Dihydroquinolines, synthesis

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

A number of dihydroquinolines have been prepared by treating aniline derivatives with acetone or mesityl oxide in the presence of iodine. In these cases aromatization to the fully unsaturated quinoline would require the loss of methane, a process known as the Riehm quinoline synthesis. Such Skraup/Doebner-von Miller-type reactions are often low yielding due to large amounts of competing polymerization. For example, aniline 37 reacts with mesityl oxide to give dihydroquinolines 39, albeit in low yield. ... 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

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. 

The photocyclization of enamides to quinolines or isoquinolines has become an important reaction in the synthesis of alkaloids 219,358). It has recently been applied in the preparation of the isoquinoline alkaloid polycarpine 359). The principle of the reaction is demonstrated in the preparation of dihydroquinolines 360> (3.39) and of spirocyclohexaneisoquinoline derivatives (3.40) 361K In each case the electrocyclic ring closure product undergoes a subsequent 1,5-hydrogen shift. 

The synthesis, X-ray structure and solid state NMR of 4,4-dimethyl-l,2-ditellurolane 75 have been reported <98PS(136-8)291>. Chemoselective oxidation of 1,2-dithiole derivatives using dimethyldioxirane to give products such as 76 has been described <00SUL169>. Cycloaddition of dihydroquinoline-fused l,2-dithiole-3-thiones 77 with DMAD gives the spiro 1,3-dithioles 78 <99CHE587>. Dicationic thiatelluroles such as 79 have been prepared <00AG(E)1318>, anti cancer properties have been claimed for the simple dithiolopyrrolones... 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

Recendy, we found that A -allyl-o-vii rlaniline 44 gave 1,2-dihydroquinoline 45 by normal RCM and developed silyl enol ether-ene metathesis for the novel synthesis of 4-siloxy-1,2-dihydroquinoline and demonstrated a convenient entry to quinolines and 1,2,3,4-tetrahydroquinoline [13], We also have found a novel selective isomerization of terminal olefin to give the corresponding enamide 46 using rathenium carbene catalyst [Ru] and silyl enol ether [14], which represented a new synthetic route to a series of substituted indoles 47 [12], We also succeeded an unambiguous characterization of mthenium hydride complex [RuH] with ACheterocyclic carbene... 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

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... 

Bismuth triflate catalyzes the synthesis of 1,2-dihydroquinolines in an improved version of Skraup s procedure [74]. Accordingly, treatment of aniline with... 

Very recently, Fujii and Ohno developed a route for the synthesis of dihydroquinoline and chromene derivatives under mild reaction conditions. Hydroarylation leads to a highly selective formation of six-membered rings, depending on the carbon (terminal or central allenic) that reacts with the aryl moiety [50]. 

The synthesis of CMDBSSu involves the random carboxymethylation of hydroxyl groups on the glucose units, the benzylamidation of some of the carboxylic groups with benzylamine in the presence of N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ) to carboxymethyl dextran benzylamide (CMDB), the sulfonation of phenyl rings and sulfation of remaining hydroxyl groups at the polymer backbone (Fig. 39, [108,222]). 

The use of Sc(OTf)3 as the catalyst facilitated the Skraup synthesis of 1,2-dihydroquinolines from anilines and a variety of dialkyl ketones at mild conditions (room temperature). Nevertheless, an elevated temperature was necessary if acetophenone was employed in the cyclo condensation with anilines [109]. Microwave dielectric heating at 150 °C for 50 min was sufficient to bring about the formation of the desired 1,2-dihydroisoquinolines (Scheme 40). 

Scheme 40 Microwave-promoted Skraup synthesis of 1,2-dihydroquinolines...

An intramolecular cyclization of iV-anilino- and iV-benzyl-substituted propargyl trimethylsilyl ethers with Lewis acid catalysis provides the quinolines and isoquinolines, respectively <20040L2361>. An intramolecular aza-Diels-Alder reaction has been used as a key step in the synthesis of luotonin (Scheme 69) <20040L4913>. An analogous reaction afforded the dihydroquinoline as a single diastereomer (Equation 132) <2000TL5715>. 

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... 

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