Letter pubs.acs.org/OrgLett
Ruthenium(II)-Catalyzed C−H Oxygenations of Reusable Sulfoximine Benzamides Keshav Raghuvanshi, Daniel Zell, and Lutz Ackermann* Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße, 2, 37077 Göttingen, Germany S Supporting Information *
ABSTRACT: C−H oxygenations of synthetically meaningful sulfoximine benzamides were accomplished by a versatile ruthenium catalysis regime. The ruthenium(II) catalyst was characterized by excellent mono- and chemoselectivity as well as positional selectivity via facile base-assisted intramolecular electrophilic substitution-type (BIES) C−H activation. The synthetic utility of the approach was reflected by high functional group tolerance and sulfoximine removal in a traceless fashion. Table 1. C−H Oxygenation of Sulfoximine Benzamide 1aa
C−H activation has emerged as a transformative platform in molecular synthesis,1 enabling applications to material sciences2 and pharmaceutical industries,3 among others. In this context, C−H oxygenations have been identified as step-economical tools for the efficient preparation of substituted phenols,4 with notable recent progress accomplished by means of versatile high-valent ruthenium(II) catalysis.5 Thus, broadly applicable C−H hydroxylations proved viable, predominantly exploiting the iodine(III)-mediated ruthenium(II)carboxylate regime, as reported by inter alia Rao6 and Ackermann,7 among others.8 Recently, sulfoximines were elegantly identified by Sahoo9 and Bolm10 as versatile auxiliaries in C−H transformations. In spite of these undisputed advances, ruthenium-catalyzed C−H oxygenations of removable sulfoximine benzamides have unfortunately thus far proven elusive, despite the unique synthetic utility of substituted sulfoximines.11 Within our program on ruthenium-catalyzed C−H activation,12 we have now devised reaction conditions for the first positional selective C−H oxygenation of N-sulfoximine amides by ruthenium catalysis, on which we report herein. Notable features of our findings include (i) expedient iodine(III)- and silver(I)-free C−H oxygenations, (ii) mechanistic insights into a facile C−H activation, and (iii) ruthenium-catalyzed C−H benzoxylation with weakly coordinating13 sulfoximines that are readily removed14 in a traceless fashion. At the outset of our studies, we probed various reaction conditions for the envisioned ruthenium-catalyzed C−H oxygenation of sulfoximine benzamide 1a (Table 1). Among a variety of sacrificial oxidants, inexpensive (NH4)2S2O8 proved most effective for the preparation of the desired product 3aa (entries 1−8). We were pleased to find that the user-friendly KPF6 enabled the C−H benzoxylation under silver(I)-free reaction conditions, with [{RuCl2(p-cymene)}2] guaranteeing the best catalytic efficacy. In sharp contrast typical cobalt, © XXXX American Chemical Society
entry
[TM]
additive
oxidant
3aa (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
[{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2] [RuCl3·nH2O] [{RhCp*Cl2}2] Pd(OAc)2 [MnBr(CO)5] [Cp*Co(CO)I2] [{RuCl2(p-cymene)}2] − [{RuCl2(p-cymene)}2] [{RuCl2(p-cymene)}2]
AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgBF4 KPF6b KPF6b KPF6b KPF6b KPF6b KPF6b − KPF6b NaPF6b KPF6b
Ag2O PhI(OAc)2 PhI(TFA)2 KHSO5 K2S2O8 (NH4)2S2O8 (NH4)2S2O8 TBHP (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8
− − − 16 11 38 7 − 23 − − − − − − 46 81
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [{RuCl2(pcymene)}2] (5.0 mol %), additive (20 mol %), (NH4)2S2O8 (2.0 equiv), DCE (2.0 mL), 110 °C, 24 h. bAdditive (0.5 equiv).
Received: December 31, 2016
A
DOI: 10.1021/acs.orglett.6b03898 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters manganese, palladium, or rhodium catalysts fell short in delivering the desired product 3aa under otherwise identical reaction conditions (entries 9−17), highlighting the challenging nature of the C−H oxygenation by the weakly coordinating sulfoximines. With the optimized ruthenium(II) catalyst in hand, we tested its versatility in the C−H oxygenation with diversely decorated benzoic acids 2. Thus, electronically differentiated substrates 2 provided the oxygenated products 3 with excellent positional selectivity through sulfoximine-assisted C−H activation (Scheme 1). In contrast, aliphatic acids gave as of yet
Scheme 2. C−H Benzoxylations of Arenes 1
Scheme 1. C−H Oxygenation with Acids 2
Scheme 3. Intermolecular Competition Experiments
unsatisfactory results. The robustness of the ruthenium(II) catalysis manifold was reflected by fully tolerating a wealth of valuable electrophilic functional groups, including chloro, bromo, ester, or nitro substituents. These features should prove instrumental for further postsynthetic diversification of the thus obtained oxygenated products 3.15 Likewise, the heteroaromatic carboxylic acid 1l was identified as an amenable substrate. Thereafter, we explored the viable substrate scope with variously decorated sulfoximine benzamides 1 (Scheme 2). We were pleased to find that the C−H oxygenations of the parent substrate 1b as well as of the para-substituted congeners 1c and 1d occurred with excellent levels of monoselectivity. The positional selectivity of meta-substituted arene 1e within an intramolecular competition experiment was governed by steric interactions to furnish the desired ester 3ea as the sole product. In consideration of the unique selectivity features displayed by the ruthenium(II)-catalyzed C−H oxygenation, we became attracted to delineating its mode of action. To this end, intermolecular competition experiments between electronically differentiated arenes 1 indicated that electron-rich arenes 1 reacted preferentially (Scheme 3a). Likewise, electron-rich
aromatic carboxylic acids proved to be inherently more reactive than their electron-deficient counterparts (Scheme 3b). Further, the high chemoselectivity of the ruthenium(II) catalyst was reflected within competition experiments between aryl and alkyl carboxylic acids 2 (Scheme 3c), which can be rationalized by the carboxylate-assisted C−H metalation regime.16 Subsequently, we observed a significant H/D scrambling upon the addition of an isotopically labeled cosolvent. The H/ D exchange solely occurred at the more electron-rich benzamide motif, while the phenyl group of the sulfoximine moiety remained unchanged. The deuterium incorporation in the reisolated substrate [Dn]-1b is hence supportive of a facile C−H metalation event (Scheme 4a). In good agreement with this observation, a minor kinetic isotope effect (KIE) of only kH/kD ≈ 1.7 was determined by independent reactions (Scheme 4b). These observations, and the preferential B
DOI: 10.1021/acs.orglett.6b03898 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Use of Isotopically Labeled Compounds
Scheme 6. Traceless Removal of Sulfoximine 6
scope. The C−H functionalization protocol featured high functional group tolerance, exploiting sulfoximines that were removed in a traceless fashion. Mechanistic studies provided strong evidence for a facile BIES C−H ruthenation, along with a kinetically relevant oxidation-induced reductive elimination.
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ASSOCIATED CONTENT
S Supporting Information *
transformation of electron-rich arenes, can be rationalized in terms of a base-assisted intramolecular electrophilic substitution-type (BIES)17 C−H metalation event to be operative. Based on our mechanistic studies, we propose the catalytic cycle to be initiated by the facile sulfoximine-induced C−H ruthenation from a ruthenium(II) biscarboxylate 418 complex (Scheme 5). Thereafter, a rate-determining oxidation-induced
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.6b03898. Experimental procedures, characterization data, 1H and 13 C NMR spectra for compounds (PDF)
Scheme 5. Plausible Catalytic Cycle
Corresponding Author
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AUTHOR INFORMATION
*E-mail:
[email protected]. ORCID
Lutz Ackermann: 0000-0001-7034-8772 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Support by the European Research Council under the European Community’s Seventh Framework Program (FP7 2007−2013)/ERC Grant Agreement No. 307535, and the DAAD (fellowship to K.R.) is gratefully acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.6b03898 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.6b03898 Org. Lett. XXXX, XXX, XXX−XXX
