Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3921
66.9, 54.9, 33.4, 19.1, 18.3. Anal. Calcd for C12H16N2‚H2C2O4
(oxalate): C, 60.43; H, 6.47; N, 10.07. Found: C, 60.12; H, 6.47;
N, 9.73.
in this way will allow preparation of series of imidazo-
lines in which the electronic properties are varied over a
wide range, without changing the chiral environment
around the donor nitrogen.
(S)-2-(2-F lu or op h en yl)-4-isop r op yl-1-(4-m eth ylp h en yl)-
4,5-d ih yd r oim id a zole 6d : from N-(2-fluorobenzoyl)valinol;27 1
H
This new route to enantiopure imidazolines has several
advantageous features. It uses readily accessible starting
materials, involves simple transformations, and has very
wide scope. Being modular, our route allows independent
variation of the 1-, 2-, and 4-/5-substituents, so it should
be amenable to combinatorial synthesis of libraries of
imidazolines. Our work makes enantiopure imidazolines
more readily available than before, and it will allow a
more thorough exploration of their use in medicinal
chemistry and in asymmetric synthesis.25
NMR (300 MHz, CDCl3) δ 0.99 (d, 3H, J ) 6.7 Hz), 1.05 (d, 3H,
J ) 6.7 Hz), 1.96 (m, 1H), 2.22 (s, 3H), 3.68 (t, 1H, J ) 7.0 Hz),
4.00-4.14 (m, 2H), 6.65 (d, 2H, J ) 8.6 Hz), 6.90-6.96 (m, 3H),
7.13 (dt, 1H, J ) 1.2, 7.6 Hz), 7.26-7.36 (m, 1H), 7.54 (dt, 1H,
J ) 1.8, 7.3 Hz); 13C (75 MHz, CDCl3) δ 161.6, 158.0, 139.6, 133.2,
131.8, 131.2, 129.6, 124.2, 121.3, 120.8, 116.2, 70.3, 55.3, 33.3,
21.0, 19.0, 18.1. Anal. Calcd for C19H21N2F‚H2C2O4 (oxalate): C,
65.28; H, 5.96; N, 7.25; F, 4.92. Found: C, 65.02; H, 6.13; N,
7.14; F, 4.71.
(S)-1-(4-Ch lor op h en yl)-2-(2-flu or op h en yl)-4-isop r op yl-
1
4,5-d ih yd r oim id a zole 6e: H NMR (300 MHz, CDCl3) δ 0.98
(d, 3H, J ) 6.7 Hz), 1.05 (d, 3H, J ) 6.7 Hz), 1.94 (m, 1H), 3.69
(t, 1H, J ) 7.9 Hz), 3.99-4.14 (m, 2H), 6.66 (d, 2H, J ) 8.8 Hz),
6.96 (ddd, 1H, J ) 1.2, 8.5, 9.9 Hz), 7.07 (d, 2H, J ) 8.8 Hz),
7.16 (dt, 1H, J ) 1.2, 7.6 Hz), 7.33-7.41 (m, 1H), 7.56 (dt, 1H,
J ) 1.7, 7.3 Hz); 13C (75 MHz, CDCl3) δ 161.4, 157.6, 140.5, 132.1,
131.1, 129.0, 128.4, 124.6, 121.8, 120.7, 116.4, 70.5, 54.9, 33.2,
19.0, 18.2. Anal. Calcd for C18H18N2FCl: C, 68.25; H, 5.69; N,
8.85; Cl, 11.22; F, 6.00. Found: C, 67.80; H, 5.84; N, 8.70; Cl,
11.27; F, 5.88.
Exp er im en ta l Section
Hydroxy amide starting materials were synthesized according
to literature procedures.26-30 Column chromatography was car-
ried out using Merck aluminum oxide 90 (Brockmann activity
II to III) (1097) or Merck silica gel 60 (230-400 mesh) (9385).
Oxalates of oily imidazolines were prepared by adding solutions
of oxalic acid (1 equiv) in Et2O (1 mL) to solutions of the
imidazolines (100 mg) in Et2O (1 mL) and filtering off the
precipitated salts.
(S)-2-(2-F lu or op h en yl)-4-isop r op yl-1-(4-t r iflu or om et h -
ylp h en yl)-4,5-d ih yd r oim id a zole 6f: 1H NMR (300 MHz,
CDCl3) δ 0.99 (d, 3H, J ) 6.7 Hz), 1.07 (d, 3H, J ) 6.7 Hz), 1.96
(m, 1H), 3.78 (m, 1H), 4.05-4.16 (m, 2H), 6.73 (d, 2H, J ) 8.5
Hz), 6.99 (ddd, 1H, J ) 1.2, 8.5, 9.9 Hz), 7.21 (dt, 1H, J ) 1.2,
7.6 Hz), 7.34-7.46 (m, 3H), 7.58 (dt, 1H, J ) 1.7, 7.3 Hz); 13C
(75 MHz, CDCl3) δ 161.5, 157.1, 144.5, 132.4, 131.0, 126.2, 124.8,
124.2, 120.5, 119.0, 116.5, 70.4, 54.3, 33.1, 19.0, 18.2. Anal. Calcd
for C19H18N2F4.: C, 65.14; H, 5.14; N, 8.00; F, 21.72. Found: C,
65.19; H, 5.20; N, 7.79; F, 21.72.
(S)-2-(2-F lu or op h en yl)-4-isop r op yl-1-m et h yl-4,5-d ih y-
d r oim id a zole 6g: 1H NMR (300 MHz, CDCl3) δ 0.94 (d, 3H,
J ) 6.9 Hz), 1.02 (d, 3H, J ) 6.9 Hz), 1.85 (m, 1H), 2.68 (s, 3H),
3.10 (t, 1H, J ) 9.3 Hz), 3.52 (dd, 1H, J ) 9.3, 10.4 Hz), 3.93
(ddd, 1H, J ) 6.0, 9.3, 10.4 Hz), 7.06-7.20 (m, 2H), 7.35-7.43
(m, 1H), 7.48 (dt, 1H, J ) 1.9, 7.2 Hz); 13C (75 MHz, CDCl3) δ
162.4, 161.7, 158.4, 131.6, 131.2, 124.5, 116.1, 71.2, 55.8, 34.8,
33.3, 19.2, 18.3.
(4S,5S)-4-Meth yl-1-(4-m eth ylp h en yl)-2,5-d ip h en yl-4,5-d i-
h yd r oim id a zole 6h : from N-benzoylnorephedrine;28 1H NMR
(300 MHz, CDCl3) δ 1.45 (d, 3H, J ) 6.7 Hz), 2.16 (s, 3H), 4.10
(m, 1H), 4.42 (d, 1H, J ) 7.1 Hz), 6.60 (d, 2H, J ) 8.5 Hz), 6.85
(d, 2H, J ) 8.5 Hz), 7.24-7.41 (m, 8H), 7.60-7.63 (m, 2H); 13C
(75 MHz, CDCl3) δ 162.4, 143.5, 134.4, 130.2, 129.6, 129.3, 129.1,
128.3, 127.9, 126.9, 124.3, 78.2, 70.1, 22.6, 21.0. Anal. Calcd for
C23H22N2‚C2H2O4 (oxalate): C, 72.12; H, 5.77; N, 6.73. Found:
C, 72.03; H, 5.52; N, 6.78.
(S)-4-Isop r op yl-1-(4-m et h ylp h en yl)-2-p h en yl-4,5-d ih y-
d r oim id a zole 6a (Meth od A). A solution of N-benzoylvalinol26
(1 g, 4.8 mmol) in thionyl chloride (1.41 mL, 19.2 mmol) was
stirred for 4 h at reflux (reaction completion was confirmed by
NMR) to form the chloroalkylimidoyl chloride. Excess thionyl
chloride was removed by rotary evaporation, and the crude
dichloride was dissolved in dry diethyl ether (10 mL). Any
insoluble impurities were removed by filtration. Dry triethyl-
amine (2 mL, 14.4 mmol) was added, followed by p-toluidine
(0.565 g, 5.28 mmol), and the reaction mixture was stirred for 3
h at room temperature. The solution was washed with 10%
NaOH (20 mL) and the aqueous was extracted with dichlo-
romethane (2 × 20 mL). The combined organics were washed
with brine and dried over MgSO4, and the solvent was removed
in vacuo. The resulting crude oil was then distilled at 135 °C,
0.1 mbar, using a Kugelrohr apparatus, to yield the imidazoline
as a pale yellow oil, 0.84 g (63%): [R]23 ) -6.2 (c 0.3, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 0.95 (d, 3H, J ) 6.6 Hz), 1.03 (d,
3H, J ) 6.6 Hz), 1.95 (m, 1H), 2.24 (s, 3H), 3.63 (m, 1H), 4.05
(m, 2H), 6.66 (d, 2H, J ) 8.2 Hz), 6.94 (d, 2H, J ) 8.2 Hz), 7.22-
7.34 (m, 3H) 7.51 (m, 2H); 13C (75 MHz, CDCl3) δ 161.8, 141.1,
133.1, 131.8, 129.9, 129.5, 129.0, 128.3, 122.9, 70.3, 56.8, 33.3,
20.9, 19.1, 18.1. Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N,
10.06. Found: C, 81.87; H, 7.85; N, 9.72.
(S)-4-Isop r op yl-1-m e t h yl-2-p h e n yl-4,5-d ih yd r oim id a -
zole 6b: 1H NMR (300 MHz, CDCl3) δ 0.93 (d, 3H, J ) 6.7 Hz),
1.01 (d, 3H, J ) 6.7 Hz), 1.85 (m, 1H), 2.76 (s, 3H), 3.07 (t, 1H,
J ) 9.3 Hz), 3.52 (t, 1H, J ) 9.3 Hz), 3.87 (m, 1H), 7.39 (m, 3H)
7.52 (m, 2H); 13C (75 MHz, CDCl3) δ 166.7, 131.2, 129.7, 128.3,
128.2, 70.2, 56.2, 36.2, 33.2, 19.1, 18.0. Anal. Calcd for C13H18N2‚
C2H2O4 (oxalate): C, 61.63; H, 6.90; N, 9.58. Found: C, 61.42;
H, 6.73; N, 9.23.
(S)-4-Isop r op yl-2-p h en yl-4,5-d ih yd r oim id a zole 6c: 1H
NMR (300 MHz, CDCl3) δ 0.90 (d, 3H, J ) 6.7 Hz), 0.96 (d, 3H,
J ) 6.7 Hz), 1.77 (m, 1H), 3.52 (dd, 1H, J ) 7.5, 11.6 Hz), 3.71-
3.89 (m, 2H), 4.80 (broad s, 1H), 7.35-7.46 (m, 3H), 7.79 (m,
2H); 13C (75 MHz, CDCl3) δ 164.0, 130.9, 130.5, 128.6, 127.4,
(R)-1-Meth yl-2,4-d ip h en yl-4,5-d ih yd r oim id a zole 6i: from
N-benzoylphenylglycinol;29 1H NMR (300 MHz, CDCl3) δ 2.84
(s, 3H), 3.32 (t, 1H, J ) 10.0 Hz), 3.96 (t, 1H, J ) 10.0 Hz), 5.20
(t, 1H, J ) 10.0 Hz), 7.25-7.44 (m, 8H), 7.63 (m, 2H); 13C (75
MHz, CDCl3) δ 168.1, 144.7, 131.4, 130.2, 128.74, 128.70, 128.6,
127.2, 126.9, 67.9, 62.1, 36.6. Anal. Calcd for C16H16N2‚C2H2O4
(oxalate): C, 66.26; H, 5.52; N, 8.59. Found: C, 65.96; H, 5.56;
N, 8.43. The ee was measured by HPLC using a Chiralcel OD
H column, with 80:20 hexane/2-propanol as eluent and UV
detection at 254 nm. With a flow rate of 0.7 mLmin-1, tR(S) )
47 min and tR(R) ) 53 min.
(S)-4-Isop r op yl-1-(4-m eth ylp h en yl)-2-(2-p yr id yl)-4,5-d i-
h yd r oim id a zole 6j (Meth od B). A solution of N-(picolinoyl)-
valinol (5.0 g, 24 mmol) in chloroform (10 mL) and thionyl
chloride (2.2 mL, 26.4 mmol) was stirred at reflux for 2 h
(completion was confirmed by 1H NMR) to form the chloropi-
colinamide. Phosphorus pentachloride (5.0 g, 24 mmol) was
added, and the resulting suspension was stirred at reflux for a
further 2 h (reaction completion was monitored by 1H NMR).
The solution was cooled to 0 °C and a solution of p-toluidine
(2.8 g, 26.4 mmol) in triethylamine (10 mL, 72 mmol) and
chloroform (25 mL) was added via cannula. The solution was
stirred at 0 °C for 30 min and then at reflux for 12 h. The
chloroform was removed in vacuo and 20% NaOH (100 mL) was
added to the crude product. The aqueous was extracted with
(25) We have obtained high enantioselectivity in several reactions
using imidazolines as ligands or catalysts.
(26) Lewanowicz, A.; Lipinski, J .; Siedlecka, R.; Skarzewski, J .;
Baert, F. Tetrahedron 1998, 54, 6571-6586.
(27) Schultz, A. G.; Pinto, D. J . P.; Welch, M. J . Org. Chem. 1988,
53, 1372-1380.
(28) Colman, B.; Sousa, S. E. de; O’Brien, P.; Towers, T. D.; Watson,
W. Tetrahedron: Asymmetry 1999, 10, 4175-4182.
(29) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.; Ham, W.-H. J .
Org. Chem. 1999, 64, 9450-9458.
(30) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J . Am.Chem. Soc.
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