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The Science of Synthesis Editorial Board, together with the volume editors and authors, is constantly reviewing the whole field of synthetic organic chemistry as presented in Science of Synthesis and evaluating significant developments in synthetic methodology. Four annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.
J.-Y. Mérour and B. Joseph
Formally, azaindoles are the products of replacing the benzene ring of indole with a pyridine ring. This results in four isomeric azaindoles: 1H-pyrrolo[3,2-b]pyridine (1, 4-azaindole), 1H-pyrrolo[3,2-c]pyridine (2, 5-azaindole), 1H-pyrrolo[2,3-c]pyridine (3, 6-azaindole), and 1H-pyrrolo[2,3-b]pyridine (4, 7-azaindole; ? Scheme 1). These systems are occasionally called diazaindenes: 1,4-diazaindene (1), 1,5-diazaindene (2), 1,6-diazaindene (3), and 1,7-diazaindene (4).
Scheme 1 Structures of Azaindoles
Historically, the first azaindole derivative was synthesized by Fischer in 1885 by decomposition of harmonic acid[1] and it was later identified as 7-methyl-1H-pyrrolo[2,3-c]pyridine (5) by Perkin and Robinson.[2,3] In 1943, 1H-pyrrolo[2,3-b]pyridine (4) was isolated from coal tar by Kruber.[4] Simple azaindole structures do not occur in nature but polycyclic 1H-pyrrolo[2,3-b]pyridine derivatives 6-9 named variolins were isolated in 1994 from the Antarctic sponge Kirkpatrickia variolosa (? Scheme 2). Variolins are the first examples of either terrestrial or marine natural products with an azaindole framework.[5,6]
Scheme 2 Structures of 7-Methyl-1H-pyrrolo[2,3-c]pyridine and Variolins[5,6]
A very important feature of azaindole derivatives, compared to those of indole, is the association of an electron-rich pyrrole ring fused to an electron-poor pyridine ring. Azaindoles show the typical reactivity of both component systems with a reduced and varying degree that decreases electron density in the five-membered pyrrole ring and increases electron density in the six-membered pyridine ring. Functional-group transformations of both rings and side-chain substituents generally proceed normally. Perhaps most significant to azaindole transformations are: (1) the use of organometallic, particularly organolithium, derivatives as nucleophiles, and (2) cross-coupling processes, most often using palladium as catalyst, with halogen, tin, zinc, boron, and trifluoromethanesulfonate derivatives of azaindoles. Several excellent general reviews of azaindole chemistry are available.[7-19]
The electronic structures have been the subject of numerous theoretical studies. In 1976, a SCF-CI p-electron semiempirical method showed that the nitrogen of the pyrrole ring is a p-donor and a s-acceptor whereas the nitrogen of the pyridine ring is a s- and p-acceptor.[20] In 1983, Catalán and co-workers carried out ab initio calculations using a STO-3G minimal basis set for the four azaindoles and their tautomeric forms (? Table 1).[21,22] The most interesting features are the minimal dependence of the charge distribution of the five-membered ring depending on the position of the pyridine nitrogen atom. The geometry of the pyrrole ring is also little affected in the four isomeric azaindoles. As for indoles, the C3 of azaindoles possesses the highest electronic density, which correlates with experimental behavior, but Catalán found that azaindoles are less reactive than indole toward electrophilic reagents. Comparison of the fused pyridine ring to pyridine itself shows C4 and C6 of 1H-pyrrolo[2,3-b]pyridine to be the likely sites of nucleophilic attack, but they show less electron depletion than the C2 and C4 of pyridine itself. In prototropic tautomerism, the accumulation of charge is found at C3 and N1 as indicated by ab initio calculations and in the drawings of resonance contributors. Other ab initio studies have been performed on substituted azaindoles.[22,23]
Table 1 Charge Densities for Azaindoles[21]
A semiempirical AM1 study was carried out to calculate the enthalpies of formation, ionization energies, electron affinities, energy differences between HOMO and LUMO, atom charges, bond orders, and dipole moments (? Table 2).[24,25] The stability of the four azaindoles decreases in the order: 1H-pyrrolo[3,2-c]pyridine (2)>1H-pyrrolo[2,3-c]pyridine (3)>1H-pyrrolo[3,2-b]pyridine (1)>1H-pyrrolo[2,3-b]pyridine (4).
Regarding the values of dipole moments, 1H-pyrrolo[3,2-b]pyridine (2) is the most polar and 1H-pyrrolo[2,3-b]pyridine (4) is the least polar compound, which reflects to some extent the value of the charge on the N1 atom.[24]
The values of the charges on carbons C2 and C3 (q2 and q3) indicate that C3 is a nucleophilic center (as in indole, ? Table 2). In addition it seems that 1H-pyrrolo[3,2-c]pyridine (2) is the most reactive and 1H-pyrrolo[3,2-b]pyridine (1) is the least reactive. The authors established a correlation between the calculated physicochemical parameters and the Hammett para substituent and inductive constants.
Table 2 Ionization Energies, Dipole Moments, and Atom Charges of Azaindoles[25]
1H-Pyrrolo[2,3-b]pyridine (4) can exist in a second tautomeric form, 7H-pyrrolo[2,3-b]pyridine (10), as shown by spectroscopic methods. The difference in enthalpy between the two forms is 66.9 kJmol-1, which indicates an endothermic process for the N1 to N7 proton transfer (? Scheme 3). It is assumed that this process occurs via dimer formation.[25,26] For the three other isomers, the enthalpy of activation for such a process is high, precluding the existence of comparable tautomeric forms. Other AM1 studies have been performed on substituted azaindoles.[27-29]
Scheme 3 Tautomeric Equilibrium of 1H-Pyrrolo[2,3-b]pyridine and 7H-Pyrrolo[2,3-b]pyridine[25]
In 10% deuterated sulfuric acid (D2SO4), a slow hydrogen exchange occurs only at C3 for 1H-pyrrolo[3,2-b]pyridine (1) and 1H-pyrrolo[3,2-c]pyridine (2). At 150 °C in 27.5% deuterated sulfuric acid, the same C3 exchange is observed with 4-methyl-1H-pyrrolo[2,3-b]pyridine with additional exchanges at C2 and C5.[30]
Indole derivatives do not show appreciable basic properties but this is not the case for azaindoles. Of the two nitrogen atoms present in an azaindole, only the pyridine nitrogen shows appreciable basicity because the lone pair is not involved in the aromaticity. The various pKa values for...
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