7-chloro-azaindole

Only a few examples of nucleophilic substitution have been reported - displacement of halogen a and y to the pyridine nitrogen can be carried out under vigorous conditions or with long reaction times. No Chichibabin substitutions have been reported. Reaction of 4-chloro-7-azaindole with a secondary amine results in normal substitution of the halogen, but reaction with primary amines gives 5-azaindole rearrangement products by the sequence shown below. ... 

Chloro-7-azaindole undergoes nucleophilic displacement with cyanide the hahde is available via the A -oxide. ... 

Azaindoles formation, 2, 599 NMR, 4, 499 1-Azaindolizine nucleophilic attack, 4, 458 1-Azaindolizine, 5-chloro-reaction with alkoxides, 4, 458... 

Halopyrimidines also couple with stannanes of heterocycles such as furans [41], azaindoles [42], pyridines [43-46], thiazoles, pyrroles [46] and thiophenes [47], A representative example is the coupling of 3-tributylstannyl-7-azaindole 72 with 5-bromopyrimidine to furnish heterobiaryl 73 after acidic hydrolysis [42]. Moreover, a selective substitution at the 5-position was achieved when 4-chloro-5-iodopyrimidine 74 was allowed to react with 2-thienylstannane to provide thienylpyrimidine 75 [47]. 

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). 

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 ring-closure of isopropyl methyl ketone 3-pyridylhydrazone (181) is said to give exclusively 2,3,3-trimethyl-4-azaindole (182),413 whereas acetone 2-chloro-5-pyridylhydrazone gives 5-chloro-2-methyl 4-azaindole.418 No product of attack at the y-position was reported. 

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). 

Sodium hydride (0.36 mmol) was added to 5-hydroxy-7-azaindole (0.36 mmol) dissolved in 1.5 ml DMF at 0°C, then treated with 4-chloro-5-methylpyrrolo[2,l-f] [l,2,4]triazine-6-carboxylic acid ethyl ester (0.32mmol), and stirred 16 hours at ambient temperature. The reaction was quenched with 20 ml saturated NH4C1 solution, then extracted three times with 25 ml EtOAc, and the extract washed with 50 ml brine. The solution was dried, then concentrated, and the residue purified by preparative HPLC, RT = 7.12 minute. 

The series of unsubstituted, 6-chloro-, and 6-methoxy-4-methyl-7-azaindoles were nitrated at —10° to give the corresponding 3-nitro compounds in 56,57, and 60 %yield, respectively. At 0°, the methoxy isomer gave what appeared to be the 1,3-dinitro compound, which decomposed explosively on heating. 

Robison, and Robison were the first to prepare 7-azagramine (3-dimethylaminoniethyl-7-azaindole), finding the following procedure to give optimum yields. The azaindole, 10% excess dimethyl-amine hydrochloride, and one molar equivalent of paraformaldehyde are refluxed together in w-butanol for 30 minutes, followed by evaporation under reduced pressure. The residue is extracted with dilute acid, from which the base is precipitated with sodium carbonate. This procedure has been used with only minor variations on a variety of 7-azaindoles. Williamson obtained 7-azagramine in 99% yield on a 0.2-mole scale, compared to 81%. Other 7-azagramines prepared similarly are l-phenyl-4-methyl (72%), ° l-butyl-4-methyl (64%), 6-chloro-4-methyl (60%), 4-methyl (28%), 2-methyl, and 5-methyl (60%). In the case of the last two 4-methyl compounds, it was found that the best yields were obtained with use of a 3 1 molar ratio of dimethylamine hydrochloride and only a 15-minute reflux period. With the 6-chloro-4-methyl isomer, some (6%) of the bis-(7-aza-3-indolyl)methylene by-product was formed. 

The Vilsmeier reagent gave 3-carboxaldehydes of 1-phenyl-(76%), 1-butyl- (48%), and 6-chloro- (25%) -4-methyl-7-azaindoles. The aldehydes can also be obtained from the grammes, and this is the way in which 7-azaindole- and 4-methyl-7-azaindole-3-carboxaldehydes were prepared (see Section IV,F,1). 

The treatment of 2,5-dimethyl-4-azaindole with ethyl magnesium bromide, followed by benzyl chloride, gave 3-benzyl-2,5-dimethyl-4-azaindole. Cyanomethylation of 6-unsubstituted, 6-chloro-, and 6-methoxy-4-methyl-7-azaindole with potassium cyanide and formalin in ethanol at 120° gave the corresponding ethyl 3-acetates in 30, 32, and 3 % yields, respectively. No nitrile-containing product was isolated. 

Phenyl-4-methyl-7azaindole-3-carboxaldehyde (148, B = H, R = Ph Scheme 10) was reduced with sodium borohydride to the 3-hydroxymethyl compound (145, R = H, R = Ph) in quantitative yield,whereas the 6-chloro compound (145, R = C1, R = H) was obtained in only 10 % yield. Treatment of 145 (R = H, R =Ph) with thionyl chloride gave the 3-chloromethyl compound (146), isolated in 99 % yield as the hydrochloride. With sodium bicarbonate in water, the 3-chloromethyl salt (146) is hydrolyzed rapidly back to the hydroxymethyl compound (145). An attempt to synthesize the 3-acetonitrile (147) by heating the 3-chloromethyl salt (146) with sodium cyanide in ethanol produced only the bisazaindolylmethylene ether (50%). Use of acetone cyanohydrin gave the acetonitrile (147) (50 %). It was hydrolyzed to give l-phenyl-4-methyl-7-azaindole-... 

Ethyl 4-methyl-7-azaindole-3-acetate (155, R = H), obtained from the attempted cyanomethylation of the indole, was hydrolyzed to the 3-acetic acid (156, R = H) (54%), which was treated in succession by thionyl chloride and ammonia to give the 3-acetamide (157) (78%). Reduction with lithium aluminium hydride gave the azatryptamine (150, R = R = R" = H) in 94% yield. The 6-chloro ester (155, R = Cl) was hydrolyzed also to the acid (156, R = Cl.) ... 

The importance of azaellipticines is illustrated by the fact that 204 (BD-40) is undergoing clinical trials 10,98). Using their new 1-chloroellipticine synthesis (Scheme 20), Bisagni et al. 74) have described an extremely concise route to 10-chloro-5,6-dimethyl-5ff-pyrido[3, 4 4,5]pyrrolo[2,3-g]isoquinoline (208) and the side-chain amine derivatives 209-211 (Scheme 35). Formylation of 1-methyl -5-azaindole (205), followed by reaction with the lithiochloropyridine 124, gave... 

The reactivity of 4-chloro-l-methyl-5-azaindole, for which data is available, towards nucleophilic substitution of chlorine by piperidine can be usefully compared with that of some related systems it is significantly less reactive than the most closely related bicyclic systems, probably due to increased electron density in the six-membered ring resulting from donation from N-1. 

The VNS cyanomethylation of 2-chloro-5-nitropyridine affords the corresponding nitropyridyl-substituted acetonitrile that undergoes hydrogenative cyclization into 5-chloro-6-azaindole (Scheme 68), a key starting material for the synthesis of potential Xa factor inhibitor [186]. 

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