5- Amino-7-azaindole

Palladium-catalyzed reactions of arylboronic acids have been utilized to craft precursors for constructing indole rings. Suzuki found that tris(2-ethoxyethenyl)borane (149) and catechol-derived boranes 150 readily couple with o-iodoanilines to yield 151, which easily cyclize to indoles 152 with acid [158]. Kumar and co-workers used this method to prepare 5-(4-pyridinyl)-7-azaindoles from 6-amino-5-iodo-2-methyl-3,4 -bipyridyl [159], A similar scheme with catechol-vinyl sulfide boranes also leads to indoles [160]. A Suzuki protocol has been employed by Sun and co-workers to synthesize a series of 6-aryloxindoles [161]. 

The one-pot synthesis of 4-azaindole is also initiated by photoirradiation 3-amino-2-chloro-pyridine and acetaldehyde are the starting materials (Fontan et al. 1981 Scheme 7.37). 

The conversion of 3-amino-4-oxo-l,jc-naphthyridines (117) into the corresponding 3-diazo-4-oxo compounds (118) followed by photolysis results in the formation of azaindoles (119) via nitrogen evolution and ring contraction (56LA(599)233, 60JCS1794). 

OH-DPAT = 8-Hydroxy-2-(di-n-propylamine)tetralin CP93129 = 5-Hydroxy-3(4-l,2,5,6-tetrahydropyridyl)-4-azaindole LY334370 = 5-(4-fluorobenzoyl)amino-3-(l-methylpiperidin-4-yl)-l -indole fumarate SB204741 = A/-(l-methyl-5-indolyl)-/V -(3-methyl-5-isothiazolyl)urea WAY100635 = N-tert-Butyl 3-4-(2-methoxyphenyl)piperazin-l-yl-2-phenylpropanamide. 

Certain 2-amino-3-ketones 193 also serve, via the agency of hydrochloric acid, as intermediates for the synthesis of 7-azaindole derivatives 194 (Scheme 57) (88JOC2740). 

Amino-l,6-naphthyridin-4-one (148), upon irradiation with UV light in the presence of sodium nitrite loses nitrogen to afford the 3-carboxy-5-azaindole (149).85,158 This reaction has also been carried out on the corresponding derivatives of 1,7-naphthyridine158 159 and 7-carboxy-l,8-naphthyridine85 to give the expected 1,6- and 1,7-azaindoles. 

A range of imines and enamines, formed from tir/Zw-haloaminopyridines and ketones, may be converted to a variety of substituted 4-, 5-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reaction <2005S2571>. As an example, 4-amino-3-iodopyridine is converted to azaindole 85 in 46% yield by condensation with ketone 86 followed by Heck reaction of the resulting enamine (Equation 59). 

Our interest in expanding the acylative pyrrole annulation approach to additional heterocyclic systems has led to an efficient synthesis of pyrrolo[3,2-c]pyridin-2-ones and pyrido[3,4-6]pyrrolizidin-l-ones starting from 4-chloro-N-benzyl-2(l//)-pyridinone and amino acid salts.811 Over the years pyrrolo[3,2-c]pyridines (5-azaindoles)41 have been of interest for applications as elements in new drug design, nucleotide analogues,42 and biochemical tools. However, available synthetic routes to multifunctionalized members from this class of heterocyclic structures are limited.41 43... 

The photostimulated reactions of vie aminohalo pyridines with acetone or pinacolone enolate ions lead to azaindoles in high yields (75-95%) [67]. When the amino group is protected as pivaloylamino derivative, (as in 17, Sch. 20), the analogs of substitution compounds 18 obtained by the photoinduced reaction of 2-amino-3-iodo-, 3-amino-4-iodo- and 4-amino-3-iodopyridines with acetone or pinacolone enolate ions, afford 5-, 6- and 7-azaindoles in almost quantitative yields by cyclization upon deprotection of the amino group and dehydration under acidic conditions (for example, see Sch. 20) [67]. 

The reaction of A-methyl-A-acetyl-2-chloro-3-amino tion in THF-hexane (-78 °C) gave azaindole in 83% yield used to prepare the key intermediate for the synthesis of Eupolauramine339. Thus, o-metallation of 3-bromopyridine and treatment with MeNCO gave the anion 319, which reacts with PhCOCH2Br forming the product 320 (equation 191). 

The discovery of serotonin and the development of amino acid analogs as antimetabolites initiated the current interest in azaindoles during the last decade. In addition to providing interesting azalogs of tryptamine and tryptophan, azaindoles have stimulated much research owing to their synthetic elusiveness and variety of properties. 

Clayton and Kenyon prepared 5-methyl, 2,5-dimethyl-, and 2-phenyl-5-methyl-4-azaindole in 12,55, and 67 % yields, respectively, by treatment of the corresponding formyl, acetyl, and benzoyl derivatives of 3-amino-2,6-dimethylpyridine with sodium ethoxide at 310° for 15 minutes. The phenyl compound was prepared also by Protiva et al in 1 % yield. 

The limitations of this approach to the synthesis of azaindoles are (i) unavailability of other amino- or chloroethylpyridines suitable for cyclization (ii) adaptation to the synthesis of the other azaindoles and Hi) the necessity of high temperature and pressure for cyclization, requiring specialized equipment for large-scale preparations. For those applications already investigated it does offer a unique and useful method for the synthesis of a variety of 7-azaindole derivatives. 

Bernstein et al. synthesized 6-amino-2,3-diphenyl-7-azaindole (77) in 89% yield by heating nearly equimolar amounts of 2,6-diaminopyridine, its hydrochloride salt, and benzoin at 185°. 

Reisch obtained 7-azaindole in 54 % yield by heating 3-ethynyl-pyridine with sodium amide in ammonia-saturated pseudocumenol at 170-180° for 16 hours, 2-amino-3-ethynylpyridine being formed as an intermediate. 

Good evidence for nitration at the 3-position was provided by Clayton and Kenyon. l-Benzoyl-2,5-dimethyl-4-azaindole was nitrated in 60 % yield, and followed with potassium permanganate oxidation in aqueous acetone gave 3-benzamido-6-methylpicolinic acid. Alkaline hydrolysis of the nitration product gave 3-nitro-2,5-dimethyl-4-azaindole (85% yield), which was also obtained by direct nitration of 2,5-dimethyl-4-azaindole in low yield. In addition, reduction gave the 3-amino compound, which was identical to that obtained by catalytic reduction of the product formed by coupling the azaindole with benzenediazonium chloride. 

Nitro-7-azaindole was obtained in 83% yield at 0°, and was reduced to the 3-amino compound, which is unstable as the free base,... 

The first attempt to prepare an azaindole as an azalog of biologically active compounds appears to have been made by Bernstein et al. They synthesized 6-amino-2,3-diphenyl-7-azaindole and tested it for antimalarial activity against Plasmodium lophurae. It showed little activity. 

On exposure to UV radiation in the presence of sodium nitrite, 3-amino-l,6-naphthyridine-4( 17/)-one eliminates a nitrogen molecule being thus converted into 5-azaindole-3-carboxylic acid (1958MI1, 1960JCS1794). 

It is even possible to hthiate a methyl in the presence of a free amino group and this can be made the means to synthesise 6-azaindoles (pyrrolo[2,3-c]pyridines)." ... 

The introdnction of an amino acid side-chain onto 4-, 5-, 6- and 7-azaindoles by an enzyme-catalysed alkylation with serine is an impressive demonstration of the power of biological methods. ... 

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