Nitro quaternary salts

Morley and Simpson prepared quaternary salts from 4-phenoxy-quinazoline and 6- and 7-nitro-derivatives of 4-anilino- and 4-acet-amido-quinazohne. 6-Nitro-4-aminoquinazoline, however, could not be quatemized under the fairly mild conditions used by the... 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

As seen in many of the above examples, acetic anhydride and zinc chloride each make effective condensation catalysts for the free bases, presumably by efficient coordination with the ring nitrogen. The quaternary salts condense readily in the presence of piperidine. Potassium hydroxide, methoxide or piperidinium acetate are suitable for condensations with 2- and 4-methylpyridine AAoxides. For example, the Claisen condensation is effective with these Af-oxides using ethoxide catalyst (Scheme 45) but the reaction fails with the parent picolines unless activated by nitro substitution (69JHC775). 

A number of diastereoisomeric pairs of quaternary salts of 5-nitro-tetrahydro-l,3-oxazine derivatives (11a and lib) were prepared by the action of n-alkyl bromides or iodides on 5-nitrotetrahydro-1,3-oxazines.61 The products contained at the 3-equatorial position the n-alkyl derived from the alkyl bromide (or iodide), 6a and 6b [Eqs. (4) and (5)]. 

From the quaternary salts of the 3-alkoxycarbonyl-4-oxo-4/f-pyrido-[l,2-a]pyrimidines (71), Landquist obtained the corresponding carboxylic acids by acidic hydrolysis and the 2-alkylaminopyridines by alkaline hydrolysis. 137 Ammonia generally cleaved the C-4—N-5 bond of the quaternary esters, except for the 7-nitro derivative in which the N-l —C-9a bond underwent cleavage. 

Nevertheless, the 9-methyl derivative of 71 failed to produce a quaternary salt because of the steric hindrance effect of the methyl group,137 as did 2-rnethyl-3-nitro-4-oxo-4//-pyrido[l,2- ]pyrimidine37 because of the electron deficiency of the ring. When the pyridopyrimidine bore a substituent containing a nitrogen atom more basic than N-l, the quaternization occurred in that side chain.42... 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

By using nitroenamines as initial reagents it is possible to obtain the quaternary salts of 4-nitroisothiazoles [502, 505] and4-nitro-l,2,3-triazoles [506], Phenylazide and methylazide react with olefines and form corresponding 4-nitro-l,2,3-triazole and also two isomeric triazoles [507] (Scheme 77). 

Photochromism of 4-nitro-, 6-nitro-, and 4,6-dinitro-5-methylbenzimidazole bases and their quaternary salts has been examined by pulse photolysis [1404], Generated neutral medium anions of aci-nitroacids have, in case of compounds with 4-nitro groups, the lifetimes 3 orders more than those of 6-nitroisomers [1404],... 

Koolpe, G.A., Lovejoy, S.M., Goff, D.A., Lin, K.Y., Leung, D.S., Bedford, C.D., Musallam, H.A., Koplovitz, L, Harris, R.N. (1991). Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 5. Structure-activity relationships for side-chain nitro-, sulfone-, amino-, and aminosulfonyl-substituted analogues for therapy against anticholinesterase intoxication. J. Med. Chem. 34 1368-76. 

The quaternization of 1-substituted imidazoles is a facile reaction which leads to a stable quaternary salt via an 5n2 reaction (Scheme 16) which may be affected by steric factors. It has been shown (78AHC(22)7l) that the effects of fV-aryl substituents on rate constants for the quaternization of imidazoles can be correlated using a Hammett equation. The value of p (-0.45) for the ethylation of imidazoles shows little sensitivity to substituent effects, but this is to be expected since the basic pK values of the fV-aryl compounds do not vary widely, and the rate of alkylation must depend on the basicity of the nitrogen being quaternized. Certainly the expected sequence of reactivities, 1-methyl > 1-benzyl > 1-phenyl, is observed in the ethylation of 1-substituted imidazoles with iodoethane in ethanol or acetone, and although only qualitative observations are available, l-methyl-4-and -5-chloroimidazoles react less readily than 1-methylimidazole. Considerable experimental difficulty is experienced in quaternizing nitro-substituted imidazoles. 

Other derivatives were synthesized where the 3 substituent was in turn an halide [14], a nitrogen quaternary salt-containing side chains [15], an O-alkylamine [15], a nitro group [15], an azido group [16], a functionalized C-2 unit [17]. Several fluorinated analogues of Combretastatins A-1 and A-4 were synthesized and their in vitro anticancer properties determined. The most active fluoro analogue 3 -deoxy-3 -fluoro-combretastatin A-4 retains the potent cell growth inhibitory properties of Combretastatin A-4 [14]. 

Alkylidene derivatives 123 have been prepared by condensation of benzothiazin-3-ones with aldehydes52 and by reductive cyclization of the nitro acids 124.162 Quaternary salts of benzothiazines also condense readily... 

The rate constant for the individual transitions may depend on a variety of features, such as substitution, medium and temperature. One important parameter is the height of the activation barrier between t and p. If the rate constant for the step 11 — 1 p is of the size comparable to that for the step t -> 3t, both processes may contribute to tram-> cis photoisomerization. For most nitrostilbenes examined, is substantial and for 4-nitro-, 4,4 -dinitrostilbene, and 4,4 -NMS a singlet pathway has been ruled out. However, for 4,4 -NDS in nonpolar solvents [160] and for quaternary salts of 4-nitrostyrylquinolinium [229], a contribution of the singlet mechanism has been concluded. 

Phenacylquinoxalinium bromide (67) reacts with nitromethane in the presence of sodium carbonate to give the 3-nitro compound 68 in 41% yield. The quaternary salt 67 has also been reacted with dimethyl acetylenedicarboxylate to give the 1 1 adduct 69. ... 

Salts 470 72 were obtained from amine 427 and bromoketones or bromoacet-aldehyde. They were later converted into imidazo[4,5-c]imidazo[l,2-a]pyridine derivatives 473, 474 and 477 by treatment with alkali. However, ketones like phenacyl bromide and its />-nitro- and /7-methyl-substituted analogues do not give stable quaternary salts with amine 427 yielding instead tricyclic bases 475 and 476 (86KG227). 

Sagitullina and co-workers synthesized a number of nitropyridines and their quaternary salts using a two-component Hantzsch 1,4-dihydropyridine synthesis. Treatment of 2-nitro-l,3-diphenylpropenone 258 with p-aminocrotonate derivatives 259, 210, 217 and 263 in acetic acid at room temperature gave the corresponding 1,4-dihydropyridine derivatives in modest yields. The corresponding salts (not shown) were produced using dimethylsulfate and methyl fluorosulfonate. 

Nitro-3-picoline (MI-368) is hydrolyzed on standing to l-(3 -methyl-4 -pyridyl)-3-methyl-4-pyridone and 3-methyl-4-pyridone. 4-Nitropyridine and benzyl bromide give iV-benzyl-3,5-dibromo-4-pyridone (MI-369) in 33% yield. The quaternary salt first formed is hydrolyzed to the 4-pyridone. Oxidation of hydrogen bromide by the nitrous acid product provides the bromine and water. The yield is increased to 71%by the addition of bromine. 3,5-Dibromo-4-chloro-pyridine and benzyl bromide in base also give XII-369. Similarly, 3-methyl-4-nitropyridine and benzyl bromide give W-benzyl-3-bromo-5-methyl-4-... 

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