JOURNAL OF CHEMICAL RESEARCH 2013 723
Table 1
stirred for 10 h. Then the reaction mixture was poured into ice HCl (2M,
50 mL). The organic layer was separated, and the aqueous phase was
extracted with dichloromethane (3×45 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was removed
in vacuo to give the white solid 15.7 g (88 mol, 93%). M.p. 53.5–55 °C
[lit.12. 52–53 °C]. IR (cm–1) 2897, 2854, 1683, 1430, 1019, 605. 1H NMR
(500 MHz, CDCl3) δ 2.00 (s, 3H), 1.95 (s, 3H), 1.71 (s, 6H), 1.62 (d,
J=12.1 Hz, 6H). ESI-MS m/z: 179.1 (M+ 1)+.
2-(3-Hydroxy-1-adamantyl)-2-oxoethanoic acid (4): A solution of
ketone 3 (15.7 g, 88 mmol) in water (180 mL) was treated with KOH
(4.9 g, 88 mmol). The reaction mixture was heated to 50 °C, then
KMnO4 (41.7 g, 264 mmol) was added and the internal temperature
was kept below 80 °C. After the completion of the addition, the reaction
mixture was vigorously stirred for 12 h at 80 °C. At this point HPLC
assay indicated the disappearance of the starting material. The reaction
mixture was filtered, the aqueous layer was acidified with 12N HCl to
pH=1 and extracted with EtOAc (3×60 mL). The combined organic
layers were dried over MgSO4 and evaporated in vacuo to obtain a
residue (17.7 g), The residue was recrystallised from water (17 mL) to
give the desired 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid 4 (15.8 g,
704 mmol) as colourless needles, yield 80%. M.p. 164–165 °C [lit.5
162–164 °C]. IR (cm–1) 3399, 2933, 2861, 1712, 1689. 1H NMR (500 MHz,
DMSO) δ 14.39 (s, 0H), 4.75 (s, 1H), 2.18 (s, 2H), 1.67 (s, 3H), 1.54 (d,
J=25.9 Hz, 3H). ESI-MS m/z: 225.1 (M+ 1)+.
Yield/%a,b
KMnO4
/equiv.
KOH
Temp
/°C
Entry
/equiv.
4
4ac
30
8
–
–
15
14
20
5
7
–
3
7
1
2
3
4
5
6
7
8
9
2.0
3.0
4.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
1.0
1.0
1.0
0.5
2.0
3.0
1.0
1.0
1.0
80
80
80
80
80
80
80
60
70
90
65
85
78
75
70
74
66
79
80
84
<2
<2d
<2e
10
<2
<2
12
10
10
<2f
aYields of 4 were determined by HPLC.
bThe optimal reaction conditions were given, 3.0 equiv. of KMnO4, 1.0 equiv.
of KOH, H2O as solvent, 80 °C, 12 h.
cThe structure of compound 4 and by-product 4a were confirmed by
comparing with the reported data10.
d,e,fDifferent unknown impurities.
prepared by a Grignard reaction. In this approach, the oxidation
reaction introduced the hydroxyl and carboxyl group by a one-
pot reaction. Since the crude product was purified by simple
recrystallisation, this will be very attractive for large scale
manufacture. Further studies are currently underway in our
laboratory.
2-(1-Adamantyl)-2-oxoethanoic acid (4a): The mother liquor of 4 from
the crystallisation was extracted with EtOAc (3×10 mL), dried with
MgSO4, and concentrated to give a residue of 4a (0.8 g,3.84 mmol) as a
light yellow solid, M.p. 100.5–103 °C [lit.12 102–104 °C]. IR (cm–1) 2906,
2887, 1720. 1H NMR (500 MHz, CDCl3) δ 7.47 (brs, 1H), 2.09 (s, 3H),
2.02, 2.01 (2 s, 6H), 1.78–1.71 (m, 6H). ESI-MS m/z: 209.1 (M+ 1)+.
Experimental
Melting points were determined with a SGW X-4 micro melting
point apparatus. IR spectra were determined on a Bruker Vertex 70
spectrophotometer. 1H NMR spectra were recorded using Avance
500 MHz spectrometer. ESI-MS were recorded on Waters Quaptro
Premier XE Mass Spectrometer. HPLC were determined on Dionex
Ultimate 3000.
N-Methoxy-N-methyl-1-adamantanecarboxamide (2): 1-Adamantane
carboxylic acid 1 (18.0 g, 100 mmol) was suspended in CH2Cl2 (100 mL),
and CDI (17.3 g, 110 mmol) was added to the mixture to maintain the
temperature at 25 °C. Then the mixture was stirred 0.5 h at the same
temperature. N-Methoxymethanamine hydrochloride (10.7 g, 110 mmol)
was added, and the mixture was stirred for another 2 h. Then HCl (2 M,
45 mL) was added, the organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (2×30 mL). The combined organic
layers were washed with sat. NaHCO3 (30 mL), dried over MgSO4 and
concentrated to give the pale yellow powder 2 (21.2 g, 95 mmol), 95%.
M.p. 57.5–59 °C [lit.11 59–60 °C]. IR (cm–1): 2905, 2852, 2667, 1734, 1641,
1547, 1450, 1352, 1310, 1180, 999. H NMR (500 MHz, CDCl3) δ 3.68
(s, 3H), 3.17 (s, 3H), 2.00 (brs, 9H), 1.72 (brs, 6H). ESI-MS m/z: 224.2
(M+ 1)+.
Adamantan-1-yl-ethan-1-one (3): A dry three-necked flask equipped
with a magnetic stirrer bar and a N2 balloon was charged with CH3MgCl
(34.8 mL, 100 mol, 3 M in THF), and then a solution of the above
Weinreb amide 2 (21.2 g, 95 mmol) in THF (100 mL) was added at 10 °C.
The resulting mixture was allowed to warm to room temperature and
This work was supported by Zhejiang Hisoar Pharmaceutical
Co., Ltd. and the Shanghai Science and Technology Commission
(No. 12495810800).
Received 30 August 2013; accepted 26 September 2013
Paper 1302151 doi: 10.3184/174751913X13824450734344
Published online: 6 December 2013
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