3-Formylchromones in Guareschi synthesis of 5-(2-hydroxybenzoyl)-2- pyridones

Article abstract of DOI:10.1055/s-2004-832852

A set of 5-(2-hydroxybenzoyl)-pyrid-2-ones, which are analogous to cardiotonic drugs such as milrinone, has been prepared in high yield by recyclization of 3-formylchromones with acetic acid amides having at the α-position an electron-withdrawing group. The best reaction conditions were found to be heating in DMF in the presence of Me₃SiCl as a promoter and water scavenger.

Full text of DOI:10.1055/s-2004-832852

LETTER
2287
3-Formylchromones in Guareschi Synthesis of 5-(2-Hydroxybenzoyl)-
2-pyridones
3
-Formylchrom
e
one
s
in
G
r
g
Synthesis ey V. Ryabukhin,a,b Andrey S. Plaskon,b Dmitriy M. Volochnyuk,*a Andrey A. Tolmachevb
a
‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kiev, Ukraine
b
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
Fax +380(44)5373253; E-mail: dov@fosfor.kiev.ua
Received 6 May 2004
Abstract: A set of 5-(2-hydroxybenzoyl)-pyrid-2-ones, which are
analogous to cardiotonic drugs such as milrinone, has been prepared
in high yield by recyclization of 3-formylchromones with acetic
acid amides having at the a-position an electron-withdrawing
group. The best reaction conditions were found to be heating in
DMF in the presence of Me3SiCl as a promoter and water scaven-
ger.
Key words: 3-formylchromones, cyanoacetamides, 2-pyridones,
recyclization, chlorotrimethylsilane, parallel synthesis
Figure 1 The structures of the cAMP PDE III inhibitors.
ing a carbonyl function at the meso-position, such as 2-
2-Pyridones play an important theoretical and practical dimethylaminomethylene-1,3-diones (enamine diones).5
role in heterocyclic chemistry.1 Recently, interest in these The widely used latent 1,3-dialdehydes, having at the
compounds was reignited by the discovery of a new class meso-position a masked 2-hydroxybenzoyl fragment, are
of non-glycosidic cardiotonic agents, the cyclic adenosine 3-formylchromones.6 There are literature data on the reac-
3¢,5¢-monophosphate (cAMP) specific phosphodiesterase tion of 3-formylchromones with cyanoacetamide afford-
(PDEIII) inhibitors, which have been used for the treat- ing 5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydro-pyridine-3-
ment of congestive heart failure. All these agents are char- carbonitriles; however the reaction is accompanied with
acterized by the presence of the 2-pyridone nucleus, side reactions.7 Herein, we wish to report new reaction
prototypes being amrinone2 and particularly milrinone.3 conditions, under which only the targeted products form
Searches for analogues of milrinone have revealed that 2- in nearly quantitative yield. This makes the reaction a very
oxo-3-pyridinecarbonitriles (1) having a carbonyl moiety attractive tool for designing libraries of compounds via
at the 5-position also exhibited a significant ionotropic ac- semi-automated parallel synthesis.
tivity (Figure 1)4
3-Formylchromones (1) react with cyanoacetamide (2) in
The convenient method for synthesis of 2-oxo-3-pyridine- DMF solution at 100 ° in the presence of Me3SiCl8 yield-
carbonitriles having a carbonyl moiety at the 5-position is ing 5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-
the Guareschi reaction of cyanoacetamide as 1,3-CCN-bi- carbonitriles (6) as a single product of recyclization
nucleophile with different 1,3-CCC-bielectrophiles hav- (Scheme 1).9 This reaction is a general one; not only does
Scheme 1
SYNLETT 2004, No. 13, pp 2287–2290
0
3
.1
1
.2
0
0
4
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832852; Art ID: D11604ST
© Georg Thieme Verlag Stuttgart · New York

2288
S. V. Ryabukhin et al.
LETTER
Scheme 2
cyanoacetamide produce favorable results, but primary by-product iminopyrone 11 and its recyclization product,
and secondary amides of acetic acid having an p-electron- pyridone 10.7,14 On the other hand, under our condition,
withdrawing group at the a-position 3–5 do as well, af- Me3SiCl acts as a water scavenger, thus preventing the
fording the corresponding pyridones 6–9 (Scheme 1, formation of ketoaldehyde 13. Even if ketoaldehyde 13
Table 1). However, it should be noted that the use of sub- forms in the reaction mixture, it is silylated by excess of
strates bearing an active acetyl group, such as 3-oxobutan- Me3SiCl to form the O-silylated intermediate 14. This in-
amide (5), complicates the reaction and lowers the yield of termediate is unreactive with respect to the nitrile group,
targeted product 9.
but is able to form either chromone 12 or the targeted py-
ridone 6 (Scheme 2). Finally, any water present in the re-
action mixture would react with Me3SiCl to release HCl,
which catalyzes the reaction.
1
The structure of novel products was confirmed by H
NMR,10 13C NMR,11 IR spectroscopy,12 mass spectro-
metry,13 and elemental analysis.
Our attempts to extend the procedure to primary enamines
such as b-aminocrotonitrile and alkyl b-crotonates failed.
In this case, due to harsh reaction conditions, destruction
of starting enamines occurs and the targeted pyridines
were detected only in trace amounts. For the same reason
we have not been able to developed the preparative proce-
dure for interaction of 3-formylchromones with cy-
anoacetic acid thioamide and its derivatives.
We suggest that Me3SiCl plays several roles in the reac-
tion. One can imagine that the reaction occurs by the fol-
lowing mechanism. The first stage is the aldol
condensation of the amide methylene group with the alde-
hyde function of the the chromone leading to open-chain
products 12.6f,7 Subsequently, 12 could undergo either re-
cyclization to provide targeted pyridone 6 or cleavage of
the chromone ring by water, formed in the first stage, to
afford ketoaldehyde 13 that then leads to side reactions.
The latter can undergo 6-exo-dig cyclization of the enol
with the nitrile function, finally leading to formation of
Table 1 Yields and Melting Points of 2-Pyridones Obtaineda
Chromone Amide Product
R
R¢
EWG
CN
CN
CN
CN
CN
CN
CN
CN
Yield (%)b
Mp (°C, solvent)c
[M + 1]d
1a
1c
1d
1e
1d
1b
1d
1e
2
6a
H
H
75
73
84
70
85
72
70
84
263–265e (MeCN) 241
2
6c
F
H
265–266 (MeCN)
269–270 (MeCN)
262–263 (MeCN)
235–236 (MeCN)
181–182 (MeOH)
182–183 (MeOH)
205–206 (MeOH)
259
275
271
365
297
333
353
2
6d
Cl
H
2
6e
OMe
Cl
H
3a
3b
3c
3d
7da
7bb
7dc
7ed
CH2Ph
Me
Cl
CH(CH3)2
CH2CH2OMe
OMe
1d
3e
7de
Cl
CN
75
227–228 (MeCN)
315
Synlett 2004, No. 13, 2287–2290 © Thieme Stuttgart · New York

LETTER
3-Formylchromones in Guareschi Synthesis
2289
Table 1 Yields and Melting Points of 2-Pyridones Obtaineda (continued)
Chromone Amide Product
R
R¢
EWG
CN
Yield (%)b
Mp (°C, solvent)c
183–184 (MeCN)
178–179 (MeOH)
178–179 (MeOH)
[M + 1]d
351
1d
1e
1b
3f
3f
3g
7df
7ef
Cl
Ph
90
84
80
OMe Ph
Me
CN
347
7bg
CN
399
1d
1a
3h
3i
7dh
7ai
Cl
H
CN
CN
78
87
206–207 (MeCN)
202–203 (MeCN)
352
324
1d
3j
7dj
Cl
CN
72
220–221 (MeOH)
359
1b
1d
1b
4a
4b
4c
8ba
8db
8bc
Me
Cl
CH2Ph
Ph
CONHCH2Ph
CONHPh
81
88
86
159–160 (MeOH)
232–233 (MeCN)
259–260 (MeCN)
453
445
515
Me
1d
4d
8dd
Cl
90
228–229 (MeCN)
473
1c
1c
4e
4f
8ce
8cf
F
F
78
73
155–156 (MeOH)
166–167 (MeOH)
441
417
1b
4g
8bg
Me
79
140–141 (MeOH)
541
1e
1e
5a
5b
9ea
9eb
OMe
H
COMe
COMe
62
68
189–190 (MeOH)
201–202 (MeOH)
288
302
OMe Me
a Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
b Yields refer to pure isolated product.
c Melting points are uncorrected.
d APSI MS, Agilent 1100\DAD\MSD VL G1965a instrument.
e Lit. 266–268 °C (dec.).7a
Vol. 2; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press
Ltd.: Oxford, 1984, 315.
Acknowledgment
The authors acknowledge Turov A. V., Alekseev S. A. (Department
of Chemistry of Kyiv National Taras Shevchenko University) and
Mazepa A. V. (Bogatsky Physico-Chemical Institute, National Aca-
demy of Sciences of Ukraine, Department Molecular Structure) for
spectral measurement.
(2) Farah, A. E.; Alousi, A. A. Life Sci. 1978, 22, 1139.
(3) Alousi, A. A.; Canter, J. M.; Monterano, M. J.; Fort, D. J.;
Ferrari, R. A. J. Cardiovasc. Pharmacol. 1983, 5, 792.
(4) (a) Fossa, P.; Boggia, R.; Presti, E. L.; Dorigo, P.; Floreani,
M. Farmaco 1997, 52, 523. (b) Mosti, L.; Schenone, P.; Del
Mar Mahiques, M.; Dorigo, P.; Fracarollo, D.; Santostasi,
G.; D’Amico, M.; Falciani, M.; Lampa, E. Farmaco 1994,
49, 559. (c) Dorigo, P.; Gaion, R. M.; Belluco, P.;
Fraccarollo, D.; Maragno, I.; Bombieri, G.; Benetollo, F.;
Mosti, L.; Orsisns, F. J. Med. Chem. 1993, 36, 2475.
(5) (a) Abu Shanab, F. A.; Redhouse, A. D.; Thompson, J. B.;
Wacefield, B. J. Synthesis 1995, 557. (b) Mosti, L.;
Schenone, P.; Menozzi, G. J. Heterocycl. Chem. 1985, 22,
1503.
References
(1) (a) Scriven, E. F. V. Pyridines and their Benzo Derivatives:
(ii) Reactivity at Ring Atoms, In Comprehensive
Heterocyclic Chemistry, Vol. 2; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon Press Ltd.: Oxford, 1984, 165. (b) Uff,
B. C. Pyridines and their Benzo Derivatives: (iii) Reactivity
of Substituents, In Comprehensive Heterocyclic Chemistry,
Synlett 2004, No. 13, 2287–2290 © Thieme Stuttgart · New York

2290
S. V. Ryabukhin et al.
LETTER
(6) For related cyclization reaction of 3-formylchromones, see:
(a) Jones, W. D.; Albrecht, W. L. J. Org. Chem. 1976, 41,
706. (b) The cyclization of 3-formylchromones with
amidines and 5-aminopyrazole afforded 5-(2-
d, 3JHH = 7.6 Hz, CH), 8.66 (1 H, 4JHH = 2.0 Hz, 4-HPy), 8.72
(1 H, d, 4JHH = 2.0 Hz, 6-HPy), 9.80 (1 H, t, 4JHH = 5.6 Hz, 6-
HPy), 10.18 (1 H, s, OH). Compound 9ea: 1H NMR (400
MHz, DMSO-d6): d = 2.59 (3 H, s, COCH3), 3.74 (3 H, s,
OCH3), 6.84 (1 H, d, 4JHH = 2.7 Hz, CH), 6.89 (1 H, d,
3JHH = 9.0 Hz, CH), 6.96 (1 H, dd, 3JHH = 9.0 Hz, 4JHH = 2.7
Hz, CH), 8.00 (1 H, d, 4JHH = 3.0 Hz, 4-HPy), 8.39 (1 H, d,
4JHH = 3.0 Hz, 6-HPy), 9.76 (1 H, s, OH), 12.55 (1 H, br s,
NH). Compound 9eb: 1H NMR (400 MHz, DMSO-d6):
d = 2.57 (3 H, s, COCH3), 3.63 (3 H, s, NCH3), 3.74 (3 H, s,
OCH3), 6.84 (1 H, d, 4JHH = 2.7 Hz, CH), 6.89 (1 H, d,
3JHH = 9.0 Hz, CH), 6.96 (1 H, dd, 3JHH = 9.0 Hz, 4JHH = 2.7
Hz, CH), 8.29 (1 H, d, 4JHH = 3.0 Hz, 4-HPy), 8.56 (1 H, d,
4JHH = 3.0 Hz, 6-HPy), 9.75 (1 H, s, OH).
hydroxybenzoyl)-pyrimidines. See: Löwe, W. Synthesis
1976, 274. (c) See also: Petersen, U.; Heitzer, H. Liebigs
Ann. Chem. 1976, 1663. (d) See further: Quiroga, J.; Mejia,
D.; Insuasty, B.; Abonita, R.; Nogueras, M.; Sanches, A.;
Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2002, 35, 51. (e)
The cyclization of 3-formylchromones with aminohetero-
cycles afforded fused b-(2-hydroxybenzoyl)pyridines. See:
Haas, G.; Stanton, J. L.; von Srerecher, A.; Wenk, P. J.
Heterocycl. Chem. 1981, 18, 607. (f) With hydrazines:
Eiden, F.; Haverland, H. Arch. Pharm. (Weinheim, Ger.)
1968, 301, 819. (g) See also: Ghosh, C. K.; Mukhopadhyay,
K. K. J. Indian Chem. Soc. 1978, 55, 386. (h) With
NH2OH·HCl: Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.;
Zehnder, L. P.; Park, F.; Kim, M.; Tran, T. T. J. Org. Chem.
1999, 64, 8736. (i) With o-phenylenediamine: Ghosh, C.
K.; Khan, S. Synthesis 1980, 701. (j) For conversion into
pyrroles and thiofenes: Fitton, A. O.; Frost, J. R.;
(11) Typical 13C MNR data (Varian Mercury-400 spectrometer)
of pyridones obtained: Compound 7bb: 13C NMR (100
MHz, DMSO-d6): d = 20.4 [(CH3)2CH], 21.3 (CH3), 50.3
[(CH3)2CH], 102.7 (3-CPy), 116.4 (CN), 117.3 (5-CPy), 117.4
(CH), 124.2 (Cq), 128.8 (CH), 131.1 (CH), 134.9 (Cq), 146.2
(4-CHPy), 147.2 (6-CHPy), 154.3 (2-CPy), 159.5 (Cq), 190.7
(C=O). Compound 7ef: 13C NMR (100 MHz, DMSO-d6):
d = 56.1 (CH3O), 104.3 (3-CPy), 114.1 (5-CPy), 116.1 (CN),
117.3 (CH), 118.5 (CH), 120.8 (CH), 124.6 (Cq), 127.2
(CH), 129.9 (CH), 130.0 (CH), 139.8 (Cq), 148.3 (4-CHPy),
150.1 (6-CHPy), 150.2 (2-CPy), 152.8 (Cq), 159.5 (Cq), 190.1
(C=O). Compound 8ba: 13C NMR (100 MHz, DMSO-d6):
d = 20.4 (CH3), 43.1 (CH2), 53.5 (CH2), 117.1 (3-CPy), 118.2
(5-CPy), 119.5 (CH), 124.9 (CH), 127.5 (CH), 128.0 (CH),
128.4 (CH), 128.5 (Cq), 128.6 (CH), 129.0 (CH), 129.3
(CH), 130.6 (CH), 134.3 (Cq), 136.5 (Cq), 139.5 (Cq), 143.9
(4-CHPy), 148.9 (6-CHPy), 154.1 (2-CPy), 161.9 (Cq), 162.9
(CONH), 192.1 (C=O). Compound 9ea: 13C NMR (100
MHz, DMSO-d6): d = 31.1 (COCH3), 56.1 (CH3O), 114.1
(CH), 116.8 (5-CPy), 118.1 (CH), 119.6 (Cq), 125.7 (CH),
126.3 (3-CPy), 142.9 (4-CHPy), 146.9 (6-CHPy), 149.9 (Cq),
152.6 (2-CPy), 161.5 (Cq), 191.2 (COAr), 196.7 (COCH3).
Compound 9eb: 13C NMR (100 MHz, DMSO-d6): d = 31.2
(COCH3), 38.7 (NCH3), 56.1 (CH3O), 114.1 (CH), 116.5 (5-
CPy), 118.2 (CH), 119.8 (Cq), 124.8 (CH), 125.5 (3-CPy),
142.6 (4-CHPy), 149.8 (Cq), 150.2 (6-CHPy), 152.6 (2-CPy),
161.5 (Cq), 191.5 (COAr), 196.9 (COCH3).
(12) Typical IR data (Nexus-470 spectrometer) of pyridones
obtained: Compound 7bb: IR (KBr): n = 3400–2700 (br,
OH), 3068, 2985, 2932, 2226 (C≡N), 1671 (C=O), 1654
(C=OPy), 1630, 1577, 1532, 1482 cm–1. Compound 7ef: IR
(KBr): n = 3470–3150 (br, OH), 2231 (C≡N), 1677 (C=O),
1660 (C=OPy), 1539, 1508, 1417 cm–1. Compound 8ba: IR
(KBr): n = 3600–3100 (br, OH), 3288 (NH), 3056, 3023,
2952, 1675 (C=O), 1664 (sh, C=OPy), 1632 (CONHCH2Ph),
1603, 1528 cm–1. Compound 9ea: IR (KBr): n = 3600–3200
(br, OH, NH), 3056, 2917, 2835, 1685 (COMe), 1665
(C=OPh), 1637, 1593, 1485, 1218 cm–1. Compound 9eb:
3500–3100 (br, OH), 3078, 2960, 1677 (COMe), 1646
(C=OPy), 1538, 1508, 1413 cm–1.
Suschitzky, H.; Houghton, P. G. Synthesis 1977, 133. (k)
For conversation into 4-(2¢-hydroxybenzoyl)salicylic esters
see: Langer, P.; Holtz, E. Synlett 2003, 402.
(7) (a) Nohara, A.; Ishiguro, T.; Sanno, Y. Tetrahedron Lett.
1974, 1183. (b) Hishmat, O. H.; El-Naem, Sh. I.; Magd-El-
Din, A. A.; Fawzy, N. M.; Abd, E. l.-AalAS. Egypt. J. Chem.
2000, 43, 87.
(8) For using Me3SiCl as condensation agent see:
(a) Ryabykhin, S. V.; Plaskon, A. S.; Tverdokhlebov, A. V.;
Tolmachev, A. A. Synth. Commun. 2004, 34, 1483.
(b) Heaney, H.; Papageorgeogu, G.; Wilkins, R. F.
Tetrahedron 1997, 53, 2941. (c) For using Me3SiI as
condensation agent see: Sabitha, G.; Reddy, G. S. K. K.;
Reddy, K. B.; Yadav, J. S. Synthesis 2004, 263. (d)Sabitha,
G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S. Synlett
2003, 858. (e) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.;
Yadav, J. S. Tetrahedron Lett. 2003, 44, 4129.
(9) General Procedure: Amide 2–5 or 12 (2 mmol) and
appropriate chromone 1 (2 mmol) were placed in a 10 mL
flask and dissolved in DMF (5 mL). Chlorotrimethylsilane
(10 mmol) was added dropwise to the solution. The flask
was thoroughly sealed with a rubber stopper and heated on a
water-bath for 10 h. After cooling the flask was opened
(Caution! Excessive pressure inside!) and the reaction
mixture was poured into H2O (25 mL). The precipitate
formed was filtered and washed with small amount of i-
PrOH and than with MeOH. Recrystallization from an
appropriate solvent yielded targeted compounds.
(10) Typical 1H MNR data (Varian Mercury-400 spectrometer)
of pyridones obtained: Compound 6a: 1H NMR (400 MHz,
DMSO-d6): d = 6.91–6.99 (2 H, m, CH), 7.34–7.41 (2 H, m,
CH), 8.05 (1 H, d, 4JHH = 2.8 Hz, 4-HPy), 8.31 (1 H, d,
4JHH = 2.8 Hz, 6-HPy), 10.28 (1 H, s, NH), 13.11 (1 H, br s,
OH). Compound 7bb: 1H NMR (400 MHz, DMSO-d6):
d = 1.42 [6 H, d, 3JHH = 7.6 Hz, (CH3)2CH], 2.30 (3 H, s,
CH3), 5.09 [1 H, hep, 3JHH = 7.6 Hz, (CH3)2CH], 6.86 (1 H,
d, 3JHH = 8.4 Hz, CH), 7.16–7.20 (2 H, m, CH), 8.19 (1 H, d,
4JHH = 2.4 Hz, 4-HPy), 8.35 (1 H, d, 4JHH = 2.4 Hz, 6-HPy),
10.08 (1 H, s, OH). Compound 7ef: 1H NMR (400 MHz,
DMSO-d6): d = 3.77 (3 H, s, CH3), 6.90–6.99 (3 H, m, CH),
7.50–7.60 (5 H, m, CH), 8.27 (1 H, d, 4JHH = 2.4 Hz, 4-HPy),
8.42 (1 H, d, 4JHH = 2.4 Hz, 6-HPy), 9.89 (1 H, s, OH).
Compound 8ba: 1H NMR (400 MHz, DMSO-d6): d = 2.28
(3 H, s, CH3), 4.52 (2 H, d, 3JHH = 5.6 Hz, CH2), 5.32 (2 H,
s, CH2), 6.87 (1 H, d, 3JHH = 8.4 Hz, CH), 7.15 (1 H, s, CH),
7.19–7.21 (2 H, m, CH), 7.25–7.38 (7 H, m, CH), 7.39 (2 H,
(13) Typical MS data (MX-1321 instrument) of pyridones
obtained: Compound 6a: MS (EI, 70 eV): m/z (%) = 240
(39) [M+], 147 (19), 121 (86), 120 (100), 92 (45), 65 (54), 39
(43). Compound 7ef: MS (EI, 70 eV): m/z (%) = 346 (30)
[M+], 254 (11), 150 (100). Compound 8ba: MS (EI, 70 eV):
m/z (%) = 452 (19) [M+], 106 (100), 91 (54). Compound
9ea: MS (EI, 70 eV): m/z (%) = 287 (76) [M+], 272 (10), 150
(100), 135 (21), 43 (24).Compound 9eb: MS (EI, 70 eV):
m/z (%) = 301 (64) [M+], 286 (17), 150 (100), 135 (12).
(14) For related interactions of enolates with nitrile groups
affording 2-pyridone ring see: Bondavalli, F.; Bruno, O.; Lo
Presty, E.; Menozzy, G.; Mosti, L. Synthesis 1999, 1169.
Synlett 2004, No. 13, 2287–2290 © Thieme Stuttgart · New York