Copper(II)-catalyzed cross dehydrogenative coupling reaction of N-hydroxyphthalimide with alkanes and ethers via unactivated C(sp³)–H activation at room temperature

Abstract

A copper(II)-catalyzed cross dehydrogenative coupling reaction between N-hydroxyphthalimide and unactivated C(sp³)–H bonds of alkanes and ethers using Selectfluor as an oxidant is described. This efficient reaction system shows mild conditions and a broad substrate scope for the generation of O-substituted N-hydroxyphthalimide derivatives.

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The formation of C–O bonds has emerged as a research topic of great interest because of the potential opportunity for developing useful methodologies to synthesize a variety of organic compounds.¹ N-Hydroxyphthalimide (NHPI) is employed as a cheap and nontoxic catalyst for the oxidation of certain hydrocarbons.² In the presence of a metal catalyst and oxidant, NHPI is transformed into the phthalimide N-oxyl (PINO) radical, which is an active catalytic species capable of abstracting a hydrogen atom from hydrocarbons, that is responsible for the reaction.³ Recently, much attention has been paid to O-substituted NHPI derivatives as these compounds are widely used in medicinal chemistry. These derivatives can be readily converted to the corresponding alcohols or O-substituted hydroxylamine species,⁴ and O-substituted hydroxylamines are employed as intermediates in the synthesis of compounds with biological and pharmacological activities.^5–8 In view of the importance of O-substituted NHPI derivatives, copper or metal-free catalyzed oxidative cross-coupling between NHPI and C(sp³)–H bonds to prepare various O-substituted NHPI derivatives has been well developed (Scheme 1).⁹ Moreover, copper(II)-catalyzed dioxygenation of alkenes using air and NHPI leading to β-keto-N-alkoxyphthalimides has been reported by Punniyamurthy and co-workers (Scheme 1).¹⁰ Although the above-mentioned elegant methods appear to be general and efficient, the cross dehydrogenative coupling (CDC) reaction between NHPI and unactivated C(sp³)–H still remains a major challenge.

Scheme 1 Methods of C–O bond formation using N-hydroxyphthalimide.

Selectfluor is one of the most stable, mild, and inexpensive electrophilic fluorination reagents.¹¹ It has been widely employed to introduce fluorine atoms into organic molecules.¹² Besides its fluorination ability, when combined with a copper salt, this electrophilic reagent can be used to facilitate C–H abstraction.¹³ For example, the Zhang group reported Selectfluor-mediated copper-catalyzed selective benzylic C–O cyclization for synthesizing 4H-3,1-benzoxazines.^13a Recently, our group has uncovered an example of copper-catalyzed esterification of unactivated C(sp³)–H bonds of hydrocarbons using Selectfluor as the oxidant. The mechanism of our previous work suggested that the cationic N-radicals generated from Selectfluor could abstract hydrogen atoms from alkanes, which plays an important role in the reaction.^13b To our knowledge, the CDC reaction between NHPI and a variety of C(sp³)–H has been described, while the direct C(sp³)–O bond formation using the NHPI reaction with unactivated C(sp³)–H of alkanes and ethers has scarcely been reported. Taking the possible radical mechanism for C–H functionalization using Selectfluor as the oxidant into account, herein, we report an effective copper-catalyzed oxidative cross-coupling reaction of NHPI with alkanes and ethers in the presence of Selectfluor (Scheme 1).

The reaction of cyclohexane (2) and a stoichiometric amount of NHPI (1) was selected as a model reaction. The reaction efficiency was investigated upon the variation of copper salts and oxidants (Table 1). For an initial study, cyclohexane and a stoichiometric amount of NHPI were treated with 2.5 equiv. of Selectfluor in nondehydrated CH₃CN at room temperature for 1 h, and the oxygenated PINO adduct 2a was obtained in only 29% yield (Table 1, entry 1). We found that copper salts can significantly improve the reaction yield, which prompted us to optimize the reaction conditions so as to make the reaction synthetically valuable. Gratifyingly, the reaction occurred to produce the PINO adduct 2a in 50% yield when the substrates were stirred with 0.1 equiv. of Cu(OAc)₂·H₂O (Table 1, entry 2). Using the same catalyst but running the reaction at 40 °C lowered the yield of 2a (Table 1, entry 3). Surprisingly, when decreasing the catalyst loading from 0.1 equiv. to 0.05 equiv., the yield of 2a was improved to 60% (Table 1, entry 4). Further decrease of the catalyst loading lowered the yield of 2a (Table 1, entry 5). When we changed the loading amount of Selectfluor, the yield of 2a was not further improved (Table 1, entries 6 and 7). We also added NHTf₂ or Zn(OTf)₂ to the reaction mixture, both of which failed to improve the reaction efficiency (Table 1, entries 8 and 9). A set of other copper sources were screened, such as Cu(OTf)₂, Cu(OAc)₂, CuCl₂, CuBr₂, CuBr and CuI, and they were less active and gave 2a in 42%, 47%, 49%, 52%, 41%, 38% yields, respectively (Table 1, entries 10–15). Control experiments showed that no desired product 2a was detected in the absence of Selectfluor (Table 1, entry 16). Other widely used common oxidants such as O₂, TBHP, Na₂S₂O₈, 2-iodoxybenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and PhI(OAc)₂ were also tested under similar reaction conditions for 12 h and showed negligible activity (Table 1, entries 17–22), thus highlighting the unique oxidizing ability of Selectfluor for the present reaction. It was found that both catalysts and oxidants had a significant effect on the outcome of the reaction. Among several catalysts (entries 4, 10–15, Table 1) and oxidants (entries 4, 17–22, Table 1) screened, Cu(OAc)₂·H₂O was the best choice of catalyst and Selectfluor to be the best choice of oxidant.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Oxidant (eq.)	T (°C)	Yield^b (%)
a Reactions were carried out with oxidant, cyclohexane (2) (2 mL), NHPI (1) (1 mmol), catalyst (5 mol%) in CH3CN (10 mL) at room temperature for 1 h, unless otherwise noted.b Yield of the isolated product 2a based on NHPI.c HNTf2 (0.1 equiv.) was added.d Zn(OTf)2 (0.1 equiv.) was added.e Reaction performed under a nitrogen atmosphere.f Reactions performed for 12 h.
1	—	Selectfluor (2.5)	rt	29
2	Cu(OAc)2·H2O (10)	Selectfluor (2.5)	rt	50
3	Cu(OAc)2·H2O (10)	Selectfluor (2.5)	40	43
4	Cu(OAc)2·H2O (5)	Selectfluor (2.5)	rt	60
5	Cu(OAc)2·H2O (2)	Selectfluor (2.5)	rt	40
6	Cu(OAc)2·H2O (5)	Selectfluor (2.0)	rt	48
7	Cu(OAc)2·H2O (5)	Selectfluor (3.0)	rt	57
8^c	Cu(OAc)2·H2O (5)	Selectfluor (2.5)	rt	58
9^d	Cu(OAc)2·H2O (5)	Selectfluor (2.5)	rt	55
10	Cu(OTf)2 (5)	Selectfluor (2.5)	rt	42
11	Cu(OAc)2 (5)	Selectfluor (2.5)	rt	47
12	CuCl2 (5)	Selectfluor (2.5)	rt	49
13	CuBr2 (5)	Selectfluor (2.5)	rt	52
14	CuBr (5)	Selectfluor (2.5)	rt	41
15	CuI (5)	Selectfluor (2.5)	rt	38
16^e	Cu(OAc)2·H2O (5)	—	rt	n.d.
17^f	Cu(OAc)2·H2O (5)	O2	rt	n.d.
18^f	Cu(OAc)2·H2O (5)	TBHP (4.0)	rt	Trace
19^f	Cu(OAc)2·H2O (5)	Na2S2O8 (2.5)	rt	<10
20^f	Cu(OAc)2·H2O (5)	IBX (2.5)	rt	<10
21^f	Cu(OAc)2·H2O (5)	DDQ (2.5)	rt	Trace
22^f	Cu(OAc)2·H2O (5)	PhI(OAc)2 (2.5)	rt	<10

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With the optimized conditions in hand, we subsequently explored the reaction scope by using a variety of alkanes and ethers. Firstly, we explored other cycloalkanes, such as cyclooctane, cyclopentane, and cyclododecane, reacted with NHPI, and they each give rise to one distinct PINO adduct (Table 2, 2a–2d). Interestingly, when the adamantane was used as a reagent, no tertiary C(sp³)–H bond cross-dehydrogenative coupling product was detected, while the secondary C(sp³)–H bond cross-dehydrogenative coupling product 2e was obtained in 37% yield (Table 2, 2e). Straight-chain paraffin was also used in this reaction; however, no desired product was isolated from the substrate of normal hexane. To further expand the substrate scope, a series of cyclic ethers were also tested (Table 2, 2f–2i). As the results were summarized in Table 2, most cyclic ethers were found to be good coupling partners and obtained the desired products in 70–89% yields (Table 2, 2f–2i), and the PINO adduct 2f was obtained in much higher yield than previously described.^9a Notably, the application of this methodology has been extend to various acyclic ethers with products isolated with a moderate yield (Table 2, 2j–2r). To our surprise, PINO adducts containing a halogen atom could be obtained in much higher yields (Table 2, 2k and 2l), compared to the products 2m and 2j (Table 2, 2m and 2j). The coupling of NHPI with cyclopentyl methyl ether, tert-butyl methyl ether and tert-butyl ethyl ether afforded the coupled products 2n, 2o, and 2p in moderate yields (40%, 61% and 30%, respectively, Table 2). In the reaction of 1,2-dimethoxyethane with NHPI, two regioisomers (see compounds 2q and 2r, Table 2) were obtained in a moderate combined yield. To our delight, this method was further expanded to the unactivated C(sp³)–H bonds of the thioethers, such as tetrahydrothiophene and dibutylsulfane, and provided the corresponding products 2s and 2t in 88% and 70% yield, respectively. N-Hydroxysuccinimide (NHSI) contains a structure similar to NHPI. We tried to carry out this reaction using NHSI and tetrahydrofuran, unfortunately, no desired product was isolated (Table 2, ND). Overall, this reaction system exhibited a good scope with respect to various ethers, thioethers and cycloalkanes in synthetically useful yields of O-substituted NHPI derivatives.

Table 2 Synthesis of O-substituted derivatives of N-hydroxyphthalimide^a

a Reaction conditions: NHPI (1 mmol, 1 equiv.), alkanes or ethers (2 mL), Cu(OAc)₂·H₂O (5 mol%), Selectfluor (2.5 equiv., 2.5 mmol), CH₃CN (10 mL), at room temperature for 1 h, isolated yield based on NHPI.b 4.0 mmol substrate was used.c 1 mmol N-hydroxysuccinimide (NHSI) was used, ND = no drug.

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In order to gain insights into the reaction mechanism of the present transformation, a control experiment was carried out (Scheme 2). Addition of the radical-trapping reagent 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) to the model reaction mixture could completely inhibit the reaction, and 1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidine was detected by electrospray ionization analysis (see ESI†). These results indicated that the present reaction may proceed via a radical path way. In addition, the Punniyamurthy group and Chang group have demonstrated that the copper(II) salt can react with NHPI to produce a PINO radical. Moreover, an unusual interplay between copper(I) salt and Selectfluor was unveiled by Lectka and co-workers, and the detailed reaction mechanism was revealed to be a radical chain mechanism in which copper acts as an initiator.¹⁴ The mechanism of our previous work suggested that cationic N-radicals generated from Selectfluor could abstract hydrogen atoms from RH to produce R radicals, which play an important role in the reaction.^13b

Scheme 2 Control experiment for a radical based mechanism.

A plausible catalytic cycle was proposed (Scheme 3). First, NHPI may react with Cu^II(OAc)₂ to produce a PINO radical and get Cu^I(OAc) and AcOH. Then, the copper(I) salts were oxidized to generate a copper(II) species by Selectfluor to complete the catalytic cycle. Hydrocarbon R–H was oxidized to R˙ by cationic N-radical A, and NHPI also was turned into a PINO radical by cationic N-radicals A. Finally, capture of the R˙ by the PINO radical gives the desired PINO adduct 2a.

Scheme 3 Postulated mechanism.

In summary, we have developed a convenient protocol for the synthesis of O-substituted NHPI derivatives by the oxidative cross-coupling reaction of NHPI with alkanes and ethers under action of Cu(OAc)₂·H₂O and Selectfluor at room temperature, offering a new possibility for the C–O bond forming methodology in synthetic chemistry. It is an interesting transformation, exhibiting a good scope with respect to various ethers, cycloalkanes and thioethers in synthetically useful yields of O-substituted NHPI derivatives. This reaction could be effective at room temperature with broad substrate scope, and the use of the inexpensive copper salt as the catalyst makes this process attractive.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21406200) and the Special Program for Key Basic Research of the Ministry of Science and Technology, China (No. 2014CB460608) for financial help. We also thank Dr Xin-Peng Jiang at Zhejiang University of Technology for his help in paper modification.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization data. See DOI: 10.1039/c6ra14697j

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