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V. Kelsen et al. / Tetrahedron 63 (2007) 10693–10697
with diethylether and ethyl acetate. The aqueous phase was
extracted with MTBE. The organic phases were then mixed
and acidified at 0 ꢁC (concd HCl). The precipitate was fil-
tered, washed with MTBE, dissolved in dichloromethane,
and made basic at 0 ꢁC (NaOH 35%). After phase separation
the aqueous phase was extracted twice with dichlorome-
thane. The organic phases were washed with brine, dried
over MgSO4, and evaporated. The crude was finally recrys-
tallized from MTBE yielding 3 (1.02 g, 67%) as a white
solid. Mp 96 ꢁC (lit.10 mp 97–98 ꢁC), [a]2D3 ꢀ127.1 (c 0.7,
CHCl3) (lit.10 [a]D25 ꢀ127.7 (c 0.6, CHCl3)); 1H NMR
(200 MHz, CDCl3): d¼0.90 (d, J¼7.2 Hz, 3H), 0.94 (d,
J¼7.2 Hz, 3H), 1.16 (s, 2H), 1.77 (m, 1H), 3.88 (d,
J¼1.6 Hz, 1H), 7.15–7.21 (m, 2H), 7.26–7.34 (m, 4H),
7.48 (d, J¼7.6 Hz, 2H), 7.60 (d, J¼8.0 Hz, 2H).
was added a solution of 6 (1.32 g, 3.5 mmol) in DMF
(10 mL). After 1.5 h, the orange solution was transferred
via cannula into a second flask containing the Merrifield
resin (0.80 g, 1.75 mmol) priorly swelled for 1 h in DMF
(5 mL) and KI (146 mg, 0.88 mmol). The suspension was
then heated to 80 ꢁC and stirred gently for 60 h. After cool-
ing, the resin was filtered and washed subsequently with
DMF, water, THF, and finally diethylether. After drying un-
der vacuum, F was obtained as a pale orange solid (0.94 g).
The average nitrogen content (elemental analysis from 3 al-
iquots) was 2.77% indicating a loading of 0.99 mmol/g
(70% yield from initial resin Cl content).
3.4. General procedure for ethylation of aldehydes
A suspension of F (50 mg, 5 mol %) in toluene (1 mL) was
stirred under argon at room temperature for 30 min. A solu-
tion of diethylzinc in toluene (1.1 mL, 1.1 mmol) was then
added. After 20 min, the aldehyde (1 mmol) was added
and the suspension was stirred for 4–6 h. the mixture was
then cooled at 0 ꢁC and hydrolyzed with satd NH4Cl
(5 mL). The resin was then recovered by filtration. The aque-
ous phase was extracted with dichloromethane (3ꢂ5 mL)
and the collected organic phases dried over MgSO4 and
evaporated yielding the crude product, which was analyzed
by chiral GC. Purification by column chromatography
yielded the chiral alcohols in yields reported in Table 2
with spectroscopic data identical to those of the known prod-
ucts. Catalyst F was washed with NH4OH (5 mL), water
(5 mL), THF (5 mL), and diethylether (5 mL) and dried un-
der vacuum after which it can be used. The same sample of F
was reused five times in the ethylation of benzaldehyde. Af-
ter each experiment, the above work-up was repeated and the
nitrogen content measured (elemental analysis) giving 2.68,
2.67, 2.66, 2.65, 2.67% for runs 1, 2, 3, 4, 5, respectively.
3.2.3. (2S)-2-({[5-({[tert-Butyl(dimethyl)silyl]oxy}me-
thyl)pyridin-2-yl]methyl}amino)-3-methyl-1,1-diphenyl-
butan-1-ol (5). Compounds 3 (1.89 g, 7.43 mmol) and 2
(1.91 g, 7.43 mmol) were placed in a flask equipped with
a Dean–Stark and dissolved in toluene (150 mL). The mix-
ture was then refluxed under nitrogen overnight. After cool-
ing at room temperature, the solvent was evaporated yielding
1
4 as an orange viscous oil. H NMR (200 MHz, CDCl3):
d¼0.10 (m, 6H), 0.58 (d, J¼7 Hz, 3H), 0.94 (m, 9H), 1.08
(d, J¼7 Hz, 2H), 1.86 (m, 1H), 3.47 (m, 1H), 3.95 (d,
J¼6 Hz, 1H), 4.82 (s, 2H), 5.49 (s, 1H), 7.18–7.71 (m,
12H), 8.71 (s, 1H). Compound 4 was used as such in the
next step. To a solution of 4 in 1,2-dichlorethane (30 mL)
was added portionwise sodium triacetoxyborohydride
(3.40 g, 15.83 mmol). The suspension was stirred for five
days at room temperature. The medium was hydrolyzed
with satd Na2CO3 and the organic phase extracted with di-
chloromethane, dried over MgSO4, and evaporated yielding
5 quantitatively (1.84 g, 97%) as a red viscous oil, for which
purification was not necessary. 1H NMR (200 MHz, CDCl3):
d¼0.10 (s, 6H), 0.93 (m, 15H), 2.00 (m, 1H), 3.41 (m, 2H),
3.60 (s, 1H), 4.71 (s, 2H), 6.85 (d, J¼8 Hz, 1H), 7.13–7.75
(m, 11H), 8.46 (s, 1H). 13C NMR (200 MHz, CDCl3):
d¼ꢀ5.0, 16.3, 18.6, 22.8, 26.2, 29.2, 55.6, 62.9, 69.0,
78.9, 122.3, 126.4, 127.4, 128.1, 128.5, 134.7, 135.3,
145.8, 147.6, 149.5, 162.2.
1
3.4.1. 1-Phenylpropanol. Yield: 97%, ee: 93%. H NMR
(200 MHz, CDCl3): d¼0.89 (t, J¼8 Hz, 3H), 1.76 (m, 2H),
2.15 (m, 1H), 4.55 (t, J¼6 Hz, 1H), 7.28 (m, 5H). Chiral
GC conditions: (60–150 ꢁC, 5 ꢁC/min): tR (R)¼33.92, tR
(S)¼35.21.
3.4.2. 1-(2-Methoxy-phenyl)propanol. Yield: 88%, ee:
90% 1H NMR (200 MHz, CDCl3): d¼0.94 (t, J¼8 Hz,
3H), 1.73–1.87 (m, 2H), 2.66 (s, 1H), 3.83 (s, 3H), 4.77 (t,
J¼8 Hz, 1H), 6.85–6.98 (m, 2H), 7.19–7.31 (m, 2H). Chiral
GC conditions (60–180 ꢁC, 5 ꢁC/min): tR (S)¼37.34, tR
(R)¼38.02.
3.2.4. (2S)-2-({[5-(Hydroxymethyl)pyridin-2yl]methyl}-
amino-3-methyl-1,1-diphenylbutan-1-ol (6). A solution
of 5 (2.937 g, 6 mmol) in anhydrous THF (15 mL) was placed
under a nitrogen atmosphere and was treated by a THF solu-
tion of tetrabutylammonium fluoride (6 mL, 6 mmol). After
1 h the mixture was evaporated. The residue was purified by
column chromatography using a 20:80 hexane–ethyl acetate
mixture yielding 6 (1.63 g, 72%) as a gummy solid. [a]D19
ꢀ43 (c 2.14, CHCl3). 1H NMR (200 MHz, CDCl3): d¼0.84
(d, J¼7.1 Hz, 3H), 0.91 (d, J¼7.1 Hz, 3H), 1.99 (m, 1H),
3.45 (m, 2H), 3.60 (s, 1H), 4.50 (s, 2H), 6.81 (d, J¼8 Hz,
1H), 7.11–7.73 (m, 11H), 8.29 (s, 1H). 13C NMR
(200 MHz, CDCl3): d¼15.73, 22.33, 28.53, 54.70, 61.23,
68.22, 78.64, 122.02, 125.37, 125.44, 125.78, 126.13,
127.57, 127.70, 135.07, 145.00, 148.53, 157.66.
3.4.3. 1-(4-Chloro-phenyl)propanol. Yield: 80%, ee: 88%.
1H NMR (200 MHz, CDCl3): d¼0.85 (t, J¼8 Hz, 3H), 1.64–
1.78 (m, 2H), 2.70 (s, 1H), 4.48 (t, J¼8 Hz, 1H), 7.17–7.33
(m, 4H). Chiral GC conditions (80–180 ꢁC, 5 ꢁC/min): tR
(R)¼35.36, tR (S)¼36.37.
3.4.4. 1-(1,3-Benzodioxol-5-yl)propan-1-ol. Yield: 58%,
1
ee: 86%. H NMR (200 MHz, CDCl3): d¼0.87 (t, J¼8 Hz,
3H), 1.64–1.77 (m, 2H), 2.35 (s, 1H), 4.45 (t, J¼7 Hz, 1H),
5.92 (s, 2H), 6.75–6.77 (m, 2H), 6.83 (s, 1H). Chiral GC con-
ditions (80–180 ꢁC, 5 ꢁC/min): tR (R)¼55.55, tR (S)¼56.45.
3.3. Grafting of 6 on the Merrifield resin
To a suspension of sodium hydride (139.2 mg, 3.5 mmol) in
DMF (9.5 mL) cooled at 0 ꢁC under a nitrogen atmosphere
3.4.5. 1-Naphtalen-2-yl-propanol. Yield: 82%, ee: 86%. 1H
NMR (200 MHz, CDCl3): d¼0.86 (t, J¼8 Hz, 3H), 1.71–