4-, 5-, 6-, 7-Azaindoles basicity

A bicyclic system, 5-azaindole, may be mentioned here because it owes its relatively high basic strength (p/sTg = 8 3) to a resonance stabilization of the cation [71] which is analogous to that of 4-aminopyridinium ion (Adler and Albert, 1960). Nmr spectra of the cations of 5-azaindole and its 1-phenyl derivatives have recently been reported (Dvoryantseva et al., 1973). 

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... 

If the basic center in the ESPT molecule is not suitably disposed to form a direct hydrogen bond with the dissociable proton, involvement of protons from the solvent medium becomes necessary and the processes is biprotonic (e.g., 5- and 6-aminoindazole [68,69], 7-azaindole monomer [70]). This type of ESPT has recently been called ESDPT. The dimer of 7-aminoindazole shows ESDPT between the two monomeric units that are suitably hydrogen-bonded [71]. Femtosecond studies by Douhal et al. [72] has suggested a mechanism in which the two protons are transferred in sequence. Some other molecules in which ESDPT has been observed are I-II-pyrrolo[3,2-//]quinoline [73], [2,2 -bipyridyl]-3,3 -diol [74,75],... 

AHCS1, p. 528). Ab initio (STO-3G) calculations of the geometry, charge distribution, and gas-phase basicity of azaindoles concluded that the structure of five-membered ring is almost unaffected by the position of the aza-N atom (83T2851). 

Several modifications of the Mannich reaction were tried with 5-azaindole, but no isolatable product could be obtained. Since the Mannich conditions are usually acidic (pH 5-7), it seems the difference in reactivity between 5- and 7-azaindole can be accounted for by the greater basic strength (pK 8.26 ) of the former compared to the latter (pK 4.59 ). As noted above, protonation of the pyridine nitrogen has the effect of lowering the electron availability at the 3-position. Under the conditions of the reaction 5-azaindole would exist almost entirely in the protonated form (101), which is stabilized by resonance with the pnra-quinonoid canonical form (102), thus lowering the electron density of the pyrrole ring further. Protonation of 7-azaindole would be only partial, with mostly neutral molecule present. Also, the orfAo-quinonoid form (104) of the protonated species (103) is unimportant (see Section V,B,2). 

The relative basic strengths of the parent azaindoles have been explained on the basis of resonance stabilization of the cations. -In the case of protonated 5-azaindole (101) and. 6-azaindole (171) resonance with the para-quinonoid forms 102 and 172 adds to greater stabilization than the or Ao-quinonoid type necessary for the cation pairs 103<->104 and 173<-> 74. Further, if the azaindoles are regarded as substituted aminopyridines, comparison with suitable model compounds permits a reasonable evaluation of the pK values. A vinyl group is base-weakening (-1) in the 3-position of pyridine accounting... 

It was noted above (Section IV,C,3) that the failure of 5-azaindole to undergo the Mannich reaction could be accounted for by its high basic strength. Difficulty might be expected also for 6-azaindole, and less so for 4-azaindole. The only attempt reported was successful with ethyl 5-methoxy-6-azaindole-3-carboxylate, but the predicted pK for 5-methoxy-6-azaindole would be ca. 5.9, which may be lowered further by the electron-withdrawing ester group. It will be of interest to see how the parent azaindoles differ in these reactions. 

Adler and Albert have reported the partition coefficients for the parent azaindoles. The oleyl alcohol-water solubility ratio for the neutral molecules at 25° are 53.2, 36.8,17.3, and 13.1 for 7-, 6-, 5-, and 4-azaindole, respectively. For comparison, indole, which is not basic, is more lipid-soluble, with a ratio of 85.7. The order for the azaindoles does not parallel their basic strength. The per cent of ionization at pH 7. 4 was also calculated and for the above order is 0.15,78.02, 87.87, and 27.75%, respectively. The effects of these properties on the biological activity of the azaindoles is discussed also (see below). 

In the synthesis of Vemurafenib (Scheme 26) the 5-bromo-7-azaindole part of 113 is made by a Sonogashira reaction (Scheme 42) [73]. Thus, reaction between pyridine 161 and 2-methyl-but-3-yne-2-ol 162 catalysed by PdCl2(PPh3)2, Cul and Et3N yielded the protected pyridine-acetylene 163 in 93% yield. This was deprotected under basic conditions to yield 164, which was cyclised to 165 using tBuOK in NMP for an overall 62% yield. 

---