Checked by Antje Grützmann, Thomas Hache, and Ekkehard Winterfeldt.
1. Procedure
2. Notes
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)-2H-pyran (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 ice-cooled, 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 by mild rotary evaporation (or distillation at atmospheric pressure). The crude product is dissolved in
100 mL of ether and washed with
brine (50 mL), and the aqueous phase is back-extracted with
ether (25 mL). The combined organic phases are concentrated and the residue is dissolved in
200 mL of methanol.
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 MgSO
4, 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 to give
7.8 g (
94%) of
4-hexyn-1-ol, which is >95% pure by GC analysis (
30 m, Supelco SPB-5 capillary column).
4. The spectrum is as follows:
1H NMR (300 MHz, CDCl
3) 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).
6. The reaction is easily monitored by TLC (silica gel, 1:1
ether-
ethyl acetate): mesylate R
f = 0.9, amine R
f = 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, CDCl
3) 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 C
13H
17N).
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 in
aluminum 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 is apparent 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 C
14H
18NI).
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 with no noticeable decomposition. Anal. Calcd. for C
18H
22INO
4: C, 48.77; H, 5.00; N, 3.16. Found: C, 48.70; H, 5.00; N, 3.09.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The present procedure illustrates the use of added iodide anion to promote the Mannich cyclization of an alkyne to afford 3-alkylidenepiperidines. As illustrated in Table I a variety of nonbasic nucleophiles with nucleophilic constants
5 η-CH
3I >5.8 are useful promoters of formaldiminium ion-alkyne cyclizations.
3 Piperidines containing both endocyclic and exocyclic allylic unsaturation can be efficiently assembled in this way from readily available alkynol precursors (see Table I).
3 To the limits of
1H NMR detection at 500 MHz all nucleophile-promoted cyclizations that form 3-alkylidenepiperidines occur with complete anti-stereoselectivity.
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