The application of this robust transformation to a broader range of substrates, known as the Tsuji-Wacker reaction, facilitated the conversion of terminal olefins to methyl ketones with such high regioselectivity that terminal olefins can often be considered masked methyl ketones.5. The synthetic utility of the Tsuji-Wacker oxidation stems from its efficiency and broad functional group compatibility, and modifications to the original conditions have further expanded its applications.6,7,8 While traditional Tsuji-Wacker conditions exhibit Markovnikov regioselectivity, which mainly forms methyl ketone. products (135) with only trace amounts of aldehyde (136) (Scheme 3.1A), a notable modification reported by the Grubbs group reverses this trend, allowing selective formation of aldehydes as the major products instead ( Scheme 3.1B).9 Early investigations in aldehyde-selective Tsuji–. However, with the modern capabilities of the nitrite-modified Tsuji-Wacker reaction, we hypothesized that this sequence could be accomplished in a single.
Inspired by the robustness of this transformation on such sterically encumbered substrates, we recognized an opportunity to expand the synthetic impact of the nitrite-modified Tsuji–Wacker reaction by exploiting the inherent reactivity of the aldehyde products. We hypothesized that the subsequent reductive amination of the aldehyde could influence the formal anti-Markovnik hydroamination of the olefinic starting material. We chose alkene 143a as the substrate for our formal hydroamination studies because of its excellent performance in the Tsuji–Wacker oxidation.
After full conversion of the olefin under aldehyde-selective Tsuji-Wacker conditions, filtration through a silica plug and subsequent treatment of the residue with amine and NaBH(OAc)3 at ambient temperature in DCE allowed access to the reductive amination products in good to excellent condition. returns (Table 3.3). For example, sodium borohydride reduction of the crude aldehyde afforded formal anti-Markovnikov hydration product 149 in good yield (Scheme 3.3).
CONCLUDING REMARKS
EXPERIMENTAL SECTION
MATERIALS AND METHODS
Data for 1 H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Infrared spectra (IR) were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin film samples on KBr plates, and are reported in absorption frequency (cm–1).
PREPARATIVE PROCEDURES
- CATALYST OPTIMIZATION
- GENERAL EXPERIMENTAL PROCEDURES
- SUBSTRATE SYNTHESIS AND CHARACTERIZATION DATA
- ALDEHYDE CHARACTERIZATION DATA
The reaction was stirred under an oxygen atmosphere at 23 °C for 14 h, after which the reaction mixture was diluted with water (4 mL) and extracted with dichloromethane (3 x 5 mL). Alkene 143 or 146 (0.20 mmol, 1.00 equiv) was added dropwise via syringe and the reaction mixture was sparged with oxygen for another minute. The reaction was stirred under an oxygen atmosphere at 23 °C until TLC analysis indicated consumption of the starting material.
The organic extracts were dried over sodium sulfate, and then filtered and concentrated in vacuo. The reaction was stirred under an oxygen atmosphere at 23 °C for 12 h, when TLC analysis showed consumption of the starting material. Stirring was continued at 23 °C for 5 h, at which time the reaction was diluted with diethyl ether (3 mL), washed with saturated sodium bicarbonate (5 mL), and extracted with diethyl ether (3 x 5 mL).
The organic extracts were dried over sodium sulfate, and then filtered and concentrated under reduced pressure. After complete addition, the internal thermometer was removed and the mixture was stirred at 23 °C for 12 h, at which time the reaction mixture was diluted with diethyl ether and washed sequentially with cold 5% aqueous hydrochloric acid (15 ml) and saturated. aqueous sodium bicarbonate (15 mL). The organic layer was dried over sodium sulfate, and then filtered and concentrated under reduced pressure.
The organic extracts were washed with brine (20 mL) and dried over magnesium sulfate before filtration and concentration under reduced pressure. The resulting mixture was stirred at 23°C for 24 hours, at which time the reaction was quenched with water and transferred to a separatory funnel. The organic extracts were washed with brine (10 mL) and dried over magnesium sulfate before filtration and concentration under reduced pressure.
The crude residue was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to give alkene 143c as a colorless oil (653 mg, 74% yield). When TLC analysis indicated complete consumption of starting material, the reaction was quenched with acetone (2.0 mL) and 2N NaOH (2.0 mL). A saturated aqueous potassium carbonate solution was added and the mixture was extracted with dichloromethane (2 x 20 mL).
The combined organic extracts were dried over sodium sulfate before filtration and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (5% ethyl acetate in hexanes) to give tetralin 143j as a colorless oil (50.3 mg, 96% yield).
Ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-5-oxopentanoate (144d)
AMINE CHARACTERIZATION DATA
Amine 148a was prepared from 143a using general procedure B, column eluent: 25% ethyl acetate in hexanes with 0.5% triethylamine. Amine 148b was prepared from 143a using general procedure B, column eluent: 8% → 25% ethyl acetate in hexanes with 0.5% triethylamine. Amine 148c was prepared from 143a using general procedure B, column eluent: 8% ethyl acetate in hexanes with 0.5% triethylamine.
Amine 148d was prepared from 143a using General Procedure B, column eluent: 6% ethyl acetate in hexanes with 0.5% triethylamine. Amine 148e was prepared from 143a using General Procedure B, column eluent: 10% ethyl 148e was prepared from 143a using General Procedure B, column eluent: 10% ethyl acetate in hexanes with 0.5% triethylamine.
ALKENE TRANSFORMATION PROCEDURES AND CHARACTERIZATION DATA
The solvent was removed under reduced pressure, and the residue was loaded onto a short plug of silica gel, eluted with 30% ethyl acetate in hexanes (100 mL). Sodium borohydride (11.3 mg, 0.30 mmol, 1.50 equiv) was added in one portion, and the resulting mixture was stirred at 23 °C for 2 h, after which the reaction with acetone and 2 N aqueous sodium hydroxide (2 ml) has been extinguished. ). Filtration and concentration afforded the crude product, which was purified by silica gel column chromatography (35% ethyl acetate in hexanes) to afford alcohol 14 as a colorless oil (39.7 mg, 85% yield).
The solvent was removed under reduced pressure and the residue was loaded onto a short plug of silica gel, eluting with 30% ethyl acetate in hexanes (100). After one hour, trimethylsilyl cyanide (26 µl, 0.21 mmol, 1.05 equiv) was added. and the resulting mixture was stirred at 23 °C for 7 hours, after which the volatiles were removed under reduced pressure. The resulting crude residue was purified by column chromatography over silica gel (20% ethyl acetate in hexanes) to give α-aminonitrile. 150 as a colorless oil (59.6 mg, 86% yield).
Carbomethoxy methylene triphenyl phosphorane (100.3 mg, 0.30 mmol, 1.50 eq.) was added in one portion and the resulting mixture was stirred at 23 °C for 20 hours, at which time the reaction was transferred to a separatory funnel with diethyl ether and washed. sequentially with water (5 mL) and brine (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to a crude yellow oil. Purification by column chromatography on silica gel (10% ethyl acetate in hexanes) afforded the α,β-unsaturated methyl ester 151 as a colorless oil (49.3 mg, 86% yield).
Alkene 143a (107 mg, 0.50 mmol, 1.00 equiv) was added dropwise via syringe and the reaction mixture was sparged with oxygen for an additional minute. The reaction mixture was cooled to 23°C and treated with saturated aqueous sodium bicarbonate and ethyl acetate. The crude residue was purified by column chromatography over silica gel (20% ethyl acetate in hexanes) to give indole 152 as a yellow oil (86.1 mg, 57% yield).
The crude residue obtained was purified by silica gel column chromatography (8% ethyl acetate in hexanes) to give the tri-ester 153 as a colorless oil (45.0 mg, 82% yield). The resulting mixture was stirred at 60 °C for 24 h, at which time the reaction was quenched with water (4 mL), diluted with diethyl ether (2 mL), and washed with 5%. The crude residue obtained was purified by silica gel column chromatography (8% ethyl acetate in hexanes) to give alkyne 154 as a colorless oil (35.0 mg, 77% yield).
NOTES AND REFERENCES
For reviews on the use of enantioselective decarboxylative allylic alkylations in total synthesis, see: Hong, A. 15). For selected examples of total syntheses using enantioselective decarboxylative allylic alkylation, see: (a) Trost, B. 17) CuCl and anhydrous CuCl2 were also examined as copper sources, but the use of CuCl2•2H2O resulted in the highest yields. These compounds reacted slowly and only low yields (32–37%) of the aldehyde product were obtained, often contaminated by the enal side product. 21) For general reviews on hydroamination, see: (a) Müller, T.
