Organic Syntheses, CV 8, 315
Submitted by Kohei Tamao, Neyoshi Ishida, Yoshihiko Ito, and Makoto Kumada
1.
Checked by Vinh D. Tran and Larry E. Overman.
1. Procedure
A.
1-[(Isopropoxydimethylsilyl)methyl]cyclohexanol. A
500-mL, three-necked flask is equipped with a
pressure-equalizing dropping funnel, a
magnetic stirrer, a
three-way stopcock, and a
reflux condenser connected with a
nitrogen bubbler. The flask is charged with
magnesium turnings (2.43 g, 100 mg-atm) that are dried under a rapid stream of
nitrogen with a heat gun. After the flask is cooled to room temperature, the rate of
nitrogen flow is reduced. Several milliliters of a solution of
(isopropoxydimethylsilyl)methyl chloride (16.67 g, 100 mmol) (Note
1) in dry
tetrahydrofuran (THF) (120 mL) (Note
2) and about
50 μL of 1,2-dibromoethane are added. The mixture is stirred at room temperature and within a few minutes an exothermic reaction starts. The remaining solution is added dropwise at room temperature over ca. 45 min at such a rate as to maintain a gently exothermic reaction. After the addition is complete, the tan-gray mixture is refluxed for 0.5 hr and then cooled to 0°C with an
ice bath. A solution of freshly distilled
cyclohexanone (7.36 g, 75 mmol) in dry
THF (30 mL) is added dropwise with stirring over 30 min. The resultant mixture is stirred at 0°C for another 30 min (Note
3) and then hydrolyzed by dropwise addition of an aqueous
10% solution of ammonium chloride (100 mL) at 0°C over 10 min. The organic layer is separated. The aqueous layer is extracted with four
40-mL portions of diethyl ether. The combined organic layer and extracts are washed once with aqueous saturated
sodium chloride, dried over
magnesium sulfate, filtered into a
500-mL round-bottomed flask and concentrated with a
rotary evaporator below room temperature (Note
4) at water aspirator pressure. A colorless oil remains (Note
5).
B.
1-(Hydroxymethyl)cyclohexanol The 500-mL, round-bottomed flask containing the crude
1-[(isopropoxydimethylsilyl)methyl]cyclohexanol is equipped with a magnetic stirrer and a
thermometer, and is kept open to air throughout the reaction. The flask is charged with
tetrahydrofuran (75 mL),
methanol (75 mL) (Note
6),
potassium hydrogen carbonate (7.5 g 75 mmol), and
potassium fluoride (8.7 g, 150 mmol) (Note
7). To the stirred mixture is added
30% hydrogen peroxide (28.0 mL, 247.5 mmol) in one portion at room temperature. A somewhat cloudy organic layer and a milky-white, heavy inorganic layer result. After several minutes an exothermic reaction begins which is controlled by intermittent, brief cooling with a
water bath to maintain the temperature at 40–50°C (Note
8). After about 30 min the exothermic reaction ceases. The mixture is then stirred at room temperature for 2 hr (Note
9). The remaining
hydrogen peroxide is decomposed by careful dropwise addition (Note
10) of an aqueous
50% solution of sodium thiosulfate pentahydrate (ca. 30 mL) with stirring over 30 min, during which time the temperature is maintained near 30°C by intermittent cooling with an ice bath (Note
11). A negative starch-iodide test is observed (Note
12). A white precipitate forms and
diethyl ether (ca. 100 mL) is added to ensure further precipitation. The mixture is filtered with suction and the filter cake is washed with three
20-mL portions of diethyl ether. The combined filtrate and washes are concentrated with a rotary evaporator at 50°C at water aspirator pressure until much of the water has been removed. The remaining oil is diluted with
diethyl ether (ca. 200 mL), transferred to a
separatory funnel, and washed with saturated aqueous
sodium chloride solution to remove the remaining water. The organic layer is separated, dried over
magnesium sulfate, filtered, and concentrated with a rotary evaporator to give a colorless solid. The solid is dissolved in a
10 : 1 mixture of hexane–ethyl acetate (75 mL) at reflux, and the hot solution is filtered. The filtrate is allowed to cool to room temperature and finally is kept at 0°C for 2 hr. The crystals are separated with suction, washed with cold
hexane/ethyl acetate (10 : 1, 10 mL), and dried under high vacuum at room temperature. There is obtained
7.54 g (
77%) of
1-(hydroxymethyl)cyclohexanol as white crystals, mp
76.0–76.2°C (Note
13) and (Note
14).
2. Notes
3. The color of the mixture lightened slightly.
4. Care must be taken not to raise the temperature since β-elimination of the β-hydroxysilane can result.
5. The remaining oil appeared as one spot on silica gel TLC,
Rf = 0.8 (
hexane/ethyl acetate 1 : 1), and showed the following
1H NMR spectrum (CDCl
3, 300 MHz) δ: 0.19 (s, 6 H, Si(CH
3)
2), 1.01 (s, 2 H, CH
2Si), 1.20 (d, 6 H,
J = 6, CH(CH
3)
2), 1.38–1.75 (m, 10 H, (CH
2)
5), 3.5 (s, OH), 4.04 (septet, 1 H,
J = 6, OCH(CH
3)
2).
6. Commercial reagent-grade THF and
methanol are used without further purification.
7.
Potassium fluoride of anhydrous grade was purchased from Nakarai Chemicals. Ltd. This must be weighed quickly because it is highly hygroscopic. The checkers used material purchased from Allied Chemical Company.
8. The oxidation is so exothermic that the temperature reaches 60–65°C in 10 min if no external cooling is applied.
9. Completion of the oxidation was confirmed by TLC on
silica gel:
Rf of the product diol is 0.4 (
hexane/
ethyl acetate 1 : 1).
10. Care must be taken not to add the thiosulfate solution in one portion; otherwise a violent, uncontrollable reaction might suddenly occur.
11. The reaction temperature should be monitored carefully. If it falls below 10°C, the cooling bath should be removed to allow the mixture to warm to ca. 30°C.
12. If the test is still positive, thiosulfate solution should be added until a negative test is attained. The checkers found EM Quant Peroxide Test Strips obtained from EM Science to be more sensitive than conventional KI-Starch test paper.
13. The reported melting point is
75–76°C.
3
14.
1-(Hydroxymethyl)cyclohexanol exhibits the following spectral properties:
1H NMR (300 MHz, CDCl
3) δ: 1.25–1.70 (broad m, 10 H, (CH
2)
5), 2.12 (s, 1 H, OH), 2.37 (t, 1 H,
J = 6, OH), 3.45 (d, 2 H,
J = 6, CH
2OH); IR (KBr) cm
−1: 3700–3020 (strong), 2920 (strong), 2845 (strong). Mass spectrum (24 eV):
m/z (relative intensity) 130 (M
+, 0.3), 99 (100), 81 (67). High-resolution mass spectrum: calcd. for C
7H
14O
2, 130.0992; found, 130.0969.
3. Discussion
Although nucleophilic hydroxymethylating agents (hydroxymethyl anion synthons) or alkoxymethyl anions could be of great use in synthetic organic chemistry,
6 only a few agents of this type have been developed so far. They include MeOH/TiCl
4/
hv,
7 Bu
3SnCH
2OH/BuLi,
8 tert-BuOCH
2Li,
9 HSiR
3/CO/Co
2(CO)
8,
10 PhCH
2OCH
2Cl/SmI
2,
11 ArCO
2CH
2Li/LiAlH
4,
12 R
2BCH
2Li/[O],
13 14 and (Me
3SiO)CH=C(OSiMe
3)
2.
15 These methods are not as convenient or widely applicable as the method reported here. Two points deserve comment.

In addition to the (isopropoxydimethylsilyl)methyl Grignard reagent, (isoPrO)Me
2SiCH
2MgCl (
1), the (diisopropoxymethylsilyl)methyl counterpart, (isoPro)
2MeSiCH
2MgCl (
2), has also been used as a nucleophilic hydroxymethylating agent.
16 Despite labile alkoxy group(s) on silicon, the Grignard reagents are readily prepared in a normal manner in greater than 90% yields, and are sufficiently stable to be stored at room temperature for at least 2 days with little decrease in activity. The monoisopropoxy Grignard reagent (
1) is recommended as the reagent of first choice. Its precursor,
(isopropoxydimethylsilyl)methyl chloride, is readily available at lower cost, and the reaction products, (iso-PrO)Me
2SiCH
2E, are more stable not only to aqueous workup under weakly basic and acidic conditions but also to silica gel chromatography.
The present method is based on the oxidative cleavage reaction of the silicon–carbon bond by
hydrogen peroxide.
17 The presence of at least one heteroatom on silicon is essential for the oxidative cleavage. Thus, the silicon-carbon bonds in hydro-, fluoro-, chloro-, alkoxy-, or aminosilanes are cleaved oxidatively to give the corresponding hydroxylated products. Although the oxidation may be performed in several ways, the following conditions (involving weak base and fluoride ion) may be the most efficient and most widely applicable:
30% H2O2 (1.2 equiv/Si-C bond), KHCO
3 (1 molar equiv), KF (2 molar equiv),
MeOH/THF (1 : 1), room temperature. Under these conditions, the reaction usually occurs exothermically and is typically complete in several hours. Functional groups such as olefin, aldehyde, ketone, ester, amine, ether, ketal and
tert-butyldimethylsiloxy groups, and furan, thiophene, and pyridine rings are stable under the oxidation conditions. The oxidation proceeds with complete retention of configuration at an
sp3 carbon. The oxidation has been considered to proceed through intramolecular migration of an organic group from silicon to the adjacent oxygen atom in penta- or hexacoordinate hydroperoxysilicon intermediates, as shown in Scheme 1, where X stands for a functional group. The oxidation has found a variety of synthetic applications.
18

Several representative examples of nucleophilic hydroxymethylation of aldehydes, ketones, organic halides, tosylates, and epoxides are summarized in Table 1. The oxidation conditions given in the original literature are not necessarily optimum, and results may be improved by use of the oxidation method employed here. These results, summarized in Table I, demonstrate the general applicability of the silicon-based nucleophilic hydroxymethylation.
This preparation is referenced from:
TABLE I
NUCLEOPHILIC HYDROXYMETHYLATION OF ALDEHYDES, KETONES, ORGANIC HALIDES, ALCOHOLS, AND EPOXIDESa
|
Starting Material |
Product |
Overall isolated yield (%) |
Ref. |
|
|
|
67 |
4 |
|
|
75 |
19 |
|
|
86 |
4 |
|
|
65 |
4 |
|
|
63 |
4 |
|
|
79 |
16 |
|
|
87 |
16 |
|
|
52 |
20 |
|
|
86 |
16 |
|
|
65 |
16 |
|
|
67 |
21 |
|
|
74 |
21 |
|
aIntroduction of the silylmethyl group into organic halides, tosylates, and epoxides is achieved by nickel-, palladium-, or copper-catalyzed cross-coupling reactions.
|
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved