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DOI:10.15227/orgsyn.068.0188

Organic Syntheses, Coll. Vol. 8, p.358 (1993); Vol. 68, p.188 (1990).

REGIOSELECTIVE SYNTHESIS OF TETRAHYDROPYRIDINES:
1-(4-METHOXYPHENYL)-1,2,5,6-TETRAHYDROPYRIDINE[Pyridine, 1,2,3,6-tetrahydro-1-(4-methoxyphenyl)-]

Submitted by Larry E. Overman, Chris J. Flann, and Thomas C. Malone1.
Checked by Ronald C. Newbold and Andrew S. Kende.

1. Procedure
A. Preparation of (Z)-4-(trimethylsilyl)-3-butenyl 4-methylbenzenesulfonate. An oven-dried, 1-L,
round-bottomed flask is equipped with a magnetic stirring bar and purged with dry argon or nitrogen.
The flask is charged with 17.3 g (0.120 mol) of (Z)-4-(trimethylsilyl)-3-buten-1-ol (Note 1) and 290 mLof dry pyridine (Note 2). The reaction mixture is cooled to 0°C in an ice–water bath and 25.2 g (0.132mol) of p-toluenesulfonyl chloride (Note 3) is added to the solution. When the p-toluenesulfonyl
chloride is completely dissolved, the flask containing the reaction mixture is sealed and placed in arefrigerator at −20°C for 24 hr (Note 4). The reaction mixture is then poured into a rapidly stirring
mixture of 200 g of ice and 200 mL of water contained in a 2-L Erlenmeyer flask. The resulting mixture
is transferred to a 2-L separatory funnel and extracted with five 200-mL portions of ether. The
combined organic phases are washed with five 200-mL portions of ice-cold aqueous 6 N hydrochloricacid (Note 5) and 200 mL of water. The organic phase is dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure using a rotary evaporator to give 29.2 g (82%) ofcrude (Z)-4-(trimethylsilyl)-3-butenyl 4-methylbenzenesulfonate as a light-yellow oil (Note 6).
B. Preparation of N-(4-methoxyphenyl)-(Z)-4-(trimethylsilyl)-3-butenamine. A 250-mL, threenecked, round-bottomed flask is equipped with a magnetic stirring bar, a 250-mL addition funnel, and agas inlet tube. The flask is flushed with argon or nitrogen and charged with 41.5 g (0.337 mol) of 4methoxyaniline (Note 7) and then heated to 65°C. The stirring melt is degassed (Note 8), 20.2 g (67.8mmol) of (Z)-4-(trimethylsilyl)-3-butenyl 4-methylbenzenesulfonate is added over 15 min, and theresulting solution is maintained at 65°C for 3 hr. The reaction product is allowed to cool to ca. 50°C andis then transferred to a 500-mL separatory funnel using 250 mL of chloroform. The chloroform solutionis washed with two 100-mL portions of 1 M sodium hydroxide and the combined aqueous phases areextracted 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 isdistilled 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-(4methoxyphenyl)-(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, twonecked 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 (Note11), 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). Thereaction 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 arotary 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 sodiumhydroxide and the aqueous washings are extracted with 50 mL of dichloromethane. The combinedorganic 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 isdissolved 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 awhite crystalline solid, mp 49–51°C (Note 15) and (Note 16).

2. Notes
1. The trimethylsilyl butenol was prepared as described in another Organic Syntheses procedure (Org.
Synth., Coll. Vol. VIII, 1993, 609).
2. Pyridine is freshly distilled from calcium hydride under an argon atmosphere.
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
4. During this time, pyridinium hydrochloride precipitates from the solution as white needles.
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. 1HNMR (CDCl3, 250 MHz) δ: 0.13 (s, 9 H, SiCH3), 2.49–2.58 (m, 5 H), 4.14 (apparent t, 2 H, J = 6.9,CH2OR), 5.69 (d, 1 H, J = 14.1, R3SiCH=CH), 6.17 (overlapping dt, 1 H, J = 14.1 J = 7.2,
R3SiCH=CH), 7.40 (apparent d, 2 H, J = 7.8, aryl H), 7.85 (apparent d, 2 H, J = 8.3, aryl H). Gaschromatographic analysis using a 25-m 5% methyl-phenylsilicone column showed that this sample was>92% pure and contained several unidentified impurities.
7. 4-Methoxyaniline (p-anisidine) was purchased from Aldrich Chemical Company, Inc.
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 (CDCl3, 250 MHz) δ: 0.14 (s, 9 H, SiCH3), 2.42–2.51 (apparent q, 2 H, J = 7,=CHCH2), 3.15 (t, 2 H, J = 6.8, CH2NR), 3.76 (s, 3 H, ArOCH3), 5.67 (d, 1 H, J = 14.1, R3SiCH=CH),
6.32 (overlapping dt, 1 H, J = 14.1 and 7.3, R3SiCH=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
C14H23NOSi: 249.1549). Gas-chromatographic analysis using a 25-m 5% methylphenylsilicone capillarycolumn showed that this sample was >95% pure. Two impurities of similar retention time, presumed tobe 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.
12. p-Toluenesulfonic acid monohydrate was purchased from Aldrich Chemical Company, Inc. and issuitable for use after storage for 24 hr in a vacuum desiccator over phosphorus pentoxide.
13. Acetonitrile was purchased from Mallinkrodt, 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 C12H15NO: 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 thefollowing 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, OCH3), 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 materialmelts at 50–52°C and gave the following elemental analysis. Anal. calcd. for C12H15NO: 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 thefollowing elemental analysis. Anal. calcd. for C14H17NO5: 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)-3butenamines with aldehydes.3,4,5 6 Representative examples are summarized in Table I. Cyclizations withparaformaldehyde occur readily in refluxing acetonitrile, while cyclizations with other aldehydes
require higher temperatures. Tetrahydropyridines with substituents at atoms −1, −2, −3, and −4 havebeen regioselectively prepared in this way. In no case was any trace of a regioisomerictetrahydropyridine detected.

TABLE I
PREPARATION OF SUBSTITUTED 1,2,5,6-TETRAHYDROPYRIDINES3,4

1R

2R

3R

R

C3H7H

H

H

4Cyclization StepConditions (Temp., °C;
Yield (%)
Time, hr)80; 1.5614-Methoxybenzyl

HH

H80; 1.591

Cyclohexyl

H

H

H110; 1054a

Ph

H

H

H80; 0.7
614-Methoxyphenyl

H

H

H80; 184

C3H7C6H13H

H120; 48544-Methoxybenzyl C6H13HH120; 7264

PhC6H13HH80; 368

Iso-C4H9HHCH380; 266

Iso-C4H9HHPh80; 283

C3H7HSiMe3H80; 1.282

In this case the reaction of a cyanomethyl tertiary amine with silver trifluoroacetatein chloroform was used to initiate the cyclization instead of the reaction of analdehyde with a secondary amine salt.

aThe 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 ofthe 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 isof particular value for the synthesis of 1-aryl-substituted tetrahydropyridines that are difficult to access,since they are not generally available from pyridine precursors.
Iminium ion-vinylsilane cyclizations closely related to the one described here have been used toprepare indolizidine alkaloids of the pumiliotoxin A7 and elaeokanine3 families, indole alkaloids,8amaryllidaceae alkaloids,9 and the antibiotic (+)-streptazolin.10 The ability of the silicon substituent tocontrol the position, and in some cases stereochemistry, of the unsaturation in the product heterocycle
was a key feature of each of these syntheses.
Alternative methods of preparing 1-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine have not beenreported.
This preparation is referenced from:zOrg. Syn. Coll. Vol. 8, 609

References and Notes
1. Department of Chemistry, University of California, Irvine, CA 92717.
2. Fieser, L. F.; Fieser, M. "Reagents for Organic Syntheses," Wiley: New York, 1967, Vol. I, p.
1180.
3. Overman, L. E.; Malone, T. C.; Meier, G. P. J. Am. Chem. Soc. 1983, 109, 6993; Flann, C. J.;
Malone, T. C.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6097.
4. Overman, L. E. Lect. Heterocycl. Chem. 1985, 8, 59; Blumenkopf, T. A.; Overman, L. E. Chem.
Rev. 1986, 86, 857.
5. Fowler, F. W. in "Comprehensive Heterocyclic Chemistry," Katritzky, A. R.; Rees, C. W., Eds.;
Pergammon Press: London, 1984, Vol. 2, Part 2A, pp. 365–394;
6. Coutts, R. T.; Scott, J. R. Can. J. Pharm. Sci. 1971, 6, 78.
7. Overman, L. E.; Bell, K. L. J. Am. Chem. Soc. 1981, 103, 1851; Overman, L. E.; Bell, K. L.; Ito,F. J. Am. Chem. Soc. 1984, 106, 4192; Overman, L. E.; Lin, N.-H. J. Org. Chem. 1985, 50, 3669.
8. Overman, L. E.; Malone, T. C. J. Org. Chem. 1982, 47, 5297.
9. Overman, L. E.; Burk, R. M. Tetrahedron Lett. 1984, 25, 5737.
10. Flann, C. J.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)potassium carbonate (584-08-7)hydrochloric acid (7647-01-0)
ether (60-29-7)acetonitrile (75-05-8)
sodium hydroxide (1310-73-2)
chloroform (67-66-3)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
pyridine (110-86-1)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
Indole (120-72-9)
hexane (110-54-3)
argon (7440-37-1)
calcium hydride (7789-78-8)
silver trifluoroacetate (2966-50-9)
p-Toluenesulfonyl chloride (98-59-9)
phosphorus pentoxide (1314-56-3)
p-toluenesulfonic acid monohydrate (6192-52-5)
1-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridine,
Pyridine, 1,2,3,6-tetrahydro-1-(4-methoxyphenyl)- (133157-31-0)(Z)-4-(Trimethylsilyl)-3-butenyl 4-methylbenzenesulfonate (87682-62-0)(Z)-4-(Trimethylsilyl)-3-buten-1-ol (87682-77-7)
N-(4-Methoxyphenyl)-(Z)-4-(trimethylsilyl)-3-butenamine (133157-30-9)
4-methoxyaniline,
p-anisidine (104-94-9)

pyridinium hydrochloride (628-13-7)
4-piperidone
paraformaldehyde (30525-89-4)
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