Multicomponent synthesis of highly substituted 2-pyridones

Article abstract of DOI:10.1055/s-2007-967992

A novel synthesis of polyfunctionalised pyridones, structurally related to cardiotonic agent milrinone is described. The procedure consists of an Ugi four-component reaction of 3-formylchromones, followed by a base-promoted ring-opening/ring-closing proce

Full text of DOI:10.1055/s-2007-967992

LETTER
327
Multicomponent Synthesis of Highly Substituted 2-Pyridones
Multicomponent
S
n
ynthesis of
Pa
yridones G. Neo,a Rosa María Carrillo,a Susana Barriga,a Edelmiro Momán,b Stefano Marcaccini,c Carlos F. Marcos*a
a
b
c
Laboratorio de Química Orgánica y Bioorgánica, LOBO, Departamento de Química Orgánica, Facultad de Veterinaria, Universidad de
Extremadura, 10071 Cáceres, Spain
Centre for Synthesis & Chemical Biology, Department of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland,
123 St. Stephens Green, Dublin 2, Ireland
Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, 50019 Sesto Fiorentino FI, Italy
Fax +34(927)257110; E-mail: cfernan@unex.es
Received 14 June 2006
As part of our studies on the synthetic utility of multicom-
ponent reactions, we have reported a two-step synthesis of
6-carboxamido-2-pyridones 2 (Figure 1).5 Recently, Beck
and co-workers have also reported a synthesis of 2-pyri-
Abstract: A novel synthesis of polyfunctionalised pyridones,
structurally related to cardiotonic agent milrinone is described. The
procedure consists of an Ugi four-component reaction of 3-formyl-
chromones, followed by a base-promoted ring-opening/ring-closing
process. Variation of three of the four components in the Ugi dones based on an Ugi four-component condensation.6
reaction allows access to the final products with a combinatorial
distribution of substituents.
Now we describe a new multicomponent strategy for the
synthesis of 5-aroyl-2-pyridone derivatives 8 related to
Key words: cyclisations, drugs, heterocycles, multicomponent
reactions, pyridines
milrinone.
We envisaged that formylchromones 3 could be trans-
formed to 5-aroyl-2-pyridones 8 through an Ugi reaction,
followed by an intramolecular cyclisation, with concomi-
tant opening of the pyranone ring of the chromone
(Scheme 1). In the past we have successfully applied
similar ring-switching strategies for the synthesis of other
heterocyclic systems.7
2-Pyridones constitute an important type of heterocycles,
which have shown varying biological activities. In partic-
ular 2-pyridones containing H-bond acceptor substituents
in position 5 constitute a relatively new class of specific
phosphodiesterase 3 (PDE3) inhibitors. These compounds
have been proposed as an advantageous alternative to
classic digitalis glycosides for the acute treatment of
congestive heart failure (CHF).1 In fact, milrinone (1;
Figure 1) is a 3-cyano-substituted pyridone that has been
launched by Sterling Winthrop for the clinical treatment
of patients with severe heart failure.2
Recently, the synthesis of 5-(2-hydroxybenzoyl)-2-oxo-
1,2-dihydropyridine-3-carbonitriles by the reaction of cy-
anoacetamide with 3-formylchromones has been report-
ed.8 A limitation of this method is the impossibility of
introducing substituents in position 6 of the pyridine
nucleus. Substituents in this position could be useful in
structure-activity relationship (SAR) studies. Further-
more, they may be important to enhance the PDE3A inhi-
bition (the principal mechanism of action of milrinone
analogues) and reduce a secondary activity related to an-
tagonism towards endogenous adenosine at the A1 recep-
tor.4c We think that an amide group in position 6 could
provide an extra H-bond with PDE3A Gln331, which is a
conserved residue in the superfamily of PDEs, essential
for the binding of inhibitors to the active site.9 Cyclisation
of Ugi adducts 7 would directly give 2-pyridones with an
amide substituent in the desired position.
Ph
N
N
Ph
O
N
R
COX
O
N
Me
H
milrinone (1)
2
Figure 1
A number of synthetic methods for the preparation of 2-
pyridones have been reported,3 and some of them have
been used to obtain milrinone analogues with improved
activity.4 Particularly, 2-oxo-3-pyridinecarbonitriles hav-
ing a carbonyl moiety at the 5-position exhibited a signif-
icant ionotropic activity. However, flexible syntheses of
polyfunctionalised 2-pyridones from easily available
starting materials are still required.
Accordingly, we performed the reaction between 3-
formylchromone (3, R1 = H), aniline (4, R2 = Ph), cyclo-
hexyl isocyanide (5, R3 = c-C6H11) and cyanoacetic acid
(6), by simply combining the four components in metha-
nol solution.10 Stirring the mixture at room temperature
readily led to the formation of a precipitate of the expected
Ugi four-component adduct 7a, which was isolated essen-
tially pure in a 67% yield.11
Subsequent treatment of 7a with potassium hydroxide in
methanol12 resulted in the immediate formation of an or-
ange precipitate, which was filtered and identified as the
potassium enolate 8a.13 As anticipated, the base promoted
SYNLETT 2007, No. 2, pp 0327–0329
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967992; Art ID: D17006ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
7

328
A. G. Neo et al.
LETTER
an intramolecular addition–elimination reaction of the
methylene alpha to the nitrile group onto the chromone
endocyclic double bond. Consequently the six-membered
pyranone ring was opened and a new pyridone ring was
formed (Scheme 1).
H
R2
H
O
N
R1
O
OMe
9
O
O
Figure 2
R1
NC
H
O
R2
O
nitrogen, and, more importantly, on the amide group at
position 6. On the other hand, pyridone carbon-4 remains
unsubstituted, as in all active milrinone analogues report-
ed in the literature.
3
O
O
N
H
N
MeOH
R1
R3
R2NH2
r.t., 24 h
O
4
NC
O
OH
R3NC
In summary, we have developed a practical method that
allows access, in just two reaction steps, to highly func-
tionalised pyridines with a variety of substituents. The ex-
perimental simplicity of this method and the possibility to
isolate both the intermediates and the final products by
simple filtration, with a reasonable grade of purity, makes
it suitable for combinatorial synthesis. This strategy could
be easily applied to the synthesis of libraries of analogues
of the inotropic/vasodilator agent milrinone.
5
6
7
H
R3
R2
K
O
N
HO
O
KOH
MeOH
N
O
R1
CN
8
Scheme 1
Table 1 Results of the Ugi and Cyclisation Steps in the Synthesis of
2-Pyridone Derivatives
In order to study the scope of the method, we applied the
same procedure to different formylchromones 3, amines 4
and isocyanides 5 (Table 1).10,12 The Ugi condensation
accommodates a variety of aliphatic and aromatic iso-
cyanides and aromatic amines. However, electron-
deficient anilines form electrophilic Schiff bases with
formylchromone, which suffer conjugate addition of a
solvent molecule. The resulting stable enamine 9
(Figure 2)14 does not react further with the isocyanide and
the carboxylic acid. The addition of methanol, though,
seems to be reversible, as the methoxy group in 9 is ex-
changed with an ethoxy group when the enamines are
heated in ethanol. Although Ugi reactions are normally
favoured in protic solvents, we explored the use of non-
nucleophilic solvents in order to avoid the undesired
formation of enamine 9. For example, good results could
be obtained for p-chloroaniline (Table 1, entry d) using
toluene in the presence of ammonium chloride.15,16
R1
R2
R3
Yield of 7 Yield of 8
(%)a
67
49
68
48c
63
47
54
55
55
27
50
45
(%)b
75
75
84
58
51
79
59
57
22
61
62
62
a
b
c
d
e
f
H
Ph
c-C6H11
H
4-MeC6H4 c-C6H11
H
4-FC6H4
4-ClC6H4
Ph
c-C6H11
c-C6H11
t-Bu
H
H
H
4-MeC6H4 t-Bu
g
h
i
H
4-FC6H4
Ph
t-Bu
H
C5H11
H
4-FC6H4
4-FC6H4
Ph
C5H11
j
H
2,6-Me2C6H3
c-C6H11
t-Bu
The Ugi adducts usually precipitate from the reaction me-
dium, and can be isolated by simple filtration in moderate
to good yields and high degree of purity.11 After base-pro-
moted cyclisation, pyridones were isolated, also in high
yields and purity, as the corresponding potassium enolates
8, which precipitate as easily filterable yellow-orange
solids. The enolates have been characterized in their ionic
form, and their IR, 1H NMR, 13C NMR, MS and ACC–MS
spectroscopic data are in agreement with the proposed
structure.13 Table 1 summarises the results of the Ugi and
cyclisation reactions.
k
l
Me
Me
Ph
a Experimental procedure and representative data are given in refs. 10
and 11.
b Experimental procedure and representative data are given in refs. 12
and 13.
c Experimental procedure is described in ref. 16.
Acknowledgment
We thank Consejería de Educación Ciencia y Tecnología of Junta
de Extremadura and FEDER (2PR04A003 & 3PR05C022) for the
financial support.
As different 3-formylchromones 3, amines 4 and iso-
cyanides 5 are easily available; a wide variety of substitu-
ents can be introduced on the salicyl ring, on the pyridone
Synlett 2007, No. 2, 327–329 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of Pyridones
329
J = 18.5 Hz, 1 H), 3.17 (d, J = 18.5 Hz, 1 H,), 1.13–2.02 (m,
10 H). 13C NMR (100 MHz, CDCl3): d = 175.83 (C), 167.79
(C), 162.88 (C), 158.06 (CH), 155.75 (C), 138.34 (C),
134.03 (CH), 129.78 (CH), 129.51 (CH), 125.84 (CH),
125.57 (CH), 123.30 (C), 118.17 (CH), 117.93 (C), 113.81
(C), 55.84 (CH), 48.98 (CH), 32.66 (CH2), 26.51 (CH2),
25.39 (CH2), 24.72 (CH2). MS (EI): m/z (%) = 444 (<1) [M+
+ 1], 318 (12), 250 (100), 172 (3), 130 (5), 77 (2). HRMS:
m/z calcd for C26H25N3O4: 443.1849; found: 443.1845.
(12) Cyclisation of the Ugi Adducts (7): General Procedure: A
0.5 M solution of KOH in EtOH (1 mL, 0.5 mmol) was
added to a solution of the Ugi adduct (7, 0.5 mmol) in EtOH
(1 mL). The mixture was stirred for 8 h at r.t. and the orange-
yellow precipitate obtained was filtered and washed with i-
Pr2O, yielding compound 8 in an essentially pure form.
(13) Representative Data for Potassium 5-Cyano-2-
cyclohexylcarbamoyl-6-oxo-1-phenyl-1,6-dihydro-2H-
pyridin-3-ylidene(2-hydroxyphenyl)methanolate (8a):
Yield: 75%; orange solid; mp 275 °C (dec.). IR: 3439, 2928,
2194, 1679, 1607, 1554, 1520, 1240, 771 cm–1. 1H NMR
(400 MHz, DMSO): d = 10.66 (s, 1 H), 7.56 (d, J = 8.1 Hz,
1 H), 7.31 (t, J = 8.0 Hz, 2 H), 7.23 (t, J = 7.1 Hz, 2 H), 7.11–
7.19 (m, 3 H), 7.06 (s, 1 H), 6.86 (s, 1 H), 6.84 (s, 1 H), 5.28
(s, 1 H), 3.47–3.55 (m, 1 H), 1.04–1.75 (m, 10 H). 13C NMR
(100 MHz, DMSO): d = 183.28 (C), 169.91 (C), 164.31 (C),
156.83 (C), 147.65 (CH), 143.47 (C), 130.64 (CH), 129.59
(CH), 128.30 (CH), 125.68 (CH), 125.24 (C), 124.91 (CH),
122.21 (C), 118.34 (CH), 116.33 (CH), 105.83 (C), 78.28
(C), 62.07 (CH), 47.03 (CH), 32.34 (CH2), 31.93 (CH2),
25.42 (CH2), 25.23 (CH2), 23.85 (CH2). MS (FAB): m/z
(%) = 520 (100) [M+ + K], 482 (96) [M+ +1], 444 (18), 376
(29), 356 (19), 355 (72), 338 (62), 317 (29). HRMS (FAB):
m/z calcd for C26H25KN3O4: 482.1482; found: 482.1487.
(14) Enamines 9 were identified by 1H NMR and 13C NMR as the
major products obtained in the reactions with 4-chloro-
aniline, 3,5-dichloroaniline, 4-nitroaniline and 1-amino-
naphthalene. For example 1H NMR data of (Z)-3-[(4-
chlorophenylamino)methylene]-2,3-dihydro-2-methoxy-
chromen-4-one (9; R1 = H, R2 = 4-ClC6H4), obtained from 4-
chloroaniline and 3-formylchromone, was identical to the
published data: (a) Fitton, A. O.; Frost, J. R.; Suschitzky, H.
Tetrahedron Lett. 1975, 16, 2099. (b) Fitton, A. O.; Frost, J.
R.; Houghton, P. G.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1979, 1691.
References and Notes
(1) Dorigo, P.; Gaion, R. M.; Belluco, P.; Fraccarollo, D.;
Maragno, I.; Bombieri, G.; Benetollo, F.; Mosti, L.; Orsini,
F. J. Med. Chem. 1993, 36, 2475.
(2) Information obtained from the Investigational Drugs
Database (IDDB, www.iddb3.com).
(3) For recent examples, see: (a) Chen, Y. H.; Zhang, H. J.;
Nan, F. J. J. Comb. Chem. 2004, 6, 684. (b) Hachiya, L.;
Ogura, K.; Shimizu, M. Synthesis 2004, 1349; and the
references therein.
(4) See, for example: (a) Fossa, P.; Menozzi, G.; Dorigo, P.;
Floreani, M.; Mosti, L. Bioorg. Med. Chem. 2003, 11, 4749.
(b) Altomare, C.; Cellamare, S.; Summo, L.; Fossa, P.;
Mosti, L.; Carotti, A. Bioorg. Med. Chem. 2000, 8, 909.
(c) Dorigo, P.; Fraccarollo, D.; Gaion, R. M.; Santostasi, G.;
Borea, P. A.; Floreani, M.; Mosti, L.; Maragno, I. Gen.
Pharmacol. 1997, 28, 781. (d) Mosti, L.; Schenone, P.;
Iester, M.; Dorigo, P.; Gaion, R. M.; Fraccarollo, D. Eur. J.
Med. Chem. 1993, 28, 853.
(5) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Heterocycles 1997, 45, 1589.
(6) Beck, B.; Picard, A.; Herdtweck, E.; Dömling, A. Org. Lett.
2004, 6, 39.
(7) (a) Marcaccini, S.; Pepino, R.; Marcos, C. F.; Polo, C.;
Torroba, T. J. Heterocycl. Chem. 2000, 37, 1501.
(b) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Synthesis 1997, 1389.
(8) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synlett 2004, 2287.
(9) Jeon, Y. H.; Heo, Y. S.; Kim, C. M.; Hyun, Y. L.; Lee, T. G.;
Ro, S.; Cho, J. M. CMLS, Cell. Mol. Life Sci. 2005, 62, 1198.
(10) Synthesis of the Ugi adducts (7): General Procedure for
Method A: 3-Formylchromone (3; R1 = H) or 6-methyl-2-
formylchromone (3; R1 = CH3, 5 mmol) was dissolved in
MeOH (5 mL). Amine 4 (5 mmol) was added, and the
mixture was stirred for 15 min at r.t. Isocyanide 5 (5 mmol)
and cyanoacetic acid (6; 5 mmol) were successively added
and the mixture was stirred for 24–48 h at r.t. An abundant
precipitate was formed, which was filtered and successively
washed with i-PrOH and i-Pr2O, yielding a product pure
enough to be used in the following reaction. For analytical
purposes it may be further purified by recrystallisation from
EtOH.
(11) Representative Data: 2-Cyano-N-[cyclohexyl-
carbamoyl(4-oxo-4H-chromen-3-yl)methyl]-N-phenyl-
acetamide (7a): Yield: 67%; white solid; mp 217–218 °C.
IR: 3336, 2931, 2360, 1650, 1543, 1466, 761 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.15 (d, J = 8.1 Hz, 1 H), 8.03 (s, 1
H), 7.64 (t, J = 7.1 Hz, 1 H), 7.03–7.60 (m, 7 H), 6.47 (d,
J = 8.4 Hz, 1 H), 6.31 (s, 1 H), 3.76–3.83 (m, 1 H), 3.33 (d,
(15) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859.
(16) Synthesis of the Ugi Adducts; Method B: Equimolar
amounts of the four components and NH4Cl were stirred in
toluene for 48 h at r.t. The resulting precipitate was filtered
and successively washed with i-PrOH and hexanes.
Synlett 2007, No. 2, 327–329 © Thieme Stuttgart · New York

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