Synlett, Table of Contents Synlett 2013; 24(20): 2695-2700DOI: 10.1055/s-0033-1340010 letter © Georg Thieme Verlag Stuttgart · New YorkRapid and Selective in situ Reduction of Pyridine-N-oxides with Tetrahydroxydiboron Allyn T. Londregan* CVMED Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA Fax: +1(860)7154695 Email: allyn.t.londregan@pfizer.com , David W. Piotrowski CVMED Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA Fax: +1(860)7154695 Email: allyn.t.londregan@pfizer.com , Jun Xiao CVMED Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA Fax: +1(860)7154695 Email: allyn.t.londregan@pfizer.com› Author AffiliationsRecommend Article Abstract Buy Article All articles of this category 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 Key words N-oxide reduction - tetrahydroxydiboron - selective reduction - in situ reduction - pyridine Full Text References 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. 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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. Supplementary Material Supplementary Material Supporting Information
