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General procedure
for N
-(2-hydroxyalkyl)formamide(1) preparation: Following a procedure by
Meyers et al.,
[26]
a solution
of l-valinol (1.90 g, 18.4 mmol) in ethyl
formate (10 mL, >3 equiv) was heated at reflux under nitrogen
for 3 h. Excess ethyl formate was removed in vacuo, yielding
(S)-N-[1-(hydroxymethyl)-2-methylpropyl]formamide,
as a white solid, 2.11 g (87%), mp 82-83 °C, [α]D
22 +38.8
(c 0.27, CHCl3). (The product
was a 65:35 mixture of two conformers, and NMR signals are indicated
as Hmaj and Hmin for the major and minor conformers,
respectively.) IR (KBr) 3362, 3171, 2832, 1666, 1538, 1385, 1241,
1054 cm-1. 1H NMR
(300 MHz, CDCl3) δ 0.92 (d, 3 Hmin, J = 6.7 Hz, CH3), 0.93
(d, 3 Hmaj, J = 6.7
Hz, CH3), 0.96 (d, 3 Hmin, J = 6.0 Hz, CH3), 0.97
(d, 3 Hmaj, J = 6.9
Hz, CH3), 1.77-1.91 [m,
1 Hmaj & 1 Hmin, CH(CH3)2],
2.72 (br, s, 1 Hmin, OH), 3.07-3.19 (m, 1 Hmin,
NCH), 3.54-3.79 (m, 4 Hmaj & 1 Hmin,
CH2Omaj
, OHmaj,
NCHmaj, CHOHmin),
4.01-4.03 (m, 1 Hmin, CHO), 6.55 (d, 1 Hmaj, J = 7.9 Hz, NH), 6.81 (br t,
1 Hmin, J = 8 Hz, NH),
7.98 (d, 1 Hmin, J = 11.7
Hz, HCO), 8.21 (d, 1 Hmaj, J = 1.7
Hz, HCO). 13C NMR (75 MHz, CDCl3) δ 18.4
(CH3), 18.6 (CH3), 19.4 (CH3),
1.96 (CH3), 28.9 [C(CH3)2],
29.2 [C(CH3)2],
55.9 (NCH), 60.8 (NCH), 63.0
(CH2), 63.3 (CH2),
162.4 (C=O), 165.8 (C=O). Anal. Calcd for C6H13NO2:
C, 54.94; H, 9.99; N, 10.68. Found: C, 54.71; H, 9.87; N, 10.60.
MS (EI) m/z (rel.
intensity) 132 (M+ + 1, 4), 101 (28),
100 (100), 88 (18), 72 (31), 71 (15), 60 (75), 55(85).
<A NAME="RD19102ST-17">17</A>
General procedure
for N
-(2-chloroalkyl)formamide(2) preparation: A solution of (S)-N-[1-(hydroxymethyl)-2-methylpropyl]formamide 1 (1.90 g, 14.5 mmol) and thionyl chloride
(1.28 mL, 2.05 g, 17.4 mmol, 1.2 equiv) in chloroform (30 mL) was
stirred for 3 h at 50 °C. It was washed with aqueous 1
M NaOH (2 × 30mL) and the aqueous layer was extracted with
chloroform. The combined organic layers were dried over MgSO4 and
the solvent was removed in vacuo affording (S)-N-[1-(chloromethyl)-2-methylpropyl]formamide,
as a dark solid, 2.1 g (86%), which was used in the next
step without purification, mp 44-45 °C, [α]D
21 -47.8
(c 0.21, CHCl3). (The product
existed as a 85:15 mixture of two conformers, and NMR signals are indicated
as Hmaj and Hmin for the major and minor conformers,
respectively.) IR (KBr) 3225, 2898, 1678, 1547, 1381, 1260, 1025,
894 cm-1. 1H NMR
(270 MHz, CDCl3) δ 0.89-1.01 (m, 6
Hmaj & 6 Hmin, CH3), 1.88-2.01 [m,
1 Hmaj & 1 Hmin, CH(CH3)2],
3.07-3.19 (m, 1 Hmin, NCH), 3.22-3.38 (m,
1 Hmin, CHOHmin),
3.63-3.74 (m, 2 Hmaj & 1 Hmin, CH2Omaj
, CHOHmin),
4.01-4.09 (m, 1 Hmaj, NCH), 5.89-6.03 (br,
1 Hmaj, NH), 6.05-6.19 (br, 1 Hmin,
NH), 8.05 (d, 1 Hmin, J = 11.5
Hz, HCO), 8.21 (br s, 1 Hmaj, HCO). 13C
NMR (75 MHz, CDCl3) δ 18.1 (CH3),
18.9 (CH3), 19.4 (CH3), 19.7 (CH3),
29.4 [C(CH3)2],
30.5 [C(CH3)2],
46.6 (CH2), 47.1 (CH2), 53.8 (NCH), 59.7
(NCH), 161.1 (C=O), 164.6 (C=O). Anal.
Calcd for C6H12NOCl: C, 48.17; H, 8.08; N,
9.36; Cl, 23.70. Found: C, 48.37; H, 7.85; N, 9.12; Cl, 24.01. MS
(EI) m/z (rel.
intensity) 150 (M+ + 1, 1), 108 (10),
106 (32), 100 (29), 78 (24), 72 (17), 70 (10), 61.0 (11), 55 (13),
46 (14), 45.0 (20), 43.0 (100%).
<A NAME="RD19102ST-18">18</A>
General procedure
for imidazoline(3) preparation: A solution
of (S)-N-[1-(chloromethyl)-2-methylpropyl]form-amide
(1.90 g, 12.7 mmol) and 4-trifluoromethylaniline (1.96 g, 12.2 mmol)
in chloroform (30 mL) was cooled to 0 °C, and PCl5 (3.42
g, 16.5 mmol, 1.3 equiv) was added with care. The suspension was
refluxed for 2 h, cooled and washed with aqueous 1 M NaOH (4 × 30
mL). The aqueous layer was extracted with chloroform. The combined
organic layers were dried over MgSO4 and the solvent
was removed in vacuo providing the crude (S)-4-isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazole,
which was recrystallised (CH2Cl2/toluene)
yielding the pure compound, as a white solid, 2.71 g (87%),
mp 94-95 °C, [α]20
D +195.2 (c
0.21, CHCl3). IR (KBr) 3063, 2975, 1606, 1529, 1386, 1314,
1196 cm-1. 1H NMR
(300 MHz, CDCl3) δ 0.96 (d, 3H, J = 6.8 Hz, CH3),
1.01 (d, 3H, J = 6.8 Hz, CH3),
1.82-1.92 (m, 1H, CH(CH3)2),
3.40 (dd, 1 H, J = 8.3, 9.3
Hz, 5-H), 3.73 (dd, 1 H, J = 9.3,
10.3 Hz, 5-H), 4.05-4.14 (m, 1 H, 4-H), 6.96 (m, 2 H, HAr),
7.56 (m, 2 H, HAr), 7.62 (d, 1 H, J = 1.8 Hz,
2-H). 13C NMR (75 MHz, CDCl3) δ 18.2
(CH3), 18.7 (CH3), 33.0 (C(CH3)2),
48.7 (5-C), 72.5 (4-C), 113.5 (CAr), 126.8 (q, J = 3.8 Hz, CAr),
127.0 (quat., CAr), 147.5 (2-C) (CF3, CCF3 signals were not detected
above noise). Anal. Calcd for C13H15N2F3:
C, 60.93; H, 5.90; N; 10.93; F, 22.24. Found C, 60.55; H, 5.94;
N, 10.80; F, 21.76. MS (EI) m/z (rel. intensity) 256 (M+,
11), 213 (100), 166 (10), 95 (4), 69 (4), 68 (6), 42 (12), 41 (21).
<A NAME="RD19102ST-19">19</A>
Jones RCF.
Nichols JR.
Tetrahedron
Lett.
1990,
31:
1771
<A NAME="RD19102ST-20">20</A>
General procedure for 2-hydroxyalkylimidazoline
(4, 5) preparation:
In a similar manner to the procedure of Jones et al,
[19]
a 2.5 M solution of
BuLi in hexanes (4.11 mL, 10.25 mmol, 1.3 equiv) was added to a
solution of (S)-4-isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazole
(2.02 g, 7.8 mmol) in THF (20 mL) at -78 °C. The
solution changed to a dark colour indicating formation of the anion
and after 15 min trimethylacetaldehyde (0.74 g, 0.93 mL, 8.58 mmol, 1.1
equiv) was added and the solution was brought to r.t. and stirred
for 15 h. The reaction mixture was added to a saturated solution
of ammonium chloride and the aqueous layer was extracted with chloroform.
The combined organic layers were dried over MgSO4 and
the solvent was removed in vacuo furnishing the crude product as
a mixture of two diastereomers (55:45), which was chromatographed
on silica (EtOAc/petroleum spirit, 80:20) to give 4b, as an oil, 1.02g (38%), and
then 5b, as an oil, 820 mg (32%).
An imidazolinium p-nitrobenzoate salt
of adduct 4b was formed by combining equimolar
amounts of the hydroxy-imidazoline and p-nitrobenzoic
acid in chloroform. The product was filtered off and recrystallised
(EtOAc), yielding the pure imidazolinium salt. (S)-1-[(S)-4-Isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazol-2-yl]-2,2-dimethyl-1-propanol
4b, mp (imidazolinium p-nitrobenzoate)
211-214 °C, [α]D
22 -135.2
(c 0.26, CHCl3). IR (thin film) 3368, 2958, 2872, 1608,
1521, 1324, 1118, 843, 810 cm-1. 1H
NMR (300 MHz, CDCl3) δ 0.82 [s, 9 H, C(CH3)3],
0.86 (d, 3 H, J = 6.8 Hz, CH3),
0.93 (d, 3 H, J = 6.8 Hz, CH3),
1.75-1.83 [m, 1 H, CH(CH3)2],
3.37 (dd, 1 H, J = 9.3, 6.2
Hz, 5-H), 3.87-3.95 (m, 1 H, 4-H), 4.15 (dd, 1 H, J = 10.4, 9.3 Hz, 5-H), 4.22 [s,
1 H, CH(OH)], 7.12 (m, 2 H,
HAr), 7.57-7.61 (m, 2 H, HAr). 13C
NMR (75 MHz, CDCl3) δ 17.4 (CH3),
18.5 (CH3), 25.7 [CH3)3],
32.3 [CH(CH3)2],
36.9 [C(CH3)3],
58.9 (5-C), 68.9 [CH(OH)], 73.5 (4-C), 123.7 (CAr),
126.7 (q, J = 3.7 Hz, CAr),
145.9 (quat. C
Ar), 164.5 (2-C)
(CF3, CCF3 signals
were not detected above noise). Anal. Calcd for C25H30N3O5F3 (imidazolinium p-nitrobenzoate) C, 58.93; H, 5.93; N,
8.25; F, 11.19. Found: C, 58,49; H, 5.80; N, 7.96; F, 10.90. MS (EI)
m/z (rel.
intensity) 342 (M+ + 1, 2), 286 (92),
285 (39), 213 (100), 187 (23), 174 (25), 145 (11). (R)-1-[(S)-4-Isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydro-imidazol-2-yl]-2,2-dimethyl-1-propanol
4b, [α]23
D +109.3 (c
0.22, CHCl3). IR (thin film) 3398, 2960, 2873, 1604, 1524,
1475, 1325, 845 cm-1. 1H
NMR (300 MHz, CDCl3) δ 0.82 [s, 9 H,
C(CH
3)3],
0.98 [d, 3 H, J = 6.7
Hz, CH3], 1.07 (d, 3 H, J = 6.7
Hz, CH3), 1.77-1.88 [m, 1 H, CH(CH3)2], 3.66
(dd, 1 H, J = 8.7, 9.4 Hz, 5-H),
3.83 (dd, 1 H, J = 10.1, 8.7
Hz, 5-H), 3.88-3.97 (m, 1 H, 4-H), 4.25 [s, 1
H, CH(OH)], 7.13 (m, 2 H, HAr),
7.58 (m, 2 H, HAr). 13C
NMR (75 MHz, CDCl3) δ 18.9 (CH3),
19.7 (CH3), 25.9 [(CH3)3], 33.7 [CH(CH3)2],
37.0 [C(CH3)3],
57.1 (5-C), 70.2 [CH(OH)], 73.4 (4-C), 122.9 (CAr),
126.7 (q, J = 3.7 Hz, CAr),
145.1 (quat., CAr), 164.1 (2-C) (CF3, CCF3 signals were not detected
above noise). MS (EI) m/z (rel.
intensity) 342 (M+ + 1, 3), 286 (52),
285 (32), 213 (64), 145 (31), 142 (29), 57 (75), 41 (100%).
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Macedo E.
Moberg C.
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Mosher HS.
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This assignment was supported by NOESY
experiments and molecular mechanics calculations, as will be described
in the full paper.
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Peters DAV.
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Lane AC.
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Roach AG.
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Stillings MR.
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<A NAME="RD19102ST-25">25</A>
General procedure
for diethylzinc additions: According to a procedure by Soai
et al,
[27]
a 1 M solution
of diethylzinc in hexane (2.2 mL, 2.2 mmol) was added to a solution
of the chiral catalyst (6 mol%) and the aldehyde (1 mmol)
in toluene (2 mL). The mixture was stirred until alkylation was complete
(typically 15 h). The reaction was quenched by addition of dilute
aqueous HCl. The mixture was extracted with dichloromethane and
dried over MgSO4. The resulting oil was purified by flash
chromatography on silica (EtOAc) yielding the product. Optical rotations
were measured after further purification by kugelrohr distillation.
1-Phenyl-1-propanol: ee values were determined by HPLC analysis using
a Chiralcel OD column, with 1% 2-propanol in hexane as
eluent, at 1 mL/ min; retention times 21.5 min (R), 26.9 min (S).
1-(1-Naphthyl)-1-propanol: ee values were determined by HPLC analysis
using a Chiralcel OD-H column, with 10% 2-propanol in hexane
as eluent; retention times; 17.8 min (S),
32.3 min (R). 1-(Cyclohexyl)-1-propanol:
ee values were determined by comparison of [α]D values
with that reported.
[28]
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Dieckmann DA.
Boes M.
Meyers AI.
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1989,
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Soai K.
Yokayama S.
Hayasaka T.
J.
Org. Chem.
1991,
56:
4264
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Marker RE.
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