Boron-Mediated Aldol Reaction of Carboxylic Esters
(c) By th e sta n d a r d r ea ction : The concentration of a
c-Hex2BOTf solution can be estimated by the standard reac-
tion. For example, benzyl acetate (2.0 mmol) was treated with
a c-Hex2BOTf solution (1.0 mL) and Et3N (0.16 mL, 1.15 mmol)
in CH2Cl2 (10 mL) at -78 °C for 2 h, followed by i-PrCHO
(0.135 mL) at -78 °C for 1 h. The reaction was allowed to
warm to room temperature for 1 h, then quenched with pH
7.0 buffer solution and MeOH (1:1, 10 mL). Oxidative workup
with 30% H2O2 solution gave a crude reaction mixture and
the conversion was determined by 1H NMR to give the
concentration of the c-Hex2BOTf solution used.
poured into water (500 mL). Extractive workup and chroma-
tography afforded 3f (13.3 g, 95%).
(1R,2S)-3f: mp 123-124 °C; [R]23 -6.31 (c 2.06, CHCl3).
D
(1S,2R)-3f: mp 123-124 °C, [R]23 6.43 (c 2.05, CHCl3). 1H
D
NMR (CDCl3) (concentration dependent; 9 mg/0.5 mL) δ 1.03
(3H, d, J ) 7.0 Hz), 2.14 (1H, -OH), 2.29 (3H, s), 2.65 (6H, s),
3.82 (1H, dq, J ) 1.9 and 7.0 Hz), 4.54 (1H, A of ABq, J AB
)
16.1 Hz), 4.77 (1H, B of ABq, J AB ) 16.1 Hz), 5.00 (1H, br s),
1
6.93 (2H, s), 7.04-7.08 (2H, m), 7.10-7.36 (8H, m); H NMR
(CDCl3) (109 mg/0.5 mL) 1.02 (3H, d, J ) 7.0 Hz), 2.27 (3H,
s), 2.34 (1H, -OH), 2.62 (6H, s), 3.82 (1H, dq, J ) 1.9 and 7.0
Hz), 4.56 (1H, A of ABq, J AB ) 16.1 Hz), 4.75 (1H, B of ABq,
J AB ) 16.1 Hz), 4.96 (1H, br s), 6.91 (2H, s), 7.04-7.08 (2H,
m), 7.10-7.36 (8H, m); 13C NMR (CDCl3) δ 10.1, 20.8, 22.9,
48.9, 59.5, 76.5, 125.4, 127.1, 127.2, 127.6, 128.0, 128.4, 132.0,
133.4, 138.6, 140.0, 142.2, 142.5; FAB-MS (m-NBA), 424
(MH+); HR-MS, found 424.1951, calcd for C25H30NO3S 424.1946.
Anal. Calcd for C25H29NO3S: C, 70.89; H, 6.90; N, 3.31.
Found: C, 70.91; H, 6.95; N, 3.32.
Errors in these methods were less than 10%.
Syn th esis of Ch ir a l P r op ion a te Rea gen ts 1f a n d 1c.
2-(N-Mesitylen esu lfon yl)am in o-1-ph en yl-1-pr opan ol (2b):
To a stirred solution of recrystallized norephedrine (30.2 g,
0.20 mol) and triethylamine (33.4 mL, 0.24 mol) in methylene
chloride (400 mL) was added mesitylenesulfonyl chloride (43.8
g, 0.20 mol) at 0 °C. The reaction mixture was stirred at 0 °C
to room temperature for 2 h and diluted with diethyl ether
(600 mL). The mixture was washed successively with 100 mL
each of water, 1 M HCl, water, saturated sodium hydrogen-
carbonate solution, and brine and dried over anhydrous sodium
sulfate. The filtered organic solution was concentrated to give
an oily residue, which was dissolved in methylene chloride (50
mL). Hexane (100 mL) was added to the solution in portions
with swirling to cause crystallization. An additional hexane
(300 mL) was added and the crystalline 2b (60.8 g) was
isolated by filtration. Concentration of the mother liquor
afforded the second crop of 2b (6.0 g, total yield ∼100%).
2-(N-Met h yl-N-(2,3,4,5,7,8,9,10-oct a h yd r oa n t h r a cen e-
su lfon yl))a m in o-1-p h en yl-1-p r op a n ol (3c) (ep h ed r in e a s
a sta r tin g m a ter ia l). To a solution of ephedrine (5.8 g, 35
mmol) in CH2Cl2 (100 mL) at 0 °C was added triethylamine
(7.0 mL, 50 mmol). After 5 min, octahydroanthracenesulfonyl
chloride23 (11 g, 38.7 mmol) was added, and the solution was
allowed to warm to room temperature for 1 h. The reaction
was quenched with water and the mixture was washed with
1 M HCl, water, and brine. The organic layer was dried over
anhydrous MgSO4 and the solvent was removed. The residue
was recrystallized from diethyl ether and hexane to give 3c
as colorless crystals, (13.8 g, 95%). (1S,2R)-3c: mp 122-123
(1R,2S)-2b: mp 121-122 °C; [R]23 -12.4 (c 2.12, CHCl3).
D
(1S,2R)-2b: mp 120.5-121.5 °C; [R]23 12.8 (c 2.12, CHCl3).
D
1H NMR (CDCl3) (concentration dependent; 10 mg/0.5 mL) δ
0.87 (3H, d, J ) 6.8 Hz), 2.30 (3H, s), 2.52 (1H, -OH), 2.66
(6H, s), 3.53 (1H, m), 4.76 (1H, br, -NH), 4.82 (1H, d, J ) 8.8
Hz), 6.96 (2H, s), 7.20-7.36 (5H, m); 1H NMR (CDCl3) (100
mg/0.5 mL) δ 0.88 (3H, d, J ) 6.8 Hz), 2.32 (3H, s), 2.68 (6H,
s), 3.08 (1H, -OH), 3.51 (1H, m), 4.81 (1H, br, -NH), 5.23
(1H, br), 6.98 (2H, s), 7.20-7.36 (5H, m);13C NMR (CDCl3) δ
14.3, 20.9, 22.9, 54.6, 75.6, 125.9, 127.5, 128.3, 132.0, 134.2,
138.9, 140.5, 142.2; FAB-MS (m-NBA) 334 (MH+); HR-MS,
found 334.1487, calcd for C18H24NO3S 334.1477. Anal. Calcd
for C18H23NO3S: C, 64.84; H, 6.95; N, 4.20. Found: C, 64.94;
H, 6.98; N, 4.17.
°C; [R]21D -10.62 (c 1.32, CHCl3). (1R,2S)-3c: mp 121-122 °C;
1
[R]21 10.16 (c 3.7, CHCl3). H NMR (CDCl3) δ 1.13 (3H, d, J
D
) 6.9 Hz), 1.70 (8H, br), 2.10 (1H, br), 2.75 (4H, br), 2.88 (3H,
s), 3.08 (4H, m), 3.94 (1H, dq, J ) 3.0 and 6.9 Hz), 6.99 (1H,
s), 7.16 (2H, d, J ) 7.5 Hz), 7.22-7.27 (3H, m); 13C NMR
(CDCl3) δ 10.1, 21.9, 23.2, 27.6, 29.1, 30.3, 57.0, 125.6, 127.5,
128.3, 135.1, 135.6, 136.1, 137.6, 142.2; FAB-MS (m-NBA), 414
(MH+); HR-MS, found 414.2093, calcd for C24H32NO3S 414.2105.
Anal. Calcd for C24H31NO3S: C, 69.70; H, 7.55; N, 3.39.
Found: C, 69.81; H, 7.45; N, 3.32.
2-(N-Ben zyl-N-m esit ylen esu lfon yl)a m in o-1-p h en yl-1-
p r op yl P r op ion a te (1f). Propionyl chloride (3.8 mL, 42.5
mmol) was added dropwise at 0 °C to a solution of 3f (15.0 g,
35.4 mmol) and pyridine (3.7 mL, 46.0 mmol) in methylene
chloride (200 mL). The reaction was stirred at room temper-
ature for 13 h and diluted with diethyl ether (300 mL). The
mixture was washed successively with 100 mL each of water,
1 M HCl, water, saturated sodium hydrogencarbonate solution,
and brine, and dried with anhydrous sodium sulfate. The
filtered organic solution was concentrated to give a crystalline
residue, which was triturated with hexane to give 1f (16.8 g,
∼100%). (1R,2S)- and (1S,2R)-1f exist as polymorphic forms.
Recrystallization from hot ethyl acetate (4 mL/g of 1f) and
hexane (ethyl acetate:hexane ) 1:2) afforded higher melting
2-(N-Ben zyl-N-m esit ylen esu lfon yl)a m in o-1-p h en yl-1-
p r op a n ol (3f). P r oced u r e A, w ith K2CO3 a n d Bn Cl-Bu 4NI
(su ita ble for a la r ge-sca le p r ep a r a tion ). A mixture of 2b
(16.7 g, 0.05 mol), benzyl chloride (6.90 mL, 0.06 mol),
tetrabutylammonium iodide (200 mg), and potassium carbon-
ate (8.4 g, 0.06 mol) in acetonitrile (100 mL) was heated under
reflux for 17 h. The cooled mixture was filtered and the salt
was washed with diethyl ether. The combined organic layers
were concentrated and the residue was crystallized from
methylene chloride (25 mL) and hexane (100 mL) to give 3f
(17.0 g, 80%). An additional 3.2 g (15%) of 3f was isolated by
chromatography of the mother liquor on silica gel (100 g) with
10% ethyl acetate in hexane.
crystals. (1R,2S)-1f: mp 124, 147-148 °C; [R]23 11.1 (c 2.24,
D
CHCl3). (1S,2R)-1f: mp 124, 147-148 °C; [R]23D -11.2 (c 2.38,
CHCl3); 1H NMR (CDCl3) δ 1.01 (3H, t, J ) 7.4 Hz), 1.12 (3H,
d, J ) 7.0 Hz), 2.14 (2H, m), 2.27 (3H, s), 2.51 (6H, s), 4.04
(1H, dq, J ) 4.0 and 7.0 Hz), 4.60 (1H, A of ABq, J AB ) 16.6
Hz), 4.72 (1H, B of ABq, J AB ) 16.6 Hz), 5.84 (1H, d, J ) 3.9
Hz), 6.87 (2H, s), 6.88-6.96 (2H, m), 7.13-7.35 (8H, m); 13C
NMR (CDCl3) δ 8.5, 12.3, 20.6, 22.7, 27.1, 47.9, 56.5, 77.7,
125.6, 126.8, 127.1, 127.5, 128.1 (2C), 131.9, 133.2, 138.4,
138.5, 139.8, 142.3, 172.2; FAB-MS (m-NBA), 480 (MH+); HR-
MS, found 480.2208, calcd for C28H34NO4S 480.2209. Anal.
Calcd for C28H33NO4S: C, 70.12; H, 6.93; N, 2.92. Found: C,
70.40; H, 6.97; N, 2.90.
P r oced u r e B, w ith K2CO3, Bn Br (fa ster r ea ction ). A
mixture of 2b (3.3 g, 10 mmol), benzyl bromide (1.43 mL, 12
mmol), and K2CO3 (2.09 g, 15 mmol) in acetonitrile (40 mL)
was heated under reflux for 7 h. The cooled mixture was
filtered and the salt was washed with diethyl ether. Organic
layers were combined, concentrated, and purified by flash
chromatography to afford 3f (4.0 g, 95%) and N,O-dibenzyl
compound (0.25 g, 5%).
P r oced u r e C, w ith t-Bu OK a s a Ba se (con ven ien t for
a sm a ll-sca le p r ep a r a tion ). This procedure was used for the
preparation of the R2 ) Me series from norephedrine with MeI
in place of benzyl bromide.
To a stirred solution of 2b (11 g, 33 mmol) in DMF (150
mL) was added t-BuOK (3.70 g, 33 mmol) at room temperature.
After 15 min, benzyl bromide (3.93 mL, 33 mmol) was added.
The mixture was stirred at room temperature for 3 h and
(23) 1,2,3,4,6,7,8,9-Ocatahydroanthracenesulfonyl chloride was pre-
pared from 1,2,3,4,6,7,8,9-octahydroanthracene by the literature method.
Schro¨ter, G. Chem. Ber. 1924, 57, 2003.
J . Org. Chem, Vol. 67, No. 15, 2002 5255