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DOI: 10.1039/C3CC47174H

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Copper-Catalyzed ortho-Halogenation of Protected Anilines Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5

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A practical Cu-catalyzed direct ortho-halogenation of anilines under aerobic conditions has been developed. The reaction shows typically excellent mono-substitution selectivity, high ortho-regiocontrol and large functional group tolerance. Oxidative coupling reactions under O2 are extremely attractive from academic and industrial standpoints.1-3 In this context, Cu has proven to be a versatile oxidant in coupling reactions, many of which can be rendered catalytic under aerobic conditions.4 In spite of this, Cu-catalyzed aerobic aryl C−H functionalization5 has only recently begun to draw attention. Most precedents deal with base-promoted reactions at acidic C−H bonds (pKa < 35; polyfluoroarenes or 1,2-azoles),6 whilst base-free activation of “inert” aryl C−H bonds has been seldom explored. In a pioneering work, Yu reported the Cucatalyzed o-functionalization of 2-arylpyridines.7 The aerobic Cu-catalyzed cyclization (hence intramolecular) of anilides has also been disclosed.8,9 Cu-catalysis allows new activation modes that could result in novel patterns of reactivity or selectivity. For instance, Cu II has been proposed to induce SET oxidations10 involving cation-radical intermediates. Halogenated anilines are versatile precursors for heterocyclic frameworks that have been historically accessed through electrophilic halogenation or o-directed-lithiation. Pd- or Rhcatalyzed C−H halogenation has recently provided useful alternative approaches.11 However, limitations still remain in terms of scope, mono-/disubstitution selectivity, and enviromental impact (expensive/toxic metals, stoichiometric oxidant, chlorinated solvents and/or strong acids). Cu-catalyzed/promoted o-halogenation strategies12 have been exclusively applied to arenes with a non-removable 2-pyridyl (or a related heteroaryl) directing group. Yu et al. reported the o-halogenation of 2-arylpyridines using X2CHCHX 2 (X = Cl, Br) as halogen source.7 Chlorination of 2-arylpyridines with PhCOCl/Li2CO313 or LiCl14 was also reported. In all cases, controlling mono- vs disubstitution was problematic. Paucity of Cu-catalyzed o-C−H functionalization methods arises from challenges in the activation mechanism (different from typical cyclometalation) and lack of suitable removable directing groups.10b,15 Herein we disclose a Cu-catalyzed ohalogenation of anilines that relies on a readily removable Nsulfonyl directing group. This method uses convenient X + source, N-halosuccinimides (NXS, X = Cl, Br)/industrially friendly solvent (CH3CN), operates under aerobic conditions, and displays high regio- and mono-halogenation selectivity. This journal is © The Royal Society of Chemistry [year]

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On the basis of our previous results on N-(2-pyridyl)sulfonyldirected C−H functionalization,16 we initially examined the prospective o-chlorination of N-(2-pyridyl)sulfonyl aniline (1) under Yu‘s conditions (20 mol% CuCl2 in Cl2CHCHCl2, O2 at 130 °C). 7 Gratifyingly, the o-chloroaniline 1-Cl was isolated as the only product (78% yield, Scheme 1). Both electron-rich and electron-deficient derivatives performed well (products 2Cl and 3-Cl, 94% and 89% yield, respectively). A striking feature of this reaction was that no di-o-chlorination occurred.

Scheme 1 Initial Cu-catalyzed aerobic o-chlorination of anilines. 60

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Despite these encouraging results, the industrially disfavored solvent Cl2CHCHCl2 and heating at 130 °C for 24 h were important drawbacks. Therefore, it was deemed appropriate to develop a more efficient and environmentally benign protocol. After some investigation (see ESI), we were keen to find that selective o-chlorination of aniline 1 was cleanly achieved in the presence of 10 mol % CuCl2 using NCS (1.2 equiv), upon heating for 4 h at 100 °C in MeCN under O2 (Scheme 2). 17 The o-chloroaniline 1-Cl was obtained in 95% isolated yield with excellent regiocontrol (only traces of the p-Cl derivative were detected by GC) and complete mono-substitution selectivity. An attempt to lower the amount of CuCl2 to 5 mol % resulted in the competitive formation of the p-Cl aniline derivative 1-(p)-Cl (o/p = 3:1), likely via an electrophilic substitution pathway. Consistent with this result, product 1(p)-Cl was formed in 90% isolated yield in the absence of Cucatalyst, illustrating also the complementarity between the Cucatalyzed and uncatalyzed reactions (Scheme 2).

Scheme 2 Cu-catalyzed vs uncatalyzed aerobic NCS-o-chlorination of 1. Conditions: O2 (1 atm), MeCN, 100 ºC, 4 h.

A screening of protecting groups revealed that the NH(SO2Py)- group was uniquely effective for the formation of 1Cl (Table 1). The NH-Ts aniline 4 led to the p-Cl product with very high selectivity (entry 2), suggesting that the lack of the [journal], [year], [vol], 00–00 | 1

Chemical Communications Accepted Manuscript

Published on 07 October 2013. Downloaded by University of York on 07/10/2013 18:31:39.

Beatriz Urones, Ángel Manu Martínez, Nuria Rodríguez,* Ramón Gómez Arrayás,* Juan C. Carretero*

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substitution provided synthetically useful yields, particularly those with bulky or electron withdrawing substituents19 [(1719)-Br, 52-64%], although the o-regiocontrol proved to be less efficient than in the chlorination reaction. In fact, the CuBr2-catalyzed NBS-bromination of the parent aniline 1 provided a 1:1 mixture of o- and p-substitution (in the absence of Cu only p-bromination was observed; see ESI). NHSO2Py H

NXS (1.2 equiv)

NHSO2Py

(X = Cl, Br)

X

CuX2 (10 mol %), O2 (1 atm)

R

R

MeCN, 100 ºC, 4-8 h

50-89% yielda

Published on 07 October 2013. Downloaded by University of York on 07/10/2013 18:31:39.

p-substituted anilines

Table 1 Optimization of the N-directing/protecting group

NHSO2Py

NHSO2Py

X

OMe

2-Cl, 89% 2-Br, 88%b

NHSO2Py

Entry 1 2 3 4 5 6

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PG / R (substrate) SO2(2-Py) / H (1) Ts / H (4) Ac / H (5) H/H C(O)(2-Py) / H (6) SO2(2-Py) / Me (7)

o-Cla 79 (95) 6 10 34 12 10

b

p-Cla

di-Cla

Copper-catalyzed ortho-halogenation of protected anilines.

A practical Cu-catalyzed direct ortho-halogenation of anilines under aerobic conditions has been developed. The reaction shows typically excellent mon...
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