REFERENCES AND NOTES
- Sreenivasulu , B. , Rao , G. R. , Mogilaiah , K. and Reddy , K. R. 1988 . Ind. J. Chem. , 27B : 200 – 202 .
- Sreenivasulu , B. , Rao , G. R. , Mogilaiah , K. and Reddy , K. R. 1996 . Ind. J. Chem. , 35B : 339 – 344 .
- Cheng , C. and Yan , S. 1982 . The Friedlander Synthesis of Quinolines Edited by: Dauten , W. , Boswell , G. , Danishefsky , S. , Gschwend , H. , Heck , R. , Hirschmann , R. , Kende , A. , Paquette , L. , Posner , G. and Trost , B. M. Vol. 28 , 37 New York : Organic Reactions; John Wiley .
- Thumm , R. P. 1992 . Synlett , : 1
- Moorman , A. E. , Yen , C. H. and Yu , S. 1987 . Syn. Commun. , 17 : 1695 – 1699 .
- Majewicz , T. G. and Caluwe , P. 1974 . J. Org. Chem. , 39 : 720 – 721 .
- Turner , J. 1983 . J. Org. Chem. , 48 : 3401 – 3408 .
- Synthesis of 2-(pivaloylamino)pyridine 2. To a 3-L, 3-neck flask charged with 100 g (1.06 mol) 2-aminopyridine 1 in MTBE (1100 mL) was added 160mL (1.17 mol) triethylamine. The solution was then cooled to 0°C, whereupon 136mL (1.13 mol) pivaloyl chloride was added dropwise such that the internal temperature was less than 20°C. The solution was stirred for 2 h at r.t. and a white precipitate was observed. After the reaction was complete, cooled H2O (1 × 300 mL) was added. The layers were separated and the organic layer was washed with H2O (1×300 mL), sat. NaHCO3 (1×300 mL), then brine solution (1×300 mL). The organic layer was dried over Na2SO4. Sodium sulfate was filtered off and MTBE was distilled under reduced pressure and replaced with THF (other solvents may be used, see text). The crude material was used in the formylation step without further purification. Typical assay yield is 94%. 1H NMR (400 MHz, CDCl3): δ 8.25 (m, 2H, H-3, H-6), 8.04 (br, 1H, N-H), 7.70 (m, 1H, H-4), 7.03 (m, 1H, H-5), 1.32 (s, 9H, t-butyl). 13C NMR (100.6MHz, CDCl3): δ 177.0, 151.6, 147.6, 138.4, 119.7, 113.9, 39.8, 27.5. m.p. 69°–71°C (lit.[6] m.p. 71°–73°C)
- Avedano , C. , Ubeda , J. I. and Villacampa , M. 1998 . Synthesis , : 1176 – 1180 .
- Hegedus , L. , Lipshutz , B. , Nozaki , H. , Reetz , M. , Rittmeyer , P. , Smith , K. , Totter , F. and Yamamoto , H. 1994 . Organometallics in Synthesis: A Manual Edited by: Shlosser , M. 129 – 133 . New York : John Wiley .
- Typical synthesis of 2-amino-3-pyridinecarboxaldehyde 4. To a 100-mL flask was charged 2.5 g (14 mmol) of 2-(pivaloylamino)pyridine 2 and 30mL of THP. This solution was cooled to −20°C, whereupon t-BuLi (1.6 M in pentane, 2.3 equiv.) was added over a 30-min period such that the internal temperature was below −5°C. The solution was then aged for 2.5 h at 0°C, after which 2.2mL DMF (28 mmol) was added such that the internal temperature was less than 5°C. The solution was aged at 0°C for 1 h, then allowed to warm slowly to r.t. After the reaction was complete, the solution was cooled to −10°C and quenched with 3N HCl (77 mmol), keeping the temperature below 0°C. The aqueous layer was separated and excess THP was distilled in vacuo. The aqueous layer was heated overnight at 100°C. The reaction mixture was cooled to room temperature, then washed with MTBE (2×10mL). The aqueous layer was cooled to 0°C after the addition of 15mL of isopropyl acetate (IPAC) and 5 g NaCl. To the mixture was added 5 N NaOH at a rate such that the internal temperature was less than 15°C until pH 10.3. The organic layer was separated. The aqueous layer was re-extracted with IPAC (2×15 mL). The combined organic layers were concentrated under reduced pressure to give 1.59 g crude material consisting mainly of product and traces of starting material. The desired 2-amino-3-pyridinecarboxal-dehyde was easily purified by SiO2 column chromatography, eluting first with 2:1 hexane:EtOAc then with 1:1 hexane:EtOAc after pivalamide staring material had eluted completely. Fractions containing desired compound were concentrated under vacuum to give 1.33 g yellow crystals (78% isolated yield based on pivalamide 2 starting material). 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H, CHO), 8.22 (m, 1H, H-6), 7.76 (m, 1H, H-4), 7.04 (br, 2H, N-H), 6.69 (m, 1H, H-5). 13C NMR (100.6 MHz, CDCl3) δ 192.6, 158.4, 154.6, 144.2, 113.8, 112.8. m.p. 97°–99°C (lit.[6] m.p. 98°–99°C)
- On large-scale synthesis (0.49 mol of 2, nBuLi and THF conditions), the IPAc solution containing crude 4 was passed through a silica-gel pad (2:1 wt/wt silica : crude wt. of 4). The filtered solution was concentrated under reduced pressure to give 46.0 g of 4 in 96 wt% purity. This material was heated to 70°C in EtOAc (75mL), then gradually cooled to 50°C and seeded. After 30 min stirring at 50°C, methylcyclohexane (295 mL) was added (50 mL/h) and allowed to cool overnight. The crystals were filtered and washed with 4:1 methylcyclohexane, then dried to give 37.5 g of 4 (97.9 wt% purity by HPLC method based on analytical standard, 58% overall yield from 1)
- Analytical data: 5a:1H NMR (400 MHz, CDCl3): δ 9.02 (dd, J = 2.0, 4.3 Hz, 1H), 8.94 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 2.0, 8.1 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 4.3, 8.1 Hz, 1H), 2.76 (t, J = 7.6 Hz,2H), 1.70 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) δ 155.2, 155.0, 152.5, 136.6, 136.4, 134.9, 122.5, 122.0, 34.9, 24.1, 13.6. HRMS m/z calc. for C11H12N (M+H) 173.1073, found 173.1077. 5b: 1H NMR (400 MHz, CDCl3): δ 9.05 (m, 2H), 8.15 (m, 2H), 7.42 (m, 2H). 13C NMR (100.6 MHz, CDCl3): δ 156.1, 153.6, 137.1, 122.8, 122.1. m.p. 91°–93°C. 5c: 1H NMR (400 MHz, CDCl3): δ 9.44 (d, J = 2.4 Hz, 1H), 9.14 (d, J = 3.9 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.73 (m, 2H), 7.50 (m, 4H). 13C NMR (75.5 MHz, CDCl3): δ 155.5, 153.4, 153.1, 137.2, 137.0, 135.0, 133.9, 129.3, 128.5, 127.5, 122.6, 122.5. Anal. calc. for C14H10N2: C, 81.53; H, 4.89; N, 13.58. Found: C, 81.24; H, 4.74; N, 13.60. m.p. 128.5°–129.5°C