nBu₄NI-catalyzed intermolecular C–O cross-coupling reactions: synthesis of alkyloxyamines

Abstract

A practical and simple nBu₄NI-catalyzed C–O bond formation for the synthesis of alkyloxyamines was achieved under metal-free conditions. The reaction is applicable to the coupling of a range of benzylic and allylic hydrocarbons with N-hydroxyphthalimide and is tolerant of various functional groups. The reaction mechanism was primarily investigated and a radical process was proposed.

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Selective direct C–H bond functionalization is emerging as a valuable tool for the synthesis of natural products and medicinal compounds.¹ The formation of C–O bonds is of fundamental importance in organic synthesis,² and alkyloxyamines are widely employed in the synthesis of pharmaceuticals and functional materials.³ N-Hydroxyphthalimide (NHPI) is not only a cheap, nontoxic catalyst for C–H bond functionalization by using an in situ generated phthalimide N-oxyl (PINO) radical, but also a precursor of oxime ethers.⁴ In recent years, NHPI has been also utilized as a stoichiometric reactant for the construction of the C–O bond in organic synthesis.⁵ In 2008, Chang and co-workers reported a highly efficient protocol for the benzyl or allylic C–H functionalization of simple hydrocarbons using stoichiometric amounts of N-hydroxyphthalimide and PhI(OAc)₂ in the presence of a CuCl catalyst (Scheme 1, eqn a).^5b Although the above-mentioned elegant methods appear to be general and efficient, new synthetic methods are still required.

Scheme 1 Different pathways for the synthesis of alkyloxyamines.

In our previous communication, nBu₄NI-catalyzed C–N cross coupling imidation reaction of C(sp³)–H bond of simple ketones and N–H bond in imides with TBHP as an environmentally benign oxidant was described.⁶ Taking the possible radical amination mechanism for C–H functionalization into account, we envisaged that benzylic and allylic C–H bond could be selectively oxygenated by using appropriate oxygen-centered radicals. Herein, we report a straightforward and versatile method to obtain alkyloxyamines by nBu₄NI-catalyzed intermolecular highly selective benzylic and allylic C–O bond formation from readily available benzylic and allylic hydrocarbons with NHPI (Scheme 1, eqn b). To the best of our knowledge, an example of a direct transformation from readily available hydrocarbons and NHPI to alkyloxyamines via a formal C(sp³)–H functionalization under metal-free conditions has not been reported until this work.

Initially, o-xylene 1a and NHPI 2 were selected as the model substrates to optimize the reaction conditions (Table 1). To our delight, the combination of nBu₄NI (0.2 equiv.) and tert-butyl hydroperoxide (TBHP, 2 equiv.) exhibited excellent catalytic activity and gave the desired product 3a in 85% yield (entry 1). Ethyl acetate and dichloromethane (DCM) were effective to provide 3a in 73% and 55% yield, respectively (Table 1, entries 2 and 3). Other catalysts such as KI, NH₄I, I₂ and NIS gave unsatisfactory results (Table 1, entries 4–7). TBHP was found to play an important role in the process. As shown in Table 1, TBHP was the most effective peroxide in the process. Other peroxides such as Na₂S₂O₈, di-tert-butylperoxide (TBP) and 30% H₂O₂ did not perform well (Table 1, entries 8–10). In addition, the reaction in the absence of nBu₄NI or TBHP did not work (Table 1, entries 11 and 12). The best yield of 3a (92%; entry 13) was obtained at 100 °C, whereas at higher temperatures no appreciable increase in yield was obtained. Upon decreasing the temperature to 90 °C or 70 °C, 3a was obtained in 81% or 52% yield (Table 1, entries 14 and 15). It should be noted that this coupling reaction was performed under environmentally benign condition (with tert-butyl alcohol and water as by-products) without utilizing metal or stoichiometric amount of hypervalent iodine(III) species.^5b–f

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant^b	Catalyst	Solvent	T (°C)	Yield^c (%)
a Reaction conditions: 1a (1.5 mmol), 2 (0.3 mmol), oxidant (0.6 mmol), catalysts (0.06 mmol), solvent (3.0 mL), 2 h.b TBHP (70% in water).c Yield of the isolated product.d H2O2 30% in water.
1	TBHP	nBu4NI	CH3CN	130	85
2	TBHP	nBu4NI	EtOAc	130	73
3	TBHP	nBu4NI	DCM	130	55
4	TBHP	KI	CH3CN	130	25
5	TBHP	NH4I	CH3CN	130	28
6	TBHP	I2	CH3CN	130	0
7	TBHP	NIS	CH3CN	130	Trace
8	Na2S2O8	nBu4NI	CH3CN	130	0
9	TBP	nBu4NI	CH3CN	130	Trace
10	H2O2^d	nBu4NI	CH3CN	130	0
11	—	nBu4NI	CH3CN	130	Trace
12	TBHP	—	CH3CN	130	Trace
13	TBHP	nBu4NI	CH3CN	100	92
14	TBHP	nBu4NI	CH3CN	90	81
15	TBHP	nBu4NI	CH3CN	70	52

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The generality of the C–H functionalization reaction was next examined. As described in Table 2, a broad range of toluene derivatives were investigated. Both toluene and xylenes could be successfully converted to the corresponding products in good to excellent yields (3a–d). Remarkably, the benzylic oxidation was also highly selective, affording only mono-oxidation products, and no multi-oxidation or aromatic C–H oxidation products were detected. Toluene substrates with various functional groups were effective. In general, toluene substrates bearing electron-donating substituents provided higher yields than those containing electron-withdrawing substituents on the aromatic ring (3d–i). Halo-substituted toluene substrates (1h, 1j–m) were tolerated in the oxidation reaction, and could be very useful for further transformations. In addition, starting from ethylbenzene (1n), indane (1o) and 1,2,3,4-tetrahydronaphthalene (1p), 3n, 3o and 3p could be obtained in 70–90% yields. Moreover, 2-methylfuran (1q) and 1-methylnaphthalene (1r) were also tolerated in this protocol, furnishing the desired products in good yields (3q, r). Next, the regioselectivity of the reaction was studied. 2-(1-(p-tolyl)ethoxy)isoindoline-1,3-dione (3s) and 2-((4-ethylbenzyl)oxy)isoindoline-1,3-dione (3s′) were obtained after 2 hours in 86% total yield in a ratio of 3 : 1 from 1-ethyl-4-methylbenzene (1s).

Table 2 Oxygenation of benzyl C–H substrates with NHPI 2^a,b

a Standard reaction conditions: 1 (1.5 mmol), 2 (0.3 mmol), TBHP (0.6 mmol, 70% in water), nBu₄NI (0.06 mmol), CH₃CN (3.0 mL), 100 °C, 2 h.b Yield of the isolated products.c 0.9 mmol 1 was used.

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To further explore the potential of this efficient C–H functionalization reaction, several alkenes were examined as substrates to react with NHPI (2) under the optimized reaction conditions (Table 3). Alkenes 4a–d led to linear (E)-allyl-PINO derivatives 5a–d in good yields and with high regioselectivity. In addition, cyclic alkenes such as cyclohexene 4e and cyclopentene 4f gave the corresponding compounds in 88% and 70% yields. Notably, under these conditions, the dioxygenation of alkenes products were not obtained in the works of Woerpel, Punniyamurthy and Liang et al.^5c–e

Table 3 Oxygenation of allyl C–H substrates with NHPI 2^a,b

a Standard reaction conditions: 4 (0.9 mmol), 2 (0.3 mmol), TBHP (0.6 mmol, 70% in water), nBu₄NI (0.06 mmol), CH₃CN (3.0 mL), 100 °C, 2 h.b Yield of the isolated products.c 1.5 mmol 4 was used.

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The protocol was further explored for the gram scale oxidation of ethylbenzene 1n as a representative example (eqn (1)). As above, the reaction smoothly occurred with 72% yield. In addition, the obtained PINO adducts could be readily converted to the corresponding alcohols or hydroxylamine species (eqn (2)).⁷ For example, product 3b can be transformed into phenylmethanol 6a in 70% yield by cleavage of the N–O bond with Mo(CO)₆, while 3n underwent reaction to afford 1-phenylethanol 6b in 78% yield. The reaction of 3b with hydrazine produced O-benzylhydroxylamine 7a in 71% yield. Similar results were observed with 3n, furnishing O-(1-phenylethyl)hydroxylamine 7b in 70% yield.

Several control experiments were performed to probe the reaction mechanism. The competitive oxidation involving toluene 1b and its deuterated derivative 1b-d₈ were performed (eqn (3)). Obvious kinetic isotope effects (k_H/k_D = 13/1) was observed, indicating that the cleavage of benzyl C–H bond is involved in the rate-determining step. When the radical scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.) was added to the reaction of ethylbenzene (1n) under the optimal condition, after 2 h, a TEMPO-captured product 8 was isolated (24%) and only a trace amount of 3n was detected. The results indicates that the benzyl radical was involved under the catalytic system.⁸

Although the mechanistic details of this transformation are not very clear at the moment, based on the experimental results and literature precedent, a possible mechanism was proposed in Scheme 2. Initially, the tert-butoxyl and tert-butylperoxyl radicals form catalytically (Scheme 2a).⁹ tert-Butoxyl or tert-butylperoxyl radicals then reacts with NHPI to generate NIPO radical, a fairly stable but highly reactive free radical, which has been proposed as a key intermediate in NHPI mediated oxidations (Scheme 2b).^4a,10 Subsequently tert-butoxyl, tert-butylperoxyl or NIPO radical induces the homolysis of a benzyl C–H bond to give the benzyl radical (Scheme 2c).¹¹ Finally, the recombination of the benzyl radical and PINO radical will lead to the PINO adducts 3b (Scheme 2d).

Scheme 2 Proposed mechanism.

In summary, we have reported a novel nBu₄NI catalyzed operationally simple method for the C–H functionalization of hydrocarbons. Various alkyloxyamines products were obtained in good to excellent yields using TBHP (70% in water) as an inexpensive and environmentally friendly oxidant. Importantly, this metal-free catalyzed C–O bond formation makes use of simple, inexpensive starting materials and demonstrates excellent regioselectivity in all cases. Further investigations to gain a detailed mechanistic understanding of this reaction and apply this strategy in other oxidative coupling reactions are currently in progress.

Acknowledgements

We gratefully acknowledge the Foundation of Henan Educational Committee (15A150029) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra12691f

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