Efficient and fast Heck vinylation of 2-bromo-6-methyl pyridines with methylacrylate. Application to the synthesis of 6-methyl cyclopenta[b]pyridinone

Article abstract of DOI:10.1016/j.tet.2005.03.008

Heck vinylation of 2-bromo-6-methyl-3-substituted pyridines using η³-allylpalladium chloride dimer/P(o-Tol)₃ complex/toluene and dimethylacetamide (DMA) as co-solvent with methyl acrylate is reported. Electronic and steric effects were investigated engaging diversely 2-bromo-3,6-disubstituted pyridines. As application, a new synthesis of the 6-methyl cyclopenta[b]pyridinone building-block connecting Heck vinylation, alkene reduction and Dieckmann condensation is described.

Full text of DOI:10.1016/j.tet.2005.03.008

Tetrahedron 61 (2005) 4569–4576
Efficient and fast Heck vinylation of 2-bromo-6-methyl pyridines
with methylacrylate. Application to the synthesis of
6-methyl cyclopenta[b]pyridinone
†
Nicolas Robert, Christophe Hoarau, Sylvain Celanire, Pierre Ribereau, Alain Godard,
´
Guy Queguiner and Francis Marsais
´
*
´
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, INSA-IRCOF, Place E. Blondel, BP 08,
76131 Mont-Saint-Aignan Cedex, France
Received 10 December 2004; revised 22 February 2005; accepted 3 March 2005
Available online 19 March 2005
Abstract—Heck vinylation of 2-bromo-6-methyl-3-substituted pyridines using h3-allylpalladium chloride dimer/P(o-Tol)3 complex/toluene
and dimethylacetamide (DMA) as co-solvent with methyl acrylate is reported. Electronic and steric effects were investigated engaging
diversely 2-bromo-3,6-disubstituted pyridines. As application, a new synthesis of the 6-methyl cyclopenta[b]pyridinone building-block
connecting Heck vinylation, alkene reduction and Dieckmann condensation is described.
q 2005 Published by Elsevier Ltd.
1. Introduction
Herein, we report a new quantitative and fast kinetic Heck
vinylation of a panel of 3-substituted-2-bromo-6-methyl-
pyridines using h3-allylpalladium chloride dimer/P(o-Tol)3
complex/toluene and dimethylacetamide (DMA) as
co-solvent. As direct application the 6-methyl cyclo-
The Heck palladium-catalyzed vinylation reaction is one of
the most attractive tools for the C–C bond formation in
organic synthesis.1 In contrast to Kumada, Suzuki, Stille and
others cross-coupling reactions using vinylmetal com-
pounds, the Heck-type olefination is a more functional
group tolerant and low cost reaction. Among numerous
examples of Heck reactions of halopyridines we counted
only, to the best of our knowledge, 11 Heck vinylation
reactions of 2-halopyridines with acrylate derivatives
allowing good to moderate yields.2 Nitrogen-based hetero-
aryls such as pyridines represent highly efficient ligands
in-themselves.3 Thus 2-halopyridines revealed as bad
substrates for Heck vinylation probably due to the formation
after oxidation step of a pyridyl-bridge palladium dimer
preventing further coupling reaction steps.4,5 Recently we
focused our research program on an efficient preparation of
numerous 3-substituted-6-methyl-pyridine acrylates I
applied to a straightforward route to new annulated-
cycloalkylpyridines II. This framework is present in
¨
penta[b]pyridinone 1 as precursor of novel 8-azasteroıd
analogues6e was ready prepared via a reduction/Dieckmann
condensation sequence.
2. Results and discussion
2.1. Synthesis of 2-bromo-6-methylpyridines
Treatment of 2-hydroxy-6-methylnicotinic acid 2 with
POBr3 in refluxed chlorobenzene followed by cold
methanol treatment directly provided 2-bromo-6-methyl-
nicotinate 3 (Scheme 1). DIBAL reduction of 2-bromo-6-
methyl 3-cyanopyridine 4 afforded 2-bromo-3-formyl-6-
methyl pyridine 5. The protected 2-bromo-3-hydroxy-6-
methylpyridines 8, 9 were synthesized in a two steps
procedure, bromination of 6-methyl-3-hydroxypyridine 6
affording 2-bromo-3-hydroxy-6-methylpyridine 7 followed
by methoxymethyl (MOM) or triflate (OTf) protection of
the hydroxyl group (Scheme 1).
numerous biologically active compounds6,2i such as novel
6a,e
¨
8-azasteroıd analogues
III and natural product such as
cananodine7 IV (Fig. 1).
Keywords: Heck; Vinylation; Pyridine; Picoline; Cyclopenta[b]pyridinone.
*
2.2. Heck vinylation reaction of 2-bromopyridines with
methyl acrylate
Corresponding author. Tel.: C33 2 35 52 24 75; fax: C33 2 35 52 29 62;
e-mail: francis.marsais@insa-rouen.fr
† Present address. UCB-Pharma, Chemin du Foriest, 1420 Braine
L’Alleud, Belgium.
We were first interested on the Heck coupling reaction of
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.03.008

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N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
Figure 1.
2-bromo-6-methylnicotinate 3 with methyl acrylate in order
to prepare the cyclopenta[c]pyridinone 1. The initial
different assays were summarized in Table 1. Standard
Heck conditions for heteroaromatic system [Pd(OAc)2/
P(o-tol)3 (1:2), DMF, 130 8C, 24 h]8 were completely
inefficient with our substrates (entry 1). Following the
Jeffery’s conditions9a,b using tetrabutylammonium salts9c as
phase-transfer catalyst and a more polar solvent such as
dimethylacetamide (DMA), the 2-pyridyl acrylate com-
pound 20 was obtained only in poor 10% yield (entry 2).
Note that any improvement was observed by replacing
NaOAc by K2CO3 and Cs2CO3 bases or over a 48 h
refluxing period. We thus decided to use the recent Little
and Fu conditions [Pd2(dba)3/P(tBu)3 (1:4), Dioxane, reflux,
24 h]10 affording a modest 56% yield of 2-pyridyl acrylate
20 (entry 3). A survey of the literature revealed that Reider
and co-workers2f carried out the Heck coupling reaction of
6-butyl-2-bromo-3-formyl pyridine with ter-butyl acrylate
in 85% yield using allylpalladium chloride dimer catalyst,
tri-o-tolylphosphine and sodium acetate in toluene during a
20 h refluxing period. Using the same conditions the
2-pyridyl acrylate 20 was obtained in 45% yield (entry 4).
It should be easily improved using a more polar co-solvent,
dimethylacetamide (DMA). Surprisingly complete con-
version was obtained in only 5 h (GC-MS monitoring)
leading to 84% of pure product (entry 5). Longer refluxing
period decreases the yield and higher temperature reaction
led to rapid decomposition of the catalyst as black palladium
mirror.
Scheme 1. (a) POBr3, chlorobenzene, Py then MeOH, O 8C, 70%
(b) DIBAL-H, toluene, K78 8C, 93% (c) Br2, Py, 69% (d) MOMCl,
DIPEA, CH2Cl2, 76% (e) Tf2O, Py, CH2Cl2, 95%.
Table 1. Heck vinylation of 2-bromo-6-methyl nicotinate with methyl acrylate
Entry
Catalyst/ligand
Base
Solvent/temperature (8C)
Time (h)
Yielda
1
2
3
4
5
Pd(OAc)2, P(o-tol)3 (1:2)
Pd(OAc)2, P(o-tol)3 (1:2) Bu4NHSO4 (1eq.)
Pd2(dba)3, P(tBu)3 (1:4)
Et3N
DMF, 130
DMA, 100
Dioxane, 85
24
48
24
20
5
—
10
56
45
84
NaOAc
Cs2CO3
NaOAc
NaOAc
[(h3-(C3H4)Pd(m-Cl)]2, (o-Tol)3P (1:2)
[(h3-(C3H4)Pd(m-Cl)]2, (o-Tol)3P (1:2)
Toluene, 100
Toluene/DMA (3:1), 100
a Isolated yields, average two runs. DMF: dimethylformamide; DMA: N,N-dimethylacetamide.

N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
4571
The efficiency of this new Heck vinylation procedure was
then tested with a large panel of 3-substituted 2-bromo-6-
methyl pyridines substrates (Table 2, entries 1–4). Heck
vinylations of 3-carboxy 6-methyl pyridine derivatives 4, 5
gave excellent 81 and 91% yields (entries 1–2). The same
reaction carried out without DMA failed. It should be noted
that the original Heck condition [Pd(OAc)2/P(o-tol)3 (1:4),
DMF, 130 8C, 24 h]8 failed with 3-cyano compound 4 and
gave only 8% of 2-pyridyl acrylate 22 starting with the
3-formyl-6-methyl pyridine 5. In a similar way Little and
Fu’s conditions [Pd2(dba)3/P(tBu)3 (1:4), CsCO3
(1.1 equiv), Dioxane, reflux, 24 h]10 was surprisingly
inefficient with the 3-carboxy-6-methyl pyridine substrates
4, 5. Protected 3-hydroxy-6-methyl pyridine derivatives 8–9
could be easily coupled with methyl acrylate using the new
procedure (entries 3,4). Moreover, Heck coupling reaction
Table 2. Heck vinylation of 2-bromopyridine derivatives with methylacrylate
Entry
1
R1
R2
Product
Yielda
81
CH3
CN
4
5
8
21
22
23
2
3
CH3
CH3
CHO
91
82
OMOM
4
CH3
CH3
OTf
9
24
25
26
27
28
29
61
65
92
98
99
36
5
H
10
11
12
13
14
6
Br
H
7
OCH3
CO2CH3
H
H
H
8
10
CO2CH3
11
12
13
14
15
H
H
H
H
H
CN
CHO
OMOM
OTf
15
16
17
18
19
30
31
32
33
34
35
42
27
9
H
None
a Isolated yields, average of two runs.

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N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
of the 3-pyridyl triflate 9 with methyl acrylate occurred
selectively at the C-2 position. We further extended our
procedure to 3 or 6-substituted 2-bromopyridines (entries
5–8, 10–14, Table 2) in order to study the influence of steric
and electronic effects. We first observed that the Heck
vinylation with methyl acrylate of diversely 2-bromo-
pyridines 11–13 substituted at the C-6 position as well as
with electron donor and withdrawing electron groups
successfully gave good to excellent yields of 2-pyridyl-
acrylates 26–28 (entries 5–8, Table 2).
3. Conclusion
The use of h3-allylpalladium chloride dimer/P(o-Tol)3 in
the presence of toluene associated to dimethylacetamide
(DMA) as a co-solvent provided a convenient catalyst
system for fast Heck vinylation 2-bromo-3,6-disubstituted
pyridines and 2-bromo-6-disubstituted pyridines. The
efficiency of the catalyst system with 2-bromo-3-substituted
pyridines is however lower. Application to the synthesis of
the potential starting material for the synthesis of
¨
6e
8-azasteroıd analogue 6-methyl-cyclopenta[b]pyridinone
1 was achieved via a reduction/Dieckmann condensation
sequence in 57% yield over three steps starting from
commercially available 2-hydroxy-3-carboxy-6-methyl
pyridine 2. Moreover, Heck vinylation of the 2-bromo-3-
triflyl-6-methyl pyridine 9 with methyl acrylate provides
selectively the (3-triflyl-6-methyl 2-pyridyl) acrylate 24
which could be a good candidate for the synthesis of
cananodine.7
Note that Pd-olefination of 6-methyl-2-bromopyridine 10,
the less hindrered model at C-6 position, occurred in a more
modest 65% yield. These results suggest that steric
hindrance at C-6 position is the main factor of a successful
Heck vinylation probably by preventing the coordination of
the nitrogen atom of the pyridine with the catalyst likely
avoiding the formation of the unreactive pyridyl-bridge
palladium dimer after the oxidation step.3,4
Heck vinylation of 2-bromopyridines 14–16 only substi-
tuted at C-3 position afforded 2-pyridylacrylates 29–31 in
36–42% modest yields (entries 10–12). We noticed that a
20 h refluxing period or the use of 20 mol% catalyst do not
improve the yield and surprisingly more than 50% of
starting material was already recovered. Further assays with
protected 3-hydroxy pyridine 17 and 3-pyridyl triflate 18
provided the corresponding 2-pyridyl acrylates 32, 33 with
poor 27 and 9% yields, respectively (entries 13,14).
Furthermore, the Heck vinylation of the naked 2-bromo-
pyridine 19 failed under new conditions (entries 15). The
results clearly show that the yield of Heck vinylation
depend on the chelating power of the group at C-3 position
(CHOOCO2CH3wCNOOMOMwOTf) which competes
with the nitrogen atom of the pyridine as potential ligand
and should prevent partially the formation of the unreactive
dimer.3,4
4. Experimental
4.1. General
Tetrahydrofuran (THF), ether (Et2O) were pre-dried with
pellets of KOH and distilled over sodium benzophenone
ketyl under Ar before use. CH2Cl2, NEt3 and toluene were
distilled from CaH2. Methanol and ethanol were distilled
from magnesium turning. dimethylacetamide was distilled
˚
under 4 A molecular sieves. For flash chromatography,
Merck silica gel (70–230 mesh) was used. The melting
points were measured on a Kofler melting points apparatus
and were not corrected. The 1H NMR and 13C NMR spectra
were recorded with a Bruker Avance-300 spectrometer
operating at 300 MHz. Commercially available starting
materials were used without further purification. Infrared
spectra were recorded on a Perkin-Elmer IRTF 1650
spectrophotometer. Elemental analysis of compounds was
carried out on a Carlo Erba 1160. Mass spectrum was
recorded on a JEOL JMS AX-500 spectrometer, in
electronic impact (EI). The starting compounds 4, 10–13,
15, 16, 19 are commercially available. The compounds 14,13
1814 are prepared according to the procedures described in
literature.
2.3. Application to the synthesis of 6-methyl-
cyclopenta[b]pyridinone
We applied our new procedure to propose the synthesis of
the 6-methyl-cyclopenta[b]pyridinone 1 which has been
only once reported but in a poor 5.5% global yield over four
steps from cyclopenta-1,3-dione.11 A two-steps sequence
was thus envisioned from b-2-pyridyl acrylate 20. Hydro-
genation of the double-bond under soft condition provided
the diester compound 35 followed by a Dieckmann
condensation-decarboxylation12 sequence to give the
6-methyl-cyclopenta[b]pyridinone 1 in a 81% overall
yield (Scheme 2).
4.2. Synthesis of 2-bromo pyridines substrates
4.2.1. Methyl 2-bromo-6-methylpyridine-3-carboxylate
(3). Phosphoryl tribromide (6.14 g, 21.4 mmol) was added
by small portion to a solution of nicotonic acid 2 (1.43 g,
9.3 mmol), pyridine (251 ml) and chlorobenzene (30 ml) at
Scheme 2. (a) H2 (1 atm), Pd/C (10 mol%), MeOH, rt, 94% (b) MeONa (1.5 equiv), THF, refux, 2 h then HCl (4.5 M), reflux 86%.

N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
4573
room temperature under N2. The mixture was refluxed for
1 h and concentrated under vacuum before treating with an
excess of cold methanol (4 ml). The solution was stirred for
an additional 1 h and again concentrated under vacuum. The
residue was dissolved in (15 ml) and freeze water was added
(10 ml). The pH was adjusted to 8 by adding K2CO3 before
extraction of the product with CH2Cl2. The organic layer
was washed with 10% aq Na2CO3 (10 ml), satd aq. NH4Cl
(10 ml) and dried (MgSO4). After evaporation of the solvent
the crude oil was chromatographied on silica gel using
AcOEt/Petrol (30:70) as eluent to give 3 as a colourless oil
(1.50 g, 70%); 1H NMR (CDCl3) d 2.39 (s, 3H, CH3), 3.74
(s, 3H, CO2CH3), 7.02 (d, 1H, JZ7.8 Hz, H5pyr), 7.80 (d,
1H, JZ7.8 Hz, H4pyr); 13C NMR (CDCl3) d 24.0,
52.4,121.7, 125.8, 139.6, 162.3, 165.0; IR (KBr) n 2953,
1732 (C]O ester), 1589, 1493, 1345, 1275–1249, 1145,
1051. Anal. Calcd for C8H8BrNO2 (230.08): C, 41.77; H,
3.51; N, 6.09. Found: C, 41.73; H, 3.42; N, 6.24%.
0 8C under N2. The solution was stirred for 1 h at 0 8C and
for 12 h at room temperature and then quenched with water
(10 ml). Extraction with CH2Cl2 (2!15 ml), washing with
brine, drying with MgSO4 and concentration in vacuo afford
8 a colorless oil (660 mg, 76%) which was used without
further purification; 1H NMR (CDCl3) d 2.37 (s, 3H, CH3),
3.40 (s, 3H, CH2OCH3), 5.12 (s, 2H, OCH2O), 6.92 (d, 1H,
JZ8.3 Hz, H5), 7.22 (d, 1H, JZ8.3 Hz, H4); 13C NMR
(CDCl3) d 23.4, 56.7, 95.5, 123.2, 124.2, 132.5, 148.8,
152.3; IR (KBr) n 2958–2926, 1557, 1455, 1269, 1156,
1062, 972; m/z (EI) 231.0(98%), 233.0(100%); Anal. Calcd
for C8H10BrNO2 (232.11): C, 41.40; H, 4.34; N, 6.04.
Found: C, 41.48; H, 4.21; N, 6.37%.
4.2.5. 2-bromo-6-methylpyridin-3-yl trifluoromethane-
sulfonate (9). A solution of 2-bromo-6-methylpyridin-3-ol
7 (1 g, 5.3 mmol) and pyridine (800 ml, 10.6 mmol) in
CH2Cl2 (30 ml) was cooled to 0 8C before adding slowly
triflic anhydride (1.08 ml, 6.4 mmol). The mixture was
stirred for 1 h at 0 8C and for 12 h at room temperature and
quenched by addition of water (10 ml). The pH of the
aqueous phase was adjusted to 9 by adding K2CO3 before
extraction with CH2Cl2. The organic layer was washed with
water and brine, dried (MgSO4). After evaporation of the
solvent, the crude product was chromatographed on silica
gel using AcOEt/Petrol (20:80) as eluent to give of 9 as a
4.2.2. 2-bromo-6-methylpyridine-3-carbaldehyde (5). A
solution of 2-bromo-6-methylpyridine-3-carbonitrile 4 (1 g,
5.1 mmol) in toluene (15 ml) was cooled at K60 8C.
Diisobutylaluminium hydride (3.4 ml of 1.5 M solution in
toluene, 5.12 mmol) was added dropwise over a 45 min
period while the temperature was maintained under
K50 8C. The solution was stirred for 2.5 h at K50 8C and
then carefully quenched by the dropwise addition of a
mixture of 2 M sulfuric acid (10 ml), toluene (6 ml), and
THF (3 ml). The resulted mixture was stirred for 16 h at
room temperature and water (15 ml) was added. The organic
layer was separated, washed with water (10 ml), brine and
concentrated in vacuo to afford 5 as a yellow solid (929 mg,
93%) which was used without further purification; mp
1
yellow oil (1.62 g, 95%); H NMR (CDCl3) d 2.37 (s, 3H,
CH3), 7.02 (d, 1H, JZ8.3 Hz, H5), 7.33 (d, 1H, JZ8.3 Hz,
H4); 13C NMR (CDCl3) d 23.9, 1186.7, 123.9, 131.1, 134.7,
142.9, 159.9; IR (KBr) n 1584–1565, 1431, 1217, 1139,
1052; m/z (EI) 319(98%), 321(100%); Anal. Calcd for
C7H5BrF3NO3S (320.09): C, 26.27; H, 1.57; N, 4.38.
Found: C, 26.27; H, 1.69; N, 4.49%.
1
66 8C; H NMR (CDCl3) d 2.63 (s, 3H, CH3), 7.27 (d, 1H,
JZ7.6 Hz, H5pyr), 8.07 (d, 1H, JZ7.6 Hz, H4pyr), 10.30 (s,
1H, CHO); 13C NMR (CDCl3) d 25.1, 123.5, 128.5, 138.4,
145.2, 166.1, 191.4; IR (KBr) n 3346, 2886, 1979,
1690(C]O ester), 1584, 1341, 1058, m/z (EI) 200.0;
Anal. Calcd for C7H6BrNO (199.98): C, 42.03; H, 3.02;
N, 7.00. Found: C, 42.36; H, 2.85; N, 7.21%.
4.2.6. 2-bromo-3-(methoxymethoxy)pyridine (17). The
procedure described above, using 2-bromopyridin-3-ol
(647 mg, 3.72 mmol) instead of 2-bromo-6-methylpyridin-
1
3-ol, gave 17 (527 mg, 65%) as a colorless oil; H NMR
(CDCl3) d 3.46 (s, 3H, CH2OCH3), 5.22 (s, 2H, OCH2O),
7.15 (dd, 1H, JZ8.1, 4.5 Hz, H5), 7.36 (dd, 1H, JZ1.1,
8.1 Hz, H4), 7.97 (dd, 1H, JZ4.5, 1.1 Hz, H3); 13C NMR
(CDCl3) d 56.9, 95.3, 123.5, 123.8, 133.7, 142.9, 151.1; IR
(KBr) n 2959–2933, 1560, 1452, 1414, 1270, 1156, 1092–
1053, 971; m/z (EI) 217(98%), 219(100%); Anal. Calcd for
C7H8BrNO2 (218.07): C, 38.56; H, 3.70; N, 6.42. Found: C,
38.59; H, 3.98; N, 6.88%.
4.2.3. 2-bromo-6-methylpyridin-3-ol (7). A solution of
bromide (1.14 ml, 22.2 mmol) in pyridine (20 ml) was
slowly added over a 10 min period to a solution of
6-methylpyridin-3-ol 6 (2.2 g, 20.2 mmol) in pyridine
(40 ml) at room temperature. The reaction mixture was
stirred for an additional 1.5 h and concentrated under
vacuum. Water was added (15 ml) until complete precipi-
tation. The beige solid obtained corresponding to 7 was
filtered, washed by cool water and dry under reduced
pressure (2.6 g, 69%); mp 186–187 8C; 1H NMR (CDCl3) d
2.30 (s, 3H, CH3), 6.98 (d, 1H, JZ8.0 Hz, H5pyr), 7.12 (d,
1H, JZ8.0 Hz, H4pyr), 10.25 (1H, OH); 13C NMR (CDCl3) d
22.6, 123.6, 124.1, 129.3, 148.8, 149.0; IR (KBr) n 2923–
2431, 1560, 1494, 1293, 1218, 1083; m/z (EI) 187.0(98%),
189(100%); Anal. Calcd for C6H6BrNO (188.02): C, 38.33;
H, 3.22; N, 7.45. Found: C, 38.15; H, 3.14; N, 7.53%.
4.3. Synthesis of pryridine acrylates (20–34)
4.3.1. Methyl 2-((E)-2-(methoxycarbonyl)vinyl)-6-
methylpyridine-3-carboxylate (20). A degassed mixture
of methyl 2-bromo-6-methylpyridine-3-carboxylate 3
(0.30 g, 1.3 mmol), methyl acrylate (293 ml, 3.3 mmol),
allylpalladium chloride dimer Pd2(allyl2Cl2) (24 mg,
0.065 mmol), P(o-Tol)3 (40 mg, 0.13 mmol), Na2CO3
(320 mg, 3.9 mmol), toluene (2.53 ml) and dimethyaceta-
mide DMA (0.84 ml) was heated in a sealed tube at 115 8C
for 5 h. The reaction mixture was filtrated though Celite,
washed with AcOEt and concentrated in vacuo. The residue
was chromatographied on silica gel using AcOEt/Petrol
(30:70) as eluent to afford 20 (256 mg, 84%) as a white
solid; mp 66–67 8C; 1H NMR (CDCl3) d 2.60 (s, 3H, CH3),
3.82(s, 3H, CO2CH3pyr), 3.94 (s, 3H, CO2CH3acry), 7.09 (d,
4.2.4. 2-bromo-3-(methoxymethoxy)-6-methylpyridine
(8).
Diisopropylethylenediamine
DIPEA
(2 ml,
11.1 mmol) and chloro(methoxy)methane (565 ml,
7.5 mmol) was added to a solution of 2-bromo-6-methyl-
pyridin-3-ol 7 (700 mg, 3.7 mmol) in dry CH2Cl2 (45 ml) at

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N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
1H, JZ15.4 Hz, H), 7.19 (d, 1H, JZ8.1 Hz, H5), 8.11 (d,
1H, JZ8.1 Hz, H4), 8.51 (D, 1H, JZ15.4 Hz, H), 13C NMR
(CDCl3) d 25.2, 52.2, 53.0, 123.6, 123.8, 125.1, 139.2,
141.28, 152.2, 162.3, 166.7, 167.6; IR (KBr) n 2933–2953,
1714 (C]O ester); 1588, 1466–1438, 1319–1170, 1077
(C–O); m/z (EI) 235.0; Anal. Calcd for C12H13NO4
(235.09): C, 61.28; H, 5.56; N, 5.95. Found: C, 61.34; H,
5.39; N, 6.08%.
4.3.6. (E)-Methyl 3-(6-methylpyridin-2-yl)acrylate (25).
The procedure described above, using 2-bromo-6-methyl-
pyridine 10, gave 25 (150 mg, 65%) as a beige solid; mp
72 8C; 1H NMR (CDCl3) d 2.92 (s, 3H, CH3), 3.75 (s, 3H),
6.87 (d, 1H, JZ15.8 Hz, Hacry); 7.06 (d, 1H, JZ7.5 Hz, H5),
7.16 (d, 1H, JZ7.5 Hz, H3), 7.52 (d, 1H, JZ7.5 Hz, H4),
7.61 (d, 1H, JZ15.8 Hz, Hacry); 13C NMR (CDCl3) d 24.5,
51.7, 121.2, 121.5, 124.0, 136.8, 143.9, 152.1, 158.9, 167.3;
IR (KBr) n 3407, 3026–2960, 1723, 1591–1577, 1473, 1344,
1202; m/z (EI) 177.0 Anal. Calcd for C10H11NO2 (177.21):
C, 67.78; H, 6.26; N, 7.90. Found: C, 67.78; H, 6.21; N,
7.87%.
4.3.2. (E)-Methyl 3-(3-cyano-6-methylpyridin-2-yl)acryl-
ate (21). The procedure described above, using 2-bromo-6-
methylpyridine-3-carbonitrile 4, gave 21 (213 mg, 81%) as
a yellow solid; mp 138 8C; 1H NMR (CDCl3) d 2.64 (s, 3H,
CH3), 3.86 (s, 3H, CO2CH3), 7.25 (d, 1H, JZ8.1 Hz, H5),
7.26 (d, 1H, JZ15.2 Hz, Hacry), 7.85 (d, 1H, JZ8.1 Hz, H4),
7.97 (d, 1H, JZ15.2 Hz, Hacry); 13C NMR (CDCl3) d 25.1,
52.1, 106.8, 116.1, 123.6, 126.4, 137.9, 140.3, 154.1, 163.1,
166.4; IR (KBr) n 3071–2963, 2225 (C^N), 1721 (C]O
ester), 1583, 1457, 1179; m/z (EI) 202.0; Anal. Calcd for
C11H10N2O2 (202.19): C, 65.34; H, 4.98; N, 13.85. Found:
C, 65.24; H, 4.34; N, 13.22%.
4.3.7. (E)-Methyl 3-(6-bromopyridin-2-yl)acrylate (26).
The procedure described above, using 2,6-dibromopyridine
1
11, gave 26 (290 mg, 92%): white powder; mp 138 8C; H
NMR (CDCl3) d 3.81 (s, 3H, CO2CH3), 6.96 (s, 1H, JZ
15.6 Hz, Hacry), 7.33 (d, 1H, JZ7.5 Hz), 7.42 (d, 1H, JZ
7.5 Hz), 7.55 (d, 1H, JZ7.5 Hz), 7.56 (d, 1H, JZ15.6 Hz,
Hacry); 13C NMR (CDCl3) d 52.0, 123.0, 123.4, 128.7,
139.0, 141.6, 142.6, 154.0, 166.9; IR (KBr) n 2924, 1727,
1646, 1571–1549, 1437, 1320–1300, 1209–1121, 973; m/z
(EI) 241(100%), 243(98%); Anal. Calcd for C9H8BrNO2
(242.11): C, 44.66; H, 3.33; N, 5.79. Found: C, 44.49; H,
3.62; N, 5.72%.
4.3.3. (E)-Methyl 3-(3-formyl-6-methylpyridin-2-yl)-
acrylate (22). The procedure described above, using
2-bromo-6-methylpyridine-3-carbaldehyde 5, gave 22
1
(243 mg, 91%) as a yellow solid; mp 110 8C; H NMR
(CDCl3) d 2.65 (s, 3H, CH3), 3.85 (s, 3H, CO2CH3), 7.20 (d,
1H, JZ15.2 Hz, Hacry), 7.32 (d, 1H, JZ8.0 Hz, H5), 8.07 (d,
1H, JZ8.0 Hz, H4), 8.47 (d, 1H, JZ15.2 Hz, Hacry), 10.40
(s, 1H, CHO); 13C NMR (CDCl3) d 25.1, 51.9, 124.3, 126.3,
127.0, 137.9, 138.4, 152.7, 163.8, 164.8, 190.0; IR (KBr) n
2962, 1725, 1699, 1562, 1452, 1300, 1200, 1181; m/z (EI)
205.0; Anal. Calcd for C11H11NO3 (205.25): C, 64.38; H,
5.40; N, 6.83. Found: C, 64.22; H, 5.46; N, 6.52%.
4.3.8. (E)-Methyl 3-(6-methoxypyridin-2-yl)acrylate
(27). The procedure described above, using 2-bromo-6-
methoxypyridine 12, gave 27 (246 mg, 98%): colourless oil;
1H NMR (CDCl3) d 3.78 (s, 3H, CO2CH3), 3.91 (s, 3H,
OMe), 6.89 (d, 1H, JZ8.3 Hz, H5), 6.90 (d, 1H, JZ8.3 Hz,
H3), 6.93 (d, 1H, JZ15.4 Hz, Hacry), 7.51 (d, 1H, JZ8.3 Hz,
H4), 7.54 (d, 1H, JZ15.4 Hz, Hacry); 13C NMR (CDCl3) d
51.7, 53.2, 112.8, 118.4, 121.2, 138.9, 143.2, 150.0, 163.6,
167.4; IR (KBr) n 3407, 3026–2960, 1723, 1591–1577,
1473, 1344, 1202; m/z (EI) 193.0; Anal. Calcd for
C10H11NO3 (193.23): C, 62.17; H, 5.74; N, 7.25. Found:
C, 62.26; H, 5.73; N, 7.07%.
4.3.4. (E)-Methyl 3-(3-(methoxymethoxy)-6-methylpyri-
din-2-yl)acrylate (23). The procedure described above,
using 2-bromo-3-(methoxymethoxy)-6-methylpyridine 8,
1
gave 23 (253 mg, 82%): colourless oil; H NMR (CDCl3)
d 2.36 (s, 3H, CH3), 3.44 (s, 3H, CH2OCH3), 3.78 (s, 3H,
CO2CH3), 5.19 (s, 2H, OCH2O), 7.00 (d, 1H, JZ15.8 Hz,
Hacry), 7.05 (d, 1H, JZ8.7 Hz, H5), 7.34 (d, 1H, JZ8.7 Hz,
4.3.9. Methyl 6-((E)-2-(methoxycarbonyl)vinyl)pyridine-
2-carboxylate (28). The procedure described above, using
methyl 6-bromopyridine-2-carboxylate 13, gave 28
(285 mg, 99%): beige powder; mp 112 8C; 1H NMR
(CDCl3) d 3.80 (s, 3H, CO2CH3), 3.99 (s, 3H, CO2CH3),
6.95 (d, 1H, JZ15.8 Hz, Hacry), 7.61 (d, 1H, JZ7.9 Hz),
7.75 (d, 1H, JZ15.8 Hz, Hacry), 7.85 (d, 1H, JZ7.9 Hz, H4),
8.06 (d, 1H, JZ7.9 Hz); 13C NMR (CDCl3) d 52.3, 53.4,
123.8, 125.7, 126.7, 138.2, 143.1, 148.7, 153.6, 165.8,
167.1; IR (KBr) n 2964–2852, 1725, 1458, 1438, 1316–
1301, 1245, 1155, 977; m/z (EI) 221.0 Anal. Calcd for
C11H11NO4 (221.22): C, 59.73; H, 5.01; N, 6.33. Found: C,
59.81; H, 5.14; N, 6.13%.
H4), 8.05 (d, 1H, JZ15.8 Hz, Hacry);
13C NMR (CDCl3) d
24.0, 52.1, 56.7, 95.0, 121.8, 123.2, 125.4, 138.5, 144.9,
150.7, 151.8, 168.1; IR (KBr) n 2955–2842, 1717, 1637,
1740–1436, 1320, 1250, 1167; m/z (EI) 237.0; Anal. Calcd
for C12H15NO4 (237.30): C, 60.75; H, 6.37; N, 5.90. Found:
C, 60.64; H, 6.24; N, 5.86%.
4.3.5. 2-((E)-2-(Methoxycarbonyl)vinyl)-6-methylpyri-
din-3-yl trifluoromethanesulfonate (24). The procedure
described above, using 2-bromo-6-methylpyridin-3-yl tri-
fluoromethanesulfonate 9, gave 24 (258 mg, 61%) as a
1
yellow oil; H NMR (CDCl3) d 2.59 (s, 3H, CH3), 3.82 (s,
4.3.10. Methyl 2-((E)-2-(methoxycarbonyl)vinyl)pyri-
dine-3-carboxylate (29). The procedure described above,
using methyl 2-bromopyridine-3-carboxylate 14, gave 29
(110 mg, 36%): yellow oil; 1H NMR (CDCl3) d 3.81(s, 3H,
CO2CH3.), 3.95 (s, 3H, CO2CH3), 7.10 (d, 1H, JZ15.1 Hz,
Hacry), 7.34 (dd, 1H, JZ7.9, 4.9 Hz, H5), 8.22 (dd, 1H, JZ
1.9, 8.1 Hz, H4), 8.48 (d, 1H, JZ15.4 Hz, Hacry), 8.73 (dd,
1H, JZ1.9, 4.9 Hz, H6); 13C NMR (CDCl3) d 52.2, 53.1,
123.9, 125.4, 125.9, 138.9, 140.9, 152.7, 152.9, 166.4,
3H, CO2CH3), 7.15 (d, 1H, JZ15.4 Hz, Hacry), 7.22 (d, 1H,
JZ8.6 Hz, H5), 7.53 (d, 1H, JZ8.6 Hz, H4), 7.83 (d, 1H,
JZ15.4 Hz, Hacry); 13C NMR (CDCl3) d 24.5, 52.3, 116.7,
121.0, 125.8, 125.9, 130.3, 134.8, 143.6, 144.6, 159.2,
166.9; IR (KBr) n 3248, 3079–2850, 1727, 1454–1428,
1216, 1136; m/z (EI) 325.0; Anal. Calcd for C11H10F3NO5S
(325.29): C, 40.62; H, 3.10; N, 4.31; S,9.86. Found: C,
40.63; H, 2.97; N, 4.31; S, 9.74%.

N. Robert et al. / Tetrahedron 61 (2005) 4569–4576
4575
167.5; IR (KBr) n 3046–2854, 1717 (C]O ester); 1588,
1630, 1560, 1421, 1284–1258, 1083 (C–O); m/z (EI) 221.0.
2H, JZ7.5 Hz, CH2CO2CH3), 3.47 (t, 2H, JZ7.5 Hz,
CH2CH2CO2CH3), 3.619 (s, 3H, CO2CH3), 3.89 (s, 3H,
CO2CH3), 7.04 (d, 1H, JZ7.9 Hz, H5pyr), 8.05 (d, 1H, JZ
7.9 Hz, H4pyr); 13C NMR (CDCl3) d 24.9, 31.9, 33.1, 51.8,
52.5, 121.1, 122.6, 139.3, 160.8, 161.6, 167.1 (CO2CH3-pyr),
174.2 (CO2CH3-aliph); IR (KBr) n 2995–2953, 1727, 1592,
1436, 1369, 1279–1257, 1196–1141, 1081; m/z (EI) 237.0;
Anal. Calcd for C12H15NO4 (237.21): C, 60.76; H, 6.37; N,
5.90. Found: C, 60.75; H, 6.38; N, 5.86%.
4.3.11. (E)-Methyl 3-(3-cyanopyridin-2-yl)acrylate (30).
The procedure described above, using 2-bromopyridine-3-
carbonitrile 15, gave 30 (86 mg, 35%): yellow oil; 1H NMR
(CDCl3) d 3.85 (s, 3H, CO2CH3), 7.23 (d, 1H, JZ15.4 Hz,
Hacry), 7.40 (dd, 1H, JZ4.5, 7.9 Hz, H5), 7.98 (d, 1H, JZ
15.4 Hz, Hacry), 7.97 (dd, 1H, JZ1.5, 7.9 Hz, H4), 8.17 (dd,
1H, JZ1.5, 4.5 Hz, H6); 13C NMR (CDCl3) d 52.5, 110.1,
116.0, 122.2, 127.0, 138.1, 140.8, 153.3, 155.1, 166.6; IR
(KBr) n 3077, 2947–2853, 2229, 1724, 1557, 1437, 1312,
1245–1172, 977; m/z (EI) 188.0.
4.3.16. 6,7-Dihydro-2-methylcyclopenta[b]pyridin-5-one
(1). Sodium methoxide (68 mg, 1.26 mmol) was added to a
solution of diester 35 (200 mg, 0.84 mmol) in THF (6 ml)
under N2. The mixture was warmed to reflux during 2 h. The
solvent was removed under vacuo and 2 ml of HCl 4.5 M
was added. The mixture was stirred 2 h at reflux. The pH
was then adjusted to 8 by adding K2CO3 before extraction
with CH2Cl2 The organic layer was washed with 10% aq
Na2CO3 (5 ml), satd aq. NH4Cl (5 ml) and dried (MgSO4).
After evaporation of the solvent the crude oil was
chromatographied on silica gel using AcOEt as eluent to
4.3.12. (E)-Methyl 3-(3-formylpyridin-2-yl)acrylate (31).
The procedure described above, using 2-bromopyridine-3-
1
carbaldehyde 16, gave 31 (104 mg, 42%): yellow oil; H
NMR (CDCl3) d 3.84 (s, 3H, CO2CH3), 7.18 (d, 1H, JZ
15.4 Hz, Hacry), 7.46 (dd, 1H, JZ7.9, 4.5 Hz, H5), 8.17 (dd,
1H, JZ7.9, 1.5 Hz, H4), 8.47 (d, 1H, JZ15.4 Hz, Hacry),
8.80 (dd, 1H, JZ4.5, 1.5 Hz, H6), 10.43 (s, 1H, CHO); 13
C
1
NMR (CDCl3) d 52.5, 124.8, 126.9, 129.7, 138.1, 138.8,
153.6, 154.1, 167.2, 190.6, IR (KBr) n 2957, 1724–1702,
1560, 1438, 1308, 1189,–1170; m/z (EI) 191.0; Anal. Calcd
for C10H9NO3 (191.19): C, 62.82; H, 4.74; N, 7.33. Found:
C, 62.90; H, 4.78; N, 6.64%.
give 3 as a beige oil (107 mg, 86%); H NMR (CDCl3) d
2.66 (s, 3H, CH3), 2.76 (t, 2H, JZ6.0 Hz, CH2CH2-C]O),
3.22 (t, 2H, JZ6.0 Hz, CH2–C]O), 7.17 (d, 1H, JZ7.9 Hz,
H5pyr), 7.90 (d, 1H, JZ7.9 Hz, H4pyr); 13C NMR (CDCl3) d
25.7, 29.1, 36.2, 122.8, 128.4, 132.4, 166.5, 174.9, 205.1
(C]O); IR (KBr) 2925–2854, 1723 (C]O), 1590, 1307,
1107, 1031; m/z (EI) 147.0; Anal. Calcd for C9H9NO
(147.16): C, 73.45; H, 6.16; N, 9.52. Found: C, 73.42; H,
6.33; N, 9.23%.
4.3.13. (E)-Methyl 3-(3-(methoxymethoxy)pyridin-2-
yl)acrylate (32). The procedure described above, using
2-bromo-3-(methoxymethoxy)pyridine 17, gave 32 (78 mg,
27%): colourless oil; 1H NMR (CDCl3) d 3.42 (s, 3H,
CH2OCH3), 3.74 (s, 3H, CO2CH3), 5.19 (s, 2H, OCH2O),
6.95 (d, 1H, JZ15.8 Hz, Hacry), 7.17 (dd, 1H, JZ4.1,
8.6 Hz, H5), 7.41 (dd, 1H, JZ8.6, 1.1 Hz, H4), 8.05 (d, 1H,
JZ15.8 Hz, Hacry), 8.20 (dd, 1H, JZ1.1, 4.1 Hz, H6); 13C
NMR (CDCl3) d 52.1, 56.8, 94.8, 122.1, 122.5, 125.6, 138.2,
143.1, 143.2, 152.7, 168.0; IR (KBr) n 3360, 2953–2925,
1714, 1575, 1442, 1309, 1201–1165, 983; m/z (EI) 223.0;
Anal. Calcd for C11H13NO4 (223.28): C, 59.19; H, 5.87; N,
6.27. Found: C, 59.26; H, 6.43; N, 6.41%.
References and notes
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¨
W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7. (e) Brase, S.;
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din-2-yl)acrylate (33). The procedure described above,
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de Meijere, A. In Metal-catalysed Cross-coupling Reactions;
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1
gave 33 (36 mg, 9%): yellow oil; H NMR (CDCl3) d 3.77
(s, 3H, CO2CH3), 7.10 (d, 1H, JZ15.4 Hz, Hacry), 7.34 (dd,
1H, JZ8.3, 4.5 Hz, H5), 7.65 (d, 1H, JZ8.3, 1.5 Hz, H4),
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4.5 Hz, H6); 13C NMR (CDCl3) d 52.5, 114.4, 125.9, 126.2,
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pyridine-3-carboxylate (35). A degassed suspension of
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methyl propenoate 20 (3.04 g, 12.92 mmol) in MeOH
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4576
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