Checked by Edward R. Holler, Jr. and Bruce E. Smart.
1. Procedure
A.
8-n-Butyl-2-hydroxytricyclo[7.3.1.02,7]tridecan-13-one. A
2-L, three-necked, round-bottomed flask is equipped with a
magnetic stirring bar, a
thermometer, a
500-mL pressure-equalizing dropping funnel, and a
reflux condenser fitted with a
nitrogen gas inlet tube that is attached to a mineral oil bubbler. The flask is flushed with
nitrogen and then charged with
1.0 L (947 g, 9.65 mol) of cyclohexanone (Note
1). The
cyclohexanone is stirred and heated to 70–75°C under
nitrogen, a solution of
9.0 g (0.14 mol) of potassium hydroxide (Note
2) in
150 mL of absolute ethanol is added in one portion, and then a solution of
150 mL (122 g, 1.4 mol) of pentanal (Note
3) in
140 mL of absolute ethanol is added dropwise over a 8-hr period while maintaining the reaction mixture at 70–75°C. The reaction mixture is stirred and held at 70–75°C for an additional 12 hr, and then allowed to cool to room temperature. The reaction flask is immersed in an
ice bath, the inner wall of the flask is scratched with a
glass rod to initiate crystallization, and the mixture is kept at 0°C for 4 hr to complete the crystallization. The colorless crude product is collected by vacuum filtration and washed with
200 mL of cold ether. The filtrates are combined and concentrated to approximately 200 mL with a
rotary evaporator. The precipitated white solid is collected by filtration and washed with water (2 × 200 mL) and
200 mL of cold ether to give a second crop of crude product. The two crops ae combined and recrystallized by dissolving in hot
methanol (3 mL per gram of solid), boiling until cloudiness occurs and cooling slowly to room temperature, then to 0°C. The white crystals are collected by vacuum filtration to give
228–230 g (
61–62%) of
8-n-butyl-2-hydroxytricyclo[7.3.1.02,7]tridecan-13-one, mp
140–141°C (Note
4).
B.
9-n-Butyl-1,2,3,4,5,6,7,8-octahydroacridine. A
2-L, three necked flask equipped with a
mechanical stirrer, a
glass stopper, and a reflux condenser is charged with
70 g (0.91 mol) of ammonium acetate,
309 g (1.55 mol) of cupric acetate monohydrate (Note
5) and
750 mL of glacial acetic acid. The mixture is stirred and heated at reflux for 15 min under
nitrogen. The resulting solution is allowed to cool below reflux and
200 g (0.76 mol) of 8-n-butyl-2-hydroxytricyclo-[7.3.1.02,7]-tridecan-13-one is added in several portions. The blue-green reaction mixture is then refluxed under
nitrogen for 3 hr with efficient stirring to control foaming. The mixture is allowed to cool to room temperature and then chilled in an ice bath for 3 hr (Note
6). The precipitated
cuprous acetate is collected by vacuum filtration using a
medium porosity fritted glass funnel and washed with
200 mL of ether. The combined filtrates are mixed with 500 g of ice in a
4-L beaker and stirred rapidly as
1600 mL of concentrated ammonium hydroxide is added slowly along with additional ice (ca. 300 g) to avoid local heating and boiling of the
ether (final pH 10–11). The resulting mixture is separated and the aqueous layer is extracted with
ether (400 mL, then 2 × 200 mL). The combined
ether layers are washed with
200 mL of 20% aqueous ammonium hydroxide, followed by
200 mL of saturated aqueous sodium chloride, and dried over anhydrous
magnesium sulfate. The drying agent is removed by filtration and washed with
200 mL of ether. The combined filtrates are concentrated to minimum volume with a rotary evaporator and the resulting solid is dried to constant weight under vacuum (1 mm) to give
173–177 g (
91–96%) of beige solid, mp
36–38°C (Note
7). The product may be used directly in procedure C or further purified by adding a solution of material in
dichloromethane to a
column of Woelm neutral alumina and eluting with
dichloromethane. The solvent is removed on a rotary evaporator to give
148 g (
86%) of white crystalline solid, mp
41–43°C (Note
7).
C.
9-n-Butyl-1,2,4,5,6,7,8-octahydroacridine N-oxide. A
2-L, round-bottomed flask equipped with a mechanical stirrer or a powerful
magnetic stirrer and a reflux condenser fitted with a
nitrogen inlet tube is flushed with
nitrogen and charged with
38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine,
42.7 g (0.51 mol) of sodium bicarbonate, and
890 mL of methanol. The resulting mixture is stirred as
110 g (0.18 mol) of Oxone® (Note
8) is added, followed by 360 mL of distilled water. The suspension is stirred under
nitrogen at 48–50°C for 12–24 hr (Note
9). The mixture is cooled to room temperature and filtered, and the filter cake is washed with
methanol (2 × 50 mL). The
methanol is removed from the combined filtrates with a rotary evaporator, and the resulting mixture
(volume: ca 200 mL) is extracted with dichloromethane (3 × 100 mL). The combined extracts are washed with water (2 × 50 mL) and dried over
magnesium sulfate. The drying agent is removed by filtration, the filtrate is concentrated with a rotary evaporator, and the residual solid is dried under vacuum (0.1–0.5 mm) to give
40.0 g (
99%) of
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a cream colored solid, mp
92–94°C (Note
10),(Note
11),(Note
12).
D.
9-n-Butyl-1,2,3,4,5,6,7,8-octahydroacridin-4-ol. Crude
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide (38.9 g, 0.15 mol) is placed in a
1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, a glass stopper, and a reflux condenser fitted with a
nitrogen inlet tube and a 500-mL addition funnel.
Acetic anhydride (300 mL) is placed in the addition funnel, deaerated by sparging with
helium for 30 min, and then added rapidly to the nitrogen-purged reaction flask. The reaction mixture is stirred and heated in a 100–110°C
oil bath for 2 hr. The reflux condenser is replaced by a simple distillation head and approximately 280 mL of
acetic anhydride is removed by distillation at water-aspirator pressure (25–35 mm). To the brown residue is added
470 mL of 3 M aqueous hydrochloric acid, and the resulting mixture is refluxed under
nitrogen for 1.5 hr. The mixture is allowed to cool to room temperature, chilled in an ice bath, and made alkaline (pH 12–13) by slowly adding about
550 mL of cold 4 M aqueous sodium hydroxide. The resulting cloudy mixture is extracted with
chloroform (3 × 150 mL) and the combined extracts are dried over anhydrous
sodium sulfate. The drying agent is removed by filtration and the filtrate is concentrated to dryness with a rotary evaporator. The brown residue is recrystallized from
75 mL of ethyl acetate, and the collected product is recrystallized again from
50 mL of ethyl acetate (Note
13) to give
26–28 g (
67–72%) of
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridin-4-ol as a light beige solid, mp
105–106°C (Note
14).
2. Notes
1.
Cyclohexanone (99.8%) was obtained from Aldrich Chemical Company, Inc. and was used without purification.
3.
Pentanal (99%) was obtained from Aldrich Chemical Company, Inc., redistilled under a static atmosphere of
nitrogen (bp 103°C), and used immediately.
4. The product has the following spectroscopic properties:
1H NMR (300 MHz, CDCl
3) δ: 0.89 (t, 3 H,
J = 6, CH
3), 1.1–2.3 (m, 23 H, CH
2, CH), 2.44 (m, 1 H, CH
2), 2.72 (s, 1 H, OH); IR (KBr) cm
−1: 3413 (s), 2931 (s), 2857 (s), 1703 (s), 1455 (m), 1406 (m), 1378 (m), 1352 (m), 1285 (m), 1267 (m), 1206 (m), 1140 (m), 968 (m), 931 (m); mass spectrum
m/z (relative abundance, 70 eV): 264 (M
+, 10), 167 (85), 166 (100). The submitters report that a second recrystallization gives analytically pure material, mp
141–142°C. Anal. calcd. for C
17H
28O
2: C, 77.22; H, 10,67. Found: C, 77.34; H, 10.51.
6. Alternatively, the stoppered reaction flask may be allowed to stand overnight in a
refrigerator or
freezer. In this case the flask should stand at room temperature for 0.5–1 hr prior to filtration in order to partially melt the
acetic acid.
7. The product is pure by TLC analysis (Alumina GF Uniplate from Analtec, Inc., 1 : 1
ethyl acetate:
hexane solvent,
Rf = 0.79) and
1H NMR analysis. The product has the following spectroscopic properties:
1H NMR (300 MHz, CDCl
3) δ: 0.96 (t, 3 H,
J = 6, CH
3), 1.42 (m, 4 H, CH
2CH
2CH
3), 1.7–1.9 (m, 8 H, H2, H3, H6, H7), 2.49 (m, 2 H, ArCH
2), 2.68 (m, 4 H, ArCH
2), 2.85 (m, 4 H, ArCH
2); IR (neat) cm
−1: 2932 (s), 2858 (s), 1565 (m), 1438 (m), 1409 (m), 1246 (w); mass spectrum,
m/z (relative abundance 70, eV): 243 (M
+, 51), 228 (6), 214 (16), 201 (64), 200 (56), 186 (100). The submitters obtained an analytically pure sample by bulb-to-bulb distillation of the initial beige product. Anal. calcd. for C
17H
25N: C, 83.89; H, 10.35; N, 5.75. Found: C, 83.58; H, 10.07; N, 5.40.
8.
Oxone®, the Du Pont Company trade name for potassium peroxymonosulfate, has the composition 2KHSO5·KHSO4·K2SO4, and was purchased from Aldrich Chemical Company, Inc.
9. Oxidation may be monitored by thin-layer chromatography (Alumina GF Uniplate, 1 : 1
ethyl acetate :
hexane). The
Rf values of the
N-oxide product and starting material are 0.3 and 0.8, respectively. The reaction is approximately 99% complete after 12 hr, but reaction times varied with different lots of
Oxone®
10. The submitters report obtaining
39 g (
96%) of pale-yellow product, mp
89–92°C, when the beige starting material from Part B, mp
36–39°C, was used without further purification. The checkers, however, obtained only an
80% yield of
N-oxide, mp
87–91°C, when crude starting material was used.
11. The product is sufficiently pure to be used directly in Part D, but may be further purified by recrystallization from
ethyl acetate :
hexane (1 : 6) to give colorless material, mp
99–101°C. The product has the following spectral properties :
1H NMR (300 MHz, CDCl
3) δ: 0.97 (t, 3 H,
J = 6, CH
3), 1.42 (m, 4 H, CH
2CH
2CH
3), 1.7–1.9 (m, 8H, H2, H3, H6, H7), 2.53 (m, 2 H, 9-CH
2), 2.69 (m, 4 H, H1, H8), 2.97 (m, 4 H, H4, H5); IR (KBr) cm
−1: 2942 (s), 2857 (s), 1477 (m), 1444 (m), 1424 (m), 1398 (m), 1350 (m), 1322 (m), 1286 (s), 1236 (m), 1096 (s).
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, a 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 × 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 TLC analysis (Alumina GF Uniplate, 1 : 1
ethyl acetate :
hexane). The checkers chromatographed a 10-g sample on a Woelm neutral alumina column (75 × 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:
1NMR (300 MHz, CDCl
3) δ: 0.96 (t, 3 H,
J = 7, CH
3), 1.41 (m, 4 H, CH
2CH
2CH
3), 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-CH
2), 2.70 (m, 4 H, H1, H8), 2.84 (m, 2 H, H5), 4.63 (m, 1 H, H4), 4.76 (s, 1 H, OH); IR (KBr) cm
−1: 3174 (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 C
17H
25NO: C, 78.72; H, 9.71; N, 5.40. Found: C, 78.81, H, 9.53, N, 5.19.
3. Discussion
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,
25,26 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.
27 28 29 30 31 32 The oxidation procedure given here avoids the formation of volatile peroxides, which occurs in ketone-catalyzed
N-oxidation of
pyridine by
persulfate.
28,31 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.
Synthesis of annelated polypyridines or hexagonal lattice receptors from
1,2,3,4,5,6,7,8-octahydroacridines requires oxidative functionalization of the 4-position (CH
2 group bonded to the
pyridine 2-position). In Step D this is accomplished by "Katada" or "Boekelheide" rearrangement of the
N-oxide. This general reaction is commonly used for selective oxidation of alkylated pyridines, although the mechanism for conversion of the acetylated
N-oxide to the 2-acetoxyalkylpyridine has not been fully elucidated.
33 34 The current procedure reflects an empirical finding that deoxygenation of the
acetic anhydride prior to addition results in slightly higher yields. Condensation of 2-alkylpyridines with
benzaldehyde, followed by ozonolysis of the
benzylidene intermediate, is a general, alternative route to 2-oxoalkylpyridines.
35 The
N-oxide rearrangement described here is superior when monofunctionalization is required, because condensation of
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine with 1 equiv of
benzaldehyde gives a mixture of monobenzylidene and dibenzylidene derivatives.
2,3,4,5,6,7,8,9 Recent work by Tilichenko has shown that 1,5-diketones may be converted to monobenzylidene derivatives before forming the pyridine ring,
36 but overall yields are lower than those for the current procedure.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
pyridine N-oxides
potassium peroxymonosulfate
m-chloroperoxybenzoic acid (MCPBA)
1,2,3,4,5,6,7,8-octahydroacridines
4-Acridinol; 9-butyl-1,2,3,4,5,6,7,8-octahydro
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ammonia (7664-41-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
ammonium acetate (631-61-8)
acetic anhydride (108-24-7)
sodium hydroxide (1310-73-2)
formaldehyde (630-08-0)
chloroform (67-66-3)
oxone (37222-66-5)
sodium bicarbonate (144-55-8)
Cyclohexanone (108-94-1)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
benzaldehyde (100-52-7)
pyridine (110-86-1)
potassium hydroxide (1310-58-3)
hydrogen peroxide (7722-84-1)
ammonium hydroxide (1336-21-6)
cupric acetate (142-71-2)
benzylidene
hydrazine (302-01-2)
hydroxylamine (7803-49-8)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
Ammonium (14798-03-9)
persulfate (13445-49-3)
cupric acetate monohydrate,
copper(II) acetate monohydrate (6046-93-1)
hexane (110-54-3)
dihydropyridine
helium (7440-59-7)
methyleneammonium
cuprous acetate (598-54-9)
pentanal (110-62-3)
2-pentylidenecyclohexanone
cyclohexanone enolate
potassium hydrogen persulfate
m-chloroperoxybenzoic acid (937-14-4)
9-n-BUTYL-1,2,3,4,5,6,7,8-OCTAHYDROACRIDIN-4-OL (99922-91-5)
8-n-Butyl-2-hydroxytricyclo[7.3.1.02,7]tridecan-13-one (24133-22-0)
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine (99922-90-4)
9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide (136528-61-5)
9-n-Butyl-1,2,4,5,6,7,8-octahydroacridine N-oxide
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