Subscribe to RSS
DOI: 10.1055/s-2006-941567
Synthesis of N-Modified 4-Aminopyridine-3-carboxylates by Ring Transformation
Publication History
Publication Date:
22 May 2006 (online)
![](https://www.thieme-connect.de/media/synlett/200609/lookinside/thumbnails/10.1055-s-2006-941567-1.jpg)
Abstract
3-Methyl-5-nitropyrimidin-4(3H)-one reacted with enaminones to cause the ring transformation leading to functionalized 4-aminopyridines. Various kinds of amino groups can be introduced at the 4-position by modifying the enaminones. The modification of its vicinal positions was also possible. In addition, a bicyclic pyridine could be synthesized by making use of the vicinal functionality of a 4-aminopyridine-3-carboxylic acid.
Key words
amino alcohols - bicyclic compounds - heterocycles - pyridines
-
1a
Konno K.Hayano K.Shirahama H.Saito H.Matsumoto T. Tetrahedron 1982, 38: 3281 -
1b
Budzikiewicz H.Horstmann C.Pufahl K.Schreiber K. Chem. Ber. 1967, 100: 2798 -
2a
Dugar S,Chakravararty S,Conte A,Axon J, andMcenroe G. inventors; PCT Int. WO 087056. ; Chem. Abstr. 2004, 141, 332209 -
2b
Kikuchi K,Oku M,Hondo T,Kimizuka T,Watanabe T,Nagakura Y,Tomiyama H,Sonegawa M,Tokuzaki K, andIwai Y. inventors; PCT Int. WO 011430. ; Chem. Abstr. 2004, 140, 163710 -
3a
Piazza GA, andPamukcu R. inventors; US Patent 6060477. ; Chem. Abstr. 2000, 132, 321870 -
3b
Benham CD.Blackburn TP.Johns A.Kotecha NR.Nikesh R.Martin RT.Thomas DR.Thompson M.Ward RW. Bioorg. Med. Chem. Lett. 1995, 5: 2455 -
3c
Baker R,Saunders J, andMacleod AM. inventors; UK Patent GB 2174695. ; Chem. Abstr. 1987, 106, 176429 -
3d
Hunkeler W, andKyburz E. inventors; Eur. Patent EP 59388. ; Chem. Abstr. 1983, 98, 53952 - 4
Yamada S.Misono T.Iwai Y. Tetrahedron Lett. 2005, 46: 2239 -
5a
Leroy F.Despres P.Bigan M.Blondeau D. Synth. Commun. 1996, 26: 2257 -
5b
Bunting JW.Kanter JP. J. Am. Chem. Soc. 1991, 113: 6950 -
5c
Radinov R.Haimova M.Simova E. Synthesis 1986, 886 -
5d
Hurd CD.Bethune VG. J. Org. Chem. 1970, 35: 1471 -
5e
Taylor EC.Driscoll JS. J. Am. Chem. Soc. 1960, 82: 3141 -
7a
Nishiwaki N.Ariga M. J. Synth. Org. Chem. Jpn. 2003, 61: 882 -
7b
Gromov SP. Heterocycles 2000, 53: 1607 -
7c
van der Plas HC. J. Heterocycl. Chem. 2000, 37: 427 -
7d
van der Plas HC. In Advances in Heterocyclic Chemistry Vol. 74:Katritzky AR. Academic Press; London: 1999. -
7e
Russinov VL.Chupakhin ON.van der Plas HC. Heterocycles 1995, 40: 441 -
8a
Nishiwaki N.Yamashita K.Azuma M.Adachi T.Tamura M.Ariga M. Synthesis 2004, 1996 -
8b
Nishiwaki N.Azuma M.Tamura M.Hori K.Tohda Y.Ariga M. Chem. Commun. 2002, 2170 -
8c
Nishiwaki N.Adachi T.Matsuo K.Wang H.-P.Matsunaga T.Tohda Y.Ariga M. J. Chem. Soc., Perkin Trans. 1 2000, 27 -
8d
Nishiwaki N.Tohda Y.Ariga M. Synthesis 1997, 1277 - 12
Bauer L.Wright GE.Mikrut BA.Bell CE. J. Heterocycl. Chem. 1965, 2: 447
References and Notes
Nitropyrimidinone 1 is readily prepared from 2-thiouracil by reduction, [12] methylation [12] and nitration [8] in 43% overall yield.
9To ethyl 3-oxobutanoate (127 µL, 1 mmol), propylamine (99 µL, 1.2 mmol) was added, and the resultant mixture was stirred without solvent at r.t. for 2 h. Excess amounts of amine and unreacted reagent were removed under reduced pressure to give enaminone 2a (170 mg, 1 mmol, quant.) as the residual yellow oil. Since enaminone 2a was sufficiently pure in the 1H NMR, it was used for the following ring trans-formation without further purification. Other enaminones were prepared in a similar way changing amines or 1,3-dicarbonyl compounds. When the reaction did not reach completion, the mixture was heated at 60 °C for a long time.
10Spectral data for 3a: yellow oil. IR (neat): 3346, 1687, 1219, 1105 cm-1. 1H NMR (400 MHz, CDCl3, TMS): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.71 (tq, J = 7.3, 6.9 Hz, 2 H), 3.19 (dt, J = 6.9, 6.9 Hz, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 6.51 (d, J = 6.1 Hz, 1 H), 8.00-8.10 (br s, 1 H), 8.21 (d, J = 6.1 Hz, 1 H), 8.87 (s, 1 H). 13C NMR (100 MHz, CDCl3, TMS): δ = 11.6 (q), 14.3 (q), 22.2 (t), 44.0 (t), 60.4 (t), 105.9 (d), 107.1 (s), 152.4 (d), 152.5 (d), 154.7 (s), 168.1 (s). Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45. Found: C, 63.19; H, 7.90; N, 13.49.
Other APCA derivatives also showed satisfactory spectral data.
Spectral Data for 16.
To a solution of pyridine derivative 3h (210 mg, 1 mmol) in THF (10 mL), NaH (60 wt%, 80 mg, 2 mmol) was added, and the mixture was heated under reflux for 1 d. After quenching with 1 M HCl (2 mL, 2 mmol), the reaction mixture was evaporated under vacuo. The residue was washed with CHCl3 (3 × 10 mL), and then extracted with EtOH (2 × 15 mL). After drying over MgSO4, the solvent was removed under reduced pressure to give 3,4-dihydro-pyrido[4,3-e][1,4]oxazepin-1-one (16, 180 mg, 1 mmol, quant.) as a pale-yellow solid. IR (nujol): 1691, 1201, 1045 cm-1. 1H NMR (400 MHz, DMSO-d
6, TMS): δ = 3.10-3.20 (m, 2 H), 3.50-3.80 (m, 2 H), 6.48 (d, J = 5.8 Hz, 1 H), 7.97 (d, J = 5.8 Hz, 1 H), 8.67 (s, 1 H), 9.50-9.60 (br s, 1 H). 13C NMR (100 MHz, DMSO-d
6, TMS): δ = 45.3 (t), 60.8 (t), 106.1 (d), 126.9 (s), 151.5 (d), 153.7 (d), 155.6 (s), 173.2 (s).