C–H Amination of Arenes with Hydroxylamine

Abstract

This Letter describes the development of a Ti IIImediated reaction for the C−H amination of arenes with hydroxylamine. This reaction is applied to a variety of electronrich (hetero)arene substrates, including a series of natural products and pharmaceuticals. It offers the advantages of mild conditions (room temperature), fast reaction rates (<30 min), compatibility with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.A niline derivatives (ArNH 2 ) appear in a wide variety of specialty chemicals, materials, natural products, and pharmaceuticals. 1 As such, synthetic methods for the formation of ArNH 2 are highly sought-after in organic synthesis. In general, the most common approaches involve transition-metal catalyzed cross-coupling, 2 arene nitration/reduction, 3 and arene C−H amination protocols. 4−6 However, due to high reagent/catalyst costs as well as reactivity concerns, processscale preparations of ArNH 2 still largely rely on nitration of the corresponding aromatic precursor followed by hydrogenation to yield the aniline products (Figure 1A). 7 We sought to develop a practical alternative to nitration/ reduction that enables the direct conversion of arenes (Ar−H) to ArNH 2 . Recent reports have shown that O-protected hydroxylamine derivatives (e.g., A−D in Figure 1B) are effective reagents for Fe-catalyzed arene C−H amination. 4−6 A key step of these reactions involves Fe-mediated N−O bond cleavage to release an aminyl radical (H 2 N • ). This radical (and/or its conjugate acid H 3 N •+ ) then reacts with the arene substrate, ultimately affording an aniline product. 8 While this is a conceptually attractive approach, in practice current methods are limited by the requirement for an electron-withdrawing substituent on oxygen to facilitate N−O bond scission. 9 These functionalized hydroxylamine derivatives can be expensive and/or require multistep synthesis, thus rendering them less practical for larger scale applications. Herein, we develop a method that accesses an analogous reaction manifold using the commodity chemical hydroxylamine as the aminating reagent (Figure 1C). This transformation is high yielding, inexpensive, and scalable and thus offers a complement to existing C−H amination methods as well as more traditional nitration/ reduction sequences.Pioneering early work by Keller, Kovacic, and Minisci demonstrated the feasibility of the Ti III -mediated amination of electron-rich arenes using hydroxylamine. 10−13 However, these early examples were very limited due to their narrow substrate scope, low yields, formation of side products, and the requirement for large excesses of arene substrate. 14 For

Hydroxylamine‐Derived Reagent as a Dual Oxidant and Amino Group Donor for the Iron‐Catalyzed Preparation of Unprotected Sulfinamides from Thiols

“…Toward this endeavour our group and others have been working on iron catalyzed aminofunctionalization of alkenes [76–82] using hydroxylamine derived reagents. Additionally, we and others reported aromatic C−H amination reactions [83–87] through the use of similar reagents. The versatile reactivity of these iron catalyzed reactions of hydroxylamine derivatives in hydrocarbon functionalization reactions prompted us to investigate their reactivity in heteroatom amination reactions.…”

“…Widely studied iron-based enzymes have recently inspired ar enewed interest in developing simple,h omogeneous iron complexes for the oxidation and amination of organic substrates. [75] Toward this endeavour our group and others have been working on iron catalyzed aminofunctionalization of alkenes [76][77][78][79][80][81][82] using hydroxylamine derived reagents.A dditionally,w ea nd others reported aromatic CÀHa mination reactions [83][84][85][86][87] through the use of similar reagents.T he versatile reactivity of these iron catalyzed reactions of hydroxylamine derivatives in hydrocarbon functionalization reactions prompted us to investigate their reactivity in heteroatom amination reactions.N otably,t he Bolm group has elegantly harnessed our previously reported iron-based amination system in as ulfoxide imidation reaction to form unprotected sulfoximines. [16] However,t he reactivity of the lower oxidation sulfur analogue like thiols [88] has remained unexplored.…”

State-owned enterprises in the shipbuilding sector

“…Earlier OECD research 21 already highlighted the changing role that large SOEs play in the international market place. The expansion of SOEs in foreign markets is not always restricted to purely commercial considerations.…”

A Metal‐Free Direct Arene C−H Amination

“…Togni and Carreira [8h] as well as Ritter [8g] reported that N ‐OTf pyridine as pyridine radical cation could be used for the construction of C−N bonds in 2019. Recently, in an iron‐catalyzed process, meta‐C−H aminated products were achieved with HOSA (hydroxylamine‐ O ‐sulfonic acid) and picolinates as directing group by Falck; [10f] and a Ti‐catalyzed arene C−H amination was reported with simple NH 2 OH ⋅ HCl by Sanford [10g] . Besides, commercially available HOSA and DPH ( O ‐(2,4‐dinitrophenyl)hydroxylamine) were used for aziridinations of olefins with rhodium as catalyst, which was reported by Kürti and Falck [11] .…”