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Especially since the year 2000, the medicinal chemistry literature on pharmaceutically
active 7-azaindole derivatives has increased exponentially; among others, their use
has been reported in the following categories:
<A NAME="RM04807SS-6A">6a</A> As constituents of anti-inflammatories:
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<A NAME="RM04807SS-6E">6e</A> As corticotropin releasing hormone antagonists:
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<A NAME="RM04807SS-6F">6f</A> As antipsychotic agents:
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<A NAME="RM04807SS-6G">6g</A> As antitussive agents:
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Curti R.
Mantovanini M.
Nano G.
Topai A.
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Reeves JD.
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<A NAME="RM04807SS-6J">6j</A> See also:
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Zadjura L.
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<A NAME="RM04807SS-6K">6k</A> As PPARγ modulators:
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de Almeida MV.
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<A NAME="RM04807SS-6Q">6q</A> As gonadotropin releasing hormone antagonists:
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<A NAME="RM04807SS-6R">6r</A> As GSK-3β inhibitors:
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<A NAME="RM04807SS-6S">6s</A> As p38 MAP kinase inhibitors: Expert Opin. Ther. Pat.
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<A NAME="RM04807SS-6T">6t</A> As Rho kinase inhibitors:
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<A NAME="RM04807SS-6U">6u</A> As CDK1 inhibitors:
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<A NAME="RM04807SS-6V">6v</A> As cannabimimetics:
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<A NAME="RM04807SS-6W">6w</A> As antihistamines:
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<A NAME="RM04807SS-6X">6x</A> As melatonin analogues:
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<A NAME="RM04807SS-6Y">6y</A> As staurosporin analogues:
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<A NAME="RM04807SS-23B">23b</A> Bromination of N1-unprotected 1 is unknown. For a high-yielding C3 bromination on N1-benzenesulfonyl protected 1, see:
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Reeves JT.
Tan Z.
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Harcken C.
Liu P.
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<A NAME="RM04807SS-23D">23d</A> Iodination: N1-unprotected 3-iodo-7-azaindole is unstable; selective C3 iodination of N1-BOC-protected 1 is possible:
Herbert R.
Wibberley DG.
J. Chem. Soc. C
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3-formyl compound, see:
Desarbre E.
Mérour J.-Y.
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Tatsugi J.
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4-Halo-7-azaindoles have been used as intermediates for other 4-substituted and also
polysubstituted 7-azaindoles, for recent examples, see:
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Allegretti M.
Arcadi A.
Marinelli F.
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For a more comprehensive overview, see Refs. 3c,d.
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Mazéas D.
Guillaumet G.
Viaud M.-C.
Heterocycles
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For a synthesis of 4,5-disubstituted 7-azaindoles from 4-substituted 7-azaindoles
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Nandan S.
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<A NAME="RM04807SS-33A">33a</A> Metalation and quenching with electrophiles of N1-arylsulfonyl-protected 7-azaindole:
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Mérour J.-Y.
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Tetrahedron
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<A NAME="RM04807SS-33C">33c</A> Arylation of N1-SEM-protected 7-azaindole:
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<A NAME="RM04807SS-34">34</A> Robison et al. had obtained 6-oxo-7-azaindole via dehydrogenation, followed by
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Henze M.
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Katritzky AR.
Lagowski JM.
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Academic Press;
New York:
1971.
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Hayashi E.
Higashino T.
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Fife WK.
Scriven EFV.
Heterocycles
1984,
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Yakhontov LN.
Krasnokutskaya DM.
Akalaev AN.
Palant IN.
Vainshtein YuI.
Khim. Geterotsikl. Soedin.
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Fife WK.
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Heterocycles
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Comins DL.
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Indirect syntheses of 6-amino-substituted 7-azaindoles have been achieved by: (1)
reacting the corresponding 6-halo-7-azaindole with ammonia or amines, but, as a rule,
require extended autoclaving at high temperatures/pressures,35a,b and (2) by extended heating at high temperatures of the corresponding 6-chloro-7-azaindoline
with amines and subsequent oxidation to the azaindole, see:
<A NAME="RM04807SS-37A">37a</A>
Yakhontov LN.
Krasnokutskaya DM.
Akalaev AN.
Dokl. Akad. Nauk SSSR
1970,
192:
118
<A NAME="RM04807SS-37B">37b</A> See also:
Yutilov YuM.
Svertilova IA.
Khim. Geterotsikl. Soedin.
1986,
91
<A NAME="RM04807SS-37C">37c</A> Oxidation/cyclization/elimination/decarboxylation of a 2,6-diaminosubstituted
pyridyl-3-β-keto ester:
Sanders WJ.
Zhang X.
Wagner R.
Org. Lett.
2004,
6:
4527
<A NAME="RM04807SS-38">38</A>
Germain J,
Askew BC,
Bauer D,
Choquette D,
Dipietro LV,
Graceffa R,
Harmanage J.-C,
Huang Q,
Kim JL,
La D,
Li A,
Nishimura N,
Nomack R,
Patel V,
Potashman M,
Riahi B,
Storz T,
Van der Plas S,
Yang K, and
Yuan C. inventors; PCT Int. Appl. WO 2007/048070.
<A NAME="RM04807SS-39">39</A>
Cox PJ,
Majid TN,
Lai JYQ,
Morley AD,
Amendola S,
Deprets S, and
Edlin C. inventors; PCT Int. Appl. WO 2001047922.
<A NAME="RM04807SS-40">40</A>
Shiotani S.
Taniguchi K.
J. Heterocycl. Chem.
1997,
34:
493
<A NAME="RM04807SS-41">41</A>
CAS & Beilstein online searches, June 2007.
<A NAME="RM04807SS-42">42</A>
The MCBA salt 3 is the most practical way to isolate the N-oxide 2 as it readily precipitates from a number of nonpolar solvents during the oxidation
of 1 with MCPBA (cf. refs. 27b,d,e). On the other hand, upon freebasing, 20%27d to 50%27e loss is typically incurred due to the high water solubility of 2.
<A NAME="RM04807SS-43">43</A>
Methyl ester formation of MCBA was also not observed.
<A NAME="RM04807SS-44A">44a</A> Ochiai and Nakayama were the first to report the formation of a cyanopyridine
(2-cyano-4-chloropyridine) from the reaction of cyanide with the corresponding O-alkyl pyridinium salt:
Ochiai E.
Nakayama I.
Yakugaku Zasshi
1945,
65:
7 ; Chem. Abstr. 1945, 45, 49933
The reaction was rediscovered and expanded independently by Okamoto/Tani and Feely/Beavers:
<A NAME="RM04807SS-44B">44b</A>
Okamoto T.
Tani H.
Chem. Pharm. Bull
1959,
7:
130
<A NAME="RM04807SS-44C">44c</A> See also:
Okamoto T.
Tani H.
Chem. Pharm. Bull
1959,
7:
925
<A NAME="RM04807SS-44D">44d</A> See also:
Okamoto T.
Tani H.
Chem. Pharm. Bull
1959,
7:
930
<A NAME="RM04807SS-44E">44e</A> See also:
Feely WE.
Beavers EM.
J. Am. Chem. Soc.
1959,
81:
4004
For later reports, see:
<A NAME="RM04807SS-44F">44f</A>
Matsumura E.
Ariga M.
Ohfuji T.
Bull. Chem. Soc. Jpn.
1970,
43:
3210
<A NAME="RM04807SS-44G">44g</A>
Botteghi C.
Schionato A.
Chelucci G.
Brunner H.
Kürzinger A.
Obermann U.
J. Organomet. Chem.
1989,
370:
17
<A NAME="RM04807SS-44H">44h</A>
Ashimori A.
Ono T.
Uchida T.
Ohtaki Y.
Fukaya C.
Watanabe M.
Yokoyama K.
Chem. Pharm. Bull.
1990,
38:
2446
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Hibino S.
Sugino E.
J. Heterocycl. Chem.
1990,
27:
1751
<A NAME="RM04807SS-44J">44j</A>
See also reviews cited in ref. 36.
<A NAME="RM04807SS-45">45</A>
A solvent screen for the O-methylation of 3 with dimethyl sulfate (data not shown) revealed MeCN(homogeneous) and butyl acetate(biphasic)
as the most favorable solvents. In MeCN, the O-methylation is very clean and proceeds
at a somewhat lower (55-60 °C) temperature than in butyl acetate (85-90 °C). On the
other hand, butyl acetate results in a clear biphasic mixture with a lower, purple
N-oxide salt phase (‘ionic liquid layer’), that can be readily separated and employed
for reaction with nucleophiles in other solvents, and a clear, upper phase (butyl
acetate) containing most of the m-chlorobenzoic acid. Although the cyanide reaction also proceeds under nonaqueous
conditions, NH4Cl-buffered aqueous cyanide provides the cleanest reaction and highest yield. A ‘blank
reaction’ with NH4Cl alone did not yield the 6-chloro product, in accordance with the observations made
with tetraalkylammonium halides under forcing conditions (vide infra).48
<A NAME="RM04807SS-46">46</A>
Increasing the steric bulk of the alkylating agent (EtI, i-PrI) did not change the regioselectivity. Other cyanating reagents [BzCN, TMSCN,62 (EtO)2P=O(CN)63] did not lead to cyanated azaindole (data not shown).
<A NAME="RM04807SS-47">47</A>
As clearly evidenced by 3
J
4,5 (8 Hz), which is the typical coupling observed between the m-, and p-protons in ortho-substituted pyridines.64
<A NAME="RM04807SS-48">48</A>
Contrary to Ohshiro’s report35 (vide supra, Scheme
[1]
), 6-chloroazaindole was not observed as a side-product under our conditions. In test
reactions of 4 with TBACl, TBABr and TBAI under forcing conditions (data not shown), no reaction
occurred with the chloride, whereas the bromide and iodide reacted via the demethylation
pathway (formation of MeBr and MeI, respectively). Thus, it appears the nature of
the leaving group at N7 strongly determines the site of nucleophilic attack at the
ambident electrophile 4.
<A NAME="RM04807SS-49A">49a</A>
Vorbrüggen H.
Krolikiewicz K.
Synthesis
1983,
316
<A NAME="RM04807SS-49B">49b</A>
Fife WK.
J. Org. Chem.
1983,
48:
1375
<A NAME="RM04807SS-50">50</A> In pyridine chemistry, 2-(alkyl/aryl)sulfonyl groups are often used to introduce
heteroatom substituents ortho to the ring nitrogen; as a rule, they are more reactive than the corresponding 2-halo
compounds, see:
Furukawa N.
Ogawa S.
Kawai T.
Oae S.
J. Chem. Soc., Perkin Trans. 1
1984,
1839
<A NAME="RM04807SS-51">51</A> The reactivity of the O-methyl-7-azaindole-N-oxide salt 4 towards alcoholates, thiolates and azoles was somewhat surprising considering the
earlier unsuccessful attempts to obtain the same types of addition products from Reissert-Henze
reactions of N-methoxypyridinium salts, see: Kiselyov A. S., Strekowski L.; J. Heterocycl. Chem.; 1993, 30: 1361
<A NAME="RM04807SS-52">52</A>
In the absence of a stronger base (typically Hünig base or K2CO3), N-methylation of the azoles dominates (data not shown). 6-N-(Heteroaromatic)-substituted 7-azaindoles have not been reported (CAS/Beilstein,
July 2007). Trace amounts of the 4-isomer are readily removed during purification;
all yields are isolated yields for chromatographed products (typically ≥95A% HPLC).
<A NAME="RM04807SS-53">53</A>
Crude 6-amino adducts are typically ∼85A% LC-pure already and require minimal purification.
<A NAME="RM04807SS-54">54</A>
It is more convenient to isolate the hitherto unknown MCBA complex 28 of 4-chloro-7-azaindole-N-oxide than the free base, since the isolation of the latter typically leads to reduced
yields.27b,28 A convenient protocol is given in the experimental part (vide supra).
<A NAME="RM04807SS-55">55</A>
Chiral N-(7-azaindolyl)-α-amino acids have not been reported (CAS/Beilstein searches July
2007).
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Katritzky AR.
Lunt E.
Tetrahedron
1969,
25:
4291
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Abramovitch RA.
Smith EM.
Chem. Heterocycl. Comp.
1974,
14 (Suppl. 2):
1
<A NAME="RM04807SS-58">58</A>
Contrary to the behavior of the corresponding N,O- and
N,S-isosters of pyrrolo[2,3-b]pyridine, where both thieno[2,3-b]-65 as well as furo[2,3-b]pyridine-N-oxide40 have been reported to give the α-cyanated product in good yields in the Reissert-Henze
reaction with benzoyl chloride and cyanide.
<A NAME="RM04807SS-59">59</A> For pyridinium salts, regioselectivity of nucleophilic attack to yield either
1,2- or 1,4-dihydropyridines has been explained by the formation of charge-transfer
complexes,62 by Pearson’s HSAB-concept,66 and by kinetic versus thermodynamic control;67 for a review, see:
Poddubnyi IS.
Chem. Heterocycl. Comp.
1995,
31:
682
<A NAME="RM04807SS-60">60</A> To the best of our knowledge, no other reports on Reissert-Henze type reactions
of 7-azaindole-N-oxide have appeared in the literature (CAS/Beilstein searches June 2007). On the
other hand, Popp et al. had reported on a failed attempt to obtain cyanated azaindole
via the classical Reissert reaction conditions:
Veeraraghavan S.
Popp FD.
J. Heterocycl. Chem.
1981,
18:
909
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Still WC.
Kahn M.
Mitra A.
J. Org. Chem.
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Kosower EM.
J. Am. Chem. Soc.
1956,
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Harusawa S.
Hamada Y.
Shioiri T.
Heterocycles
1981,
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Pretsch E.
Seibl J.
Clerc T.
Simon W.
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Springer-Verlag;
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Klemm LH.
Muchiri DR.
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1983,
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Lyle RE.
Gauthier GJ.
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