Synthesis of Chromenoimidazoles, Annulated with an Azaindole Moiety, through a Base-Promoted Domino Reaction of Cyanomethyl Quaternary Salts

The reactivity of N -cyanomethyl quaternary salts of 4-, 5- and 7-azaindoles towards salicylic aldehydes has been studied. The interaction of azaindolium salts with salicylic aldehydes proceeds as a base-promoted domino reaction, giving the corresponding chromenoimidazopyrrolopyridines. In the case of the 7-(cyanomethyl)-7-azaindolium salt, the reaction was found to be more sensitive, but the use of the 1-methyl-substituted salt allowed the synthesis of the desired compounds, incorporating the heterocyclic core of isogranulatimide C, a marine natural product.

Imidazoles annulated with a pyrrolopyridine (azaindole) moiety are known for their antiviral 1 and antitumor 2 activities. An imidazopyrrolopyridine fragment appears in the isogranulatimides (Figure 1), marine natural products isolated from the Brazilian ascidian Didemnum granulatum, which show high inhibitory activity against the G2 DNA damage checkpoint, the kinases Chk1 (IC 50 = 0.1 μM) and GSK-3 beta 3 and various other kinases. 4 Their analogues also exhibit high antiproliferative 5 and Chk1 inhibition 6 activities.
Imidazoles annulated with chromenes A (Figure 1) have recently been characterized as cytotoxic agents against HCT116 cancer cells due to their ability to induce cell cycle arrest and apoptosis without significant effects on normal cells. 7 Synthetic approaches toward the imidazopyrrolopyridine core of isogranulatimides are usually based on the construction of the pyridine ring. 8 The current project in-volves the preparation of imidazopyrrolopyridines fused with a chromene moiety through a base-promoted domino reaction of isomeric N-(cyanomethyl)azaindolium salts with o-hydroxybenzaldehydes, creating the imidazole and pyran cycles in an effective manner. 9 Recently, preliminary studies of 6-(cyanomethyl)pyrrolo [2,3-c]pyridinium salt reactivity showed the possibility of transforming such salts into chromenoimidazopyrrolopyridines, incorporating the heterocyclic core of isogranulatimide A (Scheme 1). 10 The potential of this reaction in the construction of different isomeric chromenoimidazopyrrol-

Paper Syn thesis
opyridines, among other things comprising the isogranulatimide C heterocyclic core, is the subject of this paper.
First, N-(cyanomethyl)azaindolium salts 1-3 were prepared by alkylation of the corresponding heterocycles with chloroacetonitrile or bromoacetonitrile in acetonitrile (Scheme 2). The yields for compounds 2 and 3 were 80% and 83%, respectively; the 1H-7-azaindole, which is the least nucleophilic in the azaindole series, was alkylated to give 1a in 79% yield. In the case of 1-methyl-1H-7-azaindole, the steric hindrance of the methyl group necessitated the use of the more reactive bromoacetonitrile, to provide quaternary salt 1b in 61% yield.

Scheme 2 Synthesis of N-cyanomethyl salts 1-3
The reaction of 7-(cyanomethyl)-7-azaindolium salt 1a with salicylic aldehydes under the conditions earlier optimized for the 6-azaindolium salt did not result in the formation of the target polycyclic product of the domino process, but gave coumaryl-substituted 7H-7-azaindoles 4a-c (Scheme 3). The structure of compound 4a was determined by 1 H, 13 C and 15 N NMR spectroscopy using 2D COSY, TOCSY, NOESY, HSQC, edited HSQC, HMBC, long-range HMBC, and 15 N HMBC experiments (for details, see the Supporting Information). A possible reason for this reaction pathway is initial deprotonation of N-1 and formation of the anhydrobase of the azaindole. In the absence of a positive charge on N-7 of the azaindole, the reaction loses its driving force, the intermediate B is hydrolyzed, and the final cyclization does not occur (Scheme 3). In an effort to overcome the problem, 7-(cyanomethyl)-1-methyl-7-azaindolium bromide (1b) was tested in the analogous reaction. Despite the absence of N-H in salt 1b and the impossibility of forming anhydrobases, the process still followed the undesired pathway, giving compounds 5a-d. It was hypothesized that performing the reaction under water-free conditions might avoid the hydrolysis of the imine intermediate. Therefore, the reaction was carried out in MeOH or DMF under argon atmosphere in the presence of different desiccants, including molecular sieves, and anhydrous magnesium and copper sulfate, and employing anhydrous sodium carbonate and alternative bases, but it still resulted in the formation of

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hydrolysis product 5a (Table 1, entries 1-6). Presumably, the water formed during the condensation is enough for the hydrolysis to proceed. Fortunately, performing the reaction under microwave (MW) irradiation in absolute ethanol, with molecular sieves and anhydrous potassium carbonate, eventually led to the formation of the desired products 6ac in moderate yields (Scheme 3).
The use of DBU ( . The modest yields may be associated with the instability of the products 6 under the reaction conditions and the reduction of the reaction times, achieved under microwave conditions, explains the success of the microwave approach. The optimized conditions were utilized to examine the scope of the reaction of 5-azaindolium salt 2 (Scheme 4). Thus, annulated pyrrolopyridines 7a-e were synthesized in 70-87% yield. The preparation of compounds 7 was not as sensitive to the presence of water and the reaction time; for instance, compound 7a was produced in 64% yield after reflux for 8 hours with ammonium acetate in a watermethanol mixture.
The optimized conditions were also employed to examine the reactivity of 4-(cyanomethyl)-4-azaindolium salt 3 in the domino process. Thus, it was shown that the reaction proceeded analogously, giving isomeric chromenoimidazopyrrolopyridines 8a-d (Scheme 5).
The proposed reaction mechanism is as follows: (a) Knoevenagel condensation of the salicylic aldehyde with the quaternary pyrrolopyridine salt followed by (b) nucleophilic cyclization of the phenolate anion, another (c) nucleophilic cyclization, and (d) aromatization of the imidazole to yield the target product (Scheme 6).
In conclusion, we have studied the domino reaction of 4-, 5-and 7-azaindolium salts with substituted salicylic aldehydes. The target chromenoimidazopyrrolopyridines

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were formed in all cases, providing a reliable route towards analogues of the isogranulatimide marine natural products family.

Compounds 4 and 5; General Procedure
To a solution of salt 1a or 1b (0.991 mmol) and the corresponding aldehyde (0.991 mmol) in a MeOH-H 2 O mixture (1:1, 4 mL) was added NH 4 OAc (0.991 mmol) at reflux. The reaction mixture was stirred under reflux for 3 h. Upon reaction completion, the solvent was evaporated under reduced pressure and the product was isolated by silica gel column chromatography (MeOH-CH 2 Cl 2 , 1:100 to 1:10).

Compounds 6; General Procedure
A solution of salt 1b (0.13 g, 0.516 mmol) and the corresponding aldehyde (0.512 mmol) in anhyd EtOH (4 mL) with K 2 CO 3 (0.173 g, 2.2 equiv) in a closed vial was placed into a microwave reactor, where it was heated at 150 °C for 7 min. Upon reaction completion, the mixture was diluted with H 2 O (8 mL) and EtOH (3 mL), and the formed precipitate was collected by filtration, washed with an EtOH-H 2 O mixture (7:8) (3 × 3 mL) and dried under air.

Paper Syn thesis
was heated at 150 °C for 7 min. Upon reaction completion, the mixture was diluted with H 2 O (10 mL), and the formed precipitate was collected by filtration, washed with EtOH (2 × 3 mL) and with H 2 O (1 × 3 mL), and dried under air.