C. S. Barry, N. S. Simpkins / Tetrahedron Letters 48 (2007) 8192–8195
8195
Li
R2R3NLi
Ph
OMe
Ph
OMe
O
Li
OMe
+
H
Ph
H
Ph
7. A two-necked round-bottomed flask fitted with a rubber
septum and reflux condenser was charged with
Clossen, R. D.; Napolitano, J. P.; Ecke, G. G.; Kolka, A. J.
J. Org. Chem. 1957, 22, 646
a
cinnamyl alcohol (3.0 mmol) and dry tetrahydrofuran
(15 mL) under an atmosphere of nitrogen. The solution
was cooled to ꢀ78 ꢁC and primary amine (3.0 mmol)
was added, followed by dropwise addition of n-butyll-
ithium (2.5 M hexanes, 6.0 mmol). The cold bath was
removed and the reaction mixture was allowed to warm
to room temperature over 0.5 h, then warmed to reflux
over 0.5 h and reflux maintained until all cinnamyl
alcohol was consumed as determined by TLC analysis
(1–4 h). The mixture was then cooled to room temper-
ature and partitioned between 2 M NaOHaq (30 mL) and
dichloromethane (100 mL). The layers were separated
and the aqueous phase was extracted with ethyl acetate
(4 · 50 mL). The combined organic extracts were dried
over MgSO4, filtered and concentrated in vacuo to give
the crude product.
Aminoalcohol 6a: Purification was done by column
chromatography on silica gel, eluting with 10% etha-
nol/petroleum ether and then with 20% ethanol/petrol
(2% NEt3 added) to give pure aminoalcohol 6a as a
white crystalline solid (740 mg, 51%); mp 68–70 ꢁC; mmax
(neat)/cmꢀ1 3285, 3023, 2919, 2861, 1603, 1495, 1467,
1456, 1442; dH (270 MHz, CDCl3) 2.20 (2H, br s, OH,
NH), 2.77 (1H, dd, J 13.6, 6.9, 3-HH), 2.85 (1H, dd, J
13.6, 6.9, 3- HH), 2.98 (1H, tdd, J 6.9, 5.3, 3.9, 2-H),
3.36 (1H, dd, J 10.7, 5.3, 1-HH), 3.66 (1H, dd, J 10.7,
3.9, 1-HH), 3.79 (2H, s, 10-H2), 7.15–7.35 (10H, m,
10 · Ar-H); dC (70 MHz, CDCl3) 38.2 (C-3), 51.1 (C-10),
59.4 (C-2), 62.5 (C-1), 126.6 (C-Arpara), 127.2 (C-Arpara),
128.2, 128.6, 128.7, 129.3, 138.5 (C-Aripso), 139.9 (C-
Aripso); Found (ESI): 242.1532 [MH]+, ([C16H20NO]+
requires 242.1545); m/z (ESI) 242.1511 ([MH]+, 81%),
264.1359 ([MNa]+, 17%).
Aminoalcohol 6d: Purification was done by column chro-
matography on silica gel, eluting with 80% ethyl acetate/
petrol (2% NEt3 added) to give pure aminoalcohol 6d as a
pale yellow solid (311 mg, 50%); mp 55–57 ꢁC; mmax (neat)/
cmꢀ1 3396, 3027, 2927, 2893, 1651, 1603, 1455, 1112; dH
(270 MHz, CDCl3) 2.65–2.80 (4H, m, 3-H2, 10-H2), 2.82–
2.91 (1H, m, 2-H), 3.27 (3H, s, –OMe), 3.30 (1H, dd, J 10.7,
5.5, 1-HH), 3.42 (2H, t, J 5.5, 20-H2), 3.57 (1H, dd, J 10.7,
3.8, 1-HH), 7.15–7.23 (3H, m, 3 · Ar-H), 7.24–7.31 (2H, m,
2 · Ar-H); dC (70 MHz, CDCl3) 38.2 (C-3), 46.5 (C-10), 58.8,
60.4, 62.6 (C-1), 72.3(C-20), 126.4 (C- Arpara), 128.6, 129.3,
138.7 (C-Aripso); Found (ESI): 232.1300 [MNa]+,
([C12H19NNaO2]+ requires 232.1308); m/z (ESI) 232.1300
([MNa]+).
Li
NR2
H
R2N
Ph
LiO
9. A two-necked round-bottomed flask fitted with a rubber
septum and a reflux condenser was charged with cinnamyl
alcohol (3.0 mmol) and dry tetrahydrofuran (15 mL) under
an atmosphere of nitrogen. The solution was cooled to
ꢀ78 ꢁC and secondary amine (30.0 mmol) was added,
followed by dropwise addition of n-butyllithium (2.5 M
hexanes, 6.0 mmol). The cold bath was removed and the
reaction mixture was allowed to warm to room temperature
over 0.5 h, and then warmed to reflux over 0.5 h and
maintained at reflux until all cinnamyl alcohol was
consumed as determined by TLC analysis. The mixture
was then cooled to room temperature and partitioned
between 2 M NaOHaq (30 mL) and dichloromethane
(100 mL). The layers were separated and the aqueous
phase was extracted with ethyl acetate (4 · 50 mL). The
combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo to give the crude 1,2-amino
alcohol.
Aminoalcohol 11b: Purification was done by column chro-
matography on silica gel, eluting with 15% ethanol/petrol
(2.5% NEt3 added) to give pure 11b as a pale yellow solid
(459 mg, 69%); mp 44–46 ꢁC; mmax (neat)/cmꢀ1 3443, 2919,
2881, 1604, 1496, 1455, 1377; dH (270 MHz, CDCl3) 1.39–
1.71 (6H, m, 30-H2, 40-H2, 50-H2), 2.30 (1H, dd, J 13.0, 9.4,
3-HH), 2.37– 2.47 (2H, m, 20-Hax,60-Hax), 2.67–2.77 (2H,
m, 20-Heq,60-Heq), 2.80–2.91 (1H, m, 2-H), 2.94 (1H, dd, J
13.0, 4.4, 3-HH), 3.32 (2H, d, J 7.6, 1-H2), 7.09–7.30 (5H,
m, 5 · Ar–H); dC (70 MHz, CDCl3) 24.9 (C-40), 26.8 (C-30,
C-50), 32.0 (C-3), 49.5 (C-20, C-60), 59.9 (C-2), 67.6 (C-1),
126.2 (C-Arpara), 128.6, 129.0, 139.6 (C-Aripso); Found
(ESI): 220.1674 [MH]+, ([C14H22NO]+ requires, 220.1701);
m/z (ESI) 220.1674 ([MH]+, 94%).
Aminoalcohol 11c: Purification was done by column chro-
matography on silica gel, eluting with 15% ethanol/petrol
(2.5% NEt3 added) to give pure 11c as a white crystalline
solid (372 mg, 56%); mp 85–87 ꢁC; mmax (neat)/cmꢀ1 3062,
2925, 2853, 1563, 1157; dH (270 MHz, CDCl3), 2.37 (1H,
dd, J 13.0, 9.2, 3-HH), 2.53 (2H, ddd, J 11.0, 6.1, 3.2, 20-
Hax, 60-Hax), 2.77 (2H, ddd, J 11.0, 6.1, 3.2, 20-Heq, 60-Heq),
2.80–2.90 (1H, m, 2-H), 2.97 (1H, dd, J 13.0, 4.5, 3-HH),
3.30–3.40 (2H, m, 1-H2), 3.69 (2H, ddd, J 11.0, 6.1, 3.2, 30-
Hax, 50-Hax), 3.76 (2H, ddd, J 11.0, 6.1, 3.2,30-Heq, 50-Heq)
7.09–7.31 (5H, m, 5 · Ar–H); dC (70 MHz, CDCl3) 32.0 (C-
3), 48.6 (C-20, C-60), 59.7 (C-2), 64.75 (C-1), 64.55 (C-30, C-
50), 126.4 (C-Arpara), 128.7, 129.0, 139.1 (C-Aripso); Found
(ESI): 222.1475 [MH]+, ([C13H20NO2]+ requires 222.1494);
m/z (ESI) 222.1475 ([MH]+, 42%).
8. It is possible that a concerted addition and protonation
takes place, most likely involving a lithium amide solvated
by neutral amine as shown below (this somewhat overlooks
the complications of lithium amide aggregates and possible
mixed aggregates involving the alkoxide). This type of idea
originates from one of the earliest reports in this area, see: