Efficient Synthesis of 5-Functionalised
2-Methoxypyridines and their Transformation to Bicyclic δ-Lactams,
both Accessed Using Magnesium ‘Ate’ Complexes
as Key Reagents

Jacek G. Sośnicki

doi:10.1055/s-0029-1217733

LETTER

Efficient Synthesis of 5-Functionalised 2-Methoxypyridines and their Transformation to Bicyclic δ-Lactams, both Accessed Using Magnesium ‘Ate’ Complexes as Key Reagents

Jacek G. Sośnicki*
Institute of Chemistry and Environmental Protection, West Pomeranian University of Technology, Szczecin, Al. Piastów 42, 71065 Szczecin, Poland
Fax: +48(91)4494639; e-Mail: sosnicki@ps.pl;

Abstract

All articles of this category

Abstract

Simple and efficient synthesis of 5-functionalised 2-methoxypyridines from 5-bromo-2-methoxypyridine using [n-Bu₃Mg]Li performed in noncryogenic conditions is described. Application of 5-functionalised 2-methoxypyridines in the synthesis of 1-substituted 3,6,9,9a-tetrahydroquinolizin-4-ones and 3,5,8,8a-tetrahydro-1H-quinolin-2-ones via allylation of the corresponding 5-functionalised N-allyl(or benzyl)pyridin-2-ones using [allyln-Bu₂Mg]Li followed by ring-closing metathesis is presented.

Key words

magnesium ‘ate’ complexes - magnesiates - bromine-magnesium exchange - allylation - quinolizidin-4-ones - RCM

Full Text

References

References and Notes

<A NAME="RG20309ST-1">1</A> Yorimitsu H. Oshima K. The Chemistry of Organomagnesium Ate Complexes In The Chemistry of Organomagnesium Compounds Rappoport Z. Marek I. Wiley; Chichester: 2008. Chap. 15. p.681-716

<A NAME="RG20309ST-2A">2a</A> Stefan MC. Javier AE. Osaka I. McCullough RD. Macromolecules 2009, 42: 30

<A NAME="RG20309ST-2B">2b</A> Shinozuka T. Yamamoto Y. Hasegawa T. Saito K. Naito S. Tetrahedron Lett. 2008, 49: 1619

<A NAME="RG20309ST-2C">2c</A> Gallou F. Haenggi R. Hirt H. Marterer W. Schaefer F. Seeger-Weibel M. Tetrahedron Lett. 2008, 49: 5024

<A NAME="RG20309ST-2D">2d</A> Lau SYW. Hughes G. O’Shea PD. Davies IW. Org. Lett. 2007, 9: 2239

<A NAME="RG20309ST-2E">2e</A> Fleming FF. Gudipati S. Anh Viet V. Mycka RJ. Knochel P. Org. Lett. 2007, 9: 4507

<A NAME="RG20309ST-2F">2f</A> Dolman SJ. Gosselin F. O’Shea PD. Davies IW. Tetrahedron 2006, 62: 5092

<A NAME="RG20309ST-2G">2g</A> Kii S. Akao A. Iida T. Mase T. Yasuda N. Tetrahedron Lett. 2006, 47: 1877

<A NAME="RG20309ST-2H">2h</A> Buron F. Plé N. Turck A. Marsais F. Synlett 2006, 1586

<A NAME="RG20309ST-2I">2i</A> Thomas GL. Böhner C. Ladlow M. Spring DR. Tetrahedron 2005, 61: 12153

<A NAME="RG20309ST-2J">2j</A> Trost BM. Frederiksen MU. Papillon JP. Harrington PE. Shin S. Shireman BT. J. Am. Chem. Soc. 2005, 127: 3666

<A NAME="RG20309ST-2K">2k</A> Xu J. Jain N. Sui Z. Tetrahedron Lett. 2004, 45: 6399

<A NAME="RG20309ST-2L">2l</A> Therkelsen FD. Rottländer M. Thorup N. Pedersen EB. Org. Lett. 2004, 6: 1991

<A NAME="RG20309ST-2M">2m</A> Tsuji T. Nakamura T. Yorimitsu H. Shinokubo H. Oshima K. Tetrahedron 2004, 60: 973

<A NAME="RG20309ST-2N">2n</A> Ito S. Kubo T. Morita N. Matsui Y. Watanabe T. Ohta A. Fujimori K. Murafuji T. Sugihara Y. Tajiri A. Tetrahedron Lett. 2004, 45: 2891

<A NAME="RG20309ST-2O">2o</A> Shinokubo H. Oshima K. Eur. J. Org.Chem. 2004, 2081

<A NAME="RG20309ST-2P">2p</A> Dumouchel S. Mongin F. Trécourt F. Quéguiner G. Tetrahedron 2003, 59: 8629

<A NAME="RG20309ST-2Q">2q</A> Fukuhara K. Takayama Y. Sato F. J. Am. Chem. Soc. 2003, 125: 6884

<A NAME="RG20309ST-2R">2r</A> Dumouchel S. Mongin F. Trécourt F. Quéguiner G. Tetrahedron Lett. 2003, 44: 3877

<A NAME="RG20309ST-2S">2s</A> Dumouchel S. Mongin F. Trécourt F. Quéguiner G. Tetrahedron Lett. 2003, 44: 2033

<A NAME="RG20309ST-2T">2t</A> Inoue A. Kondo J. Shinokubo H. Oshima K. Chem. Eur. J. 2002, 8: 1730

<A NAME="RG20309ST-2U">2u</A> Mase T. Houpis IN. Akao A. Dorziotis I. Emerson K. Hoang T. Iida T. Itoh T. Kamei K. Kato S. Kato Y. Kawasaki M. Lang F. Lee J. Lynch J. Maligres P. Molina A. Nemoto T. Okada S. Reamer R. Song JZ. Tschaen D. Wada T. Zewge D. Volante RP. Reider PJ. Tomimoto K. J. Org. Chem. 2001, 66: 6775

<A NAME="RG20309ST-2V">2v</A> Kondo J. Inoue A. Shinokubo H. Oshima K. Angew. Chem. Int. Ed. 2001, 40: 2085

<A NAME="RG20309ST-2W">2w</A> Inoue A. Kitagawa K. Shinokubo H. Oshima K. J. Org. Chem. 2001, 66: 4333

<A NAME="RG20309ST-2X">2x</A> Iida T. Wada T. Tomimoto K. Mase T. Tetrahedron Lett. 2001, 42: 4841

<A NAME="RG20309ST-2Y">2y</A> Kitagawa K. Inoue A. Shinokubo H. Oshima K. Angew. Chem. Int. Ed. 2000, 39: 2481

<A NAME="RG20309ST-3A">3a</A> Sośnicki JG. Struk Ł. Synlett 2009, 1812

<A NAME="RG20309ST-3B">3b</A> Bentabed-Ababsa G. Blanco F. Derdour A. Mongin F. Trécourt F. Quéguiner G. Ballesterous R. Abarca B. J. Org. Chem. 2009, 74: 163

<A NAME="RG20309ST-3C">3c</A> Hawad H. Bayh O. Hoarau C. Trécourt F. Quéguiner G. Marsais F. Tetrahedron 2008, 64: 3236

<A NAME="RG20309ST-3D">3d</A> Mulvey RE. Mongin F. Uchiyama M. Kondo Y. Angew. Chem. Int. Ed. 2007, 46: 3802

<A NAME="RG20309ST-3E">3e</A> Bayh O. Awad H. Mongin F. Hoarau C. Bischoff L. Trécourt F. Quéguiner G. Marsais F. Blanco F. Abarca B. Ballesteros R. J. Org. Chem. 2005, 70: 5190

<A NAME="RG20309ST-3F">3f</A> Mongin F. Bucher A. Bazureau JP. Bayh O. Awad H. Trécourt F. Tetrahedron Lett. 2005, 46: 7989

<A NAME="RG20309ST-3G">3g</A> Awad H. Mongin F. Trécourt F. Quéguiner G. Marsais F. Blanco F. Abarca B. Ballesteros R. Tetrahedron 2005, 61: 4779

<A NAME="RG20309ST-3H">3h</A> Awad H. Mongin F. Trécourt F. Quéguiner G. Marsais F. Tetrahedron Lett. 2004, 45: 7873

<A NAME="RG20309ST-3I">3i</A> Awad H. Mongin F. Trécourt F. Quéguiner G. Marsais F. Blanco F. Abarca B. Ballesteros R. Tetrahedron Lett. 2004, 45: 6697

<A NAME="RG20309ST-3J">3j</A> Ide M. Nakata M. Bull. Chem. Soc. Jpn. 1999, 72: 2491

<A NAME="RG20309ST-3K">3k</A> Ide M. Yasuda M. Nakata M. Synlett 1998, 936

<A NAME="RG20309ST-3L">3l</A> Yasuda M. Ide M. Matsumoto Y. Nakata M. Bull. Chem. Soc. Jpn. 1998, 71: 1417

<A NAME="RG20309ST-4A">4a</A> Hatano M. Miyamoto T. Ishihara K. Curr. Org. Chem. 2007, 11: 127

<A NAME="RG20309ST-4B">4b</A> Hatano M. Matsumura T. Ishihara K. Org. Lett. 2005, 7: 573

<A NAME="RG20309ST-4C">4c</A> Faraks J. Richey HG. Organometallics 1990, 9: 1778

<A NAME="RG20309ST-4D">4d</A> Richery HG. DeStephano J. Tetrahedron Lett. 1985, 26: 275

<A NAME="RG20309ST-4E">4e</A> Ashby EC. Chao L.-C. Laemmle J.
J. Org. Chem. 1974, 39: 3258

<A NAME="RG20309ST-4F">4f</A> Wittig G. Meyer FJ. Lange G. Justus Liebigs Ann. Chem. 1951, 571: 167

<A NAME="RG20309ST-5">5</A> See, for example: Rubiralta M. Giralt E. Diez A. Piperidines. Structure, Preparation, Reactivity and Synthetic Application of Piperidines and its Derivatives Elsevier; Amsterdam: 1991.

<A NAME="RG20309ST-6A">6a</A> Sośnicki JG. Synlett 2003, 1673

<A NAME="RG20309ST-6B">6b</A> Sośnicki JG. Westerlich S. Tetrahedron Lett. 2002, 43: 1325

<A NAME="RG20309ST-7A">7a</A> Sośnicki JG. Tetrahedron 2009, 65: 1336

<A NAME="RG20309ST-7B">7b</A> Sośnicki JG. Tetrahedron Lett. 2009, 50: 178

<A NAME="RG20309ST-7C">7c</A> Sośnicki JG. Tetrahedron 2007, 63: 11862

<A NAME="RG20309ST-8A">8a</A> Sośnicki JG. Tetrahedron Lett. 2005, 46: 4295

<A NAME="RG20309ST-8B">8b</A> Sośnicki JG. Tetrahedron Lett. 2006, 47: 6809

<A NAME="RG20309ST-9A">9a</A> Bowman WR. Bridge CF. Synth. Commun. 1999, 29: 4051

<A NAME="RG20309ST-9B">9b</A> Kunishima M. Friedman JE. Rokita SE. J. Am. Chem. Soc. 1999, 121: 4722

<A NAME="RG20309ST-9C">9c</A> Shiao M.-J. Lai L.-L. Ku W.-S. Lin P.-Y. Hwu JR. J. Org. Chem. 1998, 58: 4742

<A NAME="RG20309ST-9D">9d</A> Hwu JR. Wong FF. Huang J.-J. Tsay S.-C. J. Org. Chem. 1997, 62: 4097

<A NAME="RG20309ST-9E">9e</A> Hongo H. Nakano H. Okuyama Y. Heterocycles 1995, 40: 831

<A NAME="RG20309ST-9F">9f</A> Newkome GR. Kohli DK. Kawato T. J. Org. Chem. 1980, 45: 4508

1-Substituted quinolizidin-4-ones are biologically active species. See, for example:

<A NAME="RG20309ST-10A">10a</A> Casagrande M. Basilico N. Parapini S. Romeo S. Taramelli D. Sparatore A. Bioorg. Med. Chem. 2008, 16: 6813

<A NAME="RG20309ST-10B">10b</A> Vazanna I. Budriesi R. Terranowa E. Ioan P. Ugenti MP. Tasso B. Chiarini A. Sparatore F. J. Med. Chem. 2007, 50: 334

<A NAME="RG20309ST-10C">10c</A> Kim D.-I. Deutsch HM. Ye X. Schwerei MM. J. Med. Chem. 2007, 50: 2718

<A NAME="RG20309ST-11A">11a</A> Mahiout Z. Lomberget T. Goncalves S. Barret R. Org. Biomol. Chem. 2008, 6: 1364

<A NAME="RG20309ST-11B">11b</A> Boros EE. Burova SA. Erickson GA. Johns BA. Koble CS. Kurose N. Sharp MJ. Tabet EA. Thompson JB. Toczko MA. Org. Process Res. Dev. 2007, 11: 899

<A NAME="RG20309ST-11C">11c</A> Denton TT. Zhang X. Cashman JR. J. Med. Chem. 2005, 48: 224

<A NAME="RG20309ST-11D">11d</A> Manoso AS. Ahn C. Soheili A. Handy CJ. Correia R. Seganish WM. DeShong P. J. Org. Chem. 2004, 69: 8305

<A NAME="RG20309ST-11E">11e</A> Hodgson DM. Maxwell CR. Wisedale R. Matthews IR. Carpenter KJ. Dickenson AH. Wonnacott S. J. Chem. Soc., Perkin Trans. 1 2001, 3150

<A NAME="RG20309ST-11F">11f</A> Giblin GMP. Jones CD. Synlett 1997, 589

See, for example:

<A NAME="RG20309ST-12A">12a</A> Humphries PS. Do TQ.-Q. Wilhite DM. Tetrahedron Lett. 2009, 50: 1765

<A NAME="RG20309ST-12B">12b</A> Wroblewski B. Wigglesworth MJ. Szekeres PG. Smith GD. Rahman SS. Nicholson NH. Muir AI. Hall A. Heer JP. Gerland SL. Coates WJ. J. Med. Chem. 2009, 52: 818

<A NAME="RG20309ST-12C">12c</A> Brown A. Brown L. Brown B. Calabrese A. Ellis D. Puhalo N. Smith CR. Wallace O. Watson L. Bioorg. Med. Chem. Lett. 2008, 18: 5242

<A NAME="RG20309ST-12D">12d</A> Ebdrup S. Hoffmann H. Refsgaard F. Fledelius C. Jacobsen P. J. Med. Chem. 2007, 50: 5449

<A NAME="RG20309ST-12E">12e</A> Qu W. Kung M.-P. Hou C. Benedum TE. Kung HF. J. Med. Chem. 2007, 50: 2157

Typical Procedure of 5-Functionalisation of 2-Methoxy-pyridine
To a cooled (0 ˚C) and stirred solution of n-BuMgCl (4.2 mmol, 2.1 mL, 2.0 M in THF) in dry THF (4 mL) in a Schlenk flask, n-BuLi (8.4 mmol, 3.4 mL, 2.5 M in hexane) was added via syringe over 1 min under argon, and the mixture was stirred for 5 min. To a yellow, cooled (-2 to 0 ˚C) solution 5-bromo-2-methoxypyridine (8.4 mmol, 1.09 mL) was added via syringe. The resulting solution was stirred for 30 min at -2 to 0 ˚C, then the electrophile was added (Table [¹] ), and the mixture was continuously stirred for 30 min at 0 ˚C and 1 h at r.t. After addition of aq sat. NH₄Cl (5 mL), the aqueous layer was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and purification by distillation or flash column chromatography yielded compound 3.

Typical Procedure of Transformation of 3 to Bicyclic Lactams 7
The mixture of 3 (5.5 mmol), NaI (11 mmol), and allyl bromide (38.5 mmol) was heated in MeCN (30 mL) at 55 ˚C for 1-6 d (see Table [²] ). Subsequently, the solvent was evaporated and brine containing 1% Na₂S₂O₃ was added. The aqueous solution was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and purification by flash column chromatography yielded 4. To a cooled (0 ˚C) and stirred solution of allylMgCl (4.9 mmol, 2.45 mL, 2.0 M in THF) in dry THF (4 mL) in a Schlenk flask n-BuLi (9.8 mmol, 3.9 mL, 2.5 M in hexane) was added via syringe under argon, the mixture was stirred for 5 min and then cooled to -72 ˚C. The mixture containing 1b was next transferred via syringe to a cooled (-72 ˚C) solution of N-allylpyridin-2-one (4, 9.0 mmol) in THF (20 mL). The resulting solution was stirred for 20 min at -72 ˚C, and then aq sat. NH₄Cl (10 mL) was added. The aqueous layer was extracted with EtOAc (2 × 75 mL), and the combined organic layers were dried over MgSO₄. Filtration, concentration in vacuo, and separation by flash column chromatography yielded 5. To a solution of 1,6-diallyl lactam 5 (1.0 mmol) in dry, degassed toluene (10 mL), ruthenium catalyst 8 or 9 was added, and the reaction mixture was stirred under slowly bubbled stream of argon at 70 ˚C. After the reaction was complete (Table [²] ), the solvent was evaporated at reduced pressure, and the residue was left standing for 48 h followed by purification on column chromatography.

Selected Spectroscopic Data
2-Methoxy-5-trimethylsilanylpyridine (3b) Colorless oil. IR (film): 2956, 1586, 1556, 1488, 1352, 1286, 1250, 1116, 1026, 840 cm^-¹. MS (EI, 70 eV): m/z (%) = 181 (32) [M⁺], 180 (17), 166 (100), 136 (7). ^¹H NMR (400.1 MHz, CDCl₃): δ = 0.26 (9 H, s, Me₃Si), 3.94 (3 H, s, OCH₃), 6.74 (1 H, dd, J = 8.3, 0.8 Hz, =CH-3), 7.65 (1 H, dd, J = 8.3, 1.9 Hz, =CH-4), 8.24 (1 H, dd, J = 1.8, 0.8 Hz, =CH-6). ^¹³C NMR (100.6 MHz, CDCl₃): δ = -1.1 (Me₃Si), 53.3 (OCH₃), 110.6 (CH-3), 126.3 (C-5), 143.5 (CH-4), 151.6 (CH-6), 164.8 (C-2). HRMS (EI): m/z calcd for C₉H₁₅NOSi: 181.0923; found: 181.0922.
1-Trimethylsilanyl-3,6,9,9a-tetrahydroquinolizin-4-one (7b) Colorless oil. IR (film): 3036, 2960, 1666, 1644, 1468, 1444, 1404, 1296, 1254, 1116, 840, 760 cm^-¹. MS (EI, 70 eV): m/z (%) = 221 (79) [M⁺], 220 (100), 206 (12), 152 (14), 148 (23), 124 (23), 100 (34), 73 (28). ^¹H NMR (400.1 MHz, CDCl₃): δ = 0.15 (9 H, s, Me₃Si), 2.00-2.10 (1 H, m, CHH-9), 2.34 (1 H, dm, J = ca. 17.1 Hz, CHH-9), 2.97-3.01 (2 H, m, CH₂-3), 3.42 (1 H, dm, J = ca. 18.3 Hz, CHH-6), 4.16 (1 H, dq, J = 11.5, 3.4 Hz, CH-9a), 5.06 (1 H, dm, J = 18.3 Hz, CHH-6), 5.69-5.76 (1 H, m, =CH-7), 5.76-5.83 (1 H, m, =CH-8), 6.02 (1 H, ddd, J = 4.2, 3.2, 1.0 Hz, =CH-2). ^¹³C NMR (100.6 MHz, CDCl₃): δ = -1.1 (Me₃Si), 32.9 (CH₂-3), 34.1 (CH₂-9), 41.7 (CH₂-6), 57.6 (CH-9a), 124.8 (=CH-8), 125.0 (=CH-7), 131.1 (=CH-2), 137.21 (C-1), 166.1 (C-4). HRMS (EI): m/z calcd for C₁₂H₁₉NOSi: 221.1236; found: 221.1234.