Benzo quinolizine derivatives

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]. 

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-... 

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>. 

Many other synthetic benzo[a]quinolizine derivatives have been available, and the reader is referred to Popp and Watts (49) and to Saraf (49a) for recent reviews on these compounds. 

Attempts to achieve the thermal ring closure of the Meerwein salt 137 to the benzo[c]phenanthridine system failed the major product was the 4-acyliso-quinolinium salt 138 (79T1861). The reaction between )V-benzylaminoacetal-dehyde dialkyl acetals (139) with methyl vinyl ketone in acidic solution, leading to benzo[h]quinolizine derivatives, was newly investigated. The... 

The 1 H-doz.[ 13Jannulene (35) has been generated from the bicyclic precursor (36) by irradiation in acetone 31 the product is believed to have the stereochemistry represented in (36). l/f-Aza[13]annulene itself appears from n.m.r. studies to be endowed with significant aromatic character, whereas the A -acetyl and JV-methoxycarbonyl derivatives are not. The first 2J7-quinolizine derivative (37) has been described and is obtained along with other products by irradiation of the benzo[c]quinolizine (38) in benzene.32 The precise mechanism of this reaction... 

All substrates mentioned in the previous chapter easily undergo palladium-catalyzed aminocarbonylation also. It should be mentioned that even allylic carbonates instead of halides could be converted into carboxamides by this method, as it vas demonstrated during the total synthesis of antillatoxin [94]. The use of aryl chlorides is somewhat restricted owing to the low reactivity ofthese type of substrates in oxidative addition to palladium(O), as well as the competitive amination observed, for example, in the reaction of 1-chloroisoquinoline [95]. Functionalization of a great number of pharmaceutically important skeletons, for example, steroids [96-99], tropenes [100], benzodiazepines [101], indoles [102], benzo[c[quinolizine derivatives [103], and quinolones [104], have been carried out. 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

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). 

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). 

As in the earlier review1 this account will be restricted to the quinolizinium ion (1), the benzo[a]- (2), benzo [ft]- (3), and benzo[c]quinolizinium (4) ions, and to their derivatives. The quinolizones and compounds of similar structure (5) will be included, but the quinolizines (6 and 7) only where they appear as intermediates in synthesis or reaction. A number of trivial and unsystematic names have been used (pyridocolinium ion, dehydroquinolizinium ion for compound 1 acridizinium ion, 4u-azoniaanthracene for compound 3 phenanthridizinium ion for compounds 2 or 4), and numbering has also varied. Throughout this chapter the numbering will be as shown in formulas 1 to 4. 

In principle, most of the syntheses of quinolizones could be applied to the synthesis of benzoquinolizones by starting with the quinoline or isoquinoline equivalent of the pyridine component. Thus Kappe84 has obtained the hydroxybenzo[ ]quinolizin-4-ones 70, and the hydroxybenzo[c]quino-lizin-l-ones 71 from methylquinolines, quinolyl- or isoquinolylacetates, and malonic esters or carbon suboxide. Kato and co-workers37-38 have used the Vilsmeier derivatives of 2-quinolylacetate with diketene (Eq. 39)37 or with anhydrides (Eq. 40)38 to give benzo[e]quinolizin-l-ones. 

The arylenamide photocyclisation protocol continues to provide convenient access to intermediates of interest in alkaloid synthesis. Spirocyclic 5-lactam (55) has been prepared from cycloalkylenamide (54) and irradiation of enones (56) yields the corresponding spiroketones (57). Analogous photocyclisations have led to nitro-substituted berbine derivatives. The piperidine arylenamides (59) are efficiently photocyclised to the corresponding benzo[b]quinolizine-6-ones (60), providing convenient access to benzoquinolizidine derivatives. In contrast,... 

In a Robinson-type annelation, benzo[6]quinolizidinones (312) have been obtained by treatment of benzylamino derivatives (311) with methyl vinyl ketone in acid solution (Equation (39)) <83AJC149>. Three quinolizine bonds are also formed in the reaction between 2-silylated pyridines (313) and two equiv. of DMAD (Equation (40)) <83CB2564>. 

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