Aromatic amidines

We found that the optimal reaction protocol was to add a solution of a-bromo ketone in THF to the amidine in aqueous THF in the presence of potassium bicarbonate under vigorous reflux. Using this procedure, 2,4-disubstituted imidazoles were isolated in excellent yields with >95% purity without column chromatography. Aromatic and aliphatic a-halo ketones participate in this reaction with a variety of aromatic amidines, as indicated in Table 1. Particularly noteworthy is that reactions involving pyridylamidines or chloroacetone are substantially more robust using this process (entries 3 and 4). We have successfully used this protocol on a multi-kilogram scale. 

A number of aromatic amidines have been readily obtained by boiling a primary or secondary amine with a substituted amide in a solution of phosphorus trichloride. Several aliphatic amides undergo a similar condensation with amines and phosphorus oxychloride. An imino chloride, RC(C1)=NR, is an intermediate in this process. N-Phenylbenzarnidine, CsHsC(NHC6Hs)= NH, is obtained by the action of methanolic ammonia on... 

Pentamidine is a synthetic aromatic amidine it must be administered parenterally or by inhalation as it is unreliably absorbed from the gastrointestinal tract it does not enter the CSF. Given systemically it frequently causes nephrotoxicity, which is reversible acute hypotension and syncope are common esp-ecicdly after rapid i.v. injection. Pancreatic damage may cause h5q>oglycaemia due to insulin release. 

Many papers have been published reporting the serine protease inhibitory activity of amidine or diguanide derivatives (see chapter 21 of this volume). A series of aromatic amidine compounds was reported to inhibit platelet aggregation induced by ADP, collagen and thrombin. The most active compound was (30).lOO... 

Tidwell RR, Geratz JD, Dubovi EJ (1983) Aromatic amidines. Comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin. J Med Chem 26 294—298... 

The aromatic amidines are strong bases pK 11) quinapyramine and ethidium are quaternary (immonium) bases in equilibrium with their pseudobases (see p. 391). 

Lukyanov prepared a 2-(3-pyridyl)-4-(trifluoromethyl)imidazole via the condensation of the corresponding aromatic amidine with 3-bromo-1,1,1-trifluoroacetone followed by TFAA-promoted dehydration (Scheme 33) [47]. 

For aromatic amidines the most likely course of the electrode reaction,... 

At pH 9.5 the amidines are hydrolyzed very quickly, and polarographic measurements are almost impossible. There is, however, a report that half-wave potentials have been determined for some aromatic amidines at pH 12.5 with tetraethylammonium hydroxide as supporting electrolyte [51]. 

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

Highly electron-deficient 1,3,6-trinitrobenzene (145) treated with phenyl acet-amidines 146 in ethanol provided low yields of a dinitroindole derivatives, probably 4,6-dinitroindoles 148 (77JOC435). Formation of indole derivatives 148 can be explained by nucleophilic substitution of the activated aromatic hydrogen leading to intermediates 147, which then cyclized to the final products 148 (Scheme 22). 

Aminopyridinato ligands form a special class of anionic ligands in which an aromatic ring is part of an amidinate system. These ligands have frequently been employed in early transition metal and lanthanide coordination chemistry. Their diverse and interesting chemistry has been described in detail by Kempe et al. ° and will thus be covered here only briefly. Typical reaction pathways leading to titanium aminopyridinato complexes are outlined in Scheme 169. Metathetical as well as salt-free routes have been developed. 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

The most common method for the preparation of the fully aromatized pyrimidine skeleton is the condensation of an amidine with an a,P-unsaturated carbonyl compound. For example, Palanki and co-workers reported that the reaction of amidines 1 with a,P-unsaturated carbonyl compounds 2 produced pyrimidines 3 <00JMC3995>. 

Cyclic 1,2-diketones, 24 594 Cyclic acrolein acetals, 2 271 Cyclic amidine curing agents, 10 410 Cyclic amidines, 10 412 Cyclic (aromatic disulfide) oligomers, 23 712... 

Oxidative attack on a carbon-hydrogen bond of an alkyl group a to a nitrogen atom is not restricted to saturated aliphatic amines. In fact X in an X-N-CH- structural subunit can be virtually any common atomic grouping that can be found in stable organic molecules. For example, w-carbon hydrogens of Aralkyl-substituted aromatic cyclic amines (119), aryl amines (120), amides (121), amidines (122), A-nitrosodialkylamines (123), etc. are all subject to oxidative attack, carbinolamine formation, and in most cases release of an aldehyde or ketone depending on the substitution pattern (1° or 2°)... 

The amidine group reacted more easily than the aromatic amino group with EMME in boiling ethanol besides the condensation, ring closure usually takes place to give pyrimidinecarboxylate in good yield (e.g., 80EUP15772) (Scheme 11). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

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