Rongxiang Chena,
Bing Liub,
Wenbo Lib,
Kai-Kai Wang*a,
Changqing Miaob,
Zhizhuang Lib,
Yingjie Lvc and
Lantao Liu
*d
aSchool of Pharmacy, Xinxiang University, Xinxiang 453000, P. R. China. E-mail: wangkaikaii@163.com
bSchool of Chemistry and Materials Engineering, Xinxiang University, Xinxiang 453000, P. R. China
cXinxiang Tuoxin Pharmaceutical Company Limited, Xinxiang 453000, P. R. China
dCollege of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu, Henan 476000, P. R. China. E-mail: liult05@iccas.ac.cn
First published on 19th February 2021
A PIDA-promoted cross-dehydrogenative coupling reaction between N-hydroxyphthalimide (NHPI) and aryl ketones for efficient synthesis of N-alkoxyphthalimide products in moderate to good yields has been described. This methodology is distinguished by catalyst-free conditions, readily available starting materials, wide substrate scope and operational simplicity. In addition, a gram-scale reaction and synthetic transformation of the product into synthetically useful intermediates has been demonstrated.
In addition, due to its versatility and atom-economy potential, direct and selective C(sp3)–H bond functionalization has become one of the most powerful and efficient tool in organic synthesis in recent years, which allow direct conversion of C–H bonds to C–C and C–X bonds from simple precursors.8 Transition-metal-catalyzed C(sp3)–H functionalization has been extensively utilized for the construction of various chemical bonds. Considering the fact that these strategies are not environmentally friendly,9 therefore, great efforts have been devoted to develop metal-free free oxidative functionalization of C(sp3)–H bond. Tetrabutylammonium iodide (TBAI)/tert-butyl hydroperoxide (TBHP) has been proved as an efficient transition-metal-free system to apply in C(sp3)–H bond functionalization,10 especially through cross dehydrogenative coupling (CDC), which could assemble complicated molecules from the widely available and simple materials.11 For example, Prabhu reported a TBAI-catalyzed α-aminoxylation of ketones using TBHP as oxidant to directly construct corresponding N-alkoxyphthalimide products (Scheme 1b).12 Although many notable advances toward the synthesis of N-alkoxyphthalimide derivatives have been reported, the development of more simple, concise and efficient synthetic routes remains highly attractive. As a continuation of our previous work focused on free radical chemistry without transition metal catalyst,13 in this context, herein we disclose a novel and efficient method towards N-alkoxyphthalimides via direct cross dehydrogenative coupling of aryl ketones with NHPI without transition metal catalyst via a radical process (Scheme 1c).
As a cheap and readily available reagent, PIDA has been widely used in organic synthesis.14 For example, Zhao and co-workers described a PIDA-mediated oxygenation reaction of N,N-diaryl tertiary amines.15 Recently, a PIDA-mediated radical cyclization of o-(allyloxy)arylaldehydes with NHPI has been realized by Wang's group.16 At the outset of this investigation, we chose 1,2-diphenylethanone 1a and N-hydroxyphthalimide 2a as the model substrates to optimize the reaction conditions (Table 1). The reaction went smoothly and the desired product 3a could be obtained in 92% yield by using PIDA as the oxidant and dichloromethane as a solvent at room temperature under air atmosphere (Table 1, entry 1). Encouraged by this result, we next tested different solvents and the results indicated that dichloromethane is the optimum solvent for this transformation (entries 2–9). Meanwhile, the effect of different oxidants was also investigated; however, they significantly hampered product formation (entries 10–15). When using high valence iodine reagent 2-iodoisoindoline-1,3-dione (NIS) as an oxidant, product 3a was afforded in 61% yield (entry 16). Elevating reaction temperature to 60 °C has no perceptible effect on the reaction efficiency (entry 17). Shortening reaction time to 4 h and 1 h delivered 93% and 64% yield of the desired product, respectively (entries 18 and 19). Moreover, a control experiment suggested that the oxidant was essential for this transformation (entry 20).
Entry | Solvent | Oxidant | Yieldb (%) |
---|---|---|---|
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol, 1.2 equiv.), oxidant (0.36 mmol, 1.2 equiv.), and solvent (2.0 mL) in a test tube at room temperature for 10 h.b Isolated yields.c At 60 °C.d 1 h.e 4 h. n.d. = not detected. TBHP = tert-butyl hydroperoxide (70% in water). DTBP = di-tert-butyl peroxide. BQ = 1,4-benzoquinone. NIS = N-iodosuccinimide. | |||
1 | CH2Cl2 | PhI(OAc)2 | 92 |
2 | CHCl3 | PhI(OAc)2 | 74 |
3 | DCE | PhI(OAc)2 | 77 |
4 | Toluene | PhI(OAc)2 | <10 |
5 | THF | PhI(OAc)2 | <5 |
6 | CH3CN | PhI(OAc)2 | 77 |
7 | DMSO | PhI(OAc)2 | 13 |
8 | Acetone | PhI(OAc)2 | 53 |
9 | EtOAc | PhI(OAc)2 | 52 |
10 | CH2Cl2 | TBHP | n.d. |
11 | CH2Cl2 | DTBP | n.d. |
12 | CH2Cl2 | K2S2O8 | n.d. |
13 | CH2Cl2 | BQ | n.d. |
14 | CH2Cl2 | H2O2 | n.d. |
15 | CH2Cl2 | I2 | <5 |
16 | CH2Cl2 | NIS | 61 |
17c | CH2Cl2 | PhI(OAc)2 | 93 |
18d | CH2Cl2 | PhI(OAc)2 | 93 |
19e | CH2Cl2 | PhI(OAc)2 | 64 |
20e | CH2Cl2 | n.d. |
With the optimized reaction conditions in hand, the generality and limitation of the protocol were examined in Table 2. Firstly, the substrate scope of linear-chain aryl ketones was explored and we found that various substituents on aryl rings of aryl ketones were well tolerated under optimized reaction conditions, regardless of electron-donating and electron-withdrawing functional groups (3a–3j). The structure of 3f was confirmed by X-ray crystallographic analysis (see ESI†).17 1-(Naphthalen-2-yl)-2-phenylethanone and 1-(2-methoxyphenyl)-2-phenylethanone also exhibited excellent reactivity, in which the corresponding products 3i and 3j were isolated in 92% and 95% yield, respectively. Meanwhile, 2-aryl substituted acetophenones have also been shown to be suitable substrates to furnish the corresponding products 3k–3l in moderate to good yields. The efficiency of the reaction was not affected by the substituents on both benzene rings (3m). To our delight, 1,2-diphenylbutan-1-one and 2-phenoxy-1-phenylethanone were compatible with reaction conditions, which reacted smoothly with 2a to furnish the corresponding products in good yields (3n–3o).
a Reaction conditions: 1a (0.3 mmol, 1 equiv.), 2a (1.2 equiv., 0.36 mmol), PhI(OAc)2 (1.2 equiv., 0.36 mmol) and CH2Cl2 (2 mL) at room temperature for 4 h in a sealed tube. Isolated yield. NIPO = phthalimide N-oxyl. |
---|
![]() |
We next evaluated the scope of this C–H functionalization reaction using cyclic aryl ketones as the substrates (Table 3). Benzofuran-3(2H)-ones displayed no obvious detrimental effect on the reaction efficiency and afford the desired products 5a–5d in moderate to good yields. In addition, 1-acetylindolin-3-one was proved to be a suitable substrate to deliver product 5e in 95% yield. Moreover, 2,3-dihydro-1H-inden-1-ones also demonstrated satisfactory compatibility with the reaction (5f–5h). To our delight, 3,4-dihydronaphthalen-1(2H)-ones were shown to be slightly less efficient yet nonetheless suitable substrates, affording the desired products 5i and 5j in 96% and 58% yield, respectively.
a Reaction conditions: 4 (0.3 mmol, 1 equiv.), 2a (1.2 equiv., 0.36 mmol), PhI(OAc)2 (1.2 equiv., 0.36 mmol), and CH2Cl2 (2 mL) at room temperature for 4 h in a sealed tube. Isolated yield. |
---|
![]() |
We also inspected the scalability of this PIDA-promoted C–H functionalization reaction and the current protocol could be readily executed on a gram scale by successfully reacting 5 mmol of 1a with 2a in one pot to obtain 3a in 70% yield (Scheme 2a). The further conversion of the product 3a was also conducted. Using m-chloroperbenzoic acid as the oxidant, 3a could also be readily oxidized to afford the corresponding ester 6 in 85% yield. In addition, treatment of 3a and NEt3 led to the formation of benzil 7 in 93% yield (Scheme 2b).
To shed light on the reaction mechanism for this transformation, control experiments were performed, as shown in Scheme 3. As expected, the addition of well-known radical-trapping reagent BHT (3,5-di-tert-butyl-4-hydroxytoluene) suppressed the reaction and the substrate was recovered, which indicated that free radical intermediate may be involved in this transformation (Scheme 3a). Furthermore, when radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was subjected into the reaction system under standard conditions, no product was detected and radical adduct 8 was separated in 20% yield, which revealed a radical process was involved in this PIDA-promoted C–H functionalization reaction (Scheme 3b).
Based on the above experiments and previous studies from the literatures,12,18 we propose a plausible mechanism for this transformation, which is depicted in Scheme 4. Initially, a ligand exchange between PhI(OAc)2 and NHPI would generate intermediate I, which is converted into a PINO radical by thermal homolytic cleavage. Radical intermediate II was formed through H-abstraction of C(sp3)–H bonds by PINO radical and regenerated NHPI (Scheme 4a), which undergoes second ligand exchange and thermal homolytic cleavage with iodobenzene acetate radical to yield PINO radical (Scheme 4b). Then, the coupling reaction of radical intermediate II and PINO radical gave final product 3a (Scheme 4c).
Footnote |
† Electronic supplementary information (ESI) available: Data for new compounds and experimental procedures. CCDC 2049393. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ra00375e |
This journal is © The Royal Society of Chemistry 2021 |