Syntheses of 4-benzylpyridones via nucleophilic aromatic substitutions

Article abstract of DOI:10.1055/s-2001-17526

Different strategies were studied for the preparation of analogues of potent biarylmethanes non-nucleoside reverse transcriptase inhibitors. We undertook the study of the possible routes for the preparation of 3-cyano-4-(3,5-dimethylbenzyl)-5-ethyl-6-hydroxypyridin-2(1H)-one and its cyclic analogue 4-(3,5-dimethylbenzyl)-6-oxo-2,3,6,7-tetrahydrofuro [2,3-b] pyridine-5-carbonitrile. Preparation of the former was achieved from the anion of 4-methyl-5-ethyl-2,6-dimethoxynicotinonitrile either by a nucleophilic aromatic substitution reaction on 3,5-dimethyl iodobenzene or starting with a nucleophilic addition reaction on 3,5-dimethylcyclohexanone. Cyclic analogues were prepared by an unprecedented nucleophilic aromatic substitution of, for example, 3,5-dimethyliodobenzene with the dianion of 4-methyl-6-oxo-2,3,6,7-tetrahydrofuro[2,3-b]pyridine-5-carbonitrile. None of the herein described new compounds showed anti HIV-1 activity or cytotoxicity on cellular assays (CEM-SS and MT4).

Full text of DOI:10.1055/s-2001-17526

1806
PAPER
Syntheses of 4-Benzylpyridones via Nucleophilic Aromatic Substitutions
S
ynthese
s
of 4-Ben
v
zylpyridone
e
s via
N
ucle
s
ophilic
A
romati
L
c
S
ubstitutions . Janin,*a Christiane Huel,b Michel Legraverend,b Anne-Marie Aubertin,c Emile Bisagnib
a
UMR 176 CNRS-Institut Curie, 26 rue d’Ulm, 75248 Cedex 05, Paris, France
Fax +33(1)42346631; E-mail: Yves.Janin@curie.u-psud.fr
b
c
UMR 176 CNRS-Institut Curie and (c) U 350 INSERM-Institut Curie, Bat. 110 Campus Universitaire, F-91405 Orsay, France
INSERM U74 Institut de Virologie, 3 rue Koeberlé, F-67000 Strasbourg, France
Received 7 June 2001; revised 16 July 2001
the very active series of pyridone and HEPT derivatives
we previously reported.7–12
Abstract: Different strategies were studied for the preparation of
analogues of potent biarylmethanes non-nucleoside reverse tran-
scriptase inhibitors. We undertook the study of the possible routes
for the preparation of 3-cyano-4-(3,5-dimethylbenzyl)-5-ethyl-6-
hydroxypyridin-2(1H)-one and its cyclic analogue 4-(3,5-dimethyl-
benzyl)-6-oxo- 2,3,6,7-tetrahydrofuro [2,3-b] pyridine-5-carboni-
trile. Preparation of the former was achieved from the anion of 4-
methyl-5-ethyl-2,6-dimethoxynicotinonitrile either by a nucleo-
philic aromatic substitution reaction on 3,5-dimethyl iodobenzene
or starting with a nucleophilic addition reaction on 3,5-dimethylcy-
clohexanone. Cyclic analogues were prepared by an unprecedented
nucleophilic aromatic substitution of, for example, 3,5-dimeth-
yliodobenzene with the dianion of 4-methyl-6-oxo-2,3,6,7-tetrahy-
drofuro[2,3-b]pyridine-5-carbonitrile. None of the herein described
new compounds showed anti HIV-1 activity or cytotoxicity on cel-
lular assays (CEM-SS and MT4).
Compound 1 (Figure) was prepared via methyl function-
alization of the readily available starting material 4, which
we previously described.13 The anion of the picoline de-
rivative 4 (made with LDA) reacted in THF with 3,5-dim-
ethyliodobenzene to give the target biarylmethane 5
(Scheme 1). However, despite our efforts, separation of
compounds 4 and 5 was not possible. From the weight and
1H NMR spectra of the corresponding chromatographic
fraction, yields of 58% and 14% were inferred for com-
pounds 4 and 5, respectively. Attempts to complete this
reaction were disappointing and mostly led to the forma-
tion of numerous products. Isolation and identification of
compounds 6 and 7, that arise from the reaction of 4 with
potassium tert-butoxide in DMSO at room temperature
without any other electrophile, illustrates the inherent dif-
ficulties encountered in all our attempts under these type
of conditions.14–16 Indeed, compound 6 is possibly the re-
sult of tert-butoxide displacement of the methyl residue of
4, (as demethylation of arylmethylethers are achieved
with various anions17), whereas compound 7 probably
arises from the nucleophilic aromatic substitution of its
methoxy group by the deprotonated form of 4. The yield
of a SRN1 reaction starting with 2- or 4-picolines anions
was reported to be enhanced by a photochemical initiation
in liquid ammonia.18 Such a trial might have been
beneficial14 in our case, but was not attempted since ex-
tensive decomposition of 4 was also observed in liquid
ammonia upon addition of base.
Key words: HIV-1, pyridines, arylation, nucleophilic aromatic
substitution, SRN
1
The first HIV-1 non-nucleoside reverse transcriptase
inhibitors1–6 (NNRTIs) were discovered in the late 80’s in
the course of virus and enzyme-based screening of com-
pounds. As many new classes of NNRTIs were reported,5
the first clinical trials pointed out the quick occurrence of
HIV-1 resistant strains. Even worse, cross-resistance be-
tween different classes was observed. A few years later
the currently used concept of polychemotherapy of HIV
infection allowed the clinical development of NNRTIs.
Along with nucleoside reverse transcriptase inhibitors and
protease inhibitors, the compounds marketed represent
the third type1,3 of anti HIV drugs. Second generation of
NNRTIs under clinical development are focused on im-
proving potency against the resistant strains.2,5
From the medicinal chemistry point of view,4 it turns out
that amongst a series of NNRTIs, if most of the deriva-
tives are active on a narrow range of HIV-1 strains, some
analogues bearing somewhat ’small’ structural differenc-
es, compared to their respective series, retain an activity
on far more viral strains.2,5 These facts alone justify a thor-
ough structure-activity investigation in any series of
NNRTIs, provided that a panel of mutated HIV-1 strains
is available for testing. This paper is focused upon synthe-
ses of biarylmethanes compounds 1–3 which are related to
O
O
CN
CN
HN
HN
HO
O
( )n
2 : n = 1
3 : n = 2
1
Figure
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
1437-210X,E;2001,0,12,1806,1811,ftx,en;T04201ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of 4-Benzylpyridones via Nucleophilic Aromatic Substitutions
1807
Deprotection of 5 under any acidic conditions (HBr, BBr3
or TMSI) led to a dark material. It is likely that an acid-
catalysed electrophilic cyclization reaction of the nitrile
group followed by a quinone formation takes place. A
double demethylation of 5 to give the target pyridone 1
was however achieved in 30% yield using strongly basic
reaction conditions and microwave irradiation.20
OMe
OMe
CN
CN
N
i
N
MeO
MeO
OMe
5 (14%)
4
ii
OMe
OMe
For the preparation of cyclic analogues 2 and 3, a direct
arylation of the bisanions of compounds 13 and 14 was at-
tempted, in spite of the few examples reported. The
literature14 only mentions the successful arylation by SRN1
reaction of the enolate and carboxylate bisanion of 2-
acetylhomoveratric acid21 or arylation of dialkali salts of
1,3-diketones.22,23 However, arylation of 13 with 3,5-dim-
ethyliodobenzene in liquid ammonia using butyllithium
(2.5 equivalents) to generate lithium amide in situ led to a
nucleophilic aromatic substitution reaction. Separation of
the product from unreacted material had to be achieved
via the acetylation of the reaction mixture followed by
chromatography. Thus the acetylated dihydropyran 15
was isolated in 18% yield along with the acetylated start-
ing material in 30% yield. The same protocol applied to
14 (obtained via a condensation between acetyl- -
valerolactone24 and cyanoacetamide as reported for 2-
acetylbutyrolactone25) gave the dihydropyran 16 in a sim-
ilar yield along with the acetylated starting material.
CN
CN
CN
N
N
N
+
HO
MeO
6 (16%)
7 (15%)
Scheme 1 Reagents and conditions: i) LDA, THF, 3,5-dimethylio-
dobenzene, –78 °C to 25 °C; ii) t-BuOK, DMSO, 25 °C
In another approach, the nucleophilic reaction of 4 with
3,5-dimethylcyclohexanone (obtained by the Jones oxida-
tion of 3,5-dimethylcyclohexanol19) led to the alcohol 8. It
must be pointed out that, if the reaction was continued
overnight, the corresponding lactone 9 was also isolated.
Dehydration of 8 was achieved by using phosphorus oxy-
chloride in refluxing pyridine for a short time and mostly
led to compound 11 along with a small amount (3% as
1
judged from H NMR) of isomer 10. Treatment of this
chromatographic fraction with palladium over charcoal in
boiling decahydronaphthalene gave the separable mixture
of the corresponding hydrogenated cyclohexyl derivative
12 along with the target derivative 5 in 25% and 65%
yield, respectively. The former compound could arise
from hydrogenation of compound 10, which cannot arom-
atize without a double bond migration, and thus reacts
with the palladium-adsorbed hydrogen arising from the
transformation of 11 into 5. The fact that the 10/11 ratio
observed does not correspond to the 12/5 ratio might indi-
cate that the palladium-catalyzed isomerization of 11 into
10 is also a favoured process under the reaction condi-
tions.
OH
OAc
CN
CN
i
ii
N
N
2 (91%)
or 3 (88%)
O
O
( )n
( )n
15 : n = 1 (18%)
16 : n = 2 (16%)
13 : n = 1
14 : n = 2
Scheme 3 Reagents and conditions: i) a) NH2Li / NH3, 3,5-dimethy-
liodobenzene, –33 °C to 5 °C, b) Ac2O, MeCN, 25 °C; ii) MeOH /
NH3, CH2Cl2, 25 °C
Attempts to improve this nucleophilic aromatic substitu-
tion step were carried out on compound 13 and 3-meth-
yliodobenzene. A reaction trial with three equivalents of
butyllithium in liquid ammonia led to compound 17 in
20% yield along with 4% of compound 18 resulting from
over arylation. Addition of more butyllithium under the
same conditions did not give a better result. Addition of
three equivalents of potassium tert-butoxide in the same
solvent led to unidentified highly polar material. Two
more trials showed that the reaction proceeded in some-
what similar yield if ferrous chloride14,26 or N,N,N N -tet-
ramethylethylenediamine were added. Since we
suspected a scarce solubility of the reactant in liquid am-
monia, we undertook a trial in DMSO using potassium
tert-butoxide at room temperature, as previously de-
scribed,14,15 which showed that no arylation occurred in
our case.
OMe
OMe O
CN
N
N
O
i
+
4
MeO
MeO
OH
8 (52%)
9 (22%)
ii
OMe
OMe
CN
CN
N
N
+
MeO
MeO
10 (3%)
11 (83%)
iii
OMe
OMe
CN
CN
N
N
iv
+
1 (30%)
MeO
MeO
12 (25%)
5 (65%)
Scheme 2 Reagents and conditions: i) LDA, THF, 3,5-dimethyl-
cyclohexanone, –78 °C to 25 °C; ii) POCl3, pyridine, reflux; iii) Pd/
C, 190 °C; iv) t-BuOK, ethylene glycol, 18-C-6, microwave
Removal of the acetyl group of compounds 15, 16 and 17
was easily performed using methanolic ammonia and
gave the desired compounds 2, 3 and 19, respectively.
Synthesis 2001, No. 12, 1806–1811 ISSN 0039-7881 © Thieme Stuttgart · New York

1808
Y. L. Janin et al.
PAPER
chromatography using the same conditions led to the isolation of
pure compound 6 (0.15 g, 16%) identical with a previously de-
scribed sample;13 a second chromatographic fraction (containing
some more 6) was further purified by column chromatography over
neutral alumina (5% H2O) eluting with heptane–EtOAc (4:1) to
give compound 7 as an oil (0.14 g, 15.2%).
OAc
OR
CN
CN
N
N
i
+
13
O
O
17 : R = Ac (20%)
19 : R = H (88%)
ii
18 (4%)
5-Ethyl-4-(3’-cyano-5’-ethyl-2’-methoxy-4’-methylpyridin-6’-
yl-methyl)-2,6-dimethoxynicotinonitrile (7)
1H NMR (200 MHz): = 0.87 (t, 3 H, J = 7.2 Hz, CH3), 1.18 (t, 3
H, J = 8.0 Hz, CH3), 2.45 (d, 2 H, J = 8.0 Hz, CH2), 2.48 (s, 3 H,
CH3), 2.74 (q, 2 H, J = 7.2 Hz, CH2), 3.61 (s, 3 H, OCH3), 3.98 and
4.00 (2s, 2 3 H, 2 OCH3), 4.21 (s, 2 H, CH2).
Scheme 4 Reagents and conditions: i) a) NH2Li / NH3, 3-methylio-
dobenzene, –33 °C to 25 °C, b) Ac2O, MeCN, 25 °C; ii) MeOH / NH3,
CH2Cl2, 25 °C
13C NMR (50 MHz): = 13.1 and 13.3 (CH3), 17.7 (CH3), 19.0 and
21.2 (CH2), 35.7 (CH2), 53.6, 53.9 and 54.02 (OCH3), 89.0 (C-3),
95.4 (C-3’), 115.1 and 116.2 (CN), 117.8 (C-5), 128.8 (C-5’), 152.4
and 152.6 (C-4 and C-4’), 156.1 (C-6’), 161.7, 162.9 and 163.0 (C-
2, C-6, C-2’).
Compounds 1–3, 5, 9 and 19 were tested for their antiviral
activity on CEM-SS and MT4 cells infected with wild
type HIV-1. No significant effect was noted either on the
virus multiplication or on the cell metabolism at concen-
trations as high as 100 M. Thus, the conclusion of this
work is that our results are actually following a trend re-
cently described27 in a related case where a nitrile moiety
is also detrimental to anti HIV activity. The recently
reported28 reductive properties of 2,6-dihydroxypyridine
might also be the beginning of an explanation for the lack
of activity observed in our case. On the chemistry point of
view, this project led us to (a) devise original routes lead-
ing to compound 1–3, and (b) illustrate some unexpected
but inherent difficulties encountered in SRN1 chemistry14
with this type of highly functionalized pyridines.
MS (C.I., NH3): m/z = 381.
Preparation of Compounds 8 and 9
LDA (0.12 mol) prepared from diisopropylamine and BuLi (1.6 M)
in dry THF (80 mL, distilled over Na and benzophenone) was added
dropwise to a cooled (–78 °C) solution of compound 413 (8 g, 38.8
mmol) in anhyd THF (300 mL) under an inert atm. The solution was
stirred at –78 °C for 30 min prior to the addition of 3,5-dimethylcy-
clohexanone (14.6 g, 0.12 mol). The resulting solution was stirred
overnight, while allowing the temperature to warm-up to 25 °C, be-
fore quenching it with sat. NH4Cl. The suspension was evaporated
to dryness, the residue was dissolved in H2O, and extracted with
CH2Cl2. The organic phase was then washed with H2O, dried
(MgSO4) and concentrated to dryness using a high vacuum pump.
The residue was purified by chromatography over silica gel (hep-
tane–EtOAc, 9:1) yielding, in order of elution, the starting material
4 (0.85 g, 10%), alcohol 8 (6.75 g, 52%) and lactone 9 (recrystal-
lized from heptane; 2.98 g, 22%). In another trial, the reaction was
stirred for only 30 min at r.t. and if no lactone 9 was detected, more
starting material 4 (41%) was recovered as well as alcohol 8 (38%).
1H and 13C NMR spectra were recorded on Bruker AC-200 and
Varian multi-400 and 500 spectrometers. Unless otherwise stated,
CDCl3 was the solvent used. Chemical shifts ( ) are given in ppm
with respect to the TMS signal and coupling constants (J) are given
in Hz. Signal attribution was often confirmed by two dimensional
NMR experiments (COSY, NOESY, HMQC, HMBC). Column
chromatography was performed on Merck silica gel 60 (0.060–
0.200 mm). Unless otherwise stated, solvents were dried using acti-
vated 3Å or 4Å molecular sieves.
5-Ethyl-4-(1-hydroxy-3,5-dimethylcyclohexylmethyl)-2,6-
dimethoxynicotinonitrile (8)
Mp 117 °C.
1H NMR (400 MHz): = 0.56 (q, 1 H, J = 11.6 Hz, 1/2 CH2-4’),
0.87 (d, 6 H, J = 6.4 Hz, CH3-3’, -5’), 1.03 (t, 3 H, J = 7.3 Hz, CH3),
1.16 (m, 2 H, 1/2 CH2-2’, -6’), 1.63 (m, 3 H, 1/2 CH2-4’ and 1/2
CH2-2’, -6’), 1.73 (m, 2 H, CH-3’, -5’), 2.70 (q, 2 H, J = 7.3 Hz,
CH2), 2.96 (s, 2 H, CH2), 3.99 and 4.00 (2s, 6 H, OCH3).
13C NMR (50 MHz): = 13.5 (CH3), 19.5 (CH2), 22.1 (CH3-3’),
27.7 (CH2-4’), 43.3 (CH-3’), 44.2 (CH2), 45.9 (CH2-2’), 54.0
(OCH3), 74.2 (C-1’), 89.5 (C-3), 117.7 (C-5), 119.0 (CN), 152.3 (C-
4), 163.4 (C-2, C-6).
Antiviral Test
The capacity of the tested compounds to block HIV-1 replication
was measured in CEM-SS cells acutely infected with HIV-1 as pre-
viously described.23 Briefly, HIV-1 LA1 virus production was mea-
sured by quantification of the reverse transcriptase activity
associated with the virus particles released in the culture superna-
tant,29 except that 100 TCID50 of virus was used for infection. In
control experiments, uninfected cell cytotoxicity was determined
after 5 days of incubation using the colorimetric MTT test, based on
the property of mitochondrial dehydrogenases, which can reduce 3-
Anal. Calcd for C19H28N2O3: C, 68.65; H, 8.49; N, 8.43. Found: C,
68.63; H, 8.54; N, 8.25.
(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium
bromide
(MTT) to formazan.30 The 50% cytotoxic concentrations
(CC50 = concentration at which OD540 was reduced by half) were
derived from the computer-generated31 median effect plot of the
dose-effect data. CEM-SS cells were obtained from Peter Nara and
D. Richman through the AIDS Research and Reference Reagent
Program, Division of AIDS, NIAID, NIH.
Spiro{3,5-dimethylcyclohexane-1,3’-[5’-ethyl-6’,8’-dimethoxy-
3’,4’-dihydropyrano[3’,4’-c]pyridin-1’-one]} (9)
Mp 204 °C.
1H NMR (500 MHz): = 0.52 (q, 1 H, J = 11.6 Hz, 1/2 CH2-4), 0.81
(d, 6 H, J = 6.2 Hz, CH3-3, -5), 0.82 (m, 2 H, 1/2 CH2-2, -6), 1.01
(t, 3 H, J = 7.4 Hz, CH3), 1.65 (br d, 1 H, J = 11.6 Hz, 1/2 CH2-4),
1.93 (m, 4 H, CH-3, -5 and 1/2 CH2-2, -6), 2.48 (q, 2 H, J = 7.4 Hz,
CH2), 2.76 (s, 2 H, CH2), 3.97 and 4.03 (2s, 6 H, OCH3).
Preparation of Compounds 6 and 7 from 4
Dimethyl ether 4 (1 g, 4.8 mmol) and t-BuOK (1.09 g, 9.6 mmol)
were stirred at r.t. under an Ar atm in anhyd DMSO (20 mL; dis-
tilled over CaH2) for 48 h. The solution was concentrated to dryness
and a first chromatography over silica gel (heptane–EtOAc, 2:1) led
to the isolation of fractions with 0.5 g overall weight. A second
13C NMR (50 MHz): = 13.8 (CH3), 18.8 (CH2), 21.9 (CH3-3), 26.9
(CH2-4), 39.9 (CH-3), 43.1 (CH2-4’), 43.8 (CH2-2), 53.1 and 54.1
Synthesis 2001, No. 12, 1806–1811 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Benzylpyridones via Nucleophilic Aromatic Substitutions
1809
(OCH3), 79.8 (C-1), 99.6 (C-8’a), 114.8 (C-5’), 149.3 (C-4’a),
161.8, 162.1 and 163.1 (C-1’, C-8’, C-6’).
3-Cyano-4-(3,5-dimethylbenzyl)-5-ethyl-6-hydroxypyridin-
2(1H)-one (1)
Dimethyl ether 5 (0.25 g, 0.8 mmol), t-BuOK (0.27 g, 2.4 mmol),
crown ether 18-C-6 (0.02 g, 0.08 mmol) and anhyd ethylene glycol
(2 mL) were subjected to a 10 minute-long microwave irradiation in
a Synthewave 402 (PROLABO) microwave oven. The maximum
temperature allowed was 200 °C and the maximum/minimum irra-
diation powers were 100 W and 10 W. The resulting dark solution
was concentrated to dryness. The residue was dispersed in CH2Cl2
and the insoluble potassium salt of 1 was filtered. This solid was
further washed with CH2Cl2 and dried. This salt was then dissolved
in boiling H2O; the H2O was filtered and made acidic with 2 N HCl.
The precipitate formed was filtered off and dried in vacuo to give
pure compound 1 (0.07 g, 30%).
Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C,
68.54; H, 8.23; N, 4.01.
Dehydration of 8, Preparation of 10 and 11
Alcohol 8 (6.37 g, 19.2 mmol) was suspended in pyridine (50 mL)
and phosphorus oxychloride (5.35 mL, 57.5 mmol) was added. The
solution was refluxed for 40 min, cautiously poured into H2O, then
extracted with CH2Cl2. The organic phase was washed with H2O,
dried (MgSO4) and concentrated to dryness. The residue was puri-
fied by chromatography over silica gel (heptane–EtOAc, 10:1) to
give a mixture of 10 and 11 in a 3/97 ratio (as judged from 1H NMR
spectra) as an oil (5.35 g, 86%), which was used without further pu-
rification.
Mp 127 °C.
1H NMR (200 MHz, DMSO-d6): = 0.81 (t, 3 H, J = 7.2 Hz, CH3),
2.21 (s, 6 H, CH3), 2.32 (q, 2 H, J = 7.2 Hz, CH2), 3.90 (s, 2 H,
CH2), 6.72 (s, 2 H, CH-Ar), 6.83 (s, 1 H, CH-Ar).
13C NMR (50 MHz): = 13.6 (CH3), 18.8 (CH2), 20.9 (CH3), 36.2
(CH2), 84.2 (C-3), 114.3 (C-5), 118.5 (CN), 125.6 (CH-Ar), 127.7
(CH-Ar), 137.4 (C-Ar), 138.1 (C-Ar), 152.3 (C-4), 162.9 (C-6),
163.3 (C-2).
4-(3,5-Dimethylcyclohexyl-l-enylmethyl)-5-ethyl-2,6-
dimethoxynicotinonitrile (11)
1H NMR (MHz):
= 0.56 (m, 1 H, 1/2 CH2-4’), 0.87 (m, 6 H,
CH3-3’, -5’), 1.03 (m, 3 H, CH3), 1.60 (m, 3 H, CH2-6’ and 1/2 CH2-
4’), 1.90 (m, 1 H, CH-5’), 2.10 (m, 1 H, CH2-3’), 2.47 (q, 2 H,
J = 7.2 Hz, CH2), 3.37 (s, 2 H, CH2), 3.96 and 3.98 (2s, 6 H, OCH3),
4.96 (s, 1 H, CH-2').
Anal. Calcd for C17H18N2O2 H2O): C, 67.98; H, 6.71; N, 9.33; O,
15.98. Found: C, 67.97; H, 6.52; N, 9.21; O, 16.46.
The compound 10 was detected by its ethylenic signal at = 5.95
ppm.
Nucleophilic Aromatic Substitution, Compound 15, Typical
Procedure
Preparation of 12 and 5
The above chromatographic fraction containing 10 and 11 (4.25 g,
13.5 mmol) and 10% Pd/C (0.5 g, 0.34 mmol) was heated overnight
to reflux in decahydronaphthalene (50 mL). The suspension was fil-
tered, evaporated to dryness and the residue purified by chromatog-
raphy over silica gel (heptane–EtOAc, 12:1) to yield, in order of
elution: 12 (1.07 g, 25%), then 5 (2.79 g, 65%).
In a 500-mL three-necked flask equipped with a dry ice condenser
fitted with a KOH guard, 4-methyl-6-oxo-2,3,6,7-tetrahydrofu-
ro[2,3-b]pyridine-5-carbonitrile25 (13; 4 g, 22.7 mmol, dried under
vacuum) was dispersed in liq NH3 (250 mL). BuLi (1.6 M in hex-
ane, 36.0 mL, 56.8 mmol) was slowly added with a syringe and the
suspension was stirred in refluxing ammonia for 1 h. The 3,5-dim-
ethyliodobenzene (6.3 g, 27.2 mmol) was added to the light yellow
suspension. This mixture was stirred for 2 h in refluxing ammonia
before the temperature was allowed to rise overnight to r.t. The dark
residue obtained, containing the inseparable mixture of compound
2 along with starting material 13, was dispersed in dry MeCN (150
mL). Acetic anhydride (30 mL) was added, the solution was stirred
for 10 min, H2O (100 mL) was added, and the stirring resumed for
1 h. MeCN was removed under reduced pressure and the aqueous
phase extracted with CH2Cl2. The organic layer was washed with
H2O, dried (MgSO4) and concentrated to dryness (using a high vac-
uum pump) to remove most of the unreacted 3,5-dimethyliodoben-
zene. The residue was immediately purified by chromatography
over silica gel (heptane–EtOAc, 2:1) to yield the rather unstable
acetylated compound 15. Another more polar chromatographic
fraction contained the acetylated starting material (1.49 g, 30%). In
attempts starting with 3-methyliodobenzene, using 3 equiv (or
more) of BuLi, the bisarylated compound 18 was also isolated.
4-(3,5-Dimethylcyclohexylmethyl)-5-ethyl-2,6-
dimethoxynicotinonitrile (12)
The wax obtained contains a minor constituent (cyclohexyl isomer)
mostly visible on the 13C spectrum.
1H NMR (400 MHz): = 0.66–0.90 (m, 11 H, 3 CH, CH2, 2 CH3),
1.03 (m, 3 H, CH3), 1.40 (m, 2 H, CH2), 1.57 (m, 2 H, CH2), 2.48 (q,
2 H, J = 6.0 Hz, CH2), 2.62 (d, 2 H, J = 7.1 Hz, CH2), 3.96 and 3.98
(2s, 6 H, CH3).
13C NMR (50 MHz): = 13.7 (CH3), 19.5 (CH2), 22.5 (CH3-3’),
32.3 (CH-3’), 38.5 (CH2-4’), 38.8 (CH2-2’), 40.5 (CH2-2), 43.8
(CH-1’), 54.0 (OCH3), 88.2 (C-3), 116.6 (C-5), 117.2 (CN), 155.2
(C-4), 163.1 (C-2, C-6).
Anal. Calcd for C19H28N2O2: C, 72.12; H, 8.92; N, 8.84. Found: C,
72.01; H, 8.91; N, 8.87.
4-(3,5-Dimethylbenzyl)-5-ethyl-2,6-dimethoxynicotinonitrile
(5)
5-Cyano-4-(3,5-dimethylbenzyl)-2,3-dihydrofuro[2,3-b]pyrid-
in-6-yl Acetate (15)
Yield: 18%; wax.
Mp 100 °C.
1H NMR (200 MHz): = 0.89 (t, 3 H, J = 7.4 Hz, CH3), 2.22 (s, 6
H, CH3), 2.49 (q, 2 H, J = 7.4 Hz, CH2), 3.97 and 4.00 (2s, 6 H,
OCH3), 4.05 (s, 2 H, CH2), 6.70 (s, 2 H, CH-Ar), 6.80 (s, 1 H, CH-
Ar).
13C NMR (50 MHz): = 13.3 (CH3), 19.0 (CH2), 21.2 (CH3), 36.6
(CH2), 54.1 (OCH3), 88.5 (C-3), 116.3 (C-5), 117.7 (CN), 126.0
(CH-Ar), 128.2 (CH-Ar), 137.4 (C-Ar), 138.0 (C-Ar), 153.9 (C-4),
163.4 (C-2, C-6).
1H NMR (200 MHz): = 2.32 (s, 6 H, CH3), 2.36 (s, 3 H, CH3), 2.99
(t, 2 H, J = 8.7 Hz, CH2), 4.01 (s, 2 H, CH2), 4.68 (t, 2 H, J = 8.7
Hz, CH2), 6.76 (s, 2 H, CH-Ar), 6.87 (s, 1 H, CH-Ar).
13C NMR (50 MHz): = 20.8 (CH3), 21.2 (CH3CO), 26.5 (CH2-3),
38.0 (CH2), 70.9 (CH2-2), 95.6 (C-3a), 114.4 (C-5), 118.1 (CN),
126.6 (CH-Ar), 128.9 (C-Ar), 135.4 (C-Ar), 138.5 (C-Ar), 152.0
(C-4), 160.4 and 167.8 (C-6, C-7a), 170.2 (CO).
Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.02. Found: C,
73.13; H, 7.31; N, 9.02.
Synthesis 2001, No. 12, 1806–1811 ISSN 0039-7881 © Thieme Stuttgart · New York

1810
Y. L. Janin et al.
PAPER
6-Cyano-5-(3,5-dimethylbenzyl)-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-7-yl acetate (16)
Yield: 16%; wax.
1H NMR (200 MHz, DMSO-d6): = 1.94 (m, 2 H, CH2-3), 2.50 (s,
6 H, CH3), 2.34 (m, 2 H, CH2-4), 3.99 (s, 2 H, CH2), 4.31 (m, 2 H,
CH2-2), 6.73 (s, 2 H, CH-Ar), 6.84 (s, 1 H, CH-Ar).
1H NMR (200 MHz): = 1.96 (m, 2 H, CH2), 2.24 (s, 6 H, CH3),
2.36 (s, 3 H, CH3), 2.59 (t, 2 H, J = 6.3 Hz, CH2), 4.08 (s, 2 H, CH2),
4.32 (t, 2 H, J = 5.1 Hz, CH2), 6.67 (s, 2 H, CH-Ar), 6.84 (s, 1 H,
CH-Ar).
13C NMR (50 MHz, DMSO-d6): = 19.6 (CH2-3), 20.8 (CH3, CH2-
4), 36.8 (CH2), 67.9 (CH2-2), 93.4 (C-6), 98.9 (C-4a), 116.5 (CN),
125.4 (CH-Ar), 128.0 (CH-Ar), 135.5 (C-Ar), 137.5 (C-Ar), 157.4
(C-5), 159.8 and 160.8 (C-7, C-8a).
13C NMR (50 MHz): = 20.8 (CH2-3), 20.9 (CH3), 21.3 (CH2-4),
22.0 (CH3CO), 37.0 (CH2), 67.7 (CH2-2), 97.2 (C-4a), 114.4 (C-6),
115.3 (CN), 126.0 (CH-Ar), 128.7 (CH-Ar), 135.4 (C-Ar), 138.5
(C-Ar), 156.2 (C-5), 157.3 and 162.8 (C-7, C-8a), 167.9 (CO).
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52; O, 10.87.
Found: C, 73.14; H, 6.22; N, 9.39; O, 11.03.
4-(3-Methylbenzyl)-6-oxo-2,3,6,7-tetrahydrofuro[2,3-
b]pyridine-5-carbonitrile (19)
Yield: 88%.
5-Cyano-4-(3-methylbenzyl)-2,3-dihydrofuro[2,3-b]pyridin-6-
yl acetate (17)
Yield: 20%; wax.
Mp 260 °C (dec.).
1H NMR (200 MHz, DMSO-d6): = 2.27 (s, 3 H, CH3), 2.99 (t, 2
H, J = 7.7 Hz, CH2), 3.94 (s, 2 H, CH2), 4.64 (t, 2 H, J = 7.7 Hz,
CH2), 7.03–7.20 (m, 4 H, CH-Ar), 12.50 (br s, 1H, NH).
13C NMR (50 MHz, DMSO-d6): = 20.9 (CH3), 25.6 (CH2-3), 37.1
(CH2), 71.1 (CH2-2), 85.6 (C-5), 109.3 (C-3a), 116.5 (CN), 125.5–
127.4–128.5–129.0 (CH-Ar), 136.6 (C-Ar), 137.8 (C-Ar), 152.5 (C-
4), 165.9 and 168.5 (C-6, C-7a).
1H NMR (200 MHz): = 2.30 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 2.99
(t, 2 H, J = 8.7 Hz, CH2), 4.05 (s, 2 H, CH2), 4.66 (t, 2 H, J = 8.7
Hz, CH2), 6.97–7.18 (m, 4 H, CH-Ar).
13C NMR (50 MHz): = 20.8 (CH3), 21.4 (CH3CO), 26.5 (CH2-3),
38.1 (CH2), 70.9 (CH2-2), 95.6 (C-3a), 114.3 (C-5), 118.1 (CN),
125.8 (CH-Ar), 128.1 (C-Ar), 128.8 (CH-Ar), 129.5 (CH-Ar), 135.5
(C-Ar), 138.7 (C-Ar), 151.9 (C-4), 160.4 and 167.8 (C-6, C-7a),
170.2 (CO).
Anal. Calcd for C16H14N2O2 0.2H2O: C, 71.20; H, 5.38; N, 10.38;
O, 13.04. Found: C, 71.37; H, 5.49; N, 9.96; O, 12.98.
4-[Bis(3-methylphenyl)methyl]-5-cyano-2,3-dihydrofuro[2,3-
b]pyridin-6-yl acetate (18)
Yield: 4%; wax.
5-Methyl-7-oxo-3,4,7,8-tetrahydro-2H-pyrano[2,3-b]pyridine-
6-carbonitrile (14)
Step 1: Following the reported procedure,25 acetyl- -
valerolactone24 (3.46 g, 24.3 mmol) and cyanoacetamide (2.04 g,
24.3 mmol) were stirred in 28% aq ammonia (15 mL) for 12 days.
The suspension obtained was concentrated to dryness, the residue
was dispersed in H2O (10 mL) and acidified with 35% HCl. The re-
sulting precipitate was filtered off, washed with H2O and dried to
yield 3-cyano-2,6-dihydroxy-5-(3-hydroxypropyl)-4-methylpyri-
dine (2.2 g, 43%) as a white powder, which was used without fur-
ther purification. Step 2: this alcohol (3.2 g, 15.3 mmol) was then
refluxed in 35% HCl (40 mL) for 1 h. The solution was concentrated
to dryness and the residue was suspended and refluxed in EtOH
(100 mL) for 30 min in order to complete the heat-triggered cycli-
sation of 3-cyano-2,6-dihydroxy-5-(3-chloropropyl)-4-methylpyri-
dine. The resulting suspension was cooled, and filtered. The
obtained solid was finally washed with EtOH to give the pyranopy-
ridine 14 (2.55 g, 87%) as a slightly pink powder.
1H NMR (200 MHz): = 2.29 (s, 6 H, CH3), 2.32 (s, 3 H, CH3), 2.38
(m, 2 H, CH2), 4.51 (t, 2 H, J = 8.7 Hz, CH2), 5.81 (s, 1 H, CH),
6.79–6.87 (m, 4 H, CH-Ar), 7.06–7.23 (m, 4-H, CH-Ar).
13C NMR (50 MHz): = 20.8 (CH3), 21.5 (CH3CO), 27.4 (CH2-3),
54.0 (CH2), 70.8 (CH2-2), 95.9 (C-3a), 114.0 (C-5), 118.5 (CN),
126.3 (CH-Ar), 128.4 (C-Ar, CH-Ar), 129.1 (CH-Ar), 135.0 (C-
Ar), 138.6 (C-Ar), 154.6 (C-4), 160.7 and 167.7 (C-6, C-7a), 170.7
(CO).
Preparation of 2, 3 and 19
Compound 15, 16 or 17 was dissolved in CH2Cl2 (100 mL), an ex-
cess of methanolic ammonia was added and the solution was stirred
for 10 min. Upon complete disappearance of the starting material
(TLC monitoring), the suspension was evaporated to dryness. The
residue was dispersed in H2O, acidified with 1 N HCl and the pre-
cipitate was filtered, washed with H2O, then dried under vacuum
yielding compounds 2, 3, or 19.
3-Cyano-2,6-dihydroxy-5-(3-hydroxypropyl)-4-methylpyridine
Mp > 240 °C (dec.).
4-(3,5-Dimethylbenzyl)-6-oxo-2,3,6,7-tetrahydrofuro[2,3-
b]pyridine-5-carbonitrile (2)
Yield: 91%.
1H NMR (200 MHz, DMSO-d6): = 1.56 (m, 2 H, CH2), 2.26 (s, 3
H, CH3), 2.42 (t, 2 H, J = 7.7 Hz, CH2), 3.38 (t, 2 H, J = 6.1 Hz,
CH2).
Mp > 260 °C.
13C NMR (50 MHz, DMSO-d6): = 17.4 (CH3), 21.7 (CH2), 31.6
(CH2), 60.3 (CH2), 84.2 (C-3), 112.0 (C-5), 117.0 (CN), 152.4 (C-
4), 161.8 and 162.0 (C-2, C-6).
1H NMR (200 MHz, DMSO-d6): = 2.22 (s, 6 H, CH3), 2.97 (t, 2
H, J = 8.3 Hz, CH2), 3.89 (s, 2 H, CH2), 4.64 (t, 2 H, J = 8.3 Hz,
CH2), 6.81 (s, 2 H, CH-Ar), 6.86 (s, 1 H, CH-Ar).
5-Methyl-7-oxo-3,4,7,8-tetrahydro-2H-pyrano[2,3-b]pyridine-
6-carbonitrile (14)
Mp 260 °C (dec.).
1H NMR (200 MHz, DMSO-d6): = 1.92 (m, 2 H, CH2), 2.24 (s, 3
H, CH3), 2.44 (m, 2 H, CH2), 4.29 (m, 2 H, CH2) 12.4 (br s, 1 H,
NH).
13C NMR (50 MHz, DMSO-d6): = 17.8 (CH3), 19.7 (CH2-3), 20.9
(CH2-4), 68.1 (CH2-2), 91.6 (C-6), 99.8 (C-4a), 116.7 (CN), 157.5
(C-5), 158.6 and 160.7 (C-7, C-8a).
13C NMR (50 MHz, DMSO-d6): = 20.9 (CH3), 25.6 (CH2-3), 37.1
(CH2), 71.2 (CH2-2), 85.7 (C-5), 109.4 (C-3a), 116.6 (CN), 126.2
(CH-Ar), 128.2 (CH-Ar), 136.0 (C-Ar), 137.7 (C-Ar), 152.6 (C-4),
165.9 and 168.6 (C-6, C-7a).
Anal. Calcd for C17H16N2O2 1/3H2O: C, 71.31; H, 5.87; N, 9.78.
Found: C, 71.26; H, 5.75; N, 9.71.
5-(3,5-Dimethylbenzyl)-7-oxo-3,4,7,8-tetrahydro-2H-
pyrano[2,3-b]pyridine-6-carbonitrile (3)
Yield: 88%.
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.79. Found: C,
63.08; H, 5.33; N, 14.67.
Mp > 260 °C.
Synthesis 2001, No. 12, 1806–1811 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Benzylpyridones via Nucleophilic Aromatic Substitutions
1811
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Acknowledgement
Drs. Renée Pontikis and Daniel Dauzonne are gratefully acknow-
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MO, Orsay, France) is gratefully acknowledged for fruitful
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Synthesis 2001, No. 12, 1806–1811 ISSN 0039-7881 © Thieme Stuttgart · New York