A Convenient Synthesis of 2-(Alkylamino)pyridines
CHART 1
Douglas M. Krein and Todd L. Lowary* Department of Chemistry, The Ohio State University, Columbus, Ohio 43210
[email protected] Received January 24, 2002
Abstract: The synthesis of a series of 2-(alkylamino)pyridines (1) in three steps from 2-aminopyridine (4) is reported. The products were obtained in 67-91% overall yield from 4.
The asymmetric reduction of prochiral ketones by a complex formed from lithium aluminum hydride, (1R,2S)(-)-N-methylephedrine, and 2-(ethylamino)pyridine (1a, Chart 1) is a useful method for the synthesis of optically pure secondary alcohols.1,2 In the course of other investigations, we had the need to carry out this reduction on large scale and thus required significant quantities of 1a. When choosing among the methods reported for the preparation of 1a,1,3,4 it appeared to us that the most straightforward route would be the one illustrated in Scheme 1, which uses inexpensive 2-aminopyridine (4) as the starting material.1 Thus, 4 was treated with acetic anhydride and formic acid5 to provide the N-formyl derivative 5 in 73% yield.6 This product was then alkylated by reaction with sodium hydride and ethyl iodide affording 6 (85%). Deformylation of 6 by acid hydrolysis gave 1a in 90% yield. Although the product could be obtained by this route, the modest yield of the formylation step, and its problematic purification by distillation (the distillate often solidified in the condenser), led us to explore an alternate route to 1a. We report here that substitution of 5 with the readily available N-Boc-protected 2-aminopyridine derivative 2 allows for the efficient preparation of 1a and other 2-(alkylamino)pyridines in high overall yield. The preparation of carbamate 2 was achieved by reaction of 4 with Boc anhydride in tert-butyl alcohol (Scheme 2).7 Following evaporation of the solvent, the crude solid was recrystallized from isopropyl alcohol, providing 2 in 90% yield. Evaporation of the mother liquors and chromatography of the resulting oil provided additional product, giving 2 in a 98% total yield. (1) Kawasaki, M.; Suzuki, Y.; Terashima, S. Chem. Lett. 1984, 239. (2) Daverio, P.; Zanda, M. Tetrahedron: Asymmetry 2001, 12, 2225. (3) Kemal, O ¨ .; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1981, 1569. (4) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J. Org. Chem. 1996, 61, 4214. (5) Sheehan, J. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 1154. (6) An alternate formylation method, involving heating 4 in formic acid at reflux (Tschitschibabin, A. E.; Knunjanz, I. L. Chem. Ber. 1931, 64, 2841) provided 5 in only a 43% yield. (7) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988, 31, 2136.
SCHEME 1a
a (a) HCO H, Ac O, 0 °C f rt, 73%; (b) CH CH I, NaH, DMF, 2 2 3 2 0 °C f rt 85%; (c) 6 N HCl, 100 °C, 90%.
SCHEME 2a
a
(a) (Boc)2O, t-BuOH, rt, 98%.
Alkylation of 2 with various alkyl halides proceeded efficiently upon treatment with sodium hydride in DMF (Table 1). The yields of products (3, Chart 1) were, with one exception, uniformly excellent; only isopropyl iodide afforded the corresponding alkylated derivative (3d) in less than 90% yield. Following purification of 3a-e by chromatography, cleavage of the Boc group was achieved by treatment with TFA in CH2Cl2 containing a small amount of water. In terms of overall efficiency from 4, compounds 1a-1c and 1e are obtained in yields of 85% or better. A similar yield of 1a was also obtained when the crude reaction mixture obtained after the alkylation of 2 with ethyl iodide was directly treated with TFA/ water in CH2Cl2 (Table 1, entry 6). To summarize, we describe here an efficient route for the preparation of 2-(alkylamino)pyridines from 2-aminopyridine (4) via the readily accessible intermediate 2. Advantages of this route over the one shown in Scheme 1 are (1) the cumbersome purification of the N-formyl derivative 5 is avoided and (2) the protected aminopyridine intermediate (2) is a solid that can be readily recrystallized from the crude reaction mixture following its preparation. Furthermore, the overall yields of the final products are, in general, higher than those reported by other methods.1,3,4,8
10.1021/jo020057z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002
J. Org. Chem. 2002, 67, 4965-4967
4965
TABLE 1. Alkylation of 2 and Subsequent Deprotection
a
entry
RX
alkylation yield (%)a
alkylation product
deprotection yield (%)a
final product
overall yield from 2 (%)
1 2 3 4 5 6
CH3CH2I CH3I CH3CH2CH2I (CH3)2CHI PhCH2Br CH3CH2I
95 91 94 74 96 -
3a 3b 3c 3d 3e -
97 95 96 93 97 -
1a 1b 1c 1d 1e 1a
92 87 90 69 93 88b
Isolated yield following chromatography. b Overall yield when intermediate alkylated Boc derivative (3a) is not purified.
Experimental Section General. Solvents were distilled from the appropriate drying agents before use. Unless stated otherwise, all reactions were carried out under a positive pressure of argon and were monitored by TLC on silica gel 60 F254 (0.25 mm, E. Merck). Spots were detected under UV light. Solvents were evaporated under reduced pressure and below 40 °C (bath). Organic solutions of crude products were dried over anhydrous MgSO4. Column chromatography was performed on silica gel 60 (4060 µM). The ratio between silica gel and crude product ranged from 100 to 50:1 (w/w). Melting points are uncorrected. 1H NMR spectra were recorded at 500.12 MHz and chemical shifts are referenced to TMS (0.00 ppm). 13C NMR spectra were recorded at 125.75 MHz and 13C chemical shifts are referenced to CDCl3 (77.0 ppm). Electrospray mass spectra were recorded on samples suspended in 1:1 THF:MeOH containing NaCl. Elemental analyses were carried out in house. 2-(Formylamino)pyridine (5). To an ice-cooled solution of dry formic acid, 99% (115.07 g, 2.50 mol), was added 2-aminopyridine (23.53 g, 0.25 mol) in portions. Caution: This process is very exothermic and should be performed with care. This solution was then cooled to 0 °C with vigorous stirring while Ac2O (38.28 g, 0.38 mol) was slowly added over 1 h at such a rate that the internal temperature never exceeded 10 °C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 48 h. The mixture was then diluted with water (100 mL) and Et2O (500 mL). The organic layer was separated and extracted with water, a sat. aqueous NaHCO3 solution, and brine, before being dried and concentrated. The resulting residue was then purified by vacuum distillation to afford 5 (22.28 g, 73%) as a clear, colorless oil that immediately solidified to a white solid upon cooling. Note: During the distillation, the distillate may solidify in the condenser. Rf 0.35 (hexanes/EtOAc, 1:1); mp 70-71 °C [lit.6 mp 71 °C]; IR νmax (KBr): 3265, 3059, 2968, 1700, 1588, 1462 cm-1. All peaks in the 1H and 13C NMR spectra were doubled. This is presumably due to restricted rotation about the amide bond. 1H NMR (500 MHz, CDCl3, δ) 10.20 (br. s, 1 H), 9.99 (br. s, 1 H), 9.34 (d, 1 H, J ) 10.6 Hz), 8.54 (s, 1 H), 8.34 (br. t, 2 H, J ) 5.0 Hz), 8.27 (d, 1 H, J ) 8.4 Hz), 7.75 (dt, 1 H, J ) 9.0, 1.8 Hz), 7.68 (dt, 1 H, J ) 7.8, 1.8 Hz), 7.12-7.05 (m, 2 H), 6.94 (d, 1 H, J ) 8.2 Hz); 13C NMR (125 MHz, CDCl , δ) 163.1, 159.6, 151.1, 151.0, 148.6, 3 147.4, 138.9, 138.7, 120.2, 119.8, 115.2, 110.6. Anal. Calcd for C6H6N2O: C, 59.01; H, 4.95. Found: C, 58.96; H, 5.31. HRMS (ESI) calcd for (M + Na+) C6H6N2O: 145.0372. Found: 145.0373. 2-(Formyl(ethyl)amino)pyridine (6). Compound 5 (1.22 g, 10.0 mmol) was dissolved in anhydrous DMF (30 mL), and the solution was cooled to 0 °C in an ice/water bath. Sodium hydride (0.50 g, 60% suspension in oil, 12.5 mmol) was added in portions such that the internal temperature was maintained
