Rapid and Selective in situ Reduction of Pyridine-N-oxides with Tetra­hydroxydiboron

Abstract

Pyridine-N-oxides are often used as reactive precursors in the syntheses of substituted pyridines. Isolation and subsequent reduction of the associated pyridine-N-oxide intermediates can be challenging. We have discovered that tetrahydroxydiboron functions as a mild, versatile, and remarkably selective reducing agent for pyridine-N-oxides and may be used in an in situ fashion, thus ­obviating the isolation of N-oxide-containing intermediates

Key words

N-oxide reduction - tetrahydroxydiboron - selective ­reduction - in situ reduction - pyridine

• References and Notes

• 1a Youssif S. ARKIVOC 2001; (i): 242
• 1b Albini A, Silvio P. Heterocyclic N-Oxides . CRC Press; New York: 1991
• 2a Londregan AT, Jennings S, Wei L. Org. Lett. 2011; 13: 1840
• 2b Londregan AT, Jennings S, Wei L. Org. Lett. 2010; 12: 5254
• 2c Paudler WW, Jovanovic MV. J. Org. Chem. 1983; 48: 1064
• 2d Abramovitch RA, Shinkai I. Acc. Chem. Res. 1976; 9: 192
• 2e Katritzky AR, Lunt E. Tetrahedron 1969; 25: 4291
• 2f Johnson RM. J. Chem. Soc. B. 1966; 1058

Recent representative examples:
• 3a Zhang S, Liao L, Zhang F, Duan X. J. Org. Chem. 2013; 78: 2720
• 3b Tan Y, Barrios-Landeros F, Hartwig JF. J. Am. Chem. Soc. 2012; 134: 3683
• 3c Gosselin F, Savage SJ, Blaquiere N, Staben ST. Org. Lett. 2012; 14: 862
• 3d Zhao H, Wang R, Chen P, Gregg BT, Hsia MM, Zhang W. Org. Lett. 2012; 14: 1872
• 3e Duric S, Tzschucke CC. Org. Lett. 2011; 13: 2310
• 3f Sun H, Gorelsky SI, Stuart DR, Campeau LC, Fagnou K. J. Org. Chem. 2010; 75: 8180
• 3g Huestis MP, Fagnou K. Org. Lett. 2009; 11: 1357
• 3h Campeau LC, Schipper DJ, Fagnou K. J. Am. Chem. Soc. 2008; 130: 3266
• 3i Campeau LC, Megan BL, Leclerc JP, Villemure E, Gorelsky S, Fagnou K. J. Am. Chem. Soc. 2008; 130: 3276
• 3j Cho SH, Hwang SJ, Chang S. J. Am. Chem. Soc. 2008; 130: 9254
• 3k Andersson H, Fredrik A, Olsson R. Org. Lett. 2007; 9: 1335
• 3l Campeau L, Rousseaux S, Fagnou K. J. Am. Chem. Soc. 2005; 127: 18020
• 4a Mai W, Yuan J, Li Z, Sun G, Qu L. Synlett 2012; 145
• 4b Deng G, Ueda K, Yanagisawa S, Itami K, Li CJ. Chem. Eur. J. 2009; 15: 333
• 4c Minisci F. Synthetic and Mechanistic Organic Chemistry . Springer; Berlin/Heidelberg: 1976
• 4d Dyall LK, Pausacker KH. J. Chem. Soc. 1961; 18

Catalytic hydrogenation is commonly used to reduce pyridine-N-oxides. Other contemporary methods include:
• 5a Kokatla HP, Thomson PF, Bae S, Doddi VR, Lakshman MK. J. Org. Chem. 2011; 76: 7842
• 5b Mikami Y, Noujima A, Mitsudome T, Mizugaki T, Jitsukawa K, Kaneda K. Chem. Eur. J. 2011; 17: 1768
• 5c Ponaras AA, Zaim O. J. Heterocycl. Chem. 2007; 44: 487
• 5d Singh KS, Reddy MS, Mangle M, Ganesh KR. Tetrahedron 2007; 63: 126
• 5e Yoo BW, Choi JW, Yoon CM. Tetrahedron Lett. 2006; 47: 125
• 5f Saini A, Kumar S, Sandhu JS. Synlett 2006; 395
• 5g Sanz R, Escribano J, Fernández Y, Aguado R, Pedrosa MR, Francisco J. Synlett 2005; 1389
• 5h Bjørsvik HR, Gambarotti C, Jensen VR, Gonzalez RR. J. Org. Chem. 2005; 70: 3218
• 5i Kumar S, Saini A, Sandhu JS. Tetrahedron Lett. 2005; 46: 8737
• 5j Jie Z, Rammoorty V, Fischer B. J. Org. Chem. 2002; 67: 711
• 5k Ilias M, Barman DC, Prajapati D, Sandhu JS. Tetrahedron Lett. 2002; 43: 1877
• 5l Boruah M, Konwar D. Synlett 2001; 795
• 5m Ram SR, Chary KP, Iyengar DS. Synth. Commun. 2000; 30: 3511
• 5n Yadav JS, Subba Reddy BV, Muralidhar Reddy M. Tetrahedron Lett. 2000; 41: 2663
• 5o Malinowski M. Synthesis 1987; 732
• 5p Zhang Y, Lin R. Synth. Commun. 1987; 17: 329
• 5q Hitomi S, Naofumi S, Osuka A. Chem. Lett. 1980; 4: 459
• 6 Reaction temperatures range from 70–120 °C with reaction times between 4 h and 24 h.
• 7 2,6-Dimethylpyridine-N-oxide was reported as a challenging reduction substrate by Lakshman and co-workers.^5a The reduction with bis(catecholato)diboron required 24 h at 120 °C to afford a 65% yield of 2,6-lutidine
• 8 The use of pinacol and catechol in the synthesis of bis(alkoxy)diborons is inherently wasteful and inefficient, see: Molander GA, Trice SL, Kennedy SM, Dreher SD, Tudge MT. J. Am. Chem. Soc. 2012; 134: 11667
• 9 See Supporting Information for additional examples of pyridine-N-oxide reduction with tetrahydroxydiboron.
• 10 Ethylenediamine (20 mol equiv).
• 11 Londregan AT, Storer G, Wooten C, Yang X, Warmus J. Tetrahedron Lett. 2009; 50: 1986
• 12 General Procedure The appropriate aminopyridine-N-oxide (13, 1.00 equiv) and carboxylic acid/acid chloride (14, 1.20 equiv) were combined in DMF (0.50 M) and treated with i-Pr₂EtN (2.5 equiv) and HATU (1.2 equiv). The reaction was stirred at r.t. until the initial coupling was deemed complete by LC–MS (usually 1–2 h). The reaction was then treated with tetrahydroxydiboron (5, 2.00 equiv) in a single portion (Note: exotherm evident). After stirring for 10 min, the reaction was quenched with H₂O (10 mL), which resulted in the precipitation of most products. The solids were filtered, washed with H₂O, and air-dried to afford the desired products in sufficient purity. For those reactions where precipitation of solid was not evident, the desired products were extracted with EtOAc (3 × 10 mL), washed with brine, dried (Na₂SO₄), and evacuated. These crude materials were purified by silica gel column chromatography. Analytical Data for Entry 3 ¹H NMR (400 MHz, CDCl₃): δ = 9.30 (br s, 1 H), 8.50 (d, J = 8.2 Hz, 1 H), 8.33 (m, 1 H), 8.14 (d, J = 7.0 Hz, 2 H), 7.89–7.96 (m, 1 H), 7.86 (d, J = 7.0 Hz, 2 H), 7.21 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.3, 152.3, 148.5, 138.7, 132.8, 129.3, 120.7, 118.8, 115.3, 114.6. MS: m/z = 224.1 [M + H]⁺. Analytical Data for Entry 10 ¹H NMR (400 MHz, CDCl₃): δ = 10.45 (s, 1 H), 8.43 (s, 1 H), 8.30–8.38 (m, 1 H), 8.16 (d, J = 8.20 Hz, 1 H), 8.13 (s, 1 H), 7.73–7.84 (m, 1 H), 7.06–7.16 (dd, J = 7.0, 5.1, 1 H), 3.88 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.5, 152.9, 148.4, 140.0, 138.6, 133.8, 119.9, 118.5, 114.9. MS: m/z = 203.2 [M + H]⁺.
• 13 Carter CA. G, John KD, Mann G, Martin RL, Cameron TM, Baker RT, Bishop KL, Broene RD, Westcott SA. ACS Symp. Ser. 2002; 822: 70
• 14 A noticeable exothermic reaction was observed in most examples.