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DOI:10.15227/orgsyn.070.0111

Organic Syntheses, Coll. Vol. 9, p.46 (1998); Vol. 70, p.111 (1992).

(E)-1-BENZYL-3-(1-IODOETHYLIDENE)PIPERIDINE:
NUCLEOPHILE-PROMOTED ALKYNE-IMINIUM IONCYCLIZATIONS[Piperidine, 3-(iodoethylidene)-1-(phenylmethyl)-(E)-]

Submitted by H. Arnold, L. E. Overman, M. J. Sharp, and M. C. Witschel1.
Checked by Antje Grützmann, Thomas Hache, and Ekkehard Winterfeldt.

1. Procedure
A. 4-Hexyn-1-yl methanesulfonate (1). An oven-dried, 500-mL, one-necked, round-bottomed flask
equipped with a magnetic stirring bar is flushed with argon and 260 mL of dichloromethane is added(Note 1). The flask is sealed with a rubber septum inlet and cooled to ca. −10°C in an ice-salt bath. To
this flask are added via syringe 11 mL (80 mmol) of triethylamine, 5.0 g (51 mmol) of 4-hexyn-1-ol(Note 2), and 4.3 mL (56 mmol) of methanesulfonyl chloride (Note 3). The resulting solution is stirred
for an additional 30 min and then quenched by adding 30 mL of ice-water. The organic layer isseparated and washed successively with 1 M hydrochloric acid solution (30 mL), saturated aqueous
sodium bicarbonate solution (30 mL), and brine (30 mL). The organic layer is dried over magnesium
sulfate, filtered, and concentrated with a rotary evaporator to give 8.3–9.0 g (93–100%) of crude 4hexyn-1-yl methanesulfonate (1) which was used directly in the next step (Note 4).
B. N-Benzyl-4-hexyn-1-amine (2). An oven-dried, 100-mL, one-necked, round-bottomed flask
containing a magnetic stirring bar and a rubber septum inlet is flushed with argon and charged with 200
mg of sodium iodide. The crude mesylate 1, 40 mL of dimethyl sulfoxide (Note 5) and 10.9 g (102mmol) of benzylamine are added via syringe. The resulting solution is heated in an oil bath at 47–53°Cfor 5 hr (Note 6) and then allowed to cool to room temperature. The reaction solution is poured into aseparatory funnel containing 200 mL of aqueous 1% sodium hydroxide solution and the resulting
mixture is extracted with ether (3 × 100 mL). The combined ether extracts are washed with brine (50mL), dried over magnesium sulfate, filtered, and concentrated with a rotary evaporator. The residue (ca.
9 g) is purified by flash chromatography (ca. 300 g of silica gel using 1:1 hexane-ether containing 5%
triethylamine as the eluent) (Note 7) to give 7.2–7.5 g (75–79% overall) of 2 as a colorless liquid (Note8).
C. (E)-1-Benzyl-3-(1-iodoethylidene)piperidine (3). A 250-mL, one-necked, round-bottomed flask
containing a magnetic stirring bar and a reflux condenser topped with a rubber septum inlet is flushedwith argon and charged with 4.0 g (21 mmol) of alkynylamine 2, 11 g (73 mmol) of sodium iodide

(Note 9), 35 mL of 37% w/w formaldehyde solution, 5.4 g (22 mmol) of camphorsulfonic acidmonohydrate (Note 10) and 80 mL of water. The resulting mixture is heated at reflux under an argon
atmosphere for 15 min (Note 11) and then allowed to cool to room temperature. This solution is madebasic by adding 5 M aqueous potassium hydroxide solution and then poured into a separatory funnel
where it is extracted with dichloromethane (3 × 50 mL) (Note 12). The combined organic layers aredried over sodium sulfate, filtered, and concentrated with a rotary evaporator. The resulting residue ispurified by flash chromatography (ca. 150 g of silica gel, 1:1 hexane-ethyl ether containing 5%
triethylamine as eluent) to give 5.4–6.2 g (79–90%) of 3 as a colorless oil (Note 13) and (Note 14).

2. Notes
1. Dichloromethane is distilled from calcium hydride (CaH2) and added directly from the still to thereaction flask.
2. This alcohol is readily prepared in standard fashion from the tetrahydropyranyl ether of 4-pentyn-1-ol
and iodomethane: A hexane solution of butyllithium (46 mL of a 2.2 M solution, 100 mmol) is added
dropwise under an argon atmosphere to a dry ice-cooled solution of tetrahydro-2-(4-pentynyloxy)-2Hpyran (14.4 g, 84 mmol, prepared from commercially available 4-pentyn-1-ol2) in 100 mL of dry
tetrahydrofuran. After 10 min, 7.0 mL (110 mmol) of iodomethane is added dropwise to the dry icecooled, stirring solution of the alkynyllithium intermediate. The reaction mixture is maintained at dry
ice temperature for 1 hr, and, after warming to room temperature, the tetrahydrofuran is removed bymild rotary evaporation (or distillation at atmospheric pressure). The crude product is dissolved in 100mL of ether and washed with brine (50 mL), and the aqueous phase is back-extracted with ether (25mL). The combined organic phases are concentrated and the residue is dissolved in 200 mL ofmethanol. p-Toluenesulfonic acid (4 g) is added and the resulting solution is heated at reflux for 3 hr.
The solvent is removed by distillation through an 8–10 cm Vigreux column, the residue is dissolved in
100 mL of ether and this solution is extracted with 25 mL of aqueous 10% sodium carbonate solution.
After the solution is dried over MgSO4, the solvent is removed by distillation and the residue is distilled
through a 50-cm concentric tube column. The fraction boiling at 92–93°C (10 mm Hg) is collected togive 7.8 g (94%) of 4-hexyn-1-ol, which is >95% pure by GC analysis (30 m, Supelco SPB-5 capillarycolumn).
3. Triethylamine, distilled from CaH2, and methanesulfonyl chloride, vacuum distilled at ca. 60°C (20mm), are employed.
4. The spectrum is as follows: 1H NMR (300 MHz, CDCl3) δ: 1.78 (t, 3 H, J = 2.5), 1.91 (apparent
pentaplet, 2 H, J = 6.5), 2.25–2.35 (m, 2 H), 3.03 (s, 3 H), 4.35 (t, 2 H, J = 6.1).
5. Dimethyl sulfoxide, distilled at 20 mm from CaH2, and benzylamine, freshly distilled at 20 mm, areemployed.
6. The reaction is easily monitored by TLC (silica gel, 1:1 ether-ethyl acetate): mesylate Rf = 0.9, amine
Rf = 0.4.
7. This material can also be purified by vacuum distillation; however, some decomposition results.
8. This material is 97% pure by capillary GC analysis (30 m, J & W DB-5 fused silica column). Spectral
data are as follows: IR (film) cm−1: 3330, 1453, 1120, 736; 1H NMR (300 MHz, CDCl3) δ: 1.69(apparent pentaplet, 2 H, J = 7), 1.77 (t, 3 H, J = 2.5), 2.15–2.25 (m, 2 H), 2.73 (t, 2 H, J = 7.0), 3.80 (s,2 H), 7.2–7.4 (m, 5 H); MS (isobutane CI): 188 (MH), 172, 120, 91; high resolution MS (70 eV, EI)
187.1331 (187.1261 Calcd for C13H17N).
9. Fisher Certified sodium iodide is used as received.
10. Fisher Certified A.C.S. formaldehyde solution is used as received. Aldrich Chemical Company, Inc.,
camphorsulfonic acid monohydrate is recrystallized from ethyl acetate prior to use.
11. This conversion is easily monitored by TLC (silica gel, 1:1 hexane-ethyl acetate containing 5%
triethylamine): 2, Rf = 0.4, 3, Rf = 0.7.
12. The free base of this iodoamine darkens slowly when exposed to room light. The isolation procedure
should be conducted rapidly or the separatory funnel and rotary evaporator bulb should be wrapped inaluminum foil to exclude room light.
13. This material is at least 95% pure by capillary GC analysis (30 m, J & W DB-5 fused silica column);
a small unknown impurity (ca. 2%) with characteristic 1H NMR signals at δ 3.41, 4.77 and 4.92 isapparent in some chromatography fractions. Spectral data for 3 are as follows: IR (film) cm−1: 1646,1228, 1138, 1119, 1061, 739; 1H NMR δ: 1.55–1.8 (m, 2 H), 2.40 (t, 2 H, J = 6.3), 2.45 (s, 3 H), 2.56 (t,2 H, J = 5.5), 3.10 (s, 2 H), 3.57 (s, 2 H), 7.2–7.4 (m, 5 H); MS (isobutane CI): 328 (MH), 202, 200,

112, 110, 92. High resolution MS (70 eV, EI): 327.0465 (327.0484 calcd for C14H18NI).
14. The maleate salt is prepared in good yield and crystallizes as fine needles (ca. 1 g of salt/10 mL)
from absolute ethanol: mp 143–144°C. This salt can be stored at room temperature in room light withno noticeable decomposition. Anal. Calcd. for C18H22INO4: C, 48.77; H, 5.00; N, 3.16. Found: C, 48.70;
H, 5.00; N, 3.09.

Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory";
National Academy Press; Washington, DC, 1995.

3. Discussion
Simple alkynes do not undergo intramolecular reactions with weakly electrophilic iminium ions in
the absence of strong external nucleophiles.3 For example, the formaldiminium ion derived from 4hexynylamine, formaldehyde, and camphorsulfonic acid does not cyclize when maintained in
acetonitrile at 100°C for 1 hr.3 Iminium ion-alkyne cyclizations do take place in nucleophilic solvents
such as H2O4 or in non-nucleophilic solvents when a strong nucleophile is present.3
The present procedure illustrates the use of added iodide anion to promote the Mannich cyclizationof an alkyne to afford 3-alkylidenepiperidines. As illustrated in Table I a variety of nonbasic
nucleophiles with nucleophilic constants5 η-CH3I >5.8 are useful promoters of formaldiminium ionalkyne cyclizations.3 Piperidines containing both endocyclic and exocyclic allylic unsaturation can beefficiently assembled in this way from readily available alkynol precursors (see Table I).3 To the limitsof 1H NMR detection at 500 MHz all nucleophile-promoted cyclizations that form 3alkylidenepiperidines occur with complete anti-stereoselectivity.

TABLE INUCLEOPHILE-PROMOTED IMINIUM ION-ALKYNE CYCLIZATIONS3R'

OCH3RXYield

CH3 Br89%

OCH3CH3 CH3I80%

OCH3n-Bu Br

63%6

OCH3n-Bu

I
76%6

H

CH3I
81-90%

H

CH3 N372%

H

CH3 SCN
82%

OCH3H

I
56%

OCH3CH3 SPh<15%

CH3 Br
75%

CH3I
90%

CH3 N340%

Me3Si Br

44%

Me3Si I

60%

H

I
87%

The usefulness of nucleophile-promoted iminium ion-alkyne cyclizations derives from the readyavailability of alkynylamines and the subsequent transformations of the cyclization products madepossible because of their vinylic functionality (e.g., equations 1 and 2). Equation 2 illustrates use of thischemistry to elaborate an exocyclic tetrasubstituted double bond with complete stereocontrol. Net"reductive" iminium ion alkyne cyclizations can be accomplished by dehalogenation of vinyl halide
cyclization products. The conversion illustrated in equation 3 is a key step in an efficient, practicalsynthesis of the cardiotonic frog alkaloid pumiliotoxin A.7

References and Notes
1.
2.
3.
4.
5.
6.
7.

Department of Chemistry, University of California, Irvine, CA 92717.
Negishi, E.-i.; Chiu, K.-W. J. Org. Chem. 1976, 41, 3484.
Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612, 5934.
Ahmad, V. U.; Feuerherd, K. H.; Winterfeldt, E. Chem. Ber. 1977, 110, 3624.
Pearson, R. G.; Sobel, H.; Songstad, J. J. Am. Chem. Soc. 1968 90, 319.
Sharp, M. J. unpublished examples.
Overman, L. E.; Sharp, M. J. Tetrahedron Lett. 1988, 29, 901.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)brineethanol (64-17-5)hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
ethyl ether (60-29-7)acetonitrile (75-05-8)

sodium hydroxide (1310-73-2)
formaldehyde (50-00-0)
sodium bicarbonate (144-55-8)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
aluminum (7429-90-5)
potassium hydroxide (1310-58-3)
iodomethane (74-88-4)
sodium iodide (7681-82-5)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
benzylamine (100-46-9)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
hexane (110-54-3)
dimethyl sulfoxide (67-68-5)
triethylamine (121-44-8)
argon (7440-37-1)
calcium hydride (7789-78-8)
Methanesulfonyl chloride (124-63-0)
mesylate (75-75-2)
4-Pentyn-1-ol (5390-04-5)
camphorsulfonic acid (5872-08-2)
p-toluenesulfonic acid (104-15-4)(E)-1-Benzyl-3-(1-iodoethylidene)piperidine (146980-71-4)
Piperidine, 3-(iodoethylidene)-1-(phenylmethyl)-(E)4-Hexyn-1-yl methanesulfonate (68275-05-8)
4-hexyn-1-ol (928-93-8)
N-Benzyl-4-hexyn-1-amine (112069-91-7)
camphorsulfonic acid monohydrate (5872-08-2)
tetrahydro-2-(4-pentynyloxy)-2H-pyran (62992-46-5)
iodoamine
4-hexynylamine
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