Anthranils synthesis

Benzoisoxazoles (anthranils), synthesis and transformation to other heterocycles 91KFZ(1)57. 

When treated with alkaline hypochlorite solution anthranilic acid is obtained. This reaction, the first stage in the indigo synthesis, is the most important commercial outlet for phthalimide. 

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

Anthranil, 7-nitro-synthesis, 6, 407 Anthranil, 3-phenyl-thermolysis, S, 91 Anthranilonitriles indazoles from, S, 274 Anthranils... 

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

Mention must also be made of an interesting reaction (103 —> 104) that makes use of the isoxazole nucleus of anthranil as a diene in the reaction with A-phenylmaleimide. This instance is of considerable interest, for it has proved impossible to introduce into the diene synthesis other derivatives with a noncondensed isoxazole ring. ... 

Most condensations of this type start with 2-aminobenzoic acid (anthranilic acid) derivatives. In an early, extensive work on the synthesis and chemistry of dianthranilides", acid chlorides 1 were used as starting materials.2... 

Anthranilatesynthase-phosphoribosyltransferase Salmonella typhimurium, 6,582 Anthranilic acid in gravimetry, 1,530 metal complexes, 2, 795 synthesis... 

Another synthesis of diazepines (tricyclic) was carried out by reaction of an amino chloropyridine 258 and anthranilic acid [163]. First, a nucleophilic substitution occurred (Scheme 95) followed by an intramolecular amidation on compound 259 by microwave irradiation to give structure 260. The reaction was carried out at 100 °C for more than 2 h, a remarkably long time for a microwave-assisted reaction. 

Mazaleyrat, J.-P. Reboud-Ravaux, M. Wakselman, M. Synthesis and enzymic hydrolysis of cyclic peptides containing an anthranilic acid residue. Int. J. Peptide Protein Res. 1987, 30, 622-633. 

Oza VB, Petrassi HM, Purkey HE, Kelly JW. Synthesis and evaluation of anthranilic acid-based transthyretin amyloid fibril inhibitors. Bioorg Med Chem Lett 1999 9 1-6. 

Isonitriles, Anthranilates, Tetraethylammonium chloride Bossio, R. et al., J. Heterocycl. Chem., 1995, 32 (4), 1115 A one pot synthesis of heterocycles involving the above reagents and catalyst sometimes showed an induction period followed by violent reaction. 

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

The pyrimidine ring is formed from [4+2] atom fragments in the synthesis of 114 from 3-chloro-6-arylpyridazine 113 and anthranilic ester <2000HC0147> or acid <2001RRC649, 2003MOL322> (Equation 13). 

The process was also applicable to microwave-assisted reactions. Thus, 140a, 140b, and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl) were prepared in a two-step, one-pot synthesis in yields of 55%, 39%, 20%, and with 70%, 73%, 50% ee, respectively. In the first step anthranilic acid was reacted with the appropriate A-BOC-protected amino acid (glycine, L-alanine, and L-valine, respectively) in the presence of P(OPh)3 and dry pyridine under irradiation at 150 °C for 140a or conventional heating at 55 °C for 140b and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl). In the second step the resulting... 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

Cyclocondensation of the iminoethers 157 with anthranilic acid was utilized in the synthesis of compounds 158a, 158b <2004TA3045> and 158 (R2 = indol-3-ylmethyl R1 = (A )-Me, (R)-Me (A)-Pr R4 = H, (A)-Me) resulting in moderate yields with retention of configuration at all stereocenters (Equation 16) <1998T969>. 

A number of new conditions and catalysts have been used for the synthesis of quinazolinones 50 from anthranilic acids, amines and ortho esters, including bismuth trifluoroacetate with an ionic liquid <06TL3561>, lanthanum nitrate or tosic acid under solvent-free conditions at room temperature <06TL4381> and Nafion-H <06SL2507>. 

An important application of the Hofmann reaction occurs in the first technical synthesis of indigo and consists in the degradation of phthalimide to anthranilic add. See p. 372. 

The natural extension of this series to the quinoline analog of AC 252,925 was then undertaken. The synthesis route used is based on the work of E. C. Taylor which employed anthranil as a precursor to a quinoline-2,3-dicarboxylic acid derivative (11). The sequence is shown in Scheme V. 

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