An efficient route to 6-(het)aryl-2-methyl-2,3-dihydro-1H-pyridin-4-ones as potential nAChRs ligands

Article abstract of DOI:10.1016/j.tet.2004.03.085

A new efficient pathway to synthesise 6-(het)aryl-2-methyl-2,3-dihydro-1H- pyridin-4-ones is described. This reaction sequence involved, as a key step, a Suzuki cross-coupling reaction between various boronic acids and an 6-iodo-2,3-dihydropyridin-4-one. A final deprotecting step furnished the attempted products.

Full text of DOI:10.1016/j.tet.2004.03.085

Tetrahedron 60 (2004) 4861–4865
An efficient route to
6-(het)aryl-2-methyl-2,3-dihydro-1H-pyridin-4-ones
as potential nAChRs ligands
*
Nicolas Leflemme, Patrick Dallemagne and Sylvain Rault
´ ´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, UFR des Sciences Pharmaceutiques, 1 rue Vaubenard,
14032 Caen Cedex, France
Received 19 January 2004; revised 29 March 2004; accepted 30 March 2004
Abstract—A new efficient pathway to synthesise 6-(het)aryl-2-methyl-2,3-dihydro-1H-pyridin-4-ones is described. This reaction sequence
involved, as a key step, a Suzuki cross-coupling reaction between various boronic acids and an 6-iodo-2,3-dihydropyridin-4-one. A final
deprotecting step furnished the attempted products.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
large variety of heterocycles because their aminoenone
moiety can be used in various reactions leading to key
intermediates particularly useful in the synthesis of
alkaloids and pharmacologically active agents.5 In peculiar,
we have pointed out the interest of the dihydropyridinones
of type 1 (Scheme 1) as memory enhancers in relation to
their nicotinic acetylcholine receptor activity.6 Recently, we
have developed a new versatile and efficient four steps
procedure for the preparation of 6-alkyl-2-(het)aryl-2,3-
dihydro-1H-pyridin-4-ones 1,7 starting from available
b-(het)aryl-b-amino acids8 (Scheme 1).
Recently, numerous studies have focused on the synthesis of
ligands for neuronal nicotinic acetylcholine receptors
(nAChRs).1,2 Because, structures analogues of well
established nAChRs ligands have been suggested as
potential therapeutic agents for several neurological dis-
orders, including attention deficit, hyperactivity disorder,
Tourette’s syndrome, schizophrenia, Alzheimer’s and
Parkinson’s diseases.3
Moreover, most of the nAChRs ligands with high affinity
contain pyridine and cyclic amine pharmacophoric
moieties, and comprehensive reviews, which summarized
the structure–activity relationships of ligands for nAChRs,
have emphasized the importance in the ligand structure of a
p-system, such as a heteroaromatic ring or carbonyl group
as a hydrogen bond acceptor moiety, and a basic cyclic
amine group.4
With the aim to determine the influence of the double bond
position on the pharmacological properties we have
turned our attention to synthesise the isomers compounds
6-(het)aryl-2-methyl-2,3-dihydro-1H-pyridin-4-ones 2.9
2. Results and discussion
Dihydropyridinones are interesting building blocks for a
In connection with our previous works, we have studied the
Scheme 1.
Keywords: Cross-coupling; Suzuki reaction; Boronic acids; Heterocycles; Dihydropyridinone.
*
Corresponding author. Tel.: þ33-2-31-56-59-10; fax: þ33-2-31-93-11-88; e-mail address: dallemagne@pharmacie.unicaen.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.085

4862
N. Leflemme et al. / Tetrahedron 60 (2004) 4861–4865
Scheme 2. Retrosynthetic approach.
enaminone formation by the use of the acetate salt of ethyl
3-aminobutyrate and tert-butyl b-aryl-b-ketoester but
this method failed to produce the expected enaminone
intermediate 3 and instead led to degradation products
(Scheme 2).
We have therefore envisaged a second synthetic procedure
which consisted in a Suzuki cross-coupling reaction
between a protected 6-halo-2,3-dihydroprydin-4-one 4 and
various boronic acids (Scheme 2).
Scheme 3. Reagents and conditions: (a) (i) PhOCOCl (1.01 equiv.), THF,
225 8C; (ii) MeMgBr (1.05 equiv.), THF, 225 8C to room temperature;
(b) t-BuOK (4 equiv.), THF, 260 8C (91% in 2 steps); (c) (i) n-BuLi
(1.2 equiv.), THF, 260 8C; (ii) I2 (1.1 equiv.), THF, 260 8C to room
temperature; (iii) HCl 1 N (76%).
As illustrated in Scheme 3, the intermediate 4 was prepared
by applying Comins’s methodology.10 1-Acylpyridinium
Scheme 4. Reagents and conditions: (a) NaHCO3 (2.5 equiv.), 5 mol% Pd(PPh3)4, DME/H2O (v/v), reflux; (b) TFA (10 equiv.), CH2Cl2, room temperature.
Table 1. Suzuki cross-coupling reaction of 6-iodo-2,3-dihydropyridin-4-one with arylboronic acids and clivage of Boc protecting group in acidic conditions
Entry
ArB(OH)2
Cross-coupled product (isolated yield)
Deprotected product (isolated yield)
1
6a (87%)
2a (91%)
2
3
6b (78%)
6c (78%)
2b (92%)
2c (91%)
4
6d (80%)
2d (76%)

N. Leflemme et al. / Tetrahedron 60 (2004) 4861–4865
4863
Scheme 5. Reagents and conditions: (a) (i) NaNO2 (2 equiv.), HCl 6 N, 0 8C; (ii) CuCl (1.25 equiv.), 0 8C to room temperature (56%); (b) (i) n-BuLi
(1.2 equiv.), Et2O, 278 8C; (ii) B(OiPr)3 (1.2 equiv.), Et2O, 278 8C to room temperature (78%).
1
salt was formed in situ by addition of phenyl chloroformate
to 4-methoxypyridine in THF at 225 8C, and subsequent
treatment with methylmagnesium bromide afforded the
crude 1-phenoxycarbonyl-1,2-dihydropyridine.11 The latter
was converted to the N-Boc derivative 5 using t-BuOK at
260 8C in 91% overall yield for the two steps. Due to its
low stability 5 was engaged without purification in a
a-lithiation–iodation sequence12 using n-BuLi and iodine
to obtain, after an acidic workup, 6-iodo-2,3-dihydro-
pyridin-4-one 4 in 76% yield.
FT-IR System spectrometer. H NMR (400 MHz) and 13C
NMR (100 MHz) were recorded on a JEOL Lambda 400
spectrometer. Chemical shifts are expressed in ppm down-
field from the residual deuterated solvent or the internal
standard tetramethylsilane. Thin layer chromatographies
(TLC) were performed on 0.2 mm precoated plates of
silica gel 60F-254 (Merck). Visualization was made with
ultraviolet light (254 nm). Column chromatographies were
carried out using silica gel 60 (0.063–0.2 mm) (Merck).
Elemental analyses for new compounds were performed at
the ‘Institut de Recherche en Chimie Organique Fine’
(Rouen).
Intermediate 4 was then involved in a Suzuki-type cross-
coupling reaction13 with various commercial boronic acids
(Scheme 4). The use of aqueous condition14 to improve the
reactivity of the partners afforded derivatives 6 in good
yields after standard flash chromatography performed on
silica gel (Table 1).
3.1.1. tert-Butyl 6-iodo-2-methyl-1,2,3,4-tetrahydro-
pyridine-1-carboxylate (4).12a To a stirred solution of
4-methoxypyridine (2.03 mL, 20.0 mmol) in dried THF,
cooled to 225 8C, was added phenyl chloroformate
(2.53 mL, 20.2 mmol, 1.01 equiv.). The resulting reaction
mixture containing a white precipitate of pyridinium salts
was allowed to react at this temperature over 1 h, at which
point a solution of 3 M methylmagnesium bromide (7.0 mL,
21.0 mmol, 1.05 equiv.) was added dropwise. The reaction
mixture was abandoned at 225 8C for 1 h, and then allowed
to warm to room temperature under stirring for an additional
hour. The mixture was quenched with water (50 mL) and
extracted with diethyl ether (2£75 mL). The combined
organic layers were then dried (MgSO4) and the solvents
removed in vacuo. The oily residue was dissolved in dry
THF, cooled to 240 8C, and t-BuOK (8.98 g, 80.0 mmol,
4 equiv.) was added. The mixture was then abandoned at
240 8C for 2 h, and then allowed to warm to room
temperature under stirring for an additional hour. Diethyl
ether and water were then added to the mixture. The organic
layer was separated, dried over MgSO4 and concentrated to
dryness to yield 5 (4.10 g, 91%) as a yellow oil. The residue
was used without further purification in the next step. To a
solution of 5 (4.06 g, 18.0 mmol) in freshly distilled THF,
cooled to 260 8C, was added dropwise a solution of 2.5 M
n-BuLi (8.64 mL, 21.6 mmol, 1.2 equiv.). The resulting
mixture was allowed to react at this temperature over
30 min. A solution of iodine (5.03 g, 19.8 mmol, 1.1 equiv.)
in THF was then added. The reaction mixture was
abandoned at 260 8C for 2 h, and then allowed to warm
to room temperature under stirring for an additional hour.
The mixture was quenched by addition of 1 N HCl,
extracted with diethyl ether, dried over MgSO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using diethyl ether/petroleum
ether (4/6) as eluent to give 4 (4.61 g, 76%) as a yellow oil.
IR (KBr): 2978, 2932, 1722, 1668, 1549, 1369, 1324, 1158,
1121 cm21. 1H NMR (CDCl3) d 6.36 (s, 1H), 4.94 (m, 1H),
2.83 (dd, J¼17.5, 5.9 Hz, 1H), 2.34 (d, J¼17.5 Hz, 1H),
1.59 (s, 9H), 1.36 (d, J¼6.8 Hz, 3H). 13C NMR (CDCl3) d
191.0, 151.4, 128.2, 109.8, 84.5, 53.2, 43.4, 28.1, 16.2. MS
(EI) m/z (relative intensity) 337 ([Mþz], 25), 280 (20), 263
The 6-chloro-3-pyridinyl moiety confers high potency to
several types of compounds, like epibatidine15 and syn-
thetic analogues,2 acting at the nAChRs. In order to
incorporate this moiety on our dihydropyridinone structure,
we have turned our attention to synthesise the requisite
boronic acid.
Intermediate 5-bromo-2-chloropyridine 7, easily obtained
by a current Sandmeyer16 procedure from 2-amino-5-
bromopyridine, was engaged in a lithium–halogen
exchange reaction, carried out in Et2O at 278 8C using
n-BuLi, followed by the reaction with B(OiPr)3.13 The
desired boronic acid 8 is thus obtained with 78% yield
after an appropriate mild acido-basic work up and an easy
purification by recrystallisation (Scheme 5).17
Finally, protecting groups t-butoxycarbonyl were cleaved in
acid conditions using trifluoroacetic acid to give the title
6-(het)aryl-2-methyl-2,3-dihydro-1H-pyridin-4-ones 2a–d
in high yields (Table 1).
In conclusion, we have developed an efficient new method
for the synthesis of various substituted 6-(het)aryl-2-
methyl-2,3-dihydro-1H-pyridin-4-ones, based on a fast
and clean Suzuki cross-coupling reaction. The biological
evaluation of these new compounds is now under investi-
gation.
3. Experimental
3.1. General procedures
Commercial reagents were used as received without
additional purification. Melting points were determined on
¨
a Kofler melting point apparatus and are uncorrected. IR
spectra were taken with a Perkin–Elmer Spectrum BX

4864
N. Leflemme et al. / Tetrahedron 60 (2004) 4861–4865
(25), 237 (33), 236 (100), 221 (69), 193 (17), 165 (12), 110
(48), 84 (10).
1711, 1660, 1592, 1455, 1406, 1369, 1317, 1235, 1154,
1
1087, 816 cm21. H NMR (CDCl3) d 8.32 (d, J¼2.4 Hz,
1H), 7.55 (dd, J¼8.0, 2.4 Hz, 1H), 7.35 (d, J¼8.0 Hz, 1H),
5.57 (s, 1H), 5.03 (m, 1H), 2.93 (dd, J¼17.2, 5.8 Hz, 1H),
2.36 (d, J¼17.2 Hz, 1H), 1.49 (d, J¼6.7 Hz, 3H, CH3), 1.43
(s, 9H). 13C NMR (CDCl3) d 193.3, 152.1, 151.7, 150.4,
146.9, 136.0, 133.6, 123.9, 113.8, 83.4, 51.3, 43.3, 27.6,
16.7. Anal. calcd for C16H19N2O3Cl: C, 59.54; H, 5.93; N,
8.68. Found: C, 59.75; H, 5.88; N, 8.42.
3.1.2. 6-Chloropyridin-3-ylboronic acid (8). White solid
(78%). Spectroscopic data corresponds to that reported in
the literature.17
3.2. General procedure for the synthesis of tert-butyl
6-aryl-2-methyl-4-oxo-1,2,3,4-tetrahydropyridine-1-
carboxylates (6a–d)
3.3. General procedure for the synthesis of 6-aryl-2-
methyl-2,3-dihydro-1H-pyridin-4-ones (2a–d)
To a solution of 4 (500 mg, 1.48 mmol) in DME (10 mL)
was added successively arylboronic acid (1.78 mmol,
1.2 equiv.), Pd(PPh3)4 (86 mg, 5 mol%) and a solution of
NaHCO3 (312 mg, 3.71 mmol, 2.5 equiv.) in water (5 mL).
The reaction mixture was heated at reflux, TLC indicated
complete conversion of the substrate (6 h). After cooling to
room temperature, the mixture was extracted with CHCl3
(2£15 mL), then the combined organic layers were dried
over CaCl2 and the solvents were removed in vacuo to leave
the crude product which was purified by column chroma-
tography on silica gel. Elution with diethyl ether–petroleum
ether furnished 6a–d.
To a solution of tert-butyl 6-aryl-2-methyl-4-oxo-1,2,3,4-
tetrahydropyridine-1-carboxylate (0.85 mmol) in CH2Cl2
(5 mL), cooled to 0 8C, was added dropwise TFA (830 mL,
8.52 mmol, 10 equiv.). This mixture was stirred at room
temperature until complete by TLC analysis (Et2O/
petroleum ether). Once complete (4 h) the reaction mixture
was quenched with aqueous saturated K2CO3 solution,
extracted with CH2Cl2, dried over CaCl2, and concentrated
in vacuo. The residue was purified by column chromato-
graphy on silica gel using EtOAc as eluent to give 2a–d.
3.2.1. tert-Butyl 2-methyl-4-oxo-6-(thien-2-yl)-1,2,3,4-
tetrahydropyridine-1-carboxylate (6a). Yellow solid
(87%), mp 90–91 8C. IR (KBr): 3087, 2973, 2933, 1718,
3.3.1. 2-Methyl-6-(thien-2-yl)-2,3-dihydro-1H-pyridin-4-
one (2a). Yellow solid (91%), mp 155–156 8C. IR (KBr):
3288, 3071, 2963, 2926, 1605, 1572, 1505, 1449, 1339,
1275, 1248, 1166, 769, 708 cm21. 1H NMR (CDCl3) d 7.45
(dd, J¼5.1, 0.8 Hz, 1H), 7.43 (dd, J¼3.7, 0.8 Hz, 1H), 7.11
(dd, J¼5.1, 3.7 Hz, 1H), 5.50 (s, 1H), 5.24 (s, 1H), 3.94 (m,
1H), 2.46 (dd, J¼16.1, 5.1 Hz, 1H), 2.37 (dd, J¼17.4,
13.0 Hz, 1H), 1.41 (d, J¼6.3 Hz, 3H). 13C NMR (CDCl3) d
193.0, 154.3, 137.9, 128.5, 128.1, 126.6, 97.8, 49.1, 43.5,
20.3. Anal. calcd for C10H11NOS: C, 62.15; H, 5.74; N,
7.24. Found: C, 62.34; H, 5.62; N, 7.02.
1
1659, 1584, 1424, 1389, 1308, 1227, 1160, 703 cm21. H
NMR (CDCl3) d 7.43 (d, J¼4.9 Hz, 1H), 7.21 (d, J¼3.3 Hz,
1H), 7.07 (dd, J¼4.9, 3.3 Hz, 1H), 5.79 (s, 1H), 5.02 (m,
1H), 2.92 (dd, J¼17.4, 5.8 Hz, 1H), 2.35 (d, J¼17.4 Hz,
1H), 1.41 (d, J¼7.0 Hz, 3H), 1.22 (s, 9H). 13C NMR
(CDCl3) d 194.0, 152.9, 148.3, 141.5, 127.7, 127.5, 126.7,
112.5, 82.6, 51.3, 43.7, 27.5, 16.8. Anal. calcd for
C15H19NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C, 61.34;
H, 6.71; N, 4.86.
3.3.2. 2-Methyl-6-(phenyl)-2,3-dihydro-1H-pyridin-4-
one (2b). Beige solid (92%), mp 161 8C. IR (KBr): 3268,
2971, 2934, 1605, 1580, 1511, 1449, 1387, 1348, 1271,
3.2.2. tert-Butyl 2-methyl-4-oxo-6-phenyl-1,2,3,4-tetra-
hydropyridine-1-carboxylate (6b). Beige solid (78%),
mp 99 8C. IR (KBr): 3057, 3033, 2981, 2967, 2929, 1709,
1655, 1569, 1326, 1231, 1161, 768 cm21. 1H NMR (CDCl3)
d 7.41–7.33 (m, 5H), 5.63 (s, 1H), 5.04 (m, 1H), 2.98 (dd,
J¼17.3, 5.9 Hz, 1H), 2.40 (d, J¼17.3 Hz, 1H), 1.44 (d, J¼
7.0 Hz, 3H, CH3), 1.08 (s, 9H). 13C NMR (CDCl3) d 194.1,
155.0, 152.6, 138.9, 129.7, 128.4, 126.1, 112.8, 82.5, 51.3,
43.6, 27.4, 16.7. Anal. calcd for C17H21NO3: C, 71.06; H,
7.37; N, 4.87. Found: C, 70.92; H, 7.51; N, 4.71.
1
1167, 769, 694 cm21. H NMR (CDCl3) d 7.54–7.52 (m,
5H), 5.39 (s, 1H), 5.04 (s, 1H), 3.94 (m, 1H), 2.46 (dd, J¼
16.2, 5.3 Hz, 1H), 2.38 (dd, J¼16.2, 13.1 Hz, 1H), 1.41 (d,
J¼6.5 Hz, 3H). 13C NMR (CDCl3) d 193.2, 161.5, 135.7,
130.8, 128.9, 126.1, 98.5, 49.2, 43.3, 20.4. Anal. calcd for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.21; H,
7.06; N, 7.22.
3.3.3. 6-(3-Chlorophenyl)-2-methyl-2,3-dihydro-1H-pyri-
din-4-one (2c). Beige solid (91%), mp 133 8C. IR (KBr):
3255, 3080, 2973, 2932, 2887, 1605, 1574, 1514, 1447,
3.2.3. tert-Butyl 6-(3-chlorophenyl)-2-methyl-4-oxo-
1,2,3,4-tetra-hydropyridine-1-carboxylate (6c). Beige
solid (78%), mp 101 8C. IR (KBr): 3022, 2968, 2931,
2876, 1714, 1674, 1582, 1562, 1478, 1396, 1368, 1311,
1
1339, 1275, 1165, 782, 492 cm21. H NMR (CDCl3) d
7.51–7.37 (m, 4H), 5.33 (s, 1H), 5.10 (s, 1H), 3.93 (m, 1H),
2.45 (dd, J¼16.1, 4.8 Hz, 1H), 2.37 (dd, J¼16.1, 13.1 Hz,
1H), 1.41 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3) d 193.3,
160.0, 137.5, 134.9, 130.7, 130.3, 126.3, 124.2, 98.9, 49.3,
43.2, 20.3. Anal. calcd for C12H12NOCl: C, 65.02; H, 5.46;
N, 6.32. Found: C, 65.15; H, 5.79; N, 6.13.
1
1153, 799 cm21. H NMR (CDCl3) d 7.41–7.23 (m, 4H),
5.61 (s, 1H), 5.05 (m, 1H), 2.96 (dd, J¼17.3, 5.8 Hz, 1H),
2.37 (d, J¼17.3 Hz, 1H), 1.44 (d, J¼6.8 Hz, 3H, CH3), 1.12
(s, 9H). 13C NMR (CDCl3) d 193.9, 153.3, 152.2, 140.6,
134.4, 129.8, 129.5, 126.2, 124.3, 113.1, 82.8, 51.3, 43.5,
27.5, 16.7. Anal. calcd for C17H20NO3Cl: C, 63.45; H, 6.26;
N, 4.35. Found: C, 63.39; H, 6.36; N, 4.21.
3.3.4. 6-(6-Chloropyridin-3-yl)-2-methyl-2,3-dihydro-
1H-pyridin-4-one (2d). Beige solid (76%), mp 216 8C. IR
(KBr): 3256, 3104, 2968, 2927, 2891, 1613, 1591, 1567,
3.2.4. tert-Butyl 6-(6-chloropyridin-3-yl)-2-methyl-4-
oxo-1,2,3,4-tetra-hydropyridine-1-carboxylate (6d). Beige
solid (80%), mp 115 8C. IR (KBr): 3038, 3003, 2969, 2932,
1
1513, 1459, 1332, 1275, 1109, 796, 486 cm21. H NMR
(d6-DMSO) d 8.65 (d, J¼2.0 Hz, 1H), 8.07 (dd, J¼8.3,

N. Leflemme et al. / Tetrahedron 60 (2004) 4861–4865
4865
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1H), 3.78 (s, 1H), 2.28 (dd, J¼15.9, 4.3 Hz, 1H), 2.16 (dd,
J¼15.9, 13.0 Hz, 1H), 1.29 (d, J¼6.0 Hz, 3H). 13C NMR
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Acknowledgements
We appreciate the financial support provided by the
`
‘Ministere de la Recherche et de la Technologie’ for a
doctorate grant to N.L. (1999–2002) and ‘le Groupe de
Recherche Servier’.
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