7.8 dihydroquinolin 5 ones synthesis

An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a, (3-unsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. 

Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RE, Djuric SW (2007) Synthesis of substituted 3,4-dihydroquinolin-2(lH)-one derivatives by sequential Ugi/acrylanilide [6pi]-photocyclizations. Tetrahedron Lett 48 3549-3552... 

Photocyclization of acrylanilide 21 to 3,4-dihydroquinolin-2(l//)-one 22 was applied in alkaloid synthesis, but enantiocontrol was unsuccessful in solution [46]. Solid-state photolysis of 21 in the 1 1 inclusion complexes with optically active host compounds 6a-c gave 22 in almost perfect optical yields (Scheme 5) [34,47]. X-ray crystallographic analysis revealed that the configuration of the photocyclization products depended on slightly different lattice structures, which were controlled by the host molecules. 

Nakamura T, Hara O, Tamura T, Makino K, Hamada Y (2005) A facile synthesis of chroman-4-ones and 2,3-dihydroquinolin-4-ones with quaternary carbon using intramolecular Stetter reaction catalyzed by thiazolium salt. Synlett 2005 155-157... 

The development and use of environmentally friendly methods for the synthesis of quinolines and dihydroquinolines were represented in variety of publications in 2006. Many of the reports incorporated solvent free conditions. Perumal et al. showed that silica-supported NaHSO as a heterogeneous catalyst for the cyclization of 2-amino-chalcones 71 under solvent free microwave conditions results in a variety of 2,3-dihydroquinolin-4-ones 72 in high yields <06CJC1079>. Lier et al. also utilized a silica supported TaBrs catalyst to cyclize 2-amino-chalcones 71 forming a variety of 2,3-dihydroquinolin-4-ones 72 under solvent free thermal conditions <06TL2725>. The use of silica gel supported TaBrs under solvent free thermal conditions showed considerable improvement in yield for this cyclization compared to the reaction conducted in organic solvents. 

Cilostazol has been used to treat intermittent claudication in individuals widi peripheral vascular disease. A similar molecule as cilostazol may have the risk of death in patients with congestive heart failure. The synthesis of cilostazol contains a 1,3-dipolar addition for the construction of the tetrazole ring, and the resulting tetrazole was coupled with 6-hydroxy-3,4-dihydroquinolin-2(l//)-one with the aide of potassium hydroxide. ... 

This reaction was initially reported by Reissert in 1905 and extended by Grosheintz and Fischer in 1941 It is the synthesis of aldehyde involving the formation of 1 -acyl-2-cyano-1,2-dihydroquinoline derivatives from acyl chlorides, quinoline, and potassium cyanide and the subsequent hydrolysis of said dihydroquinoline derivatives under acidic conditions to produce quinaldic acid and aldehydes. The original procedure occurs smoothly for aroyl or cinnamoyl chloride in liquid SO2 but not in benzonitrile, ether, dioxane, acetone, or CHCb. However, the modification from Grosheintz and Fischer using hydrogen cyanide and 2 eq. quinoline in absolute benzene is also adaptable for aliphatic acid chlorides. This is one of the methods that converts acyl chlorides into aldehydes and is found to be superior to the normal Rosenmund Reduction. For example, o-nitrobenzoyl chloride has been converted into o-nitrobenzaldehyde in 60% yield by the current reaction, whereas the Rosenmund Reduction is not suitable for such conversion. Therefore, this reaction is referred to as the Grosheintz-Fischer-Reissert aldehyde synthesis or Reissert aldehyde synthesis. ... 

At the University of Ottawa the work of L. Benoiton and his students, especially F.M.F. Chen, gained major importance in the study of racemization during peptide synthesis. The loss of chiral purity in activated AT-methylamino acids is one of their numerous contributions. l-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), the coupling reagent mentioned on page 91 was introduced in 1968 by B. Belleau and Malek at Ottawa. 

The group of Nakagawa reported the synthesis of quinoline 71 from N-allyl o-aminostyrenes 69 by using an RCM approach. Attempted deprotection of the dihydroquinolines 70 resulted in quinolone 71 (Scheme 20). Only one example was described, in quantitative yield (01TL8029). 

Dione 112 was obtained from 10 (Jones oxidation, 56%), 11 (Se02 oxidation, 42%), and 113 (ozonolysis, 63%). One-pot synthesis of 26 from 10 is devised also [277]. Intramolecular hetero Diels-Alder (Povarov) approach has been developed by Twin and Batey [280]. Intramolecular Povarov reaction between aldehyde precursor 116 prepared from acetate 115 with aniline under the shown conditions afforded 26 in 51% yield presumably after in situ oxidation of the initially formed 1,2-dihydroquinoline (Scheme 27). 

Silica gel-supported TaBrj is an efficient catalyst for the synthesis of 2-aryl-2,3-dihydroquinolin-4(lH)-ones. The reaction takes place under solvent-free conditions for the easy and efficient isomerization of 20-aminochalcones to the corresponding 2-aryl-2,3-dihydroquinolin-4(lH)-ones (Scheme 6.36). The catalyst is easily prepared, stable, and employed under environmentally friendly conditions. The salient features of TaBrj impregnated on silica gel are rapid reaction rates, the absence of unwanted products, and improved and operational simplicity under conventional heating. This procedure has several advantages over earlier-reported features such as simplicity, fast and clean reactions, high yield, and the absence of an organic solvent (Ahmed and van Tier, 2006). 

Bose et al. were also able to successfully achieve the microwave-assisted synthesis of quinoline (72) and dihydroquinoline (73) derivative under solvent-free condition via Skraup synthesis. They demonstrated that 25 mol% of KjCoW,20 q (PDTC) was effective for one-pot reaction of aniline with alkyl vinyl ketones as shown in Scheme 6.28. This reagent was also demonstrated to be an effective catalyst for the Friedlander synthesis [67]. 

Most recently, Komiyama et al. [233] applied an oxo-tethered ruthenium(ll) complex for an efficient and scalable enantioselective synthesis of the intermediate for a p2-adrenergic receptor antagonist. The intermediate, (/f)-2-amino-l-oxyethyl-l,2-dihydroquinolin-2-one derivative, was obtained with 71 % yield and 98.6 % ee on large-scale production. 

In addition to the active esters, symmetrical anhydrides (Wieland et al., 1971) and EEDQ (N-ethoxycarbonyl- 2- ethoxy-1,2-dihydroquinoline) (Yajima and Kawatani, 1971 Sipos and Gaston, 1973) have been used for coupling of successive amino acids in solid-phase synthesis. The combination of two polymers—one, a linear polymer carrier and the other an insoluble acylating reagent—has also been tried (Heusel et aL 1977). 

Stereoselective multi-steps synthesis of fluorinated 2,3-dihydroquinolin (lH)-ones proceeding as a one-pot transformation has been described [50]. The Ts-protected 0-(2-anilino)- 0-ketoesters 75 are capable of reacting with a variety of aldehydes under mild conditions to form fluorinated quinolines 76 in good yields (up to 98 %) and high diastereo selectivities (dr up to 99 1) (Scheme 30). The compounds 76 are considered as versatile synthetic intermediates, and, indeed, they can be transformed into functionalized heterocyclic derivatives. For example, decarboxylation of compounds 76 results in the formation of 3-fluoroquinolines 77, while reduction with NaBH4 affords a-fluoro-)3-hydroxy esters 78. 

A ruthenium-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of indolin-2-ones and 3,4 dihydroquinolin-2-ones was disclosed by Chang and coworkers (Eq. (7.3)) [8]. The reactions underwent smoothly without requiring external CO atmosphere. In the presence of combined catalysts of Ru3(CO)i2/Bu4NI, a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yields in DMSO/toluene cosolvent (catalytic system A). When the reaction was conducted in the absence of halide additives in NAf-diniethylacetamide (DMA)/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yields via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. 

Saito A, Kasai J, Odaira Y, Fukaya H, Hanzawa Y. Synthesis of 2,3-dihydroquinolin-4(lJS)-ones through catalytic metathesis of o-alkynylanilines and aldehydes. J. Org. Chem. 2009 74 5644-5647. 

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