1- Methyl-7-azaindole

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

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]. 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

In a similar vein, tris-aluminium complexes have been reported in which related 2-methyl- and 2-phenyl-substituted azaindoles use their two N-centres to bridge two Group 13 metal centres. In either case the oxide itself adopts a trigonal planar geometry (angles sum to 360.0° and 359.7°, respectively) with... 

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. 

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). 

Diazaindenes ( Azaindoles ). Part II. Methyl Derivatives of 1,7-Diazaindene. (With R. Willette.)... 

Similarly, Clemo and Swan synthesized 7-azaindole (2) and its 2-methyl and 2-ethyl derivatives in low yields (3, 17, and 12 %. respectively). They failed to improve the yield by use of potassium... 

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 Robison s modification was employed for the S3mthesis of 4-azaindole, and 4-, 5-, and 6-methyl-7-azaindoles. ... 

Methyl-7-azaindole was prepared in 35 % yield by this sequence. To date it is the best method for the synthesis of 5- and 7-azaindole, and serves as a commercial preparation for the latter. 

Recent work on the thermal indolization of arylhydrazones has introduced new synthetic possibilities for azaindoles. Kelly et al. refluxed cyclohexanone and deoxybenzoin 2-pyridylhydrazones in diethylene glycol to give 5,6,7,8-tetrahydro-a-carboline (42, R = H) and 2,3-diphenyl-7-azaindole in 70 and 56% yields, respectively, compared with 53 and 12% reported earlier. Similarly, y-carboline 29 was obtained in 95 % yield from cyclohexanone 4-pyTidylhydrazone (lit. 48% ). Several 7-azaindole derivatives were prepared in the same manner. The yields ranged from 5 % for azaindolenine (31) to 88% for 3-phenyl-7-azaindole. 3,3-Dimethyl-7-azaindolenine was obtained in 47 % yield from the isobutyralaldehyde hydrazone. The novel cyclic compounds 40 and 41 were obtained from the 2-pyridylhydrazones of cyclopentanone, a-indanone, and a-tetralone in 67, 95, and 77% yields, respectively. Unfortunately, all attempts to cyclize the acetone, pyruvic acid, and ethyl pyruvate hydrazones were unsuccessful. Also, cyclohexanone and methyl ethyl ketone 5-nitro-2-... 

Crooks and Robinson have used this method to prepare 2,3-dimethyl-5-azaindole in 14.5% yield from isobutyraldehyde 4-pyridylhydrazone, obtaining none of the expected 3,3-dimethyl-5-azaindolenine. The ethyl methyl ketone hydrazone gave the same azaindole in 51.5% yield. These authors also suggest that the 3,3-dimethyl-7-azaindolenine reported by Kelly and Parrick is in fact the rearranged product 2,3-dimethyl-7-azaindole. There is no evidence to date to support either structure. 

Similar reactions were reported recently starting with 2-methyl-7 azaindole. The intermediate 2-methyl-7-azaindoline was used to prepare 5-hydroxy-, 5-methoxy-, 5-benzyloxy-, and 5-dimethylamino-... 

Cookson condensed 3-hydroxyimino-l-methyl-4-piperidone with ethyl acetoacetate in the presence of zinc to give ethyl 4,5,6,7-tetrahydro-2,6-dimethyl-6-azaindole-3-carboxylate, which was oxidized with mercuric acetate to the 6,7-dihydro compound. 

Clemo and Swan found that 2-methyl- and 2-ethyl-7-azaindole were reduced more reliably with copper chromite as catalyst under 160 atm of hydrogen at 180°. 2-Methyl-7-azaindoline (98, R = Me) was obtained in 42 % yield. They reported that Kruber s conditions gave mostly gums, from which only a little of the A-benzoyl derivatives could be isolated. Recently, however, 2-methyl-7-azaindoline (98, R = Me) was prepared on a 0.7-mole scale by use of Raney nickel under conditions identical to those used by Kruber, although no yield was reported. ... 

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