Organic Syntheses, Vol. 76, 86
Checked by Kevin Minbiole, Patrick Verhoest, and Amos B. Smith, III.
1. Procedure
E. (2S,3S)-(+)-(3-Phenylcyclopropyl)methanol. A 250-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirrer (Note
26) and an internal thermocouple probe (Note
11), is charged with
45 mL of dichloromethane (Note
20) and
1.60 mL (14.9 mmol) of 1,2-dimethoxyethane (DME) (Note
27). The solution is cooled to −10°C (internal temperature) with an
acetone/ice bath, and
1.50 mL (14.9 mmol) of diethylzinc is added (Note
28). To this stirred solution is added
2.40 mL (29.8 mmol) of diiodomethane (Note
29) over a 15-20 min period while maintaining the internal temperature between −8°C and −12°C. After the addition is complete, the resulting clear solution is stirred for 10 min at −10°C. A solution of
2.41 g (8.94 mmol) of the dioxaborolane ligand in
10 mL of dichloromethane is added via cannula under
argon over a 5-6 min period while maintaining the internal temperature below −5°C. A solution of
1.00 g (7.45 mmol) of cinnamyl alcohol (Note
30) in
10 mL of dichloromethane is immediately added via cannula under
argon over a 5-6 min period while maintaining the internal temperature under −5°C. The cooling bath is removed, and the reaction mixture is allowed to warm to room temperature and stirred for 8 hr at that temperature (Note
31).
Workup. Method A. The reaction is quenched with aqueous saturated
ammonium chloride (10 mL) and aqueous
10% hydrochloric acid (40 mL). The mixture is then diluted with
ether (60 mL) and transferred to a
separatory funnel. The reaction flask is rinsed with
ether (15 mL), and aqueous
10% hydrochloric acid (10 mL) and both solutions are transferred to the separatory funnel. The two layers are separated, and the aqueous layer is washed with
ether (20 mL). The combined organic layers are transferred to an
Erlenmeyer flask, and a solution containing
60 mL of aqueous 2 N sodium hydroxide and
10 mL of aqueous 30% hydrogen peroxide is added in one portion (Note
32). The resulting biphasic solution is stirred vigorously for 5 min. The two layers are separated and the organic layer is washed successively with aqueous
10% hydrochloric acid (50 mL), aqueous saturated
sodium sulfite (50 mL), aqueous saturated
sodium bicarbonate (50 mL), and
brine (50 mL). The organic layer is dried over
magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The crude product is left under reduced pressure (0.2 mm) overnight (12-16 hr) to remove the
butanol produced in this oxidative work-up. The product is purified by a Kugelrohr distillation (90°C, 0.8 mm) to afford
1.05 g (
95%) of
(2S,3S)-(+)-(3-phenylcyclopropyl)methanol as a colorless oil (Note
33) and (Note
34).
Workup.
Method B [with recovery of (R,R)-(+)-N,N,N',N'-tetramethyltartaric acid diamide]. The mixture is quenched with aqueous saturated
ammonium chloride (80 mL), and the resulting biphasic mixture is stirred for 5 min. The two clear layers are separated, and the aqueous layer is washed with
dichloromethane (20 mL) (Note
35). The combined organic layers are dried over
magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The residual oil is dissolved in
ether (75 mL) and water (50 mL). The resulting biphasic mixture is stirred for 1 hr. The layers are separated, and the aqueous layer is washed with
ether (20 mL). This aqueous layer is kept for
tetramethyltartaric acid diamide recovery (see below). The combined organic layers are treated with
60 mL of aqueous 2 N sodium hydroxide and
10 mL of aqueous 30% hydrogen peroxide (Note
32). The resulting biphasic mixture is stirred for 5 min. The two layers are separated and the organic layer is washed successively with aqueous
10% hydrochloric acid (50 mL), saturated aqueous
sodium sulfite (50 mL), saturated aqueous
sodium bicarbonate (50 mL), and
brine (50 mL). The organic layer is dried over
magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The crude product is left under reduced pressure (0.2 mm) overnight (12-16 hr) to remove
butanol produced in this oxidative work-up. The product is purified by a Kugelrohr distillation (90°C, 0.8 mm) to afford
1.02 g (
93%) of
(2S,3S)-(+)-(3-phenylcyclopropyl)methanol as a colorless oil.
2. Notes
1. All glassware was dried in an
oven (110°C) and after assembly was allowed to cool under an atmosphere of
argon.
2.
Magnesium turnings were purchased from Sigma-Aldrich Fine Chemicals Company Inc. and were used without further purification.
3.
Ether was freshly distilled from
sodium/benzophenone.
5. The formation of a gray cloudy suspension indicates that the reaction has started. Furthermore, the reaction is sufficiently exothermic to induce the ether to reflux even when the reaction flask is not heated. If the reaction does not start within 2 to 3 min, repeat the heating procedure.
6. Between 1.5 hr and 2 hr are needed for addition.
7. A dried
10-mL, one-necked, round-bottomed flask is charged with 1 mL of Grignard, some drops of THF (Note
8) and a crystal of
1,10-phenanthroline (Note
9). The slightly pink solution is titrated with a 0.5 M solution of
isopropyl alcohol in
benzene (Note
10). Between 3.8 and 4.2 mL (±0.2 mL) is obtained to give a clear colorless solution (three titrations).
8. THF was freshly distilled from
sodium/benzophenone.
9.
1,10-Phenanthroline was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was used without further purification.
11. A
Barnant 100, Type T Thermo-Couple Thermometer was used to monitor the internal temperature of the reaction solution.
12. Anhydrous
trimethyl borate (with <5% of methanol) was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was used without further purification. Alternatively, a non anhydrous reagent can be dried by distillation from
calcium hydride (bp
68-69°C).
13. Commercially available
(Sigma-Aldrich Fine Chemicals Company Inc.), butylmagnesium chloride, 2.0 M in
ether, can be used and a similar yield is observed.
14. Between 20 and 30 min are needed for the addition.
15. Between 1 hr and 1.5 hr are needed.
16. The amount of the
boroxine significantly increases if the solid is left under reduced pressure for a longer period of time. The boroxine is always a contaminant of the boronic acid (see discussion).
17. Sometimes a second recrystallization is needed to obtain pure
boronic acid by removing by-products resulting from autooxidation.
18. The physical properties are as follows: mp
95-97°C; 1H NMR (400 MHz, DMSO) δ: 0.56 (t, 2 H, J = 7.6), 0.83 (t, 3 H, J = 7.2), 1.31-1.19 (m, 4 H), 7.34 (br s, 2 H);
13C NMR (100 MHz, DMSO) δ: 13.9, 15.3 (br), 25.1, 26.5;
11B NMR (128.4 MHz, DMSO) δ: 32.7.
19.
Diethanolamine was purchased from Fisher Scientific Company and was used without further purification.
21.
Molecular sieves, 3Å, powder, average particle size 3-5 μ were purchased from Sigma-Aldrich Fine Chemicals Company Inc. and dried under vacuum at 250°C for 24 hr, before using.
22. A few minutes after the addition of the molecular sieves, a white precipitate forms and sometimes maintaining stirring becomes difficult.
23. The physical properties are as follows: mp
145-148°C; 1H NMR (400 MHz, CDCl
3) δ: 0.44-0.48 (m, 2 H), 0.88 (t, 3 H, J = 7.1), 1.21-1.37 (m, 4 H), 2.79 (br s, 2 H), 3.26 (br s, 2 H), 3.88 (br s, 2 H), 3.98 (br s, 2 H), 4.80-4.98 (m, 1 H);
13C NMR (100 MHz, CDCl
3) δ: 14.1, 18.4 (br), 26.5, 28.1, 51.4, 62.5;
11B NMR (128.4 MHz, CDCl
3) δ: 13.1, 32.7. Anal. Calcd for C
8H
18BNO
2: C, 56.18; H, 10.61; N, 8.19. Found: C, 56.15; H, 10.86; N, 8.07.
24.
(R,R)-(+)-N,N,N',N'-Tetramethyltartaric acid diamide was prepared from
diethyl tartrate and
dimethylamine and was freshly recrystallized with
methanol and
ethyl acetate.
3 The physical properties are as follows: mp
186-187°C [lit.
2 189-190°C];
1H NMR (400 MHz, CDCl
3) δ: 3.01 (s, 6 H), 3.13 (s, 6 H), 4.21 (br s, 2 H), 4.65 (s, 2 H);
13C NMR (100 MHz, CDCl
3) δ: 36.1, 36.9, 69.8, 170.8;
[α]20D +43° (EtOH,
c 2.03) [lit.
2 [α]20D +43° (EtOH,
c 3.0)]. This product is also commercially available from Sigma-Aldrich Fine Chemicals Company Inc.
25. The physical properties are as follows:
1H NMR (400 MHz, CDCl
3) δ: 0.85 (t, 2 H, J = 7.7); 0.87 (t, 3 H, J = 7.2), 1.29-1.41 (m, 4 H), 2.98 (s, 6 H), 3.20 (s, 6 H), 5.53 (s, 2 H);
13C NMR (100 MHz, CDCl
3) δ: 9.9 (br), 13.6, 25.0, 25.7, 35.7, 36.9, 75.6, 168.23;
11B NMR (128.4 MHz, CDCl
3) δ: 34.2;
[α]20D −104.4° (CHCl
3,
c 1.70). HRMS Calcd for C
12H
23BN
2O
4: 270.1751. Found: 270.1746. Anal. Calcd for C
12H
23BN
2O
4: C, 53.35; H, 8.58; N, 10.37. Found: C, 53.67; H, 9.07; N, 10.21.
26. All glassware was flame dried, then cooled under a flow of dry
argon.
27. DME was freshly distilled from
sodium/benzophenone.
28.
Diethylzinc is a moisture sensitive and pyrophoric liquid and must be manipulated in an inert atmosphere with gas-tight syringes. Neat
diethylzinc was purchased from Akzo Nobel Chemicals Company Inc. and was used without further purification.
29.
Diiodomethane was purchased from Acros-Fisher Scientific Company and used without further purification. If necessary,
diiodomethane can be purified if it shows any signs of slight decomposition (orange or red color develops over time):
diiodomethane is washed with aqueous saturated
sodium sulfite, dried over
sodium sulfate (Na
2SO
4), and distilled from
copper (40°C, 1.0 mm). The pale yellow liquid is collected on
copper.
30.
Cinnamyl alcohol was purchased from Sigma-Aldrich Fine Chemicals Company Inc. and was freshly purified by Kugelrohr distillation: a first fraction boiling at <70°C (1.0 mm) was discarded, and the alcohol was collected as a white solid at 80°C (1.0 mm).
31. A similar yield is obtained when the submitters stirred this mixture for 14 hr. No noticeable decomposition and side reactions are observed after slightly longer periods of time.
32.
Hydrogen peroxide was purchased from ACP Chemicals Company Inc. and used without further purification.
33. Alternatively, the product can be purified by flash chromatography on silica gel (78.5 g, 4 cm × 16 cm) using
30% ethyl acetate in hexanes as the mobile phase (800 ml) to afford
1.06 g (
96%) of the title compound.
34. The physical properties are as follows: bp
90°C, 0.8 mm; IR (film) cm
−1: 3350, 3050, 3000, 2950, 2900, 1600, 1500, 1450, 1100, 1050, 1000, 750, 700;
1H NMR (400 MHz, CDCl
3) δ: 0.92-1.01 (m, 2 H), 1.43-1.51 (m, 1 H), 1.75 (br s, 1 H), 1.82-1.86 (m, 1 H), 3.59-3.67 (m, 2 H), 7.07-7.10 (m, 2 H), 7.15-7.20 (m, 1 H), 7.25-7.30 (m, 2 H);
13C NMR (100 MHz, CDCl
3) δ: 13.8, 21.2, 25.2, 66.3, 125.6, 125.8, 128.3, 142.5;
[α]20D +82° (EtOH,
c 1.74) [lit.
4 (2R,3R)-cyclopropylmethanol >99% ee
[α]20D −92° (EtOH,
c 1.23)]. Anal. Calcd for C
10H
12O: C, 81.04 H, 8.16. Found: C, 81.15; H, 8.30. The enantiomeric excess of the product is determined precisely by GC analylsis of the corresponding
trifluoroacetate ester derivative: To a solution of 10 mg of the crude alcohol in
0.75 mL of pyridine is added
0.25 mL of trifluoroacetic anhydride (TFAA). After 30 min at room temperature, an additional
0.25 mL of TFAA is added. After 30 min, the reaction mixture is diluted with
5 mL of ether. This solution was injected directly into the GC (0.5 μL) with the following conditions: Cyclodex G-TA, 0.32 × 30 m; pressure 25 psi; isotherm: 110°C, T
r (minor) 11.5 min, T
r (major) 12.0 min; enantiomeric ratio: 29:1 (93% ee).
35. If the resulting organic layers are not clear, the combined organic layers should be washed with an additional
50 mL of aqueous saturated ammonium chloride.
36. An additional 10-15% of the diol can be recovered from the first aqueous saturated
ammonium chloride extract (Note
38): the layer is concentrated on a
rotatory evaporator and the white solid is triturated with cold
methanol (30 mL), the mixture is filtered on a Büchner funnel, and the solid is washed with cold
methanol (20 mL). The filtrate is concentrated to ca. 25 mL and treated with
2.5 g of sodium sulfide (Note
39). The resulting mixture is stirred for 30 min and then filtered on Celite (6 g, 1 cm × 4 cm). The filtrate is concentrated by rotary evaporation, and the residue is purified by flash chromatography on silica gel (75 g, 3.5 cm × 14.5 cm) by dissolving it in
10 mL of 10% methanol in
chloroform and eluting with
10% methanol in
chloroform. A recrystallization with
dichloromethane and
ethyl acetate give pure material.
37. The physical properties are identical to those of (Note
24).
38. The diol decomposes after a few hours at room temperature in this layer.
39.
Sodium sulfide was purchased from Anachemia Science and was used without further purification.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(2S,3S)-(+)-(3-Phenycyclopropyl)methanol: Cyclopropanemethanol, 2-phenyl-,(1S-trans)- (12); (110659-58-0)
Butylmagnesium bromide: Magnesium, bromobutyl- (8,9); (693-03-8)
Magnesium (8,9); (7439-95-4)
1-Bromobutane: Butane, 1-bromo- (8,9); (109-65-9)
Isopropyl alcohol: 2-Propanol (8,9); (67-63-0)
1,10-Phenanthroline (8,9); (66-71-7)
Butylboronic acid: 1-Butaneboronic acid (8); Boronic acid, butyl- (9); (4426-47-5)
Trimethyl borate: Boric acid, trimethyl ester (8,9); (121-43-7)
Diethanolamine: Ethanol, 2,2'-iminodi- (8); Ethanol, 2,2'-iminobis- (9): (111-42-2)
(4R-trans)-2-Butyl-N,N,N',N'-tetramethyl[1,3,2]dioxaborolane-4,5-dicarboxamide: 1,3,2-Dioxaborolane-4,5-dicarboxamide, 2-butyl-N,N,N'N'-tetramethyl-, (4R-trans)- (13); (161344-85-0)
(R,R)-(+)-N,N,N',N'-Tetramethyltartaric acid diamide: Tartramide, N,N,N'N'-tetramethyl-, (+)- (8); Butanediamide, 2,3-dihydroxy-N,N,N'N'-tetramethyl-, [R-(R,R)]- (9); (26549-65-5)
Dimethoxyethane: Ethane, 1,2-dimethoxy- (8,9); (110-71-4)
Diethylzinc: Zinc, diethyl- (8,9); (557-20-0)
Diiodomethane: Methane,diiodo- (8,9); (75-11-6)
Cinnamyl alcohol (8); 2-Propen-1-ol, 3-phenyl- (9); (104-54-1)
Hydrogen peroxide (8,9); (7722-84-1)
Sodium sulfite: Sulfurous acid, disodium salt (8,9); (7757-83-7)
Copper (8,9); (7440-50-8)
Trifluoroacetic anhydride: Acetic acid, trifluoro-, anhydride (8,9); (407-25-0)
Sodium sulfide (8,9); (1313-82-2)
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