Cobalt(II)-Catalyzed C–H Amination of Arenes with Simple

Letter pubs.acs.org/OrgLett

Cobalt(II)-Catalyzed C−H Amination of Arenes with Simple Alkylamines Lin-Bao Zhang,‡ Shou-Kun Zhang,‡ Donghui Wei, Xinju Zhu, Xin-Qi Hao, Jian-Hang Su, Jun-Long Niu,* and Mao-Ping Song* The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, P. R. China S Supporting Information *

ABSTRACT: A new method of cobalt-catalyzed amination of arylamides with simple alkylamines is reported through C(sp2)−H bond functionalization. For the first time, inexpensive cobalt is exploited as the catalyst in the amination of C(sp2)−H bond using simple alkylamines.

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Scheme 1. Strategies for Amination of C−H Bond

iverse C−H functionalization methodologies have been widely developed in the past decades, which allow streamlining of chemical synthesis without prefunctionalization of the coupling partners.1 However, the majority of the progress in the area of C−H activation adopted precious metal catalysts. Recently, much attention has been focused on cobaltcatalyzed C−H bond activation due to its low cost, environmental benignity, and unique catalytic reactivity compared with analogous rhodium or iridium catalysts.2 Meanwhile, the direct C−H amination of arenes has received much attention in recent years, as arylamines are essential structural fragments in pharmaceuticals.3 In this context, much effort has been made involving various metal-catalyzed C−H amination methologies.4 However, in most cases, it required the tedious preparation of preoxidized or preactivated aminating agents. Recently, cross dehydrogenative coupling (CDC) for the C(sp2)−H amination has emerged as an ideal approach, since it does not require an additional synthetic step for the preparation of C−H or N−H coupling partners.5 For example, the intramolecular aminations assisted by Cu, Pd, or Rh salts have been reported by Buchwald6 and other groups.7 Since the pioneering work of the Yu group on the C−H amination of arenes,8 more challenging intermolecular CDC-aminations have been scrutinized.9 Particularly, Daugulis and co-workers developed a novel method for Cu-catalyzed, direct amination of arenes with alkylamines.9h Subsequently, the groups of Yu,10a Carretero,10b Chen,10c and Zhang10d independently reported the Cu- or Ni-catalyzed amination protocols using different bidentate chelating auxiliaries.11 As an abundant first-row transition metal, cobalt could also be utilized in the direct C−H amination.12 In 2012, the Zhang group revealed a nitrene catalytic system for the intramolecular C−H amination (Scheme 1, eq 1).12b Afterward, a series of Co(III)-catalyzed aminations of arenes via cyclometalation of the sp2 carbon using preactivated aminating agents were developed by the groups of Kanai (Scheme 1, eq 2),13 Chang,14a and Jiao.15 More recently, Ge and co-workers described a CDC-amidation of the C(sp3)−H bond with perfluoro amides assisted by an 8-aminoquinolinyl directing © XXXX American Chemical Society

group.16 However, the Co-catalyzed amination of arenes with simple alkylamines such as morpholine is still in its infancy. Inspired by the aforementioned progress and based on our previous work on the Co-catalyzed alkoxylation and alkylation of arenes,17a−c we herein report a new method that includes Co-catalyzed amination of the unactivated C(sp2)−H bond using simple alkylamines as the convenient aminating agents with the aid of the bidentate N,O-directing group (Scheme 1, eq 3). Initially, we embarked on our study by examining the reaction of 2-benzamidopyridine 1-oxide (1a) and morpholine 2a in the presence of 20 mol % of Co(OAc)2·4H2O, 1.0 equiv of AgTFA, and 2.0 equiv of NaOAc in p-xylene at 120 °C (Table 1, entry 1). To our delight, the desired product 3aa was isolated in 23% yield and further identified by an X-ray crystallographic analysis (see Supporting Information). A lower temperature led to an increased yield possibly due to avoiding the decomposition of 2a or product 3aa (Table 1, entry 2). However, with the temperature lowered to 70 °C, the yield was Received: January 26, 2016

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DOI: 10.1021/acs.orglett.6b00241 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of the Reaction Conditionsa

Scheme 2. Substrate Scope of Arylamidesa,b

entry

oxidant

solvent

t (°C)

yieldb(%)

1 2 3 4 5 6 7 8 9 10 11c 12d

AgTFA AgTFA AgTFA NMO AgOAc AgSbF6 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3

p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene PhCF3 t-AmOH MeCN MeCN MeCN

120 85 70 85 85 85 85 85 85 85 85 85

23 44 23 18 18 N.R. 50 59 63 76 82 N.R.

a

Reaction conditions: substrate 1a (0.2 mmol), 2a (2.0 equiv), Co(OAc)2·4H2O (20 mol %), base (2.0 equiv), oxidant (2.0 equiv), solvent (1.0 mL), air atmosphere, 12 h. bIsolated yield. cAgNO3 (2.5 equiv), 2a (1.2 equiv), Co(OAc)2·4H2O (10 mol %), NaOAc (2.0 equiv), KNO3 (0.5 equiv), MeCN (0.5 mL). dIn the absence of Co(OAc)2·4H2O. The effect of other directing groups (A−J) was presented in the Supporting Information. a

Reaction conditions: substrate 1 (0.2 mmol), 2a (1.2 equiv), Co(OAc)2·4H2O (10 mol %), NaOAc (2.0 equiv), AgNO3 (2.5 equiv), KNO3 (0.5 equiv), MeCN (0.5 mL), air, 85 °C. bIsolated yield, 12 h. c1b (4.5 mmol) was used. dCoF2 (10 mol %).

decreased to 23% (Table 1, entry 3). To improve the conversion, a broad range of oxidants were screened with AgNO3 affording a superior result in 50% yield (Table 1, entries 4−7). Among the solvents examined, MeCN exhibited the best transformation, giving the product 3aa in 76% yield (Table 1, entry 10). Further screening of various cobalt salts revealed that cobalt(II) or cobalt(III) salts could promote the reaction, and the initially employed cobalt salt, Co(OAc)2·4H2O, was the optimal choice. When the amount of catalyst was reduced to 10 mol %, we were pleased to find that the reaction could still proceed efficiently with a 1:1.2 ratio of 1a and 2a, albeit at the cost of excess AgNO3. The yield of 3aa was further improved to 82% when 0.5 equiv of KNO3 was used as the additive (Table 1, entry 11). The control experiment indicated that cobalt was pivotal for the reaction (Table 1, entry 12). It was worth mentioning that the 2-aminopyridine 1-oxide (PyO) directing group played a significant role in the transformation (see Supporting Information). The electronic effect of substituted pyridine N-oxides was also taken into consideration (see Supporting Information, 4aa−9aa). Pyridine N-oxides bearing various functional groups could furnish the corresponding amination products. However, these directing groups led to inferior yields compared with 2aminopyridine 1-oxide (PyO). With the optimized reaction conditions in hand, the scope of 2-aminopyridine 1-oxide amides (1) was examined, as shown in Scheme 2. The aryl substrates bearing various substitutions were compatible with the reaction system, furnishing the corresponding aminated products 3aa−3ua in 31%−91% yields. The diaminated products were not obtained in all cases. In general, the reactivity of para-substituted substrates (1b−1e) possessing electron-donating groups was more efficient compared to that of electron-withdrawing groups (1f−1h). Furthermore, the reaction of 1b and 2a was scaled up to 4.5 mmol to provide the corresponding product in 70% yield. For meta-substituted amides 1i−1o, the reaction

proceeded exclusively at the less hindered position of the aryl ring, indicating good regioselectivity in this reaction system. Moreover, the transformations of hindered ortho-substituted amides 1p−1s proceeded smoothly and the corresponding aminated products 3pa−3sa were obtained in acceptable yields. The naphthyl substrate 1t successfully reacted at the 2-position to deliver the aminated product 3ta in 65% yield. The aminated protocol also tolerated the heterocyclic substrate (1u) and produced the desired product 3ua in 69% yield. Noteworthy, the good tolerance further extended to the halogenated substituents, especially the iodo group, which were prone to take part in Ullmann reactions or Buchwald−Hartwig reactions.3b Subsequently, the scope of secondary amines was examined for the cobalt-catalyzed amination. As summarized in Scheme 3, a wide range of six-membered cyclic secondary amines containing various functional groups were well tolerated under the optimized conditions, and the desired products 3ab−3aj were obtained in 37−83% yield. For instance, the amination of 1a proceeded efficiently with the branchedmorpholine 2b. In the case of piperidine derivatives 2c−2h, the amination products were obtained without difficulty, with even an unprotected OH group 2e well tolerated under the reaction system. Despite the relatively lower reactivity, thiomorpholine (2i) was also accessible. The Boc-protected piperazine 2j could be introduced to give the product 3aj in good yield. With respect to 1a, 4-methoxyl amide 1b afforded a higher yield (3ai vs 3bi). Unfortunately, simple secondary amines, such as methylbenzylamine 3ak (14%), were unreactive in our reaction system. Pyrrolidine as a typical five-membered cyclic amine B

DOI: 10.1021/acs.orglett.6b00241 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Substrate Scope of Secondary Aminesa,b

Information), indicating that AgNO3 served as the terminal oxidant. Based on our previous reports on the Co-catalyzed alkoxylation17a,c and above-mentioned experiments, an aromatic substitution-type process mediated by single electron transfer (SET) is possible in the reaction system. Guided by further density functional theory (DFT) calculations, a tentative pathway is proposed in the Supporting Information. However, the detailed mechanism of this amination remains for now unclear. The PyO group of the aminated products 3 could be easily removed by the simple base hydrolysis. For example, the product 3da was treated with NaOH in ethanol at 100 °C for 48 h, and the corresponding 2-morpholinobenzoic acid 1B was obtained in 94% yield (Scheme 5). Scheme 5. Removal of the Directing Group

a

Reaction conditions: substrate 1 (0.2 mmol), 2 (1.2 equiv), Co(OAc)2·4H2O (10 mol %), NaOAc (2.0 equiv), AgNO3 (2.5 equiv), KNO3 (0.5 equiv), MeCN (0.5 mL), air, 85 °C. bIsolated yield, 12 h.

In conclusion, an active Co-catalyzed intermolecular CDCamination of unactivated arenes with simple alkylamines has been developed, assisted by a PyO directing group. This reaction protocol is attractive owing to the mild reaction conditions, lower amounts of inexpensive cobalt catalyst, and easy to handle nature. The catalysis is applicable to a broad substrate scope and is compatible with various functional groups. The detailed mechanism is currently ongoing in our laboratory.

could exchange with 2-aminopyridine 1-oxide, delivering the byproduct phenyl(pyrrolidin-1-yl)methanone. The control experiments were carried out to explore the plausible reaction pathway. The lack of KIE (∼1.2) was observed in the parallel reaction of 1a and [D5]-1a with 2a (Scheme 4, eq 4). Moreover, a similar result was obtained in

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ASSOCIATED CONTENT

* Supporting Information

Scheme 4. Control Experiments

S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.6b00241. Experimental procedures, computational data, spectral data for new compounds (PDF) Single crystal X-ray diffraction data for compound 3aa (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions

the KIE measurement from two parallel reactions (Scheme 4, eq 5), indicating that C−H cleavage was not involved in the rate-limiting step. The addition of a radical quencher, 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO), 2,6-diisopropyl-4methylphenol (BHT), or p-benzoquinone (BQ) (1.0 equiv in each case; see Supporting Information), totally inhibited the reaction. The electron paramagnetic resonance (EPR) spectrum of the crude reaction mixture clearly showed the existence of a single electron (g = 2.0013; see Supporting Information). The Co(III) salts such as Co(acac)3, CoF3, or Cp*Co(CO)I2 could promote the reaction as well (Scheme 4, eq 6), which implied that the reaction process started from a Co(III) complex. Regardless of Co(II) or Co(III) salts, the reaction could not take place in the absence of Ag salts (see Supporting

‡

L.-B.Z. and S.-K.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Funding from the Natural Science Foundation of China (Nos. 21272217, 21502173) is acknowledged. REFERENCES

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