Acylurea

The activity of acylureas as hypnotic and anticonvulsant agents is dealt with in some detail later. This is again one of the cases in which the functionality rather than structure determines pharmacologic activity. Thus, acylation of urea with phenylacetyl chloride gives the anticonvulsant agent, phenacemide... 

Acylureas (A) are among the oldest known sedative-hyphotic... 

The continuing search for molecules that possess the sedative-hypnotic properties of the barbiturates but show a better pharmacologic ratio has, as shown above, taken many directions. To name only two variants, the ring has been contracted and even opened entirely in each case some activity of the parent was retained. Although at one time the acylurea functional array was thought necessary for activity, the work below shows that even... 

Acylurea derivatives are readily prepared in one step by addition of amines to acyl isocyanates in high yields (Eqs. 1 and 2)14>. 

If weak complexes present in solution consist of dimers alone (Fig. 7), association patterns of homodimers (11 and 13) are of the head-to-tail type, that of heterodimer (72) being of the head-to-head type, since the two acylurea bonds in 1 and 2 extend... 

The need of the acylurea site participating in intermolecular hydrogen bonding (cf. Figs. 11 and 12) for the complex formation is exemplified by the fact that a 1 1 mixture of JV-(p-dimethylaminophenyl)phenylacetamide (21) and JV-isobutyl-p-nitro-benzamide (22) gives no crystalline complexes under the same conditions as with 19 and 20. The trend of the complex formation often changes, when the combinations of R7 and R8 are reversed 35). 

The pattern of hydrogen bonding between a pair of acylurea derivatives revealed by X-ray analysis was consistent with that predicted by spectroscopic studies. Typical examples are illustrated in Figs. 11 and 12 35-37) two NH — O intermolecular hydrogen bonds connect the two molecules. This holds true for the other acylurea derivative 20 (R8 = CH2Ph)38) and 1 1 complexes whose crystal structures were so far determined. 

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

The reaction of amides with half equiv. of BTMA Bf3 and one equiv. of DBU in dichloromethane-methanol at room temperature gave N-substituted acylureas in fairly good yields (Fig. 34). Furthermore, in the presence of a large excess of methanol, the reaction of amides with one equiv. of BTMA Bt3 and two equiv. of DBU in dichloromethane gave methyl carbamates as main products (Fig. 35). In these reactions, we assumed that in the presence of DBU, intermediary isocyanates react with excess of amides to afford acylureas, and react with excess of methanol to afford methyl carbamates (ref. 42). 

Fig. 34. Preparation of acylureas from amides with BTMA Br3 BTMA Brj, DBU, R -OH...

NCD-4 is a nonfluorescent carbodiimide derivative that forms a fluorescent adduct with the Ca -ATPase, accompanied by inhibition of ATPase activity and phos-phoenzyme formation [376-378]. Ca protected the enzyme against the inhibition by NCD-4 and reduced the extent of labeling, suggesting that the reaction may involve the Ca " " binding site. The stoichiometry of the Ca -protected labeling was i 2mole/mol ATPase. The fluorescence emission of the modified Ca -ATPase is consistent with the formation of a protein bound A-acylurea adduct in a relatively hydrophobic environment. After tryptic proteolysis of the NCD-4 labeled ATPase the fluorescence was associated with the A2 band of 24 kDa [376,379]. 

A potential undesirable effect of DCC coupling reactions is the spontaneous rearrangement of the o-acylisourea to an inactive N-acylurea (Stewart and Young, 1984) (Figure 3.6). The rate of this rearrangement is dramatically increased in aprotic organic solvents, such as DMF. 

Allenic acylureas 152, prepared in situ from the corresponding allenic acid 151 and carbodiimides, afforded lactams in good yields [126]. 

O-acylisourea generates peptide, the theoretical yield of peptide is one equivalent and one equivalent of A,/V -dialkylurea is liberated. However, a fourth and undesirable course of action is possible because of the nature the (9-acylisourea. The latter contains a basic nitrogen atom (C=NR3) in proximity to the activated carbonyl. This atom can act as a nucleophile, giving rise to a rearrangement (path J) that produces the. V-acylurea (see Section 1.12) that is a stable inert form of the acid. This reaction is irreversible and consumes starting acid without generating peptide. The exact fate of the O-acylisourea in any synthesis depends on a multitude of factors this is addressed in Section 2.3. 

More /V-acylurea is generated if tertiary amine is present because the latter removes any protons that might prevent the rearrangement (see Section 2.12). The two intramolecular reactions also occur to a greater extent when interaction between the O-acylisourea and the /V-nucleophile is impeded by the side chain of the activated residue. This means that more 2-alkoxy-5(4//)-oxazolone and /V-acylurea are generated when the activated residues are hindered (see Section 1.4). A corollary of the above is that the best way to prepare an /V-acylurea, should it be needed, is to heat... 

NL Benoiton, FMF Chen. Reaction of A-t-butoxycarbonylamino acid anhydrides with tertiary amines and carbodiimides. New precursors for 2-f-butoxyoxazol-5(4//)-one and IV-acylureas. J Chem Soc Chem Commun 1225, 1981. 

HYDROXYBENZOTRIAZOLE AS AN ADDITIVE THAT SUPPRESSES N-ACYLUREA FORMATION BY PROTONATION OF THE O-ACYLISOUREA... 

FIGURE 2.12 1-Hydroxybenzotriazole as an additive that suppresses N-acylurea formation by protonation of the O-acylisourea (see review by Rich and Singh4). 

The existence of a protonated oxazolone has been demonstrated indirectly by a simple experiment. When p-nitrophenol was added to an excess of 2-alkoxy-5(4//)-oxazolone in dichloromethane, a yellow color appeared. The color persisted until all the p-nitrophenol had been consumed by the oxazolone. The anion of p-nitro-phenol is yellow. The explanation for the color of the mixture is the presence of the p-nitrophenoxide anion that was generated by abstraction of the proton by the oxazolone. In summary, protonation of the O-acylisourea suppresses the side reaction of oxazolone formation as well as the side reaction of A-acylurea formation and accelerates its consumption by enhancing its reactivity and generating an additional good nucleophile that consumes it. Protonation of the oxazolone suppresses epimerization by preventing its enolization and also increases the rate at which it is consumed.4 68 78 79... 

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