General Synthesis of Unsymmetrical 3,3′-(Aza)diindolylmethane Derivatives

Abstract

Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to their significant biological activities, specifically in cancer prevention and therapy. Molecular targets of DIM have been identified, e.g., the immunostimulatory G protein-coupled receptor GPR84. However, most of the reported and investigated DIM derivatives are symmetrical because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required. In the present study we developed a new, mild and efficient access to unsymmetrically substituted 3,3'-DIMs by reaction of (3-indolylmethyl)trimethylammonium iodides with a wide range of substituted indole derivatives. 7-Azaindole also led to the 3,3'-connected DIM analogue, while 4- and 5-azaindoles reacted at the N1-nitrogen atom as confirmed by X-ray crystallography. The reactions were performed in water without the requirement of a catalyst or other additives. Wide substrate scope, operational simplicity, environmentally benign workup, and high yields are further advantages of the new method. The synthetic protocol proved to be suitable for upscaling to yield gram amounts for pharmacological studies. This procedure will allow the preparation of a broad range of novel, unsymmetrical DIM derivatives to exploit their potential as novel drugs.

Decarboxylative Coupling Reaction of 2‐(1H‐Indol‐3‐yl)acetic Acids with Indole, Azaindole, Benzimidazole and Indazole Derivatives

“…Recently, we reported on a general and efficient synthetic approach towards unsymmetrical DIMs by reaction of (3‐indolylmethyl)trimethylammonium iodides with substituted indole derivatives . Although the reaction is efficient, (3‐indolylmethyl)trimethylammonium iodides have to be prepared as starting compounds requiring an additional step, and the formation of trimethylamine as a by‐product reduces the atom economy.…”

Photoinduced C(sp3)−N Bond Cleavage Leading to the Stereoselective Syntheses of Alkenes

“…On the other hand, cross-couplingp rotocols with amines/ anilines and their derivatives, [9,10] especially ammonium salts [11] as halide analogues, have also been well developed recently. [12][13][14] Amine groups occuri nm any biologically essential compounds and are widely used in industry for the preparation of pharmaceuticals and functional materials. The high stabilityo f aminoC ÀNb onds makes them very resistantt oc leavage reactions.…”

“…[9] Ammonium salts can be easily prepared from various amines/anilines, and such CÀNb onds exhibit higherr eactivity. However, whilea ryl ammoniums have provedh ighly reactive with transition-metal catalysts, [12,13] most alkyl ammoniumsa re quite inert with low-valence metal catalysts, [14] because alkyl CÀNs peciesa re weak acceptors for an electron pair or as ingle electron (SE) from transition metals. In contrast, owing to the low-lyinga romatic p*-orbital, pyridinium salts are excellent electron acceptors.…”

Synthesis of Unsymmetrical Bisindolylmethanes by Reaction of Indolylmagnesium Bromides with Sulfonyl Indoles

“…Gramines ( I , Lg=NR 2 ) can eliminate dialkylamines under basic conditions but this operation usually require high temperatures or special activating procedures . Conversion of gramines into the corresponding ammonium salts ( I , Lg=NR 3 I) allows a ready elimination of a tertiary amine resulting in an efficient addition of several azole derivatives . 3‐(1‐Arylsulfonylalkyl) indoles (sulfonyl indoles I , Lg=SO 2 Ar) have been discovered by us more than a decade ago and since then have emerged as reliable precursors of both cationic intermediates III and alkylideneindolenines V .…”

“…[7b,9] Conversion of gramines into the corresponding ammonium salts (I, Lg=NR 3 I) allows a ready elimination of a tertiary amine resulting in an efficient addition of several azole derivatives. [10] 3-(1-Arylsulfonylalkyl) indoles (sulfonyl indoles I, Lg=SO 2 Ar) have been discovered by us more than a decade ago and since then have emerged as reliable precursors of both cationic intermediates III and alkylideneindolenines V. [11] Sulfonyl indoles can be readily prepared by an acid catalyzed three component coupling of aldehydes, indoles and arylsulfinic acids and this reaction has been previously used for the synthesis of unsymmetrical arylsulfonyl bisindolylmethanes starting from indole-3-carboxaldehydes. [12] The relatively high acidity level of the indole NÀ H bond (pKa = 16.2), makes the corresponding deprotonation quite easy to carry out using commonly available bases.…”