Parent compound preparation protonation

Piper et al. [368] acylated the terminal amino group in the MTX analogues (VIII.268)-(VIII.270) with 4-chlorobenzoyl chloride to form the amides (VIII.281)-(VIII.283). More recently a series of A -acyl derivatives of the AMT analogue (VIII.275) were prepared from A -(4-amino-4-deoxy-A °-formylpteroyl-L-ornithine (VIII.274) by reaction with appropriate anhydrides to give the A -disubstituted derivatives (VIII.284)-(VIII.289) [370]. Selective hydrolysis at N ° with dilute NaOH then gave the A -acyl derivatives (VIII.290)-(VIII.295). The impetus behind these studies was a desire to improve cellular penetration, which is hindered in the parent compounds by protonation of the side-chain amino group at physiologic pH. 

When amino acid ester prodrugs of acetaminophen were prepared (Kovach et al., 1975 Pitman, 1976), the hydrobromide salt of the glycine ester showed enhanced solubility in water, but the hydrochloride salt of th -aspartic acid ester exhibited a solubility lower than that of the parent compound. The enhanced solubility resulted from the formation of a salt, while the parent drug is a weakly acidic phenol and behaves as essentially a neutral molecule in solution. The reduced solubility in the case of th0-aspartic acid ester resulted from ionization of the terminal carboxylic acid, which, with the protonated amine, gives a zwitterionic compound. The zwitterion also behaved as a molecule with an overall neutral character, as is commonly observed with zwitterion behavior in aqueous media, but its larger size resulted in a further reduced solubility. 

The nitrosation method is not recommended for a-aminoketones, but it works well for 2-amino-l,3-dicarbonyl compounds, as found by Wolff (1902) for the preparation of 3-diazopentane-2,4-dione (2.31). Cyclic diazo-a, a -diketones, such as 2-diazocyclohexane-l,3-dione (2.32, R=H) and its 5,5-dimethyl derivative (diazo-dimedone, 2.32 R=CH3), can be synthesized without major difficulties (Eistert et al., 1959 Stetter and Kiehs, 1965). The parent compound, diazomalonodialdehyde (2.33) was prepared only in 1973 by Arnold and Sanliova. The smooth formation of diazo-a,a -diketones and the decreased tendency for proton addition at the central C-atom can be explained by the resonance structures 2.31 a-c. 

Beside haloacetic acids, this reaction can be strongly accelerated by aluminum chloride, trifluoroacetate, Al(OCOCF2CF3)3, or Al(OCOCF2CF2CF3)3 (8 eq. to ArPb(OAc)3). These fluorinated carboxylic salts were readily prepared by careful addition of the given acid to resublimed aluminum chloride [65]. These catalysts allow to perform the arylation with less reactive arenes such as toluene and benzene. The main side-reaction which occurs during the aryllead(IV) tricarboxylates involving reactions in trifluoroacetic acid is the protodeplumbylation. This reaction produces the parent arene by protonation of aryllead(IV) compound, and may become the major process [65,66]. 

Acetal formation is reversible (K for MeCHO/EtOH is 0-0125) but the position of equilibrium will be influenced by the relative proportions of R OH and H2O present. Preparative acetal formation is thus normally carried out in excess R OH with an anhydrous acid catalyst. The equilibrium may be shifted over to the right either by azeotropic distillation to remove H2O as it is formed, or by using excess acid catalyst (e.g. passing HCl gas continuously) to convert H2O into the non-nucleophilic H3O . Hydrolysis of an acetal back to the parent carbonyl compound may be effected readily with dilute acid. Acetals are, however, resistant to hydrolysis induced by bases—there is no proton that can be removed from an oxygen atom, cf. the base-induced hydrolysis of hydrates this results in acetals being very useful protecting groups for the C=0 function, which is itself very susceptible to the attack of bases (cf. p. 224). Such protection thus allows base-catalysed elimination of HBr from the acetal (27), followed by ready hydrolysis of the resultant unsatu-... 

Most enamines, unfortunately, are sensitive to hydrolysis. The parent enamine, iV,iV-dimethylvinylamine, has in fact been prepared [3], but appears to be unstable. Enamines of cyclic ketones and many aldehydes can readily be isolated, however [4-7]. The instability of enamines might at first appear to diminish the utility of enamines as nucleophiles, but actually this property can be viewed as an added benefit enamines can be readily and rapidly generated catalytically by using a suitable amine and a carbonyl compound. The condensation of aldehydes or ketones with amines initially affords an imine or iminium ion, which then rapidly loses a proton to afford the corresponding enamine (Scheme 1). 

Condensations of anthranilic acid derivatives lead to the 6,12-diamino- and 6,12-dioxo-dibenzodiazocines, and the dichloro compound (279) is available from the latter (54JCS3429). Reduction of (279) via the dihydrazino compound was used to prepare the parent dibenzo[6,/][l,5]diazocine (280) (67CC1077). The NMR value (5 8.53 p.p.m.) of the 6(12) proton is indicative of the diazocine structure, presumably in a tub form, rather than the valence isomeric dibenzodiazapentalene (281). 

Ammonium carbamate is prepared from dry ice and liquid ammonia [14]. These conditions are very similar to the conditions under which we have observed the formation of amine salts. To some readers, ammonium carbamate may seem to be an exotic compound. In fact, it is manufactured industrially on a multiton scale, because on heating (usually at 100-185°C) ammonium carbamate is converted to urea and water [14-16]. Urea is important for both the agricultural and the plastics industries. The ammonium carbamate is not always isolated during urea preparation. Instead, the reactions are carried out under conditions where the carbamate is just an intermediate. Ammonium carbamate is only moderately stable and it gradually loses ammonia in air. Although the data are sparse, the rate of decomposition of carbamates in solution seems to decrease as the volatility of the parent amine decreases [17]. Free carbamic acids in solution do not decompose spontaneously to free amine and C02. Instead, the acid ionizes by reaction with water the proton is transferred from the hydronium ion to the amine and then decomposition occurs [17]. Acids catalyze the decomposition. 

Amidostannanes containing the groups Sn-NC(=0)R or Sn-NS(0)2R are easier to prepare and to handle than are the aminostannanes. The acidity of the proton on nitrogen in the parent amide is now sufficient for reaction to occur with organotin hydroxides, oxides, and alkoxides (and aminotin compounds), and, once formed, the amidostannanes are less sensitive to moisture. A variety of amidostannanes is also available from the addition of Sn-0 and Sn-N bonded compounds to nitrogen heterocumulenes. 

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