Alkyl Enol Ethers: Development in Intermolecular Organic Transformation

Abstract

Alkyl enol ethers (AEE) are versatile synthetic intermediates with a unique reactivity pattern. This review article summarizes the synthesis of AEE as well as its reactivity and how enol ether undergoes intermolecular reactions for various bond formation, leading to the construction of several useful organic molecules. The synthetic applications of alkyl enol ethers towards intermolecular bond‐forming reactions include metal‐catalyzed reactions, cycloaddition and heterocycle formation as well as rwactions in the field of natural products synthesis. The achievement of these impressive transformations prove the countless synthetic potential of AEE. The main objective of this review is to bring attentiveness among synthetic chemists to show how AEE extensively can be used to react with both electrophiles as well as nucleophiles, thereby behaving as an ambiphilic reactant. We trust that the unique reactivity pattern of alkyl enol ethers and the fundamental mechanistic idea can attract chemists in AEE chemistry. Exclusively, intermolecular reactions of AEE with other functionalized moieties have not been reviewed to the best of our knowledge.

Hetero-Diels–Alder Addition of Ethyl 2-Nitrosoacrylate to (Z)-Prop-1-enyl Ethers. Stereoselective Synthesis of a Precursor to Sacubitril

“…7.39 -7.27 (m, 5H), 4.94 (q, J = 6.6 Hz, 1H), 4.80 (d, J = 2.4 Hz, 1H), 4.41 -4.30 (m, 2H), 2.51 (dd, J = 18.6, 6.1 Hz, 1H), 2.21 (dd, J = 18.6, 12.7 Hz, 1H), 1.93 -1.83 (m, 1H), 1.39 (dd, J = 9.9, 4.2 Hz, 6H), 1.02 (d, J = 6.8 Hz, 3H). 13 Ethyl 5-methyl-6-(1-phenylethoxy)-1,2-oxazinane-3-carboxylate (±)-23: Ethyl 5-methyl-6-(1-phenylethoxy)-5,6-dihydro-4H-1,2-oxazine-3-carboxylate (±)-22 (major, 10.0 g, 34.3 mmol) was dissolved in 225 mL glacial acetic acid and the resulting solution was cooled to 0 o C. NaCNBH3 (3.23 g, 51.4 mol) was added in portions. After the addition was completed, the reaction temperature was allowed to rise to room temperature and the reaction was monitored by TLC.…”

“…1 H NMR (CDCl3, 500 MHz): δ 7.43 -7.15 (m, 5H), 4.82 (q, J = 6.6 Hz, 1H), 4.37 (d, J = 3.3 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.84 (dd, J = 12.1, 3.4 Hz, 1H), 1.97 -1.78 (m, 1H), 1.77 (dt, J = 12.9, 4.1 Hz, 1H), 1.65 (q, J = 12.9 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). 13 (5-methyl-6-(1-phenylethoxy)-1,2-oxazinan-3-yl)methanol (±)-24: Ethyl 5-methyl-6-(1-phenylethoxy)-1,2-oxazinane-3-carboxylate (±)-23 (8.8 g, 30.0 mmol) was dissolved in 200 mL dry tetrahydrofuran and to the resulting solution was added slowly and in portions LiAlH4 (2.28 g, 60.0 mol) at -20 ο C. The reaction was allowed to stir at -20 to -15 ο C until complete consumption of the raw material monitored by TLC. After about 2 hours, AcOEt and water are added dropwise to the reaction mixture, so as the temperature does not rise above -15 ο C during the addition.…”

“…1 H NMR (CDCl3, 500 MHz): δ 1 H NMR (500 MHz, cdcl3) δ 4.17 -4.10 (m, 1H), 3.96 (t, J = 7.5 Hz, 1H), 3.28 (dd, J = 16.2, 8.4 Hz, 2H), 3.06 (dd, J = 10.5, 5.3 Hz, 1H), 2.96 (s, 3H), 2.33 (dq, J = 14.1, 6.9 Hz, 1H), 1.88 -1.80 (m, 1H), 1.64 -1.57 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H). 13 C NMR (CDCl3, 125 MHz): δ 13 (1S,2R,4R)-1-isopropyl-4-methyl-2-(((Z)-prop-1-en-1-yl)oxy) cyclohexane 34: Potassium butoxide (2.24 g, 20.1 mmol, 0.36 equiv) was dissolved in 20 mL dry DMSO followed by (1S,2R,4R)-2-(allyloxy)-1isopropyl-4-methylcyclohexane (11.0 g, 56.0 mmol, 1.0 equiv) and the solution was heated at 70 o C overnight. Upon completion the reaction was left to reach room temperature and 10 ml of water were added followed by 10 ml of AcOEt.…”

“…1 H NMR (CDCl3, 500 MHz): 4.74 (d, J = 3.1 Hz, 1H), 4.63 (d, J = 3.2 Hz, 1H), 4.26 -4.08 (m, 3H), 3.85 (t, J = 10.8 Hz, 2H), 3.50 (td, J = 10.5, 4.1 Hz, 1H), 3.32 (td, J = 10.5, 4.3 Hz, 1H), 2.38 -2.17 (m, 3H), 2.07 -1.92 (m, 3H), 1.76 (ddt, J = 13.6, 10.2, 3.8 Hz, 2H), 1.70 -1.47 (m, 7H), 1.46 -1.30 (m, 4H), 1.28 (ddd, J = 10.2, 6.7, 3.1 Hz, 5H), 1.09 (dt, J = 21.3, 10.7 Hz, 2H), 1.01 (dd, J = 17.9, 7.8 Hz, 2H), 0.96 (t, J = 7.2 Hz, 6H), 0.89 (dtd, J = 14.5, 7.0, 3.3 Hz, 14H), 0.86 -0.75 (m, 5H), 0.74 (d, J = 7.0 Hz, 2H). 13 ((3S,5S,6R)-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-5methyl-1,2-oxazinan-3-yl)methanol (3S,5S,6R)-44: Ethyl carboxylate 43 (8.22 g, 25.1 mmol) was reduced to the corresponding alcohol by LiAlH4 (1.91 g, 50.2 mmol) at -20 o C in dry tetrahydrofuran according to the experimental procedure followed for the preparation of alcohol (±)-24. Crude reaction mixture was purified by flash column chromatography using neat AcOEt as the eluent affording 5.66 g of 44 as white solid (yield 79%, Rf = 0.27; PS:AcOEt = 1:2); [α]D 25 +46 ο (c = 1 CHCl3).…”

Enantioselective Organocopper-Catalyzed Hetero Diels–Alder Reaction through in Situ Oxidation of Ethers into Enol Ethers

“…Chiral ethers are essential building blocks of various natural products, pharmaceuticals, and polymers. − Such moieties can be accessed by stereoselective transformations of alkyl enol ethers (e.g., BOX–Cu-catalyzed hetero Diels–Alder reaction with 2,3-dihydrofuran; Figure A). − However, only a limited number of enol ethers are commercially available, and their synthesis and purification are often cumbersome (e.g., partial hydrogenation of alkynyl ethers, Wittig reaction). − An enabling strategy to obviate these key limitations would be to perform enantioselective transformations of enol ethers that are generated in situ by oxidation of significantly more accessible and otherwise stable alkyl ethers (Figure B). − Such an approach not only would be operationally simple but would generate less waste (vs the processes that demand preformation of enol ethers). − …”