REGIO- AND STEREOSELECTIVE INTRAMOLECULAR HYDROSILYLATION OF α-HYDROXY ENOL ETHERS: 2,3-syn-2-METHOXYMETHOXY-1,3-NONANEDIOL
Checked by Michael R. Reeder, Lisa M. Reeder, and Robert K. Boeckman, Jr..
1. Procedure
D.
2-Methoxymethoxy-1,3-nonanediol. A
500-mL, single-necked, round-bottomed flask, equipped with a three-way stopcock connected to a bubbler as above and a magnetic stirring bar, is charged with
14.79 g (73.1 mmol) of 2-methoxymethoxy-1-nonen-3-ol (Note
6). The flask is evacuated, then purged with
nitrogen, and charged with
350 mL of dry diethyl ether and
8.88 g (87.7 mmol) of triethylamine (Note
13). After the mixture is cooled to 0°C in an ice-water bath,
8.30 g (87.7 mmol) of chlorodimethylsilane is added slowly with stirring. A large quantity of salt appears immediately. The white suspension is stirred at room temperature for 1 hr. The resulting mixture is then filtered through a
sintered-glass Büchner funnel and the filter cake is washed thoroughly with
dry hexane (Note
14). The combined filtrate and washings are concentrated under reduced pressure with a rotary evaporator. Some salts usually remain in the residue and are removed by dilution of the residue with an additional
50 mL of dry hexane followed by filtration, washing the filter cake with
hexane, and concentration of the combined filtrate and washings as above. This procedure for removal of salts is repeated two to three times until the colorless residual liquid remains clear after concentration (Note
15). The residual liquid is finally subjected to high vacuum (0.4 mm) for 2 hr to complete removal of volatile material, and then transferred to a
300-mL, round-bottomed flask, equipped with a three-way stopcock and a magnetic stirring bar. The flask is evacuated, purged with
nitrogen, and charged with
73 mL of dry hexane. To this mixture is added
1.21 mL (0.35 mmol) of the previously prepared platinum catalyst solution (Note
16) at room temperature with stirring. An exothermic reaction ensues almost immediately and the temperature of the mixture rises to about 30°C in 15 min, during which time the color of the clear mixture changes to yellow. The exothermic reaction ceases in about 1 hr. After the reaction mixture is stirred for an additional 1.5 hr at room temperature, completion of the reaction is confirmed by analysis by
1H NMR (Note
17). A
7.3-g portion of activated carbon powder is then added to the lightly colored mixture to effect removal of organoplatinum species (Note
18). The black suspension is stirred for about 12 hr, and suction filtered through Celite into a
500-mL, two-necked, round-bottomed flask. The filter cake is washed with dry
hexane, and the combined filtrate and washings are concentrated by rotary evaporation (Note
19). The flask containing the residue is equipped with a magnetic stirring bar and a thermometer, and is kept open to the air throughout subsequent manipulations. The flask is charged with
73 mL of THF,
73 mL of methanol (Note
20),
7.32 g (73.1 mmol) of solid potassium hydrogen carbonate, and
8.5 g (146 mmol) of solid potassium fluoride (Note
21). To the stirred mixture is added
29.7 mL (263 mmol) of 30% hydrogen peroxide slowly at room temperature (Note
22). A somewhat cloudy upper organic layer and a milky white lower aqueous 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 about 40°C. The exothermic reaction ceases in about 2 hr. The mixture is stirred at room temperature for an additional 3 hr (Note
23). The excess
hydrogen peroxide is decomposed by careful dropwise addition of a
50% aqueous sodium thiosulfate pentahydrate solution (
20 mL) with stirring over 20 min during which time the temperature is maintained near 30°C by intermittent cooling with an ice bath (Note
24). A negative starch-iodide test is observed after addition is complete (Note
25). The mixture is concentrated by rotary evaporator at 40–50°C under reduced pressure (water aspirator). To the residual aqueous suspension is added
150 mL of anhydrous ethanol and the mixture is stirred vigorously until the sticky, pale yellow precipitate becomes granular. The mixture is concentrated as above to give a pale yellow solid. The
ethanol addition and evaporation procedure is repeated once more to insure thorough removal of water. The residue is then diluted with
150 mL of diethyl ether, the mixture is filtered with suction, and the filter cake is washed well with two
100-mL portions of diethyl ether. The combined filtrate and washings are concentrated by rotary evaporation. The residual, crude product is purified by chromatography on
250 g of silica gel with
hexane/
ethyl acetate (1:1 v/v) as eluent to give
9.34–10.62 g (
58–66%) of
2-methoxymethoxy-1,3-nonanediol (R
f = 0.2) as a colorless liquid (Note
26). The syn and anti isomers cannot be separated by column chromatography. However, separation can be effected by GLC which showed the isomer ratio to be 98:2 syn/anti (Note
27).
2. Notes
1. A powerful magnetic stirrer and a large rugby ball-shaped stirring bar can be used. The checkers suggest use of an overhead mechanical stirrer because of the viscosity of the mixture in the initial stages of the reaction, which makes efficient magnetic stirring difficult.
2.
2-Bromoethanol was obtained from Aldrich Chemical Company, Inc., and was distilled prior to use.
3.
Dimethoxymethane was purchased from the Aldrich Chemical Company, Inc., and used as received.
4. Reagent grade
phosphorus pentoxide was obtained from the J. T. Baker Chemical Company and used as received.
5.
2-Bromoethyl methoxymethyl ether exhibits the following spectral properties:
1H NMR (200 MHz, CDCl
3) δ: 3.38 (s, 3 H), 3.49 (t, 2 H, J = 6.2), 3.85 (t, 2 H, J = 6.2), 4.66 (s, 2H);
13C NMR (50 MHz, CDCl
3) δ: 30.74, 55.45, 67.79, 96.54; IR (neat) cm
−1: 2952, 2900, 1148, 1118, 1072, 1036. Anal. Calcd for C
4H
9BrO
2: C, 28.43; H, 5.37. Found: C, 28.39; H, 5.36.
6. A
powerful magnetic stirrer and a large rugby ball-shaped stirring bar can be used. The checkers suggest use of an overhead mechanical stirrer because of the large quantity of salts produced in the reaction, which makes efficient magnetic stirring difficult.
7.
Potassium hydroxide pellets are better than finely ground powder, because the powder readily solidifies into a mass upon heating causing the reaction to slow down. Sonication does not facilitate the reaction.
8. TDA-1 is not essential, but accelerates the reaction considerably.
9. Isothermal GLC analysis was performed on a 30-m × 0.32-mm ID HP-5 capillary column containing 5% phenylmethylsilicone as a stationary phase at 50°C (retention time of the
bromo ether is 3.8 min).
10.
Methoxymethyl vinyl ether exhibits the following spectral properties:
1H NMR (200 MHz, C
6D
6) δ: 3.11 (s, 3 H), 4.09 (dd, 1 H, J = 6.6, 1.4), 4.54 (s, 2 H), 4.61 (dd, 1 H, J = 14.2, 1.4), 6.32 (dd, 1 H, J = 14.2, 6.6);
13C NMR (50 MHz, C
6D
6) δ: 55.37, 90.71, 95.28, 149.94.
12. Since
2-methoxymethoxy-1-nonen-3-ol tends to decompose on attempted GLC analysis, the purity is best checked by
1H NMR.
2-Methoxymethoxy-1-nonen-3-ol exhibits the following spectral properties:
1H NMR (200 MHz, C
6D
6) δ: 0.91 (t (br), 3 H, J = 7), 1.20–1.95 (m, 11 H), 3.17 (s, 3 H), 4.02 (q (br), 1 H, J = 5), 4.35 (s, 2 H), 4.75 (d, 1H, J = 6), 4.78 (d, 1 H, J = 6);
13C NMR (50 MHz, C
6D
6) δ: 14.27, 22.99, 25.88, 29.64, 32.20, 35.73, 55.71, 72.95, 84.21, 93.87, 162.63; IR (neat) cm
−1: 3448, 2940, 2864, 1644, 1156, 1096, 1020. Anal. Calcd for C
11H
22O
3: C, 65.31; H, 10.96. Found: C, 65.48; H, 11.17.
15. Since the O-silylated product is somewhat sensitive to moisture, the filtration process should be performed quickly.
16.
Platinum catalyst preparation: a mixture of
1 g of chloroplatinic acid hexahydrate,
12.4 mL (22 equiv) of 1,3-divinyltetramethyldisiloxane (an excess), and 1.2 mL of water is heated to 65–70°C for 3.5 hr with stirring.
3 4 The initial mixture becomes homogeneous after

30 min. The solution is then cooled to room temperature, and
5 mL of aqueous saturated sodium bicarbonate (NaHCO3) solution is added. The upper, yellow-orange, organic layer was separated, dried over Na
2SO
4, and filtered affording a solution (

0.29 M) of the
platinum catalyst in disiloxane that was stored in the refrigerator until use.
17. An aliquot is taken into an NMR tube, solvent is removed under reduced pressure, C
6D
6 is added and the sample is analyzed by
1H-NMR. The following spectral and analytical data for the cyclic siloxanes were obtained. The syn/anti ratio (95/5) was determined by capillary GLC (Note
9) except that a temperature program was employed [100°C for 2 min, then increased 15°C/min to 250°C (retention times 6.46 min (anti), 6.66 min (syn)]. Each isomer was isolated by preparative GLC: Syn:
1H NMR (200 MHz, C
6D
6) δ: 0.17 (s, 3 H), 0.29 (s, 3 H), 0.78 (dd, 1 H, J = 15, 5.5), 0.92 (t (br), 3 H, J = 7), 1.03 (dd, 1 H, J = 15, 5), 1.20–1.65 (m, 7 H), 1.65–2.00 (m, 3 H), 3.23 (s, 3 H), 3.89 (dt (br), 1 H, J = 9, 4), 4.12 (q (br), 1 H, J = 5), 4.48 (d, 1 H, J = 7), 4.65 (d, 1 H, J = 7);
13C NMR (50 MHz, C
6D
6) δ: 0.28, 1.14, 14.30, 18.39, 23.04, 26.72, 29.96, 32.18, 32.33, 55.28, 77.91, 80.91, 95.16; IR (neat) cm
−1: 2963, 2864, 1470, 1254, 1150, 1102, 1046, 872. Anti:
1H NMR (200 MHz, C
6D
6) δ: 0.15 (s, 3 H), 0.23 (s, 3 H), 0.83 (dd, 1 H, J = 14.2, 7.8), 0.91 (t (br), 3 H, J = 6 ), 1.18 (dd, 1 H, J = 14, 6), 1.25–1.85 (m, 10 H), 3.26 (s, 3 H), 3.90–4.14 (m, 2 H), 4.57 (d, 1 H, J = 7), 4.73 (d, 1 H, J = 7). Anal. Calcd for C
13H
28O
3Si (isomeric mixture): C, 59.95, H, 10.84. Found: C, 59.67; H, 11.02.
18. It is essential to remove all organoplatinum species since these species rapidly decompose
hydrogen peroxide in the next oxidation step.
19. The filtrate is ordinarily colorless but may possibly be brown, owing to the presence of trace amounts of organoplatinum species.
20. Commercial
reagent grade THF and methanol are used without further purification.
21. Reagent grade anhydrous
potassium fluoride was purchased from J. T. Baker Chemical Company. This material must be weighed quickly because it is highly hygroscopic.
22. Slow, not vigorous, evolution of small bubbles of
oxygen due to a trace amount of residual organoplatinum species may be observed.
23. Since the hydrosilylation products decompose on
silica gel, consumption of the starting material cannot be monitored by TLC. Only the formation of the product diol can be detected (R
f = 0.2,
hexane/
ethyl acetate 1:1).
24.
CAUTION: The thiosulfate solution MUST NOT be added in one portion; since a sudden, violent, uncontrollable reaction could occur.
25. If the starch-iodide test is still positive for the presence of
peroxide, additional
thiosulfate solution should be added until a negative starch-iodide test is obtained.
26. The major syn isomer of
2-methoxymethoxy-1,3-nonanediol exhibits the following spectral properties:
1H NMR (200 MHz, CDCl
3) δ: 0.86 (t (br), 3 H, J = 7), 1.18–1.50 (m, 10 H), 2.52 (d, 1 H, J = 5), 2.95 (dd, 1 H, J = 8, 4), 3.35–3.50 (m, 4 H, including a sharp singlet at 3.44), 3.55–3.82 (m, 3 H), 4.71 (d, 1 H, J = 7), 4.80 (d, 1 H, J = 7);
13C NMR (50 MHz, CDCl
3) δ: 14.02, 22.54, 25.43, 29.23, 31.72, 33.31, 55.89, 63.22, 71.80, 84.12, 97.43; IR (neat) cm
−1: 3428, 2936, 1470, 1154, 1108, 1032. Anal. Calcd for C
11H
24O
4 (isomer mixture): C, 59.97; H, 10.98. Found: C, 59.78; H, 11.04.
27. The syn/anti ratio (98:2) was determined by capillary GLC on a
30-m × 0.32-mm ID HP-5 capillary column containing 5% phenylmethylsilicone as the stationary phase using the following temperature program: 100°C for 2 min, then increase 15°C/min to 250°C (retention times 6.96 min (anti), 7.55 min (syn)). The submitters report that the syn/anti ratio can be determined after conversion to the acetonide by treatment with excess
dimethoxypropane and catalytic acid. By this procedure, the isomer ratio was found to be 94.4:5.6 (syn/anti). The submitters also report that the isomers can be separated easily by chromatography on silica gel: R
f = 0.31 for the syn isomer and R
f = 0.45 for the anti isomer (
hexane/
ethyl acetate 1:1). The acetonides exhibit the following spectral properties: syn:
1H NMR (200 MHz, CDCl
3) δ: 0.85 (t (br), 3 H, J = 7), 1.15–1.75 (m, 16 H, including two sharp singlets at 1.41 and 1.42), 3.33 (q, 1 H, J = 2.0), 3.39 (s, 3 H), 3.80–4.04 (m, 3 H), 4.64 (d, 1 H, J = 7.1), 4.78 (d, 1 H, J = 7.1);
13C NMR (50 MHz, CDCl
3) δ: 14.01, 18.89, 22.53, 24.92, 29.17, 31.05, 31.72, 55.71, 62.82, 70.00, 71.30, 95.29, 98.52 (Only five signals are observed for the hexyl group). Anal. Calcd for C
14H
28O
4: C, 64.58; H, 10.84. Found: C, 64.42; H, 11.11. Anti:
1H NMR (200 MHz, CDCl
3) δ: 0.81 (t (br), 3 H, J = 6.5), 1.10–1.80 (m, 16 H, including two sharp singlets at 1.30 and 1.38), 3.23–3.38 (m, 4 H, including a sharp singlet at 3.29), 3.50–3.68 (m, 2 H), 3.90 (dd, 1 H, J = 11.4, 5.2), 4.54 (d, 1 H, J = 6.8), 4.59 (d, 1 H, J = 6.8);
13C NMR (50 MHz, CDCl
3) δ: 14.08, 19.76, 22.62, 25.06, 28.23, 29.24, 31.83, 32.34, 55.62, 63.39, 72.11, 74.48, 96.49, 98.60. The checkers found the determination of the syn/anti ratio by this procedure to be unreliable because of the presence of interfering impurities formed during conversion to the acetonide.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
In the allylic alcohol series having a terminal olefin, the reaction proceeds in the 5-endo fashion to give five-membered ring compounds selectively with the syn stereoisomer being predominant, regardless of the nature of the catalyst,
platinum or rhodium.
19 20,21 Stereoselectivity increases with an increase in bulk of the allylic substituent. In addition, much higher selectivities are attained with enol ethers (R
2 = OMOM, OTHP, SR)
5 in comparison to other systems [(R
2 = Me, SiMe
2(O-i-Pr)
22]. Stereoselectivities in cyclic enol ethers appear to be sensitive to the reaction conditions.
23 It has also been shown that the 5-endo cyclization proceeds smoothly with allyl alcohols with a terminal aryl group (R
3 = Ar), but not with an alkyl group.
24 In
homoallyl alcohols, the 5-exo type of intramolecular hydrosilylation proceeds to form five-membered cyclic compounds and eventually 1,3-diols by oxidative cleavage. Two types of 1,2-stereoselection are possible, one being anti-controlled by the allylic substituent and, the other depending upon the olefin geometries, anti to the cis substituent R
c and syn to the trans R
t.
19,20 Catalytic, asymmetric, intramolecular hydrosilylation is also possible with rhodium catalysts in the presence of optically active phosphine ligands.
15,24 In contrast, allylamines form four-membered cyclic products via 4-exo ring closure in the platinum-catalyzed hydrosilylation from which syn-1,2-amino alcohols are obtained highly stereoselectively after oxidative cleavage.
25
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
sodium benzophenone ketyl
2,3-syn-2-Methoxymethoxy-1,3-nonanediol
(diethylamino)dimethylsilane (HMe2SiNEt2)
chloroplatinic acid hydrate (H2PtCl6·6H2O)
EDTA·2Na
ethanol (64-17-5)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
ammonium chloride (12125-02-9)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
sodium carbonate (497-19-8)
PHOSPHORUS (7723-14-0)
sodium sulfate (7757-82-6)
oxygen (7782-44-7)
nitrogen (7727-37-9)
platinum,
platinum(0) (7440-06-4)
cyclohexane (110-82-7)
carbon (7782-42-5)
potassium hydroxide (1310-58-3)
sodium (13966-32-0)
2-BROMOETHANOL (540-51-2)
hydrogen peroxide,
peroxide (7722-84-1)
thiosulfate
Dimethoxymethane (109-87-5)
magnesium sulfate (7487-88-9)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
potassium fluoride (7789-23-3)
hexane (110-54-3)
triethylamine (121-44-8)
ethyl vinyl ether (109-92-2)
potassium hydrogen carbonate (298-14-6)
Heptanal (111-71-7)
calcium hydride (7789-78-8)
bromo ether
argon (7440-37-1)
rhodium (7440-16-6)
sodium thiosulfate pentahydrate
sec-butyllithium (598-30-1)
homoallyl (2154-62-3)
phosphorus pentoxide (1314-56-3)
tert-Butyllithium (594-19-4)
potassium tert-butoxide (865-47-4)
2-Methoxymethoxy-1,3-nonanediol
2-Bromoethyl methoxymethyl ether (112496-94-3)
Methoxymethyl vinyl ether (63975-05-3)
tris[2-(2-methoxyethoxy)ethyl]amine (70384-51-9)
2-Methoxymethoxy-1-nonen-3-ol (114675-31-9)
chlorodimethylsilane (1066-35-9)
1,3-divinyltetramethyldisiloxane (2627-95-4)
dimethoxypropane (4744-10-9)
1,1,3,3-tetramethyldisilazane (15933-59-2)
1,3-Nonanediol, 2-(methoxymethoxy)-, (R,R)-(±)- (114675-32-0)
disodium salt of ethylenediaminetetraacetic acid
vinylsiloxane
chloroplatinic acid hexahydrate (16941-12-1)
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