1,4-azaindoles

Azaindoles show the typical reactivity of both component systems but to a reduced and varying degree, with reduced electron density in the five-membered ring and increased electron density in the six-membered ring. 

Reactions with electrophilic reagents takes place with substitution at C-3 or by addition at the pyridine nitrogen. All the azaindoles are much more stable to acid than indole (c/. section 17.1.1) no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Mannich and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quaternisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. 

Only a few examples of nucleophilic substitution have been reported - displacement of halogen a and 7 to the pyridine nitrogen can be carried out under vigorous conditions or 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.  

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. 

Relative rates for nucleophilic displacement with piperidine in Me0(CH2)20H at I00°C  

Compounds that share the same trifluoroethanol pharmacophore, which is present in the class of the methyl benzoxazinoneamides are under evaluation at Boehringer Ingelheim and GlaxoSmithKline. BI115 is currently the most advanced nonsteroidal GC at Boehringer Ingelheim. 

Efforts have been made to develop a stereoselective synthesis for the trifluoroethanol phamacophore [72]. 

GlaxoSmithKline introduced further derivatizations around the benzylic position of the pentanol methyl benzoxazinoneamides. 

The rigidity of the central structural element can be enhanced by bridging the phenyl substituent producing a tetrahydronaphthalene or a benzocycloheptane. Substituents in the saturated part of the tetrahydronaphthalene lead to full GR agonists with increased potency and efficacy. 

The authors have also extensively studied the indoloquinoline families of alkaloids related to cryptolepine (indolo[3,2-fo]quinoline 57), applying direct and long-range 

In 1995, HSQC data were generated for an 800 [xg sample of quindolinone 

Cryptolepine (57), the parent alkaloid in the series, was studied in 1996 using long-range GHMBC data [83]. In order to observe a correlation to the N-10 

Cryptospirolepinone is the most complex member of the cryptolepis family of alkaloids, constituted as a spiro nonacyclic molecule 5 [85]. The molecule also required the acquisition of multiple long-range H- N spectra to assign all of the N resonances in the structure. Data were acquired with optimizations of 10,6,4, and 2.5 Hz. A single correlation from H-13 to the N-3 resonance was observed only in the 2.5 Hz optimized spectrum, while correlations were readily observable to the other three nitrogen resonance in the structure [86]. 

A 1999 study of the alkaloid cryptolepinone (59) also afforded N chemical shift correlation data for the 5-oxide 60, as this alkaloid undergoes facile air oxidation [87]. While transmitted electronic effects from the oxidized nitrogen to other nitrogen 

---

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

Pyrrolo[2,3-c]pyridines — see also 6-Azaindoles reaction with O-mesitylhydroxylamine, 4, 508 synthesis, 4, 516, 522 tautomerism, 4, 502 UV spectra, 4, 501... 

Pyrrolo[3,2-6]pyridines — see also 4-Azaindoles hydrogen exchange, 4, 502 quatemization, 4, 503 synthesis, 4, 527... 

Indolization of 3-pyridylhydrazone 65(67) gives 4-azaindole 66(69) as the major product. ... 

When the benzamide derivative of 3-picoline 17 was subjected to the cyclization conditions with -BuLi, the reaction failed to yield the desired indole 18. However, when -BuLi was replaced by LDA, the desired azaindole 18 was isolated in 22% yield." ... 

AHCS1, p. 528). Ab initio (STO-3G) calculations of the geometry, eharge distribution, and gas-phase basieity of azaindoles eoneluded that the strueture of five-membered ring is almost unaffeeted by the position of the aza-N atom (83T2851). 

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]. 

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. 

A similar synthesis starting with l-(2-nitrobenzyl)pyrrol-2-aldehyde used ethanol-ethyl acetate as solvent (62). Indoles are prepared in excellent yield by hydrogenation of o-nitrobenzyl ketones over Pd-on-C (i). Azaindoles are correspondingly prepared from nitropyridines (97). 

At its best, the study of solvent kies by the formalism given can be used to learn about proton content and activation in the transition state. For this reason it is known as the proton inventory technique. The kinetics of decay of the lowest-energy electronic excited state of 7-azaindole illustrates the technique.25 Laser flash photolysis techniques (Section 11.6) were used to evaluate the rate constant for this very fast reaction. From the results it was suggested that, in alcohol, a double-proton tautomerism was mediated by a single molecule of solvent such that only two protons are involved in the transition state. In water, on the other hand, the excited state tautomerism is frustrated such that two water molecules may play separate roles. Diagrams for possible transition states that can be suggested from the data are shown, where of course any of the H s might be D s. 

Rate constants" for the excited state decay of 7-azaindole in H/D solvent mixtures... 

This synthetic process is applicable to the preparation of other aromatic nitriles from aldehydes. The submitters have used it to prepare 5-bromoindole-3-carbonitrile, 7-azaindole-3-carboni-trile, j)-chlorobenzonitrile, 3,4,5-trimethoxybenzonitrile, and p-N,N-dimethylaminobenzonitrile.9 There are several advantages to its use. They include (a) readily available and inexpensive reagents, (b) a simple, time-saving procedure, and (c) fair to good yields of nitrile obtained by a one-step method. 

More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CBi receptor (CBp Ki — 0.08 nM CB2 Ki — 1.44nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) [194]. Although these compounds bind to both CBi and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects. 

Additional combinatorial variation sites allow the heterocyclic self-assembly units. Thus, it has been shown that heterocycles 11 and 14-17 can serve as A-analogous donor-acceptor ligands self-assembling with the T-analogous acceptor-donor ligands isoquinolone 12 and 7-azaindole 18 (Scheme 30) [92]. All combinations form the heterobidentate ligands exclusively upon simple mixing in the presence of a transition metal salt (proven by X-ray, NMR). 

---