Efficient Synthesis of 2‐Alkylidene‐3‐iminoindoles, Indolo[1,2‐b]isoquinolin‐5‐ones, δ‐Carbolines, and Indirubines by Domino and Sequential Reactions of Functionalized Nitriles

Abstract

The sodium hydride mediated cyclization of arylacetonitriles with oxalic acid bis(imidoyl) dichlorides, aza-analogues of oxalyl chloride, afforded functionalized 2-alkylidene-3-iminoindoles with very good regio- and E/Z selectivity. Excellent chemoselectivities were observed for functionalized substrates. Based on these results a domino "cyclization-lactamization" reaction of bis(imidoyl) chlorides with methyl 2-(cyanomethyl)benzoate was developed. This process allowed a convenient one-pot synthesis of indolo[1,2-b]isoquinolin-5-ones related to tryptanthrin. A new and convenient synthesis of delta-carbolines by intramolecular electrocyclization-elimination reactions of 2-alkylidene-3-iminoindoles was developed. It was shown that delta-carbolines selectively bind to triplex or duplex DNA (intercalation). Indirubine analogues were prepared by deprotection and lactonization of functionalized 2-alkylidene-3-iminoindoles.

Cyclization Reactions of Dianions in Organic Synthesis

“…The preparative scope of the cyclization reaction was extended to the synthesis of a great variety of 2-alkylidene-3iminoindoles. [15][16][17] A number of substituents could be introduced both at the exocyclic double bond and at the indole moiety by variation of the substituents of the nitrile and of 8, respectively.…”

“…The high E -diastereoselectivity is a result of the steric interaction between the bulky arylimino and the phenyl group. The preparative scope of the cyclization reaction was extended to the synthesis of a great variety of 2-alkylidene-3-iminoindoles. − A number of substituents could be introduced both at the exocyclic double bond and at the indole moiety by variation of the substituents of the nitrile and of 8 , respectively.

7 Cyclization of Dilithiated Phenylacetonitrile with Oxalic Acid-Bis(imidoyl) dichlorides (Mechanism A)

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Overcoming challenges in the palladium-catalyzed synthesis of electron deficient ortho-substituted aryl acetonitriles

“…The pK a values may be only partially relevant, however. There are reports that suggest weak bases such as potassium carbonate (K 2 CO 3 ) 17 and dimethylamino pyridine (DMAP) 18 are able to deprotonate 4. However, in THF the relative acidities of 4-6 might be quite different.…”

Domino Cyclization/Electrocyclization/Elimination Reactions of Arylacetonitriles with N,N′‐Bis(1‐naphthyl)oxaldiimidoyl Dichlorides: Efficient Synthesis of Fluorescent 15H‐Benzo[h]benzo[6,7]indolo[3,2‐b]quinolines

“…We have recently shown that δ-carbolines selectively bind to triplex or duplex DNA (intercalation). [5] The 6H-indolino [3,2-b]quinoline core structure occurs, for example, in the natural products cryptolepine, cryptoquindoline, biscryptolepine and neocryptolepine. [6,7] Cryptolepine and cryptoquindoline were first isolated from the West African plant Cryptolepis sanguinolenta and have been used for the treatment of Malaria.…”

“…We have recently reported [5] a new and efficient approach to 6H-indolino [3,2-b]quinolines by electrocyclization reactions of 2-alkylidene-3-iminoindoles, which are readily available from the reaction of nitriles with oxaldiimidoyl dichlorides. [11,12] Herein we wish to report the direct and efficient synthesis of 15H-benzo[h]benzo [6,7]indolo [3,2-b]quinolines by domino cyclization/electrocyclization/elimination reactions of arylacetonitriles with N,NЈ-bis(1-naphthyl)oxaldiimidoyl dichlorides (Scheme 1).…”