Synthesis of pyridone and pyridine rings by [4+2] hetero-cyclocondensation

Article abstract of DOI:10.1016/j.tetlet.2004.10.142

Substituted pyridones and pyridines have been synthesised efficiently by employing iminium salt as a key precursor. These compounds were prepared using tandem [4+2] cycloaddition/deamination between azabutadiene and dienophiles.

Full text of DOI:10.1016/j.tetlet.2004.10.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9557–9559
Synthesis of pyridone and pyridine rings by [4+2]
hetero-cyclocondensation
A e´ lig Robin, Karine Julienne, Jean Claude Meslin and David Deniaud*
Laboratoire de Synth e` se Organique, UMR CNRS 6513, Facult e´ des Sciences et des Techniques,
rue de la Houssini e` re, BP 92208, 44072 Nantes Cedex, France
2
Received 23 September 2004; revised 22 October 2004; accepted 26 October 2004
Available online 11 November 2004
Abstract—Substituted pyridones and pyridines have been synthesised efficiently by employing iminium salt as a key precursor. These
compounds were prepared using tandem [4+2] cycloaddition/deamination between azabutadiene and dienophiles.
ꢀ
2004 Elsevier Ltd. All rights reserved.
The development of new methods for the synthesis of
substituted pyridines and pyridones is a topic of current
interest because of their presence in numerous natural
products along with the wide spectrum of physiological
to investigate the behaviour of this chain, when alkyl-
ated, towards dienophiles. Indeed, alkylation of com-
pound 1 using methyl iodide provides S-methyl salt 2
which presents the azadiene chain. In our previous
paper, we described the reactivity of this diazadienium
iodide 2 with glycosylisothiocyanates for the prepara-
tion of pyrimidine nucleoside analogues. With these
considerations in mind, we have further developed an
efficient approach to a variety of 3,6-disubstituted pyri-
din-2-ones 3 and di- or trisubstituted pyridines 4,7 start-
ing from S-methyl salt 2. As shown in Scheme 1,
reaction of vinylthioamide 1 with excess of methyl io-
dide at 25ꢁC in THF for 18h afforded the corresponding
S-methyl salt 2 as the sole product due to the preferen-
tial alkylation of the more nucleophilic sulfur atom.
1
–3
activities displayed by this class of compounds.
It is
well known that these heterocycles are valuable building
blocks in natural products synthesis. Many methods for
the preparation of these heterocyclic rings systems and
their fused analogues have been described in the litera-
1
7
4–7
ture.
The most versatile and useful strategy to pro-
duce pyridine derivatives is the cyclocondensation
between 1,3-dicarbonyl compounds and a 3-amino-
8
–10
enone, 3-aminoacrylate or cyanoacetamide.
In addi-
tion, construction of pyridine and pyridone rings by
metal-mediated [2+2+2] cycloaddition of alkynes with
nitriles or isocyanates, is an efficient method and has
1
1
been largely developed. On the other hand, a hetero-
Diels–Alder methodology employing azadienes repre-
sents a straightforward approach to build nitrogen
Treatment of compound 2 with a range of ketenes, ob-
tained from the corresponding acid chlorides, led to
[4+2] cyclocondensation which gave 6-methylsulfanyl-
pyridin-2(1H)-ones 3a–c. The heterocyclisation occurred
in a regiocontrolled manner by the action of excess
(3equiv) of ketene at room temperature, and by addition
of 4equiv of triethylamine to neutralise the hydracids
1
2–15
heterocycles.
In this communication, we report
our new approach to synthesise the title compounds
using hetero-Diels–Alder reactions with versatile diaza-
dienium salt forming substrates.
1
8
(HI and HCl) generated in the reaction. The final step
consisted of deamination of the supposed intermediary
We recently reported that 2,4-diaminothiabutadiene 1
was used as useful building block in the synthesis of var-
cycloadduct giving aza-lactams 3a–c with moderate
yields. It is noteworthy that IR and C NMR spectra
1
6
13
ious thiopyrans and thiophenes. In a view to extend
this work to the preparation of pyridines we decided
indicated that compounds 3a,b existed in the 2-hydroxy-
pyridine form probably due to the presence of internal
hydrogen bonding between the OH and ester group to
increase the stability. The proof of the structure of com-
pounds 3a–c, so the total regioselectivity, was deter-
Keywords: Pyridine; Pyridone; Cycloaddition; Heterocycles.
*
Corresponding author. Tel.: +33 2 51 12 5406; fax: +33 2 51 12 54
2; e-mail: david.deniaud@chimie.univ-nantes.fr
1
3
0
mined by the C NMR spectra where the carbon
0
040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.142

9558
A. Robin et al. / Tetrahedron Letters 45 (2004) 9557–9559
H
S
NH2
S
NH
2
I
S
N
O
H
CH3I
RHC C O
THF, 18 h, rt
CH CN, Et N,
3
3
R
1
8 h, rt
N
N
N
1
2 (96%)
-
Me NH
2
H
3
a: R = CO Me (58%)
2
S
N
OH
R
S
N
O
R
3
b: R = CO Et (56%)
2
3
c: R = C H (50%)
6
5
3
a-c
Scheme 1.
H
S
NH2I
CO
CO
2
R
R
S
N
CO R
S
N
CO R
2
2
CH Cl , Et N,
-Me NH
2
2
2
3
+
1
8 h, rt
CO
2
R
CO
a (R = Me, 62%)
4b (R = Et, 66%)
2
R
N
2
N
4
2
Scheme 2.
signal in position 2 (ꢀ165ppm) is unambiguously
attributed to iminol (for 3a,b) or amide (for 3c) function
of pyrimidic ring.
Boc
N
(
Boc) O, Et N,
2
3
S
NH
N
I
S
NH2
S
2
DMAP
CH Cl , 1 h, rt
2
2
N
I
N
Preliminary antiviral and cytotoxic assays for com-
pounds 3 against HSV-1 in Vero (African Green Mon-
key) cells were performed. Unfortunately, biological
tests showed that heterocycles did not display any
anti-herpes activity.
5
(92%)
2
R = COCH3
R = CHO
6a (85%), 7a (70%)
6b (65%), 7b (65%)
60˚C, 18 h
-Me NH
2
R = CO CH
6c (60%), 7c (53%)
2
3
We continued our investigations towards pyridines by
exposing diene 2 to dialkyl acetylenedicarboxylate. The
tandem [4+2] cycloaddition/deamination reaction be-
tween compound 2 and acetylenic dienophiles in the
presence of triethylamine allowed us to prepare pyri-
R
Boc
N
S
N
S
TFA
CH Cl , 4 h, rt
2
2
R
R
1
9
dines 4a,b in satisfactory yields (Scheme 2).
7
a-c
6a-c
To complete this study we investigated the behaviour of
cationic aza-1,3-butadiene 2 with acrylic dienophiles.
The [4+2] cycloaddition with acrolein, methyl vinyl
ketone or methyl acrylate did not occur and we never
observed the formation of the pyridine skeleton.
This failure was probably due to the relative instability
of S-methyl salt 2 and the lower reactivity of the acrylic
dienophiles relative to the ketenes or acetylenedicarb-
oxylates. To increase the reactivity of iminium salt,
which has two mesomeric forms either aza-1,3-diene or
aza-2,4-diene and to block the azabuta-1,3-diene form
in the heterocyclisation process, we protected the
nitrogen atom with tert-butoxycarbonyl group (Scheme
Scheme 3.
Compound 5 thus obtained in 92% yield was converted
to dihydropyridines 6a–c by cycloaddition reaction with
acrylic dienophiles and spontaneous deamination. The
1
H NMR spectra of 6a–c showed a singlet due to the
methylene group in position 2, and thus excluded
the regioisomeric 2-substituted structure. After depro-
tection of compounds 6a–c by trifluoroacetic acid in
dichloromethane, which promoted simultaneous aro-
2
matisation, pyridines 7a–c were isolated.
2
1
2
3
).
Current interest in the pyridine skeleton justifies devel-
opment of new methods to synthesise compounds with
this basic structure. In the approach presented here,
we have shown that our method is straightforward,
regioselective and applicable to a large range of dieno-
philes. We are currently investigating the scope of
The acylation of nitrogen with di-tert-butyl dicarbonate
in presence of 4-dimethylaminopyridine and triethylam-
ine was performed in dichloromethane at room temper-
1
6,20
ature according to the reported conditions.

A. Robin et al. / Tetrahedron Letters 45 (2004) 9557–9559
9559
these reactions by extending them to other dienophiles;
the results of these studies will be reported in due course.
15. Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56,
259–5288.
6. Robin, A.; Meslin, J. C.; Deniaud, D. Synthesis 2004, 10,
633–1640.
7. Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin,
J. C.; Deniaud, D. J. Org. Chem. 2003, 68, 8283–8587.
8. Experimental procedure for pyridones 3: diazapentadi-
enium iodide 2 (1mmol) was added to a solution of acid
chloride (3mmol) in acetonitrile (10mL). After 15min of
stirring at room temperature, the reaction mixture was
cooled to 0ꢁC and triethylamine (4mmol) was added. The
mixture was stirred at room temperature for an additional
5
1
1
1
1
Acknowledgements
The authors are grateful to the French Ministry of Edu-
cation, and the CNRS for financial support.
References and notes
1
resulting residue was partitioned between CH Cl (20mL)
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4
5
2
2
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azadiene 5 (2mmol), dienophile (5mL) and hydroquinone
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2
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2
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5
7, 1–27.
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1
2