Carbon - Carbon Bond Forming Reactions at Room Temperature

C-C bond_1

Type of reaction: C-C bond formation

Reaction conditions: Solvent-free, room temperature

Synthetic strategy: One-step condensation

Catalyst: Niobium pentachloride (NbCl5)

Keywords: 1,4-Dicarbonyls, aldehydes, niobium pentachloride (NbCl5), homogeneous catalysis, solvent-free, room temperature, condensation, Knoevenagel reaction, trisubstituted alkenes

General reaction scheme

Representative entries

Experimental procedure

A round-bottomed flask was charged with a magnetic stir bar, 1,3-carbonyl compound (1; 1 mmol), and aldehyde (2; 1.2 mmol), followed by 20 mol% of NbCl5. The reaction mixture was then stirred at room temperature for required time-frame (0.75-4.0 h). After completion of the reaction, it was quenched by the addition of saturated aqueous NaHCO3 solution and the product (3) was extracted with ethyl acetate. The product was purified by column chromatography using ethyl acetate/hexane as eluent. Structure of each of the products was verified from IR, 1H NMR, 13C NMR and HRMS studies.

Characterization data of two representative compounds

(E)-Methyl 2-(4-chlorobenzylidene)-3-oxobutanoate (3a): Reddish solid; mp 80 °C; IR (KBr): 821, 1088, 1250, 1618, 1654, 1733, 2362, 2855, 2932 cm- 1; 1H NMR (300 MHz, CDCl3): d 1.16 (s, 3H), 2.58 (s, 3H), 6.11-6.12 (m, 4H), 6.27 (s, 1H); 13C NMR (75 MHz, CDCl3): d 26.5, 52.6, 129.1, 130.6, 136.8, 134.5, 140.0, 169.7, 194.3; ESIMS: m/z 261 (M+ + Na); HRMS: Calcd for C12H11O3NaCl, 261.0294; Found 261.0289.

3-(4-Methoxybenzylidene)pentane-2,4-dione (3c): Yellow liquid; IR (neat): 831, 1108, 1174, 1258, 1258, 1513, 1599, 1653, 1706, 2844, 2926, 3004 cm- 1; 1H NMR (300 MHz, CDCl3): d 2.28 (s, 3H), 2.26 (s, 3H), 3.83 (s, 3H), 6.87 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 7.37 (s, 1H); 13C NMR (75 MHz, CDCl3): d 26.2, 31.6, 55.3, 114.5, 125.2, 131.6, 139.7, 140.6, 161.6, 196.4, 206.1; ESIMS: m/z 241 (M+ + Na); HRMS: Calcd for C13H14O3Na, 241.0840; Found 241.0833.

Reference

Yadav JS, Bhunia DC, Singh VK, Srihari P. Solvent-free NbCl5 catalyzed condensation of 1,3-dicarbonyl compounds and aldehydes: A facile synthesis of trisubstituted alkenes. Tetrahedron Lett. 2009;50:2470-2473.

C-C bond_2

Type of reaction: C-C bond formation

Reaction conditions: Water, neutral conditions, room temperature

Synthetic strategy: One-step condensation

[Cage 1: adapted from Murase et al. (2012), J. Am. Chem. Soc., 134, 162]

Catalyst: Heterogeneous, a cationic coordination cage (1) (12 + charged M6L4 cage) [Cage components: (ethylene diamine)Pd(NO3)2 and 2,4,6-tripyridyl-1,3,5-triazine]

Keywords: Aromatic aldehydes, Meldrum's acid, 12 + charged cage 1 (catalyst), water, room temperature, condensation, Knoevenagel reaction, trisubstituted alkenes

General reaction scheme

Representative entries

Experimental procedure

Aldehyde (2; 0.5 mmol) and Meldrum's acid (3; 0.5 mmol) were added to an aqueous solution (5 mL) of cage (1; 15.0 mg, 5.00 × 10-3 mmol; 1 mol%), and the reaction mixture was stirred at room temperature for stipulated time (6-96 h). The product was extracted with CHCl3 (2 × 5 mL), and the organic layer was evaporated in vacuo to furnish the condensation product 4 (38-96% yield). The obtained product 4 was purified by recrystallization from refluxing ethanol. Each of the products was fully characterized from its detailed spectral studies including IR, 1H NMR, 13C NMR, MS, and also from analytical analyses.

Cage 1 - a synthetic mimic of enzymes: This technique demonstrated a unique dehydration condensation under neutral conditions in water catalyzed by the water-soluble synthetic cationic host 1. An aromatic aldehyde substrate (2; an electron-rich guest) first became efficiently encapsulated into the host's (1) hydrophobic cavity, which after then attacked by the enolate of Meldrum's acid (3) to generate oxyanion intermediate. The condensation reaction seems to be facilitated by the anionic intermediate in the cationic environment of the cage. The eventual loss of water molecule occurs smoothly within the hydrophobic cavity to form the dehydrated product (4) which is too large for the cavity and is spontaneously released from the cage, and a new incoming substrate molecule (2) occupies the position. The overall phenomenon follows the tricks of enzyme-like catalysis.

Characterization data of two representative compounds

5-((6-Methoxynaphthalen-2-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4c): Solid, mp 191.2-192.2 °C; IR (ATR): 2992, 2946, 1756, 1725, 1587, 1402, 1341, 1291, 1222, 1158, 1023, 1010 cm-1; 1H NMR (500 MHz, CDCl3): d 8.56 (br s,1H), 8.55 (br s,1H), 8.18 (dd, J = 8.8, 1.7 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H,), 7.16 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H), 1.83 (s, 6H); 13C NMR (125 MHz, CDCl3): d 163.8 (C), 160.9 (C), 160.3 (C), 158.5 (CH), 137.8 (C), 137.7 (CH), 131.7 (CH), 129.4 (CH), 128.1 (C), 127.3 (C), 127.1 (CH), 120.0 (CH), 112.7 (C), 106.0 (CH), 104.4 (C), 55.6 (CH3), 27.6 (CH3); GC-MS (EI): m/z = 312 [M]+. Anal. Calcd. for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.11; H, 5.32.

5-(Anthracen-9-ylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4d): Solid, mp 193.6-194.3 °C; IR (ATR): 3049, 3031, 3013, 2925, 2854, 1764, 1737, 1631, 1446, 1396, 1385, 1365, 1334, 1292, 1218, 1202, 1123, 1067, 1028; 1H NMR (500 MHz, CDCl3): d 9.47 (s, 1H), 8.55 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 9.1 Hz, 2H), 7.52 (t, J = 9.1 Hz, 1H), 7.50 (t, J = 8.8 Hz, 1H), 1.90 (s, 6H); 13C NMR (125 MHz, CDCl3): d 161.91 (C), 157.89 (C), 157.75 (CH), 130.94 (C), 130.29 (CH), 129.34 (CH), 128.63 (C), 127.09 (CH), 126.80 (C), 125.58 (CH), 124.52 (CH), 121.02 (C), 104.97 (C), 28.17 (CH3); GC-MS (EI): m/z = 332 [M]+. Anal. Calcd. for C21H16O4: C, 75.89; H, 4.85; Found: C, 75.66; H, 5.03.

Reference

Murase T, Nishijima Y, Fujita M. Cage-catalyzed knoevenagel condensation under neutral conditions in water. J. Am. Chem. Soc. 2012;134:162-164.

C-C bond_3

Type of reaction: C-C bond formation

Reaction conditions: Ethanol / dichloromethane, room temperature

Synthetic strategy: E or Z-Selective Knoevenagel condensation

Catalyst: Piperidine

Keywords: Aldehydes, O-acetoacetylTEMPO (2,2,6,6-tetramethylpiperidin-1-yl 3-oxobutanoate), N-methoxy-N-methyl-3-oxobutanamide, piperidine, ethanol, room temperature, E- and Z-selective Knoevenagel condensation, trisubstituted E or Z-2-alkenes

General reaction scheme

Representative entries

Experimental procedure

A typical procedure for Knoevenagel condensaton of O-acetoacetylTEMPO (1). To a cooled (0-4 °C) mixture of O-acetoacetylTEMPO (1; 243 mg, 1.0 mmol), 2-furaldehyde (2; 192 mg, 2.0 mmol), and ethanol (4 drops, 20 mg) was added piperidine (two drops, 10 mg). The mixture was allowed to warm gradually to room temperature and was stirred for 2 days. The reaction was quenched with cold aqueous ammonium chloride, and the products were extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), and...