Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis.






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Figure 1


Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.

Chemistry and Biology Of Multicomponent Reactions

Multicomponent reactions: advanced tools for sustainable organic synthesis

2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041

Ionic liquids in heterocyclic synthesis.

A Renaissance in Living Cationic Polymerization

The development of efficient Friedel–Crafts alkylations of arenes and heteroarenes using only catalytic amounts of a Lewis acid has gained much attention over the last decade. The new catalytic approaches described in this review are favoured over classical Friedel–Crafts conditions as benzyl-, propargyl- and allyl alcohols, or styrenes, can be used instead of toxic benzyl halides. Additionally, only low catalyst loadings are needed to provide a wide range of products. Following a short introduction about the origin and classical definition of the Friedel–Crafts reaction, the review will describe the different environmentally benign substrates which can be applied today as an approach towards greener processes. Additionally, the first diastereoselective and enantioselective Friedel–Crafts-type alkylations will be highlighted.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-6-6.pdf

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

The combination of a secondary benzyl alcohol and a metal triflate (e.g., La, Yb, Sc, and Hf triflate) in nitromethane was a highly effective secondary-benzylation system. Secondary benzylation of carbon (aromatic compounds, olefins, an enol acetate), nitrogen (amide derivatives), and oxygen (alcohols) nucleophiles was carried out with a secondary benzyl alcohol and 0.01−1 mol % of a metal triflate in the presence of water. Secondary benzyl alcohols and nucleophiles bearing acid-sensitive functional groups (e.g., tert-butyldimethylsilyloxy and acetoxy groups and methyl and benzyl esters) could be used for alkylation. Hf(OTf)4 was the most active catalyst for this alkylation, and trifluoromethanesulfonic acid (triflic acid, TfOH) was also a good catalyst. The catalytic activity of metal triflates and TfOH increased in the order La(OTf)3 < Yb(OTf)3 < TfOH < Sc(OTf)3 < Hf(OTf)4. A mechanistic study was also performed. The reaction of 1-phenylethanol (4a) in the presence of Sc(OTf)3 in nitromethane gave an eq...

Secondary benzylation using benzyl alcohols catalyzed by lanthanoid, scandium, and hafnium triflate

The rare earth metal and hafnium triflate-catalyzed secondary benzylation and allylation of 1,3-diketones, ketoesters, and ketoamides are described. The procedure was carried out under non-anhydrous conditions. Various 1-phenylethyl cations were generated from substituted 1-phenylethanols using 0.5 mol % of the metal triflates in CH3NO2. The cations reacted with 1,3-diketones and ketoesters to give benzylated products in high yields. Following the GC analysis, the reaction conditions were easily optimized by the selection of catalysts based on the Lewis acidity of the triflates and reaction temperature. A tertiary-alkylated diketone and a corresponding ketoester were also benzylated to afford products with a quaternary carbon atom in 57-84% yield. The ketoamide reactions required stronger Lewis acids than those used in the diketone and ketoester reactions. The reactions of benzylic alcohols possessing various substituents on the aromatic ring and dibenzoylmethane (2b) as a diketone were examined in the presence of Hf(OTf)4. Electron-rich benzylic alcohols reacted with 2b in 86-96% yield, and electron-deficient alcohol gave the desired product in 79-65% yield. Despite possessing a strong electron-withdrawing group, the reaction of 1-(4-nitrophenyl)ethanol gave the corresponding product in 61% yield. It was also possible to use allylic alcohols directly for the allylation of diketone 2b. The catalyst can be recovered by water extraction and reused up to five times.

Metal Triflate-Catalyzed Cationic Benzylation and Allylation of 1,3-Dicarbonyl Compounds

A convenient synthesis of immunosuppressive agent FTY720 (1) using the Petasis reaction was developed. 4-Octylbenzaldehyde (9) was converted into 1-ethenyl-4-octylbenzene (11) by two-step synthesis. Hydroboration of 11 using catecholborane and hydrolysis gave (E)-2-(4-octylphenyl)vinylboronic acid (4). The Petasis reaction of 4, dihydroxyacetone (3), and benzylamine following catalytic hydrogenation afforded FTY720 (1).

/pdf/a-convenient-synthesis-of-immunosuppressive-agent-fty720-5d7jpxe3gh.pdf

A convenient synthesis of immunosuppressive agent FTY720 using the petasis reaction.

Both enantiomers of cytoxazone, (−)- 1 and (+)- 1 , were synthesized using the Petasis reaction of dl -glyceraldehyde 2 , 4-methoxyphenylboronic acid 3 and ( R )-1-(1-naphthyl)ethylamine 7 , following formation of an oxazolidin-2-one ring.

Short synthesis of both enantiomers of cytoxazone using the Petasis reaction

A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6 ± 2.0 μM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, S1P1 selective agonists, did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway.

Keitaro Ishii

Papers

Secondary benzylation using benzyl alcohols catalyzed by lanthanoid, scandium, and hafnium triflate

Metal Triflate-Catalyzed Cationic Benzylation and Allylation of 1,3-Dicarbonyl Compounds

A convenient synthesis of immunosuppressive agent FTY720 using the petasis reaction.

Short synthesis of both enantiomers of cytoxazone using the Petasis reaction

Non-phosphorylated FTY720 Induces Apoptosis of Human Microglia by Activating SREBP2