Diels–Alder Cycloaddition Reactions in Sustainable Media

Abstract

Diels–Alder cycloaddition reaction is one of the most powerful strategies for the construction of six-membered carbocyclic and heterocyclic systems, in most cases with high regio- and stereoselectivity. In this review, an insight into the most relevant advances on sustainable Diels–Alder reactions since 2010 is provided. Various environmentally benign solvent systems are discussed, namely bio-based derived solvents (such as glycerol and gluconic acid), polyethylene glycol, deep eutectic solvents, supercritical carbon dioxide, water and water-based aqueous systems. Issues such as method’s scope, efficiency, selectivity and reaction mechanism, as well as sustainability, advantages and limitations of these reaction media, are addressed.

Pushing Photochemistry into Water: Acceleration of the Di‐π‐Methane Rearrangement and the Paternó‐Büchi Reaction “On‐Water”

“…But even with the above‐mentioned analytical limitations, namely a likely reduced efficiency because of limited light harvesting, the results of the Paternó‐Büchi reaction are in agreement with the ones obtained with ground‐state cycloaddition reactions, for example the Diels‐Alder reaction [19] . In the latter cases, the detailed processes that lead to the rate‐accelerating effect of water are still not fully clarified and are even considered to be specific for each particular reaction, but it is commonly accepted that a hydrophobic effect operates in the transition state [1,2] .…”

Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose

“…1 H NMR (DMSO-d 6 ): δ = 10.07 (br s, 1H), 9.39 (s, 1H), 8.84 (br s, 1H), 6.73 (d, 1H, J = 8.3 Hz), 6.62 (d, 1H, J = 8.3 Hz), 6.20 (d, 1H, J = 9.0 Hz), 5.63 (d, 1H, 8.9 Hz), 5.08 (s, 1H), 4.14 (d, 1H, 6.5 Hz), 3.74 (s, 3H), 3.59 (s, 3H), 3.27 (d, 19.5 Hz), 3.17−3.11 (m, 2H), 2.91 (br t, 1H, J = 11.8 Hz), 2.33 (dt, 1H, J = 13.9, 5.2 Hz), 1.95 (dd, 1H, J = 14.4, 3.1 Hz), 1.81 (d, J = 13.6 Hz), 1.25 (s, 3H) ppm; 13 C NMR (101 MHz, DMSO-d 6 ): δ = 203.1, 147.4, 142.0, 135.5, 132.6, 127.0, 125.3, 120.1, 114.9, 92.6, 80.9, 56.4, 54.9, 54.3, 51.6, 46.0, 40.8, 35.5, 32.9, 28.8, 27.0, 15.8 ppm; HRMS calcd for C 22 H 26 NO 4 [M + H] + , 368.1856; found, 368.1910. 17-Cyclopropylmethyl-4,5-epoxy-3,6-dimethoxy-7β-methyl-6,14-ethenomorphinan-7α-carboxaldehyde (11). 10•HCl (1.0 g, 2.721 × 10 −3 M) was dissolved in N,N-DMF; to this were added KHCO 3 (1.239 g, 0.123 M, 5.0 equiv) and CPMBr (0.50 g, 0.36 mL, 3.714 M, 1.5 equiv).…”

“…5 Generally, orvinols bind equally well to each of the three classical opioid receptors, MOR, kappa (KOR), and delta (DOR), with analogues showing different abilities to activate each opioid receptor type: for example, buprenorphine (1a) (MOR partial agonist and KOR/DOR antagonist), etorphine, and dihydroetorphine (2, 1b) (full agonists at MOR, KOR, and DOR) and diprenorphine (1c) (MOR antagonist and DOR/KOR partial agonist). 6 In veterinary practice, diprenorphine is a reversal agent (Revivon) for etorphine-induced immobilization, and 11 C-diprenorphine is utilized as a positron emission tomography imaging ligand for labeling opioid receptors in both preclinical and human clinical studies. Diprenorphine could be used as an improved overdose reversal agent due to its quick onset and its effectiveness in reversing fentanyl-and morphine-induced respiratory depression.…”

“…In our hands, attempting this method led to extensive polymerization and very low yields, but it did, in the case of methacrolein, provide some products with a favorable ratio of diastereomeric products. As the use of aqueous systems to promote Diels− Alder reactions is well known, 11 there seemed a reasonable possibility of improving these low yields. We have now found that there is a powerful aqueous solvent effect for this particular Diels−Alder reaction and that good yields (93% overall) and a far more favorable ratio of isomers can be obtained by carrying out the reaction in saturated brine at 80 °C (66% of C7β-Me 4b/33% C7α-Me 4a as determined by the ratio of aldehyde protons in 1 H NMR).…”

“…To access the N-cyclopropylmethyl series (Scheme 2), Ndemethylation of the Diels−Alder adduct (4b) followed by alkylation with cyclopropylmethyl bromide gave the key intermediate (11). Reduction afforded the 1°alcohol (12) with subsequent hydrogenation of the bridge and 3-Odemethylation, yielding 14.…”