Versatile ruthenium(II)-catalyzed C–H cyanations of benzamides

Abstract

Direct cyanations of arenes and heteroarenes bearing only weakly coordinating amides were accomplished using a robust ruthenium(II) catalyst. The user-friendly C(sp²)–H activation occurred with the assistance of carboxylate with high site-selectivity, excellent functional group tolerance and ample scope.

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Aromatic nitriles constitute key structural motifs of important pharmaceuticals, dyes, agrochemicals and natural products.^1–3 The cyano group serves as a versatile functional group that can easily be transformed into amines, ketones or aldehydes, among others.⁴ The syntheses of aryl nitriles continue to rely on classical approaches, such as the Sandmeyer⁵ or the Rosenmund–von Braun reaction,^6,7 which have severe limitations, including the use of stoichiometric or even super-stoichiometric amounts of metal cyanides as well as harsh reaction conditions. An alternative approach is represented by transition metal-catalyzed cyanations of aryl halides or boronic acids under milder reaction conditions.⁸ These catalyzed coupling reactions thereby also display a considerably improved functional group tolerance. However, this strategy exploits prefunctionalized substrates, the preparation of which requires numerous functional group interconversions and generates undesired waste.

The catalytic activation of otherwise inert C(sp²)–H bonds as latent functional groups has in recent years emerged as an increasingly viable tool for improving the atom- and step-economy of organic synthesis.⁹ Thus, Yu developed direct cyanations of 2-arylpyridines.^10,11 The research groups of Jiao¹² and Chang¹³ reported on oxidative cyanations of electron-rich substrates with nonmetallic cyano-group sources in the presence of stoichiometric sacrificial oxidants,^14,15 while Hartwig disclosed a two-step iridium-catalyzed borylation/copper-mediated cyanation protocol.¹⁶ Very recently, rhodium-catalyzed C–H cyanations of arenes were accomplished, albeit exploiting rather strongly coordinating directing groups, such as oxazolines, oximes, pyrazoles or pyridines.^17–19 Herein, we wish to disclose an alternative strategy, which involves the use of relatively inexpensive²⁰ ruthenium(II) catalysts²¹ for the first time for C(sp²)–H cyanations. Importantly, the versatile ruthenium catalyst enabled expedient C–H cyanations with easily accessible N-cyano-N-phenyl-p-toluenesulfonamide (NCTS, 2) as the most user-friendly cyanation reagent for the functionalization of only weakly coordinating²² aromatic and heteroaromatic amides – key structural scaffolds in organic synthesis and medicinal chemistry.

We initiated our studies by probing the effect of different additives and solvents on the envisioned C–H bond cyanation using synthetically useful benzamide 1a (Table 1).

Table 1 Optimization of C–H cyanation with benzamide 1a^a

Entry	Additive	Solvent	Yield (%)
a Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol%), AgSbF6 (20 mol%), additive (20 mol%), solvent (2.0 mL), 120 °C, 18 h; GC-conversion, isolated yields are given in parentheses. b AgOAc (30 mol%). c Without AgSbF6. d AgSbF6 (30 mol%). e Without [RuCl2(p-cymene)]2. f 24 h.
1	AgOAc	DCE	77 (70)
2	Cu(OAc)2	DCE	30
3^b	AgOAc	DCE	80 (67)
4^c	AgOAc	DCE	<5
5^d	AgOAc	DCE	67 (54)
6	AgOAc	1,4-Dioxane	38
7	AgOAc	o-Xylene	21
8	AgOAc	Toluene	23
9	AgOAc	DMF	<2
10^e	AgOAc	DCE	<2
11	KOAc	DCE	<5
12	CsOAc	DCE	17
13	NaOAc	DCE	90 (80)
14	NaOAc	DCE	95 (84)

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Thus, [RuCl₂(p-cymene)]₂ enabled the desired direct cyanation when using both AgSbF₆ and AgOAc as additives in DCE as the solvent (entries 1–5). DCE proved to be the solvent of choice (entries 1 and 6–9), while a test reaction illustrated that the C–H bond activation did not occur in the absence of the ruthenium catalyst (entry 10). Among a set of representative metal acetate additives,^23,24 NaOAc furnished the highest yields of the product 3a (entries 11–14).

With the optimized catalytic system in hand, we explored the effect exerted by the N-substituent at the amide moiety (Scheme 1). A variety of tertiary amides 1a–1f proved to be suitable substrates with optimal results being accomplished with the sterically hindered substrate 1a.²⁵ A comparable catalytic efficacy was obtained when performing the C–H bond cyanation on a larger 5 mmol scale.

Scheme 1 Effect of N-substituents on C–H cyanations.

Subsequently, we tested the scope of the catalytic system for the cyanation of aromatic amides 1 (Scheme 2). The robust ruthenium(II) complex proved to be highly chemo-selective. Thus, the catalyst tolerated a set of valuable electrophilic functional groups, such as ester, fluoro, chloro, bromo and even iodo groups, which should be invaluable for the further diversification of the thus obtained products 3.

Scheme 2 Scope of ruthenium-catalyzed C–H cyanation with amides 1.

The user-friendly ruthenium(II) catalyst was not limited to the functionalization of arenes. Indeed, challenging heteroaromatic substrates 1p–1u were efficiently directly functionalized both at positions C–2 (Scheme 3a) as well as C–3 (Scheme 3b). Thereby, cyanated thiophenes, furanes, benzothiophenes, benzofuranes and indoles were obtained in a chemo- and site-selective fashion.

Scheme 3 C–H cyanation with heteroaromatic amides 1.

The well-defined ruthenium(II) biscarboxylate complex 4²⁶ displayed a catalytic activity comparable to the one observed when using the in situ generated system, notably even in the absence of NaOAc (Scheme 4).

Scheme 4 Well-defined complex 4 as the catalyst.

In consideration of the unique chemo-selectivity and outstanding efficacy of our ruthenium catalyst, we became interested in delineating its mode of action. To this end, intramolecular competition experiments with meta-substituted substrates 1v–1x revealed a considerable secondary directing group effect²⁷ exerted by a methoxy substituent and, even more pronounced, by a fluoro group present in benzamides 1w and 1x, respectively (Scheme 5).

Scheme 5 Intramolecular competition experiments with meta-substituted arenes 1.

Intermolecular competition experiments between differently decorated amides indicated electron-rich arenes to be preferentially converted (Scheme 6), which can be rationalized in terms of an electrophilic-type activation mode of the cationic ruthenium species.

Scheme 6 Intermolecular competition experiments with arenes 1.

In support of this hypothesis, we observed a rather low kinetic isotope effect (KIE) of k_H/k_D ≈ 1.2 (see the ESI†). Moreover, C–H bond activation conducted in the presence of D₂O as the cosolvent revealed a reversible H/D-exchange reaction, as was observed for the reisolated starting material [D]_n-1h as well as the product [D]_n-3h (Scheme 7).

Scheme 7 H/D exchange reaction.

Based on these mechanistic studies we propose a plausible catalytic cycle to initiate a reversible C–H bond metalation on amides 1²⁸ to furnish cationic complex 6 (Scheme 8). Thereafter, coordination and insertion of NCTS (2) give rise to key intermediate 7. Subsequently, β-elimination provides the desired product 3, while proto-demetalation regenerates the cationic ruthenium(II) carboxylate catalyst 5.

Scheme 8 Plausible catalytic cycle.

In summary, we have reported on the use of relatively inexpensive ruthenium-catalyzed C(sp²)–H bond cyanation on arenes for the first time. The robust direct cyanation^29,30 occurred site-selectively on synthetically useful aromatic and heteroaromatic amides with ample scope. Experimental mechanistic studies provided strong support for a reversible C–H metalation mechanism by a cationic ruthenium(II) complex.

Support from the European Research Council under the European Community's Seventh Framework Program (FP7 2007–2013)/ERC Grant agreement no. 307535 and the Chinese Scholarship Council (fellowship to W.L.) is gratefully acknowledged.

Notes and references

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20. The prices of platinum, rhodium, gold, iridium, palladium and ruthenium were 1482, 1015, 1363, 800, 701 and 80 US$ per troy oz, respectively, as of September 2013. See: 〈http://taxfreegold.co.uk/preciousmetalpricesusdollars.html〉.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, and ¹H and ¹³C NMR spectra of products. See DOI: 10.1039/c3cc49502g

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