Metal-free intermolecular C–O cross-coupling reactions: synthesis of N-hydroxyimide esters

Abstract

Selectfluor-mediated intermolecular C–O cross coupling reaction for the synthesis of N-hydroxyimide esters was developed for the first time. The reaction is applicable to the coupling of readily available aryl and alkyl aldehydes with N-hydroxyphthalimide (NHPI) and N-hydroxysuccinimide (NHSI). The resulting active esters can be directly converted into amides in one pot.

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Carboxylic acid esters of N-hydroxyphthalimide (NHPI) are widely used as activated carboxylic acid derivatives to promote coupling reactions with most common heteronucleophiles, including amines, alcohols and thiols, in the synthesis of natural products¹ and their analogues, particularly affinity labels for cell receptors.² N-Hydroxyimide esters are traditionally synthesized from carboxylic acids and N-hydroxyphthalimide in the presence of N,N′-dicyclohexylcarbodiimide.³ However, this method suffers from several drawbacks such as the allergenic potential of the coupling agent, poor atom economy, and the formation of urea as a byproduct, which may make isolation of pure NHPI esters difficult. In this context, the most simple and efficient route for the synthesis of N-hydroxyimide esters would be oxidative C–O bond coupling between the C–H bond of the aldehyde and the O–H bond in NHPI. While such oxidative C–O bond couplings have been reported,⁴ the development of conceptually different synthetic approaches is still of great interest. In 2012, Barbas III and co-workers reported an organocatalytic cross-coupling reaction of aldehydes with N-hydroxyimides.^5a In 2015, a stepwise procedure was developed by Maity and co-workers for the synthesis of N-hydroxyimide esters via visible light photoredox catalysis (Scheme 1, eqn (a)).^5b Although the abovementioned elegant methods appear to be general and efficient, they are restricted to aryl aldehydes. Hence, practical and efficient approaches to obtain N-hydroxyimide esters from readily available starting materials are still required.

Scheme 1 Synthesis of N-hydroxyimide esters from aldehydes and NHPI.

Selectfluor is not only one of the most reactive fluorinating reagents available, but it is also safe, nontoxic, and easy to handle.⁶ In 2012, Lectka and co-workers reported C(sp³)–H fluorination that employed a combination of selectfluor, a copper(I) bisimine complex, an anionic phase-transfer catalyst and NHPI.^7a In 2013, Inoue and co-workers reported direct C(sp³)–H fluorination using a catalytic system consisting of selectfluor and N,N-dihydroxypyromellitimide (NDHPI).^7b In recent years, selectfluor has also been utilized as a versatile mediator or catalyst for various other functionalizations of organic compounds.⁸ Recently, we reported the highly selective selectfluor-mediated radical dioxygenation of alkenes^9a and direct reductive amination of tertiary anilines with aldehydes.^9b Selectfluor serves as a strong oxidant for these “fluorine-free” functionalizations. Herein, we disclose that it is also possible for selectfluor to oxidize readily available aldehydes and NHPI to produce N-hydroxyimide esters via a CDC approach under metal free conditions. To the best of our knowledge, there is no precedence of such a selectfluor-mediated methodology with readily available aldehydes and NHPI as precursors for the synthesis of N-hydroxyimide esters via a CDC approach under metal-free conditions. Herein, we disclose the first example of selectfluor-mediated intermolecular C–O cross-coupling reaction of simple aldehydes with NHPI without using any metal catalyst (Scheme 1, eqn (b)).

Recently, we developed metal-free catalyzed C–N and C–O bond formation reactions directly from C–H bonds.⁹ As part of our continuing effort towards the development of methodologies to construct C–O bonds, we attempted intermolecular C–O cross-coupling of aldehydes with NHPI. Initially, 4-chlorobenzaldehyde (1a) and NHPI (2) were selected as the model substrates to optimize the reaction conditions (Table 1). To our delight, the desired product 3a was obtained in 59% yield using selectfluor as the oxidant at 60 °C for 3 h (Table 1, entry 1). When the reaction was performed at 25 °C and 90 °C, 3a was isolated in 9% and 91% yield, respectively (Table 1, entries 2 and 3). When N-fluorobenzenesulfonimide (NFSI) was used as the oxidant, the desired product 3a was obtained in trace amounts (Table 1, entry 4). The performance of other oxidants such as tert-butyl hydroperoxide (TBHP) and 30% H₂O₂ was similarly poor (Table 1, entries 5–7). Solvent screening indicated that CH₃CN was the most suitable solvent. Other solvents such as CHCl₃, CH₂Cl₂, DMF, EtOH, and EtOAc gave relatively low, or no, yields of 3a (Table 1, entries 8–12). In addition, the reaction did not proceed in the absence of selectfluor (Table 1, entry 13). After sufficient screening, the optimal conditions eventually emerged: aldehyde 1a (1.0 equiv.), NHPI (2, 1.2 equiv.), selectfluor (1.2 equiv.), and CH₃CN (3.0 mL) at 90 °C for 3 h under air (Table 1, entry 3).

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), oxidant (0.36 mmol), solvent (3.0 mL), 3 h.b Yield of the isolated product.c TBHP (70% in water).d TBHP (5.5 M in decane).e H2O2 (30% in water).
1	Selectfluor	CH3CN	60	59
2	Selectfluor	CH3CN	25	9
3	Selectfluor	CH3CN	90	91
4	NFSI	CH3CN	90	Trace
5	TBHP^c	CH3CN	90	32
6	TBHP^d	CH3CN	90	21
7	H2O2^e	CH3CN	90	0
8	Selectfluor	CHCl3	90	Trace
9	Selectfluor	CH2Cl2	90	20
10	Selectfluor	DMF	90	0
11	Selectfluor	EtOH	90	Trace
12	Selectfluor	EtOAc	90	35
13	None	CH3CN	90	0

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With the optimized conditions in hand (Table 1, entry 3), several aldehydes as well as aliphatic aldehydes compounds were examined as substrates to react with NHPI under the optimized reaction conditions (Table 2). Aryl aldehydes with various functional groups were effective. Halosubstituted aryl aldehydes (1c, 1d, 1g–i, 1m, 1n, 1s) were tolerated in the CDC reaction, with the added benefit that the products could be very useful for further transformations. The steric effects appeared to influence the reaction; compared to 1a, the reactions of o- and m-chlorobenzaldehyde afforded 3d and 3h in 50% and 56% yields, respectively. Slightly decreased but acceptable yields were also achieved for reactions that involved other ortho-substituted aldehydes (3c, 3e, 3f). Aryl aldehyde substrates bearing electron-withdrawing substituents, such as nitro, cyano, and carboxylate, were effectively converted into the corresponding products 3j, 3o, and 3p, respectively. Similarly, substrates with electron-donating substituents on the aromatic ring underwent coupling smoothly to afford the desired products (3e, 3f, 3k, 3l, 3q, 3r) in good yields. In addition, starting from 1-naphthaldehyde (1t), cinnamic aldehyde (1u) and 3-phenylpropanal (1v), esters 3t, 3u and 3v could be obtained in 45–61% yields. Remarkably, alkyl aldehydes such as propionaldehyde (1w), butyraldehyde (1x), and pentanal (1y) were also effective in providing esters 3w–y in 50–60% yields. This work provides the first example of a direct transformation from alkyl aldehydes and NHPI to the corresponding N-hydroxyimide esters.

Table 2 Scope of the reaction of aldehydes with NHPI mediated by selectfluor^a,b

a Standard reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), selectfluor (0.36 mmol), CH₃CN (3.0 mL), 90 °C, 3 h.b Yield of the isolated products.

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Encouraged by the abovementioned results, we extended the scope of the reaction under optimized conditions to include N-hydroxysuccinimide (NHSI) as the coupling partner for aldehydes (Table 3).

Table 3 Scope of the reaction of aldehydes with NHSI mediated by selectfluor^a,b

a Standard reaction conditions: 1 (0.3 mmol), 4 (0.36 mmol), selectfluor (0.36 mmol), CH₃CN (3.0 mL), 90 °C, 1 h.b Yield of the isolated products.

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To our delight, aldehydes with electron-withdrawing or electron-donating groups could be converted to the desired products in good to excellent yields.

To demonstrate the practicality of this protocol, the C–O cross-coupling reaction was scaled-up. A gram scale oxidation of 4-chlorobenzaldehyde (1a) was easily performed under standard reaction conditions to furnish the desired product in 78% isolated yield (Scheme 2).

Scheme 2 Gram scale synthesis of N-hydroxyimide ester 3a.

The utility of N-hydroxyimide esters as synthons in organic chemistry has expanded significantly in recent years.^4,5,10 For example, treatment of amines, such as 1-propylamine, benzylamine, and 2-phenylethanamine, with 3a in EtOAc at room temperature led to the formation of amides 7a, 7b and 7c, respectively, in excellent yields (Table 4).

Table 4 Synthetic application of N-hydroxyimide esters^a,b

a Standard reaction conditions: 3a (0.2 mmol), 6 (0.6 mmol), EtOAc (2.0 mL), r.t., 3 h.b Yield of the isolated products.

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Several control experiments were performed to probe the reaction mechanism (Scheme 3). To determine whether benzoic acid was formed in situ as an active intermediate, benzoic acid was applied to the cross-coupling reaction with NHPI (Scheme 3a); the N-hydroxyimide ester product was not obtained under these conditions. When the radical scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.) was added to the reaction of 1a or 1b under the optimal conditions, the desired product 3a or 3b was not detected after 3 hours reaction time (Scheme 3b). The reaction was also inhibited by another radical scavenger, 2,6-di-tert-butyl-4-methylphenol (BHT, 2.0 equiv., Scheme 3c). All these results suggested a possible radial mechanism.

Scheme 3 Control experiments.

Although the mechanistic details of this transformation are not very clear at the moment, a possible mechanism is proposed in Scheme 4 that is based on our current experimental results and the literature precedent. Initially, selectfluor reacts with NHPI to generate a PINO radical,^7b,11 a fairly stable but highly reactive free radical.¹² Then, the PINO radical abstracts a hydrogen atom from the acetal species A, which forms from the reaction of NHPI with 1b, and the resulting radical species B (ref. 5) is further oxidized by selectfluor to obtain the PINO adduct 3b (Scheme 4, path a). On the other hand, we could not exclude another pathway: the PINO radical induces the homolysis of the benzaldehyde C–H bond to give an acyl radical.¹³ In this scenario, recombination of the acyl radical and PINO radical leads to the PINO adduct 3b (Scheme 4, path b).

Scheme 4 Plausible mechanism.

In conclusion, we have described the first example of a selectfluor-mediated intermolecular C–O cross coupling reaction of simple aldehydes with NHPI and NHSI under metal-free conditions. The resulting products can be directly converted into amides in one pot. Various aldehydes, including aliphatic aldehydes such as propionaldehyde, butyraldehyde, and pentanal, were efficiently converted to the corresponding esters, which made this CDC reaction very attractive. Further investigations to gain a detailed mechanistic understanding of this reaction and to apply this strategy in other oxidative coupling reactions are underway in our lab.

Acknowledgements

We gratefully acknowledge the Science & Technology Foundation of Henan Province, the Foundation of Henan Educational Committee (15A150029), the Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028651), the Henan province key laboratory of new opto-electronic functional materials and the AYNU-KP-A04 for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra22653a

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