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Organic Synteses vol 69 - Paquette L.A.

Paquette L.A., Boecman R.K. Organic Synteses vol 69 - John Wiley & Sons, 1990. - 174 p.
ISBN 0-471-54560-0
Download (direct link): organicsynthesesvol691990.pdf
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12. The submitters provided the following alternative procedure for conducting the oxidation with m-chloroperoxybenzoic acid (MCPBA) in place of Oxone®: Into a 1-
L, round-bottomed flask equipped with a magnetic stirrer, reflux condenser, and a 250-mL addition funnel are placed 56.3 g (0.26 mol) of MCPBA (80%) and 350 mL of dichloromethane. The suspension is stirred and a solution of 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine in 120 mL of dichloromethane is added rapidly (exotherm). When the reaction mixture ceases to boil gently from the heat of reaction, it is heated to extend the reflux period to a total of 2.5 hr. The reaction mixture is cooled to room temperature, extracted with 0.5 M aqueous sodium hydroxide (4 x 450 mL), and dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the filtrate is concentrated with a rotary evaporator, and the residual solvent is removed at 0.1 mm pressure to afford 40 g (99%) of yellow crystalline product, mp 96-100°C.
13. For both recrystallizations, the solid is taken up in boiling ethyl acetate, rapidly filtered, and the filtrate is allowed to cool slowly to room temperature. It then is stored at -5°C overnight in a refrigerator prior to collecting the crystals.
14. The product (Rf = 0.47) contains a trace of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine (Rf = 0.79) by thin-layer chromatographic analysis (Alumina GF Uniplate, 1:1 ethyl acetate:hexane). The checkers chromatographed a 10-g sample on a Woelm neutral alumina column (75 x 28 mm) using 300 mL of warm ethyl acetate as eluent to give 9.2 g of colorless product, mp 107-109°C. The original and chromatographed products have identical spectroscopic properties: 1 NMR (300 MHz, CDCI3) 8: 0.96 (t, 3 H, J = 7, CH3), 1.41 (m, 4 H, CikCtbCHa), 1.7-1.9 (m, 6 H, H2, H6, H7), 2.03 (m, 1 H, H3), 2.27 (m, 1 H, H3), 2.50 (m, 2 H, 9-CH2), 2.70 (m, 4 H, H-t, H8), 2.84 (m, 2 H, H5), 4.63 (m, 1 H, H4), 4.76 (s, 1 H, OH); IR (KBr) cm-1; 3I74 (s, br), 2942 (s), 2713 (m), 1569 (s), 1432 (s), 1407 (s), 1377 (m), 1338 (s), 1307 (s), 1253 (m), 1216 (m), 1169 (m), 1155 (s), 1094 (s), 1081 (s), 1005 (s), 962 (s), 939 (m), 893 (m). The submitters obtained an analytical sample, mp 104-105°C, by recrystallization from
ethyl acetate and drying for 6 hr at room temperature (0.1 mm). Anal. Calcd for C17H25NO: C, 78.72; H, 9.71; N,5.40. Found: C, 78.81, H, 9.53, N, 5.19.
3. Discussion
Taken together, Steps A and B of this procedure describe the most expedient, large scale approach to 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine, which is prepared in about 60% overall yield from inexpensive starting materials. This heterocycle is an important building block for "hexagonal lattice" receptors, which are relatively rigid, planar hosts for metal ions and organic molecules.2
Several methods exist for preparing pyridines that are annelated to nonaromatic rings in the [b,e] positions,3-6 but most do not also introduce an alkyl group in the 4-position. n-Butyl groups are found to lend solubility to higher molecular weight hexagonal lattice receptors. Step A of this procedure is a modification of the method of Tilichenko, who has reported the condensation of cyclohexanone with various aldehydes.7 The reaction involves the following sequence: aldol condensation to form 2-pentylidenecyclohexanone, Michael addition of cyclohexanone enolate, and intramolecular aldol condensation of the resulting 1,5-diketone. Many aldol products are formed and the yield of keto alcohol depends strongly on: 1) reaction temperature; 2) use of a large excess of cyclohexanone; and 3) prolonged addition of the aldehyde. The ease of product isolation is particularly dependent on its crystallinity and solubility.
If a substituent is not required in the 4-position of the new pyridine ring, then viable alternatives to the current procedure include trimethylhydrazonium-salt pyrolysis5 and various methods for condensing ketones or enamines with formaldehyde or methyleneammonium salts.4a’f’6d The latter methods often involve isolation of the intermediate 1,5-diketone, which is condensed with ammonia or
ammonium salts to form the pyridine ring,4b■d', The yield of this cyclization is limited by disproportionation of the intermediate dihydropyridine.8 Hydrazine4e or hydroxylamine23'43 may also be used, but yields are similar to those obtained with ammonium acetate in acetic acid. The cupric acetate/ammonium acetate method described in Step B nearly quantitatively gives annelated pyridines from various 1,5-diketone equivalents.8 Cupric acetate appears to be the oxidant of choice for intercepting dihydropyridines before disproportionation can occur.
Step C describes a method for oxidizing a pyridine to its N-oxide with Oxone® (potassium hydrogen persulfate). The more traditional oxidant, m-chloroperoxybenzoic acid (MCPBA), works equally well, but the availability of 80-85% pure MCPBA is now limited. Pyridine N-oxides may also be prepared with hydrogen peroxide in acetic acid,9'10 but reaction time is variable and removal of acetic acid is inconvenient for large scale preparations. Potassium hydrogen persulfate (Oxone®) is an inexpensive alternative to MCPBA in many oxidation reactions.11 The oxidation procedure given here avoids the formation of volatile peroxides, which occurs in ketone-catalyzed N-oxidation of pyridine by persulfate. 11b'e A 50% excess of Oxone® is used, assuming 100% activity. The submitters used Oxone® of 67-68% purity by iodometric titration. Less oxidant leads to incomplete reaction or inconveniently long reaction times.
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