Transformations of 3,4-Disubstituted Pyridines under Dissolving Metal Conditions - Partial Reduction followed by Radical Cyclisation

Abstract

The reductive alkylation of 3,4-disubstituted pyridines is reported using either sodium in ammonia or ammonia free conditions (Na, naphthalene, THF). This partial reduction process works cleanly and efficiently giving good yields of highly functionalised dihydropyridine templates. Radical cyclisation reactions were performed on these dihydropyridines and gave fused 2- and 3-ring heterocycles with defined stereochemistry.

dihydropyridine - partial reduction - radical cyclisation

References

<A NAME="RD25601ST-1">1</A>

Present address: The Dyson Perrins Laboratory, South Parks Road, Oxford, OX1 3QY. E-mail: [e-mail].

<A NAME="RD25601ST-2">2</A>

Author to whom correspondence regarding the X-ray crystal structure should be addressed.

<A NAME="RD25601ST-3A">3a</A> Donohoe TJ. McRiner AJ. Sheldrake P. Org. Lett.  2000,  2:  3861 

<A NAME="RD25601ST-3B">3b</A> Donohoe TJ. McRiner AJ. Helliwell M. Sheldrake P. J. Chem. Soc., Perkin Trans. 1  2001,  1435 

<A NAME="RD25601ST-4">4</A> Donohoe TJ. Harji RR. Cousins RPC. Tetrahedron Lett.  2000,  41:  1327 

See also:

<A NAME="RD25601ST-5A">5a</A> Kita Y. Maekawa H. Yamasaki Y. Nishiguchi I. Tetrahedron Lett.  1999,  40:  8587 

<A NAME="RD25601ST-5B">5b</A> Kita Y. Maekawa H. Yamasaki Y. Nishiguchi I. Tetrahedron  2001,  57:  2095 

For general reviews see:

<A NAME="RD25601ST-6A">6a</A> Eisner U. Kuthan J. Chem. Rev.  1972,  72:  1 

<A NAME="RD25601ST-6B">6b</A> Keay JG. In Comprehensive Organic Synthesis   Vol 8:  Trost BM. Fleming I. Pergamon; New York: 1991. 

<A NAME="RD25601ST-7">7</A> Calculations were performed on dianions derived from diesters of pyridine bearing the 2,3- and 3,4- and 2,5- substitution patterns using the AM1 semi-empirical method. These showed that the dianion derived from the 2,3-diester is the least stable of the three and may give some support to our inability to reduce this compound cleanly. See : Webster RD. Bond AM. Compton RG. J. Phys. Chem.   1996.  100:  p.10288 ; for experimentally measured reduction potentials which supplement this hypothesis

<A NAME="RD25601ST-8">8</A>

Condition A: Sodium metal (0.126 g, 5.48 mmol) was added to a stirred mixture of THF (10 mL) and freshly distilled ammonia (ca. 40 mL) at -78 °C, to form a deep blue solution. The substrate 1 (0.303 g, 1.21 mmol) was added in 15 mL THF and stirred for 15 min, by which time a deep purple colour was observed. Methyl iodide (0.28 mL, 4.5 mmol) was then added to the rapidly stirred reaction mixture, and the loss in intense colour and the appearance of a pale yellow colour was observed. Sat. ammonium chloride solution was then added after 10 s, which caused the mixture to become colourless. The ammonia was allowed to evaporate and the entire mixture was dry-loaded onto silica and the product separated as a colourless solid (0.282 g, 87%) by flash column chromatography (R _f = 0.34 (20% acetone in petrol)). Mp 79.6-80.5 °C; ¹H NMR (300 MHz; CDCl₃): δ = 7.26 (1 H, dd, J = 4.3 and 0.8 Hz), 5.99 (1 H, ddd, J = 7.8, 4.4 and 0.8 Hz), 5.86 (1 H, br), 5.02 (1 H, sept, J = 6.2 Hz), 4.99 (1 H, sept, J = 6.3 Hz), 4.53 (1 H, dd, J = 8.8 and 1.4 Hz), 1.49 (3 H, s), 1.25 (6 H, d, J = 5.9 Hz), 1.21 (6 H, d, J = 6.3 Hz); ¹³C NMR (75.4 MHz; CDCl₃): δ = 175.5, 167.5, 136.9, 123.5, 107.4, 103.5, 68.15, 66.73, 43.53, 28.13, 22.04, 21.83, 21.64.

<A NAME="RD25601ST-9">9</A>

Condition B: Sodium metal (0.133 g, 5.78 mmol) was added to a solution of naphthalene (0.848 g, 6.62 mmol) in THF (40 mL) and sonicated at r.t. for 1 h, by which time a deep green solution had formed. The solution was then cooled to -78 °C and stirred for 5 min. The substrate 1 (0.310 g, 1.23 mmol) was added in 15 mL THF and stirred for 2 h. A deep purple solution was observed. 1,4-Dibromobutane (0.52 mL, 4.3 mmol) was added dropwise over 20 s to the reaction mixture, causing a gradual loss in colour to a yellow solution. Ammonium chloride solution was added after 15 min, with no colour change. After warming to r.t., the mixure was dry loaded onto silica and the product was separated as a colourless solid (0.331 g, 69%) by gradient flash column chromatography (100% petrol to 10% acetone in petrol). Mp 103.5-105.2 °C; ¹H NMR (300 MHz; CDCl₃): δ = 7.34 (1 H, dd, J = 5.6 and 1.1 Hz), 6.30 (1 H, br), 6.09 (1 H, ddd, J = 7.8, 4.5 and 1.1 Hz), 4.99 (1 H, sept, J = 6.2 Hz), 4.97 (1 H, sept, J = 6.2 Hz), 4.38 (1 H, dd, J = 7.7 and 1.1 Hz), 3.40 (2 H, td, J = 6.9 and 2.1 Hz), 2.20-2.07 (1 H, m), 1.95-1.81 (2 H, m), 1.58-1.39 (2 H, m), 1.25-1.17 (13 H, m); ¹³C NMR (75.4 MHz; CDCl₃): δ = 175.0 167.4, 137.8, 125.0, 105.9, 100.9, 68.25, 66.85, 48.02, 36.50, 34.16, 33.18, 24.42, 22.14, 22.11, 21.91, 21.71.

<A NAME="RD25601ST-10">10</A>

X-ray data has been deposited in the Cambridge Crystallographic database (ref CCDC 173154).

For related radical cyclisations onto carbocyclic rings see:

<A NAME="RD25601ST-11A">11a</A> Curran DP. Chang C.-T. J. Org. Chem.  1989,  54:  3140 

<A NAME="RD25601ST-11B">11b</A> Curran DP. Qi H. DeMelloe NC. Lin C.-H. J. Am. Chem. Soc.  1994,  36:  8430 

<A NAME="RD25601ST-12">12</A>

M. Helliwell, unpublished work.

<A NAME="RD25601ST-13">13</A> Double P. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1998,  2005