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DOI:10.15227/orgsyn.069.0096

Organic Syntheses, Coll. Vol. 8, p.315 (1993); Vol. 69, p.96 (1990).

NUCLEOPHILIC HYDROXYMETHYLATION BY THE(ISOPROPOXYDIMETHYLSILYL)METHYL GRIGNARD
REAGENT: 1-(HYDROXYMETHYL)CYCLOHEXANOL FROMCYCLOHEXANONE[Cyclohexanemethanol, 1-hydroxy-]

Submitted by Kohei Tamao, Neyoshi Ishida, Yoshihiko Ito, and Makoto Kumada1.
Checked by Vinh D. Tran and Larry E. Overman.

1. Procedure
A. 1-[(Isopropoxydimethylsilyl)methyl]cyclohexanol. A 500-mL, three-necked flask is equippedwith 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 toroom 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 anice 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, 247.5mmol) 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 byintermittent, brief cooling with a water bath to maintain the temperature at 40–50°C (Note 8). Afterabout 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 anaqueous 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. 100mL) is added to ensure further precipitation. The mixture is filtered with suction and the filter cake iswashed 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, andwashed 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 togive 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 iskept 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
1. (Isopropoxydimethylsilyl)methyl chloride2 is readily prepared from (chlorodimethylsilyl)methylchloride by treatment with isopropyl alcohol (1.1 equiv) and triethylamine (1.1 equiv) in diethyl ether atroom temperature (0.5 hr) and then at reflux temperature (0.5 hr). After filtration of the white salt, thefiltrate is washed successively once with water, twice with 0.1 N hydrochloric acid, once with anaqueous 10% solution of sodium hydrogen carbonate and once with water, and then dried over sodium
sulfate. Filtration and distillation give the product in 80% yield, bp 65–67°C at 50 mm, as an air-stable,colorless liquid. The checkers used commercially available material purchased from Aldrich ChemicalCompany, Inc.
2. Tetrahydrofuran (THF) was distilled from lithium aluminum hydride under nitrogen (Caution: SeeOrg. Synth., Coll. Vol. V, 1973, 976 for a warning regarding the purification of tetrahydrofuran. The
checkers employed THF that had been purified by distillation from sodium and benzophenone.).
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), andshowed the following 1H NMR spectrum (CDCl3, 300 MHz) δ: 0.19 (s, 6 H, Si(CH3)2), 1.01 (s, 2 H,CH2Si), 1.20 (d, 6 H, J = 6, CH(CH3)2), 1.38–1.75 (m, 10 H, (CH2)5), 3.5 (s, OH), 4.04 (septet, 1 H, J =6, OCH(CH3)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 coolingis 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 bathshould 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. Thecheckers found EM Quant Peroxide Test Strips obtained from EM Science to be more sensitive thanconventional 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,CDCl3) δ: 1.25–1.70 (broad m, 10 H, (CH2)5), 2.12 (s, 1 H, OH), 2.37 (t, 1 H, J = 6, OH), 3.45 (d, 2 H, J= 6, CH2OH); IR (KBr) cm−1: 3700–3020 (strong), 2920 (strong), 2845 (strong). Mass spectrum (24eV): m/z (relative intensity) 130 (M+, 0.3), 99 (100), 81 (67). High-resolution mass spectrum: calcd. for
C7H14O2, 130.0992; found, 130.0969.

3. Discussion
This procedure for the preparation of 1-(hydroxymethyl)cyclohexanol is a modification of thatreported by the submitters.4 While 1-(hydroxymethyl)cyclohexanol has been conventionally preparedfrom methylenecyclohexane by dihydroxylation5a or from cyclohexanone in three steps through thecyanohydrin,5b the present method consists of an alternative route from cyclohexanone via nucleophilichydroxymethylation.
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 typehave been developed so far. They include MeOH/TiCl4/hv,7 Bu3SnCH2OH/BuLi,8 tert-BuOCH2Li,9HSiR3/CO/Co2(CO)8,10 PhCH2OCH2Cl/SmI2,11 ArCO2CH2Li/LiAlH4,12 R2BCH2Li/[O],13 14 and(Me3SiO)CH=C(OSiMe3)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)Me2SiCH2MgCl (1),the (diisopropoxymethylsilyl)methyl counterpart, (isoPro)2MeSiCH2MgCl (2), has also been used as anucleophilic 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)Me2SiCH2E, 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 byhydrogen peroxide.17 The presence of at least one heteroatom on silicon is essential for the oxidativecleavage. Thus, the silicon-carbon bonds in hydro-, fluoro-, chloro-, alkoxy-, or aminosilanes arecleaved 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 themost efficient and most widely applicable: 30% H2O2 (1.2 equiv/Si-C bond), KHCO3 (1 molar equiv),
KF (2 molar equiv), MeOH/THF (1 : 1), room temperature. Under these conditions, the reaction usuallyoccurs 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 throughintramolecular 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 afunctional 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 theoriginal 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 ofthe silicon-based nucleophilic hydroxymethylation.
This preparation is referenced from:zzOrg. Syn. Coll. Vol. 9, 493
Org. Syn. Coll. Vol. 9, 539

TABLE INUCLEOPHILIC HYDROXYMETHYLATION OF ALDEHYDES, KETONES, ORGANICHALIDES, ALCOHOLS, AND EPOXIDESaStarting Material

ProductOverall isolated yield
Ref.
(%)

67

475

1986

465

463

479

1687

1652

2086

1665

1667

2174

21

Introduction of the silylmethyl group into organic halides, tosylates, and epoxides isachieved by nickel-, palladium-, or copper-catalyzed cross-coupling reactions.

aReferences and Notes
1. Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606,Japan.
2. Andrianov, K. A.; Golubenko, M. A. Doklady Akad. Nauk S.S.S.R. 1957, 112, 257; Chem. Abstr.
1957, 51, 11987h.
3. Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070.
4. Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4245.
5. Baumgarten, H. E.; Bower, F. A.; Okamoto, T. T. J. Am. Chem. Soc. 1957, 79, 3145;Rouzaud, J.;
Cauquil, G.; Giral, L. Bull. Soc. Chim. Fr. 1964, 2908;Jones, R. A. Y.; Katritzky, A. R.; Nicol, D.
L.; Scattergood, R. J. Chem. Soc., Perkin Trans. 2 1973, 337.
6. Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239; Saavedra, J. E. in "Umpoled Synthons,
A Survey of Sources and Uses in Synthesis," Hase, T. A., Ed.; Wiley: New York, 1987, pp. 101–143.
7. Sato, T.; Kaneko, H.; Yamaguchi, S. J. Org. Chem. 1980, 45, 3778.
8. Meyer, N.; Seebach, D. Chem. Ber. 1980, 113, 1290; Still, W. C.; Mitra, A. J. Am. Chem. Soc.
1978, 100, 1927.
9. Corey, E. J.; Eckrich, T. M. Tetrahedron Lett. 1983, 24, 3165.
10. Chatani, N.; Furukawa, H.; Kato, T.; Murai, S.; Sonoda, N. J. Am. Chem. Soc. 1984, 106, 430;
Murai, T.; Kato, S.; Murai, S.; Toki, T.; Suzuki, S.; Sonoda, N. J. Am. Chem. Soc. 1984, 106,6093
11. Imamoto, T.; Takeyama, T.; Yokoyama, M. Tetrahedron Lett. 1984, 25, 3225.
12. Beak, P.; McKinnie, B. G. J. Am. Chem. Soc. 1977, 99, 5213.
13. Rathke, M. W.; Kow, R. J. Am. Chem. Soc. 1972, 94, 6854;
14. Pelter, A. Chem. Soc. Rev. 1982, 11, 191.
15. Wissner, A. Tetrahedron Lett. 1978, 2749.
16. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120; Tamao, K.; Ishida, N.
Tetrahedron Lett. 1984, 25, 4249.

17. Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983, 2, 1694; Tamao, K.;
Ishida, N. J. Organomet. Chem. 1984, 269, C37; Tamao, K.; Kumada, M.; Maeda, K.
Tetrahedron Lett. 1984, 25, 321.
18. Reviews: Tamao, K. in "Organosilicon and Bioorganosilicon Chemistry: Structure, Bonding,
Reactivity and Synthetic Application," Sakurai, H., Ed.; Halsted Press: New York, 1985, pp.
231–242; Tamao, K. J. Synth. Org. Chem. Jpn. 1988, 41, 861.
19. Joyce, R. P.; Parvez, M.; Weinreb, S. M. Tetrahedron Lett. 1986, 27, 4885.
20. Tius, M. A.; Fauq, A. J. Am. Chem. Soc. 1986, 108, 6389.
21. Tamao, K.; Ishida, N., unpublished results.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)silica gelhydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol,
MeOH (67-56-1)
diethyl ether (60-29-7)
ammonium chloride (12125-02-9)
sodium hydrogen carbonate (144-55-8)
magnesium (7439-95-4)
Cyclohexanone (108-94-1)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
Benzophenone (119-61-9)
sodium (13966-32-0)
isopropyl alcohol (67-63-0)
1,2-dibromoethane (106-93-4)hydrogen peroxide (7722-84-1)
magnesium sulfate (7487-88-9)

Tetrahydrofuran,
THF (109-99-9)
potassium fluoride (7789-23-3)
lithium aluminum hydride (16853-85-3)
hexane (110-54-3)
triethylamine (121-44-8)
potassium hydrogen carbonate (298-14-6)
Methylenecyclohexane (1192-37-6)
sodium thiosulfate pentahydrate
1-(Hydroxymethyl)cyclohexanol,
Cyclohexanemethanol, 1-hydroxy- (15753-47-6)
1-[(Isopropoxydimethylsilyl)methyl]cyclohexanol (138080-23-6)(Isopropoxydimethylsilyl)methyl chloride (18171-11-4)(chlorodimethylsilyl)methyl chloride (1719-57-9)
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