Synthesis of Nicotine and Diverse Analogues Using Intramolecular [3+2] Cycloaddition

Abstract

A new methodology is described for the novel and rapid synthesis of nicotine and its analogues from nicotinaldehyde. The major feature of the methodology is the highly effective intramolecular [3+2] cycloaddition of azomethine ylides. The reaction was studied using conventional thermal and microwave irradiation conditions.

Key words

intramolecular dipolar cycloaddition - nicotinoid heterocycles - microwaves

References and Notes

• 1a McDonald IA. Cosford N. Vernier J.-M. Ann. Rep. Med. Chem.  1995,  30:  41 
• 1b Decker MW. Arneric SP. In Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities   Arneric SP. Brioni JD. Wiley-VCH; Weinheim: 1999.  p.395 
• 2 For a review, see: Wagner FF. Comins DL. Tetrahedron  2007,  63:  8065 ; and references therein
• 3a Zhai H. Liu P. Luo S. Fang F. Zhao M. Org. Lett.  2002,  4:  4385 
• 3b Luo S. Fang F. Zhao M. Zhai H. Tetrahedron  2004,  60:  5353 
• 3c Yang X. Luo S. Fang F. Liu P. Lu Y. He M. Zhai H. Tetrahedron  2006,  62:  2240 
• 4 Comins DL. Brown JD. J. Org. Chem.  1984,  49:  1078 
• 5 Comins DL. Killpack MO. J. Org. Chem.  1990,  55:  69 
• 6 Bashiardes G. Chaussebourg V. Laverdan G. Pornet J. Chem. Commun.  2004,  122 

7

Synthesis of 4-(dimethylvinylsilanyl)pyridine-3-carboxaldehyde (5a); Typical Procedure: A solution of
n-BuLi (1.6 M in hexanes, 11.2 mmol) was slowly added to a solution of N,N,N′-trimethylethylenediamine (12 mmol) in anhydrous THF (40 mL), which was stirred and cooled at
-78 ˚C. After 30 min, 3-pyridinecarboxaldehyde (10 mmol) was slowly added and the resulting mixture was stirred for 30 min at -78 ˚C. A further solution of n-BuLi (1.6 M in hexanes, 20 mmol) was added slowly and the reaction was stirred continuously at -48 ˚C for 3 h. The reaction was cooled to -78 ˚C, and a solution of dimethylvinylchloro-silane (30 mmol) was slowly added. The mixture was stirred at -78 ˚C for 30 min then allowed to warm to room temper-ature. The reaction was quenched with brine and then extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO₄) and evaporated. The crude mixture was purified on silica gel (pentane-EtOAc, 1:1) to provide the product in 63% yield as a viscous yellow oil. ^¹H NMR (CDCl₃, 300 MHz): δ = 10.19 (s, 1 H, CH=O), 9.03 (s, 1 H, H2), 8.75 (d, J = 4.8 Hz, 1 H, H6), 7.63 (d, J = 4.8 Hz, 1 H, H5), 6.40 (dd, J = 20.3, 14.6 Hz, 1 H, H_c), 6.10 (dd, J = 14.6, 3.4 Hz, 1 H, H_b), 5.80 (dd, J = 20.3, 3.4 Hz, 1 H, H_a), 0.45 (s, 6H, SiMe₂); ^¹³C NMR (CDCl₃, 300 MHz): δ = 192.2 (CH=O), 153.5 (C6), 152.9 (C2), 150.2 (C4), 136.8 (CH=), 135.5 (C3), 133.5 (CH₂=), 130.3 (C5), -2.9 (SiMe₂).
3,8,8-Trimethyl-1,2,3,3a,8,8a-hexahydro-3,5-diaza-8-silacyclopenta[ a ]indene-2-carboxylic acid methyl ester (6b): Thermal conditions: A solution of 5a (1 mmol) and sarcosine methyl ester 9b (2 mmol) in toluene (10 mL), was stirred and heated at reflux for 6 h. After evaporation of the solvent under reduced pressure, the crude product was purified by short column chromatography on silica gel (CH₂Cl₂-MeOH, 95:5) to provide the product in 95% yield as viscous yellow oil. Microwave conditions: In a pyrex tube (2 × 15 mm), 5a (1 mmol) and sarcosine methyl ester 9b
(2 mmol) were submitted to microwave irradiation (CEM Discover apparatus; 50 W, 130 ˚C) for 5 min. After cooling, the crude mixture was purified by short column chromato-graphy on silica gel (CH₂Cl₂-MeOH, 95:5) to provide the product in 99% yield. ^¹H NMR (CDCl₃, 300 MHz): δ = 8.65 (s, 1 H, H4), 8.50 (d, J = 4.6 Hz, 1 H, H6), 7.42 (d, J = 4.6 Hz, 1 H, H7), 4.57 (dd, J = 7.4, 4.5 Hz, 1 H, H3a), 3.88-3.90 (m, 1 H, H2), 3.74 (s, 3 H, OMe), 2.55 (s, 3 H, NMe), 2.12-2.14 (m, 3 H, H1 and H8a), 0.37 (s, 3 H, SiMe), 0.27 (s, 3 H, SiMe); ^¹³C NMR (CDCl₃, 300 MHz): δ = 173.7 (C=O), 149.7 (C7a), 147.4 (C4), 147.3 (C6), 146.1 (C3b), 126.9 (C7), 70.9 (C3a), 68.32 (C2), 50.9 (OMe), 35.7 (NMe), 28.7 (C1), 27.3 (C8a), -2.0 (SiMe), -3.7 (SiMe).
1-Methyl-5-pyridin-3-yl-pyrrolidine-2-carboxylic acid methyl ester (7b): A solution of 6b (1 mmol) and TBAF (1 M in THF, 4 mL, 4 mmol) was stirred and heated at reflux for 5 h. After cooling to room temperature, the reaction was quenched with water and then extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄) and evaporated under reduced pressure. The crude mixture was purified on silica gel (CH₂Cl₂-MeOH) to provide the product in 55% yield as a viscous yellow oil. ^¹H NMR (CDCl₃, 300 MHz): δ = 8.6 (s, 1 H, H_b), 8.50 (d, J = 4.2 Hz, 1 H, H_f), 7.67 (d, J = 7.8 Hz, 1 H, H_d), 7.26 (dd, J = 7.8, 4.2 Hz, 1 H, H_e), 4.06 (dd, J = 8.5, 6.7 Hz, 1 H, H5), 3.95 (dd,
J = 8.1 Hz, 1 H, H2), 3.74 (s, 3 H, OMe), 2.40-2.60 (m, 1 H, H4), 2.26-2.36 (m, 1 H, H3), 2.24 (s, 3 H, NMe), 1.86-2.04 (m, 1H, H3), 1.76-1.80 (m, 1H, H4); ^¹³C NMR (CDCl₃, 300 MHz): δ = 174.3 (C=O), 149.2 (C_b), 148.4 (C_f), 139.3 (C_c), 134.7 (C_d), 123.5 (C_e), 65.9 (C2), 64.5 (C5), 51.1 (OMe), 35.0 (NMe), 34.0 (C4); 27.7 (C3).