PhI(OAc)2-mediated intramolecular oxidative C–N coupling and detosylative aromatization: an access to indolo[2,3-b]quinolines

A PIDA mediated intramolecular oxidative C–N coupling and subsequent detosylative aromatization to afford indolo[2,3-b]quinoline derivatives has been developed. This tandem reaction provided an efficient method for the synthesis of valuable indolo[2,3-b]quinoline derivatives.

Under mild conditions, PIDA mediated oxidant C–N coupling to afford indolo[2,3-b]quinoline derivatives has been developed with a decent substrate scope.

Indolo[2,3-b]quinolones are a kind of important poly-fused heterocycle, commonly occurring in many natural products and synthetic drugs (Fig. 1).¹ These compounds usually display diverse biological activities² such as anticancer,³ antiplasmodial,⁴ molluscicidal,⁵ and antimalarial activity⁶etc. Due to their importance, their efficient synthesis attracts chemists'' interest and many synthetic methods have been developed.⁷ Among these established methods, indolo[2,3-b]quinolones are usually prepared through construction of a pyridine cycle with indole derivatives as the starting materials catalysed by transition metals.⁸ The more attractive metal-free methods avoiding the metal contamination of products have also been reported.⁹ Initially, indole-3-aldehydes or o-amino benzaldehydes were used; these compounds were usually unstable and difficult to prepare. In 2012, Liang and co-authors reported an efficient synthesis from indoles and o-sulfamidoaryl ketones.¹⁰ This reaction is a two-step process involving iodine-promoted amination/intramolecular cyclization and subsequent detosylation in 12 M HCl. The direct intramolecular cyclization of indole derivatives through oxidative C–N coupling and detosylative aromatization was also reported. In 2016, Sekar and co-authors pioneering used Ts (4-benzenesulfonyl) as the activating group for amino group under heat (Scheme 1A).¹¹ In this reaction, 1.2 equiv. sublimed and corrosive I₂ was used as the oxidant and 2 equiv. Cs₂CO₃ as the base, only 5 examples were demonstrated. Very recently, using the special Ns (4-nitrobenzenesulfonyl) to activate the amino group, Ishihara and co-authors achieved the reaction at room temperature through iodine catalysis (Scheme 1B).¹² This reaction required 3–5 equiv. hazardous TBHP as the oxidant and relatively long reaction time (12–48 h).Open in a separate windowFig. 1Selected examples of bioactive indolo[2,3-b]quinoline derivatives.Open in a separate windowScheme 1Metal-free intramolecular cyclization for preparing indolo[2,3-b]quinolones.PhI(OAc)₂ is a common oxidant used in annulation reactions due to its easy operation and environmental benignity.¹³ With our continuing interest in exploding synthesis of heterocyclic compounds,¹⁴ we envisioned that this reaction might also be achieved with the use of PhI(OAc)₂ as the oxidant. Indeed, it worked well under the mild reaction conditions with the amino group being activated by 4-chlorobenzenesulfonyl group (Scheme 1C).Stirring a mixture of 1a and 1.2 equiv. PhI(OAc)₂ in DCM at room temperature for 12 h under an Ar atmosphere gave the product 2a in 10% yield († for details).Optimization of the reaction conditions^a

Entry	Temp. (°C)	Solvent	Yieldb (%)
1	rt	DCM	10
2c	rt	DCM	Trace
3	rt	THF	28
4	rt	Dioxane	19
5	rt	PhCF3	16
6	rt	TFE	51
7	rt	HFIP	67
8d	rt	HFIP	15
9	0	HFIP	43
10	0–rt	HFIP	82
11e	0–rt	HFIP	86

Open in a separate window^aReaction condition: 1a (0.2 mmol), PhI(OAc)₂ (0.24 mmol), solvent (2 mL), rt, Ar, 12 h.^bIsolated yield.^cPhI(TFA)₂ was used instead.^d0.4 mmol PhI(OAc)₂.^e1b was used instead.With the optimal reaction conditions in hand, we then investigated the substrate scope (