Substituted -5-azaindoles

The preparation of diversely substituted azaindoles is fairly difficult, and there are no generally applicable strategies in the literature. Research by L. Xu et al. showed that 2-substituted-5-azaindoles could be synthesized by the Pd-catalyzed coupling of aminopyridyl iodides with terminal alkynes. The coupling reaction proceeded in good yield under the conditions originally developed by Larock. Therefore, this example can be considered an extension of the Larock indole synthesis. By stopping the reaction early it was shown that the intermediate was an internal alkyne. 

The author explored the reaction chemistry of intermediates 2-6 with isocyanides. Isocyanides bearing less-bulky and bulky substituents led to mono- and bis (iminoacyl)-Zr intermediates, respectively. Upon hydrolysis, the isolated mono (iminoacyl)-Zr intermediates underwent intramolecular cyclization to afford tetra-substituted 5-azaindoles, while intramolecular cyclization of bis(iminoacyl)-Zr intermediates led to the formation of dihydropyrrolo[3,2-c]azepines. Based on the above results, the author developed zirconocene-mediated multi-component coupling of bis(alkynyl)silanes, nitriles, and isocyanides. The structure of a bis(imi-noacyl)-Zr intermediate, formed via insertion of two molecules of CyNC into the Zr-C bond, and structures of two dihydropyrrolo[3,2-c]azepines were characterized by single-crystal X-ray structural analysis (Scheme 2.9). 

Intramolecular Cyclization of i/ -Iminoacyl-Zr Complexes to Form Tetra-substituted 5-Azaindoles or Dihydropyrrolo[3,2-c]azepine Derivatives... 

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... 

Palladium-catalyzed functionalization at the 2-positions of various 5- and 7-azaindoles has been performed by the Suzuki reaction. The 2-substituted azaindoles were obtained in moderate to high yields by using Pd(OAc)2, LiCl, and KOAc in DMF at 110 °C (Eq. (39)) [70]. 

In spite of these reported successes, the Madelung cyclization offers the following disadvantages (i) the drastic conditions necessary limit its application to the synthesis of unsubstituted or alkyl- and aryl-substituted azaindoles (ii) the reaction is often, if not always, intractable and Hi) yields are erratic, often unreproducible, and subject to such variables as stirring and heating efficiency, purity of starting materials, quality (or manufacturer ) of reagents, and operator. 

Obvious disadvantages of the photochemical method, in addition to its lengthiness, are (i) its unproven adaptability to the preparation of substituted azaindoles (ii) its dependence upon the availability of suitably substituted aminopyridines and (in) the difficulties in its application to molar-scale preparations. 

The relative reaction rates of a variety of substituted azaindoles have not been studied quantitatively, making further speculations risky. Other differences in reactivity will be discussed under the appropriate reactions. A detailed study of the effect of the aza-nitrogen s position on chemical properties is glaringly lacking, which is probably due in part to the unavailability of some of the azaindoles. 

Few complete infrared spectra have been reported for the aza-indoles, although some partial band assignments have been made. In most cases, only the functional group frequencies of substituted azaindoles were reported. 

The functional group frequencies for substituted azaindoles will not be discussed here and the following references may be consulted Robison et Yakhontov et aZ.,73.77,8o.8i.84,85.io9 Blatter et al. 

These workers have used ultraviolet absorption to follow the course of dehydrogenation of 4-methyl-7-azaindoline. They also showed the spectra for the diazacarbazole derivatives (161 and 162), and these are like the spectra of the similarly substituted azaindoles. ... 

Yeung KS, Qiu Z, Farkas ME et al (2008) An efficient one-pot synthesis of i-glyoxyhc acids of electron-deficient substituted azaindoles by ionic liquid imidazolium chloroaluminatepro-moted Friedel-Crafts acylation. Tetrahedron Lett 49 6250-6253... 

In agreement with the previous data on the protonation site in azaindoles (76AHCS1, p. 529), an example of monoprotonation of 3-aryl substituted 6-azaindoles at the pyridine ring has been demonstrated by UV speetroseopy [88JCS(P2)1839]. 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

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]. 

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]. 

Other pA a studies include those on 6-substituted 7-azaindoles and 7-azaindolines,377 benzoxazolines and benzoxazolthiones substituted in the 5-, 6-, and 7-positions,378 purines, for which the basic centre appears to be located in the pyrimidine nucleus,379 4,4 -, 5,5 -, 6,6 -, and 7,7 -disubstituted leucothioindigos,380 and dyes (54).381... 

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). 

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]. 

An interesting approach to the synthesis of indoles is the combination of directed orr/w-lithiation followed by an S l reaction324. Thus, the selective or o-lithiation of 2-fluoropyridine (262) by LDA followed by iodination afforded 2-fluoro-3-iodopyridine (263) in high yield (75%). Substitution of the 2-fluorine atom under S Ar conditions is a convenient synthesis of 2-substituted 3-iodopyridines (264) (equation 169), which can react with acetone or pinacolone enolate ions in liquid ammonia, followed by acidic treatment, to give the corresponding substituted 7-azaindoles (265) [R = H, R = Me (75%), R = t-Bu (78%) R = Me, R = f-Bu (70%), R = Me (95%)] (equation 170). 

Sequential orr/w-lithiation, iodination and S l substitution was extended to the three aminopyridines (protected as pivaloylamino derivatives) providing a straightforward access to azaindoles. Thus, lithiation of the 2-,3- and 4-isomers occurred respectively at... 

Imines and enamines, formed from o-haloaminopyridines and ketones, can be converted into substituted 4-, S-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reactions <2005S2571>. 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

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