Synthesis of N-Modified 4-Aminopyridine-3-carboxylates by Ring ­Transformation

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.

amino alcohols - bicyclic compounds - heterocycles - ­pyridines

References and Notes

<A NAME="RU02406ST-1A">1a</A> Konno K. Hayano K. Shirahama H. Saito H. Matsumoto T. Tetrahedron  1982,  38:  3281 

<A NAME="RU02406ST-1B">1b</A> Budzikiewicz H. Horstmann C. Pufahl K. Schreiber K. Chem. Ber.  1967,  100:  2798 

<A NAME="RU02406ST-2A">2a</A> Dugar S, Chakravararty S, Conte A, Axon J, and Mcenroe G. inventors; PCT Int. WO  087056.  ; Chem. Abstr. 2004, 141, 332209

<A NAME="RU02406ST-2B">2b</A> Kikuchi K, Oku M, Hondo T, Kimizuka T, Watanabe T, Nagakura Y, Tomiyama H, Sonegawa M, Tokuzaki K, and Iwai Y. inventors; PCT Int. WO  011430.  ; Chem. Abstr. 2004, 140, 163710

<A NAME="RU02406ST-3A">3a</A> Piazza GA, and Pamukcu R. inventors; US Patent  6060477.  ; Chem. Abstr. 2000, 132, 321870

<A NAME="RU02406ST-3B">3b</A> 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 

<A NAME="RU02406ST-3C">3c</A> Baker R, Saunders J, and Macleod AM. inventors; UK Patent GB  2174695.  ; Chem. Abstr. 1987, 106, 176429

<A NAME="RU02406ST-3D">3d</A> Hunkeler W, and Kyburz E. inventors; Eur. Patent EP  59388.  ; Chem. Abstr. 1983, 98, 53952

<A NAME="RU02406ST-4">4</A> Yamada S. Misono T. Iwai Y. Tetrahedron Lett.  2005,  46:  2239 

<A NAME="RU02406ST-5A">5a</A> Leroy F. Despres P. Bigan M. Blondeau D. Synth. Commun.  1996,  26:  2257 

<A NAME="RU02406ST-5B">5b</A> Bunting JW. Kanter JP. J. Am. Chem. Soc.  1991,  113:  6950 

<A NAME="RU02406ST-5C">5c</A> Radinov R. Haimova M. Simova E. Synthesis  1986,  886 

<A NAME="RU02406ST-5D">5d</A> Hurd CD. Bethune VG. J. Org. Chem.  1970,  35:  1471 

<A NAME="RU02406ST-5E">5e</A> Taylor EC. Driscoll JS. J. Am. Chem. Soc.  1960,  82:  3141 

<A NAME="RU02406ST-6">6</A>

Nitropyrimidinone 1 is readily prepared from 2-thiouracil by reduction, [12] methylation [12] and nitration [8] in 43% overall yield.

<A NAME="RU02406ST-7A">7a</A> Nishiwaki N. Ariga M. J. Synth. Org. Chem. Jpn.  2003,  61:  882 

<A NAME="RU02406ST-7B">7b</A> Gromov SP. Heterocycles  2000,  53:  1607 

<A NAME="RU02406ST-7C">7c</A> van der Plas HC. J. Heterocycl. Chem.  2000,  37:  427 

<A NAME="RU02406ST-7D">7d</A> van der Plas HC. In Advances in Heterocyclic Chemistry   Vol. 74:  Katritzky AR. Academic Press; London: 1999. 

<A NAME="RU02406ST-7E">7e</A> Russinov VL. Chupakhin ON. van der Plas HC. Heterocycles  1995,  40:  441 

<A NAME="RU02406ST-8A">8a</A> Nishiwaki N. Yamashita K. Azuma M. Adachi T. Tamura M. Ariga M. Synthesis  2004,  1996 

<A NAME="RU02406ST-8B">8b</A> Nishiwaki N. Azuma M. Tamura M. Hori K. Tohda Y. Ariga M. Chem. Commun.  2002,  2170 

<A NAME="RU02406ST-8C">8c</A> Nishiwaki N. Adachi T. Matsuo K. Wang H.-P. Matsunaga T. Tohda Y. Ariga M. J. Chem. Soc., Perkin Trans. 1  2000,  27 

<A NAME="RU02406ST-8D">8d</A> Nishiwaki N. Tohda Y. Ariga M. Synthesis  1997,  1277 

<A NAME="RU02406ST-9">9</A>

To 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.

<A NAME="RU02406ST-10">10</A>

Spectral 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.

<A NAME="RU02406ST-11">11</A>

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).

<A NAME="RU02406ST-12">12</A> Bauer L. Wright GE. Mikrut BA. Bell CE. J. Heterocycl. Chem.  1965,  2:  447