Synlett 2013; 24(20): 2695-2700
DOI: 10.1055/s-0033-1340010
letter
© Georg Thieme Verlag Stuttgart · New York

Rapid 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 Affiliations
Further Information

Publication History

Received: 24 July 2013

Accepted after revision: 16 September 2013

Publication Date:
05 November 2013 (online)


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

Supporting Information

 
  • References and Notes

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  • 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).
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  • 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.