Efficient Synthesis of Carboxylic 3-Hydroxyacids
7 14 3
H O
[M+ - Et] 117.0552, found
and 1.2 equiv of iodoacetic acid in 2 mL of THF, under a nitrogen
HRMS (70 eV) calcd for C
117.0551. IR (neat): 2955, 1704, 1468 cm . R ) 0.35 (hexane/
-
1
atmosphere, was added dropwise a 0.1 M solution of SmI
2
(3.2
f
equiv) in THF at room temperature. The reaction mixture was stirred
for 3.5 h before it was quenched with 8 mL of 0.1 N HCl aqueous
EtOAc 3:1). Anal. Calcd for C
C, 57.55; H, 9.68.
7
H
14
O
3
: C, 57.51; H, 9.65. Found:
1
solution and extracted with Cl
were evaporated under reduced pressure. The crude reaction was
then diluted in 3 mL of diethyl ether, and the organic solution was
2
CH
2
(3 × 8 mL), and the solvents
3-Hydroxy-3-methyloctanoic Acid (1i). H NMR (300 MHz,
CDCl ): 6.52 (br s, 1H), 2.50 (AB syst, J ) 15.8 Hz, 2H), 1.53-
3
1.17 (m, 11H), 0.84 (t, J ) 6.2 Hz, 3H). 13C NMR (75 MHz,
washed once with an ice-cooled saturated NaHCO
The basic aqueous layer was acidified with ice-cooled 1 N HCl-
aq) to a pH of 2-3, and the product was re-extracted in the organic
layer with ice-cooled diethyl ether (3 × 5 mL). The combined
organic extracts were dried over MgSO , filtered, and evaporated
3
solution (2 mL).
CDCl ): δ 177.1 (C), 71.5 (C), 44.5 (CH ), 41.9 (CH ), 32.1 (CH ),
3
2
2
2
26.4 (CH ), 23.5 (CH ), 22.5 (CH ), 13.9 (CH ). HRMS (70 eV)
3
2
2
3
+
-
(
calcd for C H O [M
(neat): 2935, 1706, 1405, 1265, 738 cm . R ) 0.32 (hexane/
EtOAc 3:1). Anal. Calcd for C H O : C, 62.04; H, 10.41. Found:
2
H O] 156.1150, found 156.1163. IR
9
18
3
-
1
f
4
9
18
3
under reduced pressure, yielding pure 3-hydroxyacids 1, which were
directly characterized without further purification.
C, 62.10; H, 10.46.
3-Hydroxy-3-phenylbutanoic Acid (1j). H NMR (300 MHz,
CDCl ): 7.37-7.10 (m, 5H), 2.90 (d, J ) 15.8 Hz, 1H), 2.72 (d,
J ) 15.8 Hz, 1H), 1.15 (s, 3H). C NMR (75 MHz, CDCl
176.9 (C), 146.2 (C), 128.3 (CH), 127.0 (CH), 124.2 (CH), 72.8
(C), 45.9 (CH ), 30.4 (CH ). HRMS (70 eV) calcd for C H O
3
1
3
-Hydroxy-5-methylhexanoic Acid (1a). Details for 1a can be
found in ref 35.
-Hydroxy-4-methylhexanoic Acid (1b). A 1:1 mixture of
3
13
3
): δ
3
1
diastereoisomers. H NMR (300 MHz, CDCl
.83 (m, 1H), 3.81-3.75 (m, 1H), 2.45-2.28 (m, 4H), 1.47-1.29
m, 2H), 1.15-1.00 (m, 4H), 0.82-0.76 (m, 12H). 13C NMR (75
MHz, CDCl ): δ 177.9 (C), 177.8 (C), 71.6 (CH), 71.0 (CH), 39.7
2 × CH), 38.6 (CH ), 37.7 (CH ), 25.3 (CH ), 24.9 (CH ), 14.3
CH ), 13.7 (CH ), 11.6 (CH ), 11.3 (CH ). MS (70 eV, EI) m/z
28 (M O, 2), 89 (100), 71 (68), 57 (15). HRMS (70 eV)
calcd for C
neat): 3422, 2924, 1717, 1458 cm . R
:1). Anal. Calcd for C : C, 57.51; H, 9.65. Found: C, 57.47;
H, 9.60.
-Hydroxy-4,4-dimethylpentanoic Acid (1c). Details for 1c can
be found in ref 36.
-Hydroxydecanoic Acid (1d). Details for 1d can be found in
ref 37.
-Hydroxy-5,9-dimethyldec-8-enoic Acid (1e). A 1:1 mixture
3
): 5.70 (s, 2H), 3.89-
2
3
10 12
+
-
3
[M
H
2
O] 162.0680, found 162.0676. IR (neat): 2979, 2619,
-1. R ) 0.3 (hexane/EtOAc 3:1). Anal. Calcd for
(
1702, 1495 cm
f
10 12 3
C H O : C, 66.65; H, 6.71. Found: C, 66.63; H, 6.68.
3
1
(
(
1
2
2
2
2
2-(1-Hydroxycyclopentyl)acetic Acid (1k). H NMR (300 MHz,
CDCl
NMR (75 MHz, CDCl
1
3
3
): 6.62 (br s, 1H), 2.56 (s, 2H), 1.74-1.13 (m, 8H).
): δ 176.7 (C), 79.7 (C), 44.2 (CH ), 39.5
), 23.6 (2 × CH ). HRMS (70 eV) calcd for C
O] 126.0680, found 126.0673. IR (neat): 2941, 1711,
C
3
3
3
3
+
-
H
2
3
2
+
-
7
H
14
O
3
[M
H
2
O] 128.0838, found 128.0839. IR
(2 × CH
2
2
8 14 3
H O
-
1
+ -
(
3
f
) 0.3 (hexane/EtOAc
[M
H
2
-
1
7
H
14
O
3
1408, 1270 cm . R
C H O
7 12 3
2
f
) 0.35 (hexane/EtOAc 3:1). Anal. Calcd for
: C, 58.32; H, 8.39. Found: C, 58.36; H, 8.42.
-(1-Hydroxycyclohexyl)acetic Acid (1l). H NMR (300 MHz,
1
3
13
CDCl
3
): 6.14 (br s, 1H), 2.49 (s, 2H), 1.69-1.21 (m,10). C NMR
75 MHz, CDCl ): δ 176.9 (C), 70.4 (C), 45.0 (CH
), 37.2 (2 ×
), 21.8 (2 × CH ). HRMS (70 eV) calcd for
[M ] 158.0943, found 158.0957. IR (neat): 2938, 1713,
(
3
2
3
CH
C H O
10 12 3
2
), 25.3 (CH
2
2
+
3
-
1
1
1406, 1266, 985 cm . R
for C : C, 62.04; H, 10.41. Found: C, 62.09; H, 10.47.
f
) 0.3 (hexane/EtOAc 3:1). Anal. Calcd
of diastereoisomers. H NMR (300 MHz, CDCl
3
): 5.07-5.03 (m,
H), 5.05 (s, 2H), 4.20-4.00 (m, 2H), 2.56-2.34 (m, 4H), 1.97-
.92 (m, 4H), 1.75-1.50 (m, 14H), 1.43-1.11 (m, 8H), 0.95-
8
14 3
H O
2
1
0
(
4
(
1
1
Synthesis of Methyl 3-Hydroxy-5-methylhexanoate (4a). N-
Nitroso-N-methylurea (12.1 mmol) was added to a solution of KOH
.85 (m, 6H). 1 C NMR (75 MHz, CDCl
3
3
): δ 177.4 (C), 131.3
), 43.7 (CH ),
), 29.0 (CH), 28.6
), 19.9 (CH ), 18.9 (CH ),
). MS (70 eV, EI) m/z 214 (M , 7), 196 (5), 136 (100),
29 (78), 109 (48), 95 (62), 82 (61), 56 (56). HRMS (70 eV) calcd
50% (6.75 mL) and diethyl ether (12.5 mL), and the mixture was
C), 124.5 (CH), 66.1 (CH), 64.7 (CH), 43.8 (CH
1.7 (CH ), 41.1 (CH ), 37.6 (CH ), 36.5 (CH
CH), 25.6 (CH ), 25.3 (CH ), 25.2 (CH
2
2
stirred for 20 min at 0 °C. Then the mixture was cooled in the
refrigerator for 3-4 h to obtain a solution of diazomethane. To a
solution of crude 3-hydroxyacid 1a (0.5 mmol, 1 equiv) in diethyl
ether (15 mL) was added the previously prepared diazomethane
solution. The mixture was stirred for 20 min, and then the solvents
were eliminated under vacuum to give 4a, which was obtained with
2
2
2
2
3
2
2
3
3
+
7.6 (CH
3
+
for C12
924, 1714, 1378, 738 cm . R
Calcd for C12 : C, 67.26; H, 10.35. Found: C, 67.20; H, 10.31.
-Cyclohexyl-3-hydroxypropanoic Acid (1f). H NMR (300
MHz, CDCl ): 6.93 (s, 1H), 3.77 (dd, J ) 9.2, 3.1 Hz, 1H), 2.53
dd, J ) 16.3, 3.1 Hz, 1H), 2.42 (dd, J ) 16.3, 9.3 Hz, 1H), 1.91-
22 3
H O [M ] 214.1569, found 214.1567. IR (neat): 3411,
-
1
2
f
) 0.3 (hexane/EtOAc 3:1). Anal.
analytical purity. Consequently, no further purification was neces-
22 3
H O
1
1
sary. H NMR (300 MHz, CDCl
3
1
3
): 4.08-3.99 (m, 1H), 3.66 (s,
3
H), 2.45 (dd, J ) 16.4, 3.4 Hz, 1H), 2.34 (dd, J ) 16.4, 8.7 Hz,
3
H), 1.83-1.68 (m, 1H), 1.48-1.38 (m, 2H), 0.87 (d, J ) 6.6 Hz,
(
0
(
2
1
C
13
.89 (m, 11H). 1 C NMR (75 MHz, CDCl3): δ 178.1 (C), 72.2
3
6H). C NMR (75 MHz, CDCl
CH ), 45.5 (CH ), 41.5 (CH ), 24.3 (CH), 23.1 (CH
HRMS (70 eV) calcd for C
42.0967. IR (neat): 3054, 2927, 1731, 1265, 741 cm . R
3
): δ 173.4 (C), 66.0 (CH), 51.6
), 21.9 (CH ).
O] 142.0993, found
(
3
2
2
3
3
CH), 42.9 (CH), 38.4 (CH
6.0 (CH
2
), 28.7 (CH
2
), 28.1 (CH
). MS (70 eV, EI) m/z 154 (M
2
), 26.2 (CH
2
),
+
-
+
-
8
H
16
O
3
[M
H
2
2
), 25.9 (CH
2
H O, 4),
2
-
1
1
f
) 0.4
36 (10), 95 (16), 89 (100), 68 (20). HRMS (70 eV) calcd for
H
+
-
(hexane/EtOAc 3:1). Anal. Calcd for C
Found: C, 59.95; H, 10.01.
8 16 3
H O : C, 59.97; H, 10.07.
9
16
O
3
[M
2
H O] 154.0994, found 154.1021. IR (neat): 3054,
-
1
2
930, 1708, 1265, 895 cm . R
Calcd for C : C, 62.77; H, 9.36. Found: C, 62.85; H, 9.40.
-Hydroxy-4-phenylbutanoic Acid (1g). Details for 1g can be
found in ref 38.
f
) 0.3 (hexane/EtOAc 3:1). Anal.
Synthesis of Benzyl 3-Hydroxy-5-methylhexanoate (5a). To
a solution of crude 3-hydroxyacid 1a (1 equiv, 0.5 mmol) in CH
9
16 3
H O
3
-
3
CN (5.1 mL) DBU (1.05 equiv) and benzyl bromide (1.10 equiv)
were added at room temperature. The mixture was stirred overnight,
and solvents were removed on a rotary evaporator. The crude was
treated with CH Cl (10 mL) and washed with 1 N HCl and H O.
2 2 2
Finally, the solvent was removed under vacuum to give crude 5a,
1
3-Ethyl-3-hydroxypentanoic Acid (1h). H NMR (300 MHz,
CDCl
3
): 2.50 (s, 2H), 1.56 (q, J ) 7.3 Hz, 2H), 1.55 (q, J ) 7.3
13
Hz, 2H), 0.86 (t, J ) 7.3 Hz, 6H). C NMR (75 MHz, CDCl
3
): δ
).
176.9 (C), 73.8 (C), 42.0 (CH ), 7.8 (2 × CH
2
), 31.0 (2 × CH
2
2
which was purified by flash column chromatography on silica gel
1
(
hexane/EtOAc 3/1). H NMR (300 MHz, CDCl
3
): 7.25 (s, 5H),
(
35) Wang, Z.; Zhao, C.; Pierce, M. E.; Fortunak, J. M. Tetrahedron:
Asymmetry 1999, 10, 225.
36) Palomo, C.; Oiarbide, M.; Aizpurua, J. M.; Gonz a´ lez, A.; Garc ´ı a,
J. M.; Landa, C.; Odriozola, I.; Linden, A. J. Org. Chem. 1999, 64, 8193.
37) Rose, A. F.; Scheuer, P. J.; Springer, J. P.; Clardy, J. J. Am. Chem.
Soc. 1978, 100, 7665.
38) Capozzi, G.; Roelens, S.; Talami, S. J. Org. Chem. 1993, 58, 7932.
5.04 (s, 2H), 4.05-3.95 (m,1H), 2.74 (br s, 1H), 2.43 (dd, J )
1
1
1
6.9, 3.9 Hz, 1H), 2.34 (dd, J ) 16.4, 8.4 Hz, 1H), 1.73-1.61 (m,
(
H), 1.39 (dd, J ) 9.0, 5.6 Hz, 1H), 1.34 (dd, J ) 9.0, 5.6 Hz,
1
3
H), 0.83 (d, J ) 1.1 Hz, 3H), 0.81 (d, J ) 1.1 Hz, 3H). C NMR
(
(75 MHz, CDCl
(2 × CH), 128.2 (CH), 66.4 (CH
3
): δ 172.8 (C), 135.6 (C), 128.5 (2 × CH), 128.3
(
2
), 66.1 (CH), 45.5 (CH ), 41.7
2
J. Org. Chem, Vol. 71, No. 12, 2006 4431