Dihydroquinoline, substituted

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

Three tautomeric structures (1,2-dihydro 27, 1,4-dihydro 28, and 3,4-dihydro 29) are possible for N-unsubstituted dihydroquinolines, which retain the aromatic benzene ring, and two structures 27 and 28 for N-substituted derivatives. No information on the tautomerism of such dihydroquinolines and stability of the possible tautomers was available when the earlier review (76AHCS1) was published. 

The mechanism suggested earlier for the similar isomerization 34 35 involving the reaction of a 1,2-dihydroquinoline molecule with the starting quinolinium salt 33 (Scheme 11) is analogous to that of 4//-thiopyran isomerization discussed above (cf. Scheme 3) and is supported by deuterated substrate studies (85CJC412). Further support for this mechanism is the absence of such isomerization for 4-substituted derivatives such as 1,4-dimethyl-1,2-dihydroquinoline [94JCS(CC)287]. 

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 Skraup cyclization is another reaction principle that provides rapid access to the quinoline moiety. Theoclitou and Robinson have published the preparation of a 44-member library based on the 2,2,4-trisubstituted 1,2-dihydroquinoline scaffold by the Lewis acid-catalyzed cyclization of substituted anilines or aminoheterocyc-les with appropriate ketones (Scheme 6.237) [420], The best results were obtained using 10 mol% of scandium(III) triflate as a catalyst in acetonitrile as solvent at... 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

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. 

Reduction of quinolines in acid solution at a lead cathode or by dissolving zinc leads to attack on the heterocyclic ring with the formation of 4,4-coupled products, together with the tetrahydroquinoline [82,83]. In the case of 2- and 4-methyl substituted quinolines, dimeric products are obtained in 10 90 % yields. In these processes, dimerization of the one-electron addition product is in competition with further reduction to give the 1,4-dihydroquinoline, The latter is an enamine and it... 

A series of novel 4-substituted-l,4-dihydroquinolines 140 were prepared and found to exhibit moderate to excellent mammalian topo II inhibitory activity. Among the compounds prepared, in general, the nitrogen analogues are the most active compounds and the sulfur analogue is the least active one. The most potent analogue 140 (X=NH-2-pyridinyl), had a topo II potency nearly equivalent to VP-16, a clinically useful topo II interactive antitumor agent, q. (55) [197]. 

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... 

Substituted nitrosoalkenes, prepared in situ from corresponding a-bromo oximes, can be added to furan , pyrrole or indole to afford fused oxazine derivatives. Recently, there was reported a preparation of novel heterocyclic oxazinotetrahydroquinoline 355 and 356 or oxazinotetrahydroisoquinoline 357 derivatives by reaction of the corresponding dihydroquinolines or dihydroisoquinolines with a-bromo oximes 354 in the presence of NajCOj in CH2CI2 (equation... 

A reinvestigation of the experiments on the UV irradiation of l-acetyl-l,2-dihydroquinoline-2-carbonitriles (Reissert compounds) 561 unequivocally demonstrated that the rearrangement via the diradical intermediate 562 gave 4//-3,l-benzoxazines 563 and 565 rather than the benzazete derivatives described earlier. The yields and the type of products were strongly influenced by the substituent R at position 4 while irradiation of the unsubstituted quinoline 561 (R=H) gave 3,1-benzoxazine 563 in nearly quantitative yield, the amount of the corresponding methyl-substituted analog 565 that could be isolated was considerable lower, due to its irreversible isomerization via 562 to the stable cycloprop[/ ]indole derivative 564 (Scheme 107) <199811(49)121 >. 

A related reaction has been observed with alkenyl substituted 1,2-dihydroquinolines. Heating these compounds results in oxidation of the heterocycle with corresponding reduction of the double bond. A radical mechanism was also postulated to be operating in this reaction (equation 14) (75JOC2288). 

Ammonia or an amine can also be introduced between a terminal aldehyde or a ketone and a suitably placed double or triple bond, although the method is of limited use. A poor yield of 4-picoline is obtained when the aldehyde (262) is treated with ammonia or an ammonium salt (49JCS1430) and dihydroquinolines from the phenylethyl ketones (263) and hydroxylamine (76MI20800). More commonly, cyclization occurs by insertion of ammonia, amines or hydroxylamine between two triple or double bonds in the former case, pyrid-4-ones (264) are obtained (54BSF734) in the latter, a piperid-4-one (265) results (1897CB231). Amines have also been used to give N -substituted piperid-4-ones (70OMR(2)197>. In these cases a double 1,4-addition must be involved in the cyclization of the unsaturated nitrile... 

QUINAPHOS ligands are usually synthesized in a one-pot-procedure from readily available 8-substituted quinolines [8] via nucleophilic addition of a lithium reagent [9] to the azomethinic double bond and direct quenching of the resulting 1,2-dihydroquinoline amide 1 with a phosphorochloridite derived from enantio-merically pure binaphthol (1) or from 3,3 -di-t-butyl-5,5 -dimethoxybiphenyl-2,2 -diol (m) [10] (Scheme 2.1.5.1, Method A). Alternatively, the anion 1 can be reacted with an excess (in order to avoid multiple substitution) of phosphorous trichloride to obtain the corresponding phosphorous dichloridite 2, which can be isolated (Scheme 2.1.5.1, Method B). In a second step, 2 is converted into 4 by reaction with the desired diol in the presence of triethylamine. 

Table 8. Selected Examples of Sulfanyl-Substituted 4-Oxo-l,4-dihydroquinoline-3-carboxylic Acid Derivatives by Thiolation of the Respective Fluoro Derivatives3...

Azetidinones are also formed on photolysis of cis-a-phenyl-cinnamanilide (361), but in addition a small quantity of a cis-trans mixture of 3,4-diphenyl-3,4-dihydroquinolin-2-one (362) was obtained. The yield of quinolinone was considerably increased in the photocyclization of alkyl-substituted acrylanilides.389 The anilide (363) of tiglic acid, for example, was converted into the anilide (364) of angelic acid by photochemical cis-trans isomerism, and into a mixture of cis- and [Pg.103]

Substituted phenylisocyanide (34) can be used to make a dihydroquinoline compound, (35), (Scheme 23) <95CL575>. 

Intramolecular cyclization of fV-propargyl anilines in the presence of IC1 yields the dihydroquinoline, which is easily transformed into the fully saturated quinoline in high yield (Scheme 25) <20050L763>. This process was intentionally developed as a facile route to a variety of substituted quinolines. The use of iV-propargyl anilines in the presence of cuprous chloride yields the dihydroquinoline (Equation 55) <1995TL7721>. 

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>. 

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