Synthesis of functionalized pyridones via palladium catalyzed cross coupling reactions

Article abstract of DOI:10.1055/s-1998-1974

Convenient, palladium catalyzed cross coupling reaction conditions lead to novel N- and 4-substituted pyridones.

Full text of DOI:10.1055/s-1998-1974

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Synthesis of Functionalized Pyridones via Palladium Catalyzed Cross Coupling Reactions
Jian-min Fu,* Yong Chen, Arlindo L. Castelhano*
Cadus Pharmaceutical Corp. 777 Old Saw Mill River Road, Tarrytown, New York, USA 10591-6705, USA
Fax (914) 467-3565; E-mail: jfu@cadus.com, acastelhano@cadus.com
Received 10 October 1998
Abstract: Convenient, palladium catalyzed cross coupling reaction
conditions lead to novel N- and 4-substituted pyridones.
coupling between aryl triflates and boronic acids have not been
reported. Such conditions are preferred for robotic synthesis of
13
compound libraries for drug screening. Indeed, we have found that the
coupling of 4a with 2-thienyl boronic acid proceeds at room
temperature under the specific conditions of Pd(PPh ) /K CO /THF-
1
Among heteroaromatic compounds, substituted pyridones have been
3 4
2
3
found as important starting materials for the synthesis of more complex
molecules. The pyridone structure also appears in a number of natural
products such as camptothecin, and as a peptidomimetic element in
enzyme inhibitors of elastase and thrombin. We have been particularly
interested in introducing carbon-based substituents onto the pyridone
ring in compounds designed for SH2 domains of tyrosine phosphatases
and kinases, and compound libraries targeting G-protein coupled
receptors. The pyridone N-substituent introduces an element of diversity
or a site for further modification via library synthesis. In the specific
case of the N-phosphonomethyl moiety, 4a, (Scheme 1) this results in a
DMA (1:1) in a superior yield (96%) than the regular reflux conditions
2
(Pd(PPh ) /aq Na CO /DME), (entries 4 and 5, Table 1).
3
3 4
2
3
4
5
6
phosphotyrosine mimetic, a key component in ligands recognized by
protein SH2 domains implicated in cancer, inflammation and allergy.
Herein we report a very efficient synthesis for the assembly of N- and 4-
substituted pyridones through palladium catalyzed cross coupling
reactions of pyridone triflates 4a-c with aryl boronic acids or the zinc
reagent of β-iodoalanine. Coupling conditions are described that render
pyridone triflates useful in reactions with a variety of aryl, heteroaryl,
alkynyl, and alkyl coupling partners at or near room temperature.
The pyridone triflates were made by regiospecific N-alkylation of
commercial O-benzylpyridone 1 with K CO in acetonitrile (Scheme
2
3
1). Hydrogenolysis with Pd-C in methanol generated N-alkyl 4-
hydroxypyridones 3a-c. The formation of triflates 4a-c occurred rapidly
o
at -78 C with triflic anhydride and triethylamine.
Subsequently, we applied these room temperature conditions to the
coupling of 4a with other boronic acids (Scheme 2). As a preamble to
robotic synthesis, cross coupling reactions were carried out in 20ml
borosilicated vials by mixing triflate 4a with commercial boronic acids,
palladium catalyst, and potassium carbonate in 1:1 ratio of THF and
DMA. The mixture was shaken on a J-CHEM shaker for 48 h. To assure
purity, the mixture was filtered and the crude product purified by
14
preparative thin layer chromatography.
Monosubstituted phenyl
boronic acids with electron donating and electron withdrawing groups at
otho-, meta-, or para positions did not affect the outcome of the product.
Disubstituted phenyl, naphthyl, and heteroaromatic boronic acids also
gave excellent yields of coupled product. The isopropyl phosphonate
esters were further hydrolyzed with iodotrimethylsilane and N,O-
Scheme 1
bis(trimethylsilyl)acetamide in acetonitrile, followed by TFA/CH CN/
3
15
16
H O to yield the corresponding phosphonic acids.
2
The palladium catalyzed cross coupling reaction has been widely used
in organic synthesis for the construction of a variety of complex
The usefulness of the pyridone triflate intermediate 4a is also evident
with the coupling to β-iodoalanine to generate pyridone-based
7
8
molecules. Organo triflates have been reported to couple with tin,
phosphotyrosine mimetics (Scheme 3). Previous reports of the coupling
9
10
11
17,18
boron, zinc and Grignard reagents. Likewise, we successfully
coupled the pyridone triflate 4 with aryl boronic acids and phenyl
acetylene (Table 1). Although the Suzuki reaction is normally carried
out at reflux temperatures, several groups have reported the coupling of
organobromo and iodo reagents with aryl boronic acids at ambient
of halogen compounds with zinc reagents
prompted us to
investigate the coupling of triflate 4a with the zinc reagent generated in
situ from the protected β-iodoalanine, 12. After a considerable effort,
18b
the method of Jung
using THF-DMA as the solvent system and
19
Pd (dba) /o-tol P as the palladium catalyst, provided the desired
product 13 in 43% isolated yield.
2
3
3
12
20
temperature. To our knowledge, the corresponding non-aqueous

December 1998
SYNLETT
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4.
5.
(a) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.; Stille, J.
R. J. Org. Chem. 1997, 62, 1033. (b) Bernstein, P. R.; Gomes, B.
C.; Kosmider, B. J.; Vacek, E. P.; Williams, J. C. J. Med. Chem.
1995, 38, 212.
Sanderson, P. E. J.; Dyer, D. L.; Naylor-Olsen, A. M.; Vacca, J. P.;
Gardell, S. J.; Lewis, S. D.; Lucas Jr., B. J.; Lyle, E. A.; Lynch Jr.,
J. J.; Mulichak, A. M. Bioorg. & Med. Chem. Lett. 1997, 7, 1497.
Tamura, S. Y.; Semple, J. E.; Reiner, J. E.; Goldman, E. A.;
Brunck, T. K.; Lim-Wilby, M. S.; Carpenter, S. H.; Rote, W. E.;
Oldeshulte, G. L.; Richard, B. M.; Nutt, R. F.; Ripka, W. C. ibid.
1997, 7, 1543.
6.
7.
Fu, J.-min.; Castelhano, A. L. Bioorg. & Med. Chem. Lett. 1998,
8. in press.
(a) Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Snieckus, V. Chem.
Rev. 1990. 90, 879. (c) Stille, J. K. Angew. Chem. Int. Ed. Engl.
1986, 25, 508.
8.
9.
Echavarren, A. M.; Stille, J. K.; J. Am. Chem. Soc. 1987, 119,
5478.
(a) Suzuki, A.: J. Org. Chem. 1993, 58, 2201. (b) Fu, J-M.;
Snieckus, V. Tetrahedron Lett. 1990, 31, 1665. (c) Huth, A.;
Beetz, I.; Schumann, I. Tetrahedron 1989, 45, 6679.
Scheme 2
10. (a) Superchi, S.; Sotomayor, N.; Miao, G.; Joseph, B.; Snieckus, V.
Tetrahedron Lett. 1996, 37, 6057. (b) Quesnelle, C. A.; Familoni,
O. B.; Snieckus, V.; Synlett 1994, 349. (c) Arcadi, A.; Burini, A.;
Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni, B. Synlett 1990,
47.
11. Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C. A.; Snieckus,
V. J. Org. Chem. 1992, 57, 4066.
12. (a) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J. Org.
Chem. 1996, 61, 9082. (b) Anderson, J. C.; Namli, H. Synlett
1995, 765. (c) Genet, J. P.; Linquist, A.; Blart, E.; Mouries, V.;
Savignac, M. Tetrahedron Lett. 1995, 36, 1443. (d) Campi, E. M.;
Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M. J. Chem.
Soc., Chem. Commun. 1994, 2395. (e) Genet, J. P.; Blart, E.;
Savignac, M. Synlett 1992, 715.
Scheme 3
In summary, the N-alkyl, 4-pyridone triflate 4 is a versatile reagent for
palladium catalyzed cross coupling reactions with phenyl acetylene (sp
13. Non-aqueous couplings of organohalides with organoborons were
explored by Suzuki and co-workers (a) Oh-e, T.; Miyaura, N.;
Suzuki, A. Synlett 1990, 221. (b) Hoshino, Y.; Miyaura, N.;
Suzuki, A. Bull. Chem. Soc. Jpn. 1988, 61, 3008.
2
carbon) and aryl boronic acids (sp carbon) at room temperature, and
3
the zinc reagent of β-iodoalanine (sp carbon).
Acknowledgements: We are indebted to Mr. Marcus Colucci for the
LC-MS analysis of intermediates and target compounds. We thank Prof.
S. Sieberth for helpful discussions and Prof. M. Jung for a preprint of
ref. 18(b).
14. Typical cross
preparation of 5c: In
mixture of
coupling
experimental procedure for
20 mL borosilicated vial, the
a
1-diisopropyloxyphosphorylmethyl-4-trifluoro-
methanesulfonyloxy-2-pyridone (0.169 g, 0.40 mmol),
tetrakis(triphenylphosphine)- palladium(0) (0.046 g, 0.04 mmol),
3-chlorophenylboronic acid (0.069 g, 0.44 mmol) and potassium
carbonate (0.22 g, 1.60 mmol) in tetrahydrofuran-
dimethylacetamide (1:1, 4.00 mL) was shaken on J-KEM shaker
for 48 hr and then filtered with ethyl acetate as the washing
solvent. The filtrate was concentrated in vacuo to dryness
and the residue was subjected to preparative thin layer
chromatography (ethyl acetate) to give 0.14
1-diisopropyloxyphosphorylmethyl-4-(3-chlorophenyl)-2-pyrid-
one (5c) as colorless oil.
3H), 1.28 (s, 3H), 1.29 (s, 3H), 1.32 (s, 3H), 4.39-4.45 (d, J = 13.0
Hz, 2H), 4.64-4.80 (m, 2H), 6.37-6.42 (dd, J = 2.0, 7.2 Hz, 1H),
References and Notes
1.
Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R. and Rees, C. W., Eds., Vol. 2, Pergamon Press,
1984.
2.
(a) Comins, D. L.; Gao, J. Tetrahedron Lett. 1994, 35, 2819. (b)
Sieburth, S. M.; Hiel, G.; Lin, C.-H.; Kuan, D. P.; J. Org. Chem.
1994, 59, 80. (c) Schmidhauser, J. C.; Khouri, F. F. Tetrahedron
Lett. 1993, 34, 6685. (d) Sieburth, S. M.; Chen, J.-L. J. Am. Chem.
Soc. 1991, 113, 8163.
g (91%) of
1
H NMR (200 MHz, CDCl ) δ 1.25 (s,
3
3.
For total synthesis of camptothecin using substituted pyridones as
starting materials, see: (a) Comins, D. L.; Hong, H.; Saha, J. K.;
Gao, J. J. Org. Chem. 1994, 59, 5120. (b) Comins, D. L.; Hong,
H.; Gao, J. Tetrahedron Lett. 1994, 35, 5331. (c) Curran, D. P.;
Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
6.73-6.74 (d, J = 2.0 Hz, 1H), 7.35-7.42 (m, 3H), 7.52 (s, 1H),
7.55-7.59 (d, J = 7.2 Hz, 1H); C NMR (50.3 MHz, CDCl ) δ
23.7, 23.8, 23.9, 24.0, 41.1, 44.2, 72.0, 72.2, 105.3, 117.1, 124.9,
126.9, 129.5, 130.3, 135.0, 137.9, 139.2, 150.4, 161.8; IR (film) υ
13
3

1410
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SYNLETT
-1
981, 1102, 1199, 1239, 1346, 1592, 1660, 2933, 2978 cm ; MS
(ES): 386.0 (M +1), 384.0 (M +1).
18. (a) Walker, M. A.; Kaplita, K. P.; Chen, T.; King, H. D. Synlett
1997, 169. (b) Jung, M. E.; Starkey, L. S. Tetrahedron 1995, 53,
8815. (c) Smyth, M. S.; Burke, Jr., T. R. Tetrahedron Lett. 1994,
35, 551.
+
+
15. Szardenings, A. K.; Gordeev, M. F.; Patel, D. V. Tetrahedron Lett.
1996, 37, 3635.
19. Other palladium catalysts investigated and yields obtained were:
16. Biaryl phosphonic acids have been shown to inhibit phosphatases,
see Montserat, J.; Chen. L.; Lawrence, D. S.; Zhang, Z.-Y. J. Biol.
Chem. 1996, 271, 7868.
Pd (dba) /AsPh
(25%);
Pd (dba) / P(2-furyl) (14%); Pd(PPh ) (15%); PdCl (o-tol P)
2
Pd (dba) CHCl /AsPh
(21%);
2
3
3
2
3
3
3
2
3
3
3 4
2
3
(7%); Pd (dba) /dppf (0%).
2
3
17. (a) Jackson, R. F. W.; Wishart, N.; Wythes, M. J. Synlett 1993,
219. (b) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.;
Wythes, M. J. J. Org. Chem. 1992, 57, 3397. (c) Dunn, M. J.;
Jackson, R. F. W.; Stephenson, G. R. Synlett 1992, 905. (d)
Jackson, R. F. W.; Wishart, N.; Wythes, M. J. . J. Chem. Soc.,
Chem. Commun. 1992, 1587. (e) Dunn, M. J.; Jackson, R. F. W. J.
Chem. Soc., Chem. Commun. 1992, 319. (f) Jackson, R. F. W;
Wood, A.; Wythes, M. J. Synlett 1990, 735. (g) Jackson, R. F.
Wythes, M. J.; W; Wood, A. Tetrahedron Lett. 1989, 30, 5941.
(h)Jackson, R. F. W.; James, K.; Wythes, M .J.; Wood, A. J. Chem.
Soc., Chem. Commun. 1989, 644.
o
1
20. Data for compound 13: m.p. 75-77 C; H NMR (200 MHz,
CDCl ) δ 1.23 (s, 3H), 1.26 (s, 3H), 1.28 (s, 3H), 1.31 (s, 3H),
3
1.41 (s, 9H), 2.74-3.01 (m, 2H), 4.30-4.38 (dd, J = 3.6, 12.8 Hz,
2H), 4.54-4.74 (m, 3H), 5.01-5.05 (d, J = 7.8 Hz, 1H), 5.15 (s,
2H), 5.86-5.89 (d, J = 6.6 Hz, 1H), 6.32 (s, 1H), 7.26-7.37 (m,
13
6H); C NMR (50.3 MHz, CDCl ) δ 23.7, 23.8, 23.9, 24.0, 28.2,
3
37.6, 40.9, 44.1, 53.1, 67.5, 72.0, 72.2, 77.3, 80.4, 107.6, 120.3,
128.7, 135.0, 137.3, 149.5, 155.1, 161.6, 171.1; IR (film) υ 986,
-1
1165, 1243, 1365, 1597, 1665, 1711, 1745, 2931, 2977 cm ; MS
+
(ES): 551 (M +1), 495.