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Selectivity Control in Ruthenium(II)-Catalyzed C−H/N−O Activation with Alkynyl Bromides Huawen Huang, Sachiyo Nakanowatari, and Lutz Ackermann* Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstraße 2, 37077 Göttingen, Germany S Supporting Information *

ABSTRACT: C−H/N−O activation with 1-bromoalkynes was accomplished within a chemoselective ruthenium(II) catalysis manifold by means of carboxylate assistance. The exceedingly mild reaction conditions set the stage for the positional selective annulations of bromoalkynes at an ambient reaction temperature of 25 °C, placing the organic substituent distal to nitrogen in isoquinolones with a regioselectivity that is complementary to all previous protocols. C−H activation has been recognized as an increasingly viable tool in molecular syntheses,1 with transformative applications to natural product chemistry,2 pharmaceutical industries,3 and material sciences, 4 among others. Indeed, considerable advances have been achieved by means of ruthenium(II) catalysis,5 with major progress through carboxylate assistance.6 Thus, C−H activation with internal alkynes proved instrumental for establishing C−H/N−Het7 activation-based heteroarene syntheses.8 In contrast, to the best of our knowledge, all transition metal-catalyzed C−H functionalizations with electrophilic 1-haloalkynes resulted in C−H alkynylations, delivering the organic substituent at the β-position (Figure 1a).9 Furthermore, transition metal-catalyzed annulations of terminal alkynes usually placed the alkyl substituents proximal to the heteroatom (Figure 1b).10 Within our own program on sustainable C−H activation,11 we have now unraveled a novel type of domino C−H functionalizations with alkynyl halides that provides for the first time access to a complementary selectivity pattern, placing the organic substituent distal to the heteroatom in the α-position (Figure 1c). Thereby, a C−H/ N−O functionalization manifold proved viable under exceedingly mild reaction conditions at 25 °C to provide atom- and step-economical access to 3-alkoxyisoquinolines, versatile intermediates in natural product syntheses12 and key structural motifs in bioactive compounds.13 We commenced our studies by exploring the envisioned C− H/N−O activation of N-methoxybenzamide (1a) with 1bromohexyne (2a) (Table 1 and Table S1 in the Supporting Information). Hence, we observed an unexpected alkyne annulation of the electrophile 2a by substrate 1a to deliver isoquinolone 3aa with excellent levels of chemoselectivity. The C−H activation proved most effective with a catalytic system comprising [Ru(p-cymene)Cl2]2 and NaOAc in methanol as the solvent. The remarkable efficacy of our 3-methoxyisoquinolinone (3aa) synthesis was reflected by exceedingly mild reaction conditions with an ambient reaction temperature of 25 °C (entry 1). The reaction was not accomplished in the absence of the ruthenium catalyst, and a carboxylate additive © XXXX American Chemical Society

Figure 1. C−H activation with alkynes.

proved to be mandatory for catalytic activity, with best results being achieved with NaOAc as the additive (entries 3−6). Notably, solvents other than MeOH, including 1,4-dioxane, CH2Cl2, or H2O, were found ineffective as the reaction media (entry 9). With the optimized reaction conditions in hand, the generality of the mild ruthenium(II)carboxylate C−H/N−O activation was tested (Scheme 1). The robust ruthenium Received: July 21, 2017

A

DOI: 10.1021/acs.orglett.7b02247 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of Reaction Conditionsa

were introduced in a step-economical fashion, as were synthetically useful alkyl chlorides and cyanides.14 Scheme 2. Ruthenium(II)-Catalyzed C−H/N−O Annulation of Bromoalkynes 2

entry

changes from the standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9

none No [Ru] catalyst No NaOAc K2CO3 instead of NaOAc KOAc instead of NaOAc LiOAc instead of NaOAc MeOH (0.3 M) MeOH (0.4 M) 1,4-dioxane, CH2Cl2 or H2O as solvent

91 (>99) − − − 82 (85) 90 (>99) 80 (83) 59 (66) −c

a

General reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), [Ru] (5.0 mol %), base (2.0 mmol), MeOH (5.0 mL), 25 °C, 20 h. b Isolated yield. The conversion in parentheses determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. cMeOH (2.0 equiv).

Scheme 1. C−H/N−O Annulation by Benzamides 1

a

Given the unprecedented selectivity mode of our ruthenium(II) C−H/N−O functionalization, we became attracted to delineating its mode of action. To this end, first, a series of control experiments was performed. Interestingly, in the absence of benzamides 1, the bromoalkyne 2e was not converted by the ruthenium catalyst into the corresponding alkynylether, while instead substrate 2e was recovered unchanged (Scheme 3a). This observation renders an initial C−O formation unlikely to be operative. The stability of the bromoalkynes 2 was further confirmed by its recovery after the catalytic reaction when employing an excess of the substrate 2a (Scheme 3b). A manifold involving an initial C−O formation was further ruled out by the attempted C−H/N−O transformation with alkynylether 4a under otherwise identical reaction conditions (Scheme 3c). Moreover, competition experiments revealed electron-deficient benzamides 1 to react preferentially (Scheme 3d). When the ruthenium(II)-catalyzed C−H activation/annulation was conducted in the presence of deuterated methanol, the product [D]3-3aa was obtained in good yield without H/D scrambling (Scheme 4a). This observation is indicative of an irreversible C−H metalation. In good agreement with this finding, a considerable intramolecular kinetic isotope effect (KIE) of kH/kD = 3.0 was found (Scheme 4b). Moreover, an intermolecular KIE of kH/kD = 2.3 was determined by means of the initial rates for independent reactions of substrates 1a and [D]5-1a (Scheme 4c). These results are suggestive of a kinetically relevant C−H metalation step. Based on our mechanistic studies, we propose a plausible catalytic cycle for the C−H/N−O activation with bromoalkynes 2, as depicted in Scheme 5. First, the active ruthenium(II)biscarboxylate catalyst 5 is formed through initial salt metathesis, with subsequent coordination by the substrate 1 to

5.0 mmol scale.

catalyst was characterized by tolerating a wide variety of electrophilic functional groups, including fluoro, chloro, bromo, and ester substituents. In general, the substrates 1 bearing electron-deficient groups afforded higher yields than more electron-rich arenes 1. Intramolecular competition experiments with unsymmetrically decorated arenes 1k−1n occurred with excellent levels of positional control at the less congested site. It is particularly noteworthy that heteroarenes 1o and 1p also smoothly underwent the desired annulation of alkyne 1a. The robust nature of the mild ruthenium(II) catalysis was reflected by the gram-scale synthesis of product 3aa, again at a room temperature of 25 °C. Thereafter, we probed the scope of viable bromoalkynes 2 (Scheme 2). Among others, various decorated hydroxyl groups B

DOI: 10.1021/acs.orglett.7b02247 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Summary of Key Mechanistic Studies

Scheme 5. Proposed Catalytic Cycle

Finally, the synthetic utility of our C−H/N−O activation was mirrored by the late-stage modification of products 3 to the corresponding isoquinoline-1,3-diones 11 (Scheme 6). Scheme 6. Diversification of Product 3aa Scheme 4. Attempted H/D Exchange and KIE Studies

In summary, we have reported on the unprecedented C−H/ N−O annulation of 1-haloalkynes for the step-economical assembly of 4-substituted isoquinolones. Thus, a versatile ruthenium(II)biscarboxylate regime enabled C−H activations with alkynyl bromides with ample scope and high functional group tolerance at an ambient reaction temperature of 25 °C. The unique chemoselectivity of the ruthenium(II) catalysis was reflected by a regioselectivity that is complementary to all previous reports.



ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02247. Experimental procedures, characterization data, and 1H and 13C NMR spectra (PDF)



form complex 6. Thereafter, chelation-assisted C−H metalation occurs to generate ruthenacycle 7. Then, migratory alkyne insertion regioselectively delivers seven-membered metallacycle 8, which undergoes reductive elimination to form ruthenium(II) amide 9, likely proceeding through synergistic C−N reductive elimination and N−O oxidative addition. Protodemetalation of amide 9 regenerates the catalytically active complex 5, leading to bromoisoquinolone 10, which ultimately undergoes solvolysis to the desired product 3.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lutz Ackermann: 0000-0001-7034-8772 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.7b02247 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters



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ACKNOWLEDGMENTS Support by the DFG, the CSC (fellowship to H.H.), and the Japanese Student Service Organization (fellowship to S.N.) is gratefully acknowledged.



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