Benzo quinolizines

Benzo[//]quinolizine-2-carboxylic acids (1205) were also obtained in good yields by the cyclization of isopropylidene 1-tetrahydroquinolinyl-methylenemalonates (1204) by the action of polyphosphoric acid at 100-130°C for 0.5-1 hr [82BEP891046, 82BEP891537, 82JAP(K)2285, 82JAP(K) 16882 83JAP(K)90511],... 

A radical cyclization controlled by sulfur yields the tetrahydroisoquinoline (Equation 49) <1997J(P1)2291>. In the absence of the sulfur groups, only the reduced product is isolated. Further reactions that utilize radical cyclizations with vinylsulfides show a cascade reaction eventually forming the benzo[ ]quinolizine system <1999TL1149> (Equation 50). 

The Xr Scale. In 1964, Brooker and co-workers (346) suggested the use of the solvent induced bathochromic shifts of the 1,3 diethyl-5-[5-(2,3,6,7-tet-rahydro- 1H,5H- benzo- [(/]- quinolizin-9-yl)-l,3-neopentylene-2,4-pentadie-nylidene]-2-thiobarbituric acid (III) as measures of medium polarity. 

Most frequently used in these antagonism tests are reserpine and the benzo-quinolizine derivatives, tetrabenazine and Ro-4-1284. The latter 2 drugs have a more rapid onset of action and a more selective activity on the central nervous systems (CNS) than reserpine. Antagonism by test compounds of the induced hypothermia, ptosis (eyelid closure), miosis (decreased pupil diameter), and sedation is measured either separately or combined. Evidence has been presented [8] that hypothermia antagonism is a better indicator of CNS activity, as ptosis and miosis can be influenced also by drugs with a peripheral action [9]. 

The relative stereochemistry between the C(3) and C(18) stereocentres of the dodecahydroindolo[2,3-fl]benzo[ ]quinolizine skeleton of reserpine-type alkaloids has been reported from a highly torquoselective thermal triene 6k electrocyclization (Scheme 30)." ... 

In methanol, isoquinoline and the ester gave the benzo[fif]indolizine [(121), cf. Section II,D,3] while in ether the labile adduct, tetra-methyl llbH-benzo[a]quinolizine-l,2,3,4-tetracarboxylate (122) was obtained. The labile adduct is much less easily isoraerized than the 9-methyl-9aH-quinolizines derived from pyridines (Section III,F,1) but with boiling xylene or, better, with sulfuric-acetic acids the cor-... 

Chemical Name 9-Fluoro-6,7-dihydro-5-methyl-1-oxo-1 H,5H-benzo[i,j] quinolizine-2-carboxylic acid... 

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

CN 9-fluoro-6,7-dihydro-5-methyl-l-oxo-l/7,5//-benzo[y]quinolizine-2-carboxyiic acid... 

An example of this displacement between a pyridine nitrogen atom and an aryl halide is shown in Scheme 21. When 2-pyridyl acetates 138 were C-acylated with 2-halobenzoyl chlorides, the enolized products 139 resulting from the reaction suffered an intramolecular nucleophilic attack of the pyridine nitrogen atom onto the ipso-position to give benzo[c]quinolizinium salts 140 as intermediates. Loss of HC1 gas from 140 afforded benzo[c]quinolizine derivatives 141 <2002JOC2082>. 

A solution of (2,5-dimethyl-6-fluorotetrahydroquinolin-l-yl)methylene-malonate (130, R = F, R1 = Me) in toluene was added to boiling phospho-ryl chloride over a period of 2 hr, and the reaction mixture was then refluxed for another 1.5 hr to afford benzo[y]quinolizine-2-carboxylate (695, R = F, R1 = Me, R2 = Et) in 77% yield (87EUP245913). 

Optically active benzo[y]quinolizine-2-carboxylic acid (716, R = R2 = H, R1 = Me, R3 = F, R4 = Br) was prepared in the reaction of optically active 2-metyl-5-bromo-6-fluoro-l, 2,3,4-tetrahydroquinoline and EMME in polyphosphoric acid [88JAP(K)192753]. 

The ring closure of diethyl (benzo[/]quinolin-l-yl)methylenemalonate (148) was carried out by heating in polyphosphoric acid at 90-110°C to give ethyl naphtho[ 1,2,3-//]quinolizine-6-carboxylate (723) (84USP4456606). 

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) . 

S)-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-l//,5//-benzo[i,j]quinolizine-2-carboxylic acid 1-arginine salt tetrahydrate. 

As suggested by the title the principal emphasis in this chapter will be on the quinolizinium ion and its benzo analogs, with quinolizine and quinolizidine derivatives being mentioned only if they are obtained from, or transformed to, the aromatic species. For a more comprehensive treatment of these non-cationic species, the earlier reviews by Thyagarajan <65AHC(5)291> and by Mosby <61HC(15-2)1001> should be consulted. 

Although no 4-aminoquinolizinium derivatives are known, a benzo derivative, 6-amino-acridizinium ion (72 Scheme 50), has been prepared (67JOC733). In the presence of hydroxide ion the amino group loses a proton to form a benzo[6 ]quinolizin-6-imine (73). Alkaline hydrolysis opens the ring to give the amide (74). 

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. 

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