essentially pure piperidines were near quantitative in most cases,
although compounds 4a and 5a in particular were difficult to
handle and chromatograph due to their significant polarity and
water solubility.
In summary, we have discovered a highly diastereoselective
synthesis of 2,4,5-trisubstituted piperidines from simple acyclic
precursors, which should have application to the synthesis of more
complex molecules.
−78 ◦C a freshly prepared solution of sodium naphthalenide (1.2 mL
of a 1 M solution in tetrahydrofuran, 4.6 eq). After 5 min the reaction
was quenched with methanol (0.4 mL), warmed up to room temperature,
diluted with water (5 mL) and acidified to pH 1 with aqueous HCl
(2 M). The aqueous phase was washed with diethyl ether (3 × 10 mL),
basified to pH 9 with aqueous NaOH (2 M) and extracted with ethyl
acetate (4 × 10 mL). The combined organic phases were washed with
brine (10 mL), dried over MgSO4 and concentrated in vacuo to afford
piperidine 7b (0.052 g, 87%) as colourless crystals. Mp 119 ◦C; [a]D23 −49 (c
0.98 in CHCl3); mmax(CHCl3)/cm−1 3306 (O–H, N–H), 2917 (C–H), 1641
=
=
=
=
(C C aliphatic), 1602 (C C aromatic), 1493 (C C aromatic), 1455 (C
C
We thank the Engineering and Physical Sciences Research
Council for the award of a studentship to C. A. M. C.
aromatic); 1090 (C–O); dH(300 MHz, CDCl3) 1.63 (1H, ddd, J 5.1, J 9.9, J
12.9), 1.79 (3H, s), 1.91 (1H, broad s), 1.97 (1H, dt, J 3.7, J 12.9), 2.07–2.15
(1H, m), 2.72 (1H, dd, J 6.4, J 13.4), 2.87–2.94 (3H, envelope), 3.33–3.40
(1H, m), 3.99 (1H, dt, J 4.1, J 9.4), 4.94 (1H, s), 4.98 (1H, s), 7.16–7.33
(5H, m); dC(75 MHz, CDCl3) 21.2, 37.0, 38.8, 43.7, 53.4, 54.4, 66.4, 113.3,
126.4, 128.7, 129.1, 139.6, 144.4; m/z (ES+) 232 (65%, [M + H]+), 214.1
(100, [M − OH]+) [HRMS Found: (M + H)+ 232.1700. C15H22NO requires
M, 232.1701].
Notes and references
† Brønsted acid-catalysed cyclisation procedure. Preparation of (2S*,
4R*, 5S*)-2-methyl-5-iso-propenyl-1-(p-toluenesulfonyl)piperidin-4-ol 4a.
Concentrated HCl (37%, 85 lL) was added to a solution of aldehyde
3a (0.102 g, 0.33 mmol) in dichloromethane (10 mL) at −78 ◦C. The
solution was stirred at −78 ◦C overnight, after which it was quenched
by addition of water (10 mL). The aqueous phase was then extracted
with dichloromethane (4 × 10 mL). The combined organic phases were
washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to
leave a colourless oil, which was purified by flash column chromatography
(silica; ethyl acetate–hexane, 2 : 3, Rf = 0.41) to afford the piperidine
4a (0.07 g, 70%) as a colourless thick oil. [a]2D7 −3.6 (c 0.5 in CHCl3);
‡ Crystal data for 4c. C18H27NO3S, M = 337.47, monoclinic, a = 8.4757(1),
3
˚
˚
b = 19.2080(3), c = 11.8021(2) A, U = 1902.87(5) A , T = 296 K, space
group P21, Z = 4, l(Cu Ka) = 1.617 mm−1, 5917 reflections measured,
5423 unique (Rint = 0.0374) which were used in all calculations. The final
wR(F2) was 0.1035 (all data). Crystal data for 4a. C16H23NO3S, M =
˚
309.41, monoclinic, a = 22.4722(3), b = 7.8727(1), c = 19.9610(2) A,
3
˚
U = 3270.17(7) A , T = 296 K, space group C2/c, Z = 8, l(Cu Ka)
= 1.837 mm−1, 2943 reflections measured, 2689 unique (Rint = 0.0392)
which were used in all calculations. The final wR(F2) was 0.1150 (all data).
CCDC reference number 288320. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b515547a
(mmax(CHCl3)/cm−1 3525 (O–H), 2923 (C–H), 1644 (C C aliphatic), 1598
=
=
=
=
(C C aromatic), 1494 (C C aromatic), 1451 (C C aromatic), 1383 (C–
H), 1336 (SO2), 1305 (C–H), 1153 (SO2), 1088 (C–O); dH(300 MHz, CDCl3)
1.21 (3H, d, J 7.0), 1.63–1.67 (2H, envelope), 1.73 (3H, s), 1.80–1.82 (1H,
m), 2.12 (1H, broad d, J 11.8), 2.40 (3H, s), 3.30 (1H, t, J 12.7), 3.62
(1H, dd, J 4.1, J 13.2), 3.99 (1H, d, J 2.6), 4.17–4.22 (1H, m), 4.69 (1H,
s), 5.00 (1H, s), 7.27 (2H, d, J 8.1), 7.69 (2H, d, J 8.1); dC(75 MHz,
CDCl3) 18.9, 21.5, 22.8, 35.7, 37.6, 46.5, 47.4, 64.6, 112.3, 127.0, 129.7,
138.4, 143.0, 144.1; m/z (ES+) 332 (100%, [M + Na]+) [HRMS Found:
(M + Na)+ 332.1297. C16H23NNaO3S requires M, 332.1296]. Lewis acid-
catalysed cyclisation procedure. Preparation of (2R, 4S, 5S)-2-tert-butyl-
5-iso-propenyl-1-(p-toluenesulfonyl)piperidin-4-ol 5d. Methyl aluminium
dichloride (1 M solution in hexane, 480 lL, 0.48 mmol) was added to a
solution of the aldehyde 3d (0.168 g, 0.48 mmol) in chloroform (20 mL).
The solution was stirred overnight at 60 ◦C, after which it was quenched
by addition of water (20 mL). The aqueous phase was then extracted with
dichloromethane (4 × 20 mL). The combined organic phases were washed
with brine (20 mL), dried over MgSO4 and concentrated in vacuo to leave
a colourless oil, that was purified by flash column chromatography (silica;
ethyl acetate–petroleum ether, 1 : 2, Rf = 0.22) to afford piperidine 5d
as a colourless oil (0.147 g, 88%). [a]1D9 −6.0 (c 0.3 in CHCl3); (Found:
C, 64.8; H, 8.1; N, 3.8. C19H29NO3S requires C, 64.9; H, 8.3; N, 4.0%);
§ CCDC reference number 288321. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b515547a
1 J. A. Findlay, in The Alkaloids, ed. A. Brossi, Academic Press: London,
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3 For recent reviews see: S. Laschat and T. Dickner, Synthesis, 2000,
1781; P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding,
Tetrahedron, 2003, 59, 2953; M. G. P. Buffat, Tetrahedron, 2004, 60,
1701.
4 For a review see: B. B. Snider, in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2,
p. 527.
5 J. T. Williams, P. S. Bahia and J. S. Snaith, Org. Lett., 2002, 4, 3727.
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8 ORTEP-3 for Windows: L. J. Farrugia, J. Appl. Crystallogr., 1997, 30,
565.
9 F. Johnson, Chem. Rev., 1968, 68, 375; L. A. Gandon, A. G. Russell
and J. S. Snaith, Org. Biomol. Chem., 2004, 2, 2270.
10 J. C. Adelbrecht, D. Craig, B. W. Dymock and S. Thorimbert,
SYNLETT, 2000, 467.
mmax(CHCl3)/cm−1 3498 (O–H), 2964 (C–H), 1646 (C C aliphatic), 1598
=
=
(C C aromatic), 1401, 1367 (C–H), 1336 (SO2), 1084 (C–O); dH(300 MHz,
CDCl3) 1.05 (9H, s), 1.16–1.27 (1H, m), 1.30–1.38 (1H, m), 1.60 (3H, s),
1.71 (1H, s), 2.13 (1H, dd, J 4.4, J 14.0), 2.42 (3H, s), 3.04 (1H, dd, J
12.3, J 15.4), 3.79 (1H, dd, J 3.7, J 15.4), 3.91 (1H, dt, J 4.7, J 11.0), 3.99
(1H, d, J 8.1), 4.64 (1H, s), 4.89 (1H, s), 7.30 (2H, d, J 8.1), 7.73 (2H, d,
J 8.1); dC(75 MHz, CDCl3) 20.3, 21.6, 29.5, 31.7, 36.9, 46.2, 49.9, 61.4,
66.5, 113.9, 127.2, 129.9, 138.4, 142.6, 143.4; m/z (ES+) 374 (100%, [M +
Na]+) [HRMS Found: (M + Na)+ 374.1768. C19H29NNaO3S requires M,
374.1766]. Tosyl group removal procedure. Preparation of (2S, 4S, 5S)-
2-benzyl-5-iso-propenylpiperidin-4-ol 7b. To a solution of 5b (0.099 g,
0.26 mmol) in tetrahydrofuran (1.5 mL) under nitrogen was added at
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