Checked by Stephane Borrelly and Leo A. Paquette.
1. Procedure
A.
(−)-Dibenzyl tartrate. A
300-mL, one-necked, round-bottomed flask is equipped with a
magnetic stirrer,
Dean-Stark trap, and a
reflux condenser. The flask is charged with
3.0 g (20 mmol) of L-(+)-tartaric acid,
6.5 g (60 mmol) of benzyl alcohol,
47.5 mg (0.25 mmol) of p-toluenesulfonic acid monohydrate, and
40 mL of toluene (Note
1). The mixture is heated under reflux in an
oil bath (about 130°C) for 13 hr. During this period the theoretical amount of water (0.62 mL) is collected. The mixture is allowed to cool to ambient temperature, diluted with
ether, and poured into
50 mL of aqueous, saturated sodium bicarbonate. The organic phase is separated and the aqueous phase is extracted twice with
20 mL of ether. The combined organic phases are dried over
sodium sulfate. The solvent is removed with a
rotary evaporator, and the resulting crude product is triturated with
hexane-ether (20:1, 210 mL) to give white crystals of
(−)-dibenzyl tartrate. The precipitate is collected by filtration and washed with
hexane-
ether (20:1). The filtrate is further concentrated to give a second crop. The total yield is
6.2 g (
94%), mp
49–50°C (Note
2).
B.
Mono(2,6-dimethoxybenzoyl)tartaric acid. In a
250-mL, three-necked, round-bottomed flask, equipped with a
nitrogen inlet, a reflux condenser and a
magnetic stirring bar are placed
6.1 g (18.5 mmol) of dibenzyl tartrate,
100 mL of dry dichloromethane,
4 mL (28.8 mmol) of triethylamine and
50 mg (0.4 mmol) of 4-(dimethylamino)pyridine. The stirred mixture is cooled to 0°C and
3.65 g (18.2 mmol) of 2,6-dimethoxybenozyl chloride (Note
3) is added portion-wise over 1 hr. The reaction mixture is then warmed to room temperature and refluxed for 12 to 18 hr (the reaction is easily monitored by TLC). The reaction mixture is then allowed to cool down to room temperature and poured in 100 mL of water, The aqueous phase is extracted with 2 ×
75 mL of dichloromethane. The organic phases are combined, dried over
sodium sulfate, filtered and concentrated to give a viscous oil. This is purified by column chromatography on silica gel using a mixture of
hexane,
ether and
dichloromethane (3:1:5) as eluent (Note
4) to afford
7.1–7.5 g (
78–82%) of a clear oil identified as
dibenzyl mono(2,6-dimethoxybenzoyl)tartrate (Note
5). A
200-mL, pressure bottle is flushed with dry
argon and charged with
5.8 g (11.7 mmol) of the above tartrate,
100 mL of ethyl acetate, and
580 mg of 10% palladium on charcoal (Note
6). The
argon is then replaced by
hydrogen and the reaction mixture is shaken on a Parr apparatus at 20 psi and room temperature for several hours (Note
7). The mixture is filtered through a
pad of Celite and the filtrate is concentrated with a rotary evaporator, and dried completely under vacuum (80°C, ≤ 1 mm, overnight) (Note
8) to afford
3.5 g (
97%) of
mono(2,6-dimethoxybenozyl)tartaric acid as colorless solid, mp
184–186°C (Note
9). This material is practically pure and is used in Parts C, D without purification.
C. D.
(1R)-1,3,4-Trimethyl-3-cyclohexene-1-carboxaldehyde. A
100-mL, three-necked, round-bottomed flask containing a magnetic stirring bar is equipped with a rubber septum and a
three-way stopcock with an
argon inlet. The air is displaced by repeated flushing with dry
argon. The flask is charged with
1.57 g (5 mmol) of mono(2,6-dimethoxybenzoyl)tartaric acid obtained in Part B and
50 mL of dry dichloromethane (Note
10), and cooled in an
ice bath. Through the septum, with a syringe, is added dropwise
3.57 mL (5 mmol) of borane-THF solution (1.40 M) at 0°C over a period of 30 min (Note
11). The reaction mixture is stirred for 15 min at 0°C and then cooled to −78°C in a
dry ice-methanol bath. To this solution is added
4.14 mL (50 mmol) of freshly distilled methacrolein (Note
12) via a syringe dropwise. After the addition is complete,
8.49 mL (75 mmol) of 2,3-dimethyl-1,3-butadiene (Note
13) is introduced to the solution at the same temperature and the mixture is stirred for 12 hr. The cold reaction mixture is poured into 150 mL of ice-cold saturated
sodium bicarbonate and the product is extracted with three
200-mL portions of hexane (Note
14). The combined organic phases are washed with
brine (2 × 200 mL) (Note
15), dried over
sodium sulfate, filtered, and concentrated at atmospheric pressure. The residue is distilled at reduced pressure to afford
6.53 g (
86%) of
(1R)-1,3,4-trimethyl-3-cyclohexene-1-carboxaldehyde as a colorless liquid, bp
92–93°C (23 mm) (Note
16).
2. Notes
2. The physical properties are as follows:
1H NMR (200 MHz, CDCl
3) δ: 3.15 (d, 2 H, J = 7.5), 4.6 (d, 2 H, J = 7.5), 5.27 (s, 4 H), 7.35 (s, 10 H);
[α]24D −10.2° (CHCl
3,
c 1.03).
4. The purity of the ligand depends largely on the purity of the dibenzyl ester. Flash chromatography was carried out with silica gel purchased from Merck (Kieselgel 60, Art. 9385). For TLC analysis,
Merck silica gel F-254 TLC plates were used, with 3:1:5
hexane-
ether-
dichloromethane as eluent. Dibenzyl
mono(2,6-dimethoxybenzoyl)tartrate has an R
f of ca. 0.35 in this solvent system.
5. The physical properties are as follows:
1H NMR (200 MHz, CDCl
3) δ: 3.24 (d, 1 H, J = 9), 3.7 (s, 6 H), 4.89 (dd, 1 H, J = 2.5 and 9), 5.08–5.34 (4 H), 5.99 (d, 1 H, J = 2.5), 6.53 (d, 2 H, J = 8.5), 7.25–7.4 (m, 11 H);
[α]24D −60.1° (CHCl
3,
c., 1.15).
6.
Ethyl acetate was obtained from Wako Pure Chemical Industries and was used without purification. The
10% palladium on charcoal was purchased from Aldrich Chemical Company, Inc.
7. This requires 4–12 hr, depending on catalyst conditions. Progress of the reaction can be monitored by TLC.
8. Thorough drying is essential to obtain the % ee as described.
9. The physical properties are as follows:
1H NMR (200 MHz, CDCl
3) δ: 3.63 (s, 6 H), 4.61 (d, 1 H, J = 2), 5.61 (d, 1 H, J = 2), 6.38 (d, 2 H, J = 9), 7.13 (t, 1 H, J = 9);
[α]24D −73.0° (EtOH,
c 1.03).
10.
Dichloromethane was purchased from Wako Pure Chemical Industries and was dried over Linde-type 4 Å molecular sieves.
11.
Borane–THF complex was obtained from Toso-Akzo Chemical Company, Ltd. in Japan and should be titrated before use. Vigorous evolution of
hydrogen is observed during addition of
borane–
THF solution to the reaction mixture.
14. The
tartaric acid ligand can be recovered (1.52 g, 97%) from the aqueous phase by an acidification-extraction (4 N HCl-
ethyl acetate) sequence. The material is essentially pure for future use.
15. Careful washing with
brine is important to avoid foaming during distillation.
16. The physical properties are as follows:
1H NMR (200 MHz, CDCl
3) δ: 0.99 (s, 3 H), 1.3–2.1 (m, 5 H), 1.56 (s, 3 H), 1.61 (s, 3 H), 2.23 (br d, 1 H, J = 17), 9.43 (s, 1 H);
[α]23D −64.1° (CHCl
3,
c 1.0). The optical purity of this adduct was 95% as determined by 200 MHz
1H NMR spectroscopy and GC analysis (capillary column PEG, 0.25 mm × 25 m, purchased from Gaskuro Kogyo Company, Ltd. in Japan) after conversion to the corresponding chiral acetal as follows: A solution of the adduct,
(2R,4R)-(−)-pentanediol (1.2 equiv, obtained from Wako Pure Chemical Industries),
triethyl orthoformate (1.2 equiv), and
p-toluenesulfonic acid monohydrate (as a 5 mM solution) in dry
benzene is stirred at ambient temperature for 3 hr. The mixture is poured into saturated
sodium bicarbonate and the product is extracted with
ether. The combined organic phases are dried over
sodium sulfate and concentrated on a rotary evaporator. The residue is purified by flash column chromatography on silica gel using
hexane-
ethyl acetate (25:1) as eluent to give the acetal quantitatively;
1H NMR (200 MHz, CDCl
3) δ: 0.83 (s, 3 H), 1.15 (d, 3 H, J = 6), 1.28 (d, 3 H J = 6.5), 1.56 (s, 6 H), 1.2–2.06 (m, 8 H), 3.86 (m, 1 H), 4.27 (m, 1 H), 4.42 (s, 1 H; diastereomer at 4.45).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The procedure described here provides a simple and general method for the construction of optically active 3-cyclohexene-1-carboxaldehydes.
2 3 The reaction has been applied successfully to a series of α,β-unsaturated aldehydes with dienes (Table). Several methods are described in the literature for asymmetric Diels-Alder reactions of chiral α,β-unsaturated esters or amides;
4 5 6 7 little is reported, however, for the reaction of achiral, simple aldehydes.
8 9 10 11 12 The present method is characterized as a true catalytic process (only 10 mol % of chiral catalyst is needed), with good chemical and high optical yields, simple operation, preparation of both enantiomers with equal ease, and the ready availability of the starting materials.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
brine
palladium on charcoal
3-Cyclohexene-1-carboxaldehyde, 1,3,4-trimethyl-, (−)-
(−)-Dibenzyl tartrate
2,6-dimethoxybenozyl chloride
mono(2,6-dimethoxybenozyl)tartaric acid
(2R,4R)-(−)-pentanediol
Benzene (71-43-2)
ethyl acetate (141-78-6)
ether (60-29-7)
hydrogen (1333-74-0)
sodium bicarbonate (144-55-8)
sodium sulfate (7757-82-6)
calcium sulfate (7778-18-9)
toluene (108-88-3)
sodium (13966-32-0)
Benzyl alcohol (100-51-6)
tartaric acid,
L-(+)-tartaric acid (87-69-4)
triethyl orthoformate (122-51-0)
dichloromethane (75-09-2)
borane (7440-42-8)
tartrate
THF (109-99-9)
2,3-DIMETHYL-1,3-BUTADIENE (513-81-5)
hexane (110-54-3)
triethylamine (121-44-8)
methacrolein (78-85-3)
argon (7440-37-1)
4-(dimethylamino)pyridine (1122-58-3)
p-toluenesulfonic acid monohydrate (6192-52-5)
dibenzyl tartrate (622-00-4)
Mono(2,6-dimethoxybenzoyl)tartaric acid (116212-44-3)
dibenzyl mono(2,6-dimethoxybenzoyl)tartrate (158732-36-6)
(1R)-1,3,4-Trimethyl-3-cyclohexene-1-carboxaldehyde (130881-20-8)
2,6-Dimethoxybenzoyl chloride (1989-53-3)
Mono(2,6-dimethoxybenzoyl)tartrate
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