Quaternary nitrogen heterocycles

HU-211 is highly liposoluble, which makes it readily accessible to the central nervous system since it readily crosses the blood brain barrier. However, its poor solubility in water hampers development of formulations suitable for i.v. administration. In order to overcome this drawback, Popp et al. have prepared a series of water-soluble salts of glycinate esters (attached to the allylic hydroxyl) and salts of amino acid esters containing tertiary and quaternary nitrogen heterocyclics (attached to the phenolic hydroxyl) (see Figure 5.5) [201, 202]. Most of the new compounds were relatively soluble in water or 10% aqueous ethanol, and showed neuroprotective properties, attributed to the parent compound, formed on hydrolysis of the esters in vivo. 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

The sorbent of fibrous stmcture has the best kinetic characteristics in relation to noble metals, for which reaching soi ption balance does not exceed 20 minutes. The rate of soi ption balance establishment depends on the form of nitrogen in functional groups of sorbents used and decreases in a line tertiary nitrogen (linear group) > tertiary nitrogen (heterocycle) > quaternary nitrogen. 

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

Phosphines behave similarly, and compounds of the type R3P and R4P X can be so prepared. The reaction between triphenylphosphine and quaternary salts of nitrogen heterocycles in an aprotic solvent is probably the best way of dealkylating the heterocycles, for example, ... 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

Cyclization of haloamines (cyclic amines) dealkylation of quaternary salts of nitrogen heterocycles 0-45 Reaction between dihalides and cy-anamide (cyclic amines)... 

A great number of different heterocyclic residues have been used as the terminal groups of PMDs. Examples appear throughout this article. PMDs containing residues with quaternary nitrogen atoms are traditionally called cyanine dyes (qv). 

The different behavior of tertiary and quaternary carbon atoms seems to be due to either the complete neglect of overlap in these calculations or to polarization effects of the carbon-nitrogen bonds, Similar results are obtained for a series of 5-halouracils by plotting the 13C NMR chemical shifs versus 7r-electron charge densities calculated by the extended Hiickel theory [756], Though for several nitrogen heterocycles a better correla-... 

Condensation of indoles with A-alkylquinolones or TV-alkylpyridones yields yellow and orange zeromethine dyes that dye polyacrylonitrile in lightfast shades [99], If the indole nitrogen atom is unsubstituted, intensely colored anhydro bases are formed from the zeromethinecyanine dyes. Dealkylation of the heterocyclic quaternary nitrogen atom also occurs [100],... 

The quaternary salts of selenium-nitrogen heterocycles are labile to nucleophiles and can be converted to other heterocyclic systems by ring expansion [82, 103], An example is conversion of 1,2,4-selenadiazolium trifluoromethane sulfonate (67) into 1,3,5-selenadiazine (68) (Scheme 17) [104], 2,3-Dimethyl-1-benzo-l, 3-selenazolium tetrafluoroborate is readily condensed with aromatic aldehydes to 2-styrylselenazole [105] or treated with sodium hydride to give 3-methyl-2-methylene-2,3 -dihydro-1 -benzo-1,3 -selenazole [106],... 

Nitrogen heterocycles with contiguous quaternary and tertiary stereocentres (118) have been prepared in high enantiomeric purity (<95% ee) by intramolecular conju- gate addition of enolates generated from a-amino acid derivatives (117) via memory of chirality.160... 

The synthesis of azidocycloimonium fluoborates, compounds which possess a quasi-aromatic heterocyclic nucleus, has been reported by BalU and Kersting . Halogen atoms adjacent to quaternary nitrogens in heteroaromatic salts such as 154 157 undergo replacement by azide ion at low temperatures to produce the resonance stabilized azidinium salts (158). On the basis of infrared studies and reactivity towards nucleophiles, Balli has suggested that these salts are best considered as iV-diazonium compounds... 

Polyzwitterions derived from polymeric heterocyclic vinyl compounds like N-vinylimidazole [54] and vinylpyridine [55, 56], containing short carboxyalkyl substituents at the quaternary nitrogen. 

Combining the cationic component, usually quaternary ammonium cations of nitrogen heterocycles and inorganic or organic anions, numerous ionic liquids are... 

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