Checked by Ronald C. Newbold and Andrew S. Kende.
1. Procedure
B.
Preparation of N-(4-methoxyphenyl)-(Z)-4-(trimethylsilyl)-3-butenamine. A
250-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, a
250-mL addition funnel, and a
gas inlet tube. The flask is flushed with
argon or
nitrogen and charged with
41.5 g (0.337 mol) of 4-methoxyaniline (Note
7) and then heated to 65°C. The stirring melt is degassed (Note
8),
20.2 g (67.8 mmol) of (Z)-4-(trimethylsilyl)-3-butenyl 4-methylbenzenesulfonate is added over 15 min, and the resulting solution is maintained at 65°C for 3 hr. The reaction product is allowed to cool to ca. 50°C and is then transferred to a
500-mL separatory funnel using
250 mL of chloroform. The
chloroform solution is washed with two
100-mL portions of 1 M sodium hydroxide and the combined aqueous phases are extracted with
500 mL of chloroform. The combined organic phases are dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator. The crude residue is distilled through a
17-cm Vigreux column and excess
4-methoxyaniline is collected in the first fraction, bp
80–86°C (0.25 mm) (Note
9). Vacuum distillation is continued to give
10.6 g (
63% yield) of
N-(4-methoxyphenyl)-(Z)-4-(trimethylsilyl)-3-butenamine, bp
125–128°C (0.25 mm), as a pale-yellow oil (Note
10).
C.
Preparation of 1-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine. An
oven-dried, 250-mL, two-necked round-bottomed flask is equipped with a magnetic stirring bar, a
reflux condenser, and an
argon or
nitrogen inlet. The flask is flushed with
argon or
nitrogen, charged with
6.62 g (26.5 mmol) of N-(4-methoxyphenyl)-(Z)-4-(trimethylsilyl)-3-butenamine,
7.45 g (260 mmol) of paraformaldehyde (Note
11),
4.8 g (25 mmol) of p-toluenesulfonic acid monohydrate (Note
12), and
100 mL of acetonitrile (Note
13). The reaction mixture is degassed (Note
8) and heated at reflux for 1 hr (Note
14). The reaction mixture is cooled to room temperature and the excess
paraformaldehyde is removed by vacuum filtration. The reaction vessel is washed with two
25-mL portions of dichloromethane and the washings are clarified by filtration. The combined organic phases are concentrated under reduced pressure using a rotary evaporator, and the resulting solid residue is dissolved in
dichloromethane and transferred to a 500-mL separatory funnel. The organic phase is washed with two
100-mL portions of 4 M sodium hydroxide and the aqueous washings are extracted with
50 mL of dichloromethane. The combined organic phases are then washed with 100 mL of water, dried over anhydrous
potassium carbonate, filtered, and concentrated under reduced pressure using a rotary evaporator. The crude residue is dissolved in
9 : 1 hexane–ether and filtered through a
20-cm column (6-cm diameter) of silica gel. Evaporation of solvent gives
4.2 g (
84% yield) of
1-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine as a white crystalline solid, mp
49–51°C (Note
15) and (Note
16).
2. Notes
3.
p-Toluenesulfonyl chloride was purchased from Aldrich Chemical Company, Inc. and was purified by dissolving 100 g in
100 mL of chloroform, adding
1250 mL of hexane, filtering to remove insoluble impurities, and concentrating the filtrate under reduced pressure.
2
5. Caution must be exercised so that the ether layer does not become too warm during this extraction.
6. The sample has the following spectral characteristics: IR (neat) cm
−1: 1610, 1365, 1255, 1180.
1H NMR (CDCl
3, 250 MHz) δ: 0.13 (s, 9 H, SiCH
3), 2.49–2.58 (m, 5 H), 4.14 (apparent t, 2 H,
J = 6.9, CH
2OR), 5.69 (d, 1 H,
J = 14.1, R
3SiCH=CH), 6.17 (overlapping dt, 1 H,
J = 14.1
J = 7.2, R
3SiCH=CH), 7.40 (apparent d, 2 H,
J = 7.8, aryl H), 7.85 (apparent d, 2 H,
J = 8.3, aryl H). Gas-chromatographic analysis using a
25-m 5% methyl-phenylsilicone column showed that this sample was >92% pure and contained several unidentified impurities.
8. This is done by applying a mild vacuum to the reaction vessel and then filling the vessel with
argon or
nitrogen. This operation was repeated 3 times.
9. The condenser is not cooled and the collector tip is at times gently heated with a heat gun to prevent crystallization of
4-methoxyaniline in the distillation apparatus.
10. The product had the following spectral characteristics: IR (neat) cm
−1: 3390, 2950, 1608, 1246, 1040, 838;
1H NMR (CDCl
3, 250 MHz) δ: 0.14 (s, 9 H, SiCH
3), 2.42–2.51 (apparent q, 2 H,
J = 7, =CHCH
2), 3.15 (t, 2 H,
J = 6.8, CH
2NR), 3.76 (s, 3 H, ArOCH
3), 5.67 (d, 1 H,
J = 14.1, R
3SiCH=CH), 6.32 (overlapping dt, 1 H,
J = 14.1 and 7.3, R
3SiCH=CH), 6.59 (apparent d, 2 H,
J = 9.0, aryl H), 6.76 (apparent d, 2 H,
J = 9.0, aryl H). High-resolution mass spectrum (EI, 70 eV) 249.1548 (calcd. for C
14H
23NOSi: 249.1549). Gas-chromatographic analysis using a 25-m 5% methylphenylsilicone capillary column showed that this sample was >95% pure. Two impurities of similar retention time, presumed to be the (
E)-stereoisomer and the corresponding alkane, constitute 1–3% of the product mixture depending on the run, while a third, longer-retention-time impurity, the corresponding tertiary amine, represents 2% of the product mixture.
11.
Paraformaldehyde was purchased from Alpha Products, Morton/Thiokol, Inc.
14. During this time
paraformaldehyde can be seen forming on the inside of the reflux condenser.
15. The sample thus obtained is 94–97% pure by capillary GC analysis using a 25-m 5% methylphenylsilicone capillary column. This material gave the following elemental analysis. Anal. calcd. for C
12H
15NO: C, 76.15; H, 7.99; N, 7.40. Found: C, 75.49; H, 8.15; N, 7.31.
16. A purer sample may be obtained by vacuum sublimation at 60°C (0.3 mm). The material shows the following spectral characteristics: IR (KBr) cm
−1: 2831, 1514, 1249, 1210, 1190, 1035, 815;
1H NMR (250 MHz) δ: 2.4–2.7 (m, 2 H), 3.27 (t, 2 H,
J = 5.6), 3.58–3.65 (m, 2 H), 3.80 (s, 3 H, OCH
3), 5.7–5.9 (m, 2 H, RCH=CHR), 6.85–6.95 (m, 4 H, aryl H). Gas-chromatographic analysis using a 25-m 5% methylphenylsilicone column showed that this material was 98% pure and was contaminated with 1.8% of the starting secondary amine and 0.3% of the corresponding tertiary acyclic amine. This material melts at
50–52°C and gave the following elemental analysis. Anal. calcd. for C
12H
15NO: C, 76.15; H, 7.99; N, 7.40. Found: C, 76.18, H, 8.00; N, 7.40. The oxalate salt melts at 134–135°C and gave the following elemental analysis. Anal. calcd. for C
14H
17NO
5: C, 60.21; H, 6.09; N, 5.01. Found: C, 60.09; H, 6.16; N, 4.98.
3. Discussion
A variety of 1,2,5,6-tetrahydropyridines can be prepared by the reaction of (
Z)-4-(trimethylsilyl)-3-butenamines with aldehydes.
3,4,5 6 Representative examples are summarized in Table I. Cyclizations with paraformaldehyde occur readily in refluxing
acetonitrile, while cyclizations with other aldehydes require higher temperatures. Tetrahydropyridines with substituents at atoms −1, −2, −3, and −4 have been regioselectively prepared in this way. In no case was any trace of a regioisomeric tetrahydropyridine detected.
The 1,2,5,6-tetrahydropyridine ring is found in several natural products and numerous pharmacologically active materials.
5,6 This ring system is most commonly constructed by reduction of the corresponding pyridinium salt or from
4-piperidone precursors.
5 The cyclization approach reported here has the advantage of complete regiocontrol of the double-bond position. Moreover, this approach is of particular value for the synthesis of 1-aryl-substituted tetrahydropyridines that are difficult to access, since they are not generally available from
pyridine precursors.
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