1- Alkyl-l,4-dihydro

Koga, H., Itoh, A., Murayama, S., Suzue, S., Irikura, T. Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acids. 7. Med. Chem. 1980, 23, 1358-1363. 

Tire and NMR parameters of some 1-alkyl-4-benzimidazolyl-2-idene- (type 72) and l-alkyl-4-(5-methylpyrazolyl-3-idene)-l,4-dihydro pyridines (type 73) were discussed in 89CC1086 and 91JOC4223. Comparison of the shifts for DMSO-dg and CDCI3 solutions with data reported for quaternary pyridinium compounds as well as anionic species in the azole series and data obtained for mesoionic betaines of the azinium azolate class left no doubt that these heterofulvalenes have a betaine character and, therefore, the NMR signals correspond to their dipolar resonance form. 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Azomethine ylides such as 412 react with triafulvenes again by analogy with cyclopropenones. (3 + 2) Cycloaddition of the 1,3-dipole to the CVC2 bond and subsequent loss of C02 produces l,4-dihydro-4-methylene-N-alkyl pyridines 559, which as merocyanines show marked solvatochromic and thermochromic effects260. ... 

The second method is advantageous over the Gould-Jacobs method with respect to (a) the cyclization step which proceeds smoothly under mild conditions (b) one-pot synthesis of the 1-substituted derivatives and bypassing the alkylation/arylation of the Ni-position of l,4-dihydro-4-oxoquinoline-3-carboxylate, which usually gives rise to mixed N1/O4-substituted products and (c) product versatility due to the ability to utilize a wide range of alkyl-and arylamines in the step before cyclization. 

The mass spectra of a number of 3-aryl-3,4-dihydro-4-imino-l,2,3-benzotriazines (172) have been recorded and found to be similar to those of 1,2,3-benzotriazinones, i.e., initial fragmentation with loss of nitrogen. 3-Alkyl-3,4-dihydro-4-arylimino-l,2,3-benzotriazines show an... 

Almost complete retention of chirality was achieved in the alkylations of l-propionyl-l,4-dihydro-2//-3,1-benz-oxazines 242 bearing a stereogenic center in the substituent at position 2 (TBDPS = /< rt-butyldiphenylsilyl, KHMDS = potassium hexamethyldisilazide). The alkylations took place with high de s (70-92%) in favor of isomers 243, isolated after chromatographic separation. The allyl-substituted compound 243 (R = allyl) was reduced with LAH to yield the enantiopure (R)-3-methylpent-4-en-l-ol 244 and the N-unsubstituted 3,1-benzoxazine 245 as a 5 1 diastereomeric mixture (Scheme 45) <2000JOC6540>. 

Dioxo-l,4,7,10-tetrahydro-l,10-phenanthroline (72) with dimethyl sulfate gives l,4-dihydro-7-methoxy-l-methyl-4-oxo- 1,10-phenanthroline (73) rather than a quaternary salt, steric hindrance presumably preventing alkylation of both nitrogens.203 A related alkylation has also been reported.295 1,2,3,4-Tetrahydro-1,10-phenanthrolines similarly form 1-alkyl derivatives rather than 10-alkyl quaternary salts with alkyl halides.38 The rate of methylation of 1,10-phenanthroline with methyl iodide in dimethyl sulfoxide has been studied,296 and the polaro-graphic reduction of 1 -methyl- 1,10-phenanthrolinium iodide was reported.286... 

Typical 1,3-dipolar cycloreversion is found for the decomposition of alkyl-substituted 2-tetrazolines (43) (88CB1213), l,4-dihydro-l,2,3,4-tetrazol-5-ones (44), and -thiones (45) (97JHC113). For these reactions two paths are possible that can be distinguished when the substituents on N-l and N-4 are different. For 2-tetrazolines ring contraction leading to diaziridines is also possible (discussed earlier). Cycloreversion of 43 yields imines and azides (88CB1213). 

The a-hydrogens of 2,4,6-trialkyl-1,3,5-triazines are readily chlorinated or brominated in the presence of acid. The reaction is believed to occur via an ionic mechanism. The final products using an excess of chlorine or bromine are strongly dependent on the reaction conditions used (Scheme 19) (64JOC1527). 2-Alkyl-l,2-dihydro-l,3,5-triazines (36) may be rearranged in good yields to pyrimidines (Scheme 20) (79TL1241). 

Two different types of coupling processes have been cited for pyridine. The first involves the carboxylation and subsequent alkylation of the carboxylate salt to form the 1,4-dihydro-1,4-dicarboxyalkyl product (6). Reductive carboxylation of 2,2 -bipyridyl (1) followed a slightly different pathway, giving the l,4-dihydro-4,5-dicarboxyethyl product (7).36 Apparently, steric factors favor electrophilic attack on the / carbon. 

Regioselective lithiation.1 This complex undergoes selective lithiation at the orf/io-position, which can be trapped by methylation to give (2-methylpyridine)tri-carbonylchromium. The disilyl complex 2 undergoes selective lithiation at C4 because of steric effects. Reduction (DIBAH) of 1 provides (l,2-dihydro-pyridine)tri-carbonylchromium (3) after quenching (MeOH). Reaction of 1 with RLi followed by alkylation with CH3I provides the complex 4. 

The ability to overcome MDR in many 1,4-DHPs varies considerably with the nature of the 3,5-substituents. The pyridylalkyl esters are specially suitable, as in the case of NIK-250 (46) [82,83] related derivatives bearing dihydro-1,4-dioxene, dihydro-1,4-dithiane or dihydropyran substituents at C-4 [84]. Other representatives of this group that contain an alkyl group at C-4 (19 (47)) have also shown potent and selective anti-MDR activity [85]. Compounds PAK-200 (48) [86,87] and PAK 104P (49) [88] exemplify the absence of correlation between calcium channel and MDR antagonism, since neither N-alkyl-l,4-DIIPs nor pyridines have significant calcium channel-blocking activity. 

Heald repeated the same reduction of 6-nitroquinoline (147) at a higher temperature and isolated 1-ethyl-l,2-dihydro-6-nitroquinoline (148), the product of reductive alkylation. With quinoline and NBH in carboxylic acids the Aralkyl-1,2,3,4-tetrahydroquinoline 149 is obtained. Use of sodium cyanoborohydride gives reduction but no alkylation (150). In the presence of acetone, l-isopropyl-l,2,3,4-tetrahydroquinoline (151) is the predominant compound. Quinoline W-oxides undergo deoxygenation, and some ring reduction with NBH. ... 

The reaction of 3-benzoyl- (or 3-acetyl) -4-hydroxy-2//-1,2-benzothiazine 1,1-dioxide (89) with hydrazine to produce pyrazolo[4,3-c][l,2]benzothia-zine 5,5-dioxide derivatives was discussed in Section II,B,1 (See Eq. 22). Steiner141 recently reacted 3-acetyl-1,2-benzothiazines (196) with alkyl-substituted hydrazines the hydrazones (197) were usually not isolated but cyclized directly to l-substituted-l,4-dihydro-3-methylpyrazolo[4,3-c][l,2]-benzothiazine 5,5-dioxides (198) (Eq. 44). 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

Bei den nicht mehr aromatischen 2-Oxo-l-alkyl-l,2-dihydro-pyridinen tritt diese [4 + 4]-Cycloaddition bereits in konzentrierter alkoholischer oder waCriger Losung ein2>3-5. Aus 2-Oxo-l-methyl-1,2-dihydro-pyridin (IV) entsteht durch Belichtung 4,S-Dio w-3,7-dimethyl-3,7-diaza-tricydo[4.2.2.2 l dodecadien- 9,ll) (V 43% d.Th. F 222-222,5°) ... 

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