Quinolizines. IX. The Properties of 3-Hydroxyquinolizinium Salts¹

Abstract

3-Hydroxyquinolieinium salts are readily brominated to give Pbromo-3-hydroxyquinolizinium salts (3).The conversion of the 4-bromo3-hydroxyquinolizinium salts to 3-hydroxy-Lquinolizone ( 5 ) and the preparation of two quinolizinium phenol betaines 9 and 10 are described. I n previouswe have reported the synthesis and properties of I-and of 2-hydroxyquinolizinium salts. As expected, the 1-hydroxyquinolieinium salts were phenolic and underwent electrophilic substitution in position 2, l t 2 while the 2-hydroxyquinolizinium salts behaved more as quinolizones, as has been reported also for the 4-hydroxy ~e r i e s .~ Electrophilic substitution occurs in all three hydroxyquinolieinium salts1-3p5 with an ease surprising in a system carrying an over-all positive charge. In the reactions of the Z-hydroxyquinoliziniuni salts, no electrophilic substitution was observed in the 3-position (behaviour reminiscent of naphthalenes or isoquinolines) and the 3-hydroxyquinolizinium salts represent an interesting case where the ''naphthalene" pattern of substitution requires the electrophile to attack the position of expected lower electron density (position 4). I n fact, as is shown below, the site of bromination is position 4 and the "naphthalene" pattern is preserved.The synthesis of 3-hydroxyquinolizinium bromide (2, X = Br) from the diethyl acetal (1, R = C2H5) has been briefly reported16 but no yield was recorded, We have obtained the 3-hydroxyquinolizinium bromide (2, X = Br) from the dioxolane (1, R = -CH2-) in 96% yield, giving 76% over-all yield from 2-(2-pyridyl)-l13-dioxolane, and have also prepared the picrate and nitrate.7 The 3-hydroxyquinoliziniuni bromide (2) reacted readily with bromine in hydrobromic acid to give an 80% yield of a bromohydroxyquinolizinium bromide subsequently shown to have structure 3 (X = Br). This bromohydroxyquinolizinium salt reacted with silver acetate in hot acetic acid to give 3,4-dihydroxyquinoliziniuni bromide (4) , presumably via the unstable 3-hydroxy-4-acetoxy derivative. Unlike the previously reported 1,Bdihydroxyquinolizinium salt2 the 3,4-dihydroxyquinolizinium bromide was hydrolyzed by water, losing a proton to give 3-hydroxy-4-quinolizone (5) insoluble in water, but soluble in (1) For part VI11 of this series, see A. Fozard and G. Jones. (7) Professor C. K. Bradsher has informed us that he has obtained 3-hydroxyquinoliainium bromide in 48% over-all yield by a similar route, but has made no attempt t o isolate the intermediate quaternary pyridinium salt. 3030 (1964). organic solvents. The quinolizone 5 showed strong absorption a t 3424 cm. -l (intramolecularly hydrogenbonded OH) and a t 1640 cm. (pyridone carbonyP), 4 5 6 7To establish finally the position of the pyridone carbonyl in the quinolizone 5 and hence the site of bromination, the quinolizone 5 was catalytically reduced using Adams catalyst in methanol. Reduction ceased after two molecules of hydrogen had been absorbed ; properties of the reduction product (strong infrared absorption at 1640, 1590 and 1540 cm.-' in the pyr...

Novel Benzo[b]quinolizinium Cations as Uncompetitive N-Methyl-D-aspartic Acid (NMDA) Antagonists: The Relationship between log D and Agonist Independent (Closed) NMDA Channel Block

“…This compound was prepared by modification of the published procedure. 26 The ethylene glycol ketal of isoquinoline-3-carboxaldehyde27 was quatemized with chloroacetone which was then cyclized with refluxing 48% HBr. The treatment of the resuting 3-hydroxybenzo[Z>]quinolizinium bromide with KPF8 gave 2d: yield 82%; mp 261-263 °C; NMR (DMSO-de) d 7.73 (m, 1H), 7.97 (m, 2H), 8.26 (dd, J = 3.0, 8.1 Hz, 2H), 8.42 (d, J = 9.7 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 9.09 (s, 1H), 10.20 (s, 1H).…”

“…(±)-12,12-Di(3-furyl)-6,ll-ethano-8,10-dihydroxy-6,lldihydrobenzo [6]quinolizinium chloride (26): yield 32%; mp amorphous powder; NMR (DMSO-de) 2.41 (d, J = 15.0 Hz, 1H), 2.91 (dd, J = 15.0, 2.0 Hz, 1H), 5.78 (s, 1H), 6.14 (s, 1H), 6.29 (s, 1H), 6.44 (s, 1H), 6.51 (s, 2H), 7.38-7.48 (m, 4H), 7.84 (t, J = 7.0 Hz, 1H), 8.2 (d, J = 7.0 Hz, 1H), 8.37 (t, J = 7.0 Hz, 1H), 9.25 (d, J = 7.0 Hz, 1H), 9.79 (s, 1H), 10.24 (s, 1H). Anal.…”

Synthesis of 1,2-annulated and 1,2-unsubstituted pyrrolo[2,1,5-de]quinolizin-5-ones (cycl[3.3.2]azin-5-ones) via [3+2] cycloadditions of 1-oxoquinolizinium ylides with cyclic alkenes

“…The 1-and 3-oxoquinolizinium betaines (I and II in Chart 1) can be generated by deprotonation of the 1-and 3-hydroxyquinolizinium salt, which in turn can be prepared by intramolecular aldol condensation of the 2-acetyl-N-phenacyl pyridinium salt and 2-benzoyl-N-acetonyl pyridinium salt, respectively. 23 The 3-oxo betaine II was used as a dipole to take part in [3+2] cycloadditions for the synthesis of pyrrolo[2,1,5-de]quinolizin-3-ones. 17, 20 On the other hand, the only report so far on the use of the 1-oxo betaine (I) in [3+2] cycloaddition for the synthesis of the corresponding pyrrolo[2,1,5-de]quinolizin-5-ones was about the reactions with electron deficient alkenes in the presence of chromium oxide as an oxidant to give the products in rather low yield.…”

Heterocycles Containing a Ring‐Junction Nitrogen

“…An example involving the formation of a bond d to the heteroatom represents the most efficient route to prepare 3-hydroxyquinolizinium bromide [181]. This derivative is obtained by reaction of bromoacetone with 2-piconaldehyde acetal followed by acid deprotection and intramolecular condensation to give a 77% overall yield of 251 (Scheme 22.62).…”

“…Electrophilic aromatic substitution on the quinolizinium cation requires strongly electron-donating substituents such as hydroxy or amino groups for the success of this reaction [169,181]. 1-Hydroxyquinolizinium salts (219) undergo electrophilic substitution preferentially at the C2 position [187].…”