2//-Quinolizin-2-ones

Dipolar addition of pyridinium dicyanomethanide to 2,3-diphenylcyclopropenone in refluxing acetonitrile produced, with elimination of hydrogen cyanide, the 2//-quinolizin-2-one 4 in 58% yield. ... 

Some variations on the above scheme have also been successfully adapted to the synthesis of other related quinolizines. One of these involves the condensation ofpyridine-2-aldehyde with deoxybenzoin13 followed by quatemization with phenacyl halides and cyclization by treatment with dibutylamine [Eq. (4)]. 

Quinolizinium salts, 2,4,6-trimethyl-condensation reactions, 2, 539 Quinolizinones reactions, 2, 544 synthesis, 2, 567 Quinolizinones, nitro-synthesis, 2, 568 Quinolizin-4-ones nitration, 2, 529 synthesis, 2, 565 2,2 -Quinolyl... 

A further application of the Dieckmann cyclization is that leading to the synthesis of 3,4,6,12-tetrahydro-l(2jE )-indolo[2,3-6]quinolizin-l-one (398). ... 

Chemical Name 1,3,4,6,7,11 b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo-[a] quinolizin-2-one... 

Hexahydro-3(2//)-indolizinones and Octahydro-4//-quinolizin-4-ones General Procedure9111 ... 

The previously mentioned series of alkyl derivatives of tetramethyl quinolizine-l,2,3,4-tetracarboxylate, which is present as mixtures of the 4H- and 9aH- tautomers 17 and 18, was studied by 5N NMR, both experimentally and using ab initio calculations. The data are collected in Table 4. The ab initio 1SN NMR chemical shifts reproduce well the trends observed in the experimental data, but their values are ca. 72 ppm smaller than the experimental ones <2003JST719>. 

The C/C double bonds in the quinolizine system can be reduced by catalytic hydrogenation. One example, involving the transformation of an indolo[2,3- ]quinolizidine substrate 76 into compound 77, can be found in... 

Another approach to a fused quinolizine system 363 through the generation of a,7-bonds in the key step is the reaction between 2-cyanomethylpyridine and 6-ary l-3-cy ano l-methy 1th io-2//-pyran-2-one 361 under basic conditions (Scheme 82). This process involves the initial displacement of the methylthio group by the 2-cyanomethylpyridine anion to give intermediate 362, followed by base-induced cyclization onto the nitrile group <1999S1884>. 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

Dipolar cycloaddition of pyrido[2,l-A][l,3]thiazinium betaine 507 (R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 508, from which quinolizin-4-one 509 formed by a rapid cheletropic extrusion of COS (Scheme 53) <1995T6651>. 1,4-Dipolar cycloaddition of 507 and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 511 (via 510) <1995H(41)1631> and 512 <1995T6651>. 

In a similar manner, pyrano[4,3-A]quinolizines 88 can be synthesized starting with substituted pyran-2-ones 87 (Scheme 5) <1999S1884>. 

Danieli et al. 116), both of which utilize an alkylation process of 1-methyl-3,4-dihydro-(3-carboline (150) in the key ring-forming step. In the first one, treatment of 150 with a-methylene- y-butyrolactone gave enamide 172, which, when reduced with lithium aluminum hydride, afforded indolo[2,3-a]quinolizine derivative 173. The desired ethylidene substituent at C-20 has been developed from the hydroxyethyl side chain in a four-step sequence as shown below. 

Kametani and his collaborators presented two different approaches for the synthesis of ( )-yohimbine and ( )-p-yohimbine 223-226). The first one (223, 224) utilizes Stork s method for the Robinson reaction of the enamine derived from octahydroindolo[2,3-a]quinolizin-2-one (414) to produce 15,16-didehydroyohimbinone (410), prepared first by Szantay et al. (74, 221). 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

Z- and ii-oximes of benzo[a]quinolizin-2-ones 396 and 397 were converted into isomeric diazepinoisoquinolines 398 and 399, respectively, by treatment with TsCl and NaiCOs in acetone (equation 173) . 

Nitration of 1-hydroxyquinolizinium nitrate affords only a 31% yield of the betaine nitrated at the 2-position (64JCS3030). With quinolizin-4-one (14), which may be regarded as the betaine of 4-hydroxyquinolizinium ion, nitration in acetic acid at room temperature gives a 43% yield of 1,3-dinitroquinolizone. Only by use of cupric nitrate in acetic anhydride is there some mononitration (a mixture of 1- and 3-isomers), but here again the major product is the dinitro compound (64T1051). 

Hydroxyquinolizinium ion can be converted to quinolizin-2-one (77) by the action of K2CO3 (64JCS2760). PBr3 converts (77) to 2-bromoquinolizinium ion (78), while P2S5 affords quinolizine-2-thione (79) which was not purified but converted into 2-methyI-thioquinolizinium iodide (80). 

Quinolizin-4-one has proved to be a more valuable intermediate (Scheme 55) than its 2-isomer. Conversion to quinolizin-4-thione (81) (51JA3681), 4-chloroquinolizinium perchlorate (82) (63JOC1022) and 4-bromoquinolizinium bromide (83) (81H(15)213) can be accomplished. 

The reduction of a crude 4-chlorobenzo[a]quinolizinium salt by action of zinc and acetic acid made possible the transformation of benzo[a]quinolizin-4-one to benzo[a]quin-olizinium perchlorate (2) in an overall yield of 75.5% (Scheme 63) (77JOC1122). 

In a reinvestigation of earlier work (33LA(505)103) by Diels and Alder, Acheson et al. (60JCS1691) established that the stable isomer obtained by addition of two moles of dimethyl acetylenedicarboxylate to one of pyridine was the 4/7-quinolizine (96) and that this with bromine was oxidized to a quinolizinium salt (97 Scheme 65). 4iT-Quinolizines obtained from isoquinoline (62JCS748) and phenanthridine (63JCS3888) were similarly aromatized to afford benzo[a]quinolizinium (98) and dibenzo[a,c]quinolizinium ions (99) respectively. 

Another related photocyclodehydrogenation synthesis uses an N- styrylpyridinone (164 Scheme 92), which is generated by N- alkylation of pyridinone with a styryl bromide. Irradiation in acid solution in the presence of oxygen causes isomerization and cyclodehydrogenation to afford 4//-benzo[a]quinolizin-4-one (165) and its 7-phenyl derivative (166) in yields of 37% and 60% respectively (77JOC1122). 

Another type of [5 +1] reaction leading to the synthesis of an (in effect) quinolizin-4-one (198, Scheme 105) involves the concurrent replacement of the oxygen atom of a 2-benzopyrylium salt (197) by nitrogen (from ammonia), and cyclization (77CHE1183). 

Ethoxy-l-azaquinolizinium tetrafluoroborate (245), prepared by the action of triethyl-oxonium tetrafluoroborate on l-azaquinolizin-2-one (238), undergoes nucleophilic displacement by m -nitrobenzoylhydrazine (Scheme 121) to afford a l-aza-2H-quinolizine derivative (246), useful as a dye intermediate (61LA(640)98). 

One of the significant developments in the chemistry of the quinolizines since 1954 was the synthesis of the parent aromatic system, the quinolizinium ion, which was unknown until then. This was achieved by Boekelheide and Gall2 by the condensation of 2-picolyllithium with /3-cthoxypropionaldehyde followed by the steps indicated in the sequence 2 - 3 -> 4 -> 1. 

Mesoionic pyrido[2,l- >][1,3]oxazines (54) afforded 4-oxo-4//-pyrido[l,2-a]pyrimidin-l-iumolates (55) and 4//-quinolizin-4-one (56) with phenyl iso(thio)cyanates [78LA1655 79CB1585 82ZN(B)222] and dimethyl acetylenedicarboxylate (79CB1585), respectively. Reaction of 2-cyano-3-methyl-lH,6//-pyridol[l,2-a][3,l]benzoxazine-l,6-dione with ammonium acetate and hydroxylamine, hydrazines, primary aliphatic or aromatic amines, and (thio)ureas gave 5-unsubstituted and 5-substituted 2-cyano-3-methyl-l//,6H-pyrido[l,2-a]quinazoline-l,6-diones (93CCC1953). 

Dipolar cycloaddition of 1,1-dimethoxyethene to the mesoionic pyrido[2,l-6][l,3]oxazoline 59 gave the adduct 60.The similar reaction with 61 afforded quinazolin-4-one (62). When 1-dimethylamino-l-methoxyeth-ylene was applied in the latter reaction, a mixture of quinolizin-4-one (63) and the ring-opened product 64 was obtained (88CB951). 

Dipolar cycloaddition of anhydro pyrido[2,l-b][l,3]thiazinium hydroxides (128) with aryl isocyanates and dimethyl acetylenedicarboxylate gave pyrido[l,2]pyrimidines (129) and quinolizine-l,2-dicarboxylates (130), respectively (76CB3668). 1,4-Dipolar cycloaddition of pyrido[2,l-h][l,3]thi-azinium betaine (131, R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 132, from which quinolizin-4-one 133 formed by a rapid cheletropic extrusion of carbonyl sulfide (93TL5405 95T6651). 1,4-Dipolar cycloaddition of anhydro 4-hydroxyl-2-oxo-6,7,8,9-tetrahydro-2//-pyrido-[2,l-b][l,3]thiazinium hydroxides (131) and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 135 via 134 [94H(39)219 95H(41)1631] and 136 (95T6651). 

Formation of the imine and subsequent reduction can often be achieved in one pot . Thus, a microwave-assisted reductive amination-cyclisation domino reaction was used as the key step in the synthesis of perhydrocyclo-penta[ij]quinolizines from 1,5,9-triketones. This type of heterocycle is an important structural element in a series of alkaloids. The reaction of the triketone with ammonium formate in PEG-200 was performed within 1 min using microwave irradiation of370 W in a domestic microwave oven. Amixture oftwo ofthree possible stereoisomers was obtained in 87% overall yield (Scheme 4.29)52. 

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